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Sample records for adult cardiac progenitor

  1. Epigenomic Reprogramming of Adult Cardiomyocyte-Derived Cardiac Progenitor Cells

    PubMed Central

    Zhang, Yiqiang; Zhong, Jiang F; Qiu, Hongyu; Robb MacLellan, W.; Marbán, Eduardo; Wang, Charles

    2015-01-01

    It has been believed that mammalian adult cardiomyocytes (ACMs) are terminally-differentiated and are unable to proliferate. Recently, using a bi-transgenic ACM fate mapping mouse model and an in vitro culture system, we demonstrated that adult mouse cardiomyocytes were able to dedifferentiate into cardiac progenitor-like cells (CPCs). However, little is known about the molecular basis of their intrinsic cellular plasticity. Here we integrate single-cell transcriptome and whole-genome DNA methylation analyses to unravel the molecular mechanisms underlying the dedifferentiation and cell cycle reentry of mouse ACMs. Compared to parental cardiomyocytes, dedifferentiated mouse cardiomyocyte-derived CPCs (mCPCs) display epigenomic reprogramming with many differentially-methylated regions, both hypermethylated and hypomethylated, across the entire genome. Correlated well with the methylome, our transcriptomic data showed that the genes encoding cardiac structure and function proteins are remarkably down-regulated in mCPCs, while those for cell cycle, proliferation, and stemness are significantly up-regulated. In addition, implantation of mCPCs into infarcted mouse myocardium improves cardiac function with augmented left ventricular ejection fraction. Our study demonstrates that the cellular plasticity of mammalian cardiomyocytes is the result of a well-orchestrated epigenomic reprogramming and a subsequent global transcriptomic alteration. PMID:26657817

  2. Human fetal cardiac progenitors: The role of stem cells and progenitors in the fetal and adult heart.

    PubMed

    Bulatovic, Ivana; Månsson-Broberg, Agneta; Sylvén, Christer; Grinnemo, Karl-Henrik

    2016-02-01

    The human fetal heart is formed early during embryogenesis as a result of cell migrations, differentiation, and formative blood flow. It begins to beat around gestation day 22. Progenitor cells are derived from mesoderm (endocardium and myocardium), proepicardium (epicardium and coronary vessels), and neural crest (heart valves, outflow tract septation, and parasympathetic innervation). A variety of molecular disturbances in the factors regulating the specification and differentiation of these cells can cause congenital heart disease. This review explores the contribution of different cardiac progenitors to the embryonic heart development; the pathways and transcription factors guiding their expansion, migration, and functional differentiation; and the endogenous regenerative capacity of the adult heart including the plasticity of cardiomyocytes. Unfolding these mechanisms will become the basis for understanding the dynamics of specific congenital heart disease as well as a means to develop therapy for fetal as well as postnatal cardiac defects and heart failure.

  3. From ontogenesis to regeneration: learning how to instruct adult cardiac progenitor cells.

    PubMed

    Chimenti, Isotta; Forte, Elvira; Angelini, Francesco; Giacomello, Alessandro; Messina, Elisa

    2012-01-01

    Since the first observations over two centuries ago by Lazzaro Spallanzani on the extraordinary regenerative capacity of urodeles, many attempts have been made to understand the reasons why such ability has been largely lost in metazoa and whether or how it can be restored, even partially. In this context, important clues can be derived from the systematic analysis of the relevant distinctions among species and of the pathways involved in embryonic development, which might be induced and/or recapitulated in adult tissues. This chapter provides an overview on regeneration and its mechanisms, starting with the lesson learned from lower vertebrates, and will then focus on recent advancements and novel insights concerning regeneration in the adult mammalian heart, including the discovery of resident cardiac progenitor cells (CPCs). Subsequently, it explores all the important pathways involved in regulating differentiation during development and embryogenesis, and that might potentially provide important clues on how to activate and/or modulate regenerative processes in the adult myocardium, including the potential activation of endogenous CPCs. Furthermore the importance of the stem cell niche is discussed, and how it is possible to create in vitro a microenvironment and culture system to provide adult CPCs with the ideal conditions promoting their regenerative ability. Finally, the state of clinical translation of cardiac cell therapy is presented. Overall, this chapter provides a new perspective on how to approach cardiac regeneration, taking advantage of important lessons from development and optimizing biotechnological tools to obtain the ideal conditions for cell-based cardiac regenerative therapy.

  4. Differential expression of embryonic epicardial progenitor markers and localization of cardiac fibrosis in adult ischemic injury and hypertensive heart disease.

    PubMed

    Braitsch, Caitlin M; Kanisicak, Onur; van Berlo, Jop H; Molkentin, Jeffery D; Yutzey, Katherine E

    2013-12-01

    During embryonic heart development, the transcription factors Tcf21, Wt1, and Tbx18 regulate activation and differentiation of epicardium-derived cells, including fibroblast lineages. Expression of these epicardial progenitor factors and localization of cardiac fibrosis were examined in mouse models of cardiovascular disease and in human diseased hearts. Following ischemic injury in mice, epicardial fibrosis is apparent in the thickened layer of subepicardial cells that express Wt1, Tbx18, and Tcf21. Perivascular fibrosis with predominant expression of Tcf21, but not Wt1 or Tbx18, occurs in mouse models of pressure overload or hypertensive heart disease, but not following ischemic injury. Areas of interstitial fibrosis in ischemic and hypertensive hearts actively express Tcf21, Wt1, and Tbx18. In all areas of fibrosis, cells that express epicardial progenitor factors are distinct from CD45-positive immune cells. In human diseased hearts, differential expression of Tcf21, Wt1, and Tbx18 also is detected with epicardial, perivascular, and interstitial fibrosis, indicating conservation of reactivated developmental mechanisms in cardiac fibrosis in mice and humans. Together, these data provide evidence for distinct fibrogenic mechanisms that include Tcf21, separate from Wt1 and Tbx18, in different fibroblast populations in response to specific types of cardiac injury.

  5. Resident cardiac progenitor cells: at the heart of regeneration.

    PubMed

    Bollini, Sveva; Smart, Nicola; Riley, Paul R

    2011-02-01

    Stem cell therapy has recently emerged as an innovative strategy over conventional cardiovascular treatments to restore cardiac function in patients affected by ischemic heart disease. Various stem cell populations have been tested and their potential for cardiac repair has been analyzed. Embryonic stem cells retain the greatest differentiation potential, but concerns persist with regard to their immunogenic and teratogenic effects. Although adult somatic stem cells are not tumourigenic and easier to use in an autologous setting, they exist in small numbers and possess reduced differentiation potential. Traditionally the heart was considered to be a post-mitotic organ; however, this dogma has recently been challenged with the identification of a reservoir of resident stem cells, defined as cardiac progenitor cells (CPCs). These endogenous progenitors may represent the best candidates for cardiovascular cell therapy, as they are tissue-specific, often pre-committed to a cardiac fate, and display a greater propensity to differentiate towards cardiovascular lineages. This review will focus on current research into the biology of CPCs and their regenerative potential. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited".

  6. Cardiac imaging in adults

    SciTech Connect

    Jaffe, C.C.

    1987-01-01

    This book approaches adult cardiac disease from the correlative imaging perspective. It includes chest X-rays and angiographs, 2-dimensional echocardiograms with explanatory diagrams for clarity, plus details on digital radiology, nuclear medicine techniques, CT and MRI. It also covers the normal heart, valvular heart disease, myocardial disease, pericardial disease, bacterial endocarditis, aortic aneurysm, cardiac tumors, and congenital heart disease of the adult. It points out those aspects where one imaging technique has significant superiority.

  7. Alteration of cardiac progenitor cell potency in GRMD dogs.

    PubMed

    Cassano, M; Berardi, E; Crippa, S; Toelen, J; Barthelemy, I; Micheletti, R; Chuah, M; Vandendriessche, T; Debyser, Z; Blot, S; Sampaolesi, M

    2012-01-01

    Among the animal models of Duchenne muscular dystrophy (DMD), the Golden Retriever muscular dystrophy (GRMD) dog is considered the best model in terms of size and pathological onset of the disease. As in human patients presenting with DMD or Becker muscular dystrophies (BMD), the GRMD is related to a spontaneous X-linked mutation of dystrophin and is characterized by myocardial lesions. In this respect, GRMD is a useful model to explore cardiac pathogenesis and for the development of therapeutic protocols. To investigate whether cardiac progenitor cells (CPCs) isolated from healthy and GRMD dogs may differentiate into myocardial cell types and to test the feasibility of cell therapy for cardiomyopathies in a preclinical model of DMD, CPCs were isolated from cardiac biopsies of healthy and GRMD dogs. Gene profile analysis revealed an active cardiac transcription network in both healthy and GRMD CPCs. However, GRMD CPCs showed impaired self-renewal and cardiac differentiation. Population doubling and telomerase analyses highlighted earlier senescence and proliferation impairment in progenitors isolated from GRMD cardiac biopsies. Immunofluorescence analysis revealed that only wt CPCs showed efficient although not terminal cardiac differentiation, consistent with the upregulation of cardiac-specific proteins and microRNAs. Thus, the pathological condition adversely influences the cardiomyogenic differentiation potential of cardiac progenitors. Using PiggyBac transposon technology we marked CPCs for nuclear dsRed expression, providing a stable nonviral gene marking method for in vivo tracing of CPCs. Xenotransplantation experiments in neonatal immunodeficient mice revealed a valuable contribution of CPCs to cardiomyogenesis with homing differences between wt and dystrophic progenitors. These results suggest that cardiac degeneration in dystrophinopathies may account for the progressive exhaustion of local cardiac progenitors and shed light on cardiac stemness in

  8. Human progenitor cells derived from cardiac adipose tissue ameliorate myocardial infarction in rodents.

    PubMed

    Bayes-Genis, Antoni; Soler-Botija, Carolina; Farré, Jordi; Sepúlveda, Pilar; Raya, Angel; Roura, Santiago; Prat-Vidal, Cristina; Gálvez-Montón, Carolina; Montero, José Anastasio; Büscher, Dirk; Izpisúa Belmonte, Juan Carlos

    2010-11-01

    Myocardial infarction caused by vascular occlusion results in the formation of nonfunctional fibrous tissue. Cumulative evidence indicates that cell therapy modestly improves cardiac function; thus, novel cell sources with the potential to repair injured tissue are actively sought. Here, we identify and characterize a cell population of cardiac adipose tissue-derived progenitor cells (ATDPCs) from biopsies of human adult cardiac adipose tissue. Cardiac ATDPCs express a mesenchymal stem cell-like marker profile (strongly positive for CD105, CD44, CD166, CD29 and CD90) and have immunosuppressive capacity. Moreover, cardiac ATDPCs have an inherent cardiac-like phenotype and were able to express de novo myocardial and endothelial markers in vitro but not to differentiate into adipocytes. In addition, when cardiac ATDPCs were transplanted into injured myocardium in mouse and rat models of myocardial infarction, the engrafted cells expressed cardiac (troponin I, sarcomeric α-actinin) and endothelial (CD31) markers, vascularization increased, and infarct size was reduced in mice and rats. Moreover, significant differences between control and cell-treated groups were found in fractional shortening and ejection fraction, and the anterior wall remained significantly thicker 30days after cardiac delivery of ATDPCs. Finally, cardiac ATDPCs secreted proangiogenic factors under in vitro hypoxic conditions, suggesting a paracrine effect to promote local vascularization. Our results indicate that the population of progenitor cells isolated from human cardiac adipose tissue (cardiac ATDPCs) may be valid candidates for future use in cell therapy to regenerate injured myocardium. PMID:20713059

  9. Progenitor cells in the adult pancreas.

    PubMed

    Holland, Andrew M; Góñez, L Jorge; Harrison, Leonard C

    2004-01-01

    The beta-cell mass in the adult pancreas possesses the ability to undergo limited regeneration following injury. Identifying the progenitor cells involved in this process and understanding the mechanisms leading to their maturation will open new avenues for the treatment of type 1 diabetes. However, despite steady advances in determining the molecular basis of early pancreatic development, the identification of pancreatic stem cells or beta-cell progenitors and the molecular mechanisms underlying beta-cell regeneration remain unclear. Recent advances in the directed differentiation of embryonic and adult stem cells has heightened interest in the possible application of stem cell therapy in the treatment of type 1 diabetes. Drawing on the expanding knowledge of pancreas development, beta-cell regeneration and stem cell research, this review focuses on progenitor cells in the adult pancreas as a potential source of beta-cells. PMID:14737742

  10. cKit+ cardiac progenitors of neural crest origin

    PubMed Central

    Hatzistergos, Konstantinos E.; Takeuchi, Lauro M.; Saur, Dieter; Seidler, Barbara; Dymecki, Susan M.; Mai, Jia Jia; White, Ian A.; Balkan, Wayne; Kanashiro-Takeuchi, Rosemeire M.; Schally, Andrew V.; Hare, Joshua M.

    2015-01-01

    The degree to which cKit-expressing progenitors generate cardiomyocytes in the heart is controversial. Genetic fate-mapping studies suggest minimal contribution; however, whether or not minimal contribution reflects minimal cardiomyogenic capacity is unclear because the embryonic origin and role in cardiogenesis of these progenitors remain elusive. Using high-resolution genetic fate-mapping approaches with cKitCreERT2/+ and Wnt1::Flpe mouse lines, we show that cKit delineates cardiac neural crest progenitors (CNCkit). CNCkit possess full cardiomyogenic capacity and contribute to all CNC derivatives, including cardiac conduction system cells. Furthermore, by modeling cardiogenesis in cKitCreERT2-induced pluripotent stem cells, we show that, paradoxically, the cardiogenic fate of CNCkit is regulated by bone morphogenetic protein antagonism, a signaling pathway activated transiently during establishment of the cardiac crescent, and extinguished from the heart before CNC invasion. Together, these findings elucidate the origin of cKit+ cardiac progenitors and suggest that a nonpermissive cardiac milieu, rather than minimal cardiomyogenic capacity, controls the degree of CNCkit contribution to myocardium. PMID:26438843

  11. The impact of juvenile coxsackievirus infection on cardiac progenitor cells and postnatal heart development.

    PubMed

    Sin, Jon; Puccini, Jenna M; Huang, Chengqun; Konstandin, Mathias H; Gilbert, Paul E; Sussman, Mark A; Gottlieb, Roberta A; Feuer, Ralph

    2014-07-01

    Coxsackievirus B (CVB) is an enterovirus that most commonly causes a self-limited febrile illness in infants, but cases of severe infection can manifest in acute myocarditis. Chronic consequences of mild CVB infection are unknown, though there is an epidemiologic association between early subclinical infections and late heart failure, raising the possibility of subtle damage leading to late-onset dysfunction, or chronic ongoing injury due to inflammatory reactions during latent infection. Here we describe a mouse model of juvenile infection with a subclinical dose of coxsackievirus B3 (CVB3) which showed no evident symptoms, either immediately following infection or in adult mice. However following physiological or pharmacologically-induced cardiac stress, juvenile-infected adult mice underwent cardiac hypertrophy and dilation indicative of progression to heart failure. Evaluation of the vasculature in the hearts of adult mice subjected to cardiac stress showed a compensatory increase in CD31+ blood vessel formation, although this effect was suppressed in juvenile-infected mice. Moreover, CVB3 efficiently infected juvenile c-kit+ cells, and cardiac progenitor cell numbers were reduced in the hearts of juvenile-infected adult mice. These results suggest that the exhausted cardiac progenitor cell pool following juvenile CVB3 infection may impair the heart's ability to increase capillary density to adapt to increased load.

  12. SWI/SNF in cardiac progenitor cell differentiation.

    PubMed

    Lei, Ienglam; Liu, Liu; Sham, Mai Har; Wang, Zhong

    2013-11-01

    Cardiogenesis requires proper specification, proliferation, and differentiation of cardiac progenitor cells (CPCs). The differentiation of CPCs to specific cardiac cell types is likely guided by a comprehensive network comprised of cardiac transcription factors and epigenetic complexes. In this review, we describe how the ATP-dependent chromatin remodeling SWI/SNF complexes work synergistically with transcription and epigenetic factors to direct specific cardiac gene expression during CPC differentiation. Furthermore, we discuss how SWI/SNF may prime chromatin for cardiac gene expression at a genome-wide level. A detailed understanding of SWI/SNF-mediated CPC differentiation will provide important insight into the etiology of cardica defects and help design novel therapies for heart disease.

  13. Adult Stem and Progenitor Cells

    NASA Astrophysics Data System (ADS)

    Geraerts, Martine; Verfaillie, Catherine M.

    The discovery of adult stem cells in most adult tissues is the basis of a number of clinical studies that are carried out, with therapeutic use of hematopoietic stem cells as a prime example. Intense scientific debate is still ongoing as to whether adult stem cells may have a greater plasticity than previously thought. Although cells with some features of embryonic stem cells that, among others, express Oct4, Nanog and SSEA1 are isolated from fresh tissue, it is not clear if the greater differentiation potential is acquired during cell culture. Moreover, adult more pluripotent cells do not have all pluripotent characteristics typical for embryonic stem cells. Recently, some elegant studies were published in which adult cells could be completely reprogrammed to embryonic stem cell-like cells by overexpression of some key transcription factors for pluripotency (Oct4, Sox2, Klf4 and c-Myc). It will be interesting for the future to investigate the exact mechanisms underlying this reprogramming and whether similar transcription factor pathways are present and/or can be activated in adult more pluripotent stem cells.

  14. Mesp1 Marked Cardiac Progenitor Cells Repair Infarcted Mouse Hearts

    PubMed Central

    Liu, Yu; Chen, Li; Diaz, Andrea Diaz; Benham, Ashley; Xu, Xueping; Wijaya, Cori S.; Fa’ak, Faisal; Luo, Weijia; Soibam, Benjamin; Azares, Alon; Yu, Wei; Lyu, Qiongying; Stewart, M. David; Gunaratne, Preethi; Cooney, Austin; McConnell, Bradley K.; Schwartz, Robert J.

    2016-01-01

    Mesp1 directs multipotential cardiovascular cell fates, even though it’s transiently induced prior to the appearance of the cardiac progenitor program. Tracing Mesp1-expressing cells and their progeny allows isolation and characterization of the earliest cardiovascular progenitor cells. Studying the biology of Mesp1-CPCs in cell culture and ischemic disease models is an important initial step toward using them for heart disease treatment. Because of Mesp1’s transitory nature, Mesp1-CPC lineages were traced by following EYFP expression in murine Mesp1Cre/+; Rosa26EYFP/+ ES cells. We captured EYFP+ cells that strongly expressed cardiac mesoderm markers and cardiac transcription factors, but not pluripotent or nascent mesoderm markers. BMP2/4 treatment led to the expansion of EYFP+ cells, while Wnt3a and Activin were marginally effective. BMP2/4 exposure readily led EYFP+ cells to endothelial and smooth muscle cells, but inhibition of the canonical Wnt signaling was required to enter the cardiomyocyte fate. Injected mouse pre-contractile Mesp1-EYFP+ CPCs improved the survivability of injured mice and restored the functional performance of infarcted hearts for at least 3 months. Mesp1-EYFP+ cells are bona fide CPCs and they integrated well in infarcted hearts and emerged de novo into terminally differentiated cardiac myocytes, smooth muscle and vascular endothelial cells. PMID:27538477

  15. Mesp1 Marked Cardiac Progenitor Cells Repair Infarcted Mouse Hearts.

    PubMed

    Liu, Yu; Chen, Li; Diaz, Andrea Diaz; Benham, Ashley; Xu, Xueping; Wijaya, Cori S; Fa'ak, Faisal; Luo, Weijia; Soibam, Benjamin; Azares, Alon; Yu, Wei; Lyu, Qiongying; Stewart, M David; Gunaratne, Preethi; Cooney, Austin; McConnell, Bradley K; Schwartz, Robert J

    2016-01-01

    Mesp1 directs multipotential cardiovascular cell fates, even though it's transiently induced prior to the appearance of the cardiac progenitor program. Tracing Mesp1-expressing cells and their progeny allows isolation and characterization of the earliest cardiovascular progenitor cells. Studying the biology of Mesp1-CPCs in cell culture and ischemic disease models is an important initial step toward using them for heart disease treatment. Because of Mesp1's transitory nature, Mesp1-CPC lineages were traced by following EYFP expression in murine Mesp1(Cre/+); Rosa26(EYFP/+) ES cells. We captured EYFP+ cells that strongly expressed cardiac mesoderm markers and cardiac transcription factors, but not pluripotent or nascent mesoderm markers. BMP2/4 treatment led to the expansion of EYFP+ cells, while Wnt3a and Activin were marginally effective. BMP2/4 exposure readily led EYFP+ cells to endothelial and smooth muscle cells, but inhibition of the canonical Wnt signaling was required to enter the cardiomyocyte fate. Injected mouse pre-contractile Mesp1-EYFP+ CPCs improved the survivability of injured mice and restored the functional performance of infarcted hearts for at least 3 months. Mesp1-EYFP+ cells are bona fide CPCs and they integrated well in infarcted hearts and emerged de novo into terminally differentiated cardiac myocytes, smooth muscle and vascular endothelial cells. PMID:27538477

  16. Hematopoietic progenitor migration to the adult thymus

    PubMed Central

    Zlotoff, Daniel A.; Bhandoola, Avinash

    2010-01-01

    While most hematopoietic lineages develop in the bone marrow (BM), T cells uniquely complete their development in the specialized environment of the thymus. Hematopoietic stem cells with long-term self-renewal capacity are not present in the thymus. As a result, continuous T cell development requires that BM-derived progenitors be imported into the thymus throughout adult life. The process of thymic homing begins with the mobilization of progenitors out of the bone marrow, continues with their circulation in the bloodstream, and concludes with their settling in the thymus. This review will discuss each of these steps as they occur in the unirradiated and post-irradiation scenarios, focusing on the molecular mechanisms of regulation. Improved knowledge about these early steps in T cell generation may accelerate the development of new therapeutic options in patients with impaired T cell number or function. PMID:21251013

  17. Electrically Induced Calcium Handling in Cardiac Progenitor Cells

    PubMed Central

    Wagner, Mary B.

    2016-01-01

    For nearly a century, the heart was viewed as a terminally differentiated organ until the discovery of a resident population of cardiac stem cells known as cardiac progenitor cells (CPCs). It has been shown that the regenerative capacity of CPCs can be enhanced by ex vivo modification. Preconditioning CPCs could provide drastic improvements in cardiac structure and function; however, a systematic approach to determining a mechanistic basis for these modifications founded on the physiology of CPCs is lacking. We have identified a novel property of CPCs to respond to electrical stimulation by initiating intracellular Ca2+ oscillations. We used confocal microscopy and intracellular calcium imaging to determine the spatiotemporal properties of the Ca2+ signal and the key proteins involved in this process using pharmacological inhibition and confocal Ca2+ imaging. Our results provide valuable insights into mechanisms to enhance the therapeutic potential in stem cells and further our understanding of human CPC physiology.

  18. Cardiac regeneration: still a 21st century challenge in search for cardiac progenitors from stem cells and embryos.

    PubMed

    Neri, Tui; Stefanovic, Sonia; Pucéat, Michel

    2010-07-01

    Regeneration of the heart after a stroke would be the best biologic response to restore its function. However, although this phenomenon occurs in primitive organisms, the regenerative potential is lost in mammals. Thus, the search for an appropriate cardiac progenitor with the potential to differentiate into a functional cardiomyocyte in vitro and in vivo has been the subject of intensive investigation. We summarize the cardiogenic transcriptional pathway that constitutes the molecular scaffold to drive pluripotent stem cells toward a cardiac progenitor fate. Then we overview the literature on derivation of cardiac progenitors from both embryos and stem cells.

  19. Single-cell transcriptome and epigenomic reprogramming of cardiomyocyte-derived cardiac progenitor cells

    PubMed Central

    Chen, Xin; Chakravarty, Tushar; Zhang, Yiqiang; Li, Xiaojin; Zhong, Jiang F.; Wang, Charles

    2016-01-01

    The molecular basis underlying the dedifferentiation of mammalian adult cardiomyocytes (ACMs) into myocyte-derived cardiac progenitor cells (mCPCs) during cardiac tissue regeneration is poorly understood. We present data integrating single-cell transcriptome and whole-genome DNA methylome analyses of mouse mCPCs to understand the epigenomic reprogramming governing their intrinsic cellular plasticity. Compared to parental cardiomyocytes, mCPCs display epigenomic reprogramming with many differentially-methylated regions, both hypermethylated and hypomethylated, across the entire genome. Correlating well with the methylome, our single-cell transcriptomic data show that the genes encoding cardiac structure and function proteins are remarkably down-regulated in mCPCs, while those for cell cycle, proliferation, and stemness are significantly up-regulated. In addition, implanting mCPCs into infarcted mouse myocardium improves cardiac function with augmented left ventricular ejection fraction. This dataset suggests that the cellular plasticity of mammalian cardiomyocytes is the result of a well-orchestrated epigenomic reprogramming and a subsequent global transcriptomic alteration. Understanding cardiomyocyte epigenomic reprogramming may enable the design of future clinical therapies that induce cardiac regeneration, and prevent heart failure. PMID:27622691

  20. Single-cell transcriptome and epigenomic reprogramming of cardiomyocyte-derived cardiac progenitor cells.

    PubMed

    Chen, Xin; Chakravarty, Tushar; Zhang, Yiqiang; Li, Xiaojin; Zhong, Jiang F; Wang, Charles

    2016-01-01

    The molecular basis underlying the dedifferentiation of mammalian adult cardiomyocytes (ACMs) into myocyte-derived cardiac progenitor cells (mCPCs) during cardiac tissue regeneration is poorly understood. We present data integrating single-cell transcriptome and whole-genome DNA methylome analyses of mouse mCPCs to understand the epigenomic reprogramming governing their intrinsic cellular plasticity. Compared to parental cardiomyocytes, mCPCs display epigenomic reprogramming with many differentially-methylated regions, both hypermethylated and hypomethylated, across the entire genome. Correlating well with the methylome, our single-cell transcriptomic data show that the genes encoding cardiac structure and function proteins are remarkably down-regulated in mCPCs, while those for cell cycle, proliferation, and stemness are significantly up-regulated. In addition, implanting mCPCs into infarcted mouse myocardium improves cardiac function with augmented left ventricular ejection fraction. This dataset suggests that the cellular plasticity of mammalian cardiomyocytes is the result of a well-orchestrated epigenomic reprogramming and a subsequent global transcriptomic alteration. Understanding cardiomyocyte epigenomic reprogramming may enable the design of future clinical therapies that induce cardiac regeneration, and prevent heart failure.

  1. Single-cell transcriptome and epigenomic reprogramming of cardiomyocyte-derived cardiac progenitor cells.

    PubMed

    Chen, Xin; Chakravarty, Tushar; Zhang, Yiqiang; Li, Xiaojin; Zhong, Jiang F; Wang, Charles

    2016-01-01

    The molecular basis underlying the dedifferentiation of mammalian adult cardiomyocytes (ACMs) into myocyte-derived cardiac progenitor cells (mCPCs) during cardiac tissue regeneration is poorly understood. We present data integrating single-cell transcriptome and whole-genome DNA methylome analyses of mouse mCPCs to understand the epigenomic reprogramming governing their intrinsic cellular plasticity. Compared to parental cardiomyocytes, mCPCs display epigenomic reprogramming with many differentially-methylated regions, both hypermethylated and hypomethylated, across the entire genome. Correlating well with the methylome, our single-cell transcriptomic data show that the genes encoding cardiac structure and function proteins are remarkably down-regulated in mCPCs, while those for cell cycle, proliferation, and stemness are significantly up-regulated. In addition, implanting mCPCs into infarcted mouse myocardium improves cardiac function with augmented left ventricular ejection fraction. This dataset suggests that the cellular plasticity of mammalian cardiomyocytes is the result of a well-orchestrated epigenomic reprogramming and a subsequent global transcriptomic alteration. Understanding cardiomyocyte epigenomic reprogramming may enable the design of future clinical therapies that induce cardiac regeneration, and prevent heart failure. PMID:27622691

  2. Isolation and expansion of functionally-competent cardiac progenitor cells directly from heart biopsies

    PubMed Central

    Davis, Darryl R; Kizana, Eddy; Terrovitis, John; Barth, Andreas S.; Zhang, Yiqiang; Smith, Rachel Ruckdeschel; Miake, Junichiro; Marbán, Eduardo

    2010-01-01

    The adult heart contains reservoirs of progenitor cells that express embryonic and stem cell-related antigens. While these antigenically-purified cells are promising candidates for autologous cell therapy, clinical application is hampered by their limited abundance and tedious isolation methods. Methods that involve an intermediate cardiosphere-forming step have proven successful and are being tested clinically, but it is unclear whether the cardiosphere step is necessary. Accordingly, we investigated the molecular profile and functional benefit of cells that spontaneously emigrate from cardiac tissue in primary culture. Adult Wistar-Kyoto rat hearts were minced, digested and cultured as separate anatomical regions. Loosely-adherent cells that surround the plated tissue were harvested weekly for a total of five harvests. Genetic lineage tracing demonstrated that a small proportion of the direct outgrowth from cardiac samples originates from myocardial cells. This outgrowth contains sub-populations of cells expressing embryonic (SSEA-1) and stem cell-related antigens (c-Kit, abcg2) that varied with time in culture but not with the cardiac chamber of origin. This direct outgrowth, and its expanded progeny, underwent marked in vitro angiogenic/cardiogenic differentiation and cytokine secretion (IGF-1, VGEF). In vivo effects included long-term functional benefits as gauged by MRI following cell injection in a rat model of myocardial infarction. Outgrowth cells afforded equivalent functional benefits to cardiosphere-derived cells, which require more processing steps to manufacture. These results provide the basis for a simplified and efficient process to generate autologous cardiac progenitor cells (and mesenchymal supporting cells) to augment clinically-relevant approaches for myocardial repair. PMID:20211627

  3. Cardiac Rehabilitation in Older Adults.

    PubMed

    Schopfer, David W; Forman, Daniel E

    2016-09-01

    The biology of aging and the pathophysiology of cardiovascular disease (CVD) overlap, with the effect that CVD is endemic in the growing population of older adults. Moreover, CVD in older adults is usually complicated by age-related complexities, including multimorbidity, polypharmacy, frailty, and other intricacies that add to the risks of ambiguous symptoms, deconditioning, iatrogenesis, falls, disability, and other challenges. Cardiac rehabilitation (CR) is a comprehensive lifestyle program that can have particular benefit for older patients with cardiovascular conditions. Although CR was originally designed primarily as an exercise training program for younger adults after a myocardial infarction or coronary artery bypass surgery, it has evolved as a comprehensive lifestyle program (promoting physical activity as well as education, diet, risk reduction, and adherence) for a broader range of CVD (coronary heart disease, heart failure, and valvular heart disease). It provides a valuable opportunity to address and moderate many of the challenges pertinent for the large and growing population of older adults with CVD. Cardiac rehabilitation promotes physical function (cardiorespiratory fitness as well as strength and balance) that helps overcome disease and deconditioning as well as related vulnerabilities such as disability, frailty, and falls. Similarly, CR facilitates education, monitoring, and guidance to reduce iatrogenesis and promote adherence. Furthermore, CR fosters cognition, socialization, and independence in older patients. Yet despite all its conceptual benefits, CR is significantly underused in older populations. This review discusses benefits and the paradoxical underuse of CR, as well as evolving models of care that may achieve greater application and efficacy. PMID:27297002

  4. PDGFRα demarcates the cardiogenic clonogenic Sca1+ stem/progenitor cell in adult murine myocardium.

    PubMed

    Noseda, Michela; Harada, Mutsuo; McSweeney, Sara; Leja, Thomas; Belian, Elisa; Stuckey, Daniel J; Abreu Paiva, Marta S; Habib, Josef; Macaulay, Iain; de Smith, Adam J; al-Beidh, Farah; Sampson, Robert; Lumbers, R Thomas; Rao, Pulivarthi; Harding, Sian E; Blakemore, Alexandra I F; Jacobsen, Sten Eirik; Barahona, Mauricio; Schneider, Michael D

    2015-05-18

    Cardiac progenitor/stem cells in adult hearts represent an attractive therapeutic target for heart regeneration, though (inter)-relationships among reported cells remain obscure. Using single-cell qRT-PCR and clonal analyses, here we define four subpopulations of cardiac progenitor/stem cells in adult mouse myocardium all sharing stem cell antigen-1 (Sca1), based on side population (SP) phenotype, PECAM-1 (CD31) and platelet-derived growth factor receptor-α (PDGFRα) expression. SP status predicts clonogenicity and cardiogenic gene expression (Gata4/6, Hand2 and Tbx5/20), properties segregating more specifically to PDGFRα(+) cells. Clonal progeny of single Sca1(+) SP cells show cardiomyocyte, endothelial and smooth muscle lineage potential after cardiac grafting, augmenting cardiac function although durable engraftment is rare. PDGFRα(-) cells are characterized by Kdr/Flk1, Cdh5, CD31 and lack of clonogenicity. PDGFRα(+)/CD31(-) cells derive from cells formerly expressing Mesp1, Nkx2-5, Isl1, Gata5 and Wt1, distinct from PDGFRα(-)/CD31(+) cells (Gata5 low; Flk1 and Tie2 high). Thus, PDGFRα demarcates the clonogenic cardiogenic Sca1(+) stem/progenitor cell.

  5. PDGFRα demarcates the cardiogenic clonogenic Sca1+ stem/progenitor cell in adult murine myocardium

    PubMed Central

    Noseda, Michela; Harada, Mutsuo; McSweeney, Sara; Leja, Thomas; Belian, Elisa; Stuckey, Daniel J.; Abreu Paiva, Marta S.; Habib, Josef; Macaulay, Iain; de Smith, Adam J.; al-Beidh, Farah; Sampson, Robert; Lumbers, R. Thomas; Rao, Pulivarthi; Harding, Sian E.; Blakemore, Alexandra I. F.; Eirik Jacobsen, Sten; Barahona, Mauricio; Schneider, Michael D.

    2015-01-01

    Cardiac progenitor/stem cells in adult hearts represent an attractive therapeutic target for heart regeneration, though (inter)-relationships among reported cells remain obscure. Using single-cell qRT–PCR and clonal analyses, here we define four subpopulations of cardiac progenitor/stem cells in adult mouse myocardium all sharing stem cell antigen-1 (Sca1), based on side population (SP) phenotype, PECAM-1 (CD31) and platelet-derived growth factor receptor-α (PDGFRα) expression. SP status predicts clonogenicity and cardiogenic gene expression (Gata4/6, Hand2 and Tbx5/20), properties segregating more specifically to PDGFRα+ cells. Clonal progeny of single Sca1+ SP cells show cardiomyocyte, endothelial and smooth muscle lineage potential after cardiac grafting, augmenting cardiac function although durable engraftment is rare. PDGFRα− cells are characterized by Kdr/Flk1, Cdh5, CD31 and lack of clonogenicity. PDGFRα+/CD31− cells derive from cells formerly expressing Mesp1, Nkx2-5, Isl1, Gata5 and Wt1, distinct from PDGFRα−/CD31+ cells (Gata5 low; Flk1 and Tie2 high). Thus, PDGFRα demarcates the clonogenic cardiogenic Sca1+ stem/progenitor cell. PMID:25980517

  6. Characterization of epicardial-derived cardiac interstitial cells: differentiation and mobilization of heart fibroblast progenitors.

    PubMed

    Ruiz-Villalba, Adrián; Ziogas, Algirdas; Ehrbar, Martin; Pérez-Pomares, José M

    2013-01-01

    The non-muscular cells that populate the space found between cardiomyocyte fibers are known as 'cardiac interstitial cells' (CICs). CICs are heterogeneous in nature and include different cardiac progenitor/stem cells, cardiac fibroblasts and other cell types. Upon heart damage CICs soon respond by initiating a reparative response that transforms with time into extensive fibrosis and heart failure. Despite the biomedical relevance of CICs, controversy remains on the ontogenetic relationship existing between the different cell kinds homing at the cardiac interstitium, as well as on the molecular signals that regulate their differentiation, maturation, mutual interaction and role in adult cardiac homeostasis and disease. Our work focuses on the analysis of epicardial-derived cells, the first cell type that colonizes the cardiac interstitium. We present here a characterization and an experimental analysis of the differentiation potential and mobilization properties of a new cell line derived from mouse embryonic epicardium (EPIC). Our results indicate that these cells express some markers associated with cardiovascular stemness and retain part of the multipotent properties of embryonic epicardial derivatives, spontaneously differentiating into smooth muscle, and fibroblast/myofibroblast-like cells. Epicardium-derived cells are also shown to initiate a characteristic response to different growth factors, to display a characteristic proteolytic expression profile and to degrade biological matrices in 3D in vitro assays. Taken together, these data indicate that EPICs are relevant to the analysis of epicardial-derived CICs, and are a god model for the research on cardiac fibroblasts and the role these cells play in ventricular remodeling in both ischemic or non/ischemic myocardial disease. PMID:23349729

  7. Mesodermal iPSC–derived progenitor cells functionally regenerate cardiac and skeletal muscle

    PubMed Central

    Quattrocelli, Mattia; Swinnen, Melissa; Giacomazzi, Giorgia; Camps, Jordi; Barthélemy, Ines; Ceccarelli, Gabriele; Caluwé, Ellen; Grosemans, Hanne; Thorrez, Lieven; Pelizzo, Gloria; Muijtjens, Manja; Verfaillie, Catherine M.; Blot, Stephane; Janssens, Stefan; Sampaolesi, Maurilio

    2015-01-01

    Conditions such as muscular dystrophies (MDs) that affect both cardiac and skeletal muscles would benefit from therapeutic strategies that enable regeneration of both of these striated muscle types. Protocols have been developed to promote induced pluripotent stem cells (iPSCs) to differentiate toward cardiac or skeletal muscle; however, there are currently no strategies to simultaneously target both muscle types. Tissues exhibit specific epigenetic alterations; therefore, source-related lineage biases have the potential to improve iPSC-driven multilineage differentiation. Here, we determined that differential myogenic propensity influences the commitment of isogenic iPSCs and a specifically isolated pool of mesodermal iPSC-derived progenitors (MiPs) toward the striated muscle lineages. Differential myogenic propensity did not influence pluripotency, but did selectively enhance chimerism of MiP-derived tissue in both fetal and adult skeletal muscle. When injected into dystrophic mice, MiPs engrafted and repaired both skeletal and cardiac muscle, reducing functional defects. Similarly, engraftment into dystrophic mice of canine MiPs from dystrophic dogs that had undergone TALEN-mediated correction of the MD-associated mutation also resulted in functional striatal muscle regeneration. Moreover, human MiPs exhibited the same capacity for the dual differentiation observed in murine and canine MiPs. The findings of this study suggest that MiPs should be further explored for combined therapy of cardiac and skeletal muscles. PMID:26571398

  8. High Glucose Causes Human Cardiac Progenitor Cell Dysfunction by Promoting Mitochondrial Fission: Role of a GLUT1 Blocker.

    PubMed

    Choi, He Yun; Park, Ji Hye; Jang, Woong Bi; Ji, Seung Taek; Jung, Seok Yun; Kim, Da Yeon; Kang, Songhwa; Kim, Yeon Ju; Yun, Jisoo; Kim, Jae Ho; Baek, Sang Hong; Kwon, Sang-Mo

    2016-07-01

    Cardiovascular disease is the most common cause of death in diabetic patients. Hyperglycemia is the primary characteristic of diabetes and is associated with many complications. The role of hyperglycemia in the dysfunction of human cardiac progenitor cells that can regenerate damaged cardiac tissue has been investigated, but the exact mechanism underlying this association is not clear. Thus, we examined whether hyperglycemia could regulate mitochondrial dynamics and lead to cardiac progenitor cell dysfunction, and whether blocking glucose uptake could rescue this dysfunction. High glucose in cardiac progenitor cells results in reduced cell viability and decreased expression of cell cycle-related molecules, including CDK2 and cyclin E. A tube formation assay revealed that hyperglycemia led to a significant decrease in the tube-forming ability of cardiac progenitor cells. Fluorescent labeling of cardiac progenitor cell mitochondria revealed that hyperglycemia alters mitochondrial dynamics and increases expression of fission-related proteins, including Fis1 and Drp1. Moreover, we showed that specific blockage of GLUT1 improved cell viability, tube formation, and regulation of mitochondrial dynamics in cardiac progenitor cells. To our knowledge, this study is the first to demonstrate that high glucose leads to cardiac progenitor cell dysfunction through an increase in mitochondrial fission, and that a GLUT1 blocker can rescue cardiac progenitor cell dysfunction and downregulation of mitochondrial fission. Combined therapy with cardiac progenitor cells and a GLUT1 blocker may provide a novel strategy for cardiac progenitor cell therapy in cardiovascular disease patients with diabetes. PMID:27350339

  9. High Glucose Causes Human Cardiac Progenitor Cell Dysfunction by Promoting Mitochondrial Fission: Role of a GLUT1 Blocker

    PubMed Central

    Choi, He Yun; Park, Ji Hye; Jang, Woong Bi; Ji, Seung Taek; Jung, Seok Yun; Kim, Da Yeon; Kang, Songhwa; Kim, Yeon Ju; Yun, Jisoo; Kim, Jae Ho; Baek, Sang Hong; Kwon, Sang-Mo

    2016-01-01

    Cardiovascular disease is the most common cause of death in diabetic patients. Hyperglycemia is the primary characteristic of diabetes and is associated with many complications. The role of hyperglycemia in the dysfunction of human cardiac progenitor cells that can regenerate damaged cardiac tissue has been investigated, but the exact mechanism underlying this association is not clear. Thus, we examined whether hyperglycemia could regulate mitochondrial dynamics and lead to cardiac progenitor cell dysfunction, and whether blocking glucose uptake could rescue this dysfunction. High glucose in cardiac progenitor cells results in reduced cell viability and decreased expression of cell cycle-related molecules, including CDK2 and cyclin E. A tube formation assay revealed that hyperglycemia led to a significant decrease in the tube-forming ability of cardiac progenitor cells. Fluorescent labeling of cardiac progenitor cell mitochondria revealed that hyperglycemia alters mitochondrial dynamics and increases expression of fission-related proteins, including Fis1 and Drp1. Moreover, we showed that specific blockage of GLUT1 improved cell viability, tube formation, and regulation of mitochondrial dynamics in cardiac progenitor cells. To our knowledge, this study is the first to demonstrate that high glucose leads to cardiac progenitor cell dysfunction through an increase in mitochondrial fission, and that a GLUT1 blocker can rescue cardiac progenitor cell dysfunction and downregulation of mitochondrial fission. Combined therapy with cardiac progenitor cells and a GLUT1 blocker may provide a novel strategy for cardiac progenitor cell therapy in cardiovascular disease patients with diabetes. PMID:27350339

  10. Direct transcriptional reprogramming of adult cells to embryonic nephron progenitors.

    PubMed

    Hendry, Caroline E; Vanslambrouck, Jessica M; Ineson, Jessica; Suhaimi, Norseha; Takasato, Minoru; Rae, Fiona; Little, Melissa H

    2013-09-01

    Direct reprogramming involves the enforced re-expression of key transcription factors to redefine a cellular state. The nephron progenitor population of the embryonic kidney gives rise to all cells within the nephron other than the collecting duct through a mesenchyme-to-epithelial transition, but this population is exhausted around the time of birth. Here, we sought to identify the conditions under which adult proximal tubule cells could be directly transcriptionally reprogrammed to nephron progenitors. Using a combinatorial screen for lineage-instructive transcription factors, we identified a pool of six genes (SIX1, SIX2, OSR1, EYA1, HOXA11, and SNAI2) that activated a network of genes consistent with a cap mesenchyme/nephron progenitor phenotype in the adult proximal tubule (HK2) cell line. Consistent with these reprogrammed cells being nephron progenitors, we observed differential contribution of the reprogrammed population into the Six2(+) nephron progenitor fields of an embryonic kidney explant. Dereplication of the pool suggested that SNAI2 can suppress E-CADHERIN, presumably assisting in the epithelial-to-mesenchymal transition (EMT) required to form nephron progenitors. However, neither TGFβ-induced EMT nor SNAI2 overexpression alone was sufficient to create this phenotype, suggesting that additional factors are required. In conclusion, these results suggest that reinitiation of kidney development from a population of adult cells by generating embryonic progenitors may be feasible, opening the way for additional cellular and bioengineering approaches to renal repair and regeneration.

  11. Human Cardiac Progenitor Spheroids Exhibit Enhanced Engraftment Potential

    PubMed Central

    Colangelo, Donato; Gregoletto, Luca; Reano, Simone; Pietronave, Stefano; Merlin, Simone; Talmon, Maria; Novelli, Eugenio; Diena, Marco; Nicoletti, Carmine; Musarò, Antonio; Filigheddu, Nicoletta; Follenzi, Antonia; Prat, Maria

    2015-01-01

    A major obstacle to an effective myocardium stem cell therapy has always been the delivery and survival of implanted stem cells in the heart. Better engraftment can be achieved if cells are administered as cell aggregates, which maintain their extra-cellular matrix (ECM). We have generated spheroid aggregates in less than 24 h by seeding human cardiac progenitor cells (hCPCs) onto methylcellulose hydrogel-coated microwells. Cells within spheroids maintained the expression of stemness/mesenchymal and ECM markers, growth factors and their cognate receptors, cardiac commitment factors, and metalloproteases, as detected by immunofluorescence, q-RT-PCR and immunoarray, and expressed a higher, but regulated, telomerase activity. Compared to cells in monolayers, 3D spheroids secreted also bFGF and showed MMP2 activity. When spheroids were seeded on culture plates, the cells quickly migrated, displaying an increased wound healing ability with or without pharmacological modulation, and reached confluence at a higher rate than cells from conventional monolayers. When spheroids were injected in the heart wall of healthy mice, some cells migrated from the spheroids, engrafted, and remained detectable for at least 1 week after transplantation, while, when the same amount of cells was injected as suspension, no cells were detectable three days after injection. Cells from spheroids displayed the same engraftment capability when they were injected in cardiotoxin-injured myocardium. Our study shows that spherical in vivo ready-to-implant scaffold-less aggregates of hCPCs able to engraft also in the hostile environment of an injured myocardium can be produced with an economic, easy and fast protocol. PMID:26375957

  12. Type 2 Diabetes Dysregulates Glucose Metabolism in Cardiac Progenitor Cells.

    PubMed

    Salabei, Joshua K; Lorkiewicz, Pawel K; Mehra, Parul; Gibb, Andrew A; Haberzettl, Petra; Hong, Kyung U; Wei, Xiaoli; Zhang, Xiang; Li, Qianhong; Wysoczynski, Marcin; Bolli, Roberto; Bhatnagar, Aruni; Hill, Bradford G

    2016-06-24

    Type 2 diabetes is associated with increased mortality and progression to heart failure. Recent studies suggest that diabetes also impairs reparative responses after cell therapy. In this study, we examined potential mechanisms by which diabetes affects cardiac progenitor cells (CPCs). CPCs isolated from the diabetic heart showed diminished proliferation, a propensity for cell death, and a pro-adipogenic phenotype. The diabetic CPCs were insulin-resistant, and they showed higher energetic reliance on glycolysis, which was associated with up-regulation of the pro-glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3). In WT CPCs, expression of a mutant form of PFKFB, which mimics PFKFB3 activity and increases glycolytic rate, was sufficient to phenocopy the mitochondrial and proliferative deficiencies found in diabetic cells. Consistent with activation of phosphofructokinase in diabetic cells, stable isotope carbon tracing in diabetic CPCs showed dysregulation of the pentose phosphate and glycero(phospho)lipid synthesis pathways. We describe diabetes-induced dysregulation of carbon partitioning using stable isotope metabolomics-based coupling quotients, which relate relative flux values between metabolic pathways. These findings suggest that diabetes causes an imbalance in glucose carbon allocation by uncoupling biosynthetic pathway activity, which could diminish the efficacy of CPCs for myocardial repair. PMID:27151219

  13. Activation of cardiac progenitor cells through paracrine effects of mesenchymal stem cells

    SciTech Connect

    Nakanishi, Chiaki; Yamagishi, Masakazu; Yamahara, Kenichi; Hagino, Ikuo; Mori, Hidezo; Sawa, Yoshiki; Yagihara, Toshikatsu; Kitamura, Soichiro; Nagaya, Noritoshi

    2008-09-12

    Mesenchymal stem cells (MSC) transplantation has been proved to be promising strategy to treat the failing heart. The effect of MSC transplantation is thought to be mediated mainly in a paracrine manner. Recent reports have suggested that cardiac progenitor cells (CPC) reside in the heart. In this study, we investigated whether MSC had paracrine effects on CPC in vitro. CPC were isolated from the neonatal rat heart using an explant method. MSC were isolated from the adult rat bone marrow. MSC-derived conditioned medium promoted proliferation of CPC and inhibited apoptosis of CPC induced by hypoxia and serum starvation. Chemotaxis chamber assay demonstrated that MSC-derived conditioned medium enhanced migration of CPC. Furthermore, MSC-derived conditioned medium upregulated expression of cardiomyocyte-related genes in CPC such as {beta}-myosin heavy chain ({beta}-MHC) and atrial natriuretic peptide (ANP). In conclusion, MSC-derived conditioned medium had protective effects on CPC and enhanced their migration and differentiation.

  14. Implantation of cardiac progenitor cells using self-assembling peptide improves cardiac function after myocardial infarction.

    PubMed

    Tokunaga, Masakuni; Liu, Mei-Lan; Nagai, Toshio; Iwanaga, Koji; Matsuura, Katsuhisa; Takahashi, Toshinao; Kanda, Masato; Kondo, Naomichi; Wang, Pin; Naito, Atsuhiko T; Komuro, Issei

    2010-12-01

    Implantation of various types of cells into the heart has been reported to be effective for heart failure, however, it is unknown what kinds of cells are most suitable for myocardial repair. To examine which types of cells are most effective, we injected cell-Puramatrix™ (PM) complex into the border area and overlaid the cell-PM patch on the myocardial infarction (MI) area. We compared cardiac morphology and function at 2 weeks after transplantation. Among clonal stem cell antigen-1 positive cardiac progenitors with PM (cSca-1/PM), bone marrow mononuclear cells with PM (BM/PM), skeletal myoblasts with PM (SM/PM), adipose tissue-derived mesenchymal cells with PM (AMC/PM), PM alone (PM), and non-treated MI group (MI), the infarct area of cSca-1/PM was smaller than that of BM/PM, SM/PM, PM and MI. cSca-1/PM and AMC/PM attenuated ventricular enlargement and restored cardiac function in comparison with MI. Capillary density in the infarct area of cSca-1/PM was higher than that of other five groups. The percentage of TUNEL positive cardiomyocytes in the infarct area of cSca-1/PM was lower than that of MI and PM. cSca-1 secreted VEGF and some of them differentiated into cardiomyocytes and vascular smooth muscle cells. These results suggest that transplantation of cSca-1/PM most effectively prevents cardiac remodeling and dysfunction through angiogenesis, inhibition of apoptosis and myocardial regeneration. PMID:20869968

  15. Cardiomyocyte differentiation induced in cardiac progenitor cells by cardiac fibroblast-conditioned medium.

    PubMed

    Zhang, Xi; Shen, Man-Ru; Xu, Zhen-Dong; Hu, Zhe; Chen, Chao; Chi, Ya-Li; Kong, Zhen-Dong; Li, Zi-Fu; Li, Xiao-Tong; Guo, Shi-Lei; Xiong, Shao-Hu; Zhang, Chuan-Sen

    2014-05-01

    Our previous study showed that after being treated with 5-azacytidine, Nkx2.5(+) human cardiac progenitor cells (CPCs) derived from embryonic heart tubes could differentiate into cardiomyocytes. Although 5-azacytidine is a classical agent that induces myogenic differentiation in various types of cells, the drug is toxic and unspecific for myogenic differentiation. To investigate the possibility of inducing CPCs to differentiate into cardiomyocytes by a specific and non-toxic method, CPCs of passage 15 and mesenchymal stem cells (MSCs) were treated with cardiac ventricular fibroblast-conditioned medium (CVF-conditioned medium). Following this treatment, the Nkx2.5(+) CPCs underwent cardiomyogenic differentiation. Phase-contrast microscopy showed that the morphology of the treated CPCs gradually changed. Ultrastructural observation confirmed that the cells contained typical sarcomeres. The expression of cardiomyocyte-associated genes, such as alpha-cardiac actin, cardiac troponin T, and beta-myosin heavy chain (MHC), was increased in the CPCs that had undergone cardiomyogenic differentiation compared with untreated cells. In contrast, the MSCs did not exhibit changes in morphology or molecular expression after being treated with CVF-conditioned medium. The results indicated that Nkx2.5(+) CPCs treated with CVF-conditioned medium were capable of differentiating into a cardiac phenotype, whereas treated MSCs did not appear to undergo cardiomyogenic differentiation. Subsequently, following the addition of Dkk1 and the blocking of Wnt signaling pathway, CVF-conditioned medium-induced morphological changes and expression of cardiomyocyte-associated genes of Nkx2.5(+) CPCs were inhibited, which indicates that CVF-conditioned medium-induced cardiomyogenic differentiation of Nkx2.5(+) CPCs is associated with Wnt signaling pathway. In addition, we also found that the activation of Wnt signaling pathway was accompanied by higher expression of GATA-4 and the blocking of the

  16. Human Induced Pluripotent Stem Cell-Derived Cardiac Progenitor Cells in Phenotypic Screening: A Transforming Growth Factor-β Type 1 Receptor Kinase Inhibitor Induces Efficient Cardiac Differentiation.

    PubMed

    Drowley, Lauren; Koonce, Chad; Peel, Samantha; Jonebring, Anna; Plowright, Alleyn T; Kattman, Steven J; Andersson, Henrik; Anson, Blake; Swanson, Bradley J; Wang, Qing-Dong; Brolen, Gabriella

    2016-02-01

    Several progenitor cell populations have been reported to exist in hearts that play a role in cardiac turnover and/or repair. Despite the presence of cardiac stem and progenitor cells within the myocardium, functional repair of the heart after injury is inadequate. Identification of the signaling pathways involved in the expansion and differentiation of cardiac progenitor cells (CPCs) will broaden insight into the fundamental mechanisms playing a role in cardiac homeostasis and disease and might provide strategies for in vivo regenerative therapies. To understand and exploit cardiac ontogeny for drug discovery efforts, we developed an in vitro human induced pluripotent stem cell-derived CPC model system using a highly enriched population of KDR(pos)/CKIT(neg)/NKX2.5(pos) CPCs. Using this model system, these CPCs were capable of generating highly enriched cultures of cardiomyocytes under directed differentiation conditions. In order to facilitate the identification of pathways and targets involved in proliferation and differentiation of resident CPCs, we developed phenotypic screening assays. Screening paradigms for therapeutic applications require a robust, scalable, and consistent methodology. In the present study, we have demonstrated the suitability of these cells for medium to high-throughput screens to assess both proliferation and multilineage differentiation. Using this CPC model system and a small directed compound set, we identified activin-like kinase 5 (transforming growth factor-β type 1 receptor kinase) inhibitors as novel and potent inducers of human CPC differentiation to cardiomyocytes. Significance: Cardiac disease is a leading cause of morbidity and mortality, with no treatment available that can result in functional repair. This study demonstrates how differentiation of induced pluripotent stem cells can be used to identify and isolate cell populations of interest that can translate to the adult human heart. Two separate examples of phenotypic

  17. Folate deficiency inhibits proliferation of adult hippocampal progenitors.

    PubMed

    Kruman, Inna I; Mouton, Peter R; Emokpae, Roland; Cutler, Roy G; Mattson, Mark P

    2005-07-13

    Neurogenesis in the adult hippocampus may play important roles in learning and memory, and in recovery from injury. As recent findings suggest, the perturbance of homocysteine/folate or one-carbon metabolism can adversely affect both the developing and the adult brain, and increase the risk of neural tube defects and Alzheimer's disease. We report that dietary folic acid deficiency dramatically increased blood homocysteine levels and significantly reduced the number of proliferating cells in the dentate gyrus of the hippocampus in adult mice. In vitro, the perturbance of one-carbon metabolism repressed proliferation of cultured embryonic multipotent neuroepithelial progenitor cells and affected cell cycle distribution. Our results suggest that dietary folate deficiency inhibits proliferation of neuronal progenitor cells in the adult brain and thereby affects neurogenesis. PMID:15973147

  18. miR-300 mediates Bmi1 function and regulates differentiation in primitive cardiac progenitors

    PubMed Central

    Cruz, F M; Tomé, M; Bernal, J A; Bernad, A

    2015-01-01

    B lymphoma Mo-MLV insertion region 1 (Bmi1) is a polycomb-family transcriptional factor critical for self-renewal in many adult stem cells and human neoplasia. We sought to identify microRNAs regulated by Bmi1 that could play a role in multipotent cardiac progenitor cell (CPC) decisions. We found that miR-300, a poorly characterized microRNA mapping in the Dlk1-Dio3 microRNA cluster, was positively regulated by Bmi1 in CPCs. Forced expression of miR-300 in CPCs promoted an improved stemness signature with a significant increase in Oct4 levels, a reduction in senescence progression and an enhanced proliferative status via p19 activation and inhibition of p16 accumulation. Endothelial and cardiogenic differentiation were clearly compromised by sustained miR-300 expression. Additionally, RNA and protein analysis revealed a significant reduction in key cardiac transcription factors, including Nkx2.5 and Tbx5. Collectively, these results suggest that some functions attributed to Bmi1 are due to induction of miR-300, which decreases the cardiogenic differentiation potential of multipotent CPCs in vitro and promotes self-renewal. PMID:26512961

  19. Development of Bipotent Cardiac/Skeletal Myogenic Progenitors from MESP1+ Mesoderm

    PubMed Central

    Chan, Sunny Sun-Kin; Hagen, Hannah R.; Swanson, Scott A.; Stewart, Ron; Boll, Karly A.; Aho, Joy; Thomson, James A.; Kyba, Michael

    2016-01-01

    Summary The branchiomeric skeletal muscles co-evolved with new chambers of the heart to enable predatory feeding in chordates. These co-evolved tissues develop from a common population in anterior splanchnic mesoderm, referred to as cardiopharyngeal mesoderm (CPM). The regulation and development of CPM are poorly understood. We describe an embryonic stem cell-based system in which MESP1 drives a PDGFRA+ population with dual cardiac and skeletal muscle differentiation potential, and gene expression resembling CPM. Using this system, we investigate the regulation of these bipotent progenitors, and find that cardiac specification is governed by an antagonistic TGFβ-BMP axis, while skeletal muscle specification is enhanced by Rho kinase inhibition. We define transcriptional signatures of the first committed CPM-derived cardiac and skeletal myogenic progenitors, and discover surface markers to distinguish cardiac (PODXL+) from the skeletal muscle (CDH4+) CPM derivatives. These tools open an accessible window on this developmentally and evolutionarily important population. PMID:26771351

  20. Antiarrhythmic effect of growth factor-supplemented cardiac progenitor cells in chronic infarcted heart.

    PubMed

    Savi, Monia; Bocchi, Leonardo; Rossi, Stefano; Frati, Caterina; Graiani, Gallia; Lagrasta, Costanza; Miragoli, Michele; Di Pasquale, Elisa; Stirparo, Giuliano G; Mastrototaro, Giuseppina; Urbanek, Konrad; De Angelis, Antonella; Macchi, Emilio; Stilli, Donatella; Quaini, Federico; Musso, Ezio

    2016-06-01

    c-Kit(pos) cardiac progenitor cells (CPCs) represent a successful approach in healing the infarcted heart and rescuing its mechanical function, but electrophysiological consequences are uncertain. CPC mobilization promoted by hepatocyte growth factor (HGF) and IGF-1 improved electrogenesis in myocardial infarction (MI). We hypothesized that locally delivered CPCs supplemented with HGF + IGF-1 (GFs) can concur in ameliorating electrical stability of the regenerated heart. Adult male Wistar rats (139 rats) with 4-wk-old MI or sham conditions were randomized to receive intramyocardial injection of GFs, CPCs, CPCs + GFs, or vehicle (V). Enhanced green fluorescent protein-tagged CPCs were used for cell tracking. Vulnerability to stress-induced arrhythmia was assessed by telemetry-ECG. Basic cardiac electrophysiological properties were examined by epicardial multiple-lead recording. Hemodynamic function was measured invasively. Hearts were subjected to anatomical, morphometric, immunohistochemical, and molecular biology analyses. Compared with V and at variance with individual CPCs, CPCs + GFs approximately halved arrhythmias in all animals, restoring cardiac anisotropy toward sham values. GFs alone reduced arrhythmias by less than CPCs + GFs, prolonging ventricular refractoriness without affecting conduction velocity. Concomitantly, CPCs + GFs reactivated the expression levels of Connexin-43 and Connexin-40 as well as channel proteins of key depolarizing and repolarizing ion currents differently than sole GFs. Mechanical function and anatomical remodeling were equally improved by all regenerative treatments, thus exhibiting a divergent behavior relative to electrical aspects. Conclusively, we provided evidence of distinctive antiarrhythmic action of locally injected GF-supplemented CPCs, likely attributable to retrieval of Connexin-43, Connexin-40, and Cav1.2 expression, favoring intercellular coupling and spread of excitation in mended heart.

  1. Antiarrhythmic effect of growth factor-supplemented cardiac progenitor cells in chronic infarcted heart.

    PubMed

    Savi, Monia; Bocchi, Leonardo; Rossi, Stefano; Frati, Caterina; Graiani, Gallia; Lagrasta, Costanza; Miragoli, Michele; Di Pasquale, Elisa; Stirparo, Giuliano G; Mastrototaro, Giuseppina; Urbanek, Konrad; De Angelis, Antonella; Macchi, Emilio; Stilli, Donatella; Quaini, Federico; Musso, Ezio

    2016-06-01

    c-Kit(pos) cardiac progenitor cells (CPCs) represent a successful approach in healing the infarcted heart and rescuing its mechanical function, but electrophysiological consequences are uncertain. CPC mobilization promoted by hepatocyte growth factor (HGF) and IGF-1 improved electrogenesis in myocardial infarction (MI). We hypothesized that locally delivered CPCs supplemented with HGF + IGF-1 (GFs) can concur in ameliorating electrical stability of the regenerated heart. Adult male Wistar rats (139 rats) with 4-wk-old MI or sham conditions were randomized to receive intramyocardial injection of GFs, CPCs, CPCs + GFs, or vehicle (V). Enhanced green fluorescent protein-tagged CPCs were used for cell tracking. Vulnerability to stress-induced arrhythmia was assessed by telemetry-ECG. Basic cardiac electrophysiological properties were examined by epicardial multiple-lead recording. Hemodynamic function was measured invasively. Hearts were subjected to anatomical, morphometric, immunohistochemical, and molecular biology analyses. Compared with V and at variance with individual CPCs, CPCs + GFs approximately halved arrhythmias in all animals, restoring cardiac anisotropy toward sham values. GFs alone reduced arrhythmias by less than CPCs + GFs, prolonging ventricular refractoriness without affecting conduction velocity. Concomitantly, CPCs + GFs reactivated the expression levels of Connexin-43 and Connexin-40 as well as channel proteins of key depolarizing and repolarizing ion currents differently than sole GFs. Mechanical function and anatomical remodeling were equally improved by all regenerative treatments, thus exhibiting a divergent behavior relative to electrical aspects. Conclusively, we provided evidence of distinctive antiarrhythmic action of locally injected GF-supplemented CPCs, likely attributable to retrieval of Connexin-43, Connexin-40, and Cav1.2 expression, favoring intercellular coupling and spread of excitation in mended heart. PMID:26993221

  2. Chronic ethanol consumption transiently reduces adult neural progenitor cell proliferation.

    PubMed

    Rice, Ann C; Bullock, M Ross; Shelton, Keith L

    2004-06-11

    Adult neural stem/progenitor cells proliferate throughout the life of the animal in the subependymal zone and the subgranular zone of the dentate gyrus (DG). Treatments such as enriched environment, dietary restriction, running and anti-depressants increase proliferation, however, stress and opiates have been shown to decrease proliferation. While models of binge ethanol drinking decreases proliferation, few studies have characterized the effect chronic ethanol usage has on progenitor cell proliferation. In this study, we have examined changes in the progenitor cell proliferation rate following chronic ethanol consumption. Animals were given a nutritionally balanced liquid diet containing 6.5% v/v ethanol or an isocalorically balanced liquid diet. Bromodeoxyuridine (BrdU) was administered (150 mg/kg x 3) and the animals sacrificed 2 h after the last injection on days 3, 10 or 30 of the ethanol diet. Coronal brain blocks were paraffin embedded and 6 microm sections sliced and immunohistochemically stained for BrdU. Quantitation of the number of BrdU-labeled cells in the subgranular zone of the DG revealed a significant decrease only at the 3-day time-point, with recovery by the 10- and 30-day time-points. Thus, the progenitor cell proliferation rate is transiently decreased by chronic ethanol usage. This data suggests that chronic alcohol use results in a compensatory response that restores the progenitor cell proliferation rate.

  3. Multipotent progenitor cells isolated from adult human pancreatic tissue.

    PubMed

    Todorov, I; Nair, I; Ferreri, K; Rawson, J; Kuroda, A; Pascual, M; Omori, K; Valiente, L; Orr, C; Al-Abdullah, I; Riggs, A; Kandeel, F; Mullen, Y

    2005-10-01

    The supply of islet cells is a limiting factor for the widespread application of islet transplantation of type-1 diabetes. Islets constitute 1% to 2% of pancreatic tissue, leaving approximately 98% as discard after islet isolation and purification. In this report we present our data on the isolation of multipotent progenitor cells from discarded adult human pancreatic tissue. The collected cells from discarded nonislet fractions, after enzymatic digestion and gradient purification of islets, were dissociated for suspension culture in a serum-free medium. The cell clusters grown to a size of 100 to 150 mum contained cells staining for stage-specific embryonic antigens, but not insulin or C-peptide. To direct cell differentiation toward islets, clusters were recultured in a pancreatic differentiation medium. Insulin and C-peptide-positive cells by immunocytochemistry appeared within a week, reaching over 10% of the cell population. Glucagon and somatostatin-positive cells were also detected. The cell clusters were found to secrete insulin in response to glucose stimulation. Cells from the same clusters also had the capacity for differentiation into neural cells, as documented by staining for neural and glial cell markers when cultured as monolayers in media containing neurotrophic factors. These data suggest that multipotent pancreatic progenitor cells exist within the human pancreatic tissue that is typically discarded during islet isolation procedures. These adult progenitor cells can be successfully differentiated into insulin-producing cells, and thus they have the potential for treatment of type-1 diabetes mellitus. PMID:16298614

  4. Secretome from resident cardiac stromal cells stimulates proliferation, cardiomyogenesis and angiogenesis of progenitor cells.

    PubMed

    Reus, Thamile Luciane; Robert, Anny Waloski; Da Costa, Marise Brenner Affonso; de Aguiar, Alessandra Melo; Stimamiglio, Marco Augusto

    2016-10-15

    In the heart, tissue-derived signals play a central role on recruiting/activating stem cell sources to induce cardiac lineage specification for maintenance of tissue homeostasis and repair. Cardiac resident stromal cells (CRSCs) may play a pivotal role in cardiac repair throughout their secretome. Here, we performed the characterization of CRSCs and their secretome by analyzing the composition of their culture-derived extracellular matrix (ECM) and conditioned medium (CM) and by investigating their potential effect on adipose-derived stem cell (ADSC) and progenitor cell behavior. We confirmed that CRSCs are a heterogeneous cell population whose secretome is composed by proteins related to cellular growth, immune response and cardiovascular development and function. We also observed that CRSC secretome was unable to change the behavior of ADSCs, except for proliferation. Additionally, CM from CRSCs demonstrated the potential to drive proliferation and cardiac differentiation of H9c2 cells and also the ability to induce angiogenesis in vitro. Our data suggest that the CRSCs can be a source of important modulating signals for cardiac progenitor cell recruitment/activation. PMID:27404713

  5. Electrical stimulation of cardiac adipose tissue-derived progenitor cells modulates cell phenotype and genetic machinery.

    PubMed

    Llucià-Valldeperas, A; Sanchez, B; Soler-Botija, C; Gálvez-Montón, C; Prat-Vidal, C; Roura, S; Rosell-Ferrer, J; Bragos, R; Bayes-Genis, A

    2015-11-01

    A major challenge of cardiac tissue engineering is directing cells to establish the physiological structure and function of the myocardium being replaced. Our aim was to examine the effect of electrical stimulation on the cardiodifferentiation potential of cardiac adipose tissue-derived progenitor cells (cardiac ATDPCs). Three different electrical stimulation protocols were tested; the selected protocol consisted of 2 ms monophasic square-wave pulses of 50 mV/cm at 1 Hz over 14 days. Cardiac and subcutaneous ATDPCs were grown on biocompatible patterned surfaces. Cardiomyogenic differentiation was examined by real-time PCR and immunocytofluorescence. In cardiac ATDPCs, MEF2A and GATA-4 were significantly upregulated at day 14 after stimulation, while subcutaneous ATDPCs only exhibited increased Cx43 expression. In response to electrical stimulation, cardiac ATDPCs elongated, and both cardiac and subcutaneous ATDPCs became aligned following the linear surface pattern of the construct. Cardiac ATDPC length increased by 11.3%, while subcutaneous ATDPC length diminished by 11.2% (p = 0.013 and p = 0.030 vs unstimulated controls, respectively). Compared to controls, electrostimulated cells became aligned better to the patterned surfaces when the pattern was perpendicular to the electric field (89.71 ± 28.47º for cardiac ATDPCs and 92.15 ± 15.21º for subcutaneous ATDPCs). Electrical stimulation of cardiac ATDPCs caused changes in cell phenotype and genetic machinery, making them more suitable for cardiac regeneration approaches. Thus, it seems advisable to use electrical cell training before delivery as a cell suspension or within engineered tissue.

  6. Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation.

    PubMed

    Epelman, Slava; Lavine, Kory J; Beaudin, Anna E; Sojka, Dorothy K; Carrero, Javier A; Calderon, Boris; Brija, Thaddeus; Gautier, Emmanuel L; Ivanov, Stoyan; Satpathy, Ansuman T; Schilling, Joel D; Schwendener, Reto; Sergin, Ismail; Razani, Babak; Forsberg, E Camilla; Yokoyama, Wayne M; Unanue, Emil R; Colonna, Marco; Randolph, Gwendalyn J; Mann, Douglas L

    2014-01-16

    Cardiac macrophages are crucial for tissue repair after cardiac injury but are not well characterized. Here we identify four populations of cardiac macrophages. At steady state, resident macrophages were primarily maintained through local proliferation. However, after macrophage depletion or during cardiac inflammation, Ly6c(hi) monocytes contributed to all four macrophage populations, whereas resident macrophages also expanded numerically through proliferation. Genetic fate mapping revealed that yolk-sac and fetal monocyte progenitors gave rise to the majority of cardiac macrophages, and the heart was among a minority of organs in which substantial numbers of yolk-sac macrophages persisted in adulthood. CCR2 expression and dependence distinguished cardiac macrophages of adult monocyte versus embryonic origin. Transcriptional and functional data revealed that monocyte-derived macrophages coordinate cardiac inflammation, while playing redundant but lesser roles in antigen sampling and efferocytosis. These data highlight the presence of multiple cardiac macrophage subsets, with different functions, origins, and strategies to regulate compartment size.

  7. EphB4 Forward-Signaling Regulates Cardiac Progenitor Development in Mouse ES Cells

    PubMed Central

    Liu, Yanfeng; Hoyle, Dixie L.; Shen, Wei-Feng; Wu, Li-Qun; Wang, Zack Z.

    2015-01-01

    Eph receptor (Eph)-ephrin signaling plays an important role in organ development and tissue regeneration. Bidirectional signaling of EphB4– ephrinB2 regulates cardiovascular development. To assess the role of EphB4–ephrinB2 signaling in cardiac lineage development, we utilized two GFP reporter systems in embryonic stem (ES) cells, in which the GFP transgenes were expressed in Nkx2.5+ cardiac progenitor cells and in α-MHC+ cardiomyocytes, respectively. We found that both EphB4 and ephrinB2 were expressed in Nkx2.5-GFP+ cardiac progenitor cells, but not in α-MHC-GFP+ cardiomyocytes during cardiac lineage differentiation of ES cells. An antagonist of EphB4, TNYL-RAW peptides, that block the binding of EphB4 and ephrinB2, impaired cardiac lineage development in ES cells. Inhibition of EphB4–ephrinB2 signaling at different time points during ES cell differentiation demonstrated that the interaction of EphB4 and ephrinB2 was required for the early stage of cardiac lineage development. Forced expression of human full-length EphB4 or intracellular domain-truncated EphB4 in EphB4-null ES cells was established to investigate the role of EphB4-forward signaling in ES cells. Interestingly, while full-length EphB4 was able to restore the cardiac lineage development in EphB4-null ES cells, the truncated EphB4 that lacks the intracellular domain of tyrosine kinase and PDZ motif failed to rescue the defect of cardiomyocyte development, suggesting that EphB4 intracellular domain is essential for the development of cardiomyocytes. Our study provides evidence that receptor-kinase-dependent EphB4-forward signaling plays a crucial role in the development of cardiac progenitor cells. PMID:25359705

  8. Functional Effect of Pim1 Depends upon Intracellular Localization in Human Cardiac Progenitor Cells.

    PubMed

    Samse, Kaitlen; Emathinger, Jacqueline; Hariharan, Nirmala; Quijada, Pearl; Ilves, Kelli; Völkers, Mirko; Ormachea, Lucia; De La Torre, Andrea; Orogo, Amabel M; Alvarez, Roberto; Din, Shabana; Mohsin, Sadia; Monsanto, Megan; Fischer, Kimberlee M; Dembitsky, Walter P; Gustafsson, Åsa B; Sussman, Mark A

    2015-05-29

    Human cardiac progenitor cells (hCPC) improve heart function after autologous transfer in heart failure patients. Regenerative potential of hCPCs is severely limited with age, requiring genetic modification to enhance therapeutic potential. A legacy of work from our laboratory with Pim1 kinase reveals effects on proliferation, survival, metabolism, and rejuvenation of hCPCs in vitro and in vivo. We demonstrate that subcellular targeting of Pim1 bolsters the distinct cardioprotective effects of this kinase in hCPCs to increase proliferation and survival, and antagonize cellular senescence. Adult hCPCs isolated from patients undergoing left ventricular assist device implantation were engineered to overexpress Pim1 throughout the cell (PimWT) or targeted to either mitochondrial (Mito-Pim1) or nuclear (Nuc-Pim1) compartments. Nuc-Pim1 enhances stem cell youthfulness associated with decreased senescence-associated β-galactosidase activity, preserved telomere length, reduced expression of p16 and p53, and up-regulation of nucleostemin relative to PimWT hCPCs. Alternately, Mito-Pim1 enhances survival by increasing expression of Bcl-2 and Bcl-XL and decreasing cell death after H2O2 treatment, thereby preserving mitochondrial integrity superior to PimWT. Mito-Pim1 increases the proliferation rate by up-regulation of cell cycle modulators Cyclin D, CDK4, and phospho-Rb. Optimal stem cell traits such as proliferation, survival, and increased youthful properties of aged hCPCs are enhanced after targeted Pim1 localization to mitochondrial or nuclear compartments. Targeted Pim1 overexpression in hCPCs allows for selection of the desired phenotypic properties to overcome patient variability and improve specific stem cell characteristics.

  9. Smarcd3b and Gata5 promote a cardiac progenitor fate in the zebrafish embryo.

    PubMed

    Lou, Xin; Deshwar, Ashish R; Crump, J Gage; Scott, Ian C

    2011-08-01

    Development of the heart requires recruitment of cardiovascular progenitor cells (CPCs) to the future heart-forming region. CPCs are the building blocks of the heart, and have the potential to form all the major cardiac lineages. However, little is known regarding what regulates CPC fate and behavior. Activity of GATA4, SMARCD3 and TBX5 - the `cardiac BAF' (cBAF) complex, can promote myocardial differentiation in embryonic mouse mesoderm. Here, we exploit the advantages of the zebrafish embryo to gain mechanistic understanding of cBAF activity. Overexpression of smarcd3b and gata5 in zebrafish results in an enlarged heart, whereas combinatorial loss of cBAF components inhibits cardiac differentiation. In transplantation experiments, cBAF acts cell autonomously to promote cardiac fate. Remarkably, cells overexpressing cBAF migrate to the developing heart and differentiate as cardiomyocytes, endocardium and smooth muscle. This is observed even in host embryos that lack endoderm or cardiac mesoderm. Our results reveal an evolutionarily conserved role for cBAF activity in cardiac differentiation. Importantly, they demonstrate that Smarcd3b and Gata5 can induce a primitive, CPC-like state. PMID:21715426

  10. Cardiac progenitor cell-derived exosomes prevent cardiomyocytes apoptosis through exosomal miR-21 by targeting PDCD4.

    PubMed

    Xiao, J; Pan, Y; Li, X H; Yang, X Y; Feng, Y L; Tan, H H; Jiang, L; Feng, J; Yu, X Y

    2016-01-01

    Cardiac progenitor cells derived from adult heart have emerged as one of the most promising stem cell types for cardiac protection and repair. Exosomes are known to mediate cell-cell communication by transporting cell-derived proteins and nucleic acids, including various microRNAs (miRNAs). Here we investigated the cardiac progenitor cell (CPC)-derived exosomal miRNAs on protecting myocardium under oxidative stress. Sca1(+)CPCs-derived exosomes were purified from conditional medium, and identified by nanoparticle trafficking analysis (NTA), transmission electron microscopy and western blotting using CD63, CD9 and Alix as markers. Exosomes production was measured by NTA, the result showed that oxidative stress-induced CPCs secrete more exosomes compared with normal condition. Although six apoptosis-related miRNAs could be detected in two different treatment-derived exosomes, only miR-21 was significantly upregulated in oxidative stress-induced exosomes compared with normal exosomes. The same oxidative stress could cause low miR-21 and high cleaved caspase-3 expression in H9C2 cardiac cells. But the cleaved caspase-3 was significantly decreased when miR-21 was overexpressed by transfecting miR-21 mimic. Furthermore, miR-21 mimic or inhibitor transfection and luciferase activity assay confirmed that programmed cell death 4 (PDCD4) was a target gene of miR-21, and miR-21/PDCD4 axis has an important role in anti-apoptotic effect of H9C2 cell. Western blotting and Annexin V/PI results demonstrated that exosomes pre-treated H9C2 exhibited increased miR-21 whereas decreased PDCD4, and had more resistant potential to the apoptosis induced by the oxidative stress, compared with non-treated cells. These findings revealed that CPC-derived exosomal miR-21 had an inhibiting role in the apoptosis pathway through downregulating PDCD4. Restored miR-21/PDCD4 pathway using CPC-derived exosomes could protect myocardial cells against oxidative stress-related apoptosis. Therefore

  11. Multipotent adult progenitor cells on an allograft scaffold facilitate the bone repair process

    PubMed Central

    LoGuidice, Amanda; Houlihan, Alison; Deans, Robert

    2016-01-01

    Multipotent adult progenitor cells are a recently described population of stem cells derived from the bone marrow stroma. Research has demonstrated the potential of multipotent adult progenitor cells for treating ischemic injury and cardiovascular repair; however, understanding of multipotent adult progenitor cells in orthopedic applications remains limited. In this study, we evaluate the osteogenic and angiogenic capacity of multipotent adult progenitor cells, both in vitro and loaded onto demineralized bone matrix in vivo, with comparison to mesenchymal stem cells, as the current standard. When compared to mesenchymal stem cells, multipotent adult progenitor cells exhibited a more robust angiogenic protein release profile in vitro and developed more extensive vasculature within 2 weeks in vivo. The establishment of this vascular network is critical to the ossification process, as it allows nutrient exchange and provides an influx of osteoprogenitor cells to the wound site. In vitro assays confirmed the multipotency of multipotent adult progenitor cells along mesodermal lineages and demonstrated the enhanced expression of alkaline phosphatase and production of calcium-containing mineral deposits by multipotent adult progenitor cells, necessary precursors for osteogenesis. In combination with a demineralized bone matrix scaffold, multipotent adult progenitor cells demonstrated enhanced revascularization and new bone formation in vivo in an orthotopic defect model when compared to mesenchymal stem cells on demineralized bone matrix or demineralized bone matrix–only control groups. The potent combination of angiogenic and osteogenic properties provided by multipotent adult progenitor cells appears to create a synergistic amplification of the bone healing process. Our results indicate that multipotent adult progenitor cells have the potential to better promote tissue regeneration and healing and to be a functional cell source for use in orthopedic applications

  12. Multipotent adult progenitor cells on an allograft scaffold facilitate the bone repair process.

    PubMed

    LoGuidice, Amanda; Houlihan, Alison; Deans, Robert

    2016-01-01

    Multipotent adult progenitor cells are a recently described population of stem cells derived from the bone marrow stroma. Research has demonstrated the potential of multipotent adult progenitor cells for treating ischemic injury and cardiovascular repair; however, understanding of multipotent adult progenitor cells in orthopedic applications remains limited. In this study, we evaluate the osteogenic and angiogenic capacity of multipotent adult progenitor cells, both in vitro and loaded onto demineralized bone matrix in vivo, with comparison to mesenchymal stem cells, as the current standard. When compared to mesenchymal stem cells, multipotent adult progenitor cells exhibited a more robust angiogenic protein release profile in vitro and developed more extensive vasculature within 2 weeks in vivo. The establishment of this vascular network is critical to the ossification process, as it allows nutrient exchange and provides an influx of osteoprogenitor cells to the wound site. In vitro assays confirmed the multipotency of multipotent adult progenitor cells along mesodermal lineages and demonstrated the enhanced expression of alkaline phosphatase and production of calcium-containing mineral deposits by multipotent adult progenitor cells, necessary precursors for osteogenesis. In combination with a demineralized bone matrix scaffold, multipotent adult progenitor cells demonstrated enhanced revascularization and new bone formation in vivo in an orthotopic defect model when compared to mesenchymal stem cells on demineralized bone matrix or demineralized bone matrix-only control groups. The potent combination of angiogenic and osteogenic properties provided by multipotent adult progenitor cells appears to create a synergistic amplification of the bone healing process. Our results indicate that multipotent adult progenitor cells have the potential to better promote tissue regeneration and healing and to be a functional cell source for use in orthopedic applications. PMID

  13. GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway.

    PubMed

    Ishida, Hidekazu; Saba, Rie; Kokkinopoulos, Ioannis; Hashimoto, Masakazu; Yamaguchi, Osamu; Nowotschin, Sonja; Shiraishi, Manabu; Ruchaya, Prashant; Miller, Duncan; Harmer, Stephen; Poliandri, Ariel; Kogaki, Shigetoyo; Sakata, Yasushi; Dunkel, Leo; Tinker, Andrew; Hadjantonakis, Anna-Katerina; Sawa, Yoshiki; Sasaki, Hiroshi; Ozono, Keiichi; Suzuki, Ken; Yashiro, Kenta

    2016-07-26

    A surface marker that distinctly identifies cardiac progenitors (CPs) is essential for the robust isolation of these cells, circumventing the necessity of genetic modification. Here, we demonstrate that a Glycosylphosphatidylinositol-anchor containing neurotrophic factor receptor, Glial cell line-derived neurotrophic factor receptor alpha 2 (Gfra2), specifically marks CPs. GFRA2 expression facilitates the isolation of CPs by fluorescence activated cell sorting from differentiating mouse and human pluripotent stem cells. Gfra2 mutants reveal an important role for GFRA2 in cardiomyocyte differentiation and development both in vitro and in vivo. Mechanistically, the cardiac GFRA2 signaling pathway is distinct from the canonical pathway dependent on the RET tyrosine kinase and its established ligands. Collectively, our findings establish a platform for investigating the biology of CPs as a foundation for future development of CP transplantation for treating heart failure. PMID:27396331

  14. 8-Oxoguanine DNA glycosylase 1 (ogg1) maintains the function of cardiac progenitor cells during heart formation in zebrafish

    SciTech Connect

    Yan, Lifeng; Zhou, Yong; Yu, Shanhe; Ji, Guixiang; Liu, Wei; Gu, Aihua

    2013-11-15

    Genomic damage may devastate the potential of progenitor cells and consequently impair early organogenesis. We found that ogg1, a key enzyme initiating the base-excision repair, was enriched in the embryonic heart in zebrafish. So far, little is known about DNA repair in cardiogenesis. Here, we addressed the critical role of ogg1 in cardiogenesis for the first time. ogg1 mainly expressed in the anterior lateral plate mesoderm (ALPM), the primary heart tube, and subsequently the embryonic myocardium by in situ hybridisation. Loss of ogg1 resulted in severe cardiac morphogenesis and functional abnormalities, including the short heart length, arrhythmia, decreased cardiomyocytes and nkx2.5{sup +} cardiac progenitor cells. Moreover, the increased apoptosis and repressed proliferation of progenitor cells caused by ogg1 deficiency might contribute to the heart phenotype. The microarray analysis showed that the expression of genes involved in embryonic heart tube morphogenesis and heart structure were significantly changed due to the lack of ogg1. Among those, foxh1 is an important partner of ogg1 in the cardiac development in response to DNA damage. Our work demonstrates the requirement of ogg1 in cardiac progenitors and heart development in zebrafish. These findings may be helpful for understanding the aetiology of congenital cardiac deficits. - Highlights: • A key DNA repair enzyme ogg1 is expressed in the embryonic heart in zebrafish. • We found that ogg1 is essential for normal cardiac morphogenesis in zebrafish. • The production of embryonic cardiomyocytes requires appropriate ogg1 expression. • Ogg1 critically regulated proliferation of cardiac progenitor cells in zebrafish. • foxh1 is a partner of ogg1 in the cardiac development in response to DNA damage.

  15. Frs2α-deficiency in cardiac progenitors disrupts a subset of FGF signals required for outflow tract morphogenesis

    PubMed Central

    Zhang, Jue; Lin, Yongshun; Zhang, Yongyou; Lan, Yongsheng; Lin, Chunhong; Moon, Anne M.; Schwartz, Robert J.; Martin, James F.; Wang, Fen

    2009-01-01

    Summary The cardiac outflow tract (OFT) is a developmentally complex structure derived from multiple lineages and is often defective in human congenital anomalies. While emerging evidence shows that the fibroblast growth factor (FGF) is essential for OFT development, the downstream pathways mediating FGF-signaling in cardiac progenitors remain poorly understood. Here, we report that FRS2α, an adaptor protein that links FGF receptor kinases to multiple signaling pathways, mediates critical aspects of FGF-dependent OFT development. Ablation of Frs2α in mesodermal OFT progenitor cells that originate in the second heart field (SHF) affects their expansion into the OFT myocardium, resulting in OFT misalignment and hypoplasia. Moreover, Frs2α mutants had defective endothelial-mesenchymal-transition and neural crest cell recruitment into the OFT cushions, resulting in OFT septation defects. The results provide new insight into the signaling molecules downstream of FGF receptor tyrosine kinases in cardiac progenitors. PMID:18832393

  16. Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury

    SciTech Connect

    Chen, Lijuan; Wang, Yingjie; Pan, Yaohua; Zhang, Lan; Shen, Chengxing; Qin, Gangjian; Ashraf, Muhammad; Weintraub, Neal; Ma, Genshan; Tang, Yaoliang

    2013-02-15

    Highlights: ► Cardiac progenitor-derived (CPC) Exosomes protect H9C2 from apoptosis in vitro. ► CPC-exosomes protect cardiomyoyctes from MI/R induced apoptosis in vivo. ► CPC-exosomes were taken up by H9C2 with high efficiency using PKH26 labeling. ► miR-451, one of GATA4-responsive miRNA cluster, is enriched in CPC-exosomes. -- Abstract: Background: Cardiac progenitors (CPC) mediate cardioprotection via paracrine effects. To date, most of studies focused on secreted paracrine proteins. Here we investigated the CPC-derived-exosomes on protecting myocardium from acute ischemia/reperfusion (MI/R) injury. Methods and results: CPC were isolated from mouse heart using two-step protocol. Exosomes were purified from conditional medium, and confirmed by electron micrograph and Western blot using CD63 as a marker. qRT-PCR shows that CPC-exosomes have high level expression of GATA4-responsive-miR-451. Exosomes were ex vivo labeled with PKH26, We observed exosomes can be uptaken by H9C2 cardiomyoblasts with high efficiency after 12 h incubation. CPC-exosomes protect H9C2 from oxidative stress by inhibiting caspase 3/7 activation invitro. In vivo delivery of CPC-exosomes in an acute mouse myocardial ischemia/reperfusion model inhibited cardiomyocyte apoptosis by about 53% in comparison with PBS control (p < 0.05). Conclusion: Our results suggest, for the first time, the CPC-exosomes can be used as a therapeutic vehicle for cardioprotection, and highlights a new perspective for using non-cell exosomes for cardiac disease.

  17. Fibronectin and Cyclic Strain Improve Cardiac Progenitor Cell Regenerative Potential In Vitro.

    PubMed

    French, Kristin M; Maxwell, Joshua T; Bhutani, Srishti; Ghosh-Choudhary, Shohini; Fierro, Marcos J; Johnson, Todd D; Christman, Karen L; Taylor, W Robert; Davis, Michael E

    2016-01-01

    Cardiac progenitor cells (CPCs) have rapidly advanced to clinical trials, yet little is known regarding their interaction with the microenvironment. Signaling cues present in the microenvironment change with development and disease. This work aims to assess the influence of two distinct signaling moieties on CPCs: cyclic biaxial strain and extracellular matrix. We evaluate four endpoints for improving CPC therapy: paracrine signaling, proliferation, connexin43 expression, and alignment. Vascular endothelial growth factor A (about 900 pg/mL) was secreted by CPCs cultured on fibronectin and collagen I. The application of mechanical strain increased vascular endothelial growth factor A secretion 2-4-fold for CPCs cultured on poly-L-lysine, laminin, or a naturally derived cardiac extracellular matrix. CPC proliferation was at least 25% higher on fibronectin than that on other matrices, especially for lower strain magnitudes. At 5% strain, connexin43 expression was highest on fibronectin. With increasing strain magnitude, connexin43 expression decreased by as much as 60% in CPCs cultured on collagen I and a naturally derived cardiac extracellular matrix. Cyclic mechanical strain induced the strongest CPC alignment when cultured on fibronectin or collagen I. This study demonstrates that culturing CPCs on fibronectin with 5% strain magnitude is optimal for their vascular endothelial growth factor A secretion, proliferation, connexin43 expression, and alignment. PMID:27610140

  18. Fibronectin and Cyclic Strain Improve Cardiac Progenitor Cell Regenerative Potential In Vitro

    PubMed Central

    Ghosh-Choudhary, Shohini; Fierro, Marcos J.; Christman, Karen L.; Taylor, W. Robert

    2016-01-01

    Cardiac progenitor cells (CPCs) have rapidly advanced to clinical trials, yet little is known regarding their interaction with the microenvironment. Signaling cues present in the microenvironment change with development and disease. This work aims to assess the influence of two distinct signaling moieties on CPCs: cyclic biaxial strain and extracellular matrix. We evaluate four endpoints for improving CPC therapy: paracrine signaling, proliferation, connexin43 expression, and alignment. Vascular endothelial growth factor A (about 900 pg/mL) was secreted by CPCs cultured on fibronectin and collagen I. The application of mechanical strain increased vascular endothelial growth factor A secretion 2–4-fold for CPCs cultured on poly-L-lysine, laminin, or a naturally derived cardiac extracellular matrix. CPC proliferation was at least 25% higher on fibronectin than that on other matrices, especially for lower strain magnitudes. At 5% strain, connexin43 expression was highest on fibronectin. With increasing strain magnitude, connexin43 expression decreased by as much as 60% in CPCs cultured on collagen I and a naturally derived cardiac extracellular matrix. Cyclic mechanical strain induced the strongest CPC alignment when cultured on fibronectin or collagen I. This study demonstrates that culturing CPCs on fibronectin with 5% strain magnitude is optimal for their vascular endothelial growth factor A secretion, proliferation, connexin43 expression, and alignment. PMID:27610140

  19. Fibronectin and Cyclic Strain Improve Cardiac Progenitor Cell Regenerative Potential In Vitro

    PubMed Central

    Ghosh-Choudhary, Shohini; Fierro, Marcos J.; Christman, Karen L.; Taylor, W. Robert

    2016-01-01

    Cardiac progenitor cells (CPCs) have rapidly advanced to clinical trials, yet little is known regarding their interaction with the microenvironment. Signaling cues present in the microenvironment change with development and disease. This work aims to assess the influence of two distinct signaling moieties on CPCs: cyclic biaxial strain and extracellular matrix. We evaluate four endpoints for improving CPC therapy: paracrine signaling, proliferation, connexin43 expression, and alignment. Vascular endothelial growth factor A (about 900 pg/mL) was secreted by CPCs cultured on fibronectin and collagen I. The application of mechanical strain increased vascular endothelial growth factor A secretion 2–4-fold for CPCs cultured on poly-L-lysine, laminin, or a naturally derived cardiac extracellular matrix. CPC proliferation was at least 25% higher on fibronectin than that on other matrices, especially for lower strain magnitudes. At 5% strain, connexin43 expression was highest on fibronectin. With increasing strain magnitude, connexin43 expression decreased by as much as 60% in CPCs cultured on collagen I and a naturally derived cardiac extracellular matrix. Cyclic mechanical strain induced the strongest CPC alignment when cultured on fibronectin or collagen I. This study demonstrates that culturing CPCs on fibronectin with 5% strain magnitude is optimal for their vascular endothelial growth factor A secretion, proliferation, connexin43 expression, and alignment.

  20. Expression of Coxsackievirus and Adenovirus Receptor Separates Hematopoietic and Cardiac Progenitor Cells in Fetal Liver Kinase 1-Expressing Mesoderm

    PubMed Central

    Tashiro, Katsuhisa; Hirata, Nobue; Okada, Atsumasa; Yamaguchi, Tomoko; Takayama, Kazuo; Mizuguchi, Hiroyuki

    2015-01-01

    In developing embryos or in vitro differentiation cultures using pluripotent stem cells (PSCs), such as embryonic stem cells and induced pluripotent stem cells, fetal liver kinase 1 (Flk1)-expressing mesodermal cells are thought to be a heterogeneous population that includes hematopoietic progenitors, endothelial progenitors, and cardiac progenitors. However, information on cell surface markers for separating these progenitors in Flk1+ cells is currently limited. In the present study, we show that distinct types of progenitor cells in Flk1+ cells could be separated according to the expression of coxsackievirus and adenovirus receptor (CAR, also known as CXADR), a tight junction component molecule. We found that mouse and human PSC- and mouse embryo-derived Flk1+ cells could be subdivided into Flk1+CAR+ cells and Flk1+CAR− cells. The progenitor cells with cardiac potential were almost entirely restricted to Flk1+CAR+ cells, and Flk1+CAR− cells efficiently differentiated into hematopoietic cells. Endothelial differentiation potential was observed in both populations. Furthermore, from the expression of CAR, Flk1, and platelet-derived growth factor receptor-α (PDGFRα), Flk1+ cells could be separated into three populations (Flk1+PDGFRα−CAR− cells, Flk1+PDGFRα−CAR+ cells, and Flk1+PDGFRα+CAR+ cells). Flk1+PDGFRα+ cells and Flk1+PDGFRα− cells have been reported as cardiac and hematopoietic progenitor cells, respectively. We identified a novel population (Flk1+PDGFRα−CAR+ cells) with the potential to differentiate into not only hematopoietic cells and endothelial cells but also cardiomyocytes. Our findings indicate that CAR would be a novel and prominent marker for separating PSC- and embryo-derived Flk1+ mesodermal cells with distinct differentiation potentials. PMID:25762001

  1. Enrichment of a bipotent hepatic progenitor cell from naive adult liver tissue

    SciTech Connect

    Wright, Natasha; Samuelson, Lisa; Walkup, Maggie H.; Chandrasekaran, Prakash; Gerber, David A.

    2008-02-08

    Background/Aim: Recent interest in the liver stem cell field has led to the identification and characterization of several hepatic progenitor cell populations from fetal and adult tissues. We isolated a hepatic progenitor cell from naive adult liver and the current studies focus on differentiation and growth. Results: A Sca-1{sup +} hepatic progenitor cell was identified within the liver parenchyma. This cell expresses numerous liver related genes and transcription found in the developing and/or adult liver. It is located in the peri-portal region and expresses markers associated with undifferentiated hepatic cell populations, mature hepatocytes and biliary cells which distinguish it from the Sca-1{sup -} fraction. Conclusion: This hepatic progenitor cell from uninjured liver has features of both hepatocytic and biliary populations and demonstrates proliferative potential. Further studies will focus on sca-HPC subsets and conditions that regulate differentiation towards hepatic or biliary lineages.

  2. Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes

    PubMed Central

    Tarlow, Branden D.; Pelz, Carl; Naugler, Willscott E.; Wakefield, Leslie; Wilson, Elizabeth M.; Finegold, Milton J.; Grompe, Markus

    2014-01-01

    Summary Adult liver progenitor cells are biliary-like epithelial cells that emerge only under injury conditions in the periportal region of the liver. They exhibit phenotypes of both hepatocytes and bile ducts. However, their origin and their significance to injury repair remain unclear. Here, we used a chimeric lineage tracing system to demonstrate that hepatocytes contribute to the progenitor pool. RNA-sequencing, ultrastructural analysis, and in vitro progenitor assays revealed that hepatocyte-derived progenitors were distinct from their biliary-derived counterparts. In vivo lineage tracing and serial transplantation assays showed that hepatocyte-derived proliferative ducts retained a memory of their origin and differentiated back into hepatocytes upon cessation of injury. Similarly, human hepatocytes in chimeric mice also gave rise to biliary progenitors in vivo. We conclude that human and mouse hepatocytes can undergo reversible ductal metaplasia in response to injury, expand as ducts and subsequently contribute to restoration of the hepatocyte mass. PMID:25312494

  3. Foetal bovine serum-derived exosomes affect yield and phenotype of human cardiac progenitor cell culture

    PubMed Central

    Angelini, Francesco; Ionta, Vittoria; Rossi, Fabrizio; Miraldi, Fabio; Messina, Elisa; Giacomello, Alessandro

    2016-01-01

    Introduction: Cardiac progenitor cells (CPCs) represent a powerful tool in cardiac regenerative medicine. Pre-clinical studies suggest that most of the beneficial effects promoted by the injected cells are due to their paracrine activity exerted on endogenous cells and tissue. Exosomes are candidate mediators of this paracrine effects. According to their potential, many researchers have focused on characterizing exosomes derived from specific cell types, but, up until now, only few studies have analyzed the possible in vitro effects of bovine serum-derived exosomes on cell proliferation or differentiation. Methods: The aim of this study was to analyse, from a qualitative and quantitative point of view, the in vitro effects of bovine serum exosomes on human CPCs cultured either as cardiospheres or as monolayers of cardiosphere-forming cells. Results: Effects on proliferation, yield and molecular patterning were detected. We show, for the first time, that exogenous bovine exosomes support the proliferation and migration of human cardiosphere-forming cells, and that their depletion affects cardiospheres formation, in terms of size, yield and extra-cellular matrix production. Conclusion: These results stress the importance of considering differential biological effects of exogenous cell culture supplements on the final phenotype of primary human cell cultures. PMID:27340620

  4. Isolation, Characterization, and Differentiation of Progenitor Cells from Human Adult Adrenal Medulla

    PubMed Central

    Santana, Magda M.; Chung, Kuei-Fang; Vukicevic, Vladimir; Rosmaninho-Salgado, Joana; Kanczkowski, Waldemar; Cortez, Vera; Hackmann, Karl; Bastos, Carlos A.; Mota, Alfredo; Schrock, Evelin; Bornstein, Stefan R.; Cavadas, Cláudia

    2012-01-01

    Chromaffin cells, sympathetic neurons of the dorsal ganglia, and the intermediate small intensely fluorescent cells derive from a common neural crest progenitor cell. Contrary to the closely related sympathetic nervous system, within the adult adrenal medulla a subpopulation of undifferentiated progenitor cells persists, and recently, we established a method to isolate and differentiate these progenitor cells from adult bovine adrenals. However, no studies have elucidated the existence of adrenal progenitor cells within the human adrenal medulla. Here we describe the isolation, characterization, and differentiation of chromaffin progenitor cells obtained from adult human adrenals. Human chromaffin progenitor cells were cultured in low-attachment conditions for 10–12 days as free-floating spheres in the presence of fibroblast growth factor-2 (FGF-2) and epidermal growth factor. These primary human chromosphere cultures were characterized by the expression of several progenitor markers, including nestin, CD133, Notch1, nerve growth factor receptor, Snai2, Sox9, Sox10, Phox2b, and Ascl1 on the molecular level and of Sox9 on the immunohistochemical level. In opposition, phenylethanolamine N-methyltransferase (PNMT), a marker for differentiated chromaffin cells, significantly decreased after 12 days in culture. Moreover, when plated on poly-l-lysine/laminin-coated slides in the presence of FGF-2, human chromaffin progenitor cells were able to differentiate into two distinct neuron-like cell types, tyrosine hydroxylase (TH)+/β-3-tubulin+ cells and TH−/β-3-tubulin+ cells, and into chromaffin cells (TH+/PNMT+). This study demonstrates the presence of progenitor cells in the human adrenal medulla and reveals their potential use in regenerative medicine, especially in the treatment of neuroendocrine and neurodegenerative diseases. PMID:23197690

  5. Isolation, characterization, and differentiation of progenitor cells from human adult adrenal medulla.

    PubMed

    Santana, Magda M; Chung, Kuei-Fang; Vukicevic, Vladimir; Rosmaninho-Salgado, Joana; Kanczkowski, Waldemar; Cortez, Vera; Hackmann, Klaus; Bastos, Carlos A; Mota, Alfredo; Schrock, Evelin; Bornstein, Stefan R; Cavadas, Cláudia; Ehrhart-Bornstein, Monika

    2012-11-01

    Chromaffin cells, sympathetic neurons of the dorsal ganglia, and the intermediate small intensely fluorescent cells derive from a common neural crest progenitor cell. Contrary to the closely related sympathetic nervous system, within the adult adrenal medulla a subpopulation of undifferentiated progenitor cells persists, and recently, we established a method to isolate and differentiate these progenitor cells from adult bovine adrenals. However, no studies have elucidated the existence of adrenal progenitor cells within the human adrenal medulla. Here we describe the isolation, characterization, and differentiation of chromaffin progenitor cells obtained from adult human adrenals. Human chromaffin progenitor cells were cultured in low-attachment conditions for 10-12 days as free-floating spheres in the presence of fibroblast growth factor-2 (FGF-2) and epidermal growth factor. These primary human chromosphere cultures were characterized by the expression of several progenitor markers, including nestin, CD133, Notch1, nerve growth factor receptor, Snai2, Sox9, Sox10, Phox2b, and Ascl1 on the molecular level and of Sox9 on the immunohistochemical level. In opposition, phenylethanolamine N-methyltransferase (PNMT), a marker for differentiated chromaffin cells, significantly decreased after 12 days in culture. Moreover, when plated on poly-l-lysine/laminin-coated slides in the presence of FGF-2, human chromaffin progenitor cells were able to differentiate into two distinct neuron-like cell types, tyrosine hydroxylase (TH)(+)/β-3-tubulin(+) cells and TH(-)/β-3-tubulin(+) cells, and into chromaffin cells (TH(+)/PNMT(+)). This study demonstrates the presence of progenitor cells in the human adrenal medulla and reveals their potential use in regenerative medicine, especially in the treatment of neuroendocrine and neurodegenerative diseases. PMID:23197690

  6. Hiding inside? Intracellular expression of non-glycosylated c-kit protein in cardiac progenitor cells.

    PubMed

    Shi, Huilin; Drummond, Christopher A; Fan, Xiaoming; Haller, Steven T; Liu, Jiang; Malhotra, Deepak; Tian, Jiang

    2016-05-01

    Cardiac progenitor cells including c-kit(+) cells and cardiosphere-derived cells (CDCs) play important roles in cardiac repair and regeneration. CDCs were reported to contain only small subpopulations of c-kit(+) cells and recent publications suggested that depletion of the c-kit(+) subpopulation of cells has no effect on regenerative properties of CDCs. However, our current study showed that the vast majority of CDCs from murine heart actually express c-kit, albeit, in an intracellular and non-glycosylated form. Immunostaining and flow cytometry showed that the fluorescent signal indicative of c-kit immunostaining significantly increased when cell membranes were permeabilized. Western blots further demonstrated that glycosylation of c-kit was increased during endothelial differentiation in a time dependent manner. Glycosylation inhibition by 1-deoxymannojirimycin hydrochloride (1-DMM) blocked c-kit glycosylation and reduced expression of endothelial cell markers such as Flk-1 and CD31 during differentiation. Pretreatment of these cells with a c-kit kinase inhibitor (imatinib mesylate) also attenuated Flk-1 and CD31 expression. These results suggest that c-kit glycosylation and its kinase activity are likely needed for these cells to differentiate into an endothelial lineage. In vivo, we found that intracellular c-kit expressing cells are located in the wall of cardiac blood vessels in mice subjected to myocardial infarction. In summary, our work demonstrated for the first time that c-kit is not only expressed in CDCs but may also directly participate in CDC differentiation into an endothelial lineage.

  7. Molecular properties of adult mouse gastric and intestinal epithelial progenitors in their niches.

    PubMed

    Giannakis, Marios; Stappenbeck, Thaddeus S; Mills, Jason C; Leip, Douglas G; Lovett, Michael; Clifton, Sandra W; Ippolito, Joseph E; Glasscock, Jarret I; Arumugam, Manimozhiyan; Brent, Michael R; Gordon, Jeffrey I

    2006-04-21

    We have sequenced 36,641 expressed sequence tags from laser capture microdissected adult mouse gastric and small intestinal epithelial progenitors, obtaining 4031 and 3324 unique transcripts, respectively. Using Gene Ontology (GO) terms, each data set was compared with cDNA libraries from intact adult stomach and small intestine. Genes in GO categories enriched in progenitors were filtered against genes in GO categories represented in hematopoietic, neural, and embryonic stem cell transcriptomes and mapped onto transcription factor networks, plus canonical signal transduction and metabolic pathways. Wnt/beta-catenin, phosphoinositide-3/Akt kinase, insulin-like growth factor-1, vascular endothelial growth factor, integrin, and gamma-aminobutyric acid receptor signaling cascades, plus glycerolipid, fatty acid, and amino acid metabolic pathways are among those prominently represented in adult gut progenitors. The results reveal shared as well as distinctive features of adult gut stem cells when compared with other stem cell populations.

  8. Characterization of Proliferating Neural Progenitors after Spinal Cord Injury in Adult Zebrafish

    PubMed Central

    Hui, Subhra Prakash; Nag, Tapas Chandra; Ghosh, Sukla

    2015-01-01

    Zebrafish can repair their injured brain and spinal cord after injury unlike adult mammalian central nervous system. Any injury to zebrafish spinal cord would lead to increased proliferation and neurogenesis. There are presences of proliferating progenitors from which both neuronal and glial loss can be reversed by appropriately generating new neurons and glia. We have demonstrated the presence of multiple progenitors, which are different types of proliferating populations like Sox2+ neural progenitor, A2B5+ astrocyte/ glial progenitor, NG2+ oligodendrocyte progenitor, radial glia and Schwann cell like progenitor. We analyzed the expression levels of two common markers of dedifferentiation like msx-b and vimentin during regeneration along with some of the pluripotency associated factors to explore the possible role of these two processes. Among the several key factors related to pluripotency, pou5f1 and sox2 are upregulated during regeneration and associated with activation of neural progenitor cells. Uncovering the molecular mechanism for endogenous regeneration of adult zebrafish spinal cord would give us more clues on important targets for future therapeutic approach in mammalian spinal cord repair and regeneration. PMID:26630262

  9. Prospective isolation of a bipotential clonogenic liver progenitor cell in adult mice

    PubMed Central

    Dorrell, Craig; Erker, Laura; Schug, Jonathan; Kopp, Janel L.; Canaday, Pamela S.; Fox, Alan J.; Smirnova, Olga; Duncan, Andrew W.; Finegold, Milton J.; Sander, Maike; Kaestner, Klaus H.; Grompe, Markus

    2011-01-01

    The molecular identification of adult hepatic stem/progenitor cells has been hampered by the lack of truly specific markers. To isolate putative adult liver progenitor cells, we used cell surface-marking antibodies, including MIC1-1C3, to isolate subpopulations of liver cells from normal adult mice or those undergoing an oval cell response and tested their capacity to form bilineage colonies in vitro. Robust clonogenic activity was found to be restricted to a subset of biliary duct cells antigenically defined as CD45−/CD11b−/CD31−/MIC1-1C3+/CD133+/CD26−, at a frequency of one of 34 or one of 25 in normal or oval cell injury livers, respectively. Gene expression analyses revealed that Sox9 was expressed exclusively in this subpopulation of normal liver cells and was highly enriched relative to other cell fractions in injured livers. In vivo lineage tracing using Sox9creERT2-R26RYFP mice revealed that the cells that proliferate during progenitor-driven liver regeneration are progeny of Sox9-expressing precursors. A comprehensive array-based comparison of gene expression in progenitor-enriched and progenitor-depleted cells from both normal and DDC (3,5-diethoxycarbonyl-1,4-dihydrocollidine or diethyl1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate)-treated livers revealed new potential regulators of liver progenitors. PMID:21632826

  10. Human adipose stem cell and ASC-derived cardiac progenitor cellular therapy improves outcomes in a murine model of myocardial infarction

    PubMed Central

    Davy, Philip MC; Lye, Kevin D; Mathews, Juanita; Owens, Jesse B; Chow, Alice Y; Wong, Livingston; Moisyadi, Stefan; Allsopp, Richard C

    2015-01-01

    Background Adipose tissue is an abundant and potent source of adult stem cells for transplant therapy. In this study, we present our findings on the potential application of adipose-derived stem cells (ASCs) as well as induced cardiac-like progenitors (iCPs) derived from ASCs for the treatment of myocardial infarction. Methods and results Human bone marrow (BM)-derived stem cells, ASCs, and iCPs generated from ASCs using three defined cardiac lineage transcription factors were assessed in an immune-compromised mouse myocardial infarction model. Analysis of iCP prior to transplant confirmed changes in gene and protein expression consistent with a cardiac phenotype. Endpoint analysis was performed 1 month posttransplant. Significantly increased endpoint fractional shortening, as well as reduction in the infarct area at risk, was observed in recipients of iCPs as compared to the other recipient cohorts. Both recipients of iCPs and ASCs presented higher myocardial capillary densities than either recipients of BM-derived stem cells or the control cohort. Furthermore, mice receiving iCPs had a significantly higher cardiac retention of transplanted cells than all other groups. Conclusion Overall, iCPs generated from ASCs outperform BM-derived stem cells and ASCs in facilitating recovery from induced myocardial infarction in mice. PMID:26604802

  11. Sudden cardiac death in adults: causes, incidence and interventions.

    PubMed

    Walker, Wendy Marina

    Many nurses will be familiar with the unexpected death of an adult patient following a sudden, life-threatening cardiac event. It is a situation that demands sensitive nursing care and skilled interventions to provide a foundation for recovery and promote healthy bereavement. This article examines the causes and incidence of sudden cardiac death in adults. Possible reactions of those who are suddenly bereaved are described and immediate care interventions aimed at dealing with the grief process are discussed. The article concludes by identifying ways in which the incidence of sudden cardiac death may be reduced.

  12. Radial glia and neural progenitors in the adult zebrafish central nervous system.

    PubMed

    Than-Trong, Emmanuel; Bally-Cuif, Laure

    2015-08-01

    The adult central nervous system (CNS) of the zebrafish, owing to its enrichment in constitutive neurogenic niches, is becoming an increasingly used model to address fundamental questions pertaining to adult neural stem cell (NSC) biology, adult neurogenesis and neuronal repair. Studies conducted in several CNS territories (notably the telencephalon, retina, midbrain, cerebellum and spinal cord) highlighted the presence, in these niches, of progenitor cells displaying NSC-like characters. While pointing to radial glial cells (RG) as major long-lasting, constitutively active and/or activatable progenitors in most domains, these studies also revealed a high heterogeneity in the progenitor subtypes used at the top of neurogenic hierarchies, including the persistence of neuroepithelial (NE) progenitors in some areas. Likewise, dissecting the molecular pathways underlying RG maintenance and recruitment under physiological conditions and upon repair in the zebrafish model revealed shared processes but also specific cascades triggering or sustaining reparative NSC recruitment. Together, the zebrafish adult brain reveals an extensive complexity of adult NSC niches, properties and control pathways, which extends existing understanding of adult NSC biology and gives access to novel mechanisms of efficient NSC maintenance and recruitment in an adult vertebrate brain. PMID:25976648

  13. Adult retinal pigment epithelium cells express neural progenitor properties and the neuronal precursor protein doublecortin.

    PubMed

    Engelhardt, Maren; Bogdahn, Ulrich; Aigner, Ludwig

    2005-04-01

    The adult mammalian retina is devoid of any detectable neurogenesis. However, different cell types have been suggested to potentially act as neural progenitors in the adult mammalian retina in vitro, such as ciliary body (CB), Muller glia, and retinal pigment epithelium (RPE) cells. In rodents and humans, strong evidence for neural stem or progenitor properties exists only for CB-derived cells, but not for other retinal cell types. Here, we provide a comparative analysis of adult rat CB- and RPE-derived cells suggesting that the two cell types share certain neural progenitor properties in vitro. CB and RPE cells expressed neural progenitor markers such as Nestin, Flk-1, Hes1, and Musashi. They proliferated under adherent and neurosphere conditions and showed limited self-renewal. Moreover, they differentiated into neuronal and glial cells based on the expression of differentiation markers such as the young neuronal marker beta-III tubulin and the glial and progenitor markers GFAP and NG2. Expression of beta-III tubulin was found in cells with neuronal and non-neuronal morphology. A subpopulation of RPE- and CB-derived progenitor cells expressed the neurogenesis-specific protein doublecortin (DCX). Interestingly, DCX expression defined a beta-III tubulin-positive CB and RPE fraction with a distinct neuronal morphology. In summary, the data suggest that RPE cells share with CB cells the potential to de-differentiate into a cell type with neural progenitor-like identity. In addition, DCX expression might define the neuronal-differentiating RPE- and CB-derived progenitor population. PMID:15804431

  14. Human cord blood CD34+ progenitor cells acquire functional cardiac properties through a cell fusion process.

    PubMed

    Avitabile, Daniele; Crespi, Alessia; Brioschi, Chiara; Parente, Valeria; Toietta, Gabriele; Devanna, Paolo; Baruscotti, Mirko; Truffa, Silvia; Scavone, Angela; Rusconi, Francesca; Biondi, Andrea; D'Alessandra, Yuri; Vigna, Elisa; Difrancesco, Dario; Pesce, Maurizio; Capogrossi, Maurizio C; Barbuti, Andrea

    2011-05-01

    The efficacy of cardiac repair by stem cell administration relies on a successful functional integration of injected cells into the host myocardium. Safety concerns have been raised about the possibility that stem cells may induce foci of arrhythmia in the ischemic myocardium. In a previous work (36), we showed that human cord blood CD34(+) cells, when cocultured on neonatal mouse cardiomyocytes, exhibit excitation-contraction coupling features similar to those of cardiomyocytes, even though no human genes were upregulated. The aims of the present work are to investigate whether human CD34(+) cells, isolated after 1 wk of coculture with neonatal ventricular myocytes, possess molecular and functional properties of cardiomyocytes and to discriminate, using a reporter gene system, whether cardiac differentiation derives from a (trans)differentiation or a cell fusion process. Umbilical cord blood CD34(+) cells were isolated by a magnetic cell sorting method, transduced with a lentiviral vector carrying the enhanced green fluorescent protein (EGFP) gene, and seeded onto primary cultures of spontaneously beating rat neonatal cardiomyocytes. Cocultured EGFP(+)/CD34(+)-derived cells were analyzed for their electrophysiological features at different time points. After 1 wk in coculture, EGFP(+) cells, in contact with cardiomyocytes, were spontaneously contracting and had a maximum diastolic potential (MDP) of -53.1 mV, while those that remained isolated from the surrounding myocytes did not contract and had a depolarized resting potential of -11.4 mV. Cells were then resuspended and cultured at low density to identify EGFP(+) progenitor cell derivatives. Under these conditions, we observed single EGFP(+) beating cells that had acquired an hyperpolarization-activated current typical of neonatal cardiomyocytes (EGFP(+) cells, -2.24 ± 0.89 pA/pF; myocytes, -1.99 ± 0.63 pA/pF, at -125 mV). To discriminate between cell autonomous differentiation and fusion, EGFP(+)/CD34

  15. Simulated Microgravity and 3D Culture Enhance Induction, Viability, Proliferation and Differentiation of Cardiac Progenitors from Human Pluripotent Stem Cells

    PubMed Central

    Jha, Rajneesh; Wu, Qingling; Singh, Monalisa; Preininger, Marcela K.; Han, Pengcheng; Ding, Gouliang; Cho, Hee Cheol; Jo, Hanjoong; Maher, Kevin O.; Wagner, Mary B.; Xu, Chunhui

    2016-01-01

    Efficient generation of cardiomyocytes from human pluripotent stem cells is critical for their regenerative applications. Microgravity and 3D culture can profoundly modulate cell proliferation and survival. Here, we engineered microscale progenitor cardiac spheres from human pluripotent stem cells and exposed the spheres to simulated microgravity using a random positioning machine for 3 days during their differentiation to cardiomyocytes. This process resulted in the production of highly enriched cardiomyocytes (99% purity) with high viability (90%) and expected functional properties, with a 1.5 to 4-fold higher yield of cardiomyocytes from each undifferentiated stem cell as compared with 3D-standard gravity culture. Increased induction, proliferation and viability of cardiac progenitors as well as up-regulation of genes associated with proliferation and survival at the early stage of differentiation were observed in the 3D culture under simulated microgravity. Therefore, a combination of 3D culture and simulated microgravity can be used to efficiently generate highly enriched cardiomyocytes. PMID:27492371

  16. Simulated Microgravity and 3D Culture Enhance Induction, Viability, Proliferation and Differentiation of Cardiac Progenitors from Human Pluripotent Stem Cells.

    PubMed

    Jha, Rajneesh; Wu, Qingling; Singh, Monalisa; Preininger, Marcela K; Han, Pengcheng; Ding, Gouliang; Cho, Hee Cheol; Jo, Hanjoong; Maher, Kevin O; Wagner, Mary B; Xu, Chunhui

    2016-01-01

    Efficient generation of cardiomyocytes from human pluripotent stem cells is critical for their regenerative applications. Microgravity and 3D culture can profoundly modulate cell proliferation and survival. Here, we engineered microscale progenitor cardiac spheres from human pluripotent stem cells and exposed the spheres to simulated microgravity using a random positioning machine for 3 days during their differentiation to cardiomyocytes. This process resulted in the production of highly enriched cardiomyocytes (99% purity) with high viability (90%) and expected functional properties, with a 1.5 to 4-fold higher yield of cardiomyocytes from each undifferentiated stem cell as compared with 3D-standard gravity culture. Increased induction, proliferation and viability of cardiac progenitors as well as up-regulation of genes associated with proliferation and survival at the early stage of differentiation were observed in the 3D culture under simulated microgravity. Therefore, a combination of 3D culture and simulated microgravity can be used to efficiently generate highly enriched cardiomyocytes. PMID:27492371

  17. Ascl3 marks adult progenitor cells of the mouse salivary gland.

    PubMed

    Rugel-Stahl, Anastasia; Elliott, Marilyn E; Ovitt, Catherine E

    2012-05-01

    The Ascl3 transcription factor marks a subset of salivary gland duct cells present in the three major salivary glands of the mouse. In vivo, these cells generate both duct and secretory acinar cell descendants. Here, we have analyzed whether Ascl3-expressing cells retain this multipotent lineage potential in adult glands. Cells isolated from mouse salivary glands were cultured in vitro as non-adherent spheres. Lineage tracing of the Ascl3-expressing cells within the spheres demonstrates that Ascl3+ cells isolated from adult glands remain multipotent, generating both duct and acinar cell types in vitro. Furthermore, we demonstrate that the progenitor cells characterized by Keratin 5 expression are an independent population from Ascl3+ progenitor cells. We conclude that the Ascl3+ cells are intermediate lineage-restricted progenitor cells of the adult salivary glands.

  18. Cardiac mesenchymal progenitors differentiate into adipocytes via Klf4 and c-Myc

    PubMed Central

    Kami, D; Kitani, T; Kawasaki, T; Gojo, S

    2016-01-01

    Direct reprogramming of differentiated cells to pluripotent stem cells has great potential to improve our understanding of developmental biology and disorders such as cancers, and has implications for regenerative medicine. In general, the effects of transcription factors (TFs) that are transduced into cells can be influenced by pre-existing transcriptional networks and epigenetic modifications. However, previous work has identified four key TFs, Oct4, Sox2, Klf4 and c-Myc, which can reprogram various differentiated cells to generate induced pluripotent stem cells. Here, we show that in the heart, the transduction of cardiac mesenchymal progenitors (CMPs) with Klf4 and c-Myc (KM) was sufficient to drive the differentiation of these cells into adipocytes without the use of adipogenic stimulation cocktail, that is, insulin, 3-isobutyl-1-methylxanthine (IBMX) and dexamethasone. KM-transduced CMPs exhibited a gradually increased expression of adipogenic-related genes, such as C/Ebpα, Pparγ and Fabp4, activation of the peroxisome proliferator-activated receptor (PPAR) signaling pathway, inactivation of the cell cycle-related pathway and formation of cytoplasmic lipid droplets within 10 days. In contrast, NIH3T3 fibroblasts, 3T3-L1 preadipocytes, and bone marrow-derived mesenchymal stem cells transduced with KM did not differentiate into adipocytes. Both in vitro and in vivo cardiac ischemia reperfusion injury models demonstrated that the expression of KM genes sharply increased following a reperfusion insult. These results suggest that ectopic adipose tissue formation in the heart following myocardial infarction results from CMPs that express KM following a stress response. PMID:27077806

  19. Primary cilia regulate proliferation of amplifying progenitors in adult hippocampus: implications for learning and memory.

    PubMed

    Amador-Arjona, Alejandro; Elliott, Jimmy; Miller, Amber; Ginbey, Ashley; Pazour, Gregory J; Enikolopov, Grigori; Roberts, Amanda J; Terskikh, Alexey V

    2011-07-01

    Integration of new neurons into the adult hippocampus has been linked to specific types of learning. Primary cilia were found to be required for the formation of adult neural stem cells (NSCs) in the hippocampal dentate gyrus during development. However, the requirement of cilia in maintenance of adult NSCs is unknown. We developed a genetic mouse model in which fetal/perinatal brain development is unaffected, but adult hippocampal neurogenesis is constantly reduced by conditional ablation of primary cilia in adult GFAP(+) neural stem/progenitor cells. We found that this approach specifically reduces the number of hippocampal amplifying progenitors (also called type 2a cells) without affecting the number of radial NSCs (or type 1 cells). Constant reduction of adult hippocampal neurogenesis produced a delay rather than a permanent deficiency in spatial learning without affecting the retention of long-term memories. Decreased neurogenesis also altered spatial novelty recognition and hippocampus-independent cue conditioning. Here, we propose that adult hippocampal newborn neurons increase the efficiency of generating the new representations of spatial memories and that reduction of adult hippocampal neurogenesis may be biased toward cue-based strategies. This novel mouse model provides evidences that cognitive deficits associated with ciliary defects (ciliopathies) might be, in part, mediated by the deficiency of primary cilia in adult hippocampal stem/progenitor cells. PMID:21734285

  20. Primary cilia regulate proliferation of amplifying progenitors in adult hippocampus: implications for learning and memory.

    PubMed

    Amador-Arjona, Alejandro; Elliott, Jimmy; Miller, Amber; Ginbey, Ashley; Pazour, Gregory J; Enikolopov, Grigori; Roberts, Amanda J; Terskikh, Alexey V

    2011-07-01

    Integration of new neurons into the adult hippocampus has been linked to specific types of learning. Primary cilia were found to be required for the formation of adult neural stem cells (NSCs) in the hippocampal dentate gyrus during development. However, the requirement of cilia in maintenance of adult NSCs is unknown. We developed a genetic mouse model in which fetal/perinatal brain development is unaffected, but adult hippocampal neurogenesis is constantly reduced by conditional ablation of primary cilia in adult GFAP(+) neural stem/progenitor cells. We found that this approach specifically reduces the number of hippocampal amplifying progenitors (also called type 2a cells) without affecting the number of radial NSCs (or type 1 cells). Constant reduction of adult hippocampal neurogenesis produced a delay rather than a permanent deficiency in spatial learning without affecting the retention of long-term memories. Decreased neurogenesis also altered spatial novelty recognition and hippocampus-independent cue conditioning. Here, we propose that adult hippocampal newborn neurons increase the efficiency of generating the new representations of spatial memories and that reduction of adult hippocampal neurogenesis may be biased toward cue-based strategies. This novel mouse model provides evidences that cognitive deficits associated with ciliary defects (ciliopathies) might be, in part, mediated by the deficiency of primary cilia in adult hippocampal stem/progenitor cells.

  1. ISL1 cardiovascular progenitor cells for cardiac repair after myocardial infarction

    PubMed Central

    Zhuang, Zhen Wu; Huang, Yan; Mikush, Nicole; Suh, Carol; Bregasi, Alda; Wang, Lin; Chang, William; Krause, Diane S.; Young, Lawrence H.; Pober, Jordan S.

    2016-01-01

    Cardiovascular progenitor cells (CPCs) expressing the ISL1-LIM–homeodomain transcription factor contribute developmentally to cardiomyocytes in all 4 chambers of the heart. Here, we show that ISL1-CPCs can be applied to myocardial regeneration following injury. We used a rapid 3D methylcellulose approach to form murine and human ISL1-CPC spheroids that engrafted after myocardial infarction in murine hearts, where they differentiated into cardiomyocytes and endothelial cells, integrating into the myocardium and forming new blood vessels. ISL1-CPC spheroid–treated mice exhibited reduced infarct area and increased blood vessel formation compared with control animals. Moreover, left ventricular (LV) contractile function was significantly better in mice transplanted with ISL1-CPCs 4 weeks after injury than that in control animals. These results provide proof-of-concept of a cardiac repair strategy employing ISL1-CPCs that, based on our previous lineage-tracing studies, are committed to forming heart tissue, in combination with a robust methylcellulose spheroid–based delivery approach. PMID:27525311

  2. Cardiac primitive cells become committed to a cardiac fate in adult human heart with chronic ischemic disease but fail to acquire mature phenotype: genetic and phenotypic study.

    PubMed

    Nurzynska, Daria; Di Meglio, Franca; Romano, Veronica; Miraglia, Rita; Sacco, Anna Maria; Latino, Francesca; Bancone, Ciro; Della Corte, Alessandro; Maiello, Ciro; Amarelli, Cristiano; Montagnani, Stefania; Castaldo, Clotilde

    2013-01-01

    Adult human heart hosts a population of cardiac primitive CD117-positive cells (CPCs), which are responsible for physiological tissue homeostasis and regeneration. While the bona fide stem cells express telomerase, their progenies are no longer able to preserve telomeric DNA; hence the balance between their proliferation and differentiation has to be tightly controlled in order to prevent cellular senescence and apoptosis of CPCs before their maturation can be accomplished. We have examined at cellular and molecular level the proliferation, apoptosis and commitment of CPCs isolated from normal (CPC-N) and age-matched pathological adult human hearts (CPC-P) with ischemic heart disease. In the CPC-P, genes related to early stages of developmental processes, nervous system development and neurogenesis, skeletal development, bone and cartilage development were downregulated, while those involved in mesenchymal cell differentiation and heart development were upregulated, together with the transcriptional activation of TGFβ/BMP signaling pathway. In the pathological heart, asymmetric division was the prevalent type of cardiac stem cell division. The population of CPC-P consisted mainly of progenitors of cardiac cell lineages and less precursors; these cells proliferated more, but were also more susceptible to apoptosis with respect to CPC-N. These results indicate that CPCs fail to reach terminal differentiation and functional competence in pathological conditions. Adverse effects of underlying pathology, which disrupts cardiac tissue structure and composition, and cellular senescence, resulting from cardiac stem cell activation in telomere dysfunctional environment, can be responsible for such outcome.

  3. Identification of Radial Glia Progenitors in the Developing and Adult Retina of Sharks.

    PubMed

    Sánchez-Farías, Nuria; Candal, Eva

    2016-01-01

    Neural stem cells give rise to transient progenitors termed neuroepithelial cells (NECs) and radial glial cells (RGCs). RGCs represent the major source of neurons, glia and adult stem cells in several regions of the central nervous system (CNS). RGCs are mostly transient in mammals, but they are widely maintained in the adult CNS of fishes, where they continue to be morphologically similar to RGCs in the mammalian brain and fulfill similar roles as progenitors and guide for migrating neurons. The retina of fishes offers an exceptional model to approach the study of adult neurogenesis because of the presence of constitutive proliferation from the ciliary marginal zone (CMZ), containing NECs, and from adult glial cells with radial morphology (the Müller glia). However, the cellular hierarchies and precise contribution of different types of progenitors to adult neurogenesis remain unsolved. We have analyzed the transition from NECs to RGCs and RGC differentiation in the retina of the cartilaginous fish Scyliorhinus canicula, which offers a particularly good spatial and temporal frame to investigate this process. We have characterized progenitor and adult RGCs by immunohistochemical detection of glial markers as glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS). We have compared the emergence and localization of glial markers with that of proliferating cell nuclear antigen (PCNA, a proliferation maker) and Doublecortin (DCX, which increases at early stages of neuronal differentiation). During retinal development, GFAP-immunoreactive NECs located in the most peripheral CMZ (CMZp) codistribute with DCX-immunonegative cells. GFAP-immunoreactive RGCs and Müller cells are located in successive more central parts of the retina and codistribute with DCX- and DCX/GS-immunoreactive cells, respectively. The same types of progenitors are found in juveniles, suggesting that the contribution of the CMZ to adult neurogenesis implies a transition through the

  4. Identification of Radial Glia Progenitors in the Developing and Adult Retina of Sharks.

    PubMed

    Sánchez-Farías, Nuria; Candal, Eva

    2016-01-01

    Neural stem cells give rise to transient progenitors termed neuroepithelial cells (NECs) and radial glial cells (RGCs). RGCs represent the major source of neurons, glia and adult stem cells in several regions of the central nervous system (CNS). RGCs are mostly transient in mammals, but they are widely maintained in the adult CNS of fishes, where they continue to be morphologically similar to RGCs in the mammalian brain and fulfill similar roles as progenitors and guide for migrating neurons. The retina of fishes offers an exceptional model to approach the study of adult neurogenesis because of the presence of constitutive proliferation from the ciliary marginal zone (CMZ), containing NECs, and from adult glial cells with radial morphology (the Müller glia). However, the cellular hierarchies and precise contribution of different types of progenitors to adult neurogenesis remain unsolved. We have analyzed the transition from NECs to RGCs and RGC differentiation in the retina of the cartilaginous fish Scyliorhinus canicula, which offers a particularly good spatial and temporal frame to investigate this process. We have characterized progenitor and adult RGCs by immunohistochemical detection of glial markers as glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS). We have compared the emergence and localization of glial markers with that of proliferating cell nuclear antigen (PCNA, a proliferation maker) and Doublecortin (DCX, which increases at early stages of neuronal differentiation). During retinal development, GFAP-immunoreactive NECs located in the most peripheral CMZ (CMZp) codistribute with DCX-immunonegative cells. GFAP-immunoreactive RGCs and Müller cells are located in successive more central parts of the retina and codistribute with DCX- and DCX/GS-immunoreactive cells, respectively. The same types of progenitors are found in juveniles, suggesting that the contribution of the CMZ to adult neurogenesis implies a transition through the

  5. Identification of Radial Glia Progenitors in the Developing and Adult Retina of Sharks

    PubMed Central

    Sánchez-Farías, Nuria; Candal, Eva

    2016-01-01

    Neural stem cells give rise to transient progenitors termed neuroepithelial cells (NECs) and radial glial cells (RGCs). RGCs represent the major source of neurons, glia and adult stem cells in several regions of the central nervous system (CNS). RGCs are mostly transient in mammals, but they are widely maintained in the adult CNS of fishes, where they continue to be morphologically similar to RGCs in the mammalian brain and fulfill similar roles as progenitors and guide for migrating neurons. The retina of fishes offers an exceptional model to approach the study of adult neurogenesis because of the presence of constitutive proliferation from the ciliary marginal zone (CMZ), containing NECs, and from adult glial cells with radial morphology (the Müller glia). However, the cellular hierarchies and precise contribution of different types of progenitors to adult neurogenesis remain unsolved. We have analyzed the transition from NECs to RGCs and RGC differentiation in the retina of the cartilaginous fish Scyliorhinus canicula, which offers a particularly good spatial and temporal frame to investigate this process. We have characterized progenitor and adult RGCs by immunohistochemical detection of glial markers as glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS). We have compared the emergence and localization of glial markers with that of proliferating cell nuclear antigen (PCNA, a proliferation maker) and Doublecortin (DCX, which increases at early stages of neuronal differentiation). During retinal development, GFAP-immunoreactive NECs located in the most peripheral CMZ (CMZp) codistribute with DCX-immunonegative cells. GFAP-immunoreactive RGCs and Müller cells are located in successive more central parts of the retina and codistribute with DCX- and DCX/GS-immunoreactive cells, respectively. The same types of progenitors are found in juveniles, suggesting that the contribution of the CMZ to adult neurogenesis implies a transition through the

  6. Three-dimensional scaffolds of fetal decellularized hearts exhibit enhanced potential to support cardiac cells in comparison to the adult.

    PubMed

    Silva, A C; Rodrigues, S C; Caldeira, J; Nunes, A M; Sampaio-Pinto, V; Resende, T P; Oliveira, M J; Barbosa, M A; Thorsteinsdóttir, S; Nascimento, D S; Pinto-do-Ó, P

    2016-10-01

    A main challenge in cardiac tissue engineering is the limited data on microenvironmental cues that sustain survival, proliferation and functional proficiency of cardiac cells. The aim of our study was to evaluate the potential of fetal (E18) and adult myocardial extracellular matrix (ECM) to support cardiac cells. Acellular three-dimensional (3D) bioscaffolds were obtained by parallel decellularization of fetal- and adult-heart explants thereby ensuring reliable comparison. Acellular scaffolds retained main constituents of the cardiac ECM including distinctive biochemical and structural meshwork features of the native equivalents. In vitro, fetal and adult ECM-matrices supported 3D culture of heart-derived Sca-1(+) progenitors and of neonatal cardiomyocytes, which migrated toward the center of the scaffold and displayed elongated morphology and excellent viability. At the culture end-point, more Sca-1(+) cells and cardiomyocytes were found adhered and inside fetal bioscaffolds, compared to the adult. Higher repopulation yields of Sca-1(+) cells on fetal ECM relied on β1-integrin independent mitogenic signals. Sca-1(+) cells on fetal bioscaffolds showed a gene expression profile that anticipates the synthesis of a permissive microenvironment for cardiomyogenesis. Our findings demonstrate the superior potential of the 3D fetal microenvironment to support and instruct cardiac cells. This knowledge should be integrated in the design of next-generation biomimetic materials for heart repair.

  7. Wnt/β-Catenin Stimulation and Laminins Support Cardiovascular Cell Progenitor Expansion from Human Fetal Cardiac Mesenchymal Stromal Cells

    PubMed Central

    Månsson-Broberg, Agneta; Rodin, Sergey; Bulatovic, Ivana; Ibarra, Cristián; Löfling, Marie; Genead, Rami; Wärdell, Eva; Felldin, Ulrika; Granath, Carl; Alici, Evren; Le Blanc, Katarina; Smith, C.I. Edvard; Salašová, Alena; Westgren, Magnus; Sundström, Erik; Uhlén, Per; Arenas, Ernest; Sylvén, Christer; Tryggvason, Karl; Corbascio, Matthias; Simonson, Oscar E.; Österholm, Cecilia; Grinnemo, Karl-Henrik

    2016-01-01

    Summary The intrinsic regenerative capacity of human fetal cardiac mesenchymal stromal cells (MSCs) has not been fully characterized. Here we demonstrate that we can expand cells with characteristics of cardiovascular progenitor cells from the MSC population of human fetal hearts. Cells cultured on cardiac muscle laminin (LN)-based substrata in combination with stimulation of the canonical Wnt/β-catenin pathway showed increased gene expression of ISL1, OCT4, KDR, and NKX2.5. The majority of cells stained positive for PDGFR-α, ISL1, and NKX2.5, and subpopulations also expressed the progenitor markers TBX18, KDR, c-KIT, and SSEA-1. Upon culture of the cardiac MSCs in differentiation media and on relevant LNs, portions of the cells differentiated into spontaneously beating cardiomyocytes, and endothelial and smooth muscle-like cells. Our protocol for large-scale culture of human fetal cardiac MSCs enables future exploration of the regenerative functions of these cells in the context of myocardial injury in vitro and in vivo. PMID:27052314

  8. Identification of adult nephron progenitors capable of kidney regeneration in zebrafish.

    PubMed

    Diep, Cuong Q; Ma, Dongdong; Deo, Rahul C; Holm, Teresa M; Naylor, Richard W; Arora, Natasha; Wingert, Rebecca A; Bollig, Frank; Djordjevic, Gordana; Lichman, Benjamin; Zhu, Hao; Ikenaga, Takanori; Ono, Fumihito; Englert, Christoph; Cowan, Chad A; Hukriede, Neil A; Handin, Robert I; Davidson, Alan J

    2011-02-01

    Loss of kidney function underlies many renal diseases. Mammals can partly repair their nephrons (the functional units of the kidney), but cannot form new ones. By contrast, fish add nephrons throughout their lifespan and regenerate nephrons de novo after injury, providing a model for understanding how mammalian renal regeneration may be therapeutically activated. Here we trace the source of new nephrons in the adult zebrafish to small cellular aggregates containing nephron progenitors. Transplantation of single aggregates comprising 10-30 cells is sufficient to engraft adults and generate multiple nephrons. Serial transplantation experiments to test self-renewal revealed that nephron progenitors are long-lived and possess significant replicative potential, consistent with stem-cell activity. Transplantation of mixed nephron progenitors tagged with either green or red fluorescent proteins yielded some mosaic nephrons, indicating that multiple nephron progenitors contribute to a single nephron. Consistent with this, live imaging of nephron formation in transparent larvae showed that nephrogenic aggregates form by the coalescence of multiple cells and then differentiate into nephrons. Taken together, these data demonstrate that the zebrafish kidney probably contains self-renewing nephron stem/progenitor cells. The identification of these cells paves the way to isolating or engineering the equivalent cells in mammals and developing novel renal regenerative therapies.

  9. Adult stem cell and mesenchymal progenitor theories of aging

    PubMed Central

    Fukada, So-ichiro; Ma, Yuran; Uezumi, Akiyoshi

    2014-01-01

    Advances in medical science and technology allow people live longer lives, which results in age-related problems. Humans cannot avoid the various aged-related alterations of aging; in other words, humans cannot remain young at molecular and cellular levels. In 1956, Harman proposed the “free radical theory of aging” to explain the molecular mechanisms of aging. Telomere length, and accumulation of DNA or mitochondrial damage are also considered to be mechanisms of aging. On the other hand, stem cells are essential for maintaining tissue homeostasis by replacing parenchymal cells; therefore, the stem cell theory of aging is also used to explain the progress of aging. Importantly, the stem cell theory of aging is likely related to other theories. In addition, recent studies have started to reveal the essential roles of tissue-resident mesenchymal progenitors/stem cells/stromal cells in maintaining tissue homeostasis, and some evidence of their fundamental roles in the progression of aging has been presented. In this review, we discuss how stem cell and other theories connect to explain the progress of aging. In addition, we consider the mesenchymal progenitor theory of aging to describing the process of aging. PMID:25364718

  10. Raf-mediated cardiac hypertrophy in adult Drosophila

    PubMed Central

    Yu, Lin; Daniels, Joseph; Glaser, Alex E.; Wolf, Matthew J.

    2013-01-01

    SUMMARY In response to stress and extracellular signals, the heart undergoes a process called cardiac hypertrophy during which cardiomyocytes increase in size. If untreated, cardiac hypertrophy can progress to overt heart failure that causes significant morbidity and mortality. The identification of molecular signals that cause or modify cardiomyopathies is necessary to understand how the normal heart progresses to cardiac hypertrophy and heart failure. Receptor tyrosine kinase (RTK) signaling is essential for normal human cardiac function, and the inhibition of RTKs can cause dilated cardiomyopathies. However, neither investigations of activated RTK signaling pathways nor the characterization of hypertrophic cardiomyopathy in the adult fly heart has been previously described. Therefore, we developed strategies using Drosophila as a model to circumvent some of the complexities associated with mammalian models of cardiovascular disease. Transgenes encoding activated EGFRA887T, Ras85DV12 and Ras85DV12S35, which preferentially signal to Raf, or constitutively active human or fly Raf caused hypertrophic cardiomyopathy as determined by decreased end diastolic lumen dimensions, abnormal cardiomyocyte fiber morphology and increased heart wall thicknesses. There were no changes in cardiomyocyte cell numbers. Additionally, activated Raf also induced an increase in cardiomyocyte ploidy compared with control hearts. However, preventing increases in cardiomyocyte ploidy using fizzy-related (Fzr) RNAi did not rescue Raf-mediated cardiac hypertrophy, suggesting that Raf-mediated polyploidization is not required for cardiac hypertrophy. Similar to mammals, the cardiac-specific expression of RNAi directed against MEK or ERK rescued Raf-mediated cardiac hypertrophy. However, the cardiac-specific expression of activated ERKD334N, which promotes hyperplasia in non-cardiac tissues, did not cause myocyte hypertrophy. These results suggest that ERK is necessary, but not sufficient, for

  11. Doxorubicin Regulates Autophagy Signals via Accumulation of Cytosolic Ca2+ in Human Cardiac Progenitor Cells

    PubMed Central

    Park, Ji Hye; Choi, Sung Hyun; Kim, Hyungtae; Ji, Seung Taek; Jang, Woong Bi; Kim, Jae Ho; Baek, Sang Hong; Kwon, Sang Mo

    2016-01-01

    Doxorubicin (DOXO) is widely used to treat solid tumors. However, its clinical use is limited by side effects including serious cardiotoxicity due to cardiomyocyte damage. Resident cardiac progenitor cells (hCPCs) act as key regulators of homeostasis in myocardial cells. However, little is known about the function of hCPCs in DOXO-induced cardiotoxicity. In this study, we found that DOXO-mediated hCPC toxicity is closely related to calcium-related autophagy signaling and was significantly attenuated by blocking mTOR signaling in human hCPCs. DOXO induced hCPC apoptosis with reduction of SMP30 (regucalcin) and autophagosome marker LC3, as well as remarkable induction of the autophagy-related markers, Beclin-1, APG7, and P62/SQSTM1 and induction of calcium-related molecules, CaM (Calmodulin) and CaMKII (Calmodulin kinase II). The results of an LC3 puncta assay further indicated that DOXO reduced autophagosome formation via accumulation of cytosolic Ca2+. Additionally, DOXO significantly induced mTOR expression in hCPCs, and inhibition of mTOR signaling by rapamycin, a specific inhibitor, rescued DOXO-mediated autophagosome depletion in hCPCs with significant reduction of DOXO-mediated cytosolic Ca2+ accumulation in hCPCs, and restored SMP30 and mTOR expression. Thus, DOXO-mediated hCPC toxicity is linked to Ca2+-related autophagy signaling, and inhibition of mTOR signaling may provide a cardio-protective effect against DOXO-mediated hCPC toxicity. PMID:27735842

  12. GD3+ cells in the adult rat optic nerve are ramified microglia rather than O-2Aadult progenitor cells.

    PubMed

    Wolswijk, G

    1994-04-01

    The adult central nervous system (CNS) contains a population of adult oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells (O-2Aadult progenitor cells). These cells may provide a source of the new oligodendrocytes that are needed to repair demyelinated lesions. In order to examine the role of O-2Aadult progenitor cells in the regeneration of the oligodendrocyte population following demyelinating damage, it is essential to be able to identify such cells unambiguously in sections of adult CNS tissue. The present study examined whether antibodies to the ganglioside GD3 specifically label O-2Aadult progenitor cells in cultures and sections of adult optic nerve, since previous studies on the developing CNS had suggested that O-2Aperinatal progenitor cells were GD3+ in vitro and in vivo. Evidence is presented indicating that, although O-2Aadult progenitor cells in vitro were labelled with the R24 mAb (an anti-GD3 mAb), all GD3+ cells in sections of adult optic nerve bound the OX-42 mAb and the B4 isolectin derived from Griffonia Simplicifolia, and thus were not O-2Aadult progenitor cells, but ramified microglia. The data suggest that O-2Aadult progenitor cells become GD3+ when placed in culture and that ramified microglia lose GD3-expression in vitro.

  13. Biology of the Adult Hepatic Progenitor Cell: “Ghosts in the Machine”

    PubMed Central

    Darwiche, Houda; Petersen, Bryon E.

    2011-01-01

    This chapter reviews some of the basic biological principles governing adult progenitor cells of the liver and the mechanisms by which they operate. If scientists were better able to understand the conditions that govern stem cell mechanics in the liver, it may be possible to apply that understanding in a clinical setting for use in the treatment or cure of human pathologies. This chapter gives a basic introduction to hepatic progenitor cell biology and explores what is known about progenitor cell-mediated liver regeneration. We also discuss the putative stem cell niche in the liver, as well as the signaling pathways involved in stem cell regulation. Finally, the isolation and clinical application of stem cells to human diseases is reviewed, along with the current thoughts on the relationship between stem cells and cancer. PMID:21074735

  14. Unipotent, Atoh1+ progenitors maintain the Merkel cell population in embryonic and adult mice.

    PubMed

    Wright, Margaret C; Reed-Geaghan, Erin G; Bolock, Alexa M; Fujiyama, Tomoyuki; Hoshino, Mikio; Maricich, Stephen M

    2015-02-01

    Resident progenitor cells in mammalian skin generate new cells as a part of tissue homeostasis. We sought to identify the progenitors of Merkel cells, a unique skin cell type that plays critical roles in mechanosensation. We found that some Atoh1-expressing cells in the hairy skin and whisker follicles are mitotically active at embryonic and postnatal ages. Genetic fate-mapping revealed that these Atoh1-expressing cells give rise solely to Merkel cells. Furthermore, selective ablation of Atoh1(+) skin cells in adult mice led to a permanent reduction in Merkel cell numbers, demonstrating that other stem cell populations are incapable of producing Merkel cells. These data identify a novel, unipotent progenitor population in the skin that gives rise to Merkel cells both during development and adulthood.

  15. 12-Deoxyphorbols Promote Adult Neurogenesis by Inducing Neural Progenitor Cell Proliferation via PKC Activation

    PubMed Central

    Geribaldi-Doldán, Noelia; Flores-Giubi, Eugenia; Murillo-Carretero, Maribel; García-Bernal, Francisco; Carrasco, Manuel; Macías-Sánchez, Antonio J.; Domínguez-Riscart, Jesús; Verástegui, Cristina; Hernández-Galán, Rosario

    2016-01-01

    Background: Neuropsychiatric and neurological disorders frequently occur after brain insults associated with neuronal loss. Strategies aimed to facilitate neuronal renewal by promoting neurogenesis constitute a promising therapeutic option to treat neuronal death-associated disorders. In the adult brain, generation of new neurons occurs physiologically throughout the entire life controlled by extracellular molecules coupled to intracellular signaling cascades. Proteins participating in these cascades within neurogenic regions constitute potential pharmacological targets to promote neuronal regeneration of injured areas of the central nervous system. Methodology: We have performed in vitro and in vivo approaches to determine neural progenitor cell proliferation to understand whether activation of kinases of the protein kinase C family facilitates neurogenesis in the adult brain. Results: We have demonstrated that protein kinase C activation by phorbol-12-myristate-13-acetate induces neural progenitor cell proliferation in vitro. We also show that the nontumorogenic protein kinase C activator prostratin exerts a proliferative effect on neural progenitor cells in vitro. This effect can be reverted by addition of the protein kinase C inhibitor G06850, demonstrating that the effect of prostratin is mediated by protein kinase C activation. Additionally, we show that prostratin treatment in vivo induces proliferation of neural progenitor cells within the dentate gyrus of the hippocampus and the subventricular zone. Finally, we describe a library of diterpenes with a 12-deoxyphorbol structure similar to that of prostratin that induces a stronger effect than prostratin on neural progenitor cell proliferation both in vitro and in vivo. Conclusions: This work suggests that protein kinase C activation is a promising strategy to expand the endogenous neural progenitor cell population to promote neurogenesis and highlights the potential of 12-deoxyphorbols as pharmaceutical

  16. Endothelial cells are progenitors of cardiac pericytes and vascular smooth muscle cells

    PubMed Central

    Chen, Qi; Zhang, Hui; Liu, Yang; Adams, Susanne; Eilken, Hanna; Stehling, Martin; Corada, Monica; Dejana, Elisabetta; Zhou, Bin; Adams, Ralf H.

    2016-01-01

    Mural cells of the vessel wall, namely pericytes and vascular smooth muscle cells, are essential for vascular integrity. The developmental sources of these cells and molecular mechanisms controlling their progenitors in the heart are only partially understood. Here we show that endocardial endothelial cells are progenitors of pericytes and vascular smooth muscle cells in the murine embryonic heart. Endocardial cells undergo endothelial–mesenchymal transition and convert into primitive mesenchymal progenitors expressing the platelet-derived growth factor receptors, PDGFRα and PDGFRβ. These progenitors migrate into the myocardium, differentiate and assemble the wall of coronary vessels, which requires canonical Wnt signalling involving Frizzled4, β-catenin and endothelial cell-derived Wnt ligands. Our findings identify a novel and unexpected population of progenitors for coronary mural cells with potential relevance for heart function and disease conditions. PMID:27516371

  17. Isolation of neural crest derived chromaffin progenitors from adult adrenal medulla.

    PubMed

    Chung, Kuei-Fang; Sicard, Flavie; Vukicevic, Vladimir; Hermann, Andreas; Storch, Alexander; Huttner, Wieland B; Bornstein, Stefan R; Ehrhart-Bornstein, Monika

    2009-10-01

    Chromaffin cells of the adrenal medulla are neural crest-derived cells of the sympathoadrenal lineage. Unlike the closely-related sympathetic neurons, a subpopulation of proliferation-competent cells exists even in the adult. Here, we describe the isolation, expansion, and in vitro characterization of proliferation-competent progenitor cells from the bovine adrenal medulla. Similar to neurospheres, these cells, when prevented from adherence to the culture dish, grew in spheres, which we named chromospheres. These chromospheres were devoid of mRNA specific for smooth muscle cells (MYH11) or endothelial cells (PECAM1). During sphere formation, markers for differentiated chromaffin cells, such as phenylethanolamine-N-methyl transferase, were downregulated while neural progenitor markers nestin, vimentin, musashi 1, and nerve growth factor receptor, as well as markers of neural crest progenitor cells such as Sox1 and Sox9, were upregulated. Clonal analysis and bromo-2'-deoxyuridine-incorporation analysis demonstrated the self-renewing capacity of chromosphere cells. Differentiation protocols using NGF and BMP4 or dexamethasone induced neuronal or endocrine differentiation, respectively. Electrophysiological analyses of neural cells derived from chromospheres revealed functional properties of mature nerve cells, such as tetrodotoxin-sensitive sodium channels and action potentials. Our study provides evidence that proliferation and differentiation competent chromaffin progenitor cells can be isolated from adult adrenal medulla and that these cells might harbor the potential for the treatment of neurodegenerative diseases, such as Parkinson's disease. PMID:19609938

  18. Adult Olfactory Bulb Interneuron Phenotypes Identified by Targeting Embryonic and Postnatal Neural Progenitors

    PubMed Central

    Figueres-Oñate, Maria; López-Mascaraque, Laura

    2016-01-01

    Neurons are generated during embryonic development and in adulthood, although adult neurogenesis is restricted to two main brain regions, the hippocampus and olfactory bulb. The subventricular zone (SVZ) of the lateral ventricles generates neural stem/progenitor cells that continually provide the olfactory bulb (OB) with new granule or periglomerular neurons, cells that arrive from the SVZ via the rostral migratory stream. The continued neurogenesis and the adequate integration of these newly generated interneurons is essential to maintain homeostasis in the olfactory bulb, where the differentiation of these cells into specific neural cell types is strongly influenced by temporal cues. Therefore, identifying the critical features that control the generation of adult OB interneurons at either pre- or post-natal stages is important to understand the dynamic contribution of neural stem cells. Here, we used in utero and neonatal SVZ electroporation along with a transposase-mediated stable integration plasmid, in order to track interneurons and glial lineages in the OB. These plasmids are valuable tools to study the development of OB interneurons from embryonic and post-natal SVZ progenitors. Accordingly, we examined the location and identity of the adult progeny of embryonic and post-natally transfected progenitors by examining neurochemical markers in the adult OB. These data reveal the different cell types in the olfactory bulb that are generated in function of age and different electroporation conditions. PMID:27242400

  19. The Role of Cardiac Side Population Cells in Cardiac Regeneration

    PubMed Central

    Yellamilli, Amritha; van Berlo, Jop H.

    2016-01-01

    The heart has a limited ability to regenerate. It is important to identify therapeutic strategies that enhance cardiac regeneration in order to replace cardiomyocytes lost during the progression of heart failure. Cardiac progenitor cells are interesting targets for new regenerative therapies because they are self-renewing, multipotent cells located in the heart. Cardiac side population cells (cSPCs), the first cardiac progenitor cells identified in the adult heart, have the ability to differentiate into cardiomyocytes, endothelial cells, smooth muscle cells, and fibroblasts. They become activated in response to cardiac injury and transplantation of cSPCs into the injured heart improves cardiac function. In this review, we will discuss the current literature on the progenitor cell properties and therapeutic potential of cSPCs. This body of work demonstrates the great promise cSPCs hold as targets for new regenerative strategies.

  20. The Role of Cardiac Side Population Cells in Cardiac Regeneration

    PubMed Central

    Yellamilli, Amritha; van Berlo, Jop H.

    2016-01-01

    The heart has a limited ability to regenerate. It is important to identify therapeutic strategies that enhance cardiac regeneration in order to replace cardiomyocytes lost during the progression of heart failure. Cardiac progenitor cells are interesting targets for new regenerative therapies because they are self-renewing, multipotent cells located in the heart. Cardiac side population cells (cSPCs), the first cardiac progenitor cells identified in the adult heart, have the ability to differentiate into cardiomyocytes, endothelial cells, smooth muscle cells, and fibroblasts. They become activated in response to cardiac injury and transplantation of cSPCs into the injured heart improves cardiac function. In this review, we will discuss the current literature on the progenitor cell properties and therapeutic potential of cSPCs. This body of work demonstrates the great promise cSPCs hold as targets for new regenerative strategies. PMID:27679798

  1. The Role of Cardiac Side Population Cells in Cardiac Regeneration.

    PubMed

    Yellamilli, Amritha; van Berlo, Jop H

    2016-01-01

    The heart has a limited ability to regenerate. It is important to identify therapeutic strategies that enhance cardiac regeneration in order to replace cardiomyocytes lost during the progression of heart failure. Cardiac progenitor cells are interesting targets for new regenerative therapies because they are self-renewing, multipotent cells located in the heart. Cardiac side population cells (cSPCs), the first cardiac progenitor cells identified in the adult heart, have the ability to differentiate into cardiomyocytes, endothelial cells, smooth muscle cells, and fibroblasts. They become activated in response to cardiac injury and transplantation of cSPCs into the injured heart improves cardiac function. In this review, we will discuss the current literature on the progenitor cell properties and therapeutic potential of cSPCs. This body of work demonstrates the great promise cSPCs hold as targets for new regenerative strategies.

  2. The Role of Cardiac Side Population Cells in Cardiac Regeneration.

    PubMed

    Yellamilli, Amritha; van Berlo, Jop H

    2016-01-01

    The heart has a limited ability to regenerate. It is important to identify therapeutic strategies that enhance cardiac regeneration in order to replace cardiomyocytes lost during the progression of heart failure. Cardiac progenitor cells are interesting targets for new regenerative therapies because they are self-renewing, multipotent cells located in the heart. Cardiac side population cells (cSPCs), the first cardiac progenitor cells identified in the adult heart, have the ability to differentiate into cardiomyocytes, endothelial cells, smooth muscle cells, and fibroblasts. They become activated in response to cardiac injury and transplantation of cSPCs into the injured heart improves cardiac function. In this review, we will discuss the current literature on the progenitor cell properties and therapeutic potential of cSPCs. This body of work demonstrates the great promise cSPCs hold as targets for new regenerative strategies. PMID:27679798

  3. Epicardial application of cardiac progenitor cells in a 3D-printed gelatin/hyaluronic acid patch preserves cardiac function after myocardial infarction.

    PubMed

    Gaetani, Roberto; Feyen, Dries A M; Verhage, Vera; Slaats, Rolf; Messina, Elisa; Christman, Karen L; Giacomello, Alessandro; Doevendans, Pieter A F M; Sluijter, Joost P G

    2015-08-01

    Cardiac cell therapy suffers from limitations related to poor engraftment and significant cell death after transplantation. In this regard, ex vivo tissue engineering is a tool that has been demonstrated to increase cell retention and survival. The aim of our study was to evaluate the therapeutic potential of a 3D-printed patch composed of human cardiac-derived progenitor cells (hCMPCs) in a hyaluronic acid/gelatin (HA/gel) based matrix. hCMPCs were printed in the HA/gel matrix (30 × 10(6) cells/ml) to form a biocomplex made of six perpendicularly printed layers with a surface of 2 × 2 cm and thickness of 400 μm, in which they retained their viability, proliferation and differentiation capability. The printed biocomplex was transplanted in a mouse model of myocardial infarction (MI). The application of the patch led to a significant reduction in adverse remodeling and preservation of cardiac performance as was shown by both MRI and histology. Furthermore, the matrix supported the long-term in vivo survival and engraftment of hCMPCs, which exhibited a temporal increase in cardiac and vascular differentiation markers over the course of the 4 week follow-up period. Overall, we developed an effective and translational approach to enhance hCMPC delivery and action in the heart.

  4. Ischemia-Reperfusion Injury and Pregnancy Initiate Time-Dependent and Robust Signs of Up-Regulation of Cardiac Progenitor Cells

    PubMed Central

    Genead, Rami; Fischer, Helene; Hussain, Alamdar; Jaksch, Marie; Andersson, Agneta B.; Ljung, Karin; Bulatovic, Ivana; Franco-Cereceda, Anders; Elsheikh, Elzafir; Corbascio, Matthias; Smith, C. I. Edvard; Sylvén, Christer; Grinnemo, Karl-Henrik

    2012-01-01

    To explore how cardiac regeneration and cell turnover adapts to disease, different forms of stress were studied for their effects on the cardiac progenitor cell markers c-Kit and Isl1, the early cardiomyocyte marker Nkx2.5, and mast cells. Adult female rats were examined during pregnancy, after myocardial infarction and ischemia-reperfusion injury with/out insulin like growth factor-1(IGF-1) and hepatocyte growth factor (HGF). Different cardiac sub-domains were analyzed at one and two weeks post-intervention, both at the mRNA and protein levels. While pregnancy and myocardial infarction up-regulated Nkx2.5 and c-Kit (adjusted for mast cell activation), ischemia-reperfusion injury induced the strongest up-regulation which occurred globally throughout the entire heart and not just around the site of injury. This response seems to be partly mediated by increased endogenous production of IGF-1 and HGF. Contrary to c-Kit, Isl1 was not up-regulated by pregnancy or myocardial infarction while ischemia-reperfusion injury induced not a global but a focal up-regulation in the outflow tract and also in the peri-ischemic region, correlating with the up-regulation of endogenous IGF-1. The addition of IGF-1 and HGF did boost the endogenous expression of IGF and HGF correlating to focal up-regulation of Isl1. c-Kit expression was not further influenced by the exogenous growth factors. This indicates that there is a spatial mismatch between on one hand c-Kit and Nkx2.5 expression and on the other hand Isl1 expression. In conclusion, ischemia-reperfusion injury was the strongest stimulus with both global and focal cardiomyocyte progenitor cell marker up-regulations, correlating to the endogenous up-regulation of the growth factors IGF-1 and HGF. Also pregnancy induced a general up-regulation of c-Kit and early Nkx2.5+ cardiomyocytes throughout the heart. Utilization of these pathways could provide new strategies for the treatment of cardiac disease. PMID:22590612

  5. Regulatory System for Stem/Progenitor Cell Niches in the Adult Rodent Pituitary

    PubMed Central

    Yoshida, Saishu; Kato, Takako; Kato, Yukio

    2016-01-01

    The anterior lobe of the pituitary gland is a master endocrine tissue composed of five types of endocrine cells. Although the turnover rate of pituitary endocrine cells is as low as about 1.6% per day, recent studies have demonstrated that Sex-determining region Y-box 2 (SOX2)+-cells exist as pituitary stem/progenitor cells in the adult anterior lobe and contribute to cell regeneration. Notably, SOX2+-pituitary stem/progenitor cells form two types of niches in this tissue: the marginal cell layer (MCL-niche) and the dense cell clusters scattering in the parenchyma (parenchymal-niche). However, little is known about the mechanisms and factors for regulating the pituitary stem/progenitor cell niches, as well as the functional differences between the two types of niches. Elucidation of the regulatory mechanisms in the niches might enable us to understand the cell regeneration system that acts in accordance with physiological demands in the adult pituitary. In this review, so as to reveal the regulatory mechanisms of the two types of niche, we summarize the regulatory factors and their roles in the adult rodent pituitary niches by focusing on three components: soluble factors, cell surface proteins and extracellular matrixes. PMID:26761002

  6. Adult Thymic Medullary Epithelium Is Maintained and Regenerated by Lineage-Restricted Cells Rather Than Bipotent Progenitors.

    PubMed

    Ohigashi, Izumi; Zuklys, Saulius; Sakata, Mie; Mayer, Carlos E; Hamazaki, Yoko; Minato, Nagahiro; Hollander, Georg A; Takahama, Yousuke

    2015-11-17

    Medullary thymic epithelial cells (mTECs) play an essential role in establishing self-tolerance in T cells. mTECs originate from bipotent TEC progenitors that generate both mTECs and cortical TECs (cTECs), although mTEC-restricted progenitors also have been reported. Here, we report in vivo fate-mapping analysis of cells that transcribe β5t, a cTEC trait expressed in bipotent progenitors, during a given period in mice. We show that, in adult mice, most mTECs are derived from progenitors that transcribe β5t during embryogenesis and the neonatal period up to 1 week of age. The contribution of adult β5t(+) progenitors was minor even during injury-triggered regeneration. Our results further demonstrate that adult mTEC-restricted progenitors are derived from perinatal β5t(+) progenitors. These results indicate that the adult thymic medullary epithelium is maintained and regenerated by mTEC-lineage cells that pass beyond the bipotent stage during early ontogeny. PMID:26549457

  7. A Progesterone-CXCR4 Axis Controls Mammary Progenitor Cell Fate in the Adult Gland

    PubMed Central

    Shiah, Yu-Jia; Tharmapalan, Pirashaanthy; Casey, Alison E.; Joshi, Purna A.; McKee, Trevor D.; Jackson, Hartland W.; Beristain, Alexander G.; Chan-Seng-Yue, Michelle A.; Bader, Gary D.; Lydon, John P.; Waterhouse, Paul D.; Boutros, Paul C.; Khokha, Rama

    2015-01-01

    Summary Progesterone drives mammary stem and progenitor cell dynamics through paracrine mechanisms that are currently not well understood. Here, we demonstrate that CXCR4, the receptor for stromal-derived factor 1 (SDF-1; CXC12), is a crucial instructor of hormone-induced mammary stem and progenitor cell function. Progesterone elicits specific changes in the transcriptome of basal and luminal mammary epithelial populations, where CXCL12 and CXCR4 represent a putative ligand-receptor pair. In situ, CXCL12 localizes to progesterone-receptor-positive luminal cells, whereas CXCR4 is induced in both basal and luminal compartments in a progesterone-dependent manner. Pharmacological inhibition of CXCR4 signaling abrogates progesterone-directed expansion of basal (CD24+CD49fhi) and luminal (CD24+CD49flo) subsets. This is accompanied by a marked reduction in CD49b+SCA-1− luminal progenitors, their functional capacity, and lobuloalveologenesis. These findings uncover CXCL12 and CXCR4 as novel paracrine effectors of hormone signaling in the adult mammary gland, and present a new avenue for potentially targeting progenitor cell growth and malignant transformation in breast cancer.

  8. Multipotent adult hippocampal progenitor cells maintained as neurospheres favor differentiation toward glial lineages

    PubMed Central

    Oh, Jisun; Daniels, Gabrielle J.; Chiou, Lawrence S.; Ye, Eun-Ah; Jeong, Yong-Seob; Sakaguchi, Donald S.

    2014-01-01

    Adult hippocampal progenitor cells (AHPCs) are generally maintained as a dispersed monolayer population of multipotent neural progenitors. To better understand cell-cell interactions among neural progenitors and their influences on cellular characteristics, we generated free-floating cellular aggregates, or neurospheres, from the adherent monolayer population of AHPCs. Results from in vitro analyses demonstrated that both populations of AHPCs were highly proliferative under maintenance conditions, but AHPCs formed in neurospheres favored differentiation along a glial lineage and displayed greater migrational activity, than the traditionally cultured AHPCs. To study the plasticity of AHPCs from both populations in vivo, we transplanted GFP-expressing AHPCs via intraocular injection into the developing rat eyes. Both AHPC populations were capable of surviving and integrating into the developing host central nervous system, but considerably more GFP-positive cells were observed in the retinas transplanted with neurosphere AHPCs, compared to adherent AHPCs. These results suggest that the culture configuration during maintenance for neural progenitor cells (NPCs) influences cell fate and motility in vitro as well as in vivo. Our findings have implication for understanding different cellular characteristics of NPCs according to distinct intercellular architectures and for developing cell-based therapeutic strategies using lineage-committed NPCs. PMID:24844209

  9. Morphine Modulates Adult Neurogenesis and Contextual Memory by Impeding the Maturation of Neural Progenitors

    PubMed Central

    Zhang, Yue; Xu, Chi; Zheng, Hui; Loh, Horace H.; Law, Ping-Yee

    2016-01-01

    The regulation of adult neurogenesis by opiates has been implicated in modulating different addiction cycles. At which neurogenesis stage opiates exert their action remains unresolved. We attempt to define the temporal window of morphine’s inhibition effect on adult neurogenesis by using the POMC-EGFP mouse model, in which newborn granular cells (GCs) can be visualized between days 3–28 post-mitotic. The POMC-EGFP mice were trained under the 3-chambers conditioned place preference (CPP) paradigm with either saline or morphine. We observed after 4 days of CPP training with saline, the number of EGFP-labeled newborn GCs in sub-granular zone (SGZ) hippocampus significantly increased compared to mice injected with saline in their homecage. CPP training with morphine significantly decreased the number of EGFP-labeled GCs, whereas no significant difference in the number of EGFP-labeled GCs was observed with the homecage mice injected with the same dose of morphine. Using cell-type selective markers, we observed that morphine reduced the number of late stage progenitors and immature neurons such as Doublecortin (DCX) and βIII Tubulin (TuJ1) positive cells in the SGZ but did not reduce the number of early progenitors such as Nestin, SOX2, or neurogenic differentiation-1 (NeuroD1) positive cells. Analysis of co-localization between different cell markers shows that morphine reduced the number of adult-born GCs by interfering with differentiation of early progenitors, but not by inducing apoptosis. In addition, when NeuroD1 was over-expressed in DG by stereotaxic injection of lentivirus, it rescued the loss of immature neurons and prolonged the extinction of morphine-trained CPP. These results suggest that under the condition of CPP training paradigm, morphine affects the transition of neural progenitor/stem cells to immature neurons via a mechanism involving NeuroD1. PMID:27078155

  10. Morphine Modulates Adult Neurogenesis and Contextual Memory by Impeding the Maturation of Neural Progenitors.

    PubMed

    Zhang, Yue; Xu, Chi; Zheng, Hui; Loh, Horace H; Law, Ping-Yee

    2016-01-01

    The regulation of adult neurogenesis by opiates has been implicated in modulating different addiction cycles. At which neurogenesis stage opiates exert their action remains unresolved. We attempt to define the temporal window of morphine's inhibition effect on adult neurogenesis by using the POMC-EGFP mouse model, in which newborn granular cells (GCs) can be visualized between days 3-28 post-mitotic. The POMC-EGFP mice were trained under the 3-chambers conditioned place preference (CPP) paradigm with either saline or morphine. We observed after 4 days of CPP training with saline, the number of EGFP-labeled newborn GCs in sub-granular zone (SGZ) hippocampus significantly increased compared to mice injected with saline in their homecage. CPP training with morphine significantly decreased the number of EGFP-labeled GCs, whereas no significant difference in the number of EGFP-labeled GCs was observed with the homecage mice injected with the same dose of morphine. Using cell-type selective markers, we observed that morphine reduced the number of late stage progenitors and immature neurons such as Doublecortin (DCX) and βIII Tubulin (TuJ1) positive cells in the SGZ but did not reduce the number of early progenitors such as Nestin, SOX2, or neurogenic differentiation-1 (NeuroD1) positive cells. Analysis of co-localization between different cell markers shows that morphine reduced the number of adult-born GCs by interfering with differentiation of early progenitors, but not by inducing apoptosis. In addition, when NeuroD1 was over-expressed in DG by stereotaxic injection of lentivirus, it rescued the loss of immature neurons and prolonged the extinction of morphine-trained CPP. These results suggest that under the condition of CPP training paradigm, morphine affects the transition of neural progenitor/stem cells to immature neurons via a mechanism involving NeuroD1.

  11. Morphine Modulates Adult Neurogenesis and Contextual Memory by Impeding the Maturation of Neural Progenitors.

    PubMed

    Zhang, Yue; Xu, Chi; Zheng, Hui; Loh, Horace H; Law, Ping-Yee

    2016-01-01

    The regulation of adult neurogenesis by opiates has been implicated in modulating different addiction cycles. At which neurogenesis stage opiates exert their action remains unresolved. We attempt to define the temporal window of morphine's inhibition effect on adult neurogenesis by using the POMC-EGFP mouse model, in which newborn granular cells (GCs) can be visualized between days 3-28 post-mitotic. The POMC-EGFP mice were trained under the 3-chambers conditioned place preference (CPP) paradigm with either saline or morphine. We observed after 4 days of CPP training with saline, the number of EGFP-labeled newborn GCs in sub-granular zone (SGZ) hippocampus significantly increased compared to mice injected with saline in their homecage. CPP training with morphine significantly decreased the number of EGFP-labeled GCs, whereas no significant difference in the number of EGFP-labeled GCs was observed with the homecage mice injected with the same dose of morphine. Using cell-type selective markers, we observed that morphine reduced the number of late stage progenitors and immature neurons such as Doublecortin (DCX) and βIII Tubulin (TuJ1) positive cells in the SGZ but did not reduce the number of early progenitors such as Nestin, SOX2, or neurogenic differentiation-1 (NeuroD1) positive cells. Analysis of co-localization between different cell markers shows that morphine reduced the number of adult-born GCs by interfering with differentiation of early progenitors, but not by inducing apoptosis. In addition, when NeuroD1 was over-expressed in DG by stereotaxic injection of lentivirus, it rescued the loss of immature neurons and prolonged the extinction of morphine-trained CPP. These results suggest that under the condition of CPP training paradigm, morphine affects the transition of neural progenitor/stem cells to immature neurons via a mechanism involving NeuroD1. PMID:27078155

  12. Effects of addictive drugs on adult neural stem/progenitor cells.

    PubMed

    Xu, Chi; Loh, Horace H; Law, Ping-Yee

    2016-01-01

    Neural stem/progenitor cells (NSPCs) undergo a series of developmental processes before giving rise to newborn neurons, astrocytes and oligodendrocytes in adult neurogenesis. During the past decade, the role of NSPCs has been highlighted by studies on adult neurogenesis modulated by addictive drugs. It has been proven that these drugs regulate the proliferation, differentiation and survival of adult NSPCs in different manners, which results in the varying consequences of adult neurogenesis. The effects of addictive drugs on NSPCs are exerted via a variety of different mechanisms and pathways, which interact with one another and contribute to the complexity of NSPC regulation. Here, we review the effects of different addictive drugs on NSPCs, and the related experimental methods and paradigms. We also discuss the current understanding of major signaling molecules, especially the putative common mechanisms, underlying such effects. Finally, we review the future directions of research in this area. PMID:26468052

  13. Starving for more: Nutrient sensing by LIN-28 in adult intestinal progenitor cells.

    PubMed

    Luhur, Arthur; Sokol, Nicholas

    2015-01-01

    In this Extra View, we extend our recent work on the protein LIN-28 and its role in adult stem cell divisions. LIN-28 is an mRNA- and microRNA-binding protein that is conserved from worms to humans. When expressed ectopically, it promotes the reprogramming of differentiated vertebrate cells into pluripotent stem cells as well as the regeneration of vertebrate tissues after injury. However, its endogenous function in stem cell populations is less clear. We recently reported that LIN-28 is specifically expressed in progenitor cells in the adult Drosophila intestine and enhances insulin signaling within this population. Loss of lin-28 alters the division patterns of these progenitor cells, limiting the growth of the intestinal epithelium that is ordinarily caused by feeding. Thus, LIN-28 is part of an uncharacterized circuit used to remodel a tissue in response to environmental cues like nutrition. Here, we extend this analysis by reporting that the levels of LIN-28 in progenitor cells are sensitive to nutrient availability. In addition, we speculate about the role of LIN-28 in the translational control of target mRNAs such as Insulin Receptor (InR) and how such translational control may be an important mechanism that underlies the stem cell dynamics needed for tissue homeostasis and growth.

  14. Single adult kidney stem/progenitor cells reconstitute three-dimensional nephron structures in vitro.

    PubMed

    Kitamura, Shinji; Sakurai, Hiroyuki; Makino, Hirofumi

    2015-03-01

    The kidneys are formed during development from two distinct primordial tissues, the metanephric mesenchyme and the ureteric bud. The metanephric mesenchyme develops into the kidney nephron, the minimal functional unit of the kidney. A nephron consists of several segments and regulates water, electrolyte, and acid-base homeostasis in addition to secreting certain hormones. It has been predicted that the kidney will be among the last organs successfully regenerated in vitro due to its complex structure and multiple functions. Here, we show that adult kidney stem/progenitor cells (KS cells), derived from the S3 segment of adult rat kidney nephrons, can reconstitute a three-dimensional kidney-like structure in vitro. Kidney-like structures were formed when a cluster of KS cells was suspended in an extracellular matrix gel and cultured in the presence of several growth factors. Morphological analyses revealed that these kidney-like structures contained every substructure of the kidney, including glomeruli, proximal tubules, the loop of Henle, distal tubules, and collecting ducts, but no vasculature. Our results demonstrate that a cluster of tissue stem/progenitor cells has the ability to reconstitute the minimum unit of its organ of origin by differentiating into specialized cells in the correct location. This process differs from embryonic kidney development, which requires the mutual induction of two different populations of progenitors, metanephric mesenchymal cells and ureteric bud cells.

  15. miR-322/-503 cluster is expressed in the earliest cardiac progenitor cells and drives cardiomyocyte specification

    PubMed Central

    Shen, Xiaopeng; Soibam, Benjamin; Benham, Ashley; Xu, Xueping; Chopra, Mani; Peng, Xiaoping; Yu, Wei; Bao, Wenjing; Liang, Rui; Azares, Alon; Liu, Peijun; Gunaratne, Preethi H.; Mercola, Mark; Cooney, Austin J.; Schwartz, Robert J.; Liu, Yu

    2016-01-01

    Understanding the mechanisms of early cardiac fate determination may lead to better approaches in promoting heart regeneration. We used a mesoderm posterior 1 (Mesp1)-Cre/Rosa26-EYFP reporter system to identify microRNAs (miRNAs) enriched in early cardiac progenitor cells. Most of these miRNA genes bear MESP1-binding sites and active histone signatures. In a calcium transient-based screening assay, we identified miRNAs that may promote the cardiomyocyte program. An X-chromosome miRNA cluster, miR-322/-503, is the most enriched in the Mesp1 lineage and is the most potent in the screening assay. It is specifically expressed in the looping heart. Ectopic miR-322/-503 mimicking the endogenous temporal patterns specifically drives a cardiomyocyte program while inhibiting neural lineages, likely by targeting the RNA-binding protein CUG-binding protein Elav-like family member 1 (Celf1). Thus, early miRNAs in lineage-committed cells may play powerful roles in cell-fate determination by cross-suppressing other lineages. miRNAs identified in this study, especially miR-322/-503, are potent regulators of early cardiac fate. PMID:27512039

  16. Cells of renin lineage are adult pluripotent progenitors in experimental glomerular disease

    PubMed Central

    Kaverina, Natalya V.; Eng, Diana G.; Krofft, Ronald D.; Glenn, Sean T.; Duffield, Jeremy S.; Gross, Kenneth W.; Shankland, Stuart J.

    2015-01-01

    Modified vascular smooth muscle cells of the kidney afferent arterioles have recently been shown to serve as progenitors for glomerular epithelial cells in response to glomerular injury. To determine whether such cells of renin lineage (CoRL) serve as progenitors for other cells in kidney disease characterized by both glomerular and tubulointerstitial injury, permanent genetic cell fate mapping of adult CoRL using Ren1cCreER × Rs-tdTomato-R reporter mice was performed. TdTomato-labeled CoRL were almost completely restricted to the juxtaglomerular compartment in healthy kidneys. Following 2 wk of antibody-mediated focal segmental glomerulosclerosis (FSGS) or 16 wk of ⅚ nephrectomy-induced chronic kidney diseases, tdTomato-mapped CoRL were identified in both interstitial and glomerular compartments. In the interstitium, PDGFβ receptor (R)-expressing cells significantly increased, and a portion of these expressed tdTomato. This was accompanied by a decrease in native pericyte number, but an increase in the number of tdTomato cells that coexpressed the pericyte markers PDGFβ-R and NG2. These cells surrounded vessels and coexpressed the pericyte markers CD73 and CD146, but not the endothelial marker ERG. Within glomeruli of reporter mice with the ⅚ nephrectomy model, a subset of labeled CoRL migrated to the glomerular tuft and coexpressed podocin and synaptopodin. By contrast, labeled CoRL were not detected in glomerular or interstitial compartments following uninephrectomy. These observations indicate that in addition to supplying new adult podocytes to glomeruli, CoRL have the capacity to become new adult pericytes in the setting of interstitial disease. We conclude that CoRL have the potential to function as progenitors for multiple adult cell types in kidney disease. PMID:26062877

  17. Cardiac involvement in adult and juvenile idiopathic inflammatory myopathies

    PubMed Central

    Schwartz, Thomas; Diederichsen, Louise Pyndt; Lundberg, Ingrid E; Sanner, Helga

    2016-01-01

    Idiopathic inflammatory myopathies (IIM) include the main subgroups polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM) and juvenile DM (JDM). The mentioned subgroups are characterised by inflammation of skeletal muscles leading to muscle weakness and other organs can also be affected as well. Even though clinically significant heart involvement is uncommon, heart disease is one of the major causes of death in IIM. Recent studies show an increased prevalence of traditional cardiovascular risk factors in JDM and DM/PM, which need attention. The risk of developing atherosclerotic coronary artery disease is increased twofold to fourfold in DM/PM. New and improved diagnostic methods have in recent studies in PM/DM and JDM demonstrated a high prevalence of subclinical cardiac involvement, especially diastolic dysfunction. Interactions between proinflammatory cytokines and traditional risk factors might contribute to the pathogenesis of cardiac dysfunction. Heart involvement could also be related to myocarditis and/or myocardial fibrosis, leading to arrhythmias and congestive heart failure, demonstrated both in adult and juvenile IIM. Also, reduced heart rate variability (a known risk factor for cardiac morbidity and mortality) has been shown in long-standing JDM. Until more information is available, patients with IIM should follow the same recommendations for cardiovascular risk stratification and prevention as for the corresponding general population, but be aware that statins might worsen muscle symptoms mimicking myositis relapse. On the basis of recent studies, we recommend a low threshold for cardiac workup and follow-up in patients with IIM. PMID:27752355

  18. Lycium barbarum polysaccharides promotes in vivo proliferation of adult rat retinal progenitor cells

    PubMed Central

    Wang, Hua; Lau, Benson Wui-Man; Wang, Ning-li; Wang, Si-ying; Lu, Qing-jun; Chang, Raymond Chuen-Chung; So, Kwok-fai

    2015-01-01

    Lycium barbarum is a widely used Chinese herbal medicine prescription for protection of optic nerve. However, it remains unclear regarding the effects of Lycium barbarum polysaccharides, the main component of Lycium barbarum, on in vivo proliferation of adult ciliary body cells. In this study, adult rats were intragastrically administered low- and high-dose Lycium barbarum polysaccharides (1 and 10 mg/kg) for 35 days and those intragastrically administered phosphate buffered saline served as controls. The number of Ki-67-positive cells in rat ciliary body in the Lycium barbarum polysaccharides groups, in particular low-dose Lycium barbarum polysaccharides group, was significantly greater than that in the phosphate buffered saline group. Ki-67-positive rat ciliary body cells expressed nestin but they did not express glial fibrillary acidic protein. These findings suggest that Lycium barbarum polysaccharides can promote the proliferation of adult rat retinal progenitor cells and the proliferated cells present with neuronal phenotype. PMID:26889185

  19. Isolation and clonal assay of adult lung epithelial stem/progenitor cells.

    PubMed

    Bertoncello, Ivan; McQualter, Jonathan

    2011-01-01

    Adult mouse lung epithelial stem/progenitor cells (EpiSPC) can be defined in vitro as epithelial colony-forming units that are capable of self-renewal, and which when co-cultured with lung mesenchymal stromal cells (MSC) are able to give rise to differentiated progeny comprising mature lung epithelial cells. This unit describes a protocol for the prospective isolation and in vitro propagation and differentiation of adult mouse lung EpiSPC. The strategy used for selection of EpiSPC and MSC from adult mouse lung by enzymatic digestion and flow cytometry is based on the differential expression of CD45, CD31, Sca-1, EpCAM, and CD24. The culture conditions required for the differentiation (co-culture with MSC) and expansion (stromal-free culture with FGF-10 and HGF) of EpiSPC are described.

  20. Neural stem/progenitor cell properties of glial cells in the adult mouse auditory nerve

    PubMed Central

    Lang, Hainan; Xing, Yazhi; Brown, LaShardai N.; Samuvel, Devadoss J.; Panganiban, Clarisse H.; Havens, Luke T.; Balasubramanian, Sundaravadivel; Wegner, Michael; Krug, Edward L.; Barth, Jeremy L.

    2015-01-01

    The auditory nerve is the primary conveyor of hearing information from sensory hair cells to the brain. It has been believed that loss of the auditory nerve is irreversible in the adult mammalian ear, resulting in sensorineural hearing loss. We examined the regenerative potential of the auditory nerve in a mouse model of auditory neuropathy. Following neuronal degeneration, quiescent glial cells converted to an activated state showing a decrease in nuclear chromatin condensation, altered histone deacetylase expression and up-regulation of numerous genes associated with neurogenesis or development. Neurosphere formation assays showed that adult auditory nerves contain neural stem/progenitor cells (NSPs) that were within a Sox2-positive glial population. Production of neurospheres from auditory nerve cells was stimulated by acute neuronal injury and hypoxic conditioning. These results demonstrate that a subset of glial cells in the adult auditory nerve exhibit several characteristics of NSPs and are therefore potential targets for promoting auditory nerve regeneration. PMID:26307538

  1. Role of paracrine factors in stem and progenitor cell mediated cardiac repair and tissue fibrosis

    PubMed Central

    Burchfield, Jana S; Dimmeler, Stefanie

    2008-01-01

    A new era has begun in the treatment of ischemic disease and heart failure. With the discovery that stem cells from diverse organs and tissues, including bone marrow, adipose tissue, umbilical cord blood, and vessel wall, have the potential to improve cardiac function beyond that of conventional pharmacological therapy comes a new field of research aiming at understanding the precise mechanisms of stem cell-mediated cardiac repair. Not only will it be important to determine the most efficacious cell population for cardiac repair, but also whether overlapping, common mechanisms exist. Increasing evidence suggests that one mechanism of action by which cells provide tissue protection and repair may involve paracrine factors, including cytokines and growth factors, released from transplanted stem cells into the surrounding tissue. These paracrine factors have the potential to directly modify the healing process in the heart, including neovascularization, cardiac myocyte apoptosis, inflammation, fibrosis, contractility, bioenergetics, and endogenous repair. PMID:19014650

  2. Label-Retaining Cells in the Adult Murine Salivary Glands Possess Characteristics of Adult Progenitor Cells

    PubMed Central

    Chibly, Alejandro M.; Querin, Lauren; Harris, Zoey; Limesand, Kirsten H.

    2014-01-01

    Radiotherapy is the primary treatment for patients with head and neck cancer, which account for roughly 500,000 annual cases worldwide. Dysfunction of the salivary glands and associated conditions like xerostomia and dysphagia are often developed by these patients, greatly diminishing their life quality. Current preventative and palliative care fail to deliver an improvement in the quality of life, thus accentuating the need for regenerative therapies. In this study, a model of label retaining cells (LRCs) in murine salivary glands was developed, in which LRCs demonstrated proliferative potential and possessed markers of putative salivary progenitors. Mice were labeled with 5-Ethynyl-2′-deoxyuridine (EdU) at postnatal day 10 and chased for 8 weeks. Tissue sections from salivary glands obtained at the end of chase demonstrated co-localization between LRCs and the salivary progenitor markers keratin 5 and keratin 14, as well as kit mRNA, indicating that LRCs encompass a heterogeneous population of salivary progenitors. Proliferative potential of LRCs was demonstrated by a sphere assay, in which LRCs were found in primary and secondary spheres and they co-localized with the proliferation marker Ki67 throughout sphere formation. Surprisingly, LRCs were shown to be radio-resistant and evade apoptosis following radiation treatment. The clinical significance of these findings lie in the potential of this model to study the mechanisms that prevent salivary progenitors from maintaining homeostasis upon exposure to radiation, which will in turn facilitate the development of regenerative therapies for salivary gland dysfunction. PMID:25238060

  3. Label-retaining cells in the adult murine salivary glands possess characteristics of adult progenitor cells.

    PubMed

    Chibly, Alejandro M; Querin, Lauren; Harris, Zoey; Limesand, Kirsten H

    2014-01-01

    Radiotherapy is the primary treatment for patients with head and neck cancer, which account for roughly 500,000 annual cases worldwide. Dysfunction of the salivary glands and associated conditions like xerostomia and dysphagia are often developed by these patients, greatly diminishing their life quality. Current preventative and palliative care fail to deliver an improvement in the quality of life, thus accentuating the need for regenerative therapies. In this study, a model of label retaining cells (LRCs) in murine salivary glands was developed, in which LRCs demonstrated proliferative potential and possessed markers of putative salivary progenitors. Mice were labeled with 5-Ethynyl-2'-deoxyuridine (EdU) at postnatal day 10 and chased for 8 weeks. Tissue sections from salivary glands obtained at the end of chase demonstrated co-localization between LRCs and the salivary progenitor markers keratin 5 and keratin 14, as well as kit mRNA, indicating that LRCs encompass a heterogeneous population of salivary progenitors. Proliferative potential of LRCs was demonstrated by a sphere assay, in which LRCs were found in primary and secondary spheres and they co-localized with the proliferation marker Ki67 throughout sphere formation. Surprisingly, LRCs were shown to be radio-resistant and evade apoptosis following radiation treatment. The clinical significance of these findings lie in the potential of this model to study the mechanisms that prevent salivary progenitors from maintaining homeostasis upon exposure to radiation, which will in turn facilitate the development of regenerative therapies for salivary gland dysfunction.

  4. Altered differentiation of CNS neural progenitor cells after transplantation into the injured adult rat spinal cord.

    PubMed

    Onifer, S M; Cannon, A B; Whittemore, S R

    1997-01-01

    Denervation of CNS neurons and peripheral organs is a consequence of traumatic SCI. Intraspinal transplantation of embryonic CNS neurons is a potential strategy for reinnervating these targets. Neural progenitor cell lines are being investigated as alternates to embryonic CNS neurons. RN33B is an immortalized neural progenitor cell line derived from embryonic rat raphe nuclei following infection with a retrovirus encoding the temperature-sensitive mutant of SV40 large T-antigen. Transplantation studies have shown that local epigenetic signals in intact or partially neuron-depleted adult rat hippocampal formation or striatum direct RN33B cell differentiation to complex multipolar morphologies resembling endogenous neurons. After transplantation into neuron-depleted regions of the hippocampal formation or striatum, RN33B cells were relatively undifferentiated or differentiated with bipolar morphologies. The present study examines RN33B cell differentiation after transplantation into normal spinal cord and under different lesion conditions. Adult rats underwent either unilateral lesion of lumbar spinal neurons by intraspinal injection of kainic acid or complete transection at the T10 spinal segment. Neonatal rats underwent either unilateral lesion of lumbar motoneurons by sciatic nerve crush or complete transection at the T10 segment. At 2 or 6-7 wk postinjury, lacZ-labeled RN33B cells were transplanted into the lumbar enlargement of injured and age-matched normal rats. At 2 wk posttransplantation, bipolar and some multipolar RN33B cells were found throughout normal rat gray matter. In contrast, only bipolar RN33B cells were seen in gray matter of kainic acid lesioned, sciatic nerve crush, or transection rats. These observations suggest that RN33B cell multipolar morphological differentiation in normal adult spinal cord is mediated by direct cell-cell interaction through surface molecules on endogenous neurons and may be suppressed by molecules released after SCI

  5. Hhex is Required at Multiple Stages of Adult Hematopoietic Stem and Progenitor Cell Differentiation

    PubMed Central

    Goodings, Charnise; Smith, Elizabeth; Mathias, Elizabeth; Elliott, Natalina; Cleveland, Susan M.; Tripathi, Rati M.; Layer, Justin H.; Chen, Xi; Guo, Yan; Shyr, Yu; Hamid, Rizwan; Du, Yang; Davé, Utpal P.

    2015-01-01

    Hhex encodes a homeodomain transcription factor that is widely expressed in hematopoietic stem and progenitor cell populations. Its enforced expression induces T-cell leukemia and we have implicated it as an important oncogene in early T-cell precursor leukemias where it is immediately downstream of an LMO2-associated protein complex. Conventional Hhex knockouts cause embryonic lethality precluding analysis of adult hematopoiesis. Thus, we induced highly efficient conditional knockout (cKO) using vav-Cre transgenic mice. Hhex cKO mice were viable and born at normal litter sizes. At steady state, we observed a defect in B-cell development that we localized to the earliest B-cell precursor, the pro-B-cell stage. Most remarkably, bone marrow transplantation using Hhex cKO donor cells revealed a more profound defect in all hematopoietic lineages. In contrast, sublethal irradiation resulted in normal myeloid cell repopulation of the bone marrow but markedly impaired repopulation of T- and B-cell compartments. We noted that Hhex cKO stem and progenitor cell populations were skewed in their distribution and showed enhanced proliferation compared to WT cells. Our results implicate Hhex in the maintenance of LT-HSCs and in lineage allocation from multipotent progenitors especially in stress hematopoiesis. PMID:25968920

  6. Hhex is Required at Multiple Stages of Adult Hematopoietic Stem and Progenitor Cell Differentiation.

    PubMed

    Goodings, Charnise; Smith, Elizabeth; Mathias, Elizabeth; Elliott, Natalina; Cleveland, Susan M; Tripathi, Rati M; Layer, Justin H; Chen, Xi; Guo, Yan; Shyr, Yu; Hamid, Rizwan; Du, Yang; Davé, Utpal P

    2015-08-01

    Hhex encodes a homeodomain transcription factor that is widely expressed in hematopoietic stem and progenitor cell populations. Its enforced expression induces T-cell leukemia and we have implicated it as an important oncogene in early T-cell precursor leukemias where it is immediately downstream of an LMO2-associated protein complex. Conventional Hhex knockouts cause embryonic lethality precluding analysis of adult hematopoiesis. Thus, we induced highly efficient conditional knockout (cKO) using vav-Cre transgenic mice. Hhex cKO mice were viable and born at normal litter sizes. At steady state, we observed a defect in B-cell development that we localized to the earliest B-cell precursor, the pro-B-cell stage. Most remarkably, bone marrow transplantation using Hhex cKO donor cells revealed a more profound defect in all hematopoietic lineages. In contrast, sublethal irradiation resulted in normal myeloid cell repopulation of the bone marrow but markedly impaired repopulation of T- and B-cell compartments. We noted that Hhex cKO stem and progenitor cell populations were skewed in their distribution and showed enhanced proliferation compared to WT cells. Our results implicate Hhex in the maintenance of LT-HSCs and in lineage allocation from multipotent progenitors especially in stress hematopoiesis.

  7. Hematopoietic stem cells, progenitor cells and leukemic stem cells in adult myeloproliferative neoplasms.

    PubMed

    Ng, Ashley P

    2013-05-01

    The understanding of myeloproliferative neoplasms has changed dramatically since Dameshek proposed his classification over 50 years ago. Our knowledge of the types of cells which constitute the hematopoietic system and of how they are regulated has also appreciated significantly over this time. This review relates what is currently known about the acquired genetic mutations associated with adult myeloproliferative neoplasms to how they lead to the hematopoietic perturbations of myeloproliferative disease. There is a particular focus on how stem and progenitor cell compartments are affected by BCR-ABL1 and JAK2V617F mutations, and the particular issue of resistance of leukemic stem cells to conventional and targeted therapies. PMID:23013358

  8. Mechanically induced orientation of adult rat cardiac myocytes in vitro

    NASA Technical Reports Server (NTRS)

    Samuel, J.-L.; Vandenburgh, H. H.

    1990-01-01

    The present study describes the spatial orientation of a population of freshly isolated adult rat cardiac myocytes using a computerized mechanical cell stimulator device for tissue cultured cells. A continuous unidirectional stretch of the substratum at 60 to 400 microns/min for 120 to 30 min, respectively, during the cell attachment period in a serum-free medium was found to induce a significant threefold increase in the number of rod-shaped myocytes oriented parallel to the direction of movement. The myocytes orient less well with unidirectional substratum stretching after their adhesion to the substratum. Adult myocytes plated onto a substratum undergoing continuous 10-percent stretch-relaxation cycling show no significant change in the myocyte orientation or cytoskeletal organization. In addition to the type of mechanical activity, orientation of rod-shaped myocytes is dependent on the speed of the substratum, the final stretch amplitude, and the timing between initiation of substratum stretching and adhesion of myocytes to the substratum.

  9. Curcumin stimulates proliferation of embryonic neural progenitor cells and neurogenesis in the adult hippocampus.

    PubMed

    Kim, So Jung; Son, Tae Gen; Park, Hee Ra; Park, Mikyung; Kim, Min-Sun; Kim, Hyung Sik; Chung, Hae Young; Mattson, Mark P; Lee, Jaewon

    2008-05-23

    Curcumin is a natural phenolic component of yellow curry spice, which is used in some cultures for the treatment of diseases associated with oxidative stress and inflammation. Curcumin has been reported to be capable of preventing the death of neurons in animal models of neurodegenerative disorders, but its possible effects on developmental and adult neuroplasticity are unknown. In the present study, we investigated the effects of curcumin on mouse multi-potent neural progenitor cells (NPC) and adult hippocampal neurogenesis. Curcumin exerted biphasic effects on cultured NPC; low concentrations stimulated cell proliferation, whereas high concentrations were cytotoxic. Curcumin activated extracellular signal-regulated kinases (ERKs) and p38 kinases, cellular signal transduction pathways known to be involved in the regulation of neuronal plasticity and stress responses. Inhibitors of ERKs and p38 kinases effectively blocked the mitogenic effect of curcumin in NPC. Administration of curcumin to adult mice resulted in a significant increase in the number of newly generated cells in the dentate gyrus of hippocampus, indicating that curcumin enhances adult hippocampal neurogenesis. Our findings suggest that curcumin can stimulate developmental and adult hippocampal neurogenesis, and a biological activity that may enhance neural plasticity and repair.

  10. Functional response to SDF1α through over-expression of CXCR4 on adult subventricular zone progenitor cells

    PubMed Central

    Liu, Xian Shuang; Chopp, Michael; Santra, Manoranjan; Hozeska-Solgot, Ann; Zhang, Rui Lan; Wang, Lei; Teng, Hua; Liu, Mei; Zhang, Zheng Gang

    2008-01-01

    The chemokine receptor CXCR4 and its ligand, stromal cell derived factor-1α (SDF1α) regulate neuroblast migration towards the ischemic boundary after stroke. Using loss-and gain-function, we investigated the biological effect of CXCR4/SDF1α on neural progenitor cells. Neural progenitor cells, from the subventricular zone (SVZ) of the adult rat, were transfected with rat CXCR4-pLEGFP-C1 and pSIREN-RetroQ-CXCR4-siRNA retroviral vectors. Migration assay analysis showed that inhibition of CXCR4 by siRNA significantly reduced cell migration compared to the empty vector, indicating that CXCR4 mediated neural progenitor cell motility. When neural progenitor cells were cultured in growth medium containing bFGF (20 ng/ml), over-expression of CXCR4 significantly reduced the cell proliferation as measured by the number of bromodeoxyuridine+ (BrdU+) cells (26.4%) compared with the number in the control group (54.0%). Addition of a high concentration of SDF1α (500 ng/ml) into the progenitor cells with over-expression of CXCR4 reversed the cell proliferation back to the control levels (57.6%). Immunostaining analysis showed that neither over-expression nor inhibition of CXCR4 altered the population of neurons and astrocytes, when neural progenitor cells were cultured in differentiation medium. These in vitro results suggest that CXCR4/SDF1α primarily regulates adult neural progenitor cell motility but not differentiation, while over-expression of CXCR4 in the absence of SDF1α decreases neural progenitor cell proliferation. PMID:18598677

  11. Adult progenitor cell transplantation influences contractile performance and calcium handling of recipient cardiomyocytes.

    PubMed

    Lee, Joon; Stagg, Mark A; Fukushima, Satsuki; Soppa, Gopal K R; Siedlecka, Urszula; Youssef, Samuel J; Suzuki, Ken; Yacoub, Magdi H; Terracciano, Cesare M N

    2009-04-01

    Adult progenitor cell transplantation has been proposed for the treatment of heart failure, but the mechanisms effecting functional improvements remain unknown. The aim of this study was to test the hypothesis that, in failing hearts treated with cell transplantation, the mechanical properties and excitation-contraction coupling of recipient cardiomyocytes are altered. Adult rats underwent coronary artery ligation, leading to myocardial infarction and chronic heart failure. After 3 wk, they received intramyocardial injections of either 10(7) green fluorescence protein (GFP)-positive bone marrow mononuclear cells or 5 x 10(6) GFP-positive skeletal myoblasts. Four weeks after injection, both cell types increased ejection fraction and reduced cardiomyocyte size. The contractility of isolated GFP-negative cardiomyocytes was monitored by sarcomere shortening assessment, Ca(2+) handling by indo-1 and fluo-4 fluorescence, and electrophysiology by patch-clamping techniques. Injection of either bone marrow cells or skeletal myoblasts normalized the impaired contractile performance and the prolonged time to peak of the Ca(2+) transient observed in failing cardiomyocytes. The smaller and slower L-type Ca(2+) current observed in heart failure normalized after skeletal myoblast, but not bone marrow cell, transplantation. Measurement of Ca(2+) sparks suggested a normalization of sarcoplasmic reticulum Ca(2+) leak after skeletal myoblast transplantation. The increased Ca(2+) wave frequency observed in failing myocytes was reduced by either bone marrow cells or skeletal myoblasts. In conclusion, the morphology, contractile performance, and excitation-contraction coupling of individual recipient cardiomyocytes are altered in failing hearts treated with adult progenitor cell transplantation. PMID:19181964

  12. The Mineralocorticoid Agonist Fludrocortisone Promotes Survival and Proliferation of Adult Hippocampal Progenitors

    PubMed Central

    Gesmundo, Iacopo; Villanova, Tania; Gargantini, Eleonora; Arvat, Emanuela; Ghigo, Ezio; Granata, Riccarda

    2016-01-01

    Glucocorticoid receptor (GR) activation has been shown to reduce adult hippocampal progenitor cell proliferation and neurogenesis. By contrast, mineralocorticoid receptor (MR) signaling is associated with neuronal survival in the dentate gyrus of the hippocampus, and impairment of hippocampal MR has been linked to pathological conditions, such as depression or neurodegenerative disorders. Here, we aimed to further clarify the protective role of MR in adult hippocampal neurons by studying the survival and proliferative effects of the highly potent MR agonist fludrocortisone (Fludro) in adult rat hippocampal progenitor cells (AHPs), along with the associated signaling mechanisms. Fludro, which upregulated MR but not GR expression, increased survival and proliferation and prevented apoptosis in AHPs cultured in growth factor-deprived medium. These effects were blunted by the MR antagonist spironolactone and by high doses of the GR agonist dexamethasone. Moreover, they involved signaling through cAMP/protein kinase A (PKA)/cAMP response element-binding protein, phosphoinositide 3-kinase (PI3K)/Akt and its downstream targets glycogen synthase kinase-3β (GSK-3β) and mammalian target of rapamycin. Furthermore, Fludro attenuated the detrimental effects of amyloid-β peptide 1–42 (Aβ1–42) on cell survival, proliferation, and apoptosis in AHPs, and increased the phosphorylation of both PI3K/Akt and GSK-3β, which was reduced by Aβ1–42. Finally, Fludro blocked Aβ1–42-induced hyperphosphorylation of Tau protein, which is a main feature of Alzheimer’s disease. Overall, these results are the first to show the protective and proliferative role of Fludro in AHPs, suggesting the potential therapeutic importance of targeting MR for increasing hippocampal neurogenesis and for treating neurodegenerative diseases. PMID:27379018

  13. α-Aminoadipate Induces Progenitor Cell Properties of Müller Glia in Adult Mice

    PubMed Central

    Takeda, Masumi; Takamiya, Akira; Jiao, Jian-wei; Cho, Kin-Sang; Trevino, Simon G.; Matsuda, Takahiko; Chen, Dong F.

    2008-01-01

    PURPOSE Retinal Müller glia in higher vertebrates have been reported to possess progenitor cell properties and the ability to generate new neurons after injury. This study was conducted to determine the signals that can activate this dormant capacity of Müller glia in adult mice, by studying their behavior during glutamate stimulation. METHODS Various concentrations of glutamate and its analogue α-aminoadipate, which specifically binds Müller glia, were injected subretinally in adult mice. Proliferating retinal cells were labeled by subretinal injection of 5′-bromo-2′-deoxyuridine (BrdU) followed by immunohistochemistry. Müller cell fates were analyzed in retinal sections by using double immunolabeling with primary antibodies against Müller and other retinaspecific cell markers. The effects of glutamate and α-aminoadipate were also determined in purified Müller cell cultures. RESULTS Although high levels of glutamate induce retinal damage, subtoxic levels of glutamate directly stimulate Müller glia to re-enter the cell cycle and induce neurogenesis in vivo and in purified Müller cell cultures. α-Aminoadipate, which selectively target glial cells, also induced expression of progenitor cell markers by Müller cells in vitro or stimulated Müller cell migration to the outer nuclear layer (ONL) and to differentiate into photoreceptors in vivo. CONCLUSIONS Mature Müller glia in adult mice can be induced to dedifferentiate, migrate, and generate new retinal neurons and photoreceptor cells by α-aminoadipate or glutamate signaling. The results of this study suggest a novel potential strategy for treating retinal neurodegeneration, including retinitis pigmentosa and age-related macular degeneration, without transplanting exogenous cells. PMID:18326742

  14. Adult neurogenesis and cellular brain repair with neural progenitors, precursors and stem cells

    PubMed Central

    Shivraj Sohur, U; Emsley, Jason G; Mitchell, Bartley D; Macklis, Jeffrey D

    2006-01-01

    Recent work in neuroscience has shown that the adult central nervous system (CNS) contains neural progenitors, precursors and stem cells that are capable of generating new neurons, astrocytes and oligodendrocytes. While challenging the previous dogma that no new neurons are born in the adult mammalian CNS, these findings bring with them the future possibilities for development of novel neural repair strategies. The purpose of this review is to present the current knowledge about constitutively occurring adult mammalian neurogenesis, highlight the critical differences between ‘neurogenic’ and ‘non-neurogenic’ regions in the adult brain, and describe the cardinal features of two well-described neurogenic regions—the subventricular zone/olfactory bulb system and the dentate gyrus of the hippocampus. We also provide an overview of presently used models for studying neural precursors in vitro, mention some precursor transplantation models and emphasize that, in this rapidly growing field of neuroscience, one must be cautious with respect to a variety of methodological considerations for studying neural precursor cells both in vitro and in vivo. The possibility of repairing neural circuitry by manipulating neurogenesis is an intriguing one, and, therefore, we also review recent efforts to understand the conditions under which neurogenesis can be induced in non-neurogenic regions of the adult CNS. This work aims towards molecular and cellular manipulation of endogenous neural precursors in situ, without transplantation. We conclude this review with a discussion of what might be the function of newly generated neurons in the adult brain, and provide a summary of present thinking about the consequences of disturbed adult neurogenesis and the reaction of neurogenic regions to disease. PMID:16939970

  15. Efficient generation of human embryonic stem cell-derived cardiac progenitors based on tissue-specific enhanced green fluorescence protein expression.

    PubMed

    Szebényi, Kornélia; Péntek, Adrienn; Erdei, Zsuzsa; Várady, György; Orbán, Tamás I; Sarkadi, Balázs; Apáti, Ágota

    2015-01-01

    Cardiac progenitor cells (CPCs) are committed to the cardiac lineage but retain their proliferative capacity before becoming quiescent mature cardiomyocytes (CMs). In medical therapy and research, the use of human pluripotent stem cell-derived CPCs would have several advantages compared with mature CMs, as the progenitors show better engraftment into existing heart tissues, and provide unique potential for cardiovascular developmental as well as for pharmacological studies. Here, we demonstrate that the CAG promoter-driven enhanced green fluorescence protein (EGFP) reporter system enables the identification and isolation of embryonic stem cell-derived CPCs. Tracing of CPCs during differentiation confirmed up-regulation of surface markers, previously described to identify cardiac precursors and early CMs. Isolated CPCs express cardiac lineage-specific transcripts, still have proliferating capacity, and can be re-aggregated into embryoid body-like structures (CAG-EGFP(high) rEBs). Expression of troponin T and NKX2.5 mRNA is up-regulated in long-term cultured CAG-EGFP(high) rEBs, in which more than 90% of the cells become Troponin I positive mature CMs. Moreover, about one third of the CAG-EGFP(high) rEBs show spontaneous contractions. The method described here provides a powerful tool to generate expandable cultures of pure human CPCs that can be used for exploring early markers of the cardiac lineage, as well as for drug screening or tissue engineering applications.

  16. Cardiac surgery for adults with mental retardation. Dilemmas in management.

    PubMed

    Goldhaber, S Z; Reardon, F E; Goulart, D T; Rubin, I L

    1985-10-01

    In summary, cardiac surgery for adults with mental retardation raises a series of controversial legal, economic, ethical, medical, and nursing dilemmas. During the past 20 years, many improvements have taken place in the care of these patients. However, in the future, judicial and statutory mandates requiring high-quality medical care for persons with mental retardation may conflict increasingly with hospital cost-control legislation and thereby affect clinical decisions. For example, it is conceivable that elective repair of an ostium secundum atrial septal defect in an asymptomatic patient will expend the limited resources necessary to carry out emergency revascularization in a symptomatic patient with impending myocardial infarction. This issue becomes even more delicate when the asymptomatic patient is a mentally retarded ward of the state, and the symptomatic patient is a middle-aged man supporting a wife and several college-age children. There may be no easy solution to this problem, and it will provide the grist for many bioethicists. Fortunately, from a practical point of view, we do not currently have to choose between these patients to receive treatment. Our hope is that health care for mentally retarded patients will not be compromised. We believe that decisions about patient management should be based on enlightened clinical judgment rather than on preconceived notions about this population. In the quest for optimal health care delivery, the special needs of these patients should be considered when cardiac catheterization and possible cardiac surgery are contemplated. Although we have presented an approach to a patient with cardiac disease requiring cardiac surgery, we believe that this approach can be utilized for any retarded patient requiring acute medical care. Currently, because there has not been much training in this area, many physicians and nurses lack first-hand experience in caring for the mentally retarded. This inexperience may lead to

  17. In Vitro Colony Assays for Characterizing Tri-potent Progenitor Cells Isolated from the Adult Murine Pancreas.

    PubMed

    Tremblay, Jacob R; LeBon, Jeanne M; Luo, Angela; Quijano, Janine C; Wedeken, Lena; Jou, Kevin; Riggs, Arthur D; Tirrell, David A; Ku, H Teresa

    2016-01-01

    Stem and progenitor cells from the adult pancreas could be a potential source of therapeutic beta-like cells for treating patients with type 1 diabetes. However, it is still unknown whether stem and progenitor cells exist in the adult pancreas. Research strategies using cre-lox lineage-tracing in adult mice have yielded results that either support or refute the idea that beta cells can be generated from the ducts, the presumed location where adult pancreatic progenitors may reside. These in vivo cre-lox lineage-tracing methods, however, cannot answer the questions of self-renewal and multi-lineage differentiation-two criteria necessary to define a stem cell. To begin addressing this technical gap, we devised 3-dimensional colony assays for pancreatic progenitors. Soon after our initial publication, other laboratories independently developed a similar, but not identical, method called the organoid assay. Compared to the organoid assay, our method employs methylcellulose, which forms viscous solutions that allow the inclusion of extracellular matrix proteins at low concentrations. The methylcellulose-containing assays permit easier detection and analyses of progenitor cells at the single-cell level, which are critical when progenitors constitute a small sub-population, as is the case for many adult organ stem cells. Together, results from several laboratories demonstrate in vitro self-renewal and multi-lineage differentiation of pancreatic progenitor-like cells from mice. The current protocols describe two methylcellulose-based colony assays to characterize mouse pancreatic progenitors; one contains a commercial preparation of murine extracellular matrix proteins and the other an artificial extracellular matrix protein known as a laminin hydrogel. The techniques shown here are 1) dissociation of the pancreas and sorting of CD133(+)Sox9/EGFP(+) ductal cells from adult mice, 2) single cell manipulation of the sorted cells, 3) single colony analyses using microfluidic q

  18. Potential Reparative Role of Resident Adult Renal Stem/Progenitor Cells in Acute Kidney Injury

    PubMed Central

    Sallustio, Fabio; Serino, Grazia; Schena, Francesco Paolo

    2015-01-01

    Abstract Human kidney is particularly susceptible to ischemia and toxins with consequential tubular necrosis and activation of inflammatory processes. This process can lead to the acute renal injury, and even if the kidney has a great capacity for regeneration after tubular damage, in several circumstances, the normal renal repair program may not be sufficient to achieve a successful regeneration. Resident adult renal stem/progenitor cells could participate in this repair process and have the potentiality to enhance the renal regenerative mechanism. This could be achieved both directly, by means of their capacity to differentiate and integrate into the renal tissues, and by means of paracrine factors able to induce or improve the renal repair or regeneration. Recent genetic fate-tracing studies indicated that tubular damage is instead repaired by proliferative duplication of epithelial cells, acquiring a transient progenitor phenotype and by fate-restricted clonal cell progeny emerging from different nephron segments. In this review, we discuss about the properties and the reparative characteristics of high regenerative CD133+/CD24+ cells, with a view to a future application of these cells for the treatment of acute renal injury. PMID:26309808

  19. Pten deletion in adult neural stem/progenitor cells enhances constitutive neurogenesis.

    PubMed

    Gregorian, Caroline; Nakashima, Jonathan; Le Belle, Janel; Ohab, John; Kim, Rachel; Liu, Annie; Smith, Kate Barzan; Groszer, Matthias; Garcia, A Denise; Sofroniew, Michael V; Carmichael, S Thomas; Kornblum, Harley I; Liu, Xin; Wu, Hong

    2009-02-11

    Here we show that conditional deletion of Pten in a subpopulation of adult neural stem cells in the subependymal zone (SEZ) leads to persistently enhanced neural stem cell self-renewal without sign of exhaustion. These Pten null SEZ-born neural stem cells and progenies can follow the endogenous migration, differentiation, and integration pathways and contribute to constitutive neurogenesis in the olfactory bulb. As a result, Pten deleted animals have increased olfactory bulb mass and enhanced olfactory function. Pten null cells in the olfactory bulb can establish normal connections with peripheral olfactory epithelium and help olfactory bulb recovery from acute damage. Following a focal stroke, Pten null progenitors give rise to greater numbers of neuroblasts that migrate to peri-infarct cortex. However, in contrast to the olfactory bulb, no significant long-term survival and integration can be observed, indicating that additional factors are necessary for long-term survival of newly born neurons after stroke. These data suggest that manipulating PTEN-controlled signaling pathways may be a useful step in facilitating endogenous neural stem/progenitor expansion for the treatment of disorders or lesions in regions associated with constitutive neurogenesis. PMID:19211894

  20. Pten deletion in adult neural stem/progenitor cells enhances constitutive neurogenesis.

    PubMed

    Gregorian, Caroline; Nakashima, Jonathan; Le Belle, Janel; Ohab, John; Kim, Rachel; Liu, Annie; Smith, Kate Barzan; Groszer, Matthias; Garcia, A Denise; Sofroniew, Michael V; Carmichael, S Thomas; Kornblum, Harley I; Liu, Xin; Wu, Hong

    2009-02-11

    Here we show that conditional deletion of Pten in a subpopulation of adult neural stem cells in the subependymal zone (SEZ) leads to persistently enhanced neural stem cell self-renewal without sign of exhaustion. These Pten null SEZ-born neural stem cells and progenies can follow the endogenous migration, differentiation, and integration pathways and contribute to constitutive neurogenesis in the olfactory bulb. As a result, Pten deleted animals have increased olfactory bulb mass and enhanced olfactory function. Pten null cells in the olfactory bulb can establish normal connections with peripheral olfactory epithelium and help olfactory bulb recovery from acute damage. Following a focal stroke, Pten null progenitors give rise to greater numbers of neuroblasts that migrate to peri-infarct cortex. However, in contrast to the olfactory bulb, no significant long-term survival and integration can be observed, indicating that additional factors are necessary for long-term survival of newly born neurons after stroke. These data suggest that manipulating PTEN-controlled signaling pathways may be a useful step in facilitating endogenous neural stem/progenitor expansion for the treatment of disorders or lesions in regions associated with constitutive neurogenesis.

  1. Six1 regulates MyoD expression in adult muscle progenitor cells.

    PubMed

    Liu, Yubing; Chakroun, Imane; Yang, Dabo; Horner, Ellias; Liang, Jieyi; Aziz, Arif; Chu, Alphonse; De Repentigny, Yves; Dilworth, F Jeffrey; Kothary, Rashmi; Blais, Alexandre

    2013-01-01

    Quiescent satellite cells are myogenic progenitors that enable regeneration of skeletal muscle. One of the early events of satellite cell activation following myotrauma is the induction of the myogenic regulatory factor MyoD, which eventually induces terminal differentiation and muscle function gene expression. The purpose of this study was to elucidate the mechanism by which MyoD is induced during activation of satellite cells in mouse muscle undergoing regeneration. We show that Six1, a transcription factor essential for embryonic myogenesis, also regulates MyoD expression in muscle progenitor cells. Six1 knock-down by RNA interference leads to decreased expression of MyoD in myoblasts. Chromatin immunoprecipitation assays reveal that Six1 binds the Core Enhancer Region of MyoD. Further, transcriptional reporter assays demonstrate that Core Enhancer Region reporter gene activity in myoblasts and in regenerating muscle depends on the expression of Six1 and on Six1 binding sites. Finally, we provide evidence indicating that Six1 is required for the proper chromatin structure at the Core Enhancer Region, as well as for MyoD binding at its own enhancer. Together, our results reveal that MyoD expression in satellite cells depends on Six1, supporting the idea that Six1 plays an important role in adult myogenesis, in addition to its role in embryonic muscle formation. PMID:23840772

  2. Atrial natriuretic peptide inhibits cell cycle activity of embryonic cardiac progenitor cells via its NPRA receptor signaling axis.

    PubMed

    Hotchkiss, Adam; Feridooni, Tiam; Baguma-Nibasheka, Mark; McNeil, Kathleen; Chinni, Sarita; Pasumarthi, Kishore B S

    2015-04-01

    The biological effects of atrial natriuretic peptide (ANP) are mediated by natriuretic peptide receptors (NPRs), which can either activate guanylyl cyclase (NPRA and NPRB) or inhibit adenylyl cyclase (NPRC) to modulate intracellular cGMP or cAMP, respectively. During cardiac development, ANP serves as an early maker of differentiating atrial and ventricular chamber myocardium. As development proceeds, expression of ANP persists in the atria but declines in the ventricles. Currently, it is not known whether ANP is secreted or the ANP-NPR signaling system plays any active role in the developing ventricles. Thus the primary aims of this study were to 1) examine biological activity of ANP signaling systems in embryonic ventricular myocardium, and 2) determine whether ANP signaling modulates proliferation/differentiation of undifferentiated cardiac progenitor cells (CPCs) and/or cardiomyocytes. Here, we provide evidence that ANP synthesized in embryonic day (E)11.5 ventricular myocytes is actively secreted and processed to its biologically active form. Notably, NPRA and NPRC were detected in E11.5 ventricles and exogenous ANP stimulated production of cGMP in ventricular cell cultures. Furthermore, we showed that exogenous ANP significantly decreased cell number and DNA synthesis of CPCs but not cardiomyocytes and this effect could be reversed by pretreatment with the NPRA receptor-specific inhibitor A71915. ANP treatment also led to a robust increase in nuclear p27 levels in CPCs compared with cardiomyocytes. Collectively, these data provide evidence that in the developing mammalian ventricles ANP plays a local paracrine role in regulating the balance between CPC proliferation and differentiation via NPRA/cGMP-mediated signaling pathways.

  3. In vitro expansion of human cardiac progenitor cells: exploring 'omics tools for characterization of cell-based allogeneic products.

    PubMed

    Gomes-Alves, P; Serra, M; Brito, C; Ricardo, C P; Cunha, R; Sousa, M F; Sanchez, B; Bernad, A; Carrondo, M J T; Rodriguez-Borlado, L; Alves, P M

    2016-05-01

    Human cardiac stem/progenitor cells (hCPCs) have been shown to be capable to regenerate contractile myocardium. However, because of their relative low abundance in the heart, in vitro expansion of hCPC is mandatory to achieve necessary quantities for allogeneic or autologous cardiac regeneration therapy applications (10(6)-10(9) cells/patient). Up to now, cell number requirements of ongoing phase I/IIa trials have been fulfilled with production in static monolayer cultures. However, this manufacturing process poses critical limitations when moving to the following clinical phases where hundreds of patients will be enrolled. For this, increased process yield is required, while guaranteeing the quality of the cell-based products. In this work, we developed and validated a robust, scalable, and good manufacturing practice (GMP)-compatible bioprocess for the expansion of high-quality hCPC. We applied platforms extensively used by the biopharmaceutical industry, such as microcarrier technology and stirred systems, and assessed culture conditions' impact on hCPC's quality and potency, as required by regulatory agencies. Complementary analytical assays including gene expression microarrays and mass spectrometry-based approaches were explored to compare transcriptome, proteome, surface markers, and secretion profiles of hCPC cultured in static monolayers and in stirred microcarrier-based systems. Our results show that stirred microcarrier-based culture systems enabled achieving more than 3-fold increase in hCPC expansion, when compared with traditional static monolayers, while retaining cell's phenotype and similar "omics" profiles. These findings demonstrate that this change in the production process does not affect cell's identity and quality, with potential to be translated into a transversal production platform for clinical development of stem-cell therapies. PMID:26924043

  4. First-in-Human Case Study: Multipotent Adult Progenitor Cells for Immunomodulation After Liver Transplantation.

    PubMed

    Soeder, Yorick; Loss, Martin; Johnson, Christian L; Hutchinson, James A; Haarer, Jan; Ahrens, Norbert; Offner, Robert; Deans, Robert J; Van Bokkelen, Gil; Geissler, Edward K; Schlitt, Hans J; Dahlke, Marc H

    2015-08-01

    Mesenchymal stem cells and multipotent adult progenitor cells (MAPCs) have been proposed as novel therapeutics for solid organ transplant recipients with the aim of reducing exposure to pharmacological immunosuppression and its side effects. In the present study, we describe the clinical course of the first patient of the phase I, dose-escalation safety and feasibility study, MiSOT-I (Mesenchymal Stem Cells in Solid Organ Transplantation Phase I). After receiving a living-related liver graft, the patient was given one intraportal injection and one intravenous infusion of third-party MAPC in a low-dose pharmacological immunosuppressive background. Cell administration was found to be technically feasible; importantly, we found no evidence of acute toxicity associated with MAPC infusions.

  5. Ketamine in adult cardiac surgery and the cardiac surgery Intensive Care Unit: An evidence-based clinical review

    PubMed Central

    Mazzeffi, Michael; Johnson, Kyle; Paciullo, Christopher

    2015-01-01

    Ketamine is a unique anesthetic drug that provides analgesia, hypnosis, and amnesia with minimal respiratory and cardiovascular depression. Because of its sympathomimetic properties it would seem to be an excellent choice for patients with depressed ventricular function in cardiac surgery. However, its use has not gained widespread acceptance in adult cardiac surgery patients, perhaps due to its perceived negative psychotropic effects. Despite this limitation, it is receiving renewed interest in the United States as a sedative and analgesic drug for critically ill-patients. In this manuscript, the authors provide an evidence-based clinical review of ketamine use in cardiac surgery patients for intensive care physicians, cardio-thoracic anesthesiologists, and cardio-thoracic surgeons. All MEDLINE indexed clinical trials performed during the last 20 years in adult cardiac surgery patients were included in the review. PMID:25849690

  6. Identification of a common mesenchymal stromal progenitor for the adult haematopoietic niche

    PubMed Central

    Hu, Xingbin; Garcia, Mayra; Weng, Lihong; Jung, Xiaoman; Murakami, Jodi L.; Kumar, Bijender; Warden, Charles D.; Todorov, Ivan; Chen, Ching-Cheng

    2016-01-01

    Microenvironment cues received by haematopoietic stem cells (HSC) are important in regulating the choice between self-renewal and differentiation. On the basis of the differential expression of cell-surface markers, here we identify a mesenchymal stromal progenitor hierarchy, where CD45−Ter119−CD31−CD166−CD146−Sca1+(Sca1+) progenitors give rise to CD45−Ter119−CD31−CD166−CD146+(CD146+) intermediate and CD45−Ter119−CD31−CD166+CD146−(CD166+) mature osteo-progenitors. All three progenitors preserve HSC long-term multi-lineage reconstitution capability in vitro; however, their in vivo fates are different. Post-transplantation, CD146+ and CD166+ progenitors form bone only. While Sca1+ progenitors produce CD146+, CD166+ progenitors, osteocytes and CXCL12-producing stromal cells. Only Sca1+ progenitors are capable of homing back to the marrow post-intravenous infusion. Ablation of Sca1+ progenitors results in a decrease of all three progenitor populations as well as haematopoietic stem/progenitor cells. Moreover, suppressing production of KIT-ligand in Sca1+ progenitors inhibits their ability to support HSCs. Our results indicate that Sca1+ progenitors, through the generation of both osteogenic and stromal cells, provide a supportive environment for hematopoiesis. PMID:27721421

  7. Comparison of Human Embryonic Stem Cell-Derived Cardiomyocytes, Cardiovascular Progenitors, and Bone Marrow Mononuclear Cells for Cardiac Repair

    PubMed Central

    Fernandes, Sarah; Chong, James J.H.; Paige, Sharon L.; Iwata, Mineo; Torok-Storb, Beverly; Keller, Gordon; Reinecke, Hans; Murry, Charles E.

    2015-01-01

    Summary Cardiomyocytes derived from human embryonic stem cells (hESC-CMs) can improve the contractility of injured hearts. We hypothesized that mesodermal cardiovascular progenitors (hESC-CVPs), capable of generating vascular cells in addition to cardiomyocytes, would provide superior repair by contributing to multiple components of myocardium. We performed a head-to-head comparison of hESC-CMs and hESC-CVPs and compared these with the most commonly used clinical cell type, human bone marrow mononuclear cells (hBM-MNCs). In a nude rat model of myocardial infarction, hESC-CMs and hESC-CVPs generated comparable grafts. Both similarly improved systolic function and ventricular dilation. Furthermore, only rare human vessels formed from hESC-CVPs. hBM-MNCs attenuated ventricular dilation and enhanced host vascularization without engrafting long-term or improving contractility. Thus, hESC-CMs and CVPs show similar efficacy for cardiac repair, and both are more efficient than hBM-MNCs. However, hESC-CVPs do not form larger grafts or more significant numbers of human vessels in the infarcted heart. PMID:26607951

  8. Brief Report: The Deletion of the Phosphatase Regulator NIPP1 Causes Progenitor Cell Expansion in the Adult Liver.

    PubMed

    Boens, Shannah; Verbinnen, Iris; Verhulst, Stefaan; Szekér, Kathelijne; Ferreira, Monica; Gevaert, Thomas; Baes, Myriam; Roskams, Tania; van Grunsven, Leo A; Van Eynde, Aleyde; Bollen, Mathieu

    2016-08-01

    The Ppp1r8 gene encodes NIPP1, a nuclear interactor of protein phosphatase PP1. The deletion of NIPP1 is embryonic lethal at the gastrulation stage, which has hampered its functional characterization in adult tissues. Here, we describe the effects of a conditional deletion of NIPP1 in mouse liver epithelial cells. Ppp1r8(-/-) livers developed a ductular reaction, that is, bile-duct hyperplasia with associated fibrosis. The increased proliferation of biliary epithelial cells was at least partially due to an expansion of the progenitor cell compartment that was independent of liver injury. Gene-expression analysis confirmed an upregulation of progenitor cell markers in the liver knockout livers but showed no effect on the expression of liver-injury associated regulators of cholangiocyte differentiation markers. Consistent with an inhibitory effect of NIPP1 on progenitor cell proliferation, Ppp1r8(-/-) livers displayed an increased sensitivity to diet-supplemented 3,5-diethoxycarbonyl-1,4-dihydrocollidine, which also causes bile-duct hyperplasia through progenitor cell expansion. In contrast, the liver knockouts responded normally to injuries (partial hepatectomy, single CCl4 administration) that are restored through proliferation of differentiated parenchymal cells. Our data indicate that NIPP1 does not regulate the proliferation of hepatocytes but is a suppressor of biliary epithelial cell proliferation, including progenitor cells, in the adult liver. Stem Cells 2016;34:2256-2262. PMID:27068806

  9. Neutrophil adherence to isolated adult cardiac myocytes. Induction by cardiac lymph collected during ischemia and reperfusion.

    PubMed Central

    Youker, K; Smith, C W; Anderson, D C; Miller, D; Michael, L H; Rossen, R D; Entman, M L

    1992-01-01

    Canine neutrophils can be induced to adhere in vitro to isolated adult cardiac myocytes by stimulation of the neutrophils with chemotactic factors such as zymosan-activated serum (ZAS) only if the myocytes have been previously exposed to cytokines such as interleukin 1 (IL-1) or tumor necrosis factor-alpha. These cytokines induce synthesis and surface expression of intercellular adhesion molecule-1 (ICAM-1) on the myocyte, and neutrophil adhesion is almost entirely CD18 and ICAM-1 dependent. The present study examines cardiac-specific lymph collected from awake dogs during 1-h coronary occlusion and 3 d of reperfusion for its ability to induce both ICAM-1 expression in cardiac myocytes, and neutrophil-myocyte adherence. Reperfusion lymph induced ICAM-1 expression in isolated myocytes, and myocyte adherence to ZAS-stimulated neutrophils that was completely inhibited by anti-CD18 and anti-ICAM-1 monoclonal antibodies. This activity peaked at 90 min of reperfusion and persisted for up to 72 h. Preischemic lymph was not stimulatory. IL-1 appeared not to be a stimulating factor in lymph in that dilutions of lymph were found to inhibit the stimulatory effects of recombinant IL-1 beta. However, investigation of interleukin 6 (IL-6) revealed that recombinant IL-6 stimulated myocyte adhesiveness for ZAS-stimulated neutrophils (ED50 = 0.002 U/ml) and expression of ICAM-1 by isolated myocytes. IL-6 neutralizing antibody markedly reduced the ability of reperfusion lymph to stimulate adhesion and ICAM-1 expression, and estimates of levels of IL-6 in reperfusion lymph ranged from 0.035 to 0.14 U/ml. These results indicate that cytokines capable of promoting neutrophil-myocyte adhesion occur in extracellular fluid during reperfusion of ischemic myocardium, and that one of these cytokines is IL-6. Neutrophil-myocyte adhesion may be of pathogenic significance because it may enhance the cytotoxic activity of the neutrophil. Images PMID:1346618

  10. Knowledge Management in Cardiac Surgery: The Second Tehran Heart Center Adult Cardiac Surgery Database Report

    PubMed Central

    Abbasi, Kyomars; Karimi, Abbasali; Abbasi, Seyed Hesameddin; Ahmadi, Seyed Hossein; Davoodi, Saeed; Babamahmoodi, Abdolreza; Movahedi, Namdar; Salehiomran, Abbas; Shirzad, Mahmood; Bina, Peyvand

    2012-01-01

    Background: The Adult Cardiac Surgery Databank (ACSD) of Tehran Heart Center was established in 2002 with a view to providing clinical prediction rules for outcomes of cardiac procedures, developing risk score systems, and devising clinical guidelines. This is a general analysis of the collected data. Methods: All the patients referred to Tehran Heart Center for any kind of heart surgery between 2002 and 2008 were included, and their demographic, medical, clinical, operative, and postoperative data were gathered. This report presents general information as well as in-hospital mortality rates regarding all the cardiac procedures performed in the above time period. Results: There were 24959 procedures performed: 19663 (78.8%) isolated coronary artery bypass grafting surgeries (CABGs); 1492 (6.0%) isolated valve surgeries; 1437 (5.8%) CABGs concomitant with other procedures; 832 (3.3%) CABGs combined with valve surgeries; 722 (2.9%) valve surgeries concomitant with other procedures; 545 (2.2%) surgeries other than CABG or valve surgery; and 267 (1.1%) CABGs concomitant with valve and other types of surgery. The overall mortality was 205 (1.04%), with the lowest mortality rate (0.47%) in the isolated CABGs and the highest (4.49%) in the CABGs concomitant with valve surgeries and other types of surgery. Meanwhile, the overall mortality rate was higher in the female patients than in the males (1.90% vs. 0.74%, respectively). Conclusion: Isolated CABG was the most prevalent procedure at our center with the lowest mortality rate. However, the overall mortality was more prevalent in our female patients. This database can serve as a platform for the participation of the other countries in the region in the creation of a regional ACSD. PMID:23304179

  11. Migration of bone marrow progenitor cells in the adult brain of rats and rabbits.

    PubMed

    Dennie, Donnahue; Louboutin, Jean-Pierre; Strayer, David S

    2016-04-26

    Neurogenesis takes place in the adult mammalian brain in three areas: Subgranular zone of the dentate gyrus (DG); subventricular zone of the lateral ventricle; olfactory bulb. Different molecular markers can be used to characterize the cells involved in adult neurogenesis. It has been recently suggested that a population of bone marrow (BM) progenitor cells may migrate to the brain and differentiate into neuronal lineage. To explore this hypothesis, we injected recombinant SV40-derived vectors into the BM and followed the potential migration of the transduced cells. Long-term BM-directed gene transfer using recombinant SV40-derived vectors leads to expression of the genes delivered to the BM firstly in circulating cells, then after several months in mature neurons and microglial cells, and thus without central nervous system (CNS) lesion. Most of transgene-expressing cells expressed NeuN, a marker of mature neurons. Thus, BM-derived cells may function as progenitors of CNS cells in adult animals. The mechanism by which the cells from the BM come to be neurons remains to be determined. Although the observed gradual increase in transgene-expressing neurons over 16 mo suggests that the pathway involved differentiation of BM-resident cells into neurons, cell fusion as the principal route cannot be totally ruled out. Additional studies using similar viral vectors showed that BM-derived progenitor cells migrating in the CNS express markers of neuronal precursors or immature neurons. Transgene-positive cells were found in the subgranular zone of the DG of the hippocampus 16 mo after intramarrow injection of the vector. In addition to cells expressing markers of mature neurons, transgene-positive cells were also positive for nestin and doublecortin, molecules expressed by developing neuronal cells. These cells were actively proliferating, as shown by short term BrdU incorporation studies. Inducing seizures by using kainic acid increased the number of BM progenitor cells

  12. Migration of bone marrow progenitor cells in the adult brain of rats and rabbits

    PubMed Central

    Dennie, Donnahue; Louboutin, Jean-Pierre; Strayer, David S

    2016-01-01

    Neurogenesis takes place in the adult mammalian brain in three areas: Subgranular zone of the dentate gyrus (DG); subventricular zone of the lateral ventricle; olfactory bulb. Different molecular markers can be used to characterize the cells involved in adult neurogenesis. It has been recently suggested that a population of bone marrow (BM) progenitor cells may migrate to the brain and differentiate into neuronal lineage. To explore this hypothesis, we injected recombinant SV40-derived vectors into the BM and followed the potential migration of the transduced cells. Long-term BM-directed gene transfer using recombinant SV40-derived vectors leads to expression of the genes delivered to the BM firstly in circulating cells, then after several months in mature neurons and microglial cells, and thus without central nervous system (CNS) lesion. Most of transgene-expressing cells expressed NeuN, a marker of mature neurons. Thus, BM-derived cells may function as progenitors of CNS cells in adult animals. The mechanism by which the cells from the BM come to be neurons remains to be determined. Although the observed gradual increase in transgene-expressing neurons over 16 mo suggests that the pathway involved differentiation of BM-resident cells into neurons, cell fusion as the principal route cannot be totally ruled out. Additional studies using similar viral vectors showed that BM-derived progenitor cells migrating in the CNS express markers of neuronal precursors or immature neurons. Transgene-positive cells were found in the subgranular zone of the DG of the hippocampus 16 mo after intramarrow injection of the vector. In addition to cells expressing markers of mature neurons, transgene-positive cells were also positive for nestin and doublecortin, molecules expressed by developing neuronal cells. These cells were actively proliferating, as shown by short term BrdU incorporation studies. Inducing seizures by using kainic acid increased the number of BM progenitor cells

  13. SOX7-enforced expression promotes the expansion of adult blood progenitors and blocks B-cell development

    PubMed Central

    Cuvertino, Sara; Lacaud, Georges; Kouskoff, Valerie

    2016-01-01

    During embryogenesis, the three SOXF transcription factors, SOX7, SOX17 and SOX18, regulate the specification of the cardiovascular system and are also involved in the development of haematopoiesis. The ectopic expression of SOX17 in both embryonic and adult blood cells enhances self-renewal. Likewise, the enforced expression of SOX7 during embryonic development promotes the proliferation of early blood progenitors and blocks lineage commitment. However, whether SOX7 expression can also affect the self-renewal of adult blood progenitors has never been explored. In this study, we demonstrate using an inducible transgenic mouse model that the enforced expression of Sox7 ex vivo in bone marrow/stroma cell co-culture promotes the proliferation of blood progenitors which retain multi-lineage short-term engrafting capacity. Furthermore, SOX7 expression induces a profound block in the generation of B lymphocytes. Correspondingly, the ectopic expression of SOX7 in vivo results in dramatic alterations of the haematopoietic system, inducing the proliferation of blood progenitors in the bone marrow while blocking B lymphopoiesis. In addition, SOX7 expression induces extra-medullary haematopoiesis in the spleen and liver. Together, these data demonstrate that the uncontrolled expression of the transcription factor SOX7 in adult haematopoietic cells has dramatic consequences on blood homeostasis. PMID:27411892

  14. Xenotransplantation of Human Cardiomyocyte Progenitor Cells Does Not Improve Cardiac Function in a Porcine Model of Chronic Ischemic Heart Failure. Results from a Randomized, Blinded, Placebo Controlled Trial

    PubMed Central

    Jansen of Lorkeers, Sanne J.; Gho, Johannes M. I. H.; Koudstaal, Stefan; van Hout, Gerardus P. J.; Zwetsloot, Peter Paul M.; van Oorschot, Joep W. M.; van Eeuwijk, Esther C. M.; Leiner, Tim; Hoefer, Imo E.; Goumans, Marie-José; Doevendans, Pieter A.; Sluijter, Joost P. G.; Chamuleau, Steven A. J.

    2015-01-01

    Background Recently cardiomyocyte progenitor cells (CMPCs) were successfully isolated from fetal and adult human hearts. Direct intramyocardial injection of human CMPCs (hCMPCs) in experimental mouse models of acute myocardial infarction significantly improved cardiac function compared to controls. Aim Here, our aim was to investigate whether xenotransplantation via intracoronary infusion of fetal hCMPCs in a pig model of chronic myocardial infarction is safe and efficacious, in view of translation purposes. Methods & Results We performed a randomized, blinded, placebo controlled trial. Four weeks after ischemia/reperfusion injury by 90 minutes of percutaneous left anterior descending artery occlusion, pigs (n = 16, 68.5 ± 5.4 kg) received intracoronary infusion of 10 million fetal hCMPCs or placebo. All animals were immunosuppressed by cyclosporin (CsA). Four weeks after infusion, endpoint analysis by MRI displayed no difference in left ventricular ejection fraction, left ventricular end diastolic and left ventricular end systolic volumes between both groups. Serial pressure volume (PV-)loop and echocardiography showed no differences in functional parameters between groups at any timepoint. Infarct size at follow-up, measured by late gadolinium enhancement MRI showed no difference between groups. Intracoronary pressure and flow measurements showed no signs of coronary obstruction 30 minutes after cell infusion. No premature death occurred in cell treated animals. Conclusion Xenotransplantation via intracoronary infusion of hCMPCs is feasible and safe, but not associated with improved left ventricular performance and infarct size compared to placebo in a porcine model of chronic myocardial infarction. PMID:26678993

  15. A multistep procedure to prepare pre-vascularized cardiac tissue constructs using adult stem sells, dynamic cell cultures, and porous scaffolds

    PubMed Central

    Pagliari, Stefania; Tirella, Annalisa; Ahluwalia, Arti; Duim, Sjoerd; Goumans, Marie-Josè; Aoyagi, Takao; Forte, Giancarlo

    2014-01-01

    The vascularization of tissue engineered products represents a key issue in regenerative medicine which needs to be addressed before the translation of these protocols to the bedside can be foreseen. Here we propose a multistep procedure to prepare pre-vascularized three-dimensional (3D) cardiac bio-substitutes using dynamic cell cultures and highly porous biocompatible gelatin scaffolds. The strategy adopted exploits the peculiar differentiation potential of two distinct subsets of adult stem cells to obtain human vascularized 3D cardiac tissues. In the first step of the procedure, human mesenchymal stem cells (hMSCs) are seeded onto gelatin scaffolds to provide interconnected vessel-like structures, while human cardiomyocyte progenitor cells (hCMPCs) are stimulated in vitro to obtain their commitment toward the cardiac phenotype. The use of a modular bioreactor allows the perfusion of the whole scaffold, providing superior performance in terms of cardiac tissue maturation and cell survival. Both the cell culture on natural-derived polymers and the continuous medium perfusion of the scaffold led to the formation of a densely packaged proto-tissue composed of vascular-like and cardiac-like cells, which might complete maturation process and interconnect with native tissue upon in vivo implantation. In conclusion, the data obtained through the approach here proposed highlight the importance to provide stem cells with complementary signals in vitro able to resemble the complexity of cardiac microenvironment. PMID:24917827

  16. Intravenous multipotent adult progenitor cell treatment decreases inflammation leading to functional recovery following spinal cord injury

    PubMed Central

    DePaul, Marc A.; Palmer, Marc; Lang, Bradley T.; Cutrone, Rochelle; Tran, Amanda P.; Madalena, Kathryn M.; Bogaerts, Annelies; Hamilton, Jason A.; Deans, Robert J.; Mays, Robert W.; Busch, Sarah A.; Silver, Jerry

    2015-01-01

    Following spinal cord injury (SCI), immune-mediated secondary processes exacerbate the extent of permanent neurological deficits. We investigated the capacity of adult bone marrow-derived stem cells, which exhibit immunomodulatory properties, to alter inflammation and promote recovery following SCI. In vitro, we show that human multipotent adult progenitor cells (MAPCs) have the ability to modulate macrophage activation, and prior exposure to MAPC secreted factors can reduce macrophage-mediated axonal dieback of dystrophic axons. Using a contusion model of SCI, we found that intravenous delivery of MAPCs one day, but not immediately, after SCI significantly improves urinary and locomotor recovery, which was associated with marked spinal cord tissue sparing. Intravenous MAPCs altered the immune response in the spinal cord and periphery, however biodistribution studies revealed that no MAPCs were found in the cord and instead preferentially homed to the spleen. Our results demonstrate that MAPCs exert their primary effects in the periphery and provide strong support for the use of these cells in acute human contusive SCI. PMID:26582249

  17. Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

    PubMed Central

    Kilcoyne, Karen R.; Smith, Lee B.; Atanassova, Nina; Macpherson, Sheila; McKinnell, Chris; van den Driesche, Sander; Jobling, Matthew S.; Chambers, Thomas J. G.; De Gendt, Karel; Verhoeven, Guido; O’Hara, Laura; Platts, Sophie; Renato de Franca, Luiz; Lara, Nathália L. M.; Anderson, Richard A.; Sharpe, Richard M.

    2014-01-01

    Fetal growth plays a role in programming of adult cardiometabolic disorders, which in men, are associated with lowered testosterone levels. Fetal growth and fetal androgen exposure can also predetermine testosterone levels in men, although how is unknown, because the adult Leydig cells (ALCs) that produce testosterone do not differentiate until puberty. To explain this conundrum, we hypothesized that stem cells for ALCs must be present in the fetal testis and might be susceptible to programming by fetal androgen exposure during masculinization. To address this hypothesis, we used ALC ablation/regeneration to identify that, in rats, ALCs derive from stem/progenitor cells that express chicken ovalbumin upstream promoter transcription factor II. These stem cells are abundant in the fetal testis of humans and rodents, and lineage tracing in mice shows that they develop into ALCs. The stem cells also express androgen receptors (ARs). Reduction in fetal androgen action through AR KO in mice or dibutyl phthalate (DBP) -induced reduction in intratesticular testosterone in rats reduced ALC stem cell number by ∼40% at birth to adulthood and induced compensated ALC failure (low/normal testosterone and elevated luteinizing hormone). In DBP-exposed males, this failure was probably explained by reduced testicular steroidogenic acute regulatory protein expression, which is associated with increased histone methylation (H3K27me3) in the proximal promoter. Accordingly, ALCs and ALC stem cells immunoexpressed increased H3K27me3, a change that was also evident in ALC stem cells in fetal testes. These studies highlight how a key component of male reproductive development can fundamentally reprogram adult hormone production (through an epigenetic change), which might affect lifetime disease risk. PMID:24753613

  18. pH regulation in adult cardiac myocytes

    SciTech Connect

    Wallert, M.A.

    1989-01-01

    The purpose of this study is to examine the pH{sub i} regulatory mechanisms of adult ventricular myocytes, the cells that perform the pumping work of the heart. The cell system for this study was the ventricular myocyte, isolated by enzymatic dissociation from adult rate heart. In agreement with the findings on other cardiac model cells, I demonstrated the existence of a Cl{sup {minus}}/HCO{sub 3}{sup {minus}} exchanger and a Na{sup +}/H{sup +} exchanger in ventricular myocytes. The existence of the anion exchanger was demonstrated in {sup 36}Cl{sup {minus}} flux experiments and as stilbene disulfonate-inhibitable and Cl{sup {minus}} gradient-dependent intracellular pH shifts in the presence of bicarbonate. The fluorescein derivative BCECF served as a fluorescent probe of intracellular pH in the these experiments. The existence of the Na{sup +}/H{sup +} exchanger was demonstrated in pH{sub i} experiments using BCECF. Further experiments characterized the kinetics of the Na{sup +}/H{sup +} exchanger and its regulation. The steady-state pH{sub i} of ventricular myocytes was 7.16 {+-} 0.11 at pH{sub 0} = 7.4. Several agonists caused a rise in steady-state pH{sub i}: the protein kinase stimulator phorbol myristate acetate (PMA), the {alpha}{sub 1}-adrenergic agonist 6-fluoro-norepinephrine (6F-NE) and the {beta}-agonist UK14304, and ATP.

  19. Hydrogel formulation determines cell fate of fetal and adult neural progenitor cells.

    PubMed

    Aurand, Emily R; Wagner, Jennifer L; Shandas, Robin; Bjugstad, Kimberly B

    2014-01-01

    Hydrogels provide a unique tool for neural tissue engineering. These materials can be customized for certain functions, i.e. to provide cell/drug delivery or act as a physical scaffold. Unfortunately, hydrogel complexities can negatively impact their biocompatibility, resulting in unintended consequences. These adverse effects may be combated with a better understanding of hydrogel chemical, physical, and mechanical properties, and how these properties affect encapsulated neural cells. We defined the polymerization and degradation rates and compressive moduli of 25 hydrogels formulated from different concentrations of hyaluronic acid (HA) and poly(ethylene glycol) (PEG). Changes in compressive modulus were driven primarily by the HA concentration. The in vitro biocompatibility of fetal-derived (fNPC) and adult-derived (aNPC) neural progenitor cells was dependent on hydrogel formulation. Acute survival of fNPC benefited from hydrogel encapsulation. NPC differentiation was divergent: fNPC differentiated into mostly glial cells, compared with neuronal differentiation of aNPC. Differentiation was influenced in part by the hydrogel mechanical properties. This study indicates that there can be a wide range of HA and PEG hydrogels compatible with NPC. Additionally, this is the first study comparing hydrogel encapsulation of NPC derived from different aged sources, with data suggesting that fNPC and aNPC respond dissimilarly within the same hydrogel formulation.

  20. Peptidergic influences on proliferation, migration, and placement of neural progenitors in the adult mouse forebrain.

    PubMed

    Stanic, Davor; Paratcha, Gustavo; Ledda, Fernanda; Herzog, Herbert; Kopin, Alan S; Hökfelt, Tomas

    2008-03-01

    Neural progenitor proliferation, differentiation, and migration are continually ongoing processes in the subventricular zone (SVZ) and rostral migratory stream (RMS) of the adult brain. There is evidence that peptidergic systems may be involved in the molecular cascades regulating these neurogenic processes, and we examined a possible influence of neuropeptide Y (NPY) and cholecystokinin (CCK) systems in cell proliferation and neuroblast formation in the SVZ and RMS and generation of interneurons in the olfactory bulb (OB). We show that NPY and the Y1 and Y2 receptor (R) proteins are expressed in and surrounding the SVZ and RMS and that Y1R is located on neuroblasts in the anterior RMS. Mice deficient in Y1Rs or Y2Rs have fewer Ki-67-immunoreactive (ir) proliferating precursor cells and doublecortin-ir neuroblasts in the SVZ and RMS than WT mice, and less calbindin-, calretinin-, and tyrosine hydroxylase-ir interneurons in the OB. Mice lacking CCK1Rs have fewer proliferating cells and neuroblasts than normal and a shortage of interneurons in the OB. These findings suggest that both NPY and CCK through their receptors help to regulate the proliferation of precursor cells, the amount of neuroblast cells in the SVZ and RMS, and influence the differentiation of OB interneurons.

  1. Presence of circulating abnormal CD34+ progenitors in adult Langerhans cell histiocytosis

    PubMed Central

    MISERY, L; ROUGIER, N; CRESTANI, B; FAURE, M; CLAUDY, A; SCHMITT, D; VINCENT, C

    1999-01-01

    Langerhans cell histiocytosis (LCH) is related to the proliferation of cells, which are similar to Langerhans cells (LC) but possess many abnormal characteristics. Lesions are widespread and this fact suggests that LCH cells or their precursors are present in the blood of patients. In five adult patients, we have isolated and cultured CD34+ blood progenitors of dendritic cells. We studied their phenotype by flow cytometry and their functional properties in mixed culture with heterologous lymphocytes and with autologous lymphocytes in the presence of tri-nitro-phenyl antigen (TNP). The amount of CD34+ precursors was dramatically higher than controls but a high mortality occurred during the in vitro differentiation. The phenotype of surviving cells was similar to LC phenotype (CD1a+, CD83+, Lag+) but some of them expressed CD2. These cells were able to induce T cell proliferation in mixed culture. They could not initiate primary response to TNP, except in a patient treated with thalidomide. In our hands, these CD34+ cells may be precursors of LCH cells. PMID:10403933

  2. The Origin, Biology, and Therapeutic Potential of Facultative Adult Hepatic Progenitor Cells

    PubMed Central

    Shin, Soona; Kaestner, Klaus H.

    2015-01-01

    The liver plays an essential role in glucose and lipid metabolism, synthesis of plasma proteins, and detoxification of xenobiotics and other toxins. Chronic disease of this important organ is one of the leading causes of death in the United States. Following loss of tissue, liver mass can be restored by two mechanisms. Under normal conditions, or after massive loss of parenchyma by surgical resection, liver mass is maintained by division of hepatocytes. After chronic injury, or when proliferation of hepatocytes is impaired, facultative adult hepatic progenitor cells (HPCs) proliferate and differentiate into hepatocytes and cholangiocytes (biliary epithelial cells). HPCs are attractive candidates for cell transplantation because of their potential contribution to liver regeneration. However, until recently, the lack of highly specific markers has hampered efforts to better understand the origin and physiology of HPCs. Recent advances in cell isolation methods and genetic lineage tracing have enabled investigators to explore multiple aspects of HPC biology. In this review, we describe the potential origins of HPCs, the markers used to detect them, the contribution of HPCs to recovery, and the signaling pathways that regulate their biology. We end with an examination of the therapeutic potential of HPCs and their derivatives. PMID:24439810

  3. Pomalidomide reverses γ-globin silencing through the transcriptional reprogramming of adult hematopoietic progenitors.

    PubMed

    Dulmovits, Brian M; Appiah-Kubi, Abena O; Papoin, Julien; Hale, John; He, Mingzhu; Al-Abed, Yousef; Didier, Sebastien; Gould, Michael; Husain-Krautter, Sehba; Singh, Sharon A; Chan, Kyle W H; Vlachos, Adrianna; Allen, Steven L; Taylor, Naomi; Marambaud, Philippe; An, Xiuli; Gallagher, Patrick G; Mohandas, Narla; Lipton, Jeffrey M; Liu, Johnson M; Blanc, Lionel

    2016-03-17

    Current therapeutic strategies for sickle cell anemia are aimed at reactivating fetal hemoglobin. Pomalidomide, a third-generation immunomodulatory drug, was proposed to induce fetal hemoglobin production by an unknown mechanism. Here, we report that pomalidomide induced a fetal-like erythroid differentiation program, leading to a reversion of γ-globin silencing in adult human erythroblasts. Pomalidomide acted early by transiently delaying erythropoiesis at the burst-forming unit-erythroid/colony-forming unit-erythroid transition, but without affecting terminal differentiation. Further, the transcription networks involved in γ-globin repression were selectively and differentially affected by pomalidomide including BCL11A, SOX6, IKZF1, KLF1, and LSD1. IKAROS (IKZF1), a known target of pomalidomide, was degraded by the proteasome, but was not the key effector of this program, because genetic ablation of IKZF1 did not phenocopy pomalidomide treatment. Notably, the pomalidomide-induced reprogramming was conserved in hematopoietic progenitors from individuals with sickle cell anemia. Moreover, multiple myeloma patients treated with pomalidomide demonstrated increased in vivo γ-globin levels in their erythrocytes. Together, these data reveal the molecular mechanisms by which pomalidomide reactivates fetal hemoglobin, reinforcing its potential as a treatment for patients with β-hemoglobinopathies.

  4. Adult-Onset Still's Disease and Cardiac Tamponade: A Rare Association

    PubMed Central

    Silva, Doroteia; de Jesus Silva, Maria; André, Rui; Varela, Manuel Gato; Diogo, António Nunes

    2015-01-01

    Adult-onset Still's disease is a rare disorder with potentially severe clinical features, including cardiac involvement. This systemic inflammatory disease of unknown origin should be considered in the differential diagnosis of pericarditis, with or without pericardial effusion. Cardiac tamponade is a very rare sequela that requires an invasive approach, such as percutaneous or surgical pericardial drainage, in addition to the usual conservative therapy. The authors describe a case of adult-onset Still's disease rendered more difficult by pericarditis and cardiac tamponade, and they briefly review the literature on this entity. PMID:26175648

  5. Differential expression of id genes and their potential regulator znf238 in zebrafish adult neural progenitor cells and neurons suggests distinct functions in adult neurogenesis.

    PubMed

    Diotel, Nicolas; Beil, Tanja; Strähle, Uwe; Rastegar, Sepand

    2015-01-01

    Teleost fish display a remarkable ability to generate new neurons and to repair brain lesions during adulthood. They are, therefore, a very popular model to investigate the molecular mechanisms of constitutive and induced neurogenesis in adult vertebrates. In this study, we investigated the expression patterns of inhibitor of DNA binding (id) genes and of their potential transcriptional repressor, znf238, in the whole brain of adult zebrafish. We show that while id1 is exclusively expressed in ventricular cells in the whole brain, id2a, id3 and id4 genes are expressed in broader areas. Interestingly, znf238 was also detected in these regions, its expression overlapping with id2a, id3 and id4 expression. Further detailed characterization of the id-expressing cells demonstrated that (a) id1 is expressed in type 1 and type 2 neural progenitors as previously published, (b) id2a in type 1, 2 and 3 neural progenitors, (c) id3 in type 3 neural progenitors and (d) id4 in postmitotic neurons. Our data provide a detailed map of id and znf238 expression in the brain of adult zebrafish, supplying a framework for studies of id genes function during adult neurogenesis and brain regeneration in the zebrafish.

  6. The Society of Thoracic Surgeons Adult Cardiac Surgery Database: The Driving Force for Improvement in Cardiac Surgery.

    PubMed

    Winkley Shroyer, Annie Laurie; Bakaeen, Faisal; Shahian, David M; Carr, Brendan M; Prager, Richard L; Jacobs, Jeffrey P; Ferraris, Victor; Edwards, Fred; Grover, Frederick L

    2015-01-01

    Initiated in 1989, the Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database (ACSD) includes more than 1085 participating centers, representing 90%-95% of current US-based adult cardiac surgery hospitals. Since its inception, the primary goal of the STS ACSD has been to use clinical data to track and improve cardiac surgical outcomes. Patients' preoperative risk characteristics, procedure-related processes of care, and clinical outcomes data have been captured and analyzed, with timely risk-adjusted feedback reports to participating providers. In 2006, STS initiated an external audit process to evaluate STS ACSD completeness and accuracy. Given the extremely high inter-rater reliability and completeness rates of STS ACSD, it is widely regarded as the "gold standard" for benchmarking cardiac surgery risk-adjusted outcomes. Over time, STS ACSD has expanded its quality horizons beyond the traditional focus on isolated, risk-adjusted short-term outcomes such as perioperative morbidity and mortality. New quality indicators have evolved including composite measures of key processes of care and outcomes (risk-adjusted morbidity and risk-adjusted mortality), longer-term outcomes, and readmissions. Resource use and patient-reported outcomes would be added in the future. These additional metrics provide a more comprehensive perspective on quality as well as additional end points. Widespread acceptance and use of STS ACSD has led to a cultural transformation within cardiac surgery by providing nationally benchmarked data for internal quality assessment, aiding data-driven quality improvement activities, serving as the basis for a voluntary public reporting program, advancing cardiac surgery care through STS ACSD-based research, and facilitating data-driven informed consent dialogues and alternative treatment-related discussions.

  7. Current Understanding of the Pathways Involved in Adult Stem and Progenitor Cell Migration for Tissue Homeostasis and Repair.

    PubMed

    Goichberg, Polina

    2016-08-01

    With the advancements in the field of adult stem and progenitor cells grows the recognition that the motility of primitive cells is a pivotal aspect of their functionality. There is accumulating evidence that the recruitment of tissue-resident and circulating cells is critical for organ homeostasis and effective injury responses, whereas the pathobiology of degenerative diseases, neoplasm and aging, might be rooted in the altered ability of immature cells to migrate. Furthermore, understanding the biological machinery determining the translocation patterns of tissue progenitors is of great relevance for the emerging methodologies for cell-based therapies and regenerative medicine. The present article provides an overview of studies addressing the physiological significance and diverse modes of stem and progenitor cell trafficking in adult mammalian organs, discusses the major microenvironmental cues regulating cell migration, and describes the implementation of live imaging approaches for the exploration of stem cell movement in tissues and the factors dictating the motility of endogenous and transplanted cells with regenerative potential. PMID:27209167

  8. Older Adults in Cardiac Rehabilitation: A New Strategy for Enhancing Physical Function.

    ERIC Educational Resources Information Center

    Rejeski, W. Jack; Foy, Capri Gabrielle; Brawley, Lawrence R.; Brubaker, Peter H.; Focht, Brian C.; Norris, James L., III; Smith, Marci L.

    2002-01-01

    Contrasted the effect of a group-mediated cognitive- behavioral intervention (GMCB) versus traditional cardiac rehabilitation (CRP) upon changes in objective and self-reported physical function of older adults after 3 months of exercise therapy. Both groups improved significantly. Adults with lower function at the outset of the intervention…

  9. Optimizing Survival Outcomes For Adult Patients With Nontraumatic Cardiac Arrest.

    PubMed

    Jung, Julianna

    2016-10-01

    Patient survival after cardiac arrest can be improved significantly with prompt and effective resuscitative care. This systematic review analyzes the basic life support factors that improve survival outcome, including chest compression technique and rapid defibrillation of shockable rhythms. For patients who are successfully resuscitated, comprehensive postresuscitation care is essential. Targeted temperature management is recommended for all patients who remain comatose, in addition to careful monitoring of oxygenation, hemodynamics, and cardiac rhythm. Management of cardiac arrest in circumstances such as pregnancy, pulmonary embolism, opioid overdose and other toxicologic causes, hypothermia, and coronary ischemia are also reviewed.

  10. Cardiac issues in adults with the mucopolysaccharidoses: current knowledge and emerging needs.

    PubMed

    Braunlin, Elizabeth; Wang, Raymond

    2016-08-15

    The growing availability of innovative treatments for rare genetic diseases with a cardiac component-such as the mucopolysaccharidoses (MPSs)-has changed these syndromes from 'back of the textbook' curiosities of childhood to chronic, but rare, adult cardiac conditions that require both centres of expertise and knowledgeable subspecialists. The MPSs are inherited progressive lysosomal storage diseases, occurring in about 1:25 000 births and resulting from absence of functional hydrolases responsible for the degradation of glycosaminoglycans, naturally occurring complex sugars ubiquitous throughout the body. In the heart, accumulation of glycosaminoglycans occurs within the cardiac valves, the epicardial coronary arteries, the myocytes and cardiac interstitium and the walls of the great vessels. As a consequence, cardiac valve regurgitation and stenosis, diffuse coronary artery stenosis, myocardial dysfunction and aortic root dilation often occur. Haematopoietic cell transplantation and enzyme replacement therapy have changed the previously lethal natural history of the MPSs to one of survival well into adulthood. Despite this improved lifespan, the left-sided cardiac valves continue to show progressive functional involvement and cardiac valve replacement is not uncommon, especially in adults. The risk of any intervention is increased in these patients because of the systemic effects of the disease on the respiratory system and cervical cord. Our current understanding of other cardiac issues in adults with the MPSs, especially with the coronary circulation and myocardium, is meagre and more needs to be known to effectively care for this emerging population of adults. Incorporation of the MPSs, as well as other now-treatable rare diseases, into the educational curriculum of current and future adult subspecialists is an important next step. PMID:27102649

  11. Provision of Transition Education and Referral Patterns from Pediatric Cardiology to Adult Cardiac Care.

    PubMed

    Harbison, Anna L; Grady, Stafford; Chi, Kevin; Fernandes, Susan M

    2016-02-01

    ACC/AHA guidelines recommend a structured preparation for and transfer to adult-oriented cardiac care for adult survivors of pediatric onset heart disease (POHD). Given this, we sought to describe the transition and transfer practices for a cohort of young adults with POHD and to determine factors associated with successful transfer to adult-oriented cardiac care. We performed a single-center, retrospective chart review on patients ≥18 years of age, with POHD likely to require lifelong cardiac care, who were seen in outpatient pediatric cardiology (PC) between 2008 and 2011. Successful transfer was defined as the subsequent attendance at adult cardiology (AC) within 2 years of PC visit. We identified 118 patients who met study criteria. Mean age 22.4 ± 2.0 years, 59 % male, 64 % white and 40 % Hispanic. Mean transition education topics noted was 3.3 ± 1.8 out of 20 and covered the underlying cardiac disease (89 %), follow-up and current medications (56 %) and exercise limitations (34 %). Recommendations for follow-up were AC (57 %) and PC (33 %). Of those told to transfer to AC, 79 % successfully transferred. Characteristics of successful transfer included: prior cardiac surgery (p = 0.008), cardiac medication use (p = 0.006) and frequency of follow-up ≤1 year (p = 0.037). One-quarter of all subjects did not follow-up within at least 2 years. Despite published guidelines, transition education appears lacking and the approach to transfer to adult cardiac care is not consistent. Given the increased risk of morbidity and mortality in this patient population, standardization of transition education and transfer processes appear warranted. PMID:26385471

  12. Moderate Physical Activity in Healthy Adults Is Associated With Cardiac Remodeling

    PubMed Central

    Dawes, Timothy J.W.; Corden, Ben; Cotter, Sorcha; de Marvao, Antonio; Walsh, Roddy; Ware, James S.; Cook, Stuart A.

    2016-01-01

    Background— Cardiac mass and volumes are often elevated in athletes, but it is not known whether moderate physical activity is also associated with cardiac dilatation and hypertrophy in a healthy adult population. Methods and Results— In total, 1096 adults (54% female, median age 39 years) without cardiovascular disease or cardiomyopathy-associated genetic variants underwent cardiac magnetic resonance imaging to determine biventricular volumes and function. Physical activity was assessed using a validated activity questionnaire. The relationship between cardiac parameters and activity was assessed using multiple linear regression adjusting for age, sex, race, and systolic blood pressure. Logistic regression was performed to determine the effect of activity on the likelihood of subjects having cardiac dilatation or hypertrophy according to standard cardiac magnetic resonance normal ranges. Increasing physical activity was associated with greater left ventricular (LV) mass (β=0.23; P<0.0001) and elevated LV and right ventricular volumes (LV: β=0.26, P<0.0001; right ventricular: β=0.26, P<0.0001). Physical activity had a larger effect on cardiac parameters than systolic blood pressure (0.06≤β≤0.21) and a similar effect to age (−0.20≤β≤−0.31). Increasing physical activity was a risk factor for meeting imaging criteria for LV hypertrophy (adjusted odds ratio 2.1; P<0.0001), LV dilatation (adjusted odds ratio 2.2; P<0.0001), and right ventricular dilatation (adjusted odds ratio 2.2; P<0.0001). Conclusions— Exercise-related cardiac remodeling is not confined to athletes, and there is a risk of overdiagnosing cardiac dilatation or hypertrophy in a proportion of active, healthy adults. PMID:27502059

  13. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells.

    PubMed

    Butovsky, Oleg; Ziv, Yaniv; Schwartz, Adi; Landa, Gennady; Talpalar, Adolfo E; Pluchino, Stefano; Martino, Gianvito; Schwartz, Michal

    2006-01-01

    Cell renewal in the adult central nervous system (CNS) is limited, and is blocked in inflammatory brain conditions. We show that both neurogenesis and oligodendrogenesis of adult neural progenitor cells in mice are blocked by inflammation-associated (endotoxin-activated) microglia, but induced by microglia activated by cytokines (IL-4 or low level of IFN-gamma) associated with T-helper cells. Blockage was correlated with up-regulation of microglial production of tumor necrosis factor-alpha. The effect induced by IL-4-activated microglia was mediated, at least in part, by insulin-like growth factor-I. The IL-4-activated microglia showed a bias towards oligodendrogenesis whereas the IFN-gamma-activated microglia showed a bias towards neurogenesis. It thus appears that microglial phenotype critically affects their ability to support or impair cell renewal from adult stem cell.

  14. Running rescues defective adult neurogenesis by shortening the length of the cell cycle of neural stem and progenitor cells.

    PubMed

    Farioli-Vecchioli, Stefano; Mattera, Andrea; Micheli, Laura; Ceccarelli, Manuela; Leonardi, Luca; Saraulli, Daniele; Costanzi, Marco; Cestari, Vincenzo; Rouault, Jean-Pierre; Tirone, Felice

    2014-07-01

    Physical exercise increases the generation of new neurons in adult neurogenesis. However, only few studies have investigated the beneficial effects of physical exercise in paradigms of impaired neurogenesis. Here, we demonstrate that running fully reverses the deficient adult neurogenesis within the hippocampus and subventricular zone of the lateral ventricle, observed in mice lacking the antiproliferative gene Btg1. We also evaluated for the first time how running influences the cell cycle kinetics of stem and precursor subpopulations of wild-type and Btg1-null mice, using a new method to determine the cell cycle length. Our data show that in wild-type mice running leads to a cell cycle shortening only of NeuroD1-positive progenitor cells. In contrast, in Btg1-null mice, physical exercise fully reactivates the defective hippocampal neurogenesis, by shortening the S-phase length and the overall cell cycle duration of both neural stem (glial fibrillary acidic protein(+) and Sox2(+)) and progenitor (NeuroD1(+)) cells. These events are sufficient and necessary to reactivate the hyperproliferation observed in Btg1-null early-postnatal mice and to expand the pool of adult neural stem and progenitor cells. Such a sustained increase of cell proliferation in Btg1-null mice after running provides a long-lasting increment of proliferation, differentiation, and production of newborn neurons, which rescues the impaired pattern separation previously identified in Btg1-null mice. This study shows that running positively affects the cell cycle kinetics of specific subpopulations of newly generated neurons and suggests that the plasticity of neural stem cells without cell cycle inhibitory control is reactivated by running, with implications for the long-term modulation of neurogenesis.

  15. PW1 gene/paternally expressed gene 3 (PW1/Peg3) identifies multiple adult stem and progenitor cell populations

    PubMed Central

    Besson, Vanessa; Smeriglio, Piera; Wegener, Amélie; Relaix, Frédéric; Nait Oumesmar, Brahim; Sassoon, David A.; Marazzi, Giovanna

    2011-01-01

    A variety of markers are invaluable for identifying and purifying stem/progenitor cells. Here we report the generation of a murine reporter line driven by Pw1 that reveals cycling and quiescent progenitor/stem cells in all adult tissues thus far examined, including the intestine, blood, testis, central nervous system, bone, skeletal muscle, and skin. Neurospheres generated from the adult PW1-reporter mouse show near 100% reporter-gene expression following a single passage. Furthermore, epidermal stem cells can be purified solely on the basis of reporter-gene expression. These cells are clonogenic, repopulate the epidermal stem-cell niches, and give rise to new hair follicles. Finally, we demonstrate that only PW1 reporter-expressing epidermal cells give rise to follicles that are capable of self-renewal following injury. Our data demonstrate that PW1 serves as an invaluable marker for competent self-renewing stem cells in a wide array of adult tissues, and the PW1-reporter mouse serves as a tool for rapid stem cell isolation and characterization. PMID:21709251

  16. Engineered 3D bioimplants using elastomeric scaffold, self-assembling peptide hydrogel, and adipose tissue-derived progenitor cells for cardiac regeneration

    PubMed Central

    Soler-Botija, Carolina; Bagó, Juli R; Llucià-Valldeperas, Aida; Vallés-Lluch, Ana; Castells-Sala, Cristina; Martínez-Ramos, Cristina; Fernández-Muiños, Teresa; Chachques, Juan Carlos; Pradas, Manuel Monleón; Semino, Carlos E; Bayes-Genis, Antoni

    2014-01-01

    Contractile restoration of myocardial scars remains a challenge with important clinical implications. Here, a combination of porous elastomeric membrane, peptide hydrogel, and subcutaneous adipose tissue-derived progenitor cells (subATDPCs) was designed and evaluated as a bioimplant for cardiac regeneration in a mouse model of myocardial infarction. SubATDPCs were doubly transduced with lentiviral vectors to express bioluminescent-fluorescent reporters driven by constitutively active, cardiac tissue-specific promoters. Cells were seeded into an engineered bioimplant consisting of a scaffold (polycaprolactone methacryloyloxyethyl ester) filled with a peptide hydrogel (PuraMatrix™), and transplanted to cover injured myocardium. Bioluminescence and fluorescence quantifications showed de novo and progressive increases in promoter expression in bioactive implant-treated animals. The bioactive implant was well adapted to the heart, and fully functional vessels traversed the myocardium-bioactive implant interface. Treatment translated into a detectable positive effect on cardiac function, as revealed by echocardiography. Thus, this novel implant is a promising construct for supporting myocardial regeneration. PMID:24936221

  17. The number of fetal nephron progenitor cells limits ureteric branching and adult nephron endowment.

    PubMed

    Cebrian, Cristina; Asai, Naoya; D'Agati, Vivette; Costantini, Frank

    2014-04-10

    Nephrons, the functional units of the kidney, develop from progenitor cells (cap mesenchyme [CM]) surrounding the epithelial ureteric bud (UB) tips. Reciprocal signaling between UB and CM induces nephrogenesis and UB branching. Although low nephron number is implicated in hypertension and renal disease, the mechanisms that determine nephron number are obscure. To test the importance of nephron progenitor cell number, we genetically ablated 40% of these cells, asking whether this would limit kidney size and nephron number or whether compensatory mechanisms would allow the developing organ to recover. The reduction in CM cell number decreased the rate of branching, which in turn allowed the number of CM cells per UB tip to normalize, revealing a self-correction mechanism. However, the retarded UB branching impaired kidney growth, leaving a permanent nephron deficit. Thus, the number of fetal nephron progenitor cells is an important determinant of nephron endowment, largely via its effect on UB branching.

  18. Developmental origin and lineage plasticity of endogenous cardiac stem cells.

    PubMed

    Santini, Maria Paola; Forte, Elvira; Harvey, Richard P; Kovacic, Jason C

    2016-04-15

    Over the past two decades, several populations of cardiac stem cells have been described in the adult mammalian heart. For the most part, however, their lineage origins and in vivo functions remain largely unexplored. This Review summarizes what is known about different populations of embryonic and adult cardiac stem cells, including KIT(+), PDGFRα(+), ISL1(+)and SCA1(+)cells, side population cells, cardiospheres and epicardial cells. We discuss their developmental origins and defining characteristics, and consider their possible contribution to heart organogenesis and regeneration. We also summarize the origin and plasticity of cardiac fibroblasts and circulating endothelial progenitor cells, and consider what role these cells have in contributing to cardiac repair. PMID:27095490

  19. Developmental origin and lineage plasticity of endogenous cardiac stem cells.

    PubMed

    Santini, Maria Paola; Forte, Elvira; Harvey, Richard P; Kovacic, Jason C

    2016-04-15

    Over the past two decades, several populations of cardiac stem cells have been described in the adult mammalian heart. For the most part, however, their lineage origins and in vivo functions remain largely unexplored. This Review summarizes what is known about different populations of embryonic and adult cardiac stem cells, including KIT(+), PDGFRα(+), ISL1(+)and SCA1(+)cells, side population cells, cardiospheres and epicardial cells. We discuss their developmental origins and defining characteristics, and consider their possible contribution to heart organogenesis and regeneration. We also summarize the origin and plasticity of cardiac fibroblasts and circulating endothelial progenitor cells, and consider what role these cells have in contributing to cardiac repair.

  20. Early life exposure to air pollution induces adult cardiac dysfunction.

    PubMed

    Gorr, Matthew W; Velten, Markus; Nelin, Timothy D; Youtz, Dane J; Sun, Qinghua; Wold, Loren E

    2014-11-01

    Exposure to ambient air pollution contributes to the progression of cardiovascular disease, particularly in susceptible populations. The objective of the present study was to determine whether early life exposure to air pollution causes persistent cardiovascular consequences measured at adulthood. Pregnant FVB mice were exposed to filtered (FA) or concentrated ambient particulate matter (PM2.5) during gestation and nursing. Mice were exposed to PM2.5 at an average concentration of 51.69 μg/m(3) from the Columbus, OH region for 6 h/day, 7 days/wk in utero until weaning at 3 wk of age. Birth weight was reduced in PM2.5 pups compared with FA (1.36 ± 0.12 g FA, n = 42 mice; 1.30 ± 0.15 g PM2.5, n = 67 P = 0.012). At adulthood, mice exposed to perinatal PM2.5 had reduced left ventricular fractional shortening compared with FA-exposed mice (43.6 ± 2.1% FA, 33.2 ± 1.6% PM2.5, P = 0.001) with greater left ventricular end systolic diameter. Pressure-volume loops showed reduced ejection fraction (79.1 ± 3.5% FA, 35.5 ± 9.5% PM2.5, P = 0.005), increased end-systolic volume (10.4 ± 2.5 μl FA, 39.5 ± 3.8 μl PM2.5, P = 0.001), and reduced dP/dt maximum (11,605 ± 200 μl/s FA, 9,569 ± 800 μl/s PM2.5, P = 0.05) and minimum (-9,203 ± 235 μl/s FA, -7,045 ± 189 μl/s PM2.5, P = 0.0005) in PM2.5-exposed mice. Isolated cardiomyocytes from the hearts of PM2.5-exposed mice had reduced peak shortening (%PS, 8.53 ± 2.82% FA, 6.82 ± 2.04% PM2.5, P = 0.003), slower calcium reuptake (τ, 0.22 ± 0.09 s FA, 0.26 ± 0.07 s PM2.5, P = 0.048), and reduced response to β-adrenergic stimulation compared with cardiomyocytes isolated from mice that were exposed to FA. Histological analyses revealed greater picro-sirius red-positive-stained areas in the PM2.5 vs. FA group, indicative of increased collagen deposition. We concluded that these data demonstrate the detrimental role of early life exposure to ambient particulate air pollution in programming of adult cardiovascular

  1. Adult rodent neurogenic regions: the ventricular subependyma contains neural stem cells, but the dentate gyrus contains restricted progenitors.

    PubMed

    Seaberg, Raewyn M; van der Kooy, Derek

    2002-03-01

    Neurogenesis persists in two adult brain regions: the ventricular subependyma and the subgranular cell layer in the hippocampal dentate gyrus (DG). Previous work in many laboratories has shown explicitly that multipotential, self-renewing stem cells in the subependyma are the source of newly generated migrating neurons that traverse the rostral migratory stream and incorporate into the olfactory bulb as interneurons. These stem cells have been specifically isolated from the subependyma, and their properties of self-renewal and multipotentiality have been demonstrated in vitro. In contrast, it is a widely held assumption that the "hippocampal" stem cells that can be isolated in vitro from adult hippocampus reside in the neurogenic subgranular layer and represent the source of new granule cell neurons, but this has never been tested directly. Primary cell isolates derived from the precise microdissection of adult rodent neurogenic regions were compared using two very different commonly used culture methods: a clonal colony-forming (neurosphere) assay and a monolayer culture system. Importantly, both of these culture methods generated the same conclusion: stem cells can be isolated from hippocampus-adjacent regions of subependyma, but the adult DG proper does not contain a population of resident neural stem cells. Indeed, although the lateral ventricle and other ventricular subependymal regions directly adjacent to the hippocampus contain neural stem cells that exhibit long-term self-renewal and multipotentiality, separate neuronal and glial progenitors with limited self-renewal capacity are present in the adult DG, suggesting that neuron-specific progenitors and not multipotential stem cells are the source of newly generated DG neurons throughout adulthood.

  2. Cyp26b1 mediates differential neurogenicity in axial-specific populations of adult spinal cord progenitor cells.

    PubMed

    Leung, Carly; Chan, Sherwin Chun Leung; Tsang, Sze Lan; Wu, Wutian; Sham, Mai Har

    2012-08-10

    Utilization of endogenous adult spinal cord progenitor cells (SCPCs) for neuronal regeneration is a promising strategy for spinal cord repair. To mobilize endogenous SCPCs for injury repair, it is necessary to understand their intrinsic properties and to identify signaling factors that can stimulate their neurogenic potential. In this study, we demonstrate that adult mouse SCPCs express distinct combinatorial Hox genes and exhibit axial-specific stem cell properties. Lumbar-derived neurospheres displayed higher primary sphere formation and greater neurogenicity compared with cervical- and thoracic-derived neurospheres. To further understand the mechanisms governing neuronal differentiation of SCPCs from specific axial regions, we examined the neurogenic responses of adult SCPCs to retinoic acid (RA), an essential factor for adult neurogenesis. Although RA is a potent inducer of neuronal differentiation, we found that RA enhanced the generation of neurons specifically in cervical- but not lumbar-derived cells. We further demonstrate that the differential RA response was mediated by the RA-degrading enzyme cytochrome P450 oxidase b1 Cyp26b1. Lumbar cells express high levels of Cyp26b1 and low levels of the RA-synthesizing enzyme retinaldehyde dehydrogenase Raldh2, resulting in limited activation of the RA signaling pathway in these cells. In contrast, low Cyp26b1 expression in cervical spinal cord progenitor cells allows RA signaling to be readily activated upon RA treatment. The intrinsic heterogeneity and signaling factor regulation among adult SCPCs suggest that different niche factor regimens are required for site-specific mobilization of endogenous SCPCs from distinct spatial regions of the spinal cord for injury repair.

  3. Cardiac-Specific Disruption of GH Receptor Alters Glucose Homeostasis While Maintaining Normal Cardiac Performance in Adult Male Mice.

    PubMed

    Jara, Adam; Liu, Xingbo; Sim, Don; Benner, Chance M; Duran-Ortiz, Silvana; Qian, Yanrong; List, Edward O; Berryman, Darlene E; Kim, Jason K; Kopchick, John J

    2016-05-01

    GH is considered necessary for the proper development and maintenance of several tissues, including the heart. Studies conducted in both GH receptor null and bovine GH transgenic mice have demonstrated specific cardiac structural and functional changes. In each of these mouse lines, however, GH-induced signaling is altered systemically, being decreased in GH receptor null mice and increased in bovine GH transgenic mice. Therefore, to clarify the direct effects GH has on cardiac tissue, we developed a tamoxifen-inducible, cardiac-specific GHR disrupted (iC-GHRKO) mouse line. Cardiac GH receptor was disrupted in 4-month-old iC-GHRKO mice to avoid developmental effects due to perinatal GHR gene disruption. Surprisingly, iC-GHRKO mice showed no difference vs controls in baseline or postdobutamine stress test echocardiography measurements, nor did iC-GHRKO mice show differences in longitudinal systolic blood pressure measurements. Interestingly, iC-GHRKO mice had decreased fat mass and improved insulin sensitivity at 6.5 months of age. By 12.5 months of age, however, iC-GHRKO mice no longer had significant decreases in fat mass and had developed glucose intolerance and insulin resistance. Furthermore, investigation via immunoblot analysis demonstrated that iC-GHRKO mice had appreciably decreased insulin stimulated Akt phosphorylation, specifically in heart and liver, but not in epididymal white adipose tissue. These changes were accompanied by a decrease in circulating IGF-1 levels in 12.5-month-old iC-GHRKO mice. These data indicate that whereas the disruption of cardiomyocyte GH-induced signaling in adult mice does not affect cardiac function, it does play a role in systemic glucose homeostasis, in part through modulation of circulating IGF-1. PMID:27035649

  4. Autonomous isolation, long-term culture and differentiation potential of adult salivary gland-derived stem/progenitor cells.

    PubMed

    Baek, Hyunjung; Noh, Yoo Hun; Lee, Joo Hee; Yeon, Soo-In; Jeong, Jaemin; Kwon, Heechung

    2014-09-01

    Salivary gland stem/progenitor cells belong to the endodermal lineage and may serve as good candidates to replace their dysfunctional counterparts. The objective of this study was to isolate large numbers of salivary gland tissue-derived stem cells (SGSCs) from adult rats in order to develop a clinically applicable method that does not involve sorting or stem cell induction by duct ligation. We analysed SGSCs isolated from normal rat salivary glands to determine whether they retained the major characteristics of stem cells, self-renewal and multipotency, especially with respect to the various endodermal cell types. SGSCs expressed high levels of integrin α6β1 and c-kit, which are surface markers of SGSCs. In particular, the integrin α6β1(+) /c-kit(+) salivary gland cells maintained the morphology, proliferation activity and multipotency of stem cells for up to 92 passages in 12 months. Furthermore, we analysed the capacity of SGSCs to differentiate into endoderm lineage cell types, such as acinar-like and insulin-secreting cells. When cultured on growth factor reduced matrigel, the morphology of progenitor cells changed to acinar-like structures and these cells expressed the acinar cell-specific marker, α-amylase, and tight junction markers. Moreover, reverse transcription-polymerase chain reaction (RT-PCR) data showed increased expression of pancreatic cell markers, including insulin, Pdx1, pan polypeptide and neurogenin-3, when these cells formed pancreatic clusters in the presence of activin A, exendin-4 and retinoic acid. These data demonstrate that adult salivary stem/progenitor cells may serve as a potential source for cell therapy in salivary gland hypofunction and diabetes.

  5. Radionuclide angiocardiography in the clinical evaluation of cardiac malpositions in situs solitus in adults.

    PubMed

    Guit, G L; Kroon, H M; Chin, J G; Pauwels, E K; van Voorthuisen, A E

    1986-04-01

    A right-sided position of the heart in the chest in situs solitus is an abnormal feature easily discernible from a plain chest radiograph. This cardiac malposition may be due to cardiac displacement (dextroposition), which is usually a feature of lung disease, or a structural abnormality of the heart (dextrocardia). Because each condition has different clinical pathologic implications, it is important to distinguish them. Chest films, however, often provide no conclusive information. We performed radionuclide angiocardiography (RNA) in six adults with a cardiac malposition in situs solitus. It was found that morphologic data obtained from the serial images may distinguish dextroposition from dextrocardia. In addition, these images permitted us to diagnose congenitally corrected transposition, a cardiac anomaly which occurs with increased frequency in situs solitus with dextrocardia. Quantitative shunt detection performed during this procedure is helpful in the differential diagnosis of dextroposition and able to distinguish uncomplicated dextrocardia from dextrocardia associated with other cardiac abnormalities. RNA therefore is a valuable and easily performed method in the analysis of cardiac malpositions in adults.

  6. Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart.

    PubMed

    Malliaras, Konstantinos; Zhang, Yiqiang; Seinfeld, Jeffrey; Galang, Giselle; Tseliou, Eleni; Cheng, Ke; Sun, Baiming; Aminzadeh, Mohammad; Marbán, Eduardo

    2013-02-01

    Cardiosphere-derived cells (CDCs) have been shown to regenerate infarcted myocardium in patients after myocardial infarction (MI). However, whether the cells of the newly formed myocardium originate from the proliferation of adult cardiomyocytes or from the differentiation of endogenous stem cells remains unknown. Using genetic fate mapping to mark resident myocytes in combination with long-term BrdU pulsing, we investigated the origins of postnatal cardiomyogenesis in the normal, infarcted and cell-treated adult mammalian heart. In the normal mouse heart, cardiomyocyte turnover occurs predominantly through proliferation of resident cardiomyocytes at a rate of ∼1.3-4%/year. After MI, new cardiomyocytes arise from both progenitors as well as pre-existing cardiomyocytes. Transplantation of CDCs upregulates host cardiomyocyte cycling and recruitment of endogenous progenitors, while boosting heart function and increasing viable myocardium. The observed phenomena cannot be explained by cardiomyocyte polyploidization, bi/multinucleation, cell fusion or DNA repair. Thus, CDCs induce myocardial regeneration by differentially upregulating two mechanisms of endogenous cell proliferation.

  7. Programming Hippocampal Neural Stem/Progenitor Cells into Oligodendrocytes Enhances Remyelination in the Adult Brain after Injury.

    PubMed

    Braun, Simon M G; Pilz, Gregor-Alexander; Machado, Raquel A C; Moss, Jonathan; Becher, Burkhard; Toni, Nicolas; Jessberger, Sebastian

    2015-06-23

    Demyelinating diseases are characterized by a loss of oligodendrocytes leading to axonal degeneration and impaired brain function. Current strategies used for the treatment of demyelinating disease such as multiple sclerosis largely rely on modulation of the immune system. Only limited treatment options are available for treating the later stages of the disease, and these treatments require regenerative therapies to ameliorate the consequences of oligodendrocyte loss and axonal impairment. Directed differentiation of adult hippocampal neural stem/progenitor cells (NSPCs) into oligodendrocytes may represent an endogenous source of glial cells for cell-replacement strategies aiming to treat demyelinating disease. Here, we show that Ascl1-mediated conversion of hippocampal NSPCs into mature oligodendrocytes enhances remyelination in a diphtheria-toxin (DT)-inducible, genetic model for demyelination. These findings highlight the potential of targeting hippocampal NSPCs for the treatment of demyelinated lesions in the adult brain.

  8. Calsequestrins in skeletal and cardiac muscle from adult Danio rerio.

    PubMed

    Furlan, Sandra; Mosole, Simone; Murgia, Marta; Nagaraj, Nagarjuna; Argenton, Francesco; Volpe, Pompeo; Nori, Alessandra

    2016-04-01

    Calsequestrin (Casq) is a high capacity, low affinity Ca(2+)-binding protein, critical for Ca(2+)-buffering in cardiac and skeletal muscle sarcoplasmic reticulum. All vertebrates have multiple genes encoding for different Casq isoforms. Increasing interest has been focused on mammalian and human Casq genes since mutations of both cardiac (Casq2) and skeletal muscle (Casq1) isoforms cause different, and sometime severe, human pathologies. Danio rerio (zebrafish) is a powerful model for studying function and mutations of human proteins. In this work, expression, biochemical properties cellular and sub-cellular localization of D. rerio native Casq isoforms are investigated. By quantitative PCR, three mRNAs were detected in skeletal muscle and heart with different abundances. Three zebrafish Casqs: Casq1a, Casq1b and Casq2 were identified by mass spectrometry (Data are available via ProteomeXchange with identifier PXD002455). Skeletal and cardiac zebrafish calsequestrins share properties with mammalian Casq1 and Casq2. Skeletal Casqs were found primarily, but not exclusively, at the sarcomere Z-line level where terminal cisternae of sarcoplasmic reticulum are located. PMID:26585961

  9. Undernutrition during pregnancy in mice leads to dysfunctional cardiac muscle respiration in adult offspring

    PubMed Central

    Beauchamp, Brittany; Thrush, A. Brianne; Quizi, Jessica; Antoun, Ghadi; McIntosh, Nathan; Al-Dirbashi, Osama Y.; Patti, Mary-Elizabeth; Harper, Mary-Ellen

    2015-01-01

    Intrauterine growth restriction (IUGR) is associated with an increased risk of developing obesity, insulin resistance and cardiovascular disease. However, its effect on energetics in heart remains unknown. In the present study, we examined respiration in cardiac muscle and liver from adult mice that were undernourished in utero. We report that in utero undernutrition is associated with impaired cardiac muscle energetics, including decreased fatty acid oxidative capacity, decreased maximum oxidative phosphorylation rate and decreased proton leak respiration. No differences in oxidative characteristics were detected in liver. We also measured plasma acylcarnitine levels and found that short-chain acylcarnitines are increased with in utero undernutrition. Results reveal the negative impact of suboptimal maternal nutrition on adult offspring cardiac energy metabolism, which may have life-long implications for cardiovascular function and disease risk. PMID:26182362

  10. Cardiac Autonomic Function during Submaximal Treadmill Exercise in Adults with Down Syndrome

    ERIC Educational Resources Information Center

    Mendonca, Goncalo V.; Pereira, Fernando D.; Fernhall, Bo

    2011-01-01

    This study determined whether the cardiac autonomic function of adults with Down syndrome (DS) differs from that of nondisabled persons during submaximal dynamic exercise. Thirteen participants with DS and 12 nondisabled individuals performed maximal and submaximal treadmill tests with metabolic and heart rate (HR) measurements. Spectral analysis…

  11. Adult c-kit(pos) cardiac stem cells are necessary and sufficient for functional cardiac regeneration and repair.

    PubMed

    Ellison, Georgina M; Vicinanza, Carla; Smith, Andrew J; Aquila, Iolanda; Leone, Angelo; Waring, Cheryl D; Henning, Beverley J; Stirparo, Giuliano Giuseppe; Papait, Roberto; Scarfò, Marzia; Agosti, Valter; Viglietto, Giuseppe; Condorelli, Gianluigi; Indolfi, Ciro; Ottolenghi, Sergio; Torella, Daniele; Nadal-Ginard, Bernardo

    2013-08-15

    The epidemic of heart failure has stimulated interest in understanding cardiac regeneration. Evidence has been reported supporting regeneration via transplantation of multiple cell types, as well as replication of postmitotic cardiomyocytes. In addition, the adult myocardium harbors endogenous c-kit(pos) cardiac stem cells (eCSCs), whose relevance for regeneration is controversial. Here, using different rodent models of diffuse myocardial damage causing acute heart failure, we show that eCSCs restore cardiac function by regenerating lost cardiomyocytes. Ablation of the eCSC abolishes regeneration and functional recovery. The regenerative process is completely restored by replacing the ablated eCSCs with the progeny of one eCSC. eCSCs recovered from the host and recloned retain their regenerative potential in vivo and in vitro. After regeneration, selective suicide of these exogenous CSCs and their progeny abolishes regeneration, severely impairing ventricular performance. These data show that c-kit(pos) eCSCs are necessary and sufficient for the regeneration and repair of myocardial damage. PMID:23953114

  12. Clonal proliferation of multipotent stem/progenitor cells in the neonatal and adult salivary glands

    SciTech Connect

    Kishi, Teruki; Takao, Tukasa; Fujita, Kiyohide; Taniguchi, Hideki . E-mail: rtanigu@med.yokohama-cu.ac.jp

    2006-02-10

    Salivary gland stem/progenitor cells are thought to be present in intercalated ductal cells, but the fact is unclear. In this study, we sought to clarify if stem/progenitor cells are present in submandibular glands using colony assay, which is one of the stem cell assay methods. Using a low-density culture of submandibular gland cells of neonatal rats, we developed a novel culture system that promotes single cell colony formation. Average doubling time for the colony-forming cells was 24.7 (SD = {+-}7.02) h, indicating high proliferative potency. When epidermal growth factor (EGF) and hepatocyte growth factor (HGF) were added to the medium, the number of clonal colonies increased greater than those cultured without growth factors (13.2 {+-} 4.18 vs. 4.5 {+-} 1.73). The RT-PCR and immunostaining demonstrated expressing acinar, ductal, and myoepithelial cell lineage markers. This study demonstrated the presence of the salivary gland stem/progenitor cells that are highly proliferative and multipotent in salivary glands.

  13. SWI/SNF protein component BAF250a regulates cardiac progenitor cell differentiation by modulating chromatin accessibility during second heart field development.

    PubMed

    Lei, Ienglam; Gao, Xiaolin; Sham, Mai Har; Wang, Zhong

    2012-07-13

    ATP-dependent SWI/SNF chromatin remodeling complexes alter the structure of chromatin at specific loci and facilitate tissue-specific gene regulation during development. Several SWI/SNF subunits are required for cardiogenesis. However, the function and mechanisms of SWI/SNF in mediating cardiac progenitor cell (CPC) differentiation during cardiogenesis are not well understood. Our studies of the SWI/SNF chromatin remodeling complex identified that BAF250a, a regulatory subunit of the SWI/SNF, plays a key role in CPC differentiation. BAF250a ablation in mouse second heart field (SHF) led to trabeculation defects in the right ventricle, ventricular septal defect, persistent truncus arteriosus, reduced myocardial proliferation, and embryonic lethality around E13. Using an embryonic stem cell culture system that models the formation and differentiation of SHF CPCs in vivo, we have shown that BAF250a ablation in CPCs specifically inhibits cardiomyocyte formation. Moreover, BAF250a selectively regulates the expression of key cardiac factors Mef2c, Nkx2.5, and Bmp10 in SHF CPCs. Chromatin immunoprecipitation and DNase I digestion assays indicate that BAF250a regulates gene expression by binding selectively to its target gene promoters and recruiting Brg1, the catalytic subunit of SWI/SNF, to modulate chromatin accessibility. Our results thus identify BAF250a-mediated chromatin remodeling as an essential epigenetic mechanism mediating CPC differentiation.

  14. Cardiac progenitor/stem cells on myocardial infarction or ischemic heart disease: what we have known from current research.

    PubMed

    Zhang, Hao; Wang, Hong; Li, Na; Duan, Chang-En; Yang, Yue-Jin

    2014-03-01

    Stem cell therapy has become a promising method for many diseases, including ischemic heart disease and heart failure. Several kinds of stem cells have been studied for heart diseases. Of them, bone marrow stem cells (BMSCs), which have been used in many clinical trials, are the most understood one. But the effect of BMSCs is mediated by paracrine factors instead of direct turning into cardiomyocytes. On the other hand, a lot of evidences have shown that resident cardiac stem cells could turn into cardiomyocytes directly in vivo. Currently, seven kinds of resident cardiac stem cells have been discovered. However, their mechanisms, development origins, and relationships have yet to be fully understood. Moreover, two Phase I clinical trials have been performed recently. They show promising results. In this review, we will summarize the current research on these cardiac stem cells and the methods to enhance their effects in clinical applications.

  15. Reference Values for Cardiac and Aortic Magnetic Resonance Imaging in Healthy, Young Caucasian Adults

    PubMed Central

    Eikendal, Anouk L. M.; Bots, Michiel L.; Haaring, Cees; Saam, Tobias; van der Geest, Rob J.; Westenberg, Jos J. M.; den Ruijter, Hester M.; Hoefer, Imo E.; Leiner, Tim

    2016-01-01

    Background Reference values for morphological and functional parameters of the cardiovascular system in early life are relevant since they may help to identify young adults who fall outside the physiological range of arterial and cardiac ageing. This study provides age and sex specific reference values for aortic wall characteristics, cardiac function parameters and aortic pulse wave velocity (PWV) in a population-based sample of healthy, young adults using magnetic resonance (MR) imaging. Materials and Methods In 131 randomly selected healthy, young adults aged between 25 and 35 years (mean age 31.8 years, 63 men) of the general-population based Atherosclerosis-Monitoring-and-Biomarker-measurements-In-The-YOuNg (AMBITYON) study, descending thoracic aortic dimensions and wall thickness, thoracic aortic PWV and cardiac function parameters were measured using a 3.0T MR-system. Age and sex specific reference values were generated using dedicated software. Differences in reference values between two age groups (25–30 and 30–35 years) and both sexes were tested. Results Aortic diameters and areas were higher in the older age group (all p<0.007). Moreover, aortic dimensions, left ventricular mass, left and right ventricular volumes and cardiac output were lower in women than in men (all p<0.001). For mean and maximum aortic wall thickness, left and right ejection fraction and aortic PWV we did not observe a significant age or sex effect. Conclusion This study provides age and sex specific reference values for cardiovascular MR parameters in healthy, young Caucasian adults. These may aid in MR guided pre-clinical identification of young adults who fall outside the physiological range of arterial and cardiac ageing. PMID:27732640

  16. Glomerular parietal epithelial cells of adult murine kidney undergo EMT to generate cells with traits of renal progenitors

    PubMed Central

    G, Swetha; Chandra, Vikash; Phadnis, Smruti; Bhonde, Ramesh

    2011-01-01

    Abstract Glomerular parietal epithelial cells (GPECs) are known to revert to embryonic phenotype in response to renal injury. However, the mechanism of de-differentiation in GPECs and the underlying cellular processes are not fully understood. In the present study, we show that cultured GPECs of adult murine kidney undergo epithelial-mesenchymal transition (EMT) to generate cells, which express CD24, CD44 and CD29 surface antigens. Characterization by qRT-PCR and immunostaining of these clonogenic cells demonstrate that they exhibit metastable phenotype with co-expression of both epithelial (cytokeratin-18) and mesenchymal (vimentin) markers. Transcript analysis by qRT-PCR revealed high expression of metanephric mesenchymal (Pax-2, WT-1, Six-1, Eya-1, GDNF) and uteric bud (Hoxb-7, C-Ret) genes in these cells, indicating their bipotent progenitor status. Incubation of GPECs with EMT blocker Prostaglandin E2, resulted in low expression of renal progenitor markers reflecting the correlation between EMT and acquired stemness in these cells. Additional in vitro renal commitment assays confirmed their functional staminality. When injected into E13.5 kidney rudiments, the cells incorporated into the developing kidney primordia and co-culture with E13.5 spinal cord resulted in branching and tubulogenesis in these cells. When implanted under renal capsule of unilaterally nephrectomized mice, these cells differentiated into immature glomeruli and vascular ducts. Our study demonstrates that EMT plays a major role in imparting plasticity to terminally differentiated GPECs by producing metastable cells with traits of kidney progenitors. The present study would improve our understanding on epithelial cell plasticity, furthering our knowledge of its role in renal repair and regeneration. PMID:19840197

  17. A mouse model for adult cardiac-specific gene deletion with CRISPR/Cas9

    PubMed Central

    Carroll, Kelli J.; Makarewich, Catherine A.; McAnally, John; Anderson, Douglas M.; Zentilin, Lorena; Liu, Ning; Giacca, Mauro; Bassel-Duby, Rhonda; Olson, Eric N.

    2016-01-01

    Clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas)9 genomic editing has revolutionized the generation of mutant animals by simplifying the creation of null alleles in virtually any organism. However, most current approaches with this method require zygote injection, making it difficult to assess the adult, tissue-specific functions of genes that are widely expressed or which cause embryonic lethality when mutated. Here, we describe the generation of cardiac-specific Cas9 transgenic mice, which express high levels of Cas9 in the heart, but display no overt defects. In proof-of-concept experiments, we used Adeno-Associated Virus 9 (AAV9) to deliver single-guide RNA (sgRNA) that targets the Myh6 locus exclusively in cardiomyocytes. Intraperitoneal injection of postnatal cardiac-Cas9 transgenic mice with AAV9 encoding sgRNA against Myh6 resulted in robust editing of the Myh6 locus. These mice displayed severe cardiomyopathy and loss of cardiac function, with elevation of several markers of heart failure, confirming the effectiveness of this method of adult cardiac gene deletion. Mice with cardiac-specific expression of Cas9 provide a tool that will allow rapid and accurate deletion of genes following a single injection of AAV9-sgRNAs, thereby circumventing embryonic lethality. This method will be useful for disease modeling and provides a means of rapidly editing genes of interest in the heart. PMID:26719419

  18. Lung ultrasound in adult and paediatric cardiac surgery: is it time for routine use?

    PubMed

    Cantinotti, Massimiliano; Giordano, Raffaele; Volpicelli, Giovanni; Kutty, Shelby; Murzi, Bruno; Assanta, Nadia; Gargani, Luna

    2016-02-01

    Respiratory complications are common causes of morbidity and the need of repeated X-ray examinations after cardiac surgery. Ultrasound of the chest, including the lung parenchyma, has been recently introduced as a new tool to detect many pulmonary abnormalities. Despite this, the use of lung ultrasound (LUS) in adult and congenital cardiac surgery remains limited. In particular, lung ultrasound has been mainly used in the evaluation of pleural effusion (PLE), but no consensus exists on methods to quantify the volume of the effusion. Usefulness of LUS for the assessment of diaphragmatic motion in children has also been highlighted, but no clear recommendation exists regarding its routine use. Accuracy of LUS in detecting pulmonary congestion after adult cardiac surgery has been demonstrated, whereas studies in children are still scarce, and data on pneumothorax and lung consolidations are limited in the paediatric population. There are methodological and practicality issues regarding diagnostic protocols (i.e. image views and their sequential order) and instrumentation (transducers and their setting) used in different studies. It also remains unclear which practitioner-the cardiologist, intensivist, pulmonologist or the radiologist, should perform the examination. Cost analysis pertaining to extensive clinical application of lung ultrasound in cardiac surgery has never been performed. Guidelines and recommendations are warranted for a systematic and extensive use of this technique in cardiac surgery at different ages, as it could serve as a useful, versatile tool that could potentially decrease time, radiation exposure and costs. PMID:26586677

  19. Anti-Ro/SSA antibodies and cardiac arrhythmias in the adult: facts and hypotheses.

    PubMed

    Lazzerini, P E; Capecchi, P L; Laghi-Pasini, F

    2010-09-01

    It is well established that the passive trans-placental passage of anti-Ro/SSA antibodies from mother to foetus is associated with the risk to develop an uncommon syndrome named neonatal lupus (NLE), where the congenital heart block represents the most severe clinical feature. Recent evidence demonstrated that also adult heart, classically considered invulnerable to the anti-Ro/SSA antibodies, may represent a target of the arrhythmogenicity of these autoantibodies. In particular, the prolongation of the QTc interval appears the most frequent abnormality observed in adults with circulating anti-Ro/SSA antibodies, with some data suggesting an association with an increased risk of ventricular arrhythmias, also life threatening. Moreover, even though the association between anti-Ro/SSA antibodies and conduction disturbances is undoubtedly less evident in adults than in infants, from the accurate dissection of the literature data the possibility arises that sometimes also the adult cardiac conduction tissue may be affected by such antibodies. The exact arrhythmogenic mechanisms involved in foetus/newborns and adults, respectively, have not been completely clarified as yet. However, increasing evidence suggests that anti-Ro/SSA antibodies may trigger rhythm disturbances through an inhibiting cross-reaction with several cardiac ionic channels, particularly the calcium channels (L-type and T-type), but also the potassium channel hERG, whose different expression and involvement in the cardiac electrophysiology during lifespan might account for the occurrence of age-related differences.

  20. Anti-Ro/SSA antibodies and cardiac arrhythmias in the adult: facts and hypotheses.

    PubMed

    Lazzerini, P E; Capecchi, P L; Laghi-Pasini, F

    2010-09-01

    It is well established that the passive trans-placental passage of anti-Ro/SSA antibodies from mother to foetus is associated with the risk to develop an uncommon syndrome named neonatal lupus (NLE), where the congenital heart block represents the most severe clinical feature. Recent evidence demonstrated that also adult heart, classically considered invulnerable to the anti-Ro/SSA antibodies, may represent a target of the arrhythmogenicity of these autoantibodies. In particular, the prolongation of the QTc interval appears the most frequent abnormality observed in adults with circulating anti-Ro/SSA antibodies, with some data suggesting an association with an increased risk of ventricular arrhythmias, also life threatening. Moreover, even though the association between anti-Ro/SSA antibodies and conduction disturbances is undoubtedly less evident in adults than in infants, from the accurate dissection of the literature data the possibility arises that sometimes also the adult cardiac conduction tissue may be affected by such antibodies. The exact arrhythmogenic mechanisms involved in foetus/newborns and adults, respectively, have not been completely clarified as yet. However, increasing evidence suggests that anti-Ro/SSA antibodies may trigger rhythm disturbances through an inhibiting cross-reaction with several cardiac ionic channels, particularly the calcium channels (L-type and T-type), but also the potassium channel hERG, whose different expression and involvement in the cardiac electrophysiology during lifespan might account for the occurrence of age-related differences. PMID:20696018

  1. Inhibition of G9a Histone Methyltransferase Converts Bone Marrow Mesenchymal Stem Cells to Cardiac Competent Progenitors

    PubMed Central

    Yang, Jinpu; Kaur, Keerat; Ong, Li Lin; Eisenberg, Carol A.; Eisenberg, Leonard M.

    2015-01-01

    The G9a histone methyltransferase inhibitor BIX01294 was examined for its ability to expand the cardiac capacity of bone marrow cells. Inhibition of G9a histone methyltransferase by gene specific knockdown or BIX01294 treatment was sufficient to induce expression of precardiac markers Mesp1 and brachyury in bone marrow cells. BIX01294 treatment also allowed bone marrow mesenchymal stem cells (MSCs) to express the cardiac transcription factors Nkx2.5, GATA4, and myocardin when subsequently exposed to the cardiogenic stimulating factor Wnt11. Incubation of BIX01294-treated MSCs with cardiac conditioned media provoked formation of phase bright cells that exhibited a morphology and molecular profile resembling similar cells that normally form from cultured atrial tissue. Subsequent aggregation and differentiation of BIX01294-induced, MSC-derived phase bright cells provoked their cardiomyogenesis. This latter outcome was indicated by their widespread expression of the primary sarcomeric proteins muscle α-actinin and titin. MSC-derived cultures that were not initially treated with BIX01294 exhibited neither a commensurate burst of phase bright cells nor stimulation of sarcomeric protein expression. Collectively, these data indicate that BIX01294 has utility as a pharmacological agent that could enhance the ability of an abundant and accessible stem cell population to regenerate new myocytes for cardiac repair. PMID:26089912

  2. Enteroendocrine cells are generated from stem cells through a distinct progenitor in the adult Drosophila posterior midgut

    PubMed Central

    Zeng, Xiankun; Hou, Steven X.

    2015-01-01

    Functional mature cells are continually replenished by stem cells to maintain tissue homoeostasis. In the adult Drosophila posterior midgut, both terminally differentiated enterocyte (EC) and enteroendocrine (EE) cells are generated from an intestinal stem cell (ISC). However, it is not clear how the two differentiated cells are generated from the ISC. In this study, we found that only ECs are generated through the Su(H)GBE+ immature progenitor enteroblasts (EBs), whereas EEs are generated from ISCs through a distinct progenitor pre-EE by a novel lineage-tracing system. EEs can be generated from ISCs in three ways: an ISC becoming an EE, an ISC becoming a new ISC and an EE through asymmetric division, or an ISC becoming two EEs through symmetric division. We further identified that the transcriptional factor Prospero (Pros) regulates ISC commitment to EEs. Our data provide direct evidence that different differentiated cells are generated by different modes of stem cell lineage specification within the same tissues. PMID:25670791

  3. Severe Obesity in Adolescents and Young Adults Is Associated With Subclinical Cardiac and Vascular Changes

    PubMed Central

    Dolan, Lawrence M.; Khoury, Philip R.; Gao, Zhiqan; Kimball, Thomas R.; Urbina, Elaine M.

    2015-01-01

    Context: Severe obesity is the fastest growing subgroup of obesity in youth. Objective: We sought to explore the association between severe obesity and subclinical measures of cardiac and vascular structure and function in adolescents and young adults. Design, Setting, and Participants: This was a cross-sectional comparison of 265 adolescents and young adults with severe obesity (defined as body mass index [BMI] ≥120% of the 95th percentile) to 182 adolescents and young adults with obesity (defined as BMI ≥100–119th of the 95th percentile) at tertiary medical center. Main Outcomes: Noninvasive measures of cardiac and vascular structure and function were assessed. Results: Participants were a mean age of 17.9 years, 62% were non-Caucasian, and 68% were female. Systolic blood pressure, fasting insulin, C-reactive protein, IL-6, and frequency of type 2 diabetes were higher in participants with severe obesity (all P < .05). Arterial thickness and stiffness, cardiac structure, and diastolic function were also significantly worse in youth with severe obesity as measured by higher left ventricular mass index, worse diastolic function, higher carotid intima media thickness, and pulse wave velocity and lower brachial distensibility (all P < .05). Regression modeling showed that severe obesity (compared with obesity) was independently associated with each of the above outcomes after adjustment for age, race, sex, blood pressure, lipids, and inflammatory markers (P < .05). Conclusions: Adolescents and young adults with severe obesity have a more adverse cardiovascular risk profile and worse cardiac and vascular structure and function. More importantly, severe obesity is independently associated with these subclinical cardiac and vascular changes. PMID:25974736

  4. Recent insights into the molecular mechanisms involved in aging and the malignant transformation of adult stem/progenitor cells and their therapeutic implications.

    PubMed

    Mimeault, Murielle; Batra, Surinder K

    2009-04-01

    Recent advancements in tissue-resident adult stem/progenitor cell research have revealed that enhanced telomere attrition, oxidative stress, ultraviolet radiation exposure and oncogenic events leading to severe DNA damages and genomic instability may occur in these immature and regenerative cells during chronological aging. Particularly, the alterations in key signaling components controlling their self-renewal capacity and an up-regulation of tumor suppressor gene products such as p16(INK4A), p19(ARF), ataxia-telangiectasia mutated (ATM) kinase, p53 and/or the forkhead box O (FOXOs) family of transcription factors may result in their dysfunctions, growth arrest and senescence or apoptotic death during the aging process. These molecular events may culminate in a progressive decline in the regenerative functions and the number of tissue-resident adult stem/progenitor cells, and age-related disease development. Conversely, the telomerase re-activation and accumulation of numerous genetic and/or epigenetic alterations in adult stem/progenitor cells with advancing age may result in their immortalization and malignant transformation into highly leukemic or tumorigenic cancer-initiating cells and cancer initiation. Therefore, the cell-replacement and gene therapies and molecular targeting of aged and dysfunctional adult stem/progenitor cells including their malignant counterpart, cancer-initiating cells, hold great promise for treating and even curing diverse devastating human diseases. These diseases include premature aging diseases, hematopoietic, cardiovascular, musculoskeletal, pulmonary, ocular, urogenital, neurodegenerative and skin disorders and aggressive and recurrent cancers.

  5. Functional electrical stimulation helps replenish progenitor cells in the injured spinal cord of adult rats.

    PubMed

    Becker, Daniel; Gary, Devin S; Rosenzweig, Ephron S; Grill, Warren M; McDonald, John W

    2010-04-01

    Functional electrical stimulation (FES) can restore control and offset atrophy to muscles after neurological injury. However, FES has not been considered as a method for enhancing CNS regeneration. This paper demonstrates that FES dramatically enhanced progenitor cell birth in the spinal cord of rats with a chronic spinal cord injury (SCI). A complete SCI at thoracic level 8/9 was performed on 12 rats. Three weeks later, a FES device to stimulate hindlimb movement was implanted into these rats. Twelve identically-injured rats received inactive FES implants. An additional control group of uninjured rats were also examined. Ten days after FES implantation, dividing cells were marked with bromodeoxyuridine (BrdU). The "cell birth" subgroup (half the animals in each group) was sacrificed immediately after completion of BrdU administration, and the "cell survival" subgroup was sacrificed 7 days later. In the injured "cell birth" subgroup, FES induced an 82-86% increase in cell birth in the lumbar spinal cord. In the injured "cell survival" subgroup, the increased lumbar newborn cell counts persisted. FES doubled the proportion of the newly-born cells which expressed nestin and other markers suggestive of tripotential progenitors. In uninjured rats, FES had no effect on cell birth/survival. This report suggests that controlled electrical activation of the CNS may enhance spontaneous regeneration after neurological injuries.

  6. Golli myelin basic proteins stimulate oligodendrocyte progenitor cell proliferation and differentiation in remyelinating adult mouse brain.

    PubMed

    Paez, Pablo M; Cheli, Veronica T; Ghiani, Cristina A; Spreuer, Vilma; Handley, Vance W; Campagnoni, Anthony T

    2012-07-01

    Golli myelin basic proteins are necessary for normal myelination, acting via voltage and store-dependent Ca(2+) entry at multiple steps during oligodendrocyte progenitor cell (OPC) development. To date nothing is known regarding the role of golli proteins in demyelination or remyelination events. Here the effects of golli ablation and overexpression in myelin loss and recovery were examined using the cuprizone (CPZ) model of demyelination/remyelination. We found severe demyelination in the corpus callosum (CC) of golli-overexpressing mice (JOE) during the CPZ treatment, which was accompanied by an increased number of reactive astrocytes and activation of microglia/macrophages. During demyelination of JOE brains, a significant increase in the number of proliferating OPCs was found in the CC as well as in the subventricular zone, and our data indicate that these progenitors matured and fully remyelinated the CC of JOE animals after CPZ withdrawal. In contrast, in the absence of golli (golli-KO mice) delayed myelin loss associated with a smaller immune response, and a lower number of OPCs was found in these mice during the CPZ treatment. Furthermore, incomplete remyelination was observed after CPZ removal in large areas of the CC of golli-KO mice, reflecting irregular recovery of the oligodendrocyte population and subsequent myelin sheath formation. Our findings demonstrate that golli proteins sensitize mature oligodendrocytes to CPZ-induced demyelination, while at the same time stimulate the proliferation/recruitment of OPCs during demyelination, resulting in accelerated remyelination.

  7. Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis

    PubMed Central

    Huch, Meritxell; Bonfanti, Paola; Boj, Sylvia F; Sato, Toshiro; Loomans, Cindy J M; van de Wetering, Marc; Sojoodi, Mozhdeh; Li, Vivian S W; Schuijers, Jurian; Gracanin, Ana; Ringnalda, Femke; Begthel, Harry; Hamer, Karien; Mulder, Joyce; van Es, Johan H; de Koning, Eelco; Vries, Robert G J; Heimberg, Harry; Clevers, Hans

    2013-01-01

    Lgr5 marks adult stem cells in multiple adult organs and is a receptor for the Wnt-agonistic R-spondins (RSPOs). Intestinal, stomach and liver Lgr5+ stem cells grow in 3D cultures to form ever-expanding organoids, which resemble the tissues of origin. Wnt signalling is inactive and Lgr5 is not expressed under physiological conditions in the adult pancreas. However, we now report that the Wnt pathway is robustly activated upon injury by partial duct ligation (PDL), concomitant with the appearance of Lgr5 expression in regenerating pancreatic ducts. In vitro, duct fragments from mouse pancreas initiate Lgr5 expression in RSPO1-based cultures, and develop into budding cyst-like structures (organoids) that expand five-fold weekly for >40 weeks. Single isolated duct cells can also be cultured into pancreatic organoids, containing Lgr5 stem/progenitor cells that can be clonally expanded. Clonal pancreas organoids can be induced to differentiate into duct as well as endocrine cells upon transplantation, thus proving their bi-potentiality. PMID:24045232

  8. Sustained Survival and Maturation of Adult Neural Stem/Progenitor Cells after Transplantation into the Injured Brain

    PubMed Central

    Gugliotta, Marinella; Rolfe, Andrew; Reid, Wendy; McQuiston, A. Rory; Hu, Wenhui; Young, Harold

    2011-01-01

    Abstract Multipotent neural stem/progenitor cells (NS/NPCs) that are capable of generating neurons and glia offer enormous potential for treating neurological diseases. Adult NS/NPCs that reside in the mature mammalian brain can be isolated and expanded in vitro, and could be a potential source for autologous transplantation to replace cells lost to brain injury or disease. When these cells are transplanted into the normal brain, they can survive and become region-specific cells. However, it has not been reported whether these cells can survive for an extended period and become functional cells in an injured heterotypic environment. In this study, we tested survival, maturation fate, and electrophysiological properties of adult NS/NPCs after transplantation into the injured rat brain. NS/NPCs were isolated from the subventricular zone of adult Fisher 344 rats and cultured as a monolayer. Recipient adult Fisher 344 rats were first subjected to a moderate fluid percussive injury. Two days later, cultured NS/NPCs were injected into the injured brain in an area between the white matter tracts and peri-cortical region directly underneath the injury impact. The animals were sacrificed 2 or 4 weeks after transplantation for immunohistochemical staining or patch-clamp recording. We found that transplanted cells survived well at 2 and 4 weeks. Many cells migrated out of the injection site into surrounding areas expressing astrocyte or oligodendrocyte markers. Whole cell patch-clamp recording at 4 weeks showed that transplanted cells possessed typical mature glial cell properties. These data demonstrate that adult NS/NPCs can survive in an injured heterotypic environment for an extended period and become functional cells. PMID:21332258

  9. The Impact of Moderate Intensity Physical Activity on Cardiac Structure and Performance in Older Sedentary Adults

    PubMed Central

    Suboc, Tisha B.; Strath, Scott J.; Dharmashankar, Kodlipet; Harmann, Leanne; Couillard, Allison; Malik, Mobin; Haak, Kristoph; Knabel, Daniel; Widlansky, Michael E.

    2014-01-01

    Background Sedentary aging leads to adverse changes in vascular function and cardiac performance. We published improvements in vascular function with moderate intensity physical activity (PA) in continuous bouts. Whether moderate intensity PA also impacts cardiac structure and cardiovascular performance of the aging left ventricle (LV) is unknown. Methods We recruited and analyzed results from 102 sedentary older adults ages ≥ 50 from a randomized controlled trial with 3 study groups: control (group 1), a pedometer-only intervention (group 2), or a pedometer with an interactive website employing strategies to increase habitual physical activity (PA, group 3) for 12 weeks. Transthoracic echocardiograms were performed prior to and following the 12 week intervention period to assess cardiac morphology, left ventricular (LV) systolic performance, LV diastolic function, arterial and LV ventricular elastance. Step count and PA intensity/distribution were measured by pedometer and accelerometer. Results We found no significant changes in cardiac morphology. Further, we found no improvement in the aforementioned cardiac functional parameters. Comparing those who achieved the following benchmarks to those who did not showed no significant changes in cardiac structure or performance: 1)10,000 steps/day, 2) ≥ 30 minutes/day of moderate intensity physical activity, or 3) moderate intensity PA in bouts ≥ 10 minutes for ≥ 20 minutes/day Conclusions In sedentary older adults, increasing moderate intensity PA to currently recommend levels does not result in favorable changes in LV morphology or performance over 12 weeks. More prolonged exposure, higher PA intensity, or earlier initiation of PA may be necessary to see benefits. PMID:25530947

  10. High neuronal/astroglial differentiation plasticity of adult rat hippocampal neural stem/progenitor cells in response to the effects of embryonic and adult cerebrospinal fluids

    PubMed Central

    Peirouvi, T.; Yekani, F.; Azarnia, M.; Massumi, M.

    2015-01-01

    Hippocampal neural stem/progenitor cells (hipp-NS/PCs) of the adult mammalian brain are important sources of neuronal and gial cell production. In this study, the main goal is to investigate the plasticity of these cells in neuronal/astroglial differentiations. To this end, the differentiation of the hipp-NS/PCs isolated from 3-month-old Wistar rats was investigated in response to the embryonic cerebrospinal fluid (E-CSF) including E13.5, E17-CSF and the adult cerebrospinal fluid (A-CSF), all extracted from rats. CSF samples were selected based on their effects on cell behavioral parameters. Primary cell culture was performed in the presence of either normal or high levels of KCL in a culture medium. High levels of KCL cause cell depolarization, and thus the activation of quiescent NSCs. Results from immunocytochemistry (ICC) and semi-quantitative RT-PCR (sRT-PCR) techniques showed that in E-CSF-treated groups, neuronal differentiation increased (E17>E13.5). In contrast, A-CSF decreased and increased neuronal and astroglial differentiations, respectively. Cell survivability and/or proliferation (S/P), evaluated by an MTT assay, increased by E13.5 CSF, but decreased by both E17 CSF and A-CSF. Based on the results, it is finally concluded that adult rat hippocampal proliferative cells are not restricted progenitors but rather show high plasticity in neuronal/astroglial differentiation according to the effects of CSF samples. In addition, using high concentrations of KCL in the primary cell culture led to an increase in the number of NSCs, which in turn resulted in the increase in neuronal or astroglial differentiations after CSF treatment. PMID:27175157

  11. Constitutive properties of adult mammalian cardiac muscle cells

    NASA Technical Reports Server (NTRS)

    Zile, M. R.; Richardson, K.; Cowles, M. K.; Buckley, J. M.; Koide, M.; Cowles, B. A.; Gharpuray, V.; Cooper, G. 4th

    1998-01-01

    BACKGROUND: The purpose of this study was to determine whether changes in the constitutive properties of the cardiac muscle cell play a causative role in the development of diastolic dysfunction. METHODS AND RESULTS: Cardiocytes from normal and pressure-hypertrophied cats were embedded in an agarose gel, placed on a stretching device, and subjected to a change in stress (sigma), and resultant changes in cell strain (epsilon) were measured. These measurements were used to examine the passive elastic spring, viscous damping, and myofilament activation. The passive elastic spring was assessed in protocol A by increasing the sigma on the agarose gel at a constant rate to define the cardiocyte sigma-versus-epsilon relationship. Viscous damping was assessed in protocol B from the loop area between the cardiocyte sigma-versus-epsilon relationship during an increase and then a decrease in sigma. In both protocols, myofilament activation was minimized by a reduction in [Ca2+]i. Myofilament activation effects were assessed in protocol C by defining cardiocyte sigma versus epsilon during an increase in sigma with physiological [Ca2+]i. In protocol A, the cardiocyte sigma-versus-epsilon relationship was similar in normal and hypertrophied cells. In protocol B, the loop area was greater in hypertrophied than normal cardiocytes. In protocol C, the sigma-versus-epsilon relation in hypertrophied cardiocytes was shifted to the left compared with normal cells. CONCLUSIONS: Changes in viscous damping and myofilament activation in combination may cause pressure-hypertrophied cardiocytes to resist changes in shape during diastole and contribute to diastolic dysfunction.

  12. Audio-visual relaxation training for anxiety, sleep, and relaxation among Chinese adults with cardiac disease.

    PubMed

    Tsai, Sing-Ling

    2004-12-01

    The long-term effect of an audio-visual relaxation training (RT) treatment involving deep breathing, exercise, muscle relaxation, guided imagery, and meditation was compared with routine nursing care for reducing anxiety, improving sleep, and promoting relaxation in Chinese adults with cardiac disease. This research was a quasi-experimental, two-group, pretest-posttest study. A convenience sample of 100 cardiology patients (41 treatment, 59 control) admitted to one large medical center hospital in the Republic of China (ROC) was studied for 1 year. The hypothesized relationships were supported. RT significantly (p <.05) improved anxiety, sleep, and relaxation in the treatment group as compared to the control group. It appears audio-visual RT might be a beneficial adjunctive therapy for adult cardiac patients. However, considerable further work using stronger research designs is needed to determine the most appropriate instructional methods and the factors that contribute to long-term consistent practice of RT with Chinese populations.

  13. Lesion-induced accumulation of platelets promotes survival of adult neural stem / progenitor cells.

    PubMed

    Kazanis, Ilias; Feichtner, Martina; Lange, Simona; Rotheneichner, Peter; Hainzl, Stefan; Öller, Michaela; Schallmoser, Katharina; Rohde, Eva; Reitsamer, Herbert A; Couillard-Despres, Sebastien; Bauer, Hans-Christian; Franklin, Robin J M; Aigner, Ludwig; Rivera, Francisco J

    2015-07-01

    The presence of neural stem/progenitor cells (NSPCs) in specific areas of the central nervous system (CNS) supports tissue maintenance as well as regeneration. The subependymal zone (SEZ), located at the lateral ventricle's wall, represents a niche for NSPCs and in response to stroke or demyelination becomes activated with progenitors migrating towards the lesion and differentiating into neurons and glia. The mechanisms that underlie this phenomenon remain largely unknown. The vascular niche and in particular blood-derived elements such as platelets, has been shown to contribute to CNS regeneration in different pathological conditions. Indeed, intracerebroventricularly administrated platelet lysate (PL) stimulates angiogenesis, neurogenesis and neuroprotection in the damaged CNS. Here, we explored the presence of platelets in the activated SEZ after a focal demyelinating lesion in the corpus callosum of mice and we studied the effects of PL on proliferating SEZ-derived NSPCs in vitro. We showed that the lesion-induced increase in the size of the SEZ and in the number of proliferating SEZ-resident NSPCs correlates with the accumulation of platelets specifically along the activated SEZ vasculature. Expanding on this finding, we demonstrated that exposure of NSPCs to PL in vitro led to increased numbers of cells by enhanced cell survival and reduced apoptosis without differences in proliferation and in the differentiation potential of NSPCs. Finally, we demonstrate that the accumulation of platelets within the SEZ is spatially correlated with reduced numbers of apoptotic cells when compared to other periventricular areas. In conclusion, our results show that platelet-derived compounds specifically promote SEZ-derived NSPC survival and suggest that platelets might contribute to the enlargement of the pool of SEZ NSPCs that are available for CNS repair in response to injury.

  14. Lesion-induced accumulation of platelets promotes survival of adult neural stem / progenitor cells.

    PubMed

    Kazanis, Ilias; Feichtner, Martina; Lange, Simona; Rotheneichner, Peter; Hainzl, Stefan; Öller, Michaela; Schallmoser, Katharina; Rohde, Eva; Reitsamer, Herbert A; Couillard-Despres, Sebastien; Bauer, Hans-Christian; Franklin, Robin J M; Aigner, Ludwig; Rivera, Francisco J

    2015-07-01

    The presence of neural stem/progenitor cells (NSPCs) in specific areas of the central nervous system (CNS) supports tissue maintenance as well as regeneration. The subependymal zone (SEZ), located at the lateral ventricle's wall, represents a niche for NSPCs and in response to stroke or demyelination becomes activated with progenitors migrating towards the lesion and differentiating into neurons and glia. The mechanisms that underlie this phenomenon remain largely unknown. The vascular niche and in particular blood-derived elements such as platelets, has been shown to contribute to CNS regeneration in different pathological conditions. Indeed, intracerebroventricularly administrated platelet lysate (PL) stimulates angiogenesis, neurogenesis and neuroprotection in the damaged CNS. Here, we explored the presence of platelets in the activated SEZ after a focal demyelinating lesion in the corpus callosum of mice and we studied the effects of PL on proliferating SEZ-derived NSPCs in vitro. We showed that the lesion-induced increase in the size of the SEZ and in the number of proliferating SEZ-resident NSPCs correlates with the accumulation of platelets specifically along the activated SEZ vasculature. Expanding on this finding, we demonstrated that exposure of NSPCs to PL in vitro led to increased numbers of cells by enhanced cell survival and reduced apoptosis without differences in proliferation and in the differentiation potential of NSPCs. Finally, we demonstrate that the accumulation of platelets within the SEZ is spatially correlated with reduced numbers of apoptotic cells when compared to other periventricular areas. In conclusion, our results show that platelet-derived compounds specifically promote SEZ-derived NSPC survival and suggest that platelets might contribute to the enlargement of the pool of SEZ NSPCs that are available for CNS repair in response to injury. PMID:25819103

  15. C-Kit Promotes Growth and Migration of Human Cardiac Progenitor Cells via the PI3K-AKT and MEK-ERK Pathways

    PubMed Central

    Al-Maqtari, Tareq; Cao, Pengxiao; Keith, Matthew C. L.; Wysoczynski, Marcin; Zhao, John; Moore IV, Joseph B.; Bolli, Roberto

    2015-01-01

    A recent phase I clinical trial (SCIPIO) has shown that autologous c-kit+ cardiac progenitor cells (CPCs) improve cardiac function and quality of life when transplanted into patients with ischemic heart disease. Although c-kit is widely used as a marker of resident CPCs, its role in the regulation of the cellular characteristics of CPCs remains unknown. We hypothesized that c-kit plays a role in the survival, growth, and migration of CPCs. To test this hypothesis, human CPCs were grown under stress conditions in the presence or absence of SCF, and the effects of SCF-mediated activation of c-kit on CPC survival/growth and migration were measured. SCF treatment led to a significant increase in cell survival and a reduction in cell death under serum depletion conditions. In addition, SCF significantly promoted CPC migration in vitro. Furthermore, the pro-survival and pro-migratory effects of SCF were augmented by c-kit overexpression and abrogated by c-kit inhibition with imatinib. Mechanistically, c-kit activation in CPCs led to activation of the PI3K and the MAPK pathways. With the use of specific inhibitors, we confirmed that the SCF/c-kit-dependent survival and chemotaxis of CPCs are dependent on both pathways. Taken together, our findings suggest that c-kit promotes the survival/growth and migration of human CPCs cultured ex vivo via the activation of PI3K and MAPK pathways. These results imply that the efficiency of CPC homing to the injury site as well as their survival after transplantation may be improved by modulating the activity of c-kit. PMID:26474484

  16. Cardiac muscle regeneration: lessons from development

    PubMed Central

    Mercola, Mark; Ruiz-Lozano, Pilar; Schneider, Michael D.

    2011-01-01

    The adult human heart is an ideal target for regenerative intervention since it does not functionally restore itself after injury yet has a modest regenerative capacity that could be enhanced by innovative therapies. Adult cardiac cells with regenerative potential share gene expression signatures with early fetal progenitors that give rise to multiple cardiac cell types, suggesting that the evolutionarily conserved regulatory networks that drive embryonic heart development might also control aspects of regeneration. Here we discuss commonalities of development and regeneration, and the application of the rich developmental biology heritage to achieve therapeutic regeneration of the human heart. PMID:21325131

  17. Nuclear Compartmentalization of α1-Adrenergic Receptor Signaling in Adult Cardiac Myocytes

    PubMed Central

    Wu, Steven C.

    2015-01-01

    Abstract: Although convention dictates that G protein-coupled receptors localize to and signal at the plasma membrane, accumulating evidence suggests that G protein-coupled receptors localize to and signal at intracellular membranes, most notably the nucleus. In fact, there is now significant evidence indicating that endogenous alpha-1 adrenergic receptors (α1-ARs) localize to and signal at the nuclei in adult cardiac myocytes. Cumulatively, the data suggest that α1-ARs localize to the inner nuclear membrane, activate intranuclear signaling, and regulate physiologic function in adult cardiac myocytes. Although α1-ARs signal through Gαq, unlike other Gq-coupled receptors, α1-ARs mediate important cardioprotective functions including adaptive/physiologic hypertrophy, protection from cell death (survival signaling), positive inotropy, and preconditioning. Also unlike other Gq-coupled receptors, most, if not all, functional α1-ARs localize to the nuclei in adult cardiac myocytes, as opposed to the sarcolemma. Together, α1-AR nuclear localization and cardioprotection might suggest a novel model for compartmentalization of Gq-coupled receptor signaling in which nuclear Gq-coupled receptor signaling is cardioprotective. PMID:25264754

  18. Interventional and surgical treatment of cardiac arrhythmias in adults with congenital heart disease.

    PubMed

    Koyak, Zeliha; de Groot, Joris R; Mulder, Barbara J M

    2010-12-01

    Arrhythmias are a major cause of morbidity, mortality and hospital admission in adults with congenital heart disease (CHD). The etiology of arrhythmias in this population is often multifactorial and includes electrical disturbances as part of the underlying defect, surgical intervention or hemodynamic abnormalities. Despite the numerous existing arrhythmia management tools including drug therapy, pacing and ablation, management of arrhythmias in adults with CHD remains difficult and challenging. Owing to improvement in mapping and ablation techniques, ablation and arrhythmia surgery are being performed more frequently in adults with CHD. However, there is little information on the long-term results of these treatment strategies. The purpose of this article is therefore to review the available data on nonpharmacological treatment of cardiac arrhythmias in adult patients with CHD and to give an overview of the available data on the early and late outcomes of these treatment strategies.

  19. Hypoxic Preconditioning Inhibits Hypoxia-induced Apoptosis of Cardiac Progenitor Cells via the PI3K/Akt-DNMT1-p53 Pathway

    PubMed Central

    Xu, Rongfeng; Sun, Yuning; Chen, Zhongpu; Yao, Yuyu; Ma, Genshan

    2016-01-01

    Research has demonstrated that hypoxic preconditioning (HP) can enhance the survival and proliferation of cardiac progenitor cells (CPCs); however, the underlying mechanisms are not fully understood. Here, we report that HP of c-kit (+) CPCs inhibits p53 via the PI3K/Akt-DNMT1 pathway. First, CPCs were isolated from the hearts of C57BL/6 mice and further purified by magnetic-activated cell sorting. Next, these cells were cultured under either normoxia (H0) or HP for 6 hours (H6) followed by oxygen–serum deprivation for 24 hours (24h). Flow cytometric analysis and MTT assays revealed that hypoxia-preconditioned CPCs exhibited an increased survival rate. Western blot and quantitative real-time PCR assays showed that p53 was obviously inhibited, while DNMT1 and DNMT3β were both significantly up-regulated by HP. Bisulphite sequencing analysis indicated that DNMT1 and DNMT3β did not cause p53 promoter hypermethylation. A reporter gene assay and chromatin immunoprecipitation analysis further demonstrated that DNMT1 bound to the promoter locus of p53 in hypoxia-preconditioned CPCs. Together, these observations suggest that HP of CPCs could lead to p53 inhibition by up-regulating DNMT1 and DNMT3β, which does not result in p53 promoter hypermethylation, and that DNMT1 might directly repress p53, at least in part, by binding to the p53 promoter locus. PMID:27488808

  20. Gender differences in circulating endothelial progenitor cell colony-forming capacity and migratory activity in middle-aged adults.

    PubMed

    Hoetzer, Greta L; MacEneaney, Owen J; Irmiger, Heather M; Keith, Rebecca; Van Guilder, Gary P; Stauffer, Brian L; DeSouza, Christopher A

    2007-01-01

    Middle-aged women have a lower prevalence and incidence of cardiovascular events compared with men. The mechanisms responsible for this gender-specific difference are unclear. Numeric and functional impairments of bone marrow-derived circulating endothelial progenitor cells (EPCs) are associated with increased cardiovascular and cerebrovascular morbidity and mortality. It is currently unknown whether there are gender-related differences in EPC number and function in middle-aged adults. We tested the hypothesis that EPCs isolated from middle-aged women demonstrate greater colony-forming capacity and migratory activity compared with men of similar age. Peripheral blood samples were collected from 50 sedentary adults, 25 men (59 +/- 1 years of age) and 25 women (58 +/- 1 years of age). Mononuclear cells were isolated and preplated for 2 days, and nonadherent cells were further cultured for 7 days to determine EPC colony-forming units. Migratory activity of EPCs was determined using a modified Boyden chamber. The number of EPC colony-forming units was significantly higher (approximately 150%) in samples collected from women (16 +/- 3) compared with that collected from men (7 +/- 1). In addition, EPC migration (relative fluorescent units) was approximately 40% greater in women (729 +/- 74) than in men (530 +/- 67). In conclusion, these results demonstrate that EPC colony-forming capacity and migratory activity are higher in middle-aged women than in men.

  1. Enhanced genetic modification of adult growth factor mobilized peripheral blood hematopoietic stem and progenitor cells with rapamycin.

    PubMed

    Li, Lijing; Torres-Coronado, Mónica; Gu, Angel; Rao, Anitha; Gardner, Agnes M; Epps, Elizabeth W; Gonzalez, Nancy; Tran, Chy-Anh; Wu, Xiwei; Wang, Jin-Hui; DiGiusto, David L

    2014-10-01

    Genetic modification of adult human hematopoietic stem and progenitor cells (HSPCs) with lentiviral vectors leads to long-term gene expression in the progeny of the HSPCs and has been used to successfully treat several monogenic diseases. In some cases, the gene-modified cells have a selective growth advantage over nonmodified cells and eventually are the dominant engrafted population. However, in disease indications for which the gene-modified cells do not have a selective advantage, optimizing transduction of HSPC is paramount to successful stem cell-based gene therapy. We demonstrate here that transduction of adult CD34+ HSPCs with lentiviral vectors in the presence of rapamycin, a widely used mTORC1 inhibitor, results in an approximately threefold increase in stable gene marking with minimal effects on HSPC growth and differentiation. Using this approach, we have demonstrated that we can enhance the frequency of gene-modified HSPCs that give rise to clonogenic progeny in vitro without excessive increases in the number of vector copies per cell or changes in integration pattern. The genetic marking of HSPCs and expression of transgenes is durable, and transplantation of gene-modified HSPCs into immunodeficient mice results in high levels of gene marking of the lymphoid and myeloid progeny in vivo. The prior safe clinical history of rapamycin in other applications supports the use of this compound to generate gene-modified autologous HSPCs for our HIV gene therapy clinical trials.

  2. C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages.

    PubMed

    Hoeffel, Guillaume; Chen, Jinmiao; Lavin, Yonit; Low, Donovan; Almeida, Francisca F; See, Peter; Beaudin, Anna E; Lum, Josephine; Low, Ivy; Forsberg, E Camilla; Poidinger, Michael; Zolezzi, Francesca; Larbi, Anis; Ng, Lai Guan; Chan, Jerry K Y; Greter, Melanie; Becher, Burkhard; Samokhvalov, Igor M; Merad, Miriam; Ginhoux, Florent

    2015-04-21

    Although classified as hematopoietic cells, tissue-resident macrophages (MFs) arise from embryonic precursors that seed the tissues prior to birth to generate a self-renewing population, which is maintained independently of adult hematopoiesis. Here we reveal the identity of these embryonic precursors using an in utero MF-depletion strategy and fate-mapping of yolk sac (YS) and fetal liver (FL) hematopoiesis. We show that YS MFs are the main precursors of microglia, while most other MFs derive from fetal monocytes (MOs). Both YS MFs and fetal MOs arise from erythro-myeloid progenitors (EMPs) generated in the YS. In the YS, EMPs gave rise to MFs without monocytic intermediates, while EMP seeding the FL upon the establishment of blood circulation acquired c-Myb expression and gave rise to fetal MOs that then seeded embryonic tissues and differentiated into MFs. Thus, adult tissue-resident MFs established from hematopoietic stem cell-independent embryonic precursors arise from two distinct developmental programs.

  3. Cell-permeable p38 MAP kinase promotes migration of adult neural stem/progenitor cells

    PubMed Central

    Hamanoue, Makoto; Morioka, Kazuhito; Ohsawa, Ikuroh; Ohsawa, Keiko; Kobayashi, Masaaki; Tsuburaya, Kayo; Akasaka, Yoshikiyo; Mikami, Tetsuo; Ogata, Toru; Takamatsu, Ken

    2016-01-01

    Endogenous neural stem/progenitor cells (NPCs) can migrate toward sites of injury, but the migration activity of NPCs is insufficient to regenerate damaged brain tissue. In this study, we showed that p38 MAP kinase (p38) is expressed in doublecortin-positive adult NPCs. Experiments using the p38 inhibitor SB203580 revealed that endogenous p38 participates in NPC migration. To enhance NPC migration, we generated a cell-permeable wild-type p38 protein (PTD-p38WT) in which the HIV protein transduction domain (PTD) was fused to the N-terminus of p38. Treatment with PTD-p38WT significantly promoted the random migration of adult NPCs without affecting cell survival or differentiation; this effect depended on the cell permeability and kinase activity of the fusion protein. These findings indicate that PTD-p38WT is a novel and useful tool for unraveling the roles of p38, and that this protein provides a reasonable approach for regenerating the injured brain by enhancing NPC migration. PMID:27067799

  4. High throughput analysis of neural progenitor cell proliferation in adult rodent hippocampus.

    PubMed

    Henry, Sherry; Bigler, Steven; Wang, Junming

    2009-12-01

    Extensive efforts have been made to determine the status on neural progenitor cell proliferation in specific pathological conditions and to evaluate the therapeutic efficacy of drugs for preventing neurogenic deficits in neurodegenerative diseases. However, the most commonly used stereological analysis using 5-bromo-2'-deoxyuridine (BrdU) immuno-positive sections is a time consuming and labor intensive process and is often a bottle neck in neurogenic drug development, particularly when large sample sizes are needed. In addition, BrdU is toxic to new born neurons and also labels DNA damage in old cells. In this study, we established a method that quantitatively measures the number of Ki-67, an endogenous cell proliferation marker, positive cells by flow cytometry which analyzes extracted cell nuclei from rodent hippocampi in suspension. Our results demonstrate that this approach can be applied to a large number of rodent samples, can be accomplished in a short period of time (1-3 days), and can be completed in a more accurately objective manner than by using 3-D cell counting with immunohistochemically processed sections. PMID:20103852

  5. High throughput analysis of neural progenitor cell proliferation in adult rodent hippocampus

    PubMed Central

    Henry, Sherry; Bigler, Steven; Wang, Junming

    2010-01-01

    Summary Extensive efforts have been made to determine the status on neural progenitor cell proliferation in specific pathological conditions and to evaluate the therapeutic efficacy of drugs for preventing neurogenic deficits in neurodegenerative diseases. However, the most commonly used stereological analysis using 5-bromo-2′-deoxyuridine (BrdU) immuno-positive sections is a time consuming and labor intensive process and is often a bottle neck in neurogenic drug development, particularly when large sample sizes are needed. In addition, BrdU is toxic to new born neurons and also labels DNA damage in old cells. In this study, we established a method that quantitatively measures the number of Ki-67, an endogenous cell proliferation marker, positive cells by flow cytometry which analyzes extracted cell nuclei from rodent hippocampi in suspension. Our results demonstrate that this approach can be applied to a large number of rodent samples, can be accomplished in a short period of time (1-3 days), and can be completed in a more accurately objective manner than by using 3-D cell counting with immunohistochemically processed sections. PMID:20103852

  6. [Implementation of post-resuscitation care in adult cardiac arrest patients - Experts' opinion].

    PubMed

    Pellis, Tommaso; Ristagno, Giuseppe; Semeraro, Federico; Grieco, Niccolò; Fabbri, Andrea; Balzanelli, Mario; Berruto, Elisa; Scapigliati, Andrea; Sciretti, Massimiliano; Cerchiari, Erga

    2015-01-01

    Current evidence on post-resuscitation care suffers from important knowledge gaps on new treatments and prognostication, mainly because of the lack of large multicenter randomized trials. However, optimization of post-resuscitation care is crucial, and the establishment of a treatment easy to be accepted and implemented locally, based on currently available evidence, is advisable. The present article is a multisociety experts' opinion on post-cardiac arrest that aims (i) to provide schematic and clear suggestions on therapeutic interventions to be delivered following resuscitation from cardiac arrest, so as to implement local protocols with a standardized post-resuscitation care; (ii) to suggest post-resuscitation therapeutic interventions that may result in improved survival with good neurological recovery, intended as a Cerebral Performance Category (CPC) score of 1-2; and finally (iii) to propose a pragmatic and schematic approach to post-resuscitation care for rapid initiation of intensive treatments (i.e. temperature management). The suggestions reported in this document are intended for adult patients resuscitated from both out-of-hospital and in-hospital cardiac arrest. They should be considered solely as an experts' opinion aimed to improve post-cardiac arrest care and they do not represent an official national guideline.

  7. Perinatal DDT Exposure Induces Hypertension and Cardiac Hypertrophy in Adult Mice

    PubMed Central

    La Merrill, Michele A.; Sethi, Sunjay; Benard, Ludovic; Moshier, Erin; Haraldsson, Borje; Buettner, Christoph

    2016-01-01

    Background: Dichlorodiphenyltrichloroethane (DDT) was used extensively to control malaria, typhus, body lice, and bubonic plague worldwide, until countries began restricting its use in the 1970s. However, the use of DDT to control vector-borne diseases continues in developing countries. Prenatal DDT exposure is associated with elevated blood pressure in humans. Objective: We hypothesized that perinatal DDT exposure causes hypertension in adult mice. Methods: DDT was administered to C57BL/6J dams from gestational day 11.5 to postnatal day 5. Blood pressure (BP) and myocardial wall thickness were measured in male and female adult offspring. Adult mice were treated with an angiotensin converting enzyme (ACE) inhibitor, captopril, to evaluate sensitivity to amelioration of DDT-associated hypertension by ACE inhibition. We further assessed the influence of DDT exposure on the expression of mRNAs that regulate BP through renal ion transport. Results: Adult mice perinatally exposed to DDT exhibited chronically increased systolic BP, increased myocardial wall thickness, and elevated expression of mRNAs of several renal ion transporters. Captopril completely reversed hypertension in mice perinatally exposed to DDT. Conclusions: These data demonstrate that perinatal exposure to DDT causes hypertension and cardiac hypertrophy in adult offspring. A key mechanism underpinning this hypertension is an overactivated renin angiotensin system because ACE inhibition reverses the hypertension induced by perinatal DDT exposure. Citation: La Merrill M, Sethi S, Benard L, Moshier E, Haraldsson B, Buettner C. 2016. Perinatal DDT exposure induces hypertension and cardiac hypertrophy in adult mice. Environ Health Perspect 124:1722–1727; http://dx.doi.org/10.1289/EHP164 PMID:27325568

  8. Invariant natural killer T cells generated from human adult hematopoietic stem-progenitor cells are poly-functional.

    PubMed

    Sun, Wenji; Wang, Yi; East, James E; Kimball, Amy S; Tkaczuk, Katherine; Kesmodel, Susan; Strome, Scott E; Webb, Tonya J

    2015-03-01

    Invariant natural killer T (iNKT) cells constitute an important subset of T cells that can both directly and indirectly mediate anti-tumor immunity. However, cancer patients have a reduction in both iNKT cell number and function, and these deficits limit the potential clinical application of iNKT cells for cancer therapy. To overcome the problem of limited iNKT cell numbers, we investigated whether iNKT cells can be generated in vitro from bone marrow-derived adult hematopoietic stem-progenitor cells (HSPC). Our data demonstrate that co-culture of HSPC with OP9-DL1 stromal cells, results in a functional CD3(+) T cell population. These T cells can be further differentiated into iNKT cells by secondary culture with CD1d-Ig-based artificial antigen-presenting cells (aAPC). Importantly, these in vitro-generated iNKT cells are functional, as demonstrated by their ability to proliferate and secrete IFN-γ and GM-CSF following stimulation. PMID:25569376

  9. Invariant natural killer T cells generated from human adult hematopoietic stem-progenitor cells are poly-functional

    PubMed Central

    Sun, Wenji; Wang, Yi; East, James E.; Kimball, Amy S.; Tkaczuk, Katherine; Kesmodel, Susan; Strome, Scott E.; Webb, Tonya J.

    2014-01-01

    Invariant natural killer T (iNKT) cells constitute an important subset of T cells that can both directly and indirectly mediate anti-tumor immunity. However, cancer patients have a reduction in both iNKT cell number and function, and these deficits limit the potential clinical application of iNKT cells for cancer therapy. To overcome the problem of limited iNKT cell numbers, we investigated whether iNKT cells can be generated in vitro from bone marrow-derived adult hematopoietic stem-progenitor cells (HSPC). Our data demonstrate that co-culture of HSPC with OP9-DL1 stromal cells, results in a functional CD3+ T cell population. These T cells can be further differentiated into iNKT cells by secondary culture with CD1d-Ig-based artificial antigen-presenting cells (aAPC). Importantly, these in vitro-generated iNKT cells are functional, as demonstrated by their ability to proliferate and secrete IFN-γ and GM-CSF following stimulation. PMID:25569376

  10. Suppression of IL-7-dependent Effector T-cell Expansion by Multipotent Adult Progenitor Cells and PGE2.

    PubMed

    Reading, James L; Vaes, Bart; Hull, Caroline; Sabbah, Shereen; Hayday, Thomas; Wang, Nancy S; DiPiero, Anthony; Lehman, Nicholas A; Taggart, Jen M; Carty, Fiona; English, Karen; Pinxteren, Jef; Deans, Robert; Ting, Anthony E; Tree, Timothy I M

    2015-11-01

    T-cell depletion therapy is used to prevent acute allograft rejection, treat autoimmunity and create space for bone marrow or hematopoietic cell transplantation. The evolved response to T-cell loss is a transient increase in IL-7 that drives compensatory homeostatic proliferation (HP) of mature T cells. Paradoxically, the exaggerated form of this process that occurs following lymphodepletion expands effector T-cells, often causing loss of immunological tolerance that results in rapid graft rejection, autoimmunity, and exacerbated graft-versus-host disease (GVHD). While standard immune suppression is unable to treat these pathologies, growing evidence suggests that manipulating the incipient process of HP increases allograft survival, prevents autoimmunity, and markedly reduces GVHD. Multipotent adult progenitor cells (MAPC) are a clinical grade immunomodulatory cell therapy known to alter γ-chain cytokine responses in T-cells. Herein, we demonstrate that MAPC regulate HP of human T-cells, prevent the expansion of Th1, Th17, and Th22 effectors, and block the development of pathogenic allograft responses. This occurs via IL-1β-primed secretion of PGE2 and activates T-cell intrinsic regulatory mechanisms (SOCS2, GADD45A). These data provide proof-of-principle that HP of human T-cells can be targeted by cellular and molecular therapies and lays a basis for the development of novel strategies to prevent immunopathology in lymphodepleted patients. PMID:26216515

  11. Post-Acute Care Services Received by Older Adults Following a Cardiac Event: A Population-Based Analysis

    PubMed Central

    Xu, Fang; Zullo, Melissa; Shishehbor, Mehdi; Moore, Shirley M.; Rimm, Alfred A.

    2010-01-01

    Background Post-acute care (PAC) is available for older adults who need additional services after hospitalization for acute cardiac events. With the aging population and an increase in the prevalence of cardiac disease, it is important to determine current PAC use for cardiac patients to assist health care workers to meet the needs of older cardiac patients. The purpose of this study was to determine the current PAC use and factors associated with PAC use for older adults following hospitalization for a cardiac event that includes coronary artery bypass graph (CABG) and valve surgeries, myocardial infarction (MI), percutaneous coronary intervention (PCI), and heart failure (HF). Methods and Results A cross-sectional design and the 2003 Medicare Part A database were used for this study. The sample (n=1,493,521) consisted of patients aged 65 years and older discharged after their first cardiac event. Multinomial logistic regression was used to examine factors associated with PAC use. Overall, PAC use was 55% for cardiac valve surgery, 50% for MI, 45% for HF, 44% for CABG, and 5% for PCI. Medical patients use more skilled nursing facility care and surgical patients use more home health care. Only 0.1–3.4% of the cardiac patients use intermediate rehabilitation facilities. Compared to those who do not use PAC, those who use home health care and skilled nursing facility care are older, female, have a longer hospital length of stay, and more comorbidity. Asians, Hispanics and Native Americans were less likely to use PAC after hospitalization for an MI or HF. Conclusions The current rate of PAC use indicates that almost half of non-disabled Medicare patients discharged from the hospital following a cardiac event use one of these services. Healthcare professionals can increase PAC use for Asians, Hispanics and Native Americans by including culturally targeted communication. Optimizing recovery for cardiac patients who use PAC may require focused cardiac rehabilitation

  12. Long noncoding RNA H19 mediates melatonin inhibition of premature senescence of c-kit(+) cardiac progenitor cells by promoting miR-675.

    PubMed

    Cai, Benzhi; Ma, Wenya; Bi, Chongwei; Yang, Fan; Zhang, Lai; Han, Zhenbo; Huang, Qi; Ding, Fengzhi; Li, Yuan; Yan, Gege; Pan, Zhenwei; Yang, Baofeng; Lu, Yanjie

    2016-08-01

    Melatonin, a hormone secreted by the pineal gland, possesses multiple biological activities such as antitumor, antioxidant, and anti-ischemia. C-kit(+) cardiac progenitor cells (CPCs) have emerged as a promising tool for the treatment of heart diseases. However, the senescence of CPCs due to pathological stimuli leads to the decline of CPCs' functions and regenerative potential. This study was conducted to demonstrate whether melatonin antagonizes the senescence of CPCs in response to oxidative stress. Here, we found that the melatonin treatment markedly inhibited the senescent characteristics of CPCs after exposed to sublethal concentration of H2 O2 , including the increase in senescence-associated β-galactosidase (SA-β-gal)-positive CPCs, senescence-associated heterochromatin loci (SAHF), secretory IL-6 level, and the upregulation of p53 and p21 proteins. Senescence-associated proliferation reduction was also attenuated by melatonin in CPCs. Luzindole, the melatonin membrane receptor blocker, may block the melatonin-mediated suppression of premature senescence in CPCs. Interestingly, we found that long noncoding RNA H19 and its derived miR-675 were downregulated by H2 O2 in CPCs, but melatonin treatment could counter this alteration. Furthermore, knockdown of H19 or miR-675 blocked antisenescence actions of melatonin on H2 O2 -treated CPCs. It was further verified that H19-derived miR-675 targeted at the 3'UTR of USP10, which resulted in the downregulation of p53 and p21 proteins. In summary, melatonin antagonized premature senescence of CPCs via H19/miR-675/USP10 pathway, which provides new insights into pharmacological actions and potential applications of melatonin on the senescence of CPCs.

  13. Adherence to lifestyle modifications after a cardiac rehabilitation program and endothelial progenitor cells. A six-month follow-up study.

    PubMed

    Cesari, F; Marcucci, R; Gori, A M; Burgisser, C; Francini, S; Roberts, A T; Sofi, F; Gensini, G F; Abbate, R; Fattirolli, F

    2014-07-01

    An increase of endothelial progenitor cells (EPCs) among acute myocardial infarction (AMI) patients participating in a cardiac rehabilitation (CR) program has been reported, but no data on the impact of adherence to lifestyle recommendations provided during a CR program on EPCs are available. It was our aim to investigate the effect of adherence to lifestyle recommendations on EPCs, inflammatory and functional parameters after six months of a CR program in AMI patients. In 110 AMI patients (90 male/20 female; mean age 57.9 ± 9.4 years) EPCs, high sensitivity C-reactive protein (hsCRP), N-terminal pro-brain natriuretic peptide (NT-ProBNP) levels, and cardiopulmonary testings were determined at the end of the CR (T1) and at a six-month follow-up (T2). At T2 we administered a questionnaire assessing dietary habits and physical activity. At T2, we observed a decrease of EPCs (p<0.05), of hsCRP (p=0.009) and of NT-ProBNP (p<0.0001). Patient population was divided into three categories by Healthy Lifestyle (HL) score (none/low, moderate and high adherence to lifestyle recommendations). We observed a significant association between adherence to lifestyle recommendations, increase in EPCs and exercise capacity between T1 and T2 (Δ EPCs p for trend <0.05; ΔWatt max p for trend=0.004). In a multivariate logistic regression analyses, being in the highest tertile of HL score affected the likelihood of an increase of EPC levels at T2 [OR (95% confidence interval): 3.36 (1.0-10.72) p=0.04]. In conclusion, adherence to lifestyle recommendations provided during a CR program positively influences EPC levels and exercise capacity.

  14. Sleep Disruption is Associated with Increased Ventricular Ectopy and Cardiac Arrest in Hospitalized Adults

    PubMed Central

    Miner, Steven Edward Stuart; Pahal, Dev; Nichols, Laurel; Darwood, Amanda; Nield, Lynne Elizabeth; Wulffhart, Zaev

    2016-01-01

    Study Objectives: To determine whether sleep disruption increases ventricular ectopy and the risk of cardiac arrest in hospitalized patients. Methods: Hospital emergency codes (HEC) trigger multiple hospital-wide overhead announcements. In 2014 an electronic “code white” program was instituted to protect staff from violent patients. This resulted in an increase in nocturnal HEC. Telemetry data was examined between September 14 and October 2, 2014. The frequency of nocturnal announcements was correlated with changes in frequency of premature ventricular complexes per hour (PVC/h). Cardiac arrest data were examined over a 3-y period. All HEC were assumed to have triggered announcements. The relationship between nocturnal HEC and the incidence of subsequent cardiac arrest was examined. Results: 2,603 hours of telemetry were analyzed in 87 patients. During nights with two or fewer announcements, PVC/h decreased 33% and remained 30% lower the next day. On nights with four or more announcements, PVC/h increased 23% (P < 0.001) and further increased 85% the next day (P = 0.001). In 2014, following the introduction of the code white program, the frequency of all HEC increased from 1.1/day to 6.2/day (P < 0.05). The frequency of cardiac arrest/24 h rose from 0.46/day in 2012–2013 to 0.62/day in 2014 (P = 0.001). During daytime hours (06:00–22:00), from 2012 through 2014, the frequency of cardiac arrest following zero, one or at least two nocturnal HEC were 0.331 ± 0.03, 0.396 ± 0.04 and 0.471 ± 0.09 respectively (R2 = 0.99, P = 0.03). Conclusions: Sleep disruption is associated with increased ventricular ectopy and increased frequency of cardiac arrest. Citation: Miner SE, Pahal D, Nichols L, Darwood A, Nield LE, Wulffart Z. Sleep disruption is associated with increased ventricular ectopy and cardiac arrest in hospitalized adults. SLEEP 2016;39(4):927–935. PMID:26715226

  15. Cardiac side population cells and Sca-1-positive cells.

    PubMed

    Nagai, Toshio; Matsuura, Katsuhisa; Komuro, Issei

    2013-01-01

    Since the resident cardiac stem/progenitor cells were discovered, their ability to maintain the architecture and functional integrity of adult heart has been broadly explored. The methods for isolation and purification of the cardiac stem cells are crucial for the precise analysis of their developmental origin and intrinsic potential as tissue stem cells. Stem cell antigen-1 (Sca-1) is one of the useful cell surface markers to purify the cardiac progenitor cells. Another purification strategy is based on the high efflux ability of the dye, which is a common feature of tissue stem cells. These dye-extruding cells have been called side population cells because they locate in the side of dye-retaining cells after fluorescent cell sorting. In this chapter, we describe the methodology for the isolation of cardiac SP cells and Sca-1 positive cells.

  16. Endometrial adult/progenitor stem cells: pathogenetic theory and new antiangiogenic approach for endometriosis therapy.

    PubMed

    Pittatore, G; Moggio, A; Benedetto, C; Bussolati, B; Revelli, A

    2014-03-01

    The cyclical arrival of endometrial cells into the abdominal cavity through retrograde flux at menstruation represents the etiopathogenetic basis of endometriosis. The endometrium has peculiar regenerative properties linked to the presence of adult stem cells similar to mesenchymal stem cells (MSCs). Once in the abdominal cavity, these MSCs could proliferate, invade, and differentiate into endometrial cells, finally generating ectopic implants. As only differentiated endometrial cells, and not endometrial MSCs, possess steroid hormone receptors, MSCs could be responsible for the high rate of persistence/recurrence of the disease after hypoestrogenism-inducing therapies. Even angiogenesis promoted by MSCs could play an important role, as survival and proliferation of endometriotic tissue depend on the formation of new blood vessels. Inhibition of angiogenesis represents, in fact, a new, promising therapeutic approach for the disease. Further, medications directly targeting endometriosis MSCs could be effective, alone or in association with hormonal treatments, in increasing the success of medical treatment.

  17. Prenatal cocaine exposure alters progenitor cell markers in the subventricular zone of the adult rat brain

    PubMed Central

    Patel, Dhyanesh Arvind; Booze, Rosemarie M.; Mactutus, Charles F.

    2013-01-01

    Long-term consequences of early developmental exposure to drugs of abuse may have deleterious effects on the proliferative plasticity of the brain. The purpose of this study was to examine the long-term effects of prenatal exposure to cocaine, using the IV route of administration and doses that mimic the peak arterial levels of cocaine use in humans, on the proliferative cell types of the subventricular zones (SVZ) in the adult (180 days-old) rat brain. Employing immunocytochemistry, the expression of GFAP+ (type B cells) and nestin+(GFAP−) (Type C and A cells) staining was quantified in the subcallosal area of the SVZ. GFAP+ expression was significantly different between the prenatal cocaine treated group and the vehicle (saline) control group. The prenatal cocaine treated group possessed significantly lower GFAP+ expression relative to the vehicle control group, suggesting that prenatal cocaine exposure significantly reduced the expression of type B neural stem cells of the SVZ. In addition, there was a significant sex difference in nestin+ expression with females showing approximately 8–13% higher nestin+ expression compared to the males. More importantly, a significant prenatal treatment condition (prenatal cocaine, control) by sex interaction in nestin+ expression was confirmed, indicating different effects of cocaine based on sex of the animal. Specifically, prenatal cocaine exposure eliminated the basal difference between the sexes. Collectively, the present findings suggest that prenatal exposure to cocaine, when delivered via a protocol designed to capture prominent features of recreational usage, can selectively alter the major proliferative cell types in the subcallosal area of the SVZ in an adult rat brain, and does so differently for males and females. PMID:22119286

  18. Applying the Gender Lens to Risk Factors and Outcome after Adult Cardiac Surgery

    PubMed Central

    Eifert, Sandra; Guethoff, Sonja; Kaczmarek, Ingo; Beiras-Fernandez, Andres; Seeland, Ute; Gulbins, Helmut; Seeburger, Jörg; Deutsch, Oliver; Jungwirth, Bettina; Katsari, Elpiniki; Dohmen, Pascal; Pfannmueller, Bettina; Hultgren, Rebecka; Schade, Ina; Kublickiene, Karolina; Mohr, Friedrich W.; Gansera, Brigitte

    2014-01-01

    Summary Background Applying the gender lens to risk factors and outcome after adult cardiac surgery is of major clinical interest, as the inclusion of sex and gender in research design and analysis may guarantee more comprehensive cardiovascular science and may consecutively result in a more effective surgical treatment as well as cost savings in cardiac surgery. Methods We have reviewed classical cardiovascular risk factors (diabetes, arterial hypertension, hyperlipidemia, smoking) according to a gender-based approach. Furthermore, we have examined comorbidities such as depression, renal insufficiency, and hormonal influences in regard to gender. Gender-sensitive economic aspects have been evaluated, surgical outcome has been analyzed, and cardiovascular research has been considered from a gender perspective. Results The influence of typical risk factors and outcome after cardiac surgery has been evaluated from a gender perspective, and the gender-specific distribution of these risk factors is reported on. The named comorbidities are listed. Economic aspects demonstrated a gender gap. Outcome after coronary and valvular surgeries as well as after heart transplantation are displayed in this regard. Results after postoperative use of intra-aortic balloon pump are shown. Gender-related aspects of clinical and biomedical cardiosurgical research are reported. Conclusions Female gender has become an independent risk factor of survival after the majority of cardiosurgical procedures. Severely impaired left ventricular ejection fraction independently predicts survival in men, whereas age does in females. PMID:26288584

  19. Minimally invasive cardiac surgery in the adult: surgical instruments, equipment, and techniques.

    PubMed

    Kitamura, M; Uwabe, K; Hirota, J; Kawai, A; Endo, M; Koyanagi, H

    1998-09-01

    To clarify the special instruments and equipment used for minimally invasive cardiac surgery (MICS), we examined the initial experiences with MICS operations with ministernotomy or minithoracotomy at our institution. Fifty adult patients with congenital, valvular, and/or ischemic heart diseases underwent MICS operations, and all surgical procedures were completed without conversion to full sternotomy. The length of the skin incision was about 10 cm or less in all patients. Postoperative recovery was favorable, and the majority of the patients were discharged from the hospital around the end of the second postoperative week. In this series of patients, an oscillating bone saw, lifting type retractor, 2 blade spreader, cannula with a balloon, and right-angled aortic clamp among other items, were very useful for successfully performing various operations with MICS approaches and techniques. The associated results suggest that MICS with ministernotomy or minithoracotomy was feasible using special instruments and equipment and could be encouraged for adult patients with various cardiovascular diseases.

  20. Natural ECM as biomaterial for scaffold based cardiac regeneration using adult bone marrow derived stem cells.

    PubMed

    Sreejit, P; Verma, R S

    2013-04-01

    Cellular therapy using stem cells for cardiac diseases has recently gained much interest in the scientific community due to its potential in regenerating damaged and even dead tissue and thereby restoring the organ function. Stem cells from various sources and origin are being currently used for regeneration studies directly or along with differentiation inducing agents. Long term survival and minimal side effects can be attained by using autologous cells and reduced use of inducing agents. Cardiomyogenic differentiation of adult derived stem cells has been previously reported using various inducing agents but the use of a potentially harmful DNA demethylating agent 5-azacytidine (5-azaC) has been found to be critical in almost all studies. Alternate inducing factors and conditions/stimulant like physical condition including electrical stimulation, chemical inducers and biological agents have been attempted by numerous groups to induce cardiac differentiation. Biomaterials were initially used as artificial scaffold in in vitro studies and later as a delivery vehicle. Natural ECM is the ideal biological scaffold since it contains all the components of the tissue from which it was derived except for the living cells. Constructive remodeling can be performed using such natural ECM scaffolds and stem cells since, the cells can be delivered to the site of infraction and once delivered the cells adhere and are not "lost". Due to the niche like conditions of ECM, stem cells tend to differentiate into tissue specific cells and attain several characteristics similar to that of functional cells even in absence of any directed differentiation using external inducers. The development of niche mimicking biomaterials and hybrid biomaterial can further advance directed differentiation without specific induction. The mechanical and electrical integration of these materials to the functional tissue is a problem to be addressed. The search for the perfect extracellular matrix for

  1. Analysis of neural progenitors from embryogenesis to juvenile adult in Xenopus laevis reveals biphasic neurogenesis and continuous lengthening of the cell cycle.

    PubMed

    Thuret, Raphaël; Auger, Hélène; Papalopulu, Nancy

    2015-11-30

    Xenopus laevis is a prominent model system for studying neural development, but our understanding of the long-term temporal dynamics of neurogenesis remains incomplete. Here, we present the first continuous description of neurogenesis in X. laevis, covering the entire period of development from the specification of neural ectoderm during gastrulation to juvenile frog. We have used molecular markers to identify progenitors and neurons, short-term bromodeoxyuridine (BrdU) incorporation to map the generation of newborn neurons and dual pulse S-phase labelling to characterise changes in their cell cycle length. Our study revealed the persistence of Sox3-positive progenitor cells from the earliest stages of neural development through to the juvenile adult. Two periods of intense neuronal generation were observed, confirming the existence of primary and secondary waves of neurogenesis, punctuated by a period of quiescence before metamorphosis and culminating in another period of quiescence in the young adult. Analysis of multiple parameters indicates that neural progenitors alternate between global phases of differentiation and amplification and that, regardless of their behaviour, their cell cycle lengthens monotonically during development, at least at the population level.

  2. Analysis of neural progenitors from embryogenesis to juvenile adult in Xenopus laevis reveals biphasic neurogenesis and continuous lengthening of the cell cycle

    PubMed Central

    Thuret, Raphaël; Auger, Hélène; Papalopulu, Nancy

    2015-01-01

    ABSTRACT Xenopus laevis is a prominent model system for studying neural development, but our understanding of the long-term temporal dynamics of neurogenesis remains incomplete. Here, we present the first continuous description of neurogenesis in X. laevis, covering the entire period of development from the specification of neural ectoderm during gastrulation to juvenile frog. We have used molecular markers to identify progenitors and neurons, short-term bromodeoxyuridine (BrdU) incorporation to map the generation of newborn neurons and dual pulse S-phase labelling to characterise changes in their cell cycle length. Our study revealed the persistence of Sox3-positive progenitor cells from the earliest stages of neural development through to the juvenile adult. Two periods of intense neuronal generation were observed, confirming the existence of primary and secondary waves of neurogenesis, punctuated by a period of quiescence before metamorphosis and culminating in another period of quiescence in the young adult. Analysis of multiple parameters indicates that neural progenitors alternate between global phases of differentiation and amplification and that, regardless of their behaviour, their cell cycle lengthens monotonically during development, at least at the population level. PMID:26621828

  3. Intravenous multipotent adult progenitor cell therapy attenuates activated microglial/macrophage response and improves spatial learning after traumatic brain injury.

    PubMed

    Bedi, Supinder S; Hetz, Robert; Thomas, Chelsea; Smith, Philippa; Olsen, Alex B; Williams, Stephen; Xue, Hasen; Aroom, Kevin; Uray, Karen; Hamilton, Jason; Mays, Robert W; Cox, Charles S

    2013-12-01

    We previously demonstrated that the intravenous delivery of multipotent adult progenitor cells (MAPCs) after traumatic brain injury (TBI) in rodents provides neuroprotection by preserving the blood-brain barrier and systemically attenuating inflammation in the acute time frame following cell treatment; however, the long-term behavioral and anti-inflammatory effects of MAPC administration after TBI have yet to be explored. We hypothesized that the intravenous injection of MAPCs after TBI attenuates the inflammatory response (as measured by microglial morphology) and improves performance at motor tasks and spatial learning (Morris water maze [MWM]). MAPCs were administered intravenously 2 and 24 hours after a cortical contusion injury (CCI). We tested four groups at 120 days after TBI: sham (uninjured), injured but not treated (CCI), and injured and treated with one of two concentrations of MAPCs, either 2 million cells per kilogram (CCI-2) or 10 million cells per kilogram (CCI-10). CCI-10 rats showed significant improvement in left hind limb deficit on the balance beam. On the fifth day of MWM trials, CCI-10 animals showed a significant decrease in both latency to platform and distance traveled compared with CCI. Probe trials revealed a significant decrease in proximity measure in CCI-10 compared with CCI, suggesting improved memory retrieval. Neuroinflammation was quantified by enumerating activated microglia in the ipsilateral hippocampus. We observed a significant decrease in the number of activated microglia in the dentate gyrus in CCI-10 compared with CCI. Our results demonstrate that intravenous MAPC treatment after TBI in a rodent model offers long-term improvements in spatial learning as well as attenuation of neuroinflammation.

  4. Adolescents and adults differ in the immediate and long-term impact of nicotine administration and withdrawal on cardiac norepinephrine.

    PubMed

    Slotkin, Theodore A; Stadler, Ashley; Skavicus, Samantha; Seidler, Frederic J

    2016-04-01

    Cardiovascular responses to smoking cessation may differ in adolescents compared to adults. We administered nicotine by osmotic minipump infusion for 17 days to adolescent and adult rats (30 and 90 days of age, respectively) and examined cardiac norepinephrine levels during treatment, after withdrawal, and for months after cessation. In adults, nicotine evoked a significant elevation of cardiac norepinephrine and a distinct spike upon withdrawal, after which the levels returned to normal; the effect was specific to males. In contrast, adolescents did not show significant changes during nicotine treatment or in the immediate post-withdrawal period. However, beginning in young adulthood, males exposed to adolescent nicotine showed sustained elevations of cardiac norepinephrine, followed by later-emerging deficits that persisted through six months of age. We then conducted adolescent exposure using twice-daily injections, a regimen that augments stress associated with inter-dose withdrawal episodes. With the injection route, adolescents showed an enhanced cardiac norepinephrine response, reinforcing the relationship between withdrawal stress and a surge in cardiac norepinephrine levels. The relative resistance of adolescents to the acute nicotine withdrawal response is likely to make episodic nicotine exposure less stressful or aversive than in adults. Equally important, the long-term changes after adolescent nicotine exposure resemble those known to be associated with risk of hypertension in young adulthood (elevated norepinephrine) or subsequent congestive heart disease (norepinephrine deficits). Our findings reinforce the unique responses and consequences of nicotine exposure in adolescence, the period in which most smokers commence tobacco use. PMID:26993795

  5. cap alpha. -skeletal and. cap alpha. -cardiac actin genes are coexpressed in adult human skeletal muscle and heart

    SciTech Connect

    Gunning, P.; Ponte, P.; Blau, H.; Kedes, L.

    1983-11-01

    The authors determined the actin isotypes encoded by 30 actin cDNA clones previously isolated from an adult human muscle cDNA library. Using 3' untranslated region probes, derived from ..cap alpha.. skeletal, ..beta..- and ..gamma..-actin cDNAs and from an ..cap alpha..-cardiac actin genomic clone, they showed that 28 of the cDNAs correspond to ..cap alpha..-skeletal actin transcripts. Unexpectedly, however, the remaining two cDNA clones proved to derive from ..cap alpha..-cardiac actin mRNA. Sequence analysis confirmed that the two skeletal muscle ..cap alpha..-cardiac actin cDNAs are derived from transcripts of the cloned ..cap alpha..-cardiac actin gene. Comparison of total actin mRNA levels in adult skeletal muscle and adult heart revealed that the steady-state levels in skeletal muscle are about twofold greater, per microgram of total cellular RNA, than those in heart. Thus, in skeletal muscle and in heart, both of the sarcomeric actin mRNA isotypes are quite abundant transcripts. They conclude that ..cap alpha..-skeletal and ..cap alpha..-cardiac actin genes are coexpressed as an actin pair in human adult striated muscles. Since the smooth-muscle actins (aortic and stomach) and the cytoplasmic actins (..beta.. and ..gamma..) are known to be coexpressed in smooth muscle and nonmuscle cells, respectively, they postulate that coexpression of actin pairs may be a common feature of mammalian actin gene expression in all tissues.

  6. Disruption of Ah Receptor Signaling during Mouse Development Leads to Abnormal Cardiac Structure and Function in the Adult

    PubMed Central

    Carreira, Vinicius S.; Fan, Yunxia; Kurita, Hisaka; Wang, Qin; Ko, Chia-I; Naticchioni, Mindi; Jiang, Min; Koch, Sheryl; Zhang, Xiang; Biesiada, Jacek; Medvedovic, Mario; Xia, Ying; Rubinstein, Jack; Puga, Alvaro

    2015-01-01

    The Developmental Origins of Health and Disease (DOHaD) Theory proposes that the environment encountered during fetal life and infancy permanently shapes tissue physiology and homeostasis such that damage resulting from maternal stress, poor nutrition or exposure to environmental agents may be at the heart of adult onset disease. Interference with endogenous developmental functions of the aryl hydrocarbon receptor (AHR), either by gene ablation or by exposure in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AHR ligand, causes structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. To test if embryonic effects progress into an adult phenotype, we investigated whether Ahr ablation or TCDD exposure in utero resulted in cardiac abnormalities in adult mice long after removal of the agent. Ten-months old adult Ahr-/- and in utero TCDD-exposed Ahr+/+ mice showed sexually dimorphic abnormal cardiovascular phenotypes characterized by echocardiographic findings of hypertrophy, ventricular dilation and increased heart weight, resting heart rate and systolic and mean blood pressure, and decreased exercise tolerance. Underlying these effects, genes in signaling networks related to cardiac hypertrophy and mitochondrial function were differentially expressed. Cardiac dysfunction in mouse embryos resulting from AHR signaling disruption seems to progress into abnormal cardiac structure and function that predispose adults to cardiac disease, but while embryonic dysfunction is equally robust in males and females, the adult abnormalities are more prevalent in females, with the highest severity in Ahr-/- females. The findings reported here underscore the conclusion that AHR signaling in the developing heart is one potential target of environmental factors associated with cardiovascular disease. PMID:26555816

  7. Environmental Ligands of the Aryl Hydrocarbon Receptor and Their Effects in Models of Adult Liver Progenitor Cells

    PubMed Central

    Vondráček, Jan; Machala, Miroslav

    2016-01-01

    The toxicity of environmental and dietary ligands of the aryl hydrocarbon receptor (AhR) in mature liver parenchymal cells is well appreciated, while considerably less attention has been paid to their impact on cell populations exhibiting phenotypic features of liver progenitor cells. Here, we discuss the results suggesting that the consequences of the AhR activation in the cellular models derived from bipotent liver progenitors could markedly differ from those in hepatocytes. In contact-inhibited liver progenitor cells, the AhR agonists induce a range of effects potentially linked with tumor promotion. They can stimulate cell cycle progression/proliferation and deregulate cell-to-cell communication, which is associated with downregulation of proteins forming gap junctions, adherens junctions, and desmosomes (such as connexin 43, E-cadherin, β-catenin, and plakoglobin), as well as with reduced cell adhesion and inhibition of intercellular communication. At the same time, toxic AhR ligands may affect the activity of the signaling pathways contributing to regulation of liver progenitor cell activation and/or differentiation, such as downregulation of Wnt/β-catenin and TGF-β signaling, or upregulation of transcriptional targets of YAP/TAZ, the effectors of Hippo signaling pathway. These data illustrate the need to better understand the potential role of liver progenitors in the AhR-mediated liver carcinogenesis and tumor promotion. PMID:27274734

  8. Environmental Ligands of the Aryl Hydrocarbon Receptor and Their Effects in Models of Adult Liver Progenitor Cells.

    PubMed

    Vondráček, Jan; Machala, Miroslav

    2016-01-01

    The toxicity of environmental and dietary ligands of the aryl hydrocarbon receptor (AhR) in mature liver parenchymal cells is well appreciated, while considerably less attention has been paid to their impact on cell populations exhibiting phenotypic features of liver progenitor cells. Here, we discuss the results suggesting that the consequences of the AhR activation in the cellular models derived from bipotent liver progenitors could markedly differ from those in hepatocytes. In contact-inhibited liver progenitor cells, the AhR agonists induce a range of effects potentially linked with tumor promotion. They can stimulate cell cycle progression/proliferation and deregulate cell-to-cell communication, which is associated with downregulation of proteins forming gap junctions, adherens junctions, and desmosomes (such as connexin 43, E-cadherin, β-catenin, and plakoglobin), as well as with reduced cell adhesion and inhibition of intercellular communication. At the same time, toxic AhR ligands may affect the activity of the signaling pathways contributing to regulation of liver progenitor cell activation and/or differentiation, such as downregulation of Wnt/β-catenin and TGF-β signaling, or upregulation of transcriptional targets of YAP/TAZ, the effectors of Hippo signaling pathway. These data illustrate the need to better understand the potential role of liver progenitors in the AhR-mediated liver carcinogenesis and tumor promotion.

  9. Dynamic Measurement of Hemodynamic Parameters and Cardiac Preload in Adults with Dengue: A Prospective Observational Study

    PubMed Central

    Thanachartwet, Vipa; Wattanathum, Anan; Sahassananda, Duangjai; Wacharasint, Petch; Chamnanchanunt, Supat; Khine Kyaw, Ei; Jittmittraphap, Akanitt; Naksomphun, Mali; Surabotsophon, Manoon; Desakorn, Varunee

    2016-01-01

    Few previous studies have monitored hemodynamic parameters to determine the physiological process of dengue or examined inferior vena cava (IVC) parameters to assess cardiac preload during the clinical phase of dengue. From January 2013 to July 2015, we prospectively studied 162 hospitalized adults with confirmed dengue viral infection using non-invasive cardiac output monitoring and bedside ultrasonography to determine changes in hemodynamic and IVC parameters and identify the types of circulatory shock that occur in patients with dengue. Of 162 patients with dengue, 17 (10.5%) experienced dengue shock and 145 (89.5%) did not. In patients with shock, the mean arterial pressure was significantly lower on day 6 after fever onset (P = 0.045) and the pulse pressure was significantly lower between days 4 and 7 (P<0.05). The stroke volume index and cardiac index were significantly decreased between days 4 and 15 and between days 5 and 8 after fever onset (P<0.05), respectively. A significant proportion of patients with dengue shock had an IVC diameter <1.5 cm and IVC collapsibility index >50% between days 4 and 5 (P<0.05). Hypovolemic shock was observed in 9 (52.9%) patients and cardiogenic shock in 8 (47.1%), with a median (interquartile range) time to shock onset of 6.0 (5.0–6.5) days after fever onset, which was the median day of defervescence. Intravascular hypovolemia occurred before defervescence, whereas myocardial dysfunction occurred on the day of defervescence until 2 weeks after fever onset. Hypovolemic shock and cardiogenic shock each occurred in approximately half of the patients with dengue shock. Therefore, dynamic measures to estimate changes in hemodynamic parameters and preload should be monitored to ensure adequate fluid therapy among patients with dengue, particularly patients with dengue shock. PMID:27196051

  10. Plasma Fatty Acid Binding Protein 4 and Risk of Sudden Cardiac Death in Older Adults

    PubMed Central

    Djoussé, Luc; Maziarz, Marlena; Biggs, Mary L.; Ix, Joachim H.; Zieman, Susan J.; Kizer, Jorge R.; Lemaitre, Rozenn N.; Mozaffarian, Dariush; Tracy, Russell P.; Mukamal, Kenneth J.; Siscovick, David S.; Sotoodehnia, Nona

    2013-01-01

    Although fatty acid binding protein 4 (FABP4) may increase risk of diabetes and exert negative cardiac inotropy, it is unknown whether plasma concentrations of FABP4 are associated with incidence of sudden cardiac death (SCD). We prospectively analyzed data on 4,560 participants of the Cardiovascular Health Study. FABP4 was measured at baseline using ELISA, and SCD events were adjudicated through review of medical records. We used Cox proportional hazards to estimate effect measures. During a median followup of 11.8 years, 146 SCD cases occurred. In a multivariable model adjusting for demographic, lifestyle, and metabolic factors, relative risk of SCD associated with each higher standard deviation (SD) of plasma FABP4 was 1.15 (95% CI: 0.95–1.38), P = 0.15. In a secondary analysis stratified by prevalent diabetes status, FABP4 was associated with higher risk of SCD in nondiabetic participants, (RR per SD higher FABP4: 1.33 (95% CI: 1.07–1.65), P = 0.009) but not in diabetic participants (RR per SD higher FABP4: 0.88 (95% CI: 0.62–1.27), P = 0.50), P for diabetes-FABP4 interaction 0.049. In summary, a single measure of plasma FABP4 obtained later in life was not associated with the risk of SCD in older adults overall. Confirmation of our post-hoc results in nondiabetic people in other studies is warranted. PMID:24455402

  11. Adult stem cells for cardiac repair: a choice between skeletal myoblasts and bone marrow stem cells.

    PubMed

    Ye, Lei; Haider, Husnain Kh; Sim, Eugene K W

    2006-01-01

    The real promise of a stem cell-based approach for cardiac regeneration and repair lies in the promotion of myogenesis and angiogenesis at the site of the cell graft to achieve both structural and functional benefits. Despite all of the progress and promise in this field, many unanswered questions remain; the answers to these questions will provide the much-needed breakthrough to harness the real benefits of cell therapy for the heart in the clinical perspective. One of the major issues is the choice of donor cell type for transplantation. Multiple cell types with varying potentials have been assessed for their ability to repopulate the infarcted myocardium; however, only the adult stem cells, that is, skeletal myoblasts (SkM) and bone marrow-derived stem cells (BMC), have been translated from the laboratory bench to clinical use. Which of these two cell types will provide the best option for clinical application in heart cell therapy remains arguable. With results pouring in from the long-term follow-ups of previously conducted phase I clinical studies, and with the onset of phase II clinical trials involving larger population of patients, transplantation of stem cells as a sole therapy without an adjunct conventional revascularization procedure will provide a deeper insight into the effectiveness of this approach. The present article discusses the pros and cons of using SkM and BMC individually or in combination for cardiac repair, and critically analyzes the progress made with each cell type.

  12. VGF (TLQP-62)-induced neurogenesis targets early phase neural progenitor cells in the adult hippocampus and requires glutamate and BDNF signaling.

    PubMed

    Thakker-Varia, Smita; Behnke, Joseph; Doobin, David; Dalal, Vidhi; Thakkar, Keya; Khadim, Farah; Wilson, Elizabeth; Palmieri, Alicia; Antila, Hanna; Rantamaki, Tomi; Alder, Janet

    2014-05-01

    The neuropeptide VGF (non-acronymic), which has antidepressant-like effects, enhances adult hippocampal neurogenesis as well as synaptic activity and plasticity in the hippocampus, however the interaction between these processes and the mechanism underlying this regulation remain unclear. In this study, we demonstrate that VGF-derived peptide TLQP-62 specifically enhances the generation of early progenitor cells in nestin-GFP mice. Specifically, TLQP-62 significantly increases the number of Type 2a neural progenitor cells (NPCs) while reducing the number of more differentiated Type 3 cells. The effect of TLQP-62 on proliferation rather than differentiation was confirmed using NPCs in vitro; TLQP-62 but not scrambled peptide PEHN-62 increases proliferation in a cell line as well as in primary progenitors from adult hippocampus. Moreover, TLQP-62 but not scrambled peptide increases Cyclin D mRNA expression. The proliferation of NPCs induced by TLQP-62 requires synaptic activity, in particular through NMDA and metabotropic glutamate receptors. The activation of glutamate receptors by TLQP-62 activation induces phosphorylation of CaMKII through NMDA receptors and protein kinase D through metabotropic glutamate receptor 5 (mGluR5). Furthermore, pharmacological antagonists to CaMKII and PKD inhibit TLQP-62-induced proliferation of NPCs indicating that these signaling molecules downstream of glutamate receptors are essential for the actions of TLQP-62 on neurogenesis. We also show that TLQP-62 gradually activates Brain-Derived Neurotrophic Factor (BDNF)-receptor TrkB in vitro and that Trk signaling is required for TLQP-62-induced proliferation of NPCs. Understanding the precise molecular mechanism of how TLQP-62 influences neurogenesis may reveal mechanisms by which VGF-derived peptides act as antidepressant-like agents.

  13. Repair of liver mediated by adult mouse liver neuro-glia antigen 2-positive progenitor cell transplantation in a mouse model of cirrhosis

    PubMed Central

    Zhang, Hongyu; Siegel, Christopher T.; Shuai, Ling; Lai, Jiejuan; Zeng, Linli; Zhang, Yujun; Lai, Xiangdong; Bie, Ping; Bai, Lianhua

    2016-01-01

    NG2-expressing cells are a population of periportal vascular stem/progenitors (MLpvNG2+ cells) that were isolated from healthy adult mouse liver by using a “Percoll-Plate-Wait” procedure. We demonstrated that isolated cells are able to restore liver function after transplantation into a cirrhotic liver, and co-localized with the pericyte marker (immunohistochemistry: PDGFR-β) and CK19. Cells were positive for: stem cell (Sca-1, CD133, Dlk) and liver stem cell markers (EpCAM, CD14, CD24, CD49f); and negative for: hematopoietic (CD34, CD45) and endothelial markers (CD31, vWf, von Willebrand factor). Cells were transplanted (1 × 106 cells) in mice with diethylnitrosamine-induced cirrhosis at week 6. Cells showed increased hepatic associated gene expression of alpha-fetoprotein (AFP), Albumin (Alb), Glucose-6-phosphatase (G6Pc), SRY (sex determining region Y)-box 9 (Sox9), hepatic nuclear factors (HNF1a, HNF1β, HNF3β, HNF4α, HNF6, Epithelial cell adhesion molecule (EpCAM), Leucine-rich repeated-containing G-protein coupled receptor 5-positive (Lgr5) and Tyrosine aminotransferase (TAT). Cells showed decreased fibrogenesis, hepatic stellate cell infiltration, Kupffer cells and inflammatory cytokines. Liver function markers improved. In a cirrhotic liver environment, cells could differentiate into hepatic lineages. In addition, grafted MLpvNG2+ cells could mobilize endogenous stem/progenitors to participate in liver repair. These results suggest that MLpvNG2+ cells may be novel adult liver progenitors that participate in liver regeneration. PMID:26905303

  14. RE1 silencing transcription factor/neuron-restrictive silencing factor regulates expansion of adult mouse subventricular zone-derived neural stem/progenitor cells in vitro.

    PubMed

    Soldati, Chiara; Caramanica, Pasquale; Burney, Matthew J; Toselli, Camilla; Bithell, Angela; Augusti-Tocco, Gabriella; Stanton, Lawrence W; Biagioni, Stefano; Buckley, Noel J; Cacci, Emanuele

    2015-08-01

    Adult neural stem cell (aNSC) activity is tuned by external stimuli through the recruitment of transcription factors. This study examines the RE1 silencing transcription factor (REST) in neural stem/progenitor cells isolated from the subventricular zone of adult mouse brain and provides the first extensive characterization of REST-mediated control of the cellular and molecular properties. This study shows that REST knockdown affects the capacity of progenitor cells to generate neurospheres, reduces cell proliferation, and triggers cell differentiation despite the presence of growth factors. Genome- and transcriptome-wide analyses show that REST binding sites are significantly enriched in genes associated with synaptic transmission and nervous system development and function. Seeking candidate regulators of aNSC function, this study identifies a member of the bone morphogenetic protein (BMP) family, BMP6, the mRNA and protein of which increased after REST knockdown. The results of this study extend previous findings, demonstrating a reciprocal control of REST expression by BMPs. Administration of exogenous BMP6 inhibits aNSC proliferation and induces the expression of the astrocytic marker glial fibrillary acidic protein, highlighting its antimitogenic and prodifferentiative effects. This study suggests that BMP6 produced in a REST-regulated manner together with other signals can contribute to regulation of NSC maintenance and fate. PMID:25691247

  15. RE1 silencing transcription factor/neuron-restrictive silencing factor regulates expansion of adult mouse subventricular zone-derived neural stem/progenitor cells in vitro.

    PubMed

    Soldati, Chiara; Caramanica, Pasquale; Burney, Matthew J; Toselli, Camilla; Bithell, Angela; Augusti-Tocco, Gabriella; Stanton, Lawrence W; Biagioni, Stefano; Buckley, Noel J; Cacci, Emanuele

    2015-08-01

    Adult neural stem cell (aNSC) activity is tuned by external stimuli through the recruitment of transcription factors. This study examines the RE1 silencing transcription factor (REST) in neural stem/progenitor cells isolated from the subventricular zone of adult mouse brain and provides the first extensive characterization of REST-mediated control of the cellular and molecular properties. This study shows that REST knockdown affects the capacity of progenitor cells to generate neurospheres, reduces cell proliferation, and triggers cell differentiation despite the presence of growth factors. Genome- and transcriptome-wide analyses show that REST binding sites are significantly enriched in genes associated with synaptic transmission and nervous system development and function. Seeking candidate regulators of aNSC function, this study identifies a member of the bone morphogenetic protein (BMP) family, BMP6, the mRNA and protein of which increased after REST knockdown. The results of this study extend previous findings, demonstrating a reciprocal control of REST expression by BMPs. Administration of exogenous BMP6 inhibits aNSC proliferation and induces the expression of the astrocytic marker glial fibrillary acidic protein, highlighting its antimitogenic and prodifferentiative effects. This study suggests that BMP6 produced in a REST-regulated manner together with other signals can contribute to regulation of NSC maintenance and fate.

  16. Transient overexpression of cyclin D2/CDK4/GLP1 genes induces proliferation and differentiation of adult pancreatic progenitors and mediates islet regeneration

    PubMed Central

    Chen, Shuyuan; Shimoda, Masyuki; Chen, Jiaxi; Matsumodo, Shinichi

    2012-01-01

    The molecular mechanism of β-cell regeneration remains poorly understood. Cyclin D2/CDK4 expresses in normal β cells and maintains adult β-cell growth. We hypothesized that gene therapy with cyclin D2/CDK4/GLP-1 plasmids targeted to the pancreas of STZ-treated rats by ultrasound-targeted microbubble destruction (UTMD) would force cell cycle re-entry of residual G0-phase islet cells into G1/S phase to regenerate β cells. A single UTMD treatment induced β-cell regeneration with reversal of diabetes for 6 mo without evidence of toxicity. We observed that this β-cell regeneration was not mediated by self-replication of pre-existing β cells. Instead, cyclin D2/CDK4/GLP-1 initiated robust proliferation of adult pancreatic progenitor cells that exist within islets and terminally differentiate to mature islets with β cells and α cells. PMID:22373529

  17. Gestational exposure to diethylstilbestrol alters cardiac structure/function, protein expression and DNA methylation in adult male mice progeny

    SciTech Connect

    Haddad, Rami; Kasneci, Amanda; Mepham, Kathryn; Sebag, Igal A.; and others

    2013-01-01

    Pregnant women, and thus their fetuses, are exposed to many endocrine disruptor compounds (EDCs). Fetal cardiomyocytes express sex hormone receptors making them potentially susceptible to re-programming by estrogenizing EDCs. Diethylstilbestrol (DES) is a proto-typical, non-steroidal estrogen. We hypothesized that changes in adult cardiac structure/function after gestational exposure to the test compound DES would be a proof in principle for the possibility of estrogenizing environmental EDCs to also alter the fetal heart. Vehicle (peanut oil) or DES (0.1, 1.0 and 10.0 μg/kg/da.) was orally delivered to pregnant C57bl/6n dams on gestation days 11.5–14.5. At 3 months, male progeny were left sedentary or were swim trained for 4 weeks. Echocardiography of isoflurane anesthetized mice revealed similar cardiac structure/function in all sedentary mice, but evidence of systolic dysfunction and increased diastolic relaxation after swim training at higher DES doses. The calcium homeostasis proteins, SERCA2a, phospholamban, phospho-serine 16 phospholamban and calsequestrin 2, are important for cardiac contraction and relaxation. Immunoblot analyses of ventricle homogenates showed increased expression of SERCA2a and calsequestrin 2 in DES mice and greater molecular remodeling of these proteins and phospho-serine 16 phospholamban in swim trained DES mice. DES increased cardiac DNA methyltransferase 3a expression and DNA methylation in the CpG island within the calsequestrin 2 promoter in heart. Thus, gestational DES epigenetically altered ventricular DNA, altered cardiac function and expression, and reduced the ability of adult progeny to cardiac remodel when physically challenged. We conclude that gestational exposure to estrogenizing EDCs may impact cardiac structure/function in adult males. -- Highlights: ► Gestational DES changes cardiac SERCA2a and CASQ2 expression. ► Echocardiography identified systolic dysfunction and increased diastolic relaxation. ► DES

  18. Embryonic caffeine exposure acts via A1 adenosine receptors to alter adult cardiac function and DNA methylation in mice.

    PubMed

    Buscariollo, Daniela L; Fang, Xiefan; Greenwood, Victoria; Xue, Huiling; Rivkees, Scott A; Wendler, Christopher C

    2014-01-01

    Evidence indicates that disruption of normal prenatal development influences an individual's risk of developing obesity and cardiovascular disease as an adult. Thus, understanding how in utero exposure to chemical agents leads to increased susceptibility to adult diseases is a critical health related issue. Our aim was to determine whether adenosine A1 receptors (A1ARs) mediate the long-term effects of in utero caffeine exposure on cardiac function and whether these long-term effects are the result of changes in DNA methylation patterns in adult hearts. Pregnant A1AR knockout mice were treated with caffeine (20 mg/kg) or vehicle (0.09% NaCl) i.p. at embryonic day 8.5. This caffeine treatment results in serum levels equivalent to the consumption of 2-4 cups of coffee in humans. After dams gave birth, offspring were examined at 8-10 weeks of age. A1AR+/+ offspring treated in utero with caffeine were 10% heavier than vehicle controls. Using echocardiography, we observed altered cardiac function and morphology in adult mice exposed to caffeine in utero. Caffeine treatment decreased cardiac output by 11% and increased left ventricular wall thickness by 29% during diastole. Using DNA methylation arrays, we identified altered DNA methylation patterns in A1AR+/+ caffeine treated hearts, including 7719 differentially methylated regions (DMRs) within the genome and an overall decrease in DNA methylation of 26%. Analysis of genes associated with DMRs revealed that many are associated with cardiac hypertrophy. These data demonstrate that A1ARs mediate in utero caffeine effects on cardiac function and growth and that caffeine exposure leads to changes in DNA methylation.

  19. Sudden cardiac death in adults with congenitally corrected transposition of the great arteries

    PubMed Central

    McCombe, A; Touma, F; Jackson, D; Canniffe, C; Choudhary, P; Pressley, L; Tanous, D; Robinson, Peter J; Celermajer, D

    2016-01-01

    Background Congenitally corrected transposition of the great arteries (ccTGA) is a rare congenital heart disease. There have been only few reports of sudden cardiac death (SCD) in patients with ccTGA and reasonable ventricular function. Methods A retrospective review of the medical records of all patients attending our adult congenital heart centre, with known ccTGA. Results From a database of over 3500 adult patients with congenital heart disease, we identified 39 (∼1%) with ccTGA and ‘two-ventricle’ circulations. 65% were male. The mean age at diagnosis was 12.4±11.4 years and the mean age at last time of review was 34.3±11.3 years. 24 patients (56%) had a history of surgical intervention. 8 (19%) had had pacemaker implantation and 2 had had a defibrillator implanted for non-sustained ventricular tachycardia (NSVT). In 544 years of patient follow-up, there had been five cases of SCD in our population; 1 death per 109 patient-years. Two of these patients had had previously documented supraventricular or NSVT. However, they were all classified as New York Heart Association (NYHA) class I or II, and systemic (right) ventricular function had been recorded as normal, mildly or mildly–moderately impaired, at most recent follow-up. Conclusions Our experience suggests the need for improved risk stratification and/or surveillance for malignant arrhythmia in adults with ccTGA, even in those with reasonable functional class on ventricular function. PMID:27493760

  20. Hospital Resource Utilization for Common Noncardiac Diagnoses in Adult Survivors of Single Cardiac Ventricle.

    PubMed

    Seckeler, Michael D; Moe, Tabitha G; Thomas, Ian D; Meziab, Omar; Andrews, Jennifer; Heller, Elissa; Klewer, Scott E

    2015-12-01

    Single ventricle congenital heart disease (SV CHD) has transformed from a nearly universally fatal condition to a chronic illness. As the number of adults living with SV CHD continues to increase, there needs to be an understanding of health care resource utilization (HCRU), particularly for noncardiac conditions, for this patient population. We performed a retrospective database review of the University HealthSystem Consortium Clinical Database/Resource Manager for adult patients with SV CHD hospitalized for noncardiac conditions from January 2011 to November 2014. Patients with SV CHD were identified using International Classification of Disease (ICD)-9 codes associated with SV CHD (hypoplastic left heart, tricuspid atresia, and SV) and stratified into 2 groups by age (18 to 29 years and 30 to 40 years). Direct cost, length of stay (LOS), intensive care unit (ICU) admission rate and mortality data were compared with age-matched patients without CHD. There were 2,083,651 non-CHD and 590 SV CHD admissions in Group 1 and 2,131,046 non-CHD and 297 SV CHD admissions in Group 2. There was no difference in LOS in Group 1, but there were higher costs for several diagnoses. LOS and costs were higher for several diagnoses in Group 2. ICU admission rate and in-hospital mortality were higher for several diagnoses for patients with SV CHD in both groups. In conclusion, adults with SV CHD admitted for noncardiac diagnoses have higher HCRU (longer LOS and higher ICU admission rates) compared with similarly aged patients without CHD. These findings stress the importance of good primary care in this population with complex, chronic cardiac disease to prevent hospitalizations and higher HCRU. PMID:26455384

  1. Optimal range for parvalbumin as relaxing agent in adult cardiac myocytes: gene transfer and mathematical modeling.

    PubMed Central

    Coutu, Pierre; Metzger, Joseph M

    2002-01-01

    Parvalbumin (PV) has recently been shown to increase the relaxation rate when expressed in intact isolated cardiac myocytes via adenovirus gene transfer. We report here a combined experimental and mathematical modeling approach to determine the dose-response and the sarcomere length (SL) shortening-frequency relationship of PV in adult rat cardiac myocytes in primary culture. The dose-response was obtained experimentally by observing the PV-transduced myocytes at different time points after gene transfer. Calcium transients and unloaded mechanical contractions were measured. The results were as follows. At low estimated [PV] (approximately 0.01 mM), contractile parameters were unchanged; at intermediate [PV], relaxation rate of the mechanical contraction and the decay rate of the calcium transient increased with little effects on amplitude; and at high [PV] (approximately 0.1 mM), relaxation rate was further increased, but the amplitudes of the mechanical contraction and the calcium transient were diminished when compared with control myocytes. The SL shortening-frequency relationship exhibited a biphasic response to increasing stimulus frequency in controls (decrease in amplitude and re-lengthening time from 0.2 to 1.0 Hz followed by an increase in these parameters from 2.0 to 4.0 Hz). The effect of PV was to flatten this frequency response. This flattening effect was partly explained by a reduction in the variation in fractional binding of PV to calcium during beats at high frequency. In conclusion, experimental results and mathematical modeling indicate that there is an optimal PV range for which relaxation rate is increased with little effect on contractile amplitude and that PV effectiveness decreases as the stimulus frequency increases. PMID:11964244

  2. Epinephrine, but not vasopressin, improves survival rates in an adult rabbit model of asphyxia cardiac arrest.

    PubMed

    Chen, Meng-Hua; Xie, Lu; Liu, Tang-Wei; Song, Feng-Qing; He, Tao; Zeng, Zhi-yu; Mo, Shu-Rong

    2007-06-01

    Although vasopressin has been reported to be more effective than epinephrine for cardiopulmonary resuscitation in ventricular fibrillation animal models, its efficacy in asphyxia model remains controversy. The purpose of this study was to investigate the effectiveness of vasopressin vs epinephrine on restoration of spontaneous circulation (ROSC) in a rabbit model of asphyxia cardiac arrest. Cardiac arrest was induced by clamping endotracheal tube. After 5 minutes of basic life-support cardiopulmonary resuscitation, animals who had no ROSC were randomly assigned to receive either epinephrine alone (epinephrine group; 200 microg/kg) or vasopressin alone (vasopressin group; 0.8 U/kg). The coronary perfusion pressure (CPP) was calculated as the difference between the minimal diastolic aortic and simultaneously recorded right atrial pressure. Restoration of spontaneous circulation was defined as an unassisted pulse with a systolic arterial pressure of 60 mm Hg or higher for 5 minutes or longer. We induced arrest in 62 rabbits, 15 of whom had ROSC before drug administration and were excluded from analysis. The remaining 47 rabbits were randomized to epinephrine group (n = 24) and vasopressin group (n = 23). Before and after drug administration, CPP in epinephrine group increased significantly (from -4 +/- 4 to 36 +/- 9 mm Hg at peak value, P = .000), whereas CPP in vasopressin group increased only slightly (from 9 +/- 5 to 18 +/- 6 mm Hg at peak value, P = .20). After drug administration, 13 of 24 epinephrine rabbit had ROSC, and only 2 of 23 vasopressin rabbit had ROSC (P < .01). Consequently, we conclude that epinephrine, but not vasopressin, increases survival rates in this adult rabbit asphyxia model.

  3. Beating and insulting children as a risk for adult cancer, cardiac disease and asthma.

    PubMed

    Hyland, Michael E; Alkhalaf, Ahmed M; Whalley, Ben

    2013-12-01

    The use of physical punishment for children is associated with poor psychological and behavioral outcomes, but the causal pathway is controversial, and the effects on later physical health unknown. We conducted a cross-sectional survey of asthma, cancer, and cardiac patients (150 in each category, 75 male) recruited from outpatient clinics and 250 healthy controls (125 male). All participants were 40-60 years old and citizens of Saudi Arabia, where the use of beating and insults is an acceptable parenting style. Demographic data and recalled frequency of beatings and insults as a child were assessed on an 8-point scale. Beating and insults were highly correlated (ρ = 0.846). Propensity score matching was used to control for demographic differences between the disease and healthy groups. After controlling for differences, more frequent beating (once or more per month) and insults were associated with a significantly increased risk for cancer (RR = 1.7), cardiac disease (RR = 1.3) and asthma (RR = 1.6), with evidence of increased risk for cancer and asthma with beating frequency of once every 6 months or more. Our results show that a threatening parenting style of beating and insults is associated with increased risk for somatic disease, possibly because this form of parenting induces stress. Our findings are consistent with previous research showing that child abuse and other early life stressors adversely affect adult somatic health, but provide evidence that the pathogenic effects occur also with chronic minor stress. A stress-inducing parenting style, even when normative, has long term adverse health consequences. PMID:23054177

  4. HAND1 and HAND2 are expressed in the adult-rodent heart and are modulated during cardiac hypertrophy.

    PubMed

    Thattaliyath, Bijoy D; Livi, Carolina B; Steinhelper, Mark E; Toney, Glenn M; Firulli, Anthony B

    2002-10-01

    The HAND basic Helix-Loop-Helix (bHLH) transcription factors are essential for normal cardiac and extraembryonic development. Although highly evolutionarily conserved genes, HAND cardiac expression patterns differ across species. Mouse expression of HAND1 and HAND2 was reported absent in the adult heart. Human HAND genes are expressed in the adult heart and HAND1 expression is downregulated in cardiomyopathies. As rodent and human expression profiles are inconsistent, we re-examined expression of HAND1 and HAND2 in adult-rodent hearts. HAND1 and HAND2 are expressed in adult-rodent hearts and HAND2 is expressed in the atria. Induction of cardiac hypertrophy shows modulation of HAND expression, corresponding with observations in human cardiomyopathy. The downregulation of HAND expression observed in rodent hypertrophy and human cardiomyopathy may reflect a permissive role allowing, cardiomyocytes to reinitiate the fetal gene program and initiate the adaptive physiological changes that allow the heart to compensate (hypertrophy) for the increase in afterload.

  5. Snoo and Dpp Act as Spatial and Temporal Regulators Respectively of Adult Progenitor Cells in the Drosophila Trachea

    PubMed Central

    Djabrayan, Nareg J.-V.; Casanova, Jordi

    2016-01-01

    Clusters of differentiated cells contributing to organ structures retain the potential to re-enter the cell cycle and replace cells lost during development or upon damage. To do so, they must be designated spatially and respond to proper activation cues. Here we show that in the case of Drosophila differentiated larval tracheal cells, progenitor potential is conferred by the spatially restricted activity of the Snoo transcription cofactor. Furthermore, Dpp signalling regulated by endocrine hormonal cues provides the temporal trigger for their activation. Finally, we elucidate the genetic network elicited by Snoo and Dpp activity. These results illustrate a regulatory mechanism that translates intrinsic potential and extrinsic cues into the facultative stem cell features of differentiated progenitors. PMID:26942411

  6. Human embryonic and fetal mesenchymal stem cells differentiate toward three different cardiac lineages in contrast to their adult counterparts.

    PubMed

    Ramkisoensing, Arti A; Pijnappels, Daniël A; Askar, Saïd F A; Passier, Robert; Swildens, Jim; Goumans, Marie José; Schutte, Cindy I; de Vries, Antoine A F; Scherjon, Sicco; Mummery, Christine L; Schalij, Martin J; Atsma, Douwe E

    2011-01-01

    Mesenchymal stem cells (MSCs) show unexplained differences in differentiation potential. In this study, differentiation of human (h) MSCs derived from embryonic, fetal and adult sources toward cardiomyocytes, endothelial and smooth muscle cells was investigated. Labeled hMSCs derived from embryonic stem cells (hESC-MSCs), fetal umbilical cord, bone marrow, amniotic membrane and adult bone marrow and adipose tissue were co-cultured with neonatal rat cardiomyocytes (nrCMCs) or cardiac fibroblasts (nrCFBs) for 10 days, and also cultured under angiogenic conditions. Cardiomyogenesis was assessed by human-specific immunocytological analysis, whole-cell current-clamp recordings, human-specific qRT-PCR and optical mapping. After co-culture with nrCMCs, significantly more hESC-MSCs than fetal hMSCs stained positive for α-actinin, whereas adult hMSCs stained negative. Furthermore, functional cardiomyogenic differentiation, based on action potential recordings, was shown to occur, but not in adult hMSCs. Of all sources, hESC-MSCs expressed most cardiac-specific genes. hESC-MSCs and fetal hMSCs contained significantly higher basal levels of connexin43 than adult hMSCs and co-culture with nrCMCs increased expression. After co-culture with nrCFBs, hESC-MSCs and fetal hMSCs did not express α-actinin and connexin43 expression was decreased. Conduction velocity (CV) in co-cultures of nrCMCs and hESC-MSCs was significantly higher than in co-cultures with fetal or adult hMSCs. In angiogenesis bioassays, only hESC-MSCs and fetal hMSCs were able to form capillary-like structures, which stained for smooth muscle and endothelial cell markers.Human embryonic and fetal MSCs differentiate toward three different cardiac lineages, in contrast to adult MSCs. Cardiomyogenesis is determined by stimuli from the cellular microenvironment, where connexin43 may play an important role.

  7. Ambient particulate air pollution and cardiac arrhythmia in a panel of older adults in Steubenville, Ohio

    PubMed Central

    Sarnat, S E; Suh, H H; Coull, B A; Schwartz, J; Stone, P H; Gold, D R

    2006-01-01

    Objectives Ambient particulate air pollution has been associated with increased risk of cardiovascular morbidity and mortality. Pathways by which particles may act involve autonomic nervous system dysfunction or inflammation, which can affect cardiac rate and rhythm. The importance of these pathways may vary by particle component or source. In an eastern US location with significant regional pollution, the authors examined the association of air pollution and odds of cardiac arrhythmia in older adults. Methods Thirty two non‐smoking older adults were evaluated on a weekly basis for 24 weeks during the summer and autumn of 2000 with a standardised 30 minute protocol that included continuous electrocardiogram measurements. A central ambient monitoring station provided daily concentrations of fine particles (PM2.5, sulfate, elemental carbon) and gases. Sulfate was used as a marker of regional pollution. The authors used logistic mixed effects regression to examine the odds of having any supraventricular ectopy (SVE) or ventricular ectopy (VE) in association with increases in air pollution for moving average pollutant concentrations up to 10 days before the health assessment. Results Participant specific mean counts of arrhythmia over the protocol varied between 0.1–363 for SVE and 0–350 for VE. The authors observed odds ratios for having SVE over the length of the protocol of 1.42 (95% CI 0.99 to 2.04), 1.70 (95% CI 1.12 to 2.57), and 1.78 (95% CI 0.95 to 3.35) for 10.0 μg/m3, 4.2 μg/m3, and 14.9 ppb increases in five day moving average PM2.5, sulfate, and ozone concentrations respectively. The other pollutants, including elemental carbon, showed no effect on arrhythmia. Participants reporting cardiovascular conditions (for example, previous myocardial infarction or hypertension) were the most susceptible to pollution induced SVE. The authors found no association of pollution with VE. Conclusion Increased levels of ambient sulfate and ozone may increase

  8. Bench-to-bedside review: Inotropic drug therapy after adult cardiac surgery – a systematic literature review

    PubMed Central

    Gillies, Michael; Bellomo, Rinaldo; Doolan, Laurie; Buxton, Brian

    2005-01-01

    Many adult patients require temporary inotropic support after cardiac surgery. We reviewed the literature systematically to establish, present and classify the evidence regarding choice of inotropic drugs. The available evidence, while limited in quality and scope, supports the following observations; although all β-agonists can increase cardiac output, the best studied β-agonist and the one with the most favourable side-effect profile appears to be dobutamine. Dobutamine and phosphodiesterase inhibitors (PDIs) are efficacious inotropic drugs for management of the low cardiac output syndrome. Dobutamine is associated with a greater incidence of tachycardia and tachyarrhythmias, whereas PDIs often require the administration of vasoconstrictors. Other catecholamines have no clear advantages over dobutamine. PDIs increase the likelihood of successful weaning from cardiopulmonary bypass as compared with placebo. There is insufficient evidence that inotropic drugs should be selected for their effects on regional perfusion. PDIs also increase flow through arterial grafts, reduce mean pulmonary artery pressure and improve right heart performance in pulmonary hypertension. Insufficient data exist to allow selection of a specific inotropic agent in preference over another in adult cardiac surgery patients. Multicentre randomized controlled trials focusing on clinical rather than physiological outcomes are needed. PMID:15987381

  9. Comparative impact of AAV and enzyme replacement therapy on respiratory and cardiac function in adult Pompe mice

    PubMed Central

    Falk, Darin J; Soustek, Meghan S; Todd, Adrian Gary; Mah, Cathryn S; Cloutier, Denise A; Kelley, Jeffry S; Clement, Nathalie; Fuller, David D; Byrne, Barry J

    2015-01-01

    Pompe disease is an autosomal recessive genetic disorder characterized by a deficiency of the enzyme responsible for degradation of lysosomal glycogen (acid α-glucosidase (GAA)). Cardiac dysfunction and respiratory muscle weakness are primary features of this disorder. To attenuate the progressive and rapid accumulation of glycogen resulting in cardiorespiratory dysfunction, adult Gaa–/– mice were administered a single systemic injection of rAAV2/9-DES-hGAA (AAV9-DES) or bimonthly injections of recombinant human GAA (enzyme replacement therapy (ERT)). Assessment of cardiac function and morphology was measured 1 and 3 months after initiation of treatment while whole-body plethysmography and diaphragmatic contractile function was evaluated at 3 months post-treatment in all groups. Gaa–/– animals receiving either AAV9-DES or ERT demonstrated a significant improvement in cardiac function and diaphragmatic contractile function as compared to control animals. AAV9-DES treatment resulted in a significant reduction in cardiac dimension (end diastolic left ventricular mass/gram wet weight; EDMc) at 3 months postinjection. Neither AAV nor ERT therapy altered minute ventilation during quiet breathing (eupnea). However, breathing frequency and expiratory time were significantly improved in AAV9-DES animals. These results indicate systemic delivery of either strategy improves cardiac function but AAV9-DES alone improves respiratory parameters at 3 months post-treatment in a murine model of Pompe disease. PMID:26029718

  10. Inhibition of ref-1 stimulates the production of reactive oxygen species and induces differentiation in adult cardiac stem cells.

    PubMed

    Gurusamy, Narasimman; Mukherjee, Subhendu; Lekli, Istvan; Bearzi, Claudia; Bardelli, Silvana; Das, Dipak K

    2009-03-01

    Redox effector protein-1 (Ref-1) plays an essential role in DNA repair and redox regulation of several transcription factors. In the present study, we examined the role of Ref-1 in maintaining the redox status and survivability of adult cardiac stem cells challenged with a subtoxic level of H2O2 under inhibition of Ref-1 by RNA interference. Treatment of cardiac stem cells with a low concentration of H2O2 induced Ref-1-mediated survival signaling through phosphorylation of Akt. However, Ref-1 inhibition followed by H2O2 treatment extensively induced the level of intracellular reactive oxygen species (ROS) through activation of the components of NADPH oxidase, like p22( phox ), p47( phox ), and Nox4. Cardiac differentiation markers (Nkx2.5, MEF2C, and GATA4), and cell death by apoptosis were significantly elevated in Ref-1 siRNA followed by H2O2-treated stem cells. Further, inhibition of Ref-1 increased the level of p53 but decreased the phosphorylation of Akt, a molecule involved in survival signaling. Treatment with ROS scavenger N-acetyl-L-cysteine attenuated Ref-1 siRNA-mediated activation of NADPH oxidase and cardiac differentiation. Taken together, these results indicate that Ref-1 plays an important role in maintaining the redox status of cardiac stem cells and protects them from oxidative injury-mediated cell death and differentiation.

  11. The Neurogenic Factor NeuroD1 Is Expressed in Post-Mitotic Cells during Juvenile and Adult Xenopus Neurogenesis and Not in Progenitor or Radial Glial Cells

    PubMed Central

    D'Amico, Laure Anne; Boujard, Daniel; Coumailleau, Pascal

    2013-01-01

    In contrast to mammals that have limited proliferation and neurogenesis capacities, the Xenopus frog exhibit a great potential regarding proliferation and production of new cells in the adult brain. This ability makes Xenopus a useful model for understanding the molecular programs required for adult neurogenesis. Transcriptional factors that control adult neurogenesis in vertebrate species undergoing widespread neurogenesis are unknown. NeuroD1 is a member of the family of proneural genes, which function during embryonic neurogenesis as a potent neuronal differentiation factor. Here, we study in detail the expression of NeuroD1 gene in the juvenile and adult Xenopus brains by in situ hybridization combined with immunodetections for proliferation markers (PCNA, BrdU) or in situ hybridizations for cell type markers (Vimentin, Sox2). We found NeuroD1 gene activity in many brain regions, including olfactory bulbs, pallial regions of cerebral hemispheres, preoptic area, habenula, hypothalamus, cerebellum and medulla oblongata. We also demonstrated by double staining NeuroD1/BrdU experiments, after long post-BrdU administration survival times, that NeuroD1 gene activity was turned on in new born neurons during post-metamorphic neurogenesis. Importantly, we provided evidence that NeuroD1-expressing cells at this brain developmental stage were post-mitotic (PCNA-) cells and not radial glial (Vimentin+) or progenitors (Sox2+) cells. PMID:23799108

  12. Increased expression of Nkx2.2 and Olig2 identifies reactive oligodendrocyte progenitor cells responding to demyelination in the adult CNS.

    PubMed

    Fancy, Stephen P J; Zhao, Chao; Franklin, Robin J M

    2004-11-01

    Within the adult CNS, a quiescent population of oligodendrocyte progenitor cells (OPCs) become activated in response to demyelination and give rise to remyelinating oligodendrocytes. During development, OPC differentiation is controlled by several transcription factors including Olig1 and Olig2, and Nkx2.2. We hypothesized that these genes may serve similar functions in activated adult OPCs allowing them to become remyelinating oligodendrocytes and tested this hypothesis by examining their expression during the remyelination of a toxin-induced rodent model of demyelination. During the acute phase of demyelination, OPCs within the lesion increased their expression of Nkx2.2 and Olig2, two transcription factors that in combination are critical for oligodendrocyte differentiation during developmental myelination. This activation was not associated with increases in Sonic hedgehog (Shh) expression, which does not appear essential for CNS remyelination. Consistent with a role in the activation and differentiation of OPCs, these increases were delayed in old adult animals where the rate of remyelination is slowed. Our data suggest the hypothesis that increased expression of Nkx2.2 and Olig2 plays a critically important role in the differentiation of adult OPCs into remyelinating oligodendrocytes and that these genes may present novel targets for therapeutic manipulation in cases where remyelination is impaired.

  13. Adrenergic responsiveness is reduced, while baseline cardiac function is preserved in old adult conscious monkeys

    NASA Technical Reports Server (NTRS)

    Sato, N.; Kiuchi, K.; Shen, Y. T.; Vatner, S. F.; Vatner, D. E.

    1995-01-01

    To examine the physiological deficit to adrenergic stimulation with aging, five younger adult (3 +/- 1 yr old) and nine older adult (17 +/- 1 yr old) healthy monkeys were studied after instrumentation with a left ventricular (LV) pressure gauge, aortic and left atrial catheters, and aortic flow probes to measure cardiac output directly. There were no significant changes in baseline hemodynamics in conscious older monkeys. For example, an index of contractility, the first derivative of LV pressure (LV dP/dt) was similar (3,191 +/- 240, young vs. 3,225 +/- 71 mmHg/s, old) as well as in isovolumic relaxation, tau (24.3 +/- 1.7 ms, young vs. 23.0 +/- 1.0 ms, old) was similar. However, inotropic, lusitropic, and chronotropic responses to isoproterenol (Iso; 0.1 micrograms/kg), norepinephrine (NE; 0.4 micrograms/kg), and forskolin (For; 75 nmol/kg) were significantly (P < 0.05) depressed in older monkeys. For example. Iso increased LV dP/dt by by 146 +/- 14% in younger monkeys and by only 70 +/- 5% in older monkeys. Iso also reduced tau more in younger monkeys (-28 +/- 7%) compared with older monkeys (-13 +/- 3%). Furthermore, peripheral vascular responsiveness to Iso, NE, For, and phenylephrine (PE; 5 micrograms/kg) was significantly (P < 0.05) reduced in older monkeys. For example, phenylephrine (5 micrograms/kg) increased total peripheral resistence by 69 +/- 4% in younger monkeys and by only 45 +/- 3% in older monkeys. Thus in older monkeys without associated cardiovascular disease, baseline hemodynamics are preserved, but adrenergic receptor responsiveness is reduced systemically, not just in the heart.

  14. Phosphatidic acid stimulates inositol 1,4,5-trisphosphate production in adult cardiac myocytes.

    PubMed

    Kurz, T; Wolf, R A; Corr, P B

    1993-03-01

    The cellular content of phosphatidic acid can increase in response to several agonists either by phosphorylation of diacylglycerol after phospholipase C-catalyzed hydrolysis of phospholipids or directly through activation of phospholipase D. Although previous findings indicated that the generation of phosphatidic acid was exclusively a means of regulation of the cellular concentration of diacylglycerol, more recent studies have indicated that phosphatidic acid may also directly regulate several cellular functions. Accordingly, the present study was performed to assess whether phosphatidic acid could stimulate cardiac phospholipase C in intact adult rabbit ventricular myocytes. The mass of inositol 1,4,5-trisphosphate [Ins (1,4,5)P3] was determined by a specific and sensitive binding protein assay and by direct mass measurement using anion exchange chromatography for separation of selected inositol phosphates and gas chromatography and mass spectrometry for quantification of inositol monophosphate (IP1), inositol bisphosphate (IP2), inositol trisphosphate (IP3), and inositol tetrakisphosphate (IP4). Phosphatidic acid (10(-9)-10(-6) M) elicited a rapid concentration-dependent increase in Ins (1,4,5)P3 accumulation, with the peak fourfold to fivefold increase at 30 seconds of stimulation; the concentration required for 50% of maximal stimulation was 4.4 x 10(-8) M. The time course of individual inositol phosphates indicated a successive increase in the mass of IP3, IP4, IP2, and IP1 in response to stimulation with phosphatidic acid. The production of Ins (1,4,5)P3 in response to phosphatidic acid was not altered in the absence of extracellular calcium or in the presence of extracellular EGTA (10(-3) M). Thus, these findings indicate that phosphatidic acid is a potent activator of inositol phosphate production in adult ventricular myocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Origin and development of neuropil glia of the Drosophila larval and adult brain: two distinct glial populations derived from separate progenitors

    PubMed Central

    Omoto, Jaison Jiro; Yogi, Puja; Hartenstein, Volker

    2015-01-01

    Glia comprise a conspicuous population of non-neuronal cells in vertebrate and invertebrate nervous systems. Drosophila serves as a favorable model to elucidate basic principles of glial biology in vivo. The Drosophila neuropil glia (NPG), subdivided into astrocyte-like (ALG) and ensheathing glia (EG), extend reticular processes which associate with synapses and sheath-like processes which surround neuropil compartments, respectively. In this paper we characterize the development of NPG throughout fly brain development. We find that differentiated neuropil glia of the larval brain originate as a cluster of precursors derived from embryonic progenitors located in the basal brain. These precursors undergo a characteristic migration to spread over the neuropil surface while specifying/differentiating into primary ALG and EG. Embryonically-derived primary NPG are large cells which are few in number, and occupy relatively stereotyped positions around the larval neuropil surface. During metamorphosis, primary NPG undergo cell death. Neuropil glia of the adult (secondary NPG) are derived from type II lineages during the postembryonic phase of neurogliogenesis. These secondary NPG are much smaller in size but greater in number than primary NPG. Lineage tracing reveals that both NPG subtypes derive from intermediate neural progenitors of multipotent type II lineages. Taken together, this study reveals previously uncharacterized dynamics of NPG development and provides a framework for future studies utilizing Drosophila glia as a model. PMID:25779704

  16. In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure: Effects on fetal and adult cardiac gene expression and adult cardiac and renal morphology

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The mouse heart is a target of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during fetal development, and microarray analysis demonstrates significant changes in expression of cardiac genes involved in extracellular matrix (ECM) remodeling. We tested the hypothesis that developmental TCDD exposure wo...

  17. Ghrelin stimulates proliferation, migration and differentiation of neural progenitors from the subventricular zone in the adult mice.

    PubMed

    Li, Endan; Kim, Yumi; Kim, Sehee; Sato, Takahiro; Kojima, Masayasu; Park, Seungjoon

    2014-02-01

    Ghrelin has been shown to regulate neurogenesis in the hippocampus. The aim of this study was to investigate the possible influence of ghrelin on cell proliferation and neuroblast formation in the subventricular zone (SVZ) and rostral migratory system (RMS) and generation of interneurons in the olfactory bulb (OB). We found that ghrelin receptors were expressed in the SVZ-RMS-OB system. Ghrelin knockout (GKO) mice have fewer proliferating neural progenitor cells and neuroblasts in the SVZ, while ghrelin administration attenuated these changes. We also found that not only the number of BrdU-labeled cells but also the fraction of migratory neuroblasts in the RMS was decreased in the GKO mice compared with controls. Treatment of GKO mice with ghrelin restored these numbers to the wild-type control values. Far fewer BrdU/NeuN double-labeled cells were found in the OB of GKO mice than in wild-type mice 4 weeks after labeling, which were increased by ghrelin replacement. GKO mice showed less numbers of BrdU/calbindin, BrdU/calretinin and BrdU/tyrosine hydroxylase double-labeled cells in the periglomerular layer of the OB. However, these numbers were increased to wild-type values after ghrelin administration. Finally, in the GH-deficient spontaneous dwarf rats, ghrelin increased the number of progenitor cells and neuroblasts in the SVZ, without significant effect on the differentiation in the OB. These findings suggest that ghrelin is involved in the regulation of proliferation of progenitor cells in the SVZ, the number of migratory neuroblasts in the SVZ, and the differentiation of interneurons in the OB. PMID:24295570

  18. Melatonin ameliorates dexamethasone-induced inhibitory effects on the proliferation of cultured progenitor cells obtained from adult rat hippocampus.

    PubMed

    Ekthuwapranee, Kasima; Sotthibundhu, Areechun; Tocharus, Chainarong; Govitrapong, Piyarat

    2015-01-01

    Glucocorticoids, hormones that are released in response to stress, induce neuronal cell damage. The hippocampus is a primary target of glucocorticoids in the brain, the effects of which include the suppression of cell proliferation and diminished neurogenesis in the dentate gyrus. Our previous study found that melatonin, synthesized primarily in the pineal, pretreatment prevented the negative effects of dexamethasone, the glucocorticoid receptor agonist, on behavior and neurogenesis in rat hippocampus. In the present study, we attempted to investigate the interrelationship between melatonin and dexamethasone on the underlying mechanism of neural stem cell proliferation. Addition of dexamethasone to hippocampal progenitor cells from eight-week old rats resulted in a decrease in the number of neurospheres; pretreatment with melatonin precluded these effects. The immunocytochemical analyses indicated a reduction of Ki67 and nestin-positive cells in the dexamethasone-treated group, which was minimized by melatonin pretreatment. A reduction of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation and G1-S phase cell cycle regulators cyclin E and CDK2 in dexamethasone-treated progenitor cells were prevented by pretreatment of melatonin. Moreover, luzindole, a melatonin receptor antagonist blocked the positive effect of melatonin whereas RU48, the glucocorticoid receptor antagonist blocked the negative effect of dexamethasone on the number of neurospheres. Moreover, we also found that dexamethasone increased the glucocorticoid receptor protein but decreased the level of MT1 melatonin receptor, whereas melatonin increased the level of MT1 melatonin receptor but decreased the glucocorticoid receptor protein. These suggest the crosstalk and cross regulation between the melatonin receptor and the glucocorticoid receptor on hippocampal progenitor cell proliferation.

  19. Differential regulation of proliferation and neuronal differentiation in adult rat spinal cord neural stem/progenitors by ERK1/2, Akt, and PLCγ

    PubMed Central

    Chan, Wai Si; Sideris, Alexandra; Sutachan, Jhon J.; Montoya G, Jose V.; Blanck, Thomas J. J.; Recio-Pinto, Esperanza

    2013-01-01

    Proliferation of endogenous neural stem/progenitor cells (NSPCs) has been identified in both normal and injured adult mammalian spinal cord. Yet the signaling mechanisms underlying the regulation of adult spinal cord NSPCs proliferation and commitment toward a neuronal lineage remain undefined. In this study, the role of three growth factor-mediated signaling pathways in proliferation and neuronal differentiation was examined. Adult spinal cord NSPCs were enriched in the presence of fibroblast growth factor 2 (FGF2). We observed an increase in the number of cells expressing the microtubule-associated protein 2 (MAP2) over time, indicating neuronal differentiation in the culture. Inhibition of the mitogen-activated protein kinase or extracellular signal-regulated kinase (ERK) kinase 1 and 2/ERK 1 and 2 (MEK/ERK1/2) or the phosphoinositide 3-kinase (PI3K)/Akt pathways suppressed active proliferation in adult spinal cord NSPC cultures; whereas neuronal differentiation was negatively affected only when the ERK1/2 pathway was inhibited. Inhibition of the phospholipase Cγ (PLCγ) pathway did not affect proliferation or neuronal differentiation. Finally, we demonstrated that the blockade of either the ERK1/2 or PLCγ signaling pathways reduced neurite branching of MAP2+ cells derived from the NSPC cultures. Many of the MAP2+ cells expressed synaptophysin and had a glutamatergic phenotype, indicating that over time adult spinal cord NSPCs had differentiated into mostly glutamatergic neurons. Our work provides new information regarding the contribution of these pathways to the proliferation and neuronal differentiation of NSPCs derived from adult spinal cord cultures, and emphasizes that the contribution of these pathways is dependent on the origin of the NSPCs. PMID:23986655

  20. Cardiac transplantation.

    PubMed

    Shanewise, Jack

    2004-12-01

    Cardiac transplantation is a proven, accepted mode of therapy for selected patients with end-stage heart failure, but the inadequate number of suitable donor hearts available ultimately limits its application. This chapter reviews adult cardiac transplantation, with an emphasis on the anesthetic considerations of the heart transplant operation itself.

  1. An in vitro model for the assessment of stem cell fate following implantation within the infarct microenvironment identifies ISL-1 expression as the strongest predictor of c-Kit(+) cardiac progenitor cells' therapeutic potential.

    PubMed

    Sullivan, Kelly E; Burns, Laura J; Black, Lauren D

    2015-11-01

    Cell therapy has the potential to drastically improve clinical outcomes for the 1.45 million patients suffering from a myocardial infarction (MI) each year in the U.S. However, the limitations associated with this treatment - including poor engraftment, significant cell death and poor differentiation potential - have prevented its widespread application clinically. To optimize functional improvements provided by transplanted cells, there is a need to develop methods that increase cellular retention and viability, while supporting differentiation and promoting paracrine signaling. Current in vivo models are expensive, difficult to access and manipulate and are time consuming. We have developed an in vitro model of MI which allows for a straightforward, consistent and relatively accurate prediction of cell fate following injection in vivo. The model demonstrated how the infarct environment impairs cellular engraftment and differentiation, but identified an implantation strategy which enhanced cell fate in vitro. Multivariate linear regression identified variables within the model that regulated vascular differentiation potential including oxygen tension, stiffness and cytokine presence, while cardiac differentiation was more accurately predicted by Isl-1 expression in the original cell isolate than any other variable present within the model system. The model highlighted how the cells' sensitivity to the infarct variables varied from line to line, which emphasizes the importance of the model system for the prediction of cell fate on a patient specific basis. Further development of this model system could help predict the clinical efficacy of cardiac progenitor cell therapy at the patient level as well as identify the optimal strategy for cell delivery.

  2. Seipin knockout in mice impairs stem cell proliferation and progenitor cell differentiation in the adult hippocampal dentate gyrus via reduced levels of PPARγ

    PubMed Central

    Li, Guoxi; Zhou, Libin; Zhu, Ying; Wang, Conghui; Sha, Sha; Xian, Xunde; Ji, Yong; Liu, George; Chen, Ling

    2015-01-01

    ABSTRACT The seipin gene (BSCL2) was originally identified in humans as a loss-of-function gene associated with congenital generalized lipodystrophy type 2 (CGL2). Neuronal seipin-knockout (seipin-nKO) mice display a depression-like phenotype with a reduced level of hippocampal peroxisome proliferator-activated receptor gamma (PPARγ). The present study investigated the influence of seipin deficiency on adult neurogenesis in the hippocampal dentate gyrus (DG) and the underlying mechanisms of the effects. We show that the proliferative capability of stem cells in seipin-nKO mice was substantially reduced compared to in wild-type (WT) mice, and that this could be rescued by the PPARγ agonist rosiglitazone (rosi). In seipin-nKO mice, neuronal differentiation of progenitor cells was inhibited, with the enhancement of astrogliogenesis; both of these effects were recovered by rosi treatment during early stages of progenitor cell differentiation. In addition, rosi treatment could correct the decline in hippocampal ERK2 phosphorylation and cyclin A mRNA level in seipin-nKO mice. The MEK inhibitor U0126 abolished the rosi-rescued cell proliferation and cyclin A expression in seipin-nKO mice. In seipin-nKO mice, the hippocampal Wnt3 protein level was less than that in WT mice, and there was a reduction of neurogenin 1 (Neurog1) and neurogenic differentiation 1 (NeuroD1) mRNA, levels of which were corrected by rosi treatment. STAT3 phosphorylation (Tyr705) was enhanced in seipin-nKO mice, and was further elevated by rosi treatment. Finally, rosi treatment for 10 days could alleviate the depression-like phenotype in seipin-nKO mice, and this alleviation was blocked by the MEK inhibitor U0126. The results indicate that, by reducing PPARγ, seipin deficiency impairs proliferation and differentiation of neural stem and progenitor cells, respectively, in the adult DG, which might be responsible for the production of the depression-like phenotype in seipin-nKO mice. PMID

  3. Non-coding RNAs in cardiac regeneration

    PubMed Central

    Zhou, Yanli; Xiao, Junjie; Li, Xinli

    2015-01-01

    Developing new therapeutic strategies which could enhance cardiomyocyte regenerative capacity is of significant clinical importance. Though promising, methods to promote cardiac regeneration have had limited success due to the weak regenerative capacity of the adult mammalian heart. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs, miRs) and long non-coding RNAs (lncRNAs), are functional RNA molecules without a protein coding function that have been reported to engage in cardiac regeneration and repair. In light of current regenerative strategies, the regulatory effects of ncRNAs can be categorized as follows: cardiac proliferation, cardiac differentiation, cardiac survival and cardiac reprogramming. miR-590, miR-199a, miR-17-92 cluster, miR302-367 cluster and miR-222 have been reported to promote cardiomyocyte proliferation while miR-1 and miR-133 suppress that. miR-499 and miR-1 promote the differentiation of cardiac progenitors into cardiomyocyte while miR-133 and H19 inhibit that. miR-21, miR-24, miR-221, miR-199a and miR-155 improve cardiac survival while miR-34a, miR-1 and miR-320 exhibit opposite effects. miR-1, miR-133, miR-208 and miR-499 are capable of reprogramming fibroblasts to cardiomyocyte-like cells and miR-284, miR-302, miR-93, miR-106b and lncRNA-ST8SIA3 are able to enhace cardiac reprogramming. Exploring non-coding RNA-based methods to enhance cardiac regeneration would be instrumental for devising new effective therapies against cardiovascular diseases. PMID:26462179

  4. Three-Dimensional Adult Cardiac Extracellular Matrix Promotes Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

    PubMed

    Fong, Ashley H; Romero-López, Mónica; Heylman, Christopher M; Keating, Mark; Tran, David; Sobrino, Agua; Tran, Anh Q; Pham, Hiep H; Fimbres, Cristhian; Gershon, Paul D; Botvinick, Elliot L; George, Steven C; Hughes, Christopher C W

    2016-08-01

    Pluripotent stem cell-derived cardiomyocytes (CMs) have great potential in the development of new therapies for cardiovascular disease. In particular, human induced pluripotent stem cells (iPSCs) may prove especially advantageous due to their pluripotency, their self-renewal potential, and their ability to create patient-specific cell lines. Unfortunately, pluripotent stem cell-derived CMs are immature, with characteristics more closely resembling fetal CMs than adult CMs, and this immaturity has limited their use in drug screening and cell-based therapies. Extracellular matrix (ECM) influences cellular behavior and maturation, as does the geometry of the environment-two-dimensional (2D) versus three-dimensional (3D). We therefore tested the hypothesis that native cardiac ECM and 3D cultures might enhance the maturation of iPSC-derived CMs in vitro. We demonstrate that maturation of iPSC-derived CMs was enhanced when cells were seeded into a 3D cardiac ECM scaffold, compared with 2D culture. 3D cardiac ECM promoted increased expression of calcium-handling genes, Junctin, CaV1.2, NCX1, HCN4, SERCA2a, Triadin, and CASQ2. Consistent with this, we find that iPSC-derived CMs in 3D adult cardiac ECM show increased calcium signaling (amplitude) and kinetics (maximum upstroke and downstroke) compared with cells in 2D. Cells in 3D culture were also more responsive to caffeine, likely reflecting an increased availability of calcium in the sarcoplasmic reticulum. Taken together, these studies provide novel strategies for maturing iPSC-derived CMs that may have applications in drug screening and transplantation therapies to treat heart disease. PMID:27392582

  5. Incidence of inferior vena cava thrombosis detected by transthoracic echocardiography in the immediate postoperative period after adult cardiac and general surgery.

    PubMed

    Saranteas, T; Kostopanagiotou, G; Tzoufi, M; Drachtidi, K; Knox, G M; Panou, F

    2013-11-01

    Venous thromboembolism is an important complication after general and cardiac surgery. Using transthoracic echocardiography, this study assessed the incidence of inferior vena cava (IVC) thrombosis among a total of 395 and 289 cardiac surgical and major surgical patients in the immediate postoperative period after cardiac and major surgery, respectively. All transthoracic echocardiography was performed by a specialist intensivist within 24 hours after surgery with special emphasis on using the subcostal view in the supine position to visualise the IVC. Of the 395 cardiac surgical patients studied, the IVC was successfully visualised using the subcostal view in 315 patients (79.8%) and eight of these patients (2.5%) had a partially obstructive thrombosis in the IVC. In 250 out of 289 (85%) general surgical patients, the IVC was also clearly visualised, but only one patient (0.4%) had an IVC thrombosis (2.5 vs 0.4%, P <0.05). In summary, visualisation of the IVC was feasible in most patients in the immediate postoperative period after both adult cardiac and major surgery. IVC thrombosis appeared to be more common after adult cardiac surgery than general surgery. A large prospective cohort study is needed to define the risk factors for IVC thrombus and whether early thromboprophylaxis can reduce the incidence of IVC thrombus after adult cardiac surgery.

  6. Efficacy of extracorporeal cardiopulmonary resuscitation compared to conventional cardiopulmonary resuscitation for adult cardiac arrest patients: a systematic review and meta-analysis

    PubMed Central

    Ahn, Chiwon; Kim, Wonhee; Cho, Youngsuk; Choi, Kyu-Sun; Jang, Bo-Hyoung; Lim, Tae Ho

    2016-01-01

    We performed a meta-analysis to compare the impact of extracorporeal cardiopulmonary resuscitation (ECPR) to that of conventional cardiopulmonary resuscitation (CCPR) in adult patients who experience cardiac arrest of cardiac origin. A literature search was performed using criteria set forth in a predefined protocol. Report inclusion criteria were that ECPR was compared to CCPR in adult patients with cardiac arrest of cardiac origin, and that survival and neurological outcome data were available. Exclusion criteria were reports describing non-cardiac origin arrest, review articles, editorials, and nonhuman studies. The efficacies of ECPR and CCPR were compared in terms of survival and neurological outcome. A total of 38,160 patients from 7 studies were ultimately included. ECPR showed similar survival (odds ratio [OR] 2.26, 95% confidence interval [CI] 0.45–11.20) and neurologic outcomes (OR 3.14, 95% CI 0.66–14.85) to CCPR in out-of-hospital cardiac arrest patients. For in-hospital cardiac arrest (IHCA) patients, however, ECPR was associated with significantly better survival (OR 2.40, 95% CI 1.44–3.98) and neurologic outcomes (OR 2.63, 95% CI 1.38–5.02) than CCPR. Hence, ECPR may be more effective than CCPR as an adjuvant therapy for survival and neurologic outcome in cardiac-origin IHCA patients. PMID:27659306

  7. Effects of Neonatal Neural Progenitor Cell Implantation on Adult Neuroanatomy and Cognition in the Ts65Dn Model of Down Syndrome

    PubMed Central

    Rachubinski, Angela L.; Crowley, Shannon K.; Sladek, John R.; Maclean, Kenneth N.; Bjugstad, Kimberly B.

    2012-01-01

    As much of the aberrant neural development in Down syndrome (DS) occurs postnatally, an early opportunity exists to intervene and influence life-long cognitive development. Recent success using neural progenitor cells (NPC) in models of adult neurodegeneration indicate such therapy may be a viable option in diseases such as DS. Murine NPC (mNPC, C17.2 cell line) or saline were implanted bilaterally into the dorsal hippocampus of postnatal day 2 (PND 2) Ts65Dn pups to explore the feasibility of early postnatal treatment in this mouse model of DS. Disomic littermates provided karyotype controls for trisomic pups. Pups were monitored for developmental milestone achievement, and then underwent adult behavior testing at 14 weeks of age. We found that implanted mNPC survived into adulthood and migrated beyond the implant site in both karyotypes. The implantation of mNPC resulted in a significant increase in the density of dentate granule cells. However, mNPC implantation did not elicit cognitive changes in trisomic mice either neonatally or in adulthood. To the best of our knowledge, these results constitute the first assessment of mNPC as an early intervention on cognitive ability in a DS model. PMID:22558337

  8. The expansion of adult stem/progenitor cells and their marker expression fluctuations are linked with pituitary plastic adaptation during gestation and lactancy.

    PubMed

    Vaca, Alicia Maldré; Guido, Carolina Beatriz; Sosa, Liliana Del Valle; Nicola, Juan Pablo; Mukdsi, Jorge; Petiti, Juan Pablo; Torres, Alicia Ines

    2016-08-01

    Extensive evidence has revealed variations in the number of hormone-producing cells in the pituitary gland, which occur under physiological conditions such as gestation and lactancy. It has been proposed that new hormone-producing cells differentiate from stem cells. However, exactly how and when this takes place is not clear. In this work, we used immunoelectron microscopy to identify adult pituitary stem/progenitor cells (SC/P) localized in the marginal zone (MZ), and additionally, we detected GFRa2-, Sox2-, and Sox9-positive cells in the adenoparenchyma (AP) by fluorescence microscopy. Then, we evaluated fluctuations of SC/P mRNA and protein level markers in MZ and AP during gestation and lactancy. An upregulation in stemness markers was shown at term of gestation (AT) in MZ, whereas there were more progenitor cell markers in the middle of gestation and active lactancy. Concerning committed cell markers, we detected a rise in AP at beginning of lactancy (d1L). We performed a BrdU uptake analysis in MZ and AP cells. The highest level of BrdU uptake was observed in MZ AT cells, whereas in AP this was detected in d1L, followed by a decrease in both the MZ and AP. Finally, we detected double immunostaining for BrdU-GFRa2 in MZ AT cells and BrdU-Sox9 in the AP d1L cells. Taken together, we hypothesize that the expansion of the SC/P niche took place mainly in MZ from pituitary rats in AT and d1L. These results suggest that the SC niche actively participates in pituitary plasticity during these reproductive states, contributing to the origin of hormone cell populations. PMID:27302752

  9. The expansion of adult stem/progenitor cells and their marker expression fluctuations are linked with pituitary plastic adaptation during gestation and lactancy.

    PubMed

    Vaca, Alicia Maldré; Guido, Carolina Beatriz; Sosa, Liliana Del Valle; Nicola, Juan Pablo; Mukdsi, Jorge; Petiti, Juan Pablo; Torres, Alicia Ines

    2016-08-01

    Extensive evidence has revealed variations in the number of hormone-producing cells in the pituitary gland, which occur under physiological conditions such as gestation and lactancy. It has been proposed that new hormone-producing cells differentiate from stem cells. However, exactly how and when this takes place is not clear. In this work, we used immunoelectron microscopy to identify adult pituitary stem/progenitor cells (SC/P) localized in the marginal zone (MZ), and additionally, we detected GFRa2-, Sox2-, and Sox9-positive cells in the adenoparenchyma (AP) by fluorescence microscopy. Then, we evaluated fluctuations of SC/P mRNA and protein level markers in MZ and AP during gestation and lactancy. An upregulation in stemness markers was shown at term of gestation (AT) in MZ, whereas there were more progenitor cell markers in the middle of gestation and active lactancy. Concerning committed cell markers, we detected a rise in AP at beginning of lactancy (d1L). We performed a BrdU uptake analysis in MZ and AP cells. The highest level of BrdU uptake was observed in MZ AT cells, whereas in AP this was detected in d1L, followed by a decrease in both the MZ and AP. Finally, we detected double immunostaining for BrdU-GFRa2 in MZ AT cells and BrdU-Sox9 in the AP d1L cells. Taken together, we hypothesize that the expansion of the SC/P niche took place mainly in MZ from pituitary rats in AT and d1L. These results suggest that the SC niche actively participates in pituitary plasticity during these reproductive states, contributing to the origin of hormone cell populations.

  10. Resident c-kit+ cells in the heart are not cardiac stem cells

    PubMed Central

    Sultana, Nishat; Zhang, Lu; Yan, Jianyun; Chen, Jiqiu; Cai, Weibin; Razzaque, Shegufta; Jeong, Dongtak; Sheng, Wei; Bu, Lei; Xu, Mingjiang; Huang, Guo-Ying; Hajjar, Roger J.; Zhou, Bin; Moon, Anne; Cai, Chen-Leng

    2015-01-01

    Identifying a bona fide population of cardiac stem cells (CSCs) is a critical step for developing cell-based therapies for heart failure patients. Previously, cardiac c-kit+ cells were reported to be CSCs with a potential to become myocardial, endothelial and smooth muscle cells in vitro and after cardiac injury. Here we provide further insights into the nature of cardiac c-kit+ cells. By targeting the c-kit locus with multiple reporter genes in mice, we find that c-kit expression rarely co-localizes with the expression of the cardiac progenitor and myogenic marker Nkx2.5, or that of the myocardial marker, cardiac troponin T (cTnT). Instead, c-kit predominantly labels a cardiac endothelial cell population in developing and adult hearts. After acute cardiac injury, c-kit+ cells retain their endothelial identity and do not become myogenic progenitors or cardiomyocytes. Thus, our work strongly suggests that c-kit+ cells in the murine heart are endothelial cells and not CSCs. PMID:26515110

  11. Pigment Cell Progenitors in Zebrafish Remain Multipotent through Metamorphosis.

    PubMed

    Singh, Ajeet Pratap; Dinwiddie, April; Mahalwar, Prateek; Schach, Ursula; Linker, Claudia; Irion, Uwe; Nüsslein-Volhard, Christiane

    2016-08-01

    The neural crest is a transient, multipotent embryonic cell population in vertebrates giving rise to diverse cell types in adults via intermediate progenitors. The in vivo cell-fate potential and lineage segregation of these postembryonic progenitors is poorly understood, and it is unknown if and when the progenitors become fate restricted. We investigate the fate restriction in the neural crest-derived stem cells and intermediate progenitors in zebrafish, which give rise to three distinct adult pigment cell types: melanophores, iridophores, and xanthophores. By inducing clones in sox10-expressing cells, we trace and quantitatively compare the pigment cell progenitors at four stages, from embryogenesis to metamorphosis. At all stages, a large fraction of the progenitors are multipotent. These multipotent progenitors have a high proliferation ability, which diminishes with fate restriction. We suggest that multipotency of the nerve-associated progenitors lasting into metamorphosis may have facilitated the evolution of adult-specific traits in vertebrates. PMID:27453500

  12. In-hospital resuscitation: recognising and responding to adults in cardiac arrest.

    PubMed

    Simpson, Elizabeth

    2016-08-17

    Survival rates following in-hospital cardiac arrest remain low. The majority of patients who survive a cardiac arrest will be in a monitored environment, have a witnessed cardiac arrest and present with a shockable rhythm, usually ventricular fibrillation. Nurses have a responsibility to preserve safety, which requires the ability to accurately assess patients for signs of deterioration in physical health, and to provide assistance when an emergency arises in practice. Nurses must work within the limits of their competence and be able to establish the urgency of a situation. Nurses in all areas of practice must be able to recognise the signs of cardiac arrest and know the prompt response sequence required to improve the patient's chances of survival. This article focuses on inpatient resuscitation in acute healthcare environments and is aimed at staff who may be the first to respond to an in-hospital cardiac arrest. This does not include specialist units such as neurosurgery, intensive therapy units and cardiac catheterisation laboratories, where medical experts are available and clinical priorities may differ. PMID:27533415

  13. Bone marrow–derived circulating progenitor cells fail to transdifferentiate into adipocytes in adult adipose tissues in mice

    PubMed Central

    Koh, Young Jun; Kang, Shinae; Lee, Hyuek Jong; Choi, Tae-Saeng; Lee, Ho Sub; Cho, Chung-Hyun; Koh, Gou Young

    2007-01-01

    Little is known about whether bone marrow–derived circulating progenitor cells (BMDCPCs) can transdifferentiate into adipocytes in adipose tissues or play a role in expanding adipocyte number during adipose tissue growth. Using a mouse bone marrow transplantation model, we addressed whether BMDCPCs can transdifferentiate into adipocytes under standard conditions as well as in the settings of diet-induced obesity, rosiglitazone treatment, and exposure to G-CSF. We also addressed the possibility of transdifferentiation to adipocytes in a murine parabiosis model. In each of these settings, our findings indicated that BMDCPCs did not transdifferentiate into either unilocular or multilocular adipocytes in adipose tissues. Most BMDCPCs became resident and phagocytic macrophages in adipose tissues — which resembled transdifferentiated multilocular adipocytes by appearance, but displayed cell surface markers characteristic for macrophages — in the absence of adipocyte marker expression. When exposed to adipogenic medium in vitro, bone marrow cells differentiated into multilocular, but not unilocular, adipocytes, but transdifferentiation was not observed in vivo, even in the contexts of adipose tissue regrowth or dermal wound healing. Our results suggest that BMDCPCs do not transdifferentiate into adipocytes in vivo and play little, if any, role in expanding the number of adipocytes during the growth of adipose tissues. PMID:18060029

  14. Development of large-scale size-controlled adult pancreatic progenitor cell clusters by an inkjet-printing technique.

    PubMed

    Yang, Jia; Zhou, Fang; Xing, Rubo; Lin, Yuan; Han, Yanchun; Teng, Chunbo; Wang, Qian

    2015-06-01

    The generation of transplantable β-cells from pancreatic progenitor cells (PPCs) could serve as an ideal cell-based therapy for diabetes. Because the transplant efficiency depends on the size of islet-like clusters, it becomes one of the key research topics to produce PPCs with controlled cluster sizes in a scalable manner. In this study, we used inkjet printing to pattern biogenic nanoparticles, i.e., mutant tobacco mosaic virus (TMV), with different spot sizes to support the formation of multicellular clusters by PPCs. We successfully achieved TMV particle patterns with variable features and sizes by adjusting the surface wettability and printing speed. The spot sizes of cell-adhesive TMV mutant arrays were in the range of 50-150 μm diameter. Mouse PPCs were seeded on the TMV-RGD (arginine-glycine-aspartate)-patterned polystyrene (PS) substrate, which consists of areas that either favor (TMV-RGD) or prohibit (bare PS) cell adhesion. The PPCs stably attached, proliferated on top of the TMV-RGD support, thus resulting in the formation of uniform and confluent PPC clusters. Furthermore, the aggregated PPCs also maintained their multipotency and were positive for E-cadherin, indicating that the formation of cell-cell junctions is critical for enhanced cell-cell contact. PMID:25961432

  15. Myogenic progenitors and imaging single-cell flow analysis: a model to study commitment of adult muscle stem cells.

    PubMed

    Trapecar, Martin; Kelc, Robi; Gradisnik, Lidija; Vogrin, Matjaz; Rupnik, Marjan Slak

    2014-12-01

    Research on skeletal muscles suffers from a lack of appropriate human models to study muscle formation and regeneration on the regulatory level of single cells. This hampers both basic understanding and the development of new therapeutic approaches. The use of imaging multicolour flow cytometry and myogenic stem cells can help fill this void by allowing researchers to visualize and quantify the reaction of individual cultured cells to bioactives or other physiological impulses. As proof of concept, we subjected human CD56+ satellite cells to reference bioactives follistatin and Malva sylvestris extracts and then used imaging multicolor flow cytometry to visualize the stepwise activation of myogenic factors MyoD and myogenin in individual cells. This approach enabled us to evaluate the potency of these bioactives to stimulate muscle commitment. To validate this method, we used multi-photon confocal microscopy to confirm the potential of bioactives to stimulate muscle differentiation and expression of desmin. Imaging multicolor flow cytometry revealed statistically significant differences between treated and untreated groups of myogenic progenitors and we propose the utilization of this concept as an integral part of future muscle research strategies.

  16. Sufficient myocardial protection of del Nido cardioplegia regardless of ventricular mass and myocardial ischemic time in adult cardiac surgical patients

    PubMed Central

    Kim, Ji Seong; Jeong, Jin Hee; Moon, Sin Ju; Ahn, Hyuk

    2016-01-01

    Background Del Nido (DN) cardioplegic solution (CPS) has been widely used during pediatric cardiac surgery. However, its use in the field of adult cardiac surgery is not popular yet. We evaluated efficacy of DN cardioplegia in adult cardiac surgical patients. Methods Fifty-three adult patients (mean age, 54±16 years) who underwent cardiovascular surgery using DN cardioplegia were enrolled. Myocardial troponin I (TnI) level up to three days after surgery and early clinical outcomes were evaluated. Propensity score matching was performed to compare these results with those after surgery using blood cardioplegia (BC). Results DN cardioplegia was infused with an initial dose of 1,126±221 mL, and an additional 500 mL was reinfused in 15 patients 91 minutes after initial infusion. After release of aortic cross clamp (ACC), spontaneous defibrillation was achieved in 94.3% (50/53). The peak TnI level after surgery was 9.8 ng/mL (range, 2.0–90.2 ng/mL). Linear regression models demonstrated that neither left ventricular mass (LVM) nor ACC time was associated with increased level of peak TnI (P=0.928 and 0.595, respectively). Early mortality occurred in one patient (1.9%). Postoperative complications included atrial fibrillation (n=18, 34.0%), acute kidney injury (n=4, 7.5%), low cardiac output syndrome (n=1, 1.9%), and respiratory complications (n=1, 1.9%). Propensity score matching extracted 39 pairs. Spontaneous defibrillation was achieved more frequently in the DN than BC groups (37/39 vs. 12/39, P<0.001). Peak level and serial changes of TnI were not statistically different between the two groups (P=0.085 and 0.959, respectively). There were also no significant differences in early mortality and postoperative complication rates between the two groups. Conclusions DN cardioplegia is as effective as BC for adult patients in terms of myocardial protection and early clinical outcomes.

  17. A role for matrix stiffness in the regulation of cardiac side population cell function.

    PubMed

    Qiu, Yiling; Bayomy, Ahmad F; Gomez, Marcus V; Bauer, Michael; Du, Ping; Yang, Yanfei; Zhang, Xin; Liao, Ronglih

    2015-05-01

    The mechanical properties of the local microenvironment may have important influence on the fate and function of adult tissue progenitor cells, altering the regenerative process. This is particularly critical following a myocardial infarction, in which the normal, compliant myocardial tissue is replaced with fibrotic, stiff scar tissue. In this study, we examined the effects of matrix stiffness on adult cardiac side population (CSP) progenitor cell behavior. Ovine and murine CSP cells were isolated and cultured on polydimethylsiloxane substrates, replicating the elastic moduli of normal and fibrotic myocardium. Proliferation capacity and cell cycling were increased in CSP cells cultured on the stiff substrate with an associated reduction in cardiomyogeneic differentiation and accelerated cell ageing. In addition, culture on stiff substrate stimulated upregulation of extracellular matrix and adhesion proteins gene expression in CSP cells. Collectively, we demonstrate that microenvironment properties, including matrix stiffness, play a critical role in regulating progenitor cell functions of endogenous resident CSP cells. Understanding the effects of the tissue microenvironment on resident cardiac progenitor cells is a critical step toward achieving functional cardiac regeneration.

  18. A role for matrix stiffness in the regulation of cardiac side population cell function

    PubMed Central

    Qiu, Yiling; Bayomy, Ahmad F.; Gomez, Marcus V.; Bauer, Michael; Du, Ping; Yang, Yanfei; Zhang, Xin

    2015-01-01

    The mechanical properties of the local microenvironment may have important influence on the fate and function of adult tissue progenitor cells, altering the regenerative process. This is particularly critical following a myocardial infarction, in which the normal, compliant myocardial tissue is replaced with fibrotic, stiff scar tissue. In this study, we examined the effects of matrix stiffness on adult cardiac side population (CSP) progenitor cell behavior. Ovine and murine CSP cells were isolated and cultured on polydimethylsiloxane substrates, replicating the elastic moduli of normal and fibrotic myocardium. Proliferation capacity and cell cycling were increased in CSP cells cultured on the stiff substrate with an associated reduction in cardiomyogeneic differentiation and accelerated cell ageing. In addition, culture on stiff substrate stimulated upregulation of extracellular matrix and adhesion proteins gene expression in CSP cells. Collectively, we demonstrate that microenvironment properties, including matrix stiffness, play a critical role in regulating progenitor cell functions of endogenous resident CSP cells. Understanding the effects of the tissue microenvironment on resident cardiac progenitor cells is a critical step toward achieving functional cardiac regeneration. PMID:25724498

  19. Progenitor Epithelium

    PubMed Central

    Marty-Santos, Leilani

    2015-01-01

    Insulin-producing β cells within the vertebrate fetal pancreas acquire their fate in a step-wise manner. Whereas the intrinsic factors dictating the transcriptional or epigenetic status of pancreatic lineages have been intensely examined, less is known about cell–cell interactions that might constitute a niche for the developing β cell lineage. It is becoming increasingly clear that understanding and recapitulating these steps may instruct in vitro differentiation of embryonic stem cells and/or therapeutic regeneration. Indeed, directed differentiation techniques have improved since transitioning from 2D to 3D cultures, suggesting that the 3D microenvironment in which β cells are born is critical. However, to date, it remains unknown whether the changing architecture of the pancreatic epithelium impacts the fate of cells therein. An emerging challenge in the field is to elucidate how progenitors are allocated during key events, such as the stratification and subsequent resolution of the pre-pancreatic epithelium, as well as the formation of lumens and branches. Here, we assess the progenitor epithelium and examine how it might influence the emergence of pancreatic multipotent progenitors (MPCs), which give rise to β cells and other pancreatic lineages. PMID:26216134

  20. A pharmacokinetic and pharmacodynamic evaluation of milrinone in adults undergoing cardiac surgery.

    PubMed

    Butterworth, J F; Hines, R L; Royster, R L; James, R L

    1995-10-01

    Milrinone can reverse acute postischemic myocardial dysfunction after cardiopulmonary bypass, although neither the appropriate bolus dose nor its pharmacokinetics has been established for cardiac surgical patients. Consenting patients undergoing cardiac surgery received milrinone (25, 50, or 75 micrograms/kg) in an open-label, dose-escalating study if their cardiac index was < 3 L.min-1.m-2 after separation from bypass. Heart rate, mean arterial blood pressure, pulmonary capillary wedge pressure, and cardiac index were determined before and after the administration of milrinone. Timed blood samples were obtained for measurement of milrinone plasma concentrations and pharmacokinetic analysis. Twenty-nine of 60 consenting patients had cardiac indices < 3 L.min-1.m-2 after separation from bypass, received milrinone, and completed the protocol. All three bolus doses of milrinone significantly increased cardiac index. The 50- and 75-micrograms/kg doses produced significantly larger increases in cardiac index than the 25-micrograms/kg dose; however, the 75-micrograms/kg dose did not produce a significantly larger increase in cardiac index than did the 50-micrograms/kg dose. Two of 10 patients receiving milrinone 25 micrograms/kg, but no patient receiving either 50 or 75 micrograms/kg, required early epinephrine rescue when the cardiac index failed to increase by > 15%. The 75-micrograms/kg dose was associated with a case of ventricular tachycardia. The three-compartment model better described milrinone drug disposition than the two-compartment model by both visual inspection and Schwartz-Bayesian criterion. There was only limited evidence of dose-dependence, so data from all three doses are reported together (and normalized to the 50-micrograms/kg dose). Data from one patient was discarded (samples mislabeled). Using mixed-effects nonlinear regression (for n = 28), the following volumes were determined for the three compartments: V1 = 11.1 L, V2 = 16.9 L, and V3 = 363 L

  1. Pro: early extubation in the operating room following cardiac surgery in adults.

    PubMed

    Singh, Karen E; Baum, Victor C

    2012-12-01

    There is growing evidence that the general current approach in many centers of continued mechanical ventilation following cardiac surgery has evolved through historical experience rather than having a strong physiological basis in current practice. There is evidence going back several decades supporting very early (in the operating room [OR]) extubation in pediatric cardiac anesthesia. The authors provide evidence from numerous sources showing that extubation in the OR or shortly after arrival in the ICU is safe and cost-effective and is not prevented by the type of cardiac surgery or the use of cardiopulmonary bypass. They query if the paradigm should not be reversed and very early extubation be the routine unless contraindicated. Like any anesthetic technique, appropriate patient selection is called for, but this technique is widely appropriate. PMID:22798230

  2. Tumor Necrosis Factor Receptor Associated Factor 2 Signaling Provokes Adverse Cardiac Remodeling in the Adult Mammalian Heart

    PubMed Central

    Divakaran, Vijay G.; Evans, Sarah; Topkara, Veli K.; Diwan, Abhinav; Burchfield, Jana; Gao, Feng; Dong, Jianwen; Tzeng, Huei-Ping; Sivasubramanian, Natarajan; Barger, Philip M.; Mann, Douglas L.

    2013-01-01

    Background Tumor necrosis factor (TNF) superfamily ligands that provoke a dilated cardiac phenotype signal through a common scaffolding protein termed TNF receptor associated factor 2 (TRAF2); however, virtually nothing is known with regard to TRAF2 signaling in the adult mammalian heart. Methods and Results We generated multiple founder lines of mice with cardiac restricted overexpression of TRAF2 and characterized the phenotype of mice with higher expression levels of TRAF2 (MHC-TRAF2HC). MHC-TRAF2HC transgenic mice developed a time-dependent increase in cardiac hypertrophy, LV dilation and adverse LV remodeling, and a significant decrease in LV +dP/dt and −dP/dt when compared to littermate (LM) controls (p < 0.05 compared to LM). During the early phases of LV remodeling there was a significant increase in total matrix metalloproteinase (MMP) activity that corresponded with a decrease in total myocardial fibrillar collagen content. As the MHC-TRAF2HC mice aged, there was a significant decrease in total MMP activity accompanied by an increase in total fibrillar collagen content and an increase in myocardial tissue inhibitor of metalloproteinase-1 levels. There was a significant increase in NF-κB activation at 4 – 12 weeks and JNK activation at 4 weeks in the MHCs TRAF2HC mice. Transciptional profiling revealed that > 95% of the hypertrophic/dilated cardiomyopathy-related genes that were significantly upregulated genes in the MHC-TRAF2HC hearts contained κB elements in their promoters. Conclusions These results show for the first time that targeted overexpression of TRAF2 is sufficient to mediate adverse cardiac remodeling in the heart. PMID:23493088

  3. Molecular targets of chromatin repressive mark H3K9me3 in primate progenitor cells within adult neurogenic niches

    PubMed Central

    Foret, Michael R.; Sandstrom, Richard S.; Rhodes, Christopher T.; Wang, Yufeng; Berger, Mitchel S.; Lin, Chin-Hsing Annie

    2014-01-01

    Histone 3 Lysine 9 (H3K9) methylation is known to be associated with pericentric heterochromatin and important in genomic stability. In this study, we show that trimethylation at H3K9 (H3K9me3) is enriched in an adult neural stem cell niche- the subventricular zone (SVZ) on the walls of the lateral ventricle in both rodent and non-human primate baboon brain. Previous studies have shown that there is significant correlation between baboon and human regarding genomic similarity and brain structure, suggesting that findings in baboon are relevant to human. To understand the function of H3K9me3 in this adult neurogenic niche, we performed genome-wide analyses using ChIP-Seq (chromatin immunoprecipitation and deep-sequencing) and RNA-Seq for in vivo SVZ cells purified from baboon brain. Through integrated analyses of ChIP-Seq and RNA-Seq, we found that H3K9me3-enriched genes associated with cellular maintenance, post-transcriptional and translational modifications, signaling pathways, and DNA replication are expressed, while genes involved in axon/neuron, hepatic stellate cell, or immune-response activation are not expressed. As neurogenesis progresses in the adult SVZ, cell fate restriction is essential to direct proper lineage commitment. Our findings highlight that H3K9me3 repression in undifferentiated SVZ cells is engaged in the maintenance of cell type integrity, implicating a role for H3K9me3 as an epigenetic mechanism to control cell fate transition within this adult germinal niche. PMID:25126093

  4. Cyclophosphamide-induced immunosuppression protects cardiac noradrenergic nerve terminals from damage by Trypanosoma cruzi infection in adult rats.

    PubMed

    Guerra, L B; Andrade, L O; Galvão, L M; Macedo, A M; Machado, C R

    2001-01-01

    Trypanosoma cruzi-infected juvenile rats develop severe cardiac sympathetic denervation in parallel with acute myocarditis. This aspect has not been studied in adult rats, thought to be resistant to this infection. The mechanism involved in T. cruzi-induced neuronal damage remains to be completely elucidated. In juvenile rats, the mortality during the acute phase depends on T. cruzi populations, ranging from 30% to 100%. Therefore, studies of mechanisms through hazardous procedures such as immunosuppression are restricted. The current paper shows that adult rats infected with T. cruzi (Y strain) develop severe acute myocarditis and cardiac sympathetic denervation, despite null mortality and virtual absence of patent parasitaemia followed by negative haemoculture. Recovery from the myocarditis and denervation occurred but PCR studies showed persistence of parasite DNA at least until day 111 post inoculation. Immunosuppression by cyclophosphamide treatment increased the parasitaemia, prevented the acute myocarditis and the sympathetic denervation without significant alteration of the myocardial parasitism. These results argue against a direct role for parasite-derived products and implicate the inflammatory cells in the denervation process. As previous studies in juvenile animals have discarded an essential role for radiosensitive cells, the macrophages remain as the possible effectors for the T. cruzi-induced neuronal damage.

  5. 2010 Canadian Cardiovascular Society/Canadian Heart Rhythm Society Training Standards and Maintenance of Competency in Adult Clinical Cardiac Electrophysiology.

    PubMed

    Green, Martin S; Guerra, Peter G; Krahn, Andrew D

    2011-01-01

    The last guidelines on training for adult cardiac electrophysiology (EP) were published by the Canadian Cardiovascular Society in 1996. Since then, substantial changes in the knowledge and practice of EP have mandated a review of the previous guidelines by the Canadian Heart Rhythm Society, an affiliate of the Canadian Cardiovascular Society. Novel tools and techniques also now allow electrophysiologists to map and ablate increasingly complex arrhythmias previously managed with pharmacologic or device therapy. Furthermore, no formal attempt had previously been made to standardize EP training across the country. The 2010 Canadian Cardiovascular Society/Canadian Heart Rhythm Society Training Standards and Maintenance of Competency in Adult Clinical Cardiac Electrophysiology represent a consensus arrived at by panel members from both societies, as well as EP program directors across Canada and other select contributors. In describing program requirements, the technical and cognitive skills that must be acquired to meet training standards, as well as the minimum number of procedures needed in order to acquire these skills, the new guidelines provide EP program directors and committee members with a template to develop an appropriate curriculum for EP training for cardiology fellows here in Canada.

  6. Phosphatase and actin regulator 4 is associated with intermediate filaments in adult neural stem cells and their progenitor astrocytes.

    PubMed

    Cho, Hyo Min; Kim, Joo Yeon; Kim, Hyun; Sun, Woong

    2014-10-01

    Phosphatase and actin regulator 4 (Phactr4) is a newly discovered protein that inhibits protein phosphatase 1 and shows actin-binding activity. We previously found that Phactr4 is expressed in the neurogenic niche in adult mice, although its precise subcellular localization and possible function in neural stem cells (NSCs) is not yet understood. Here, we show that Phactr4 formed punctiform clusters in the cytosol of subventricular zone-derived adult NSCs and their progeny in vitro. These Phactr4 signals were not associated with F-actin fibers but were closely associated with intermediate filaments such as nestin and glial fibrillary acidic protein (GFAP) fibers. Direct binding of Phactr4 with nestin and GFAP filaments was demonstrated using Duolink protein interaction analyses and immunoprecipitation assays. Interestingly, when nestin fibers were de-polymerized during the mitosis or by the phosphatase inhibitor, Phactr4 appeared to be dissociated from nestin, suggesting that their protein interaction is regulated by the protein phosphorylation. These results suggest that Phactr4 forms functional associations with intermediate filament networks in adult NSCs.

  7. The Bone Morphogenetic Protein Type Ib Receptor Is a Major Mediator of Glial Differentiation and Cell Survival in Adult Hippocampal Progenitor Cell Culture

    PubMed Central

    Brederlau, A.; Faigle, R.; Elmi, M.; Zarebski, A.; Sjöberg, S.; Fujii, M.; Miyazono, K.; Funa, K.

    2004-01-01

    Bone morphogenetic proteins (BMPs) act as growth regulators and inducers of differentiation. They transduce their signal via three different type I receptors, termed activin receptor-like kinase 2 (Alk2), Alk3, or bone morphogenetic protein receptor Ia (BMPRIa) and Alk6 or BMPRIb. Little is known about functional differences between the three type I receptors. Here, we have investigated consequences of constitutively active (ca) and dominant negative (dn) type I receptor overexpression in adult-derived hippocampal progenitor cells (AHPs). The dn receptors have a nonfunctional intracellular but functional extracellular domain. They thus trap BMPs that are endogenously produced by AHPs. We found that effects obtained by overexpression of dnAlk2 and dnAlk6 were similar, suggesting similar ligand binding patterns for these receptors. Thus, cell survival was decreased, glial fibrillary acidic protein (GFAP) expression was reduced, whereas the number of oligodendrocytes increased. No effect on neuronal differentiation was seen. Whereas the expression of Alk2 and Alk3 mRNA remained unchanged, the Alk6 mRNA was induced after impaired BMP signaling. After dnAlk3 overexpression, cell survival and astroglial differentiation increased in parallel to augmented Alk6 receptor signaling. We conclude that endogenous BMPs mediate cell survival, astroglial differentiation and the suppression of oligodendrocytic cell fate mainly via the Alk6 receptor in AHP culture. PMID:15194807

  8. How Necessary is the Vasculature in the Life of Neural Stem and Progenitor Cells? Evidence from Evolution, Development and the Adult Nervous System

    PubMed Central

    Koutsakis, Christos; Kazanis, Ilias

    2016-01-01

    Augmenting evidence suggests that such is the functional dependance of neural stem cells (NSCs) on the vasculature that they normally reside in “perivascular niches”. Two examples are the “neurovascular” and the “oligovascular” niches of the adult brain, which comprise specialized microenvironments where NSCs or oligodendrocyte progenitor cells survive and remain mitotically active in close proximity to blood vessels (BVs). The often observed co-ordination of angiogenesis and neurogenesis led to these processes being described as “coupled”. Here, we adopt an evo-devo approach to argue that some stages in the life of a NSC, such as specification and commitment, are independent of the vasculature, while stages such as proliferation and migration are largely dependent on BVs. We also explore available evidence on the possible involvement of the vasculature in other phenomena such as the diversification of NSCs during evolution and we provide original data on the senescence of NSCs in the subependymal zone stem cell niche. Finally, we will comment on the other side of the story; that is, on how much the vasculature is dependent on NSCs and their progeny. PMID:26909025

  9. Lay Referral Patterns Involved in Cardiac Treatment Decision Making among Middle-Aged and Older Adults

    ERIC Educational Resources Information Center

    Schoenberg, Nancy E.; Amey, Cheryl H.; Stoller, Eleanor Palo; Muldoon, Susan B.

    2003-01-01

    Purpose: This study examined age and contextually related factors that are influential in lay referral patterns during cardiac treatment decision making. Design and Methods: A complementary design was used. The Myocardial Infarction (MI) Onset Study identified demographic correlates of who sought medical care for 1,388 MI (heart attack) survivors.…

  10. Past, present, and future of long-term mechanical cardiac support in adults.

    PubMed

    Christiansen, Stefan; Klocke, Anna; Autschbach, Rüdiger

    2008-01-01

    The growing number of heart failure patients and the scarcity of donor organs give rise to the development of mechanical circulatory support devices for a long-term support. After approximately 15 years of experience, these devices should be critically evaluated. The presented article gives an overview on the currently most often used mechanical circulatory support systems, describes the indications for implantation (bridge to cardiac transplantation, destination therapy, and bridge to recovery), the complications like bleeding, thromboembolic events, infections, and technical failures, and analyzes the costs of this therapy. Furthermore, alternative treatment options like cardiac transplantation, coronary artery bypass grafting, cardiac valve surgery, defibrillator implantation, multisite pacing, dynamic and passive cardiomyoplasty, partial left ventriculectomy (PLV), Myosplint implantation (Myocor, Maple Grove, MN, USA), stem cell therapy, and xenotransplantation are shortly presented, and the future of mechanical support devices is discussed. Despite a great number of patients benefitting from mechanical support devices, the treatment with these devices will only compete with other therapeutic strategies if the rates of complications and technical failures as well as the costs are significantly reduced. Furthermore, innovative therapies like biochemical influencing of the cardiac metabolism have a high potential and may play an important role in the future.

  11. Mitochondrial membrane potential in single living adult rat cardiac myocytes exposed to anoxia or metabolic inhibition.

    PubMed Central

    Di Lisa, F; Blank, P S; Colonna, R; Gambassi, G; Silverman, H S; Stern, M D; Hansford, R G

    1995-01-01

    1. The relation between mitochondrial membrane potential (delta psi m) and cell function was investigated in single adult rat cardiac myocytes during anoxia and reoxygenation. delta psi m was studied by loading myocytes with JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'- tetra-ethylbenzimidazolylcarbocyanine iodide), a fluorescent probe characterized by two emission peaks (539 and 597 nm with excitation at 490 nm) corresponding to monomer and aggregate forms of the dye. 2. De-energizing conditions applied to mitochondria, cell suspensions or single cells decreased the aggregate emission and increased the monomer emission. This latter result cannot be explained by changes of JC-1 concentration in the aqueous mitochondrial matrix phase indicating that hydrophobic interaction of the probe with membranes has to be taken into account to explain JC-1 fluorescence properties in isolated mitochondria or intact cells. 3. A different sensitivity of the two JC-1 forms to delta psi m changes was shown in isolated mitochondria by the effects of ADP and FCCP and the calibration with K+ diffusion potentials. The monomer emission was responsive to values of delta psi m below 140 mV, which hardly modified the aggregate emission. Thus JC-1 represents a unique double sensor which can provide semi-quantitative information in both low and high potential ranges. 4. At the onset of glucose-free anoxia the epifluorescence of individual myocytes studied in the single excitation (490 nm)-double emission (530 and 590 nm) mode showed a gradual decline of the aggregate emission, which reached a plateau while electrically stimulated (0.2 Hz) contraction was still retained. The subsequent failure of contraction was followed by the rise of the emission at 530 nm, corresponding to the monomer form of the dye, concomitantly with the development of rigor contracture. 5. The onset of the rigor was preceded by the increase in intracellular Mg2+ concentration ([Mg2+]i) monitored by mag-indo-1 epifluorescence

  12. Na(+)-K+ pump cycle during beta-adrenergic stimulation of adult rat cardiac myocytes.

    PubMed

    Dobretsov, M; Hastings, S L; Stimers, J R

    1998-03-01

    1. The mechanisms underlying the increase in Na(+)-K+ pump current (Ip) caused by adrenergic stimulation were investigated in cultured adult rat cardiac myocytes using the whole-cell patch-clamp technique at 31-33 degrees C. 2. In myocytes perfused internally with 50 mM Na+ (0 K+i, 20 nM Ca2+, caesium aspartate solution) and externally with 5.4 mM K+o, noradrenaline (NA) and isoprenaline (Iso) (1-50 microM) stimulated Ip by 40-45%. 3. Na(+)-dependent transient Ip measurements with 0 mM K+i and 0 mM K+o revealed no change in the total charge transferred by the Na(+)-K+ pump during the conformational change, suggesting that the pump site density was not changed by adrenergic stimulation (2630 +/- 370 pumps micron-2 in control and 2540 +/- 190 pumps micron-2 in the presence of 10 microM NA). 4. With saturating Na+i or K+o (150 and 15-20 mM, respectively), Ip was still stimulated by NA and Iso. Thus, there was no indication that adrenergic activation of the Na(+)-K+ pump was mediated by accumulation of Na+i and K+o or changes in the Na(+)-K+ pump affinity for Na+i and K+o. 5. Both Ip and its increase under adrenergic stimulation were found to depend on [K+]i. While steady-state Ip decreased from 2.2 +/- 0.1 to 1.2 +/- 0.1 pA pF-1 (P < 0.05), the stimulation of Ip by 10 microM Iso increased from 0.38 +/- 0.04 to 0.67 +/- 0.06 pA pF-1 (P < 0.05) with an increase in [K+]i from 0 to 100 mM. 6. Under conditions that cause the Ip-Vm (membrane potential) relationship to express a positive slope ([Na+]o, 150 mM; [K+]o, 5.4 mM) or a negative slope ([Na+]o, 0; [K+]o, 0.3 mM) Iso stimulated Ip with no change in the shape of Ip-Vm curves. Thus, adrenergic stimulation of the Na(+)-K+ pump was not due to an alteration of voltage-dependent steps of the pump cycle. 7. Simulation of these data with a six-step model of the Na(+)-K+ pump cycle suggested that in rat ventricular myocytes a signal from adrenergic receptors increased the Na(+)-K+ pump rate by modulating the rate of K+ de

  13. Regionally distinct responses of microglia and glial progenitor cells to whole brain irradiation in adult and aging rats.

    PubMed

    Hua, Kun; Schindler, Matthew K; McQuail, Joseph A; Forbes, M Elizabeth; Riddle, David R

    2012-01-01

    Radiation therapy has proven efficacy for treating brain tumors and metastases. Higher doses and larger treatment fields increase the probability of eliminating neoplasms and preventing reoccurrence, but dose and field are limited by damage to normal tissues. Normal tissue injury is greatest during development and in populations of proliferating cells but also occurs in adults and older individuals and in non-proliferative cell populations. To better understand radiation-induced normal tissue injury and how it may be affected by aging, we exposed young adult, middle-aged, and old rats to 10 Gy of whole brain irradiation and assessed in gray- and white matter the responses of microglia, the primary cellular mediators of radiation-induced neuroinflammation, and oligodendrocyte precursor cells, the largest population of proliferating cells in the adult brain. We found that aging and/or irradiation caused only a few microglia to transition to the classically "activated" phenotype, e.g., enlarged cell body, few processes, and markers of phagocytosis, that is seen following more damaging neural insults. Microglial changes in response to aging and irradiation were relatively modest and three markers of reactivity - morphology, proliferation, and expression of the lysosomal marker CD68- were regulated largely independently within individual cells. Proliferation of oligodendrocyte precursors did not appear to be altered during normal aging but increased following irradiation. The impacts of irradiation and aging on both microglia and oligodendrocyte precursors were heterogeneous between white- and gray matter and among regions of gray matter, indicating that there are regional regulators of the neural response to brain irradiation. By several measures, the CA3 region of the hippocampus appeared to be differentially sensitive to effects of aging and irradiation. The changes assessed here likely contribute to injury following inflammatory challenges like brain irradiation and

  14. G protein-coupled receptor kinase-2 is a novel regulator of collagen synthesis in adult human cardiac fibroblasts.

    PubMed

    D'Souza, Karen M; Malhotra, Ricky; Philip, Jennifer L; Staron, Michelle L; Theccanat, Tiju; Jeevanandam, Valluvan; Akhter, Shahab A

    2011-04-29

    Cardiac fibroblasts (CF) make up 60-70% of the total cell number in the heart and play a critical role in regulating normal myocardial function and in adverse remodeling following myocardial infarction and the transition to heart failure. Recent studies have shown that increased intracellular cAMP can inhibit CF transformation and collagen synthesis in adult rat CF; however, mechanisms by which cAMP production is regulated in CF have not been elucidated. We investigated the potential role of G protein-coupled receptor kinase-2 (GRK2) in modulating collagen synthesis by adult human CF isolated from normal and failing left ventricles. Baseline collagen synthesis was elevated in failing CF and was not inhibited by β-agonist stimulation in contrast to normal controls. β-adrenergic receptor (β-AR) signaling was markedly uncoupled in the failing CF, and expression and activity of GRK2 were increased 3-fold. Overexpression of GRK2 in normal CF recapitulated a heart failure phenotype with minimal inhibition of collagen synthesis following β-agonist stimulation. In contrast, knockdown of GRK2 expression in normal CF enhanced cAMP production and led to greater β-agonist-mediated inhibition of basal and TGFβ-stimulated collagen synthesis versus control. Inhibition of GRK2 activity in failing CF by expression of the GRK2 inhibitor, GRK2ct, or siRNA-mediated knockdown restored β-agonist-stimulated inhibition of collagen synthesis and decreased collagen synthesis in response to TGFβ stimulation. GRK2 appears to play a significant role in regulating collagen synthesis in adult human CF, and increased activity of this kinase may be an important mechanism of maladaptive ventricular remodeling as mediated by cardiac fibroblasts.

  15. Cardiac mechanics in patients with human immunodeficiency virus: a study of systolic myocardial deformation in children and young adults.

    PubMed

    Al-Naami, Ghassan; Kiblawi, Fuad; Kest, Helen; Hamdan, Ayman; Myridakis, Dorothy

    2014-08-01

    Human immunodeficiency virus (HIV) infection causes dysfunction of different organ systems. Myocardial diastolic dysfunction has been reported previously in an adult HIV population. Our aim was to study myocardial strain in children and young adults infected by HIV who have apparently normal ejection fraction. Forty HIV-infected patients (mean age 20.6 ± 1.5 years) with normal ejection fraction and 55 matched normal controls (mean age 17 ± 1.5 years) were studied by two-dimensional echocardiogram. The images were stored then exported to velocity vector imaging software for analysis. Measures considered were left-ventricular peak global systolic strain (LV S) and strain rate (LV SR) as well as right-ventricular peak global systolic strain (RV S) and strain rate (RV SR). Circumferential measures of the left ventricle included the following: LV circumferential peak global systolic strain (LV circ S), strain rate (LV circ SR), radial velocity (LV rad vel), and rotational velocity (LV rot vel) at the level of the mitral valve. Statistical significance was set at p < 0.05. The means of all longitudinal deformation parameters were significantly lower in HIV patients compared with normal controls: LV S (-14.15 vs. -19.31), LV SR (-0.88 vs. -1.30), RV S (-19.58 vs. -25.09), and RV SR (-1.34 vs. -2.13), respectively (p < 0.05). LV rot vel was lower in patients compared with controls (43.23 vs. 51.71, p = 0.025). LV circ S, LV circ SR, and LV rad vel showed no significant difference between the two groups (p ≥ 0.05). HIV infection affects longitudinal systolic cardiac strain and strain rate in children and young adults. Normal ejection fraction might be attributed to preserved circumferential myocardial deformation. Strain and strain rate may help identify HIV patients at high risk for cardiac dysfunction and allow early detection of silent myocardial depression.

  16. Stem cells in cardiac repair.

    PubMed

    Henning, Robert J

    2011-01-01

    Myocardial infarction is the leading cause of death among people in industrialized nations. Although the heart has some ability to regenerate after infarction, myocardial restoration is inadequate. Consequently, investigators are currently exploring the use of human embryonic stem cells (hESCs), skeletal myoblasts and adult bone marrow stem cells to limit infarct size. hESCs are pluripotent cells that can regenerate myocardium in infarcted hearts, attenuate heart remodeling and contribute to left ventricle (LV) systolic force development. Since hESCs can form heart teratomas, investigators are differentiating hESCs toward cardiac progenitor cells prior to transplantation into hearts. Large quantities of hESCs cardiac progenitor cells, however, must be generated, immune rejection must be prevented and grafts must survive over the long term to significantly improve myocardial performance. Transplanted autologous skeletal myoblasts can survive in infarcted myocardium in small numbers, proliferate, differentiate into skeletal myofibers and increase the LV ejection fraction. These cells, however, do not form electromechanical connections with host cardiomyocytes. Consequently, electrical re-entry can occur and cause cardiac arrhythmias. Autologous bone marrow mononuclear cells contain hematopoietic and mesenchymal stem cells. In several meta-analyses, patients with coronary disease who received autologous bone marrow cells by intracoronary injection show significant 3.7% (range: 1.9-5.4%) increases in LV ejection fraction, decreases in LV end-systolic volume of -4.8 ml (range: -1.4 to -8.2 ml) and reductions in infarct size of 5.5% (-1.9 to -9.1%), without experiencing arrhythmias. Bone marrow cells appear to release biologically active factors that limit myocardial damage. Unfortunately, bone marrow cells from patients with chronic diseases propagate poorly and can die prematurely. Substantial challenges must be addressed and resolved to advance the use of stem cells

  17. Reduced Long-Term Relative Survival in Females and Younger Adults Undergoing Cardiac Surgery: A Prospective Cohort Study

    PubMed Central

    Enger, Tone Bull; Pleym, Hilde; Stenseth, Roar; Greiff, Guri; Wahba, Alexander; Videm, Vibeke

    2016-01-01

    Objectives To assess long-term survival and mortality in adult cardiac surgery patients. Methods 8,564 consecutive patients undergoing cardiac surgery in Trondheim, Norway from 2000 until censoring 31.12.2014 were prospectively followed. Observed long-term mortality following surgery was compared to the expected mortality in the Norwegian population, matched on gender, age and calendar year. This enabled assessment of relative survival (observed/expected survival rates) and relative mortality (observed/expected deaths). Long-term mortality was compared across gender, age and surgical procedure. Predictors of reduced survival were assessed with multivariate analyses of observed and relative mortality. Results During follow-up (median 6.4 years), 2,044 patients (23.9%) died. The observed 30-day, 1-, 3- and 5-year mortality rates were 2.2%, 4.4%, 8.2% and 13.8%, respectively, and remained constant throughout the study period. Comparing observed mortality to that expected in a matched sample from the general population, patients undergoing cardiac surgery showed excellent survival throughout the first seven years of follow-up (relative survival ≥ 1). Subsequently, survival decreased, which was more pronounced in females and patients undergoing other procedures than isolated coronary artery bypass grafting (CABG). Relative mortality was higher in younger age groups, females and patients undergoing aortic valve replacement (AVR). The female survival advantage in the general population was obliterated (relative mortality ratio (RMR) 1.35 (1.19–1.54), p<0.001). Increasing observed long-term mortality seen with ageing was due to population risk, and younger age was independently associated with increased relative mortality (RMR per 5 years 0.81 (0.79–0.84), p<0.001)). Conclusions Cardiac surgery patients showed comparable survival to that expected in the general Norwegian population, underlining the benefits of cardiac surgery in appropriately selected patients. The

  18. Innovation in basic science: stem cells and their role in the treatment of paediatric cardiac failure--opportunities and challenges.

    PubMed

    Kaushal, Sunjay; Jacobs, Jeffrey Phillip; Gossett, Jeffrey G; Steele, Ann; Steele, Peter; Davis, Craig R; Pahl, Elfriede; Vijayan, Kalpana; Asante-Korang, Alfred; Boucek, Robert J; Backer, Carl L; Wold, Loren E

    2009-11-01

    Heart failure is a leading cause of death worldwide. Current therapies only delay progression of the cardiac disease or replace the diseased heart with cardiac transplantation. Stem cells represent a recently discovered novel approach to the treatment of cardiac failure that may facilitate the replacement of diseased cardiac tissue and subsequently lead to improved cardiac function and cardiac regeneration. A stem cell is defined as a cell with the properties of being clonogenic, self-renewing, and multipotent. In response to intercellular signalling or environmental stimuli, stem cells differentiate into cells derived from any of the three primary germ layers: ectoderm, endoderm, and mesoderm, a powerful advantage for regenerative therapies. Meanwhile, a cardiac progenitor cell is a multipotent cell that can differentiate into cells of any of the cardiac lineages, including endothelial cells and cardiomyocytes. Stem cells can be classified into three categories: (1) adult stem cells, (2) embryonic stem cells, and (3) induced pluripotential cells. Adult stem cells have been identified in numerous organs and tissues in adults, including bone-marrow, skeletal muscle, adipose tissue, and, as was recently discovered, the heart. Embryonic stem cells are derived from the inner cell mass of the blastocyst stage of the developing embryo. Finally through transcriptional reprogramming, somatic cells, such as fibroblasts, can be converted into induced pluripotential cells that resemble embryonic stem cells. Four classes of stem cells that may lead to cardiac regeneration are: (1) Embryonic stem cells, (2) Bone Marrow derived stem cells, (3) Skeletal myoblasts, and (4) Cardiac stem cells and cardiac progenitor cells. Embryonic stem cells are problematic because of several reasons: (1) the formation of teratomas, (2) potential immunologic cellular rejection, (3) low efficiency of their differentiation into cardiomyocytes, typically 1% in culture, and (4) ethical and political

  19. Care for the adult family members of victims of unexpected cardiac death.

    PubMed

    Zalenski, Robert; Gillum, Richard F; Quest, Tammie E; Griffith, James L

    2006-12-01

    More than 300,000 sudden coronary deaths occur annually in the United States, despite declining cardiovascular death rates. In 2000, deaths from heart disease left an estimated 190,156 new widows and 68,493 new widowers. A major unanswered question for emergency providers is whether the immediate care of the loved ones left behind by the deceased should be a therapeutic task for the staff of the emergency department in the aftermath of a fatal cardiac arrest. Based on a review of the literature, the authors suggest that more research is needed to answer this question, to assess the current immediate needs and care of survivors, and to find ways to improve care of the surviving family of unexpected cardiac death victims. This would include improving quality of death disclosure, improving care for relatives during cardiopulmonary resuscitation of their family member, and improved methods of referral for services for prevention of psychological and cardiovascular morbidity during bereavement. PMID:16946285

  20. O-GlcNAcylation Negatively Regulates Cardiomyogenic Fate in Adult Mouse Cardiac Mesenchymal Stromal Cells

    PubMed Central

    Zafir, Ayesha; Bradley, James A.; Long, Bethany W.; Muthusamy, Senthilkumar; Li, Qianhong; Hill, Bradford G.; Wysoczynski, Marcin; Prabhu, Sumanth D.; Bhatnagar, Aruni; Bolli, Roberto; Jones, Steven P.

    2015-01-01

    In both preclinical and clinical studies, cell transplantation of several cell types is used to promote repair of damaged organs and tissues. Nevertheless, despite the widespread use of such strategies, there remains little understanding of how the efficacy of cell therapy is regulated. We showed previously that augmentation of a unique, metabolically derived stress signal (i.e., O-GlcNAc) improves survival of cardiac mesenchymal stromal cells; however, it is not known whether enhancing O-GlcNAcylation affects lineage commitment or other aspects of cell competency. In this study, we assessed the role of O-GlcNAc in differentiation of cardiac mesenchymal stromal cells. Exposure of these cells to routine differentiation protocols in culture increased markers of the cardiomyogenic lineage such as Nkx2.5 and connexin 40, and augmented the abundance of transcripts associated with endothelial and fibroblast cell fates. Differentiation significantly decreased the abundance of O-GlcNAcylated proteins. To determine if O-GlcNAc is involved in stromal cell differentiation, O-GlcNAcylation was increased pharmacologically during the differentiation protocol. Although elevated O-GlcNAc levels did not significantly affect fibroblast and endothelial marker expression, acquisition of cardiomyocyte markers was limited. In addition, increasing O-GlcNAcylation further elevated smooth muscle actin expression. In addition to lineage commitment, we also evaluated proliferation and migration, and found that increasing O-GlcNAcylation did not significantly affect either; however, we found that O-GlcNAc transferase—the protein responsible for adding O-GlcNAc to proteins—is at least partially required for maintaining cellular proliferative and migratory capacities. We conclude that O-GlcNAcylation contributes significantly to cardiac mesenchymal stromal cell lineage and function. O-GlcNAcylation and pathological conditions that may affect O-GlcNAc levels (such as diabetes) should be

  1. Management of intraoperative fluid balance and blood conservation techniques in adult cardiac surgery.

    PubMed

    Vretzakis, George; Kleitsaki, Athina; Aretha, Diamanto; Karanikolas, Menelaos

    2011-02-01

    Blood transfusions are associated with adverse physiologic effects and increased cost, and therefore reduction of blood product use during surgery is a desirable goal for all patients. Cardiac surgery is a major consumer of donor blood products, especially when cardiopulmonary bypass (CPB) is used, because hematocrit drops precipitously during CPB due to blood loss and blood cell dilution. Advanced age, low preoperative red blood cell volume (preoperative anemia or small body size), preoperative antiplatelet or antithrombotic drugs, complex or re-operative procedures or emergency operations, and patient comorbidities were identified as important transfusion risk indicators in a report recently published by the Society of Cardiovascular Anesthesiologists. This report also identified several pre- and intraoperative interventions that may help reduce blood transfusions, including off-pump procedures, preoperative autologous blood donation, normovolemic hemodilution, and routine cell saver use.A multimodal approach to blood conservation, with high-risk patients receiving all available interventions, may help preserve vital organ perfusion and reduce blood product utilization. In addition, because positive intravenous fluid balance is a significant factor affecting hemodilution during cardiac surgery, especially when CPB is used, strategies aimed at limiting intraoperative fluid balance positiveness may also lead to reduced blood product utilization.This review discusses currently available techniques that can be used intraoperatively in an attempt to avoid or minimize fluid balance positiveness, to preserve the patient's own red blood cells, and to decrease blood product utilization during cardiac surgery. PMID:21345774

  2. Cardiac catheterization

    MedlinePlus

    Catheterization - cardiac; Heart catheterization; Angina - cardiac catheterization; CAD - cardiac catheterization; Coronary artery disease - cardiac catheterization; Heart valve - cardiac catheterization; Heart failure - ...

  3. Cardiac Conduction Safety during Coadministration of Artemether-Lumefantrine and Lopinavir/Ritonavir in HIV-Infected Ugandan Adults

    PubMed Central

    Byakika-Kibwika, Pauline; Lamorde, Mohammed; Lwabi, Peter; Nyakoojo, Wilson B.; Okaba-Kayom, Violet; Mayanja-Kizza, Harriet; Boffito, Marta; Katabira, Elly; Back, David; Khoo, Saye; Merry, Concepta

    2011-01-01

    Background. We aimed to assess cardiac conduction safety of coadministration of the CYP3A4 inhibitor lopinavir/ritonavir (LPV/r) and the CYP3A4 substrate artemether-lumefantrine (AL) in HIV-positive Ugandans. Methods. Open-label safety study of HIV-positive adults administered single-dose AL (80/400 mg) alone or with LPV/r (400/100 mg). Cardiac function was monitored using continuous electrocardiograph (ECG). Results. Thirty-two patients were enrolled; 16 taking LPV/r -based ART and 16 ART naïve. All took single dose AL. No serious adverse events were observed. ECG parameters in milliseconds remained within normal limits. QTc measurements did not change significantly over 72 hours although were higher in LPV/r arm at 24 (424 versus 406; P = .02) and 72 hours (424 versus 408; P = .004) after AL intake. Conclusion. Coadministration of single dose of AL with LPV/r was safe; however, safety of six-dose AL regimen with LPV/r should be investigated. PMID:22312553

  4. Sublethal exposure to crude oil during embryonic development alters cardiac morphology and reduces aerobic capacity in adult fish

    PubMed Central

    Hicken, Corinne E.; Linbo, Tiffany L.; Baldwin, David H.; Willis, Maryjean L.; Myers, Mark S.; Holland, Larry; Larsen, Marie; Stekoll, Michael S.; Rice, Stanley D.; Collier, Tracy K.; Scholz, Nathaniel L.; Incardona, John P.

    2011-01-01

    Exposure to high concentrations of crude oil produces a lethal syndrome of heart failure in fish embryos. Mortality is caused by cardiotoxic polycyclic aromatic hydrocarbons (PAHs), ubiquitous components of petroleum. Here, we show that transient embryonic exposure to very low concentrations of oil causes toxicity that is sublethal, delayed, and not counteracted by the protective effects of cytochrome P450 induction. Nearly a year after embryonic oil exposure, adult zebrafish showed subtle changes in heart shape and a significant reduction in swimming performance, indicative of reduced cardiac output. These delayed physiological impacts on cardiovascular performance at later life stages provide a potential mechanism linking reduced individual survival to population-level ecosystem responses of fish species to chronic, low-level oil pollution. PMID:21482755

  5. Extrinsic cardiac nerve segments in the domestic dog (Canis familiaris- Linnaeus, 1758). Comparative study in young and adult dogs.

    PubMed

    Brugnaro, M; De Souza, R R; Ribeiro, A A C M

    2003-08-01

    In this paper, important connections between the two main contingents of the autonomic nervous system, intrinsic and extrinsic visceral plexus were analysed. Concerning heart innervation, the territories of extrinsic innervation are very important in the treatment of congenital or acquired cardiopathy, thoracic neoplasia and aortic arch persistence, among others. This research compared young and adult extrinsic cardiac innervation and described the surgical anatomic nerve segments. Animals were perfused with a 10% formaldehyde solution in PBS (0.1 m) (pH 7.4) and submitted to macro- and meso-scopic dissection immersed in 60% acetic acid alcoholic solution and 20% hydrogen peroxide aqueous solution. The nerve segments were assigned as: right vagus nerve segment, left vagus nerve segment, right middle cervical ganglion segment, left middle cervical ganglion segment, right caudal laryngeal nerve segment, left caudal laryngeal nerve segment, right phrenic nerve segment and left phrenic nerve segment.

  6. Local Mesenchymal Stem/Progenitor Cells Are a Preferential Target for Initiation of Adult Soft Tissue Sarcomas Associated with p53 and Rb Deficiency

    PubMed Central

    Choi, Jinhyang; Curtis, Stephen J.; Roy, David M.; Flesken-Nikitin, Andrea; Nikitin, Alexander Yu.

    2010-01-01

    The cell of origin and pathogenesis of the majority of adult soft tissue sarcomas (STS) remains poorly understood. Because mutations in both the P53 and RB tumor suppressor genes are frequent in STS in humans, we inactivated these genes by Cre-loxP–mediated recombination in mice with floxed p53 and Rb. Ninety-three percent of mice developed spindle cell/pleomorphic sarcomas after a single subcutaneous injection of adenovirus carrying Cre-recombinase. Similar to human STS, these sarcomas overexpress Cxcr4, which contributes to their invasive properties. Using irradiation chimeras generated by transplanting bone marrow cells from mice carrying either the Rosa26StoploxPLacZ or the Z/EG reporter, as well as the floxed p53 and Rb genes, into irradiated p53loxP/loxPRbloxP/loxP mice, it was determined that sarcomas do not originate from bone marrow–derived cells, such as macrophages, but arise from the local resident cells. At the same time, dermal mesenchymal stem cells isolated by strict plastic adherence and low levels of Sca-1 expression (Sca-1low, CD31negCD45neg) have shown enhanced potential for malignant transformation according to soft agar, invasion, and tumorigenicity assays, after the conditional inactivation of both p53 and Rb. Sarcomas formed after transplantation of these cells have features typical for undifferentiated high-grade pleomorphic sarcomas. Taken together, our studies indicate that local Sca-1low dermal mesenchymal stem/progenitor cells are preferential targets for malignant transformation associated with deficiencies in both p53 and Rb. PMID:20864684

  7. Evaluation of the influence of pulmonary hypertension in ultra-fast-track anesthesia technique in adult patients undergoing cardiac surgery

    PubMed Central

    da Silva, Paulo Sérgio; Cartacho, Márcio Portugal Trindade; de Castro, Casimiro Cardoso; Salgado Filho, Marcello Fonseca; Brandão, Antônio Carlos Aguiar

    2015-01-01

    Objective To evaluate the influence of pulmonary hypertension in the ultra-fast-track anesthesia technique in adult cardiac surgery. Methods A retrospective study. They were included 40 patients divided into two groups: GI (without pulmonary hypertension) and GII (with pulmonary hypertension). Based on data obtained by transthoracic echocardiography. We considered as the absence of pulmonary hypertension: a pulmonary artery systolic pressure (sPAP) <36 mmHg, with tricuspid regurgitation velocity <2.8 m/s and no additional echocardiographic signs of PH, and PH as presence: a sPAP >40 mmHg associated with additional echocardiographic signs of PH. It was established as influence of pulmonary hypertension: the impossibility of extubation in the operating room, the increase in the time interval for extubation and reintubation the first 24 hours postoperatively. Univariate and multivariate analyzes were performed when necessary. Considered significant a P value <0.05. Results The GI was composed of 21 patients and GII for 19. All patients (100%) were extubated in the operating room in a medium time interval of 17.58±8.06 min with a median of 18 min in GII and 17 min in GI. PH did not increase the time interval for extubation (P=0.397). It required reintubation of 2 patients in GII (5% of the total), without statistically significant as compared to GI (P=0.488). Conclusion In this study, pulmonary hypertension did not influence on ultra-fast-track anesthesia in adult cardiac surgery. PMID:27163419

  8. Novel biomarkers for early diagnosis of acute kidney injury after cardiac surgery in adults

    PubMed Central

    Kališnik, Jurij Matija

    2016-01-01

    Acute kidney injury after cardiac surgery with cardiopulmonary bypass is a common and serious complication and it is associated with increased morbidity and mortality. Diagnosis of acute kidney injury is based on the serum creatinine levels which rise several hours to days after the initial injury. Thus, novel biomarkers that will enable faster diagnosis are needed in clinical practice. There are numerous urine and serum proteins that indicate kidney injury and are under extensive research. Despite promising basic research results and assembled data, which indicate superiority of some biomarkers to creatinine, we are still awaiting clinical application. PMID:27212976

  9. Cancer survivorship: cardiotoxic therapy in the adult cancer patient; cardiac outcomes with recommendations for patient management.

    PubMed

    Steingart, Richard M; Yadav, Nandini; Manrique, Carlos; Carver, Joseph R; Liu, Jennifer

    2013-12-01

    Many types of cancer are now curable or, if not cured, becoming a chronic illness. In 2012, it was estimated that there were more than 13,500,000 cancer survivors in the United States. Late outcomes of these survivors are increasingly related to cardiovascular disease, either as a consequence of the direct effects of cancer therapy or its adverse effects on traditional cardiac risk factors (eg, obesity, hypertension, dyslipidemia, and diabetes mellitus). This article describes the therapies that have led to advances in cancer survival and the acute and chronic cardiovascular toxicities associated with these therapies. Recommendations are made for the surveillance and management of cancer survivors. Published guidelines on the subject of cardio-oncology are reviewed in light of clinical experience caring for these patients. To supplement this cancer-related knowledge base, appropriateness criteria and guidelines for cardiac care in the general population were extrapolated to cancer survivors. The result is a series of recommendations for surveillance and management of cardiovascular disease in cancer survivors. PMID:24331191

  10. A Meta-Analysis of Renal Function After Adult Cardiac Surgery With Pulsatile Perfusion.

    PubMed

    Nam, Myung Ji; Lim, Choon Hak; Kim, Hyun-Jung; Kim, Yong Hwi; Choi, Hyuk; Son, Ho Sung; Lim, Hae Ja; Sun, Kyung

    2015-09-01

    The aim of this meta-analysis was to determine whether pulsatile perfusion during cardiac surgery has a lesser effect on renal dysfunction than nonpulsatile perfusion after cardiac surgery in randomized controlled trials. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were used to identify available articles published before April 25, 2014. Meta-analysis was conducted to determine the effects of pulsatile perfusion on postoperative renal functions, as determined by creatinine clearance (CrCl), serum creatinine (Cr), urinary neutrophil gelatinase-associated lipocalin (NGAL), and the incidences of acute renal insufficiency (ARI) and acute renal failure (ARF). Nine studies involving 674 patients that received pulsatile perfusion and 698 patients that received nonpulsatile perfusion during cardiopulmonary bypass (CPB) were considered in the meta-analysis. Stratified analysis was performed according to effective pulsatility or unclear pulsatility of the pulsatile perfusion method in the presence of heterogeneity. NGAL levels were not significantly different between the pulsatile and nonpulsatile groups. However, patients in the pulsatile group had a significantly higher CrCl and lower Cr levels when the analysis was restricted to studies on effective pulsatile flow (P < 0.00001, respectively). The incidence of ARI was significantly lower in the pulsatile group (P < 0.00001), but incidences of ARF were similar. In conclusion, the meta-analysis suggests that the use of pulsatile flow during CPB results in better postoperative renal function.

  11. Endometrial stem/progenitor cells: the first 10 years

    PubMed Central

    Gargett, Caroline E.; Schwab, Kjiana E.; Deane, James A.

    2016-01-01

    BACKGROUND The existence of stem/progenitor cells in the endometrium was postulated many years ago, but the first functional evidence was only published in 2004. The identification of rare epithelial and stromal populations of clonogenic cells in human endometrium has opened an active area of research on endometrial stem/progenitor cells in the subsequent 10 years. METHODS The published literature was searched using the PubMed database with the search terms ‘endometrial stem cells and menstrual blood stem cells' until December 2014. RESULTS Endometrial epithelial stem/progenitor cells have been identified as clonogenic cells in human and as label-retaining or CD44+ cells in mouse endometrium, but their characterization has been modest. In contrast, endometrial mesenchymal stem/stromal cells (MSCs) have been well characterized and show similar properties to bone marrow MSCs. Specific markers for their enrichment have been identified, CD146+PDGFRβ+ (platelet-derived growth factor receptor beta) and SUSD2+ (sushi domain containing-2), which detected their perivascular location and likely pericyte identity in endometrial basalis and functionalis vessels. Transcriptomics and secretomics of SUSD2+ cells confirm their perivascular phenotype. Stromal fibroblasts cultured from endometrial tissue or menstrual blood also have some MSC characteristics and demonstrate broad multilineage differentiation potential for mesodermal, endodermal and ectodermal lineages, indicating their plasticity. Side population (SP) cells are a mixed population, although predominantly vascular cells, which exhibit adult stem cell properties, including tissue reconstitution. There is some evidence that bone marrow cells contribute a small population of endometrial epithelial and stromal cells. The discovery of specific markers for endometrial stem/progenitor cells has enabled the examination of their role in endometrial proliferative disorders, including endometriosis, adenomyosis and Asherman

  12. Cardiac AAV9 Gene Delivery Strategies in Adult Canines: Assessment by Long-term Serial SPECT Imaging of Sodium Iodide Symporter Expression

    PubMed Central

    Moulay, Gilles; Ohtani, Tomohito; Ogut, Ozgur; Guenzel, Adam; Behfar, Atta; Zakeri, Rosita; Haines, Philip; Storlie, Jimmy; Bowen, Lorna; Pham, Linh; Kaye, David; Sandhu, Gurpreet; O'Connor, Michael; Russell, Stephen; Redfield, Margaret

    2015-01-01

    Heart failure is a leading cause of morbidity and mortality, and cardiac gene delivery has the potential to provide novel therapeutic approaches. Adeno-associated virus serotype 9 (AAV9) transduces the rodent heart efficiently, but cardiotropism, immune tolerance, and optimal delivery strategies in large animals are unclear. In this study, an AAV9 vector encoding canine sodium iodide symporter (NIS) was administered to adult immunocompetent dogs via epicardial injection, coronary infusion without and with cardiac recirculation, or endocardial injection via a novel catheter with curved needle and both end- and side-holes. As NIS mediates cellular uptake of clinical radioisotopes, expression was tracked by single-photon emission computerized tomography (SPECT) imaging in addition to Western blot and immunohistochemistry. Direct epicardial or endocardial injection resulted in strong cardiac expression, whereas expression after intracoronary infusion or cardiac recirculation was undetectable. A threshold myocardial injection dose that provides robust nonimmunogenic expression was identified. The extent of transmural myocardial expression was greater with the novel catheter versus straight end-hole needle delivery. Furthermore, the authors demonstrate that cardiac NIS reporter gene expression and duration can be quantified using serial noninvasive SPECT imaging up to 1 year after vector administration. These data are relevant to efforts to develop cardiac gene delivery as heart failure therapy. PMID:25915925

  13. Cardiac AAV9 Gene Delivery Strategies in Adult Canines: Assessment by Long-term Serial SPECT Imaging of Sodium Iodide Symporter Expression.

    PubMed

    Moulay, Gilles; Ohtani, Tomohito; Ogut, Ozgur; Guenzel, Adam; Behfar, Atta; Zakeri, Rosita; Haines, Philip; Storlie, Jimmy; Bowen, Lorna; Pham, Linh; Kaye, David; Sandhu, Gurpreet; O'Connor, Michael; Russell, Stephen; Redfield, Margaret

    2015-07-01

    Heart failure is a leading cause of morbidity and mortality, and cardiac gene delivery has the potential to provide novel therapeutic approaches. Adeno-associated virus serotype 9 (AAV9) transduces the rodent heart efficiently, but cardiotropism, immune tolerance, and optimal delivery strategies in large animals are unclear. In this study, an AAV9 vector encoding canine sodium iodide symporter (NIS) was administered to adult immunocompetent dogs via epicardial injection, coronary infusion without and with cardiac recirculation, or endocardial injection via a novel catheter with curved needle and both end- and side-holes. As NIS mediates cellular uptake of clinical radioisotopes, expression was tracked by single-photon emission computerized tomography (SPECT) imaging in addition to Western blot and immunohistochemistry. Direct epicardial or endocardial injection resulted in strong cardiac expression, whereas expression after intracoronary infusion or cardiac recirculation was undetectable. A threshold myocardial injection dose that provides robust nonimmunogenic expression was identified. The extent of transmural myocardial expression was greater with the novel catheter versus straight end-hole needle delivery. Furthermore, the authors demonstrate that cardiac NIS reporter gene expression and duration can be quantified using serial noninvasive SPECT imaging up to 1 year after vector administration. These data are relevant to efforts to develop cardiac gene delivery as heart failure therapy. PMID:25915925

  14. Cardiac misconceptions among healthy adults: implications for the promotion of health in the community.

    PubMed

    Figueiras, Maria João; Maroco, João; Monteiro, Rita; Caeiro, Raul

    2015-03-01

    This study sought to confirm the structure and to investigate the psychometric properties of an experimental Portuguese version of the York Cardiac Beliefs Questionnaire (YCBQ) in a general population sample. It also set out to identify the prevalent misconceptions in the community and to assess the differences according to socio-demographic characteristics. It involved a cross-sectional survey in which both test and validation samples were collected (n = 476), including participants aged between 18 and 40, recruited via e-mail and social networks. The Confirmatory Factor Analysis on both samples suggested a shorter, three factor version of the YCBQ. Also, misconceptions differed significantly according to sociodemographic variables. The validation of the YCBQ for samples in the community constitutes an important starting point to promote research on misconceptions held in the community by specific groups, as well as to provide key points for health promotion. PMID:25760124

  15. Anatomic correction of ALCAPA in an adult presenting with sudden cardiac death

    PubMed Central

    Simry, Walid; Afifi, Ahmed; Hosny, Hatem; Elguindy, Ahmed; Yacoub, Magdi

    2015-01-01

    We report on a young adult with ALCAPA, who was successfully resuscitated after collapsing in ventricular fibrillation while playing football. This was followed by anatomical correction of the anomaly with a smooth recovery and return to his daily activities. The advantages of this approach are discussed in this brief report. PMID:26779521

  16. Primary Prevention of Sudden Cardiac Death in Adults with Transposition of the Great Arteries: A Review of Implantable Cardioverter-Defibrillator Placement

    PubMed Central

    Cedars, Ari M.

    2015-01-01

    Transposition of the great arteries encompasses a set of structural congenital cardiac lesions that has in common ventriculoarterial discordance. Primarily because of advances in medical and surgical care, an increasing number of children born with this anomaly are surviving into adulthood. Depending upon the subtype of lesion or the particular corrective surgery that the patient might have undergone, this group of adult congenital heart disease patients constitutes a relatively new population with unique medical sequelae. Among the more common and difficult to manage are cardiac arrhythmias and other sequelae that can lead to sudden cardiac death. To date, the question of whether implantable cardioverter-defibrillators should be placed in this cohort as a preventive measure to abort sudden death has largely gone unanswered. Therefore, we review the available literature surrounding this issue. PMID:26413012

  17. Primary Prevention of Sudden Cardiac Death in Adults with Transposition of the Great Arteries: A Review of Implantable Cardioverter-Defibrillator Placement.

    PubMed

    Sodhi, Sandeep S; Cedars, Ari M

    2015-08-01

    Transposition of the great arteries encompasses a set of structural congenital cardiac lesions that has in common ventriculoarterial discordance. Primarily because of advances in medical and surgical care, an increasing number of children born with this anomaly are surviving into adulthood. Depending upon the subtype of lesion or the particular corrective surgery that the patient might have undergone, this group of adult congenital heart disease patients constitutes a relatively new population with unique medical sequelae. Among the more common and difficult to manage are cardiac arrhythmias and other sequelae that can lead to sudden cardiac death. To date, the question of whether implantable cardioverter-defibrillators should be placed in this cohort as a preventive measure to abort sudden death has largely gone unanswered. Therefore, we review the available literature surrounding this issue. PMID:26413012

  18. The neonate versus adult mammalian immune system in cardiac repair and regeneration.

    PubMed

    Sattler, Susanne; Rosenthal, Nadia

    2016-07-01

    The immune system is a crucial player in tissue homeostasis and wound healing. A sophisticated cascade of events triggered upon injury ensures protection from infection and initiates and orchestrates healing. While the neonatal mammal can readily regenerate damaged tissues, adult regenerative capacity is limited to specific tissue types, and in organs such as the heart, adult wound healing results in fibrotic repair and loss of function. Growing evidence suggests that the immune system greatly influences the balance between regeneration and fibrotic repair. The neonate mammalian immune system has impaired pro-inflammatory function, is prone to T-helper type 2 responses and has an immature adaptive immune system skewed towards regulatory T cells. While these characteristics make infants susceptible to infection and prone to allergies, it may also provide an immunological environment permissive of regeneration. In this review we will give a comprehensive overview of the immune cells involved in healing and regeneration of the heart and explore differences between the adult and neonate immune system that may explain differences in regenerative ability. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.

  19. Endothelial progenitor cells--an evolving story.

    PubMed

    Pearson, Jeremy D

    2010-05-01

    The first description of endothelial progenitor cells (EPC) in 1997 led rapidly to substantial changes in our understanding of angiogenesis, and within 5 years to the first clinical studies in humans using bone marrow derived EPC to enhance coronary neovascularisation and cardiac function after myocardial ischemia. However, to improve the success of this therapy a clearer understanding of the biology of EPC is needed. This article summarises recent data indicating that most EPC are not, in fact, endothelial progenitors but can be better described as angiogenic monocytes, and explores the implications this has for their future therapeutic use.

  20. When, where and how to initiate hypothermia after adult cardiac arrest.

    PubMed

    Taccone, F S; Donadello, K; Beumier, M; Scolletta, S

    2011-09-01

    Therapeutich hypothermia (TH) has been shown to improve neurological outcome and survival after witnessed cardiac arrest (CA) that is due to ventricular fibrillation. Although TH is widely used following witnessed CA as well as all forms of initial rhythm, the mortality rate after CA remains unacceptably high, and additional study is needed to understand when and how to implement hypothermia in the post-resuscitation phase. Experimental studies have emphasized the importance of initiating cooling soon after the return of spontaneous circulation (ROSC) or even during cardiopulmonary resuscitation (CPR). Clinical studies have shown that pre-hospital induction of hypothermia is feasible and has no major adverse events-even when used intra-arrest-and may provide some additional benefits compared to delayed in-hospital cooling. Thus, hypothermia use should not be limited to the Intensive Care Unit but can be initiated in the field/ambulance or in the Emergency Department, then continued after hospital admission- even during specific procedures such as coronary angiography-as part of the global management of CA patients. Various methods (both non-invasive and invasive) are available to achieve and maintain the target temperature; however, only some of these methods-which include cold fluids, ice packs, iced pads and helmet and trans-nasal cooling- are easily deployed in the pre-hospital setting. PMID:21878875

  1. Pravastatin Improves Function in Hibernating Myocardium by Mobilizing CD133+ and cKit+ Bone Marrow Progenitor Cells and Promoting Myocytes to Reenter the Growth Phase of the Cardiac Cell Cycle

    PubMed Central

    Suzuki, Gen; Iyer, Vijay; Cimato, Thomas; Canty, John M.

    2009-01-01

    HMG-CoA reductase inhibitors have been reported to increase circulating bone marrow progenitor cells (BMPCs) and variably improve global function in heart failure. The potential role of improved perfusion vs. direct effects of statins on cardiac myocytes has not been established. We chronically instrumented swine with an LAD stenosis to produce chronic hibernating myocardium with regional contractile dysfunction in the absence of heart failure. Hemodynamics, function, perfusion and histopathology were assessed in pigs treated for five-weeks with pravastatin (n=12) vs. untreated controls (n=10). Regional LAD wall thickening was depressed under baseline conditions (LAD 3.7±0.3 vs. 6.6 ±0.3 in remote regions, p<0.01). It remained unchanged in untreated animals but increased from 3.8±0.6 to 5.2±0.5 mm after pravastatin (p<0.01). There was no increase in myocardial perfusion at rest or during vasodilation. Pravastatin mobilized circulating CD133+/cKit+ BMPCs and increased myocardial tissue levels (LAD CD133+ cells from 140±33 to 884±167 cells/106myocyte nuclei and cKit+ cells from 223±49 to 953±123 cells/106myocyte nuclei). Pravastatin increased myocytes in mitosis (phospho-histone-H3; 9±5 to 43±7 nuclei/106myocyte nuclei, p<0.05) and the growth phase of the cell cycle (Ki67; 410±82 to 1261±235 nuclei/106myocyte nuclei, p<0.05) in diseased but not normal hearts. As a result, pravastatin increased LAD myocyte nuclear density from 830±41 to 1027±55 nuclei/mm2 (p<0.05). These data indicate that, in the absence of impaired endothelial function and heart failure, dysfunctional hibernating myocardium improves after pravastatin. This effect is independent of myocardial perfusion and related to mobilization of CD133+/cKit+ BMPCs which stimulate myocyte proliferation resulting in quantitative increases in myocyte nuclear density. PMID:19096024

  2. Child-to-Adult Liver Transplantation With Donation After Cardiac Death Donors: Three Case Reports.

    PubMed

    Hu, Liangshuo; Liu, Xuemin; Zhang, Xiaogang; Yu, Liang; Sha, Huanchen; Zhou, Ying; Tian, Min; Shi, Jianhua; Wang, Wanli; Liu, Chang; Guo, Kun; Lv, Yi; Wang, Bo

    2016-02-01

    Development of organ transplantation is restricted by the discrepancy between the lack of donors and increasing number of patients. The outcome of pediatric donors transplanted into adult recipients especially with donation after circulatory death (DCD) pattern has not been well studied. The aim of this paper is to describe our experience of 3 successful DCD donor child-to-adult liver transplantations lately. Three DCD donors were separately 7, 5, and 8 years old. The ratio between donor graft weight and recipient body weight was 1.42%, 1.00%, and 1.33%, respectively. Ratio between the volume of donor liver and the expected liver volume was 0.65, 0.46, and 0.60. Splenectomy was undertaken for the second recipient according to the portal vein pressure (PVP) which was observed during the operation. Two out of 3 of the recipients suffered with acute kidney injury and got recovered after renal replacement therapy. The first recipient also went through early allograft dysfunction and upper gastrointestinal bleeding. The hospital course of the third recipient was uneventful. After 1 year of follow-up visit, the first and second recipients maintain good quality of life and liver function. The third patient was followed up for 5 months until now and recovered well. DCD child-to-adult liver transplantation should only be used for comparatively matched donor and recipient. PVP should be monitored during the operation. The short-term efficacy is good, but long-term follow-up and clinical study with large sample evaluation are still needed.

  3. Child-to-Adult Liver Transplantation With Donation After Cardiac Death Donors

    PubMed Central

    Hu, Liangshuo; Liu, Xuemin; Zhang, Xiaogang; Yu, Liang; Sha, Huanchen; Zhou, Ying; Tian, Min; Shi, Jianhua; Wang, Wanli; Liu, Chang; Guo, Kun; Lv, Yi; Wang, Bo

    2016-01-01

    Abstract Development of organ transplantation is restricted by the discrepancy between the lack of donors and increasing number of patients. The outcome of pediatric donors transplanted into adult recipients especially with donation after circulatory death (DCD) pattern has not been well studied. The aim of this paper is to describe our experience of 3 successful DCD donor child-to-adult liver transplantations lately. Three DCD donors were separately 7, 5, and 8 years old. The ratio between donor graft weight and recipient body weight was 1.42%, 1.00%, and 1.33%, respectively. Ratio between the volume of donor liver and the expected liver volume was 0.65, 0.46, and 0.60. Splenectomy was undertaken for the second recipient according to the portal vein pressure (PVP) which was observed during the operation. Two out of 3 of the recipients suffered with acute kidney injury and got recovered after renal replacement therapy. The first recipient also went through early allograft dysfunction and upper gastrointestinal bleeding. The hospital course of the third recipient was uneventful. After 1 year of follow-up visit, the first and second recipients maintain good quality of life and liver function. The third patient was followed up for 5 months until now and recovered well. DCD child-to-adult liver transplantation should only be used for comparatively matched donor and recipient. PVP should be monitored during the operation. The short-term efficacy is good, but long-term follow-up and clinical study with large sample evaluation are still needed. PMID:26886643

  4. Use and Utility of Hemostatic Screening in Adults Undergoing Elective, Non-Cardiac Surgery

    PubMed Central

    Weil, Isabel A.; Seicean, Sinziana; Neuhauser, Duncan; Schiltz, Nicholas K.; Seicean, Andreea

    2015-01-01

    Introduction One view of value in medicine is outcome relative to cost of care provided. With respect to operative care, increased attention has been placed on evaluation and optimization of patients prior to undergoing an elective surgery. We examined more than 2 million patients having elective, non-cardiac surgery to assess the incidence and utility of pre-operative hemostatic screening, compared with a composite of history variables that may indicate a propensity for bleeding, to assess several important outcomes of surgery. Materials & Methods We queried the NSQIP database to identify 2,020,533 patients and compared hemostatic tests (PT, aPTT, platelet count) and history covariables indicative of potential for abnormal hemostasis. We compared outcomes across predictor values; used Person’s chi-square tests to compare differences, and logistic regression to model outcomes. Results Approximately 36% of patients had all three tests pre-operatively while 16% had none of them; 11.2% had a history predictive of potential abnormal bleeding. Outcomes of interest across the cohort included death in 0.7%, unplanned return to the operating room or re-admission within 30 days in 3.8% and 6.2% of patients; 5.3% received a transfusion during or after surgery. Sub-analyses in each of the nine surgical specialties’ most common procedures yielded similar results. Conclusion The limited predictive value of each hemostatic screening test, as well as excess costs associated with them, across a broad spectrum of elective surgeries, suggests that limiting pre-operative testing to a more select group of patients may be reasonable, equally efficacious, efficient, and cost-effective. PMID:26623648

  5. Mending broken hearts: cardiac development as a basis for adult heart regeneration and repair

    PubMed Central

    Xin, Mei; Olson, Eric N.; Bassel-Duby, Rhonda

    2013-01-01

    As the adult mammalian heart has limited potential for regeneration and repair, the loss of cardiomyocytes during injury and disease can result in heart failure and death. The cellular processes and regulatory mechanisms involved in heart growth and development can be exploited to repair the injured adult heart through ‘reawakening’ pathways that are active during embryogenesis. Heart function has been restored in rodents by reprogramming non-myocytes into cardiomyocytes, by expressing transcription factors (GATA4, HAND2, myocyte-specific enhancer factor 2C (MEF2C) and T-box 5 (TBX5)) and microRNAs (miR-1, miR-133, miR-208 and miR-499) that control cardiomyocyte identity. Stimulating cardiomyocyte dedifferentiation and proliferation by activating mitotic signalling pathways involved in embryonic heart growth represents a complementary approach for heart regeneration and repair. Recent advances in understanding the mechanistic basis of heart development offer exciting opportunities for effective therapies for heart failure. PMID:23839576

  6. Effects of pressure- or volume-overload hypertrophy on passive stiffness in isolated adult cardiac muscle cells

    NASA Technical Reports Server (NTRS)

    Kato, S.; Koide, M.; Cooper, G. 4th; Zile, M. R.

    1996-01-01

    It has been hypothesized that the changes in myocardial stiffness induced by chronic hemodynamic overloading are dependent on changes in the passive stiffness of the cardiac muscle cell (cardiocyte). However, no previous studies have examined the passive constitutive properties of cardiocytes isolated from animals with myocardial hypertrophy. Accordingly, changes in relative passive stiffness of cardiocytes isolated from animals with chronic pressure- or volume-overload hypertrophy were determined by examining the effects of anisosmotic stress on cardiocyte size. Anisosmotic stress was produced by altering superfusate osmolarity. Hypertrophied cardiocytes were enzymatically isolated from 16 adult cats with right ventricular (RV) pressure-overload hypertrophy induced by pulmonary artery banding (PAB) and from 6 adult cats with RV volume-overload hypertrophy induced by creating an atrial septal defect (ASD). Left ventricular (LV) cardiocytes from each cat served as nonhypertrophied, normally loaded, same-animal controls. Superfusate osmolarity was decreased from 305 +/- 3 to 135 +/- 5 mosM and increased to 645 +/- 4 mosM. During anisosmotic stress, there were no significant differences between hypertrophied RV and normal LV cardiocytes in pressure overload PAB cats with respect to percent change in cardiocyte area (47 +/- 2% in RV vs. 48 +/- 2% in LV), diameter (46 +/- 3% in RV vs. 48 +/- 2% in LV), or length (2.4 +/- 0.2% in RV vs. 2.0 +/- 0.3% in LV), or sarcomere length (1.5 +/- 0.1% in RV vs. 1.3 +/- 0.3% in LV). Likewise, there were no significant differences in cardiocyte strain between hypertrophied RV and normal LV cardiocytes from ASD cats. In conclusion, chronic pressure-overload hypertrophy and chronic volume-overload hypertrophy did not alter the cardiocyte response to anisosmotic stress. Thus chronic overload hypertrophy did not alter relative passive cardiocyte stiffness.

  7. The influence of patient size on dose conversion coefficients: a hybrid phantom study for adult cardiac catheterization

    NASA Astrophysics Data System (ADS)

    Johnson, Perry; Lee, Choonsik; Johnson, Kevin; Siragusa, Daniel; Bolch, Wesley E.

    2009-06-01

    In this study, the influence of patient size on organ and effective dose conversion coefficients (DCCs) was investigated for a representative interventional fluoroscopic procedure—cardiac catheterization. The study was performed using hybrid phantoms representing an underweight, average and overweight American adult male. Reference body sizes were determined using the NHANES III database and parameterized based on standing height and total body mass. Organ and effective dose conversion coefficients were calculated for anterior-posterior, posterior-anterior, left anterior oblique and right anterior oblique projections using the Monte Carlo code MCNPX 2.5.0 with the metric dose area product being used as the normalization factor. Results show body size to have a clear influence on DCCs which increased noticeably when body size decreased. It was also shown that if patient size is neglected when choosing a DCC, the organ and effective dose will be underestimated to an underweight patient and will be overestimated to an underweight patient, with errors as large as 113% for certain projections. Results were further compared with those published for a KTMAN-2 Korean patient-specific tomographic phantom. The published DCCs aligned best with the hybrid phantom which most closely matched in overall body size. These results highlighted the need for and the advantages of phantom-patient matching, and it is recommended that hybrid phantoms be used to create a more diverse library of patient-dependent anthropomorphic phantoms for medical dose reconstruction.

  8. Enrichment of vital adult cardiac muscle cells by continuous silica sol gradient centrifugation.

    PubMed

    Maisch, B

    1981-01-01

    A major improvement in the isolation of vital adult cardiocytes was achieved by isopycnic preformed continuous silica sol gradient centrifugation after perfusion of the heart with collagenase. Vital rat cardiocytes were enriched to 90-95% vital cells reproducibly and constantly by one- or two-step gradient centrifugations. The isolated cardiocytes were tolerant to calcium concentrations up to 0.03 mmol/l, to diluted human serum, and to human complement. Gentamycin (50 microgram/ml) exerted a cytotoxic effect on myocytes, whereas Penicillium and Streptomycin in concentrations of 50 IU/ml did not induce cytolysis of vital cells. Digoxin 15 ng/ml) decreased the natural decay of myocytes of 20% in 25 hours to 8%. Enriched of vital cardiocytes by silica sol gradient centrifugation following their isolation by perfusion with collagenase may be helpful for investigations depending on a high yield of vital myocardial cells. PMID:6277294

  9. Linking an Anxiety-Related Personality Trait to Cardiac Autonomic Regulation in Well-Defined Healthy Adults: Harm Avoidance and Resting Heart Rate Variability

    PubMed Central

    Kao, Lien-Cheng; Liu, Yu-Wen; Tzeng, Nian-Sheng; Kuo, Terry B. J.; Huang, San-Yuan

    2016-01-01

    Objective Anxiety trait, anxiety and depression states have all been reported to increase risks for cardiovascular disease (CVD), possibly through altering cardiac autonomic regulation. Our aim was to investigate whether the relationship between harm avoidance (HA, an anxiety-related personality trait) and cardiac autonomic regulation is independent of anxiety and depression states in healthy adults. Methods We recruited 535 physically and mentally healthy volunteers. Participants completed the Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI) and Tri-dimensional Personality Questionnaire. Participants were divided into high or low HA groups as discriminated by the quartile value. Cardiac autonomic function was evaluated by measuring heart rate variability (HRV). We obtained the time and frequency-domain indices of HRV including variance (total HRV), the low-frequency power (LF; 0.05–0.15 Hz), which may reflect baroreflex function, the high-frequency power (HF; 0.15–0.40 Hz), which reflects cardiac parasympathetic activity, as well as the LF/HF ratio. Results The BDI and HA scores showed associations with HRV parameters. After adjustment for the BDI scores and other control variables, HA is still associated with reduced variance, LF and HF power. Compared with the participants with low HA, those with high HA displayed significant reductions in variance, LF and HF power and a significant increase in their LF/HF ratio. Conclusion This study highlights the independent role of HA in contributing to decreased autonomic cardiac regulation in healthy adults and provides a potential underlying mechanism for anxiety trait to confer increased risk for CVD. PMID:27482240

  10. Cardiac and metabolic effects of chronic growth hormone and insulin-like growth factor I excess in young adults with pituitary gigantism.

    PubMed

    Bondanelli, Marta; Bonadonna, Stefania; Ambrosio, Maria Rosaria; Doga, Mauro; Gola, Monica; Onofri, Alessandro; Zatelli, Maria Chiara; Giustina, Andrea; degli Uberti, Ettore C

    2005-09-01

    Chronic growth hormone (GH)/insulin-like growth factor I (IGF-I) excess is associated with considerable mortality in acromegaly, but no data are available in pituitary gigantism. The aim of the study was to evaluate the long-term effects of early exposure to GH and IGF-I excess on cardiovascular and metabolic parameters in adult patients with pituitary gigantism. Six adult male patients with newly diagnosed gigantism due to GH secreting pituitary adenoma were studied and compared with 6 age- and sex-matched patients with acromegaly and 10 healthy subjects. Morphologic and functional cardiac parameters were evaluated by Doppler echocardiography. Glucose metabolism was assessed by evaluating glucose tolerance and homeostasis model assessment index. Disease duration was significantly longer (P<.05) in patients with gigantism than in patients with acromegaly, whereas GH and IGF-I concentrations were comparable. Left ventricular mass was increased both in patients with gigantism and in patients with acromegaly, as compared with controls. Left ventricular hypertrophy was detected in 2 of 6 of both patients with gigantism and patients with acromegaly, and isolated intraventricular septum thickening in 1 patient with gigantism. Inadequate diastolic filling (ratio between early and late transmitral flow velocity<1) was detected in 2 of 6 patients with gigantism and 1 of 6 patients with acromegaly. Impaired glucose metabolism occurrence was higher in patients with acromegaly (66%) compared with patients with gigantism (16%). Concentrations of IGF-I were significantly (P<.05) higher in patients with gigantism who have cardiac abnormalities than in those without cardiac abnormalities. In conclusion, our data suggest that GH/IGF-I excess in young adult patients is associated with morphologic and functional cardiac abnormalities that are similar in patients with gigantism and in patients with acromegaly, whereas occurrence of impaired glucose metabolism appears to be higher in

  11. Cardiac and metabolic effects of chronic growth hormone and insulin-like growth factor I excess in young adults with pituitary gigantism.

    PubMed

    Bondanelli, Marta; Bonadonna, Stefania; Ambrosio, Maria Rosaria; Doga, Mauro; Gola, Monica; Onofri, Alessandro; Zatelli, Maria Chiara; Giustina, Andrea; degli Uberti, Ettore C

    2005-09-01

    Chronic growth hormone (GH)/insulin-like growth factor I (IGF-I) excess is associated with considerable mortality in acromegaly, but no data are available in pituitary gigantism. The aim of the study was to evaluate the long-term effects of early exposure to GH and IGF-I excess on cardiovascular and metabolic parameters in adult patients with pituitary gigantism. Six adult male patients with newly diagnosed gigantism due to GH secreting pituitary adenoma were studied and compared with 6 age- and sex-matched patients with acromegaly and 10 healthy subjects. Morphologic and functional cardiac parameters were evaluated by Doppler echocardiography. Glucose metabolism was assessed by evaluating glucose tolerance and homeostasis model assessment index. Disease duration was significantly longer (P<.05) in patients with gigantism than in patients with acromegaly, whereas GH and IGF-I concentrations were comparable. Left ventricular mass was increased both in patients with gigantism and in patients with acromegaly, as compared with controls. Left ventricular hypertrophy was detected in 2 of 6 of both patients with gigantism and patients with acromegaly, and isolated intraventricular septum thickening in 1 patient with gigantism. Inadequate diastolic filling (ratio between early and late transmitral flow velocity<1) was detected in 2 of 6 patients with gigantism and 1 of 6 patients with acromegaly. Impaired glucose metabolism occurrence was higher in patients with acromegaly (66%) compared with patients with gigantism (16%). Concentrations of IGF-I were significantly (P<.05) higher in patients with gigantism who have cardiac abnormalities than in those without cardiac abnormalities. In conclusion, our data suggest that GH/IGF-I excess in young adult patients is associated with morphologic and functional cardiac abnormalities that are similar in patients with gigantism and in patients with acromegaly, whereas occurrence of impaired glucose metabolism appears to be higher in

  12. Gene Expression Profiling Supports the Neural Crest Origin of Adult Rodent Carotid Body Stem Cells and Identifies CD10 as a Marker for Mesectoderm-Committed Progenitors.

    PubMed

    Navarro-Guerrero, Elena; Platero-Luengo, Aida; Linares-Clemente, Pedro; Cases, Ildefonso; López-Barneo, José; Pardal, Ricardo

    2016-06-01

    Neural stem cells (NSCs) are promising tools for understanding nervous system plasticity and repair, but their use is hampered by the lack of markers suitable for their prospective isolation and characterization. The carotid body (CB) contains a population of peripheral NSCs, which support organ growth during acclimatization to hypoxia. We have set up CB neurosphere (NS) cultures enriched in differentiated neuronal (glomus) cells versus undifferentiated progenitors to investigate molecular hallmarks of cell classes within the CB stem cell (CBSC) niche. Microarray gene expression analysis in NS is compatible with CBSCs being neural crest derived-multipotent progenitor cells able to sustain CB growth upon exposure to hypoxia. Moreover, we have identified CD10 as a marker suitable for isolation of a population of CB mesectoderm-committed progenitor cells. CD10 + cells are resting in normoxia, and during hypoxia they are activated to proliferate and to eventually complete maturation into mesectodermal cells, thus participating in the angiogenesis necessary for CB growth. Our results shed light into the molecular and cellular mechanisms involved in CBSC fate choice, favoring a potential use of these cells for cell therapy. Stem Cells 2016;34:1637-1650.

  13. Changing practice of cardiac surgery in adult patients with congenital heart disease

    PubMed Central

    Srinathan, S K; Bonser, R S; Sethia, B; Thorne, S A; Brawn, W J; Barron, D J

    2005-01-01

    Objectives: To review 13 years’ data from a unit for grown ups with congenital heart disease (GUCH) to understand the change in surgical practice. Methods: Records were reviewed of patients over 16 years of age undergoing surgery between 1 January 1990 and 31 December 2002 in a dedicated GUCH unit. Patients with atrial septal defects were included but not those with Marfan’s syndrome or undergoing a first procedure for bicuspid aortic valves. Three equal time periods of 52 months were analysed. Results: Of 474 operations performed, 162 (34.2%) were repeat operations. The percentage of repeat operations increased from 24.8% (41 of 165) in January 1990–April 1994 to 49.7% (74 of 149) in September 1998–December 2002. Mortality was 6.3% (n  =  30). The median age decreased from 25.4 years (interquartile range 18.7) in January 1990–April 1994 to 23.9 (interquartile range 17.3) in September 1998–December 2002 (p  =  0.04). The proportion of patients with a “simple” diagnosis decreased from 45.4% (74 or 165) in January 1990–April 1994 to 27.5% (41 of 149) in September 1998–December 2002 (p  =  0.013). Pulmonary valve replacements in operated tetralogy of Fallot increased from one case in January 1990–April 1994 to 23 cases in September 1998–December 2002 and conduit replacement increased from five cases to 17. However, secundum atrial septal defect closures decreased from 35 cases to 14 (p < 0.0001). The estimated cost (not including salaries and prosthetics) incurred by an adult patient with congenital heart disease was £2290 compared with £2641 for a patient undergoing coronary artery bypass grafting. Conclusion: Despite the impact of interventional cardiology, the total number of surgical procedures remained unchanged. The complexity of the cases increased particularly with repeat surgery. Nevertheless, the patients do well with low mortality and the inpatient costs remain comparable with costs of surgery for acquired disease. PMID

  14. Preoperative evaluation of the adult patient undergoing non-cardiac surgery: guidelines from the European Society of Anaesthesiology.

    PubMed

    De Hert, Stefan; Imberger, Georgina; Carlisle, John; Diemunsch, Pierre; Fritsch, Gerhard; Moppett, Iain; Solca, Maurizio; Staender, Sven; Wappler, Frank; Smith, Andrew

    2011-10-01

    The purpose of these guidelines on the preoperative evaluation of the adult non-cardiac surgery patient is to present recommendations based on available relevant clinical evidence. The ultimate aims of preoperative evaluation are two-fold. First, we aim to identify those patients for whom the perioperative period may constitute an increased risk of morbidity and mortality, aside from the risks associated with the underlying disease. Second, this should help us to design perioperative strategies that aim to reduce additional perioperative risks. Very few well performed randomised studies on the topic are available and many recommendations rely heavily on expert opinion and are adapted specifically to the healthcare systems in individual countries. This report aims to provide an overview of current knowledge on the subject with an assessment of the quality of the evidence in order to allow anaesthetists all over Europe to integrate - wherever possible - this knowledge into daily patient care. The Guidelines Committee of the European Society of Anaesthesiology (ESA) formed a task force with members of subcommittees of scientific subcommittees and individual members of the ESA. Electronic databases were searched from the year 2000 until July 2010 without language restrictions. These searches produced 15 425 abstracts. Relevant systematic reviews with meta-analyses, randomised controlled trials, cohort studies, case-control studies and cross-sectional surveys were selected. The Scottish Intercollegiate Guidelines Network grading system was used to assess the level of evidence and to grade recommendations. The final draft guideline was posted on the ESA website for 4 weeks and the link was sent to all ESA members, individual or national (thus including most European national anaesthesia societies). Comments were collated and the guidelines amended as appropriate. When the final draft was complete, the Guidelines Committee and ESA Board ratified the guidelines.

  15. Preoperative evaluation of the adult patient undergoing non-cardiac surgery: guidelines from the European Society of Anaesthesiology.

    PubMed

    De Hert, Stefan; Imberger, Georgina; Carlisle, John; Diemunsch, Pierre; Fritsch, Gerhard; Moppett, Iain; Solca, Maurizio; Staender, Sven; Wappler, Frank; Smith, Andrew

    2011-10-01

    The purpose of these guidelines on the preoperative evaluation of the adult non-cardiac surgery patient is to present recommendations based on available relevant clinical evidence. The ultimate aims of preoperative evaluation are two-fold. First, we aim to identify those patients for whom the perioperative period may constitute an increased risk of morbidity and mortality, aside from the risks associated with the underlying disease. Second, this should help us to design perioperative strategies that aim to reduce additional perioperative risks. Very few well performed randomised studies on the topic are available and many recommendations rely heavily on expert opinion and are adapted specifically to the healthcare systems in individual countries. This report aims to provide an overview of current knowledge on the subject with an assessment of the quality of the evidence in order to allow anaesthetists all over Europe to integrate - wherever possible - this knowledge into daily patient care. The Guidelines Committee of the European Society of Anaesthesiology (ESA) formed a task force with members of subcommittees of scientific subcommittees and individual members of the ESA. Electronic databases were searched from the year 2000 until July 2010 without language restrictions. These searches produced 15 425 abstracts. Relevant systematic reviews with meta-analyses, randomised controlled trials, cohort studies, case-control studies and cross-sectional surveys were selected. The Scottish Intercollegiate Guidelines Network grading system was used to assess the level of evidence and to grade recommendations. The final draft guideline was posted on the ESA website for 4 weeks and the link was sent to all ESA members, individual or national (thus including most European national anaesthesia societies). Comments were collated and the guidelines amended as appropriate. When the final draft was complete, the Guidelines Committee and ESA Board ratified the guidelines. PMID

  16. Centrifugal pump and roller pump in adult cardiac surgery: a meta-analysis of randomized controlled trials.

    PubMed

    Saczkowski, Richard; Maklin, Michelle; Mesana, Thierry; Boodhwani, Munir; Ruel, Marc

    2012-08-01

    Centrifugal pump (CP) and roller pump (RP) designs are the dominant main arterial pumps used in cardiopulmonary bypass (CPB). Trials reporting clinical outcome measures comparing CP and RP are controversial. Therefore, a meta-analysis was undertaken to evaluate clinical variables from randomized controlled trials (RCTs). Keyword searches were performed on Medline (1966-2011), EmBase (1980-2011), and CINAHL (1981-2011) for studies comparing RP and CP as the main arterial pump in adult CPB. Pooled fixed-effects estimates for dichotomous and continuous data were calculated as an odds ratio and weighted-mean difference, respectively. The P value was utilized to assess statistical significance (P < 0.05) between CP and RP groups. Eighteen RCTs met inclusion criteria, which represented 1868 patients (CP = 961, RP = 907). The prevailing operation was isolated coronary artery bypass graft surgery (CP = 88%, RP = 87%). Fixed-effects pooled estimates were performed for end-of-CPB (ECP) and postoperative day one (PDO) for platelet count (ECP: P = 0.51, PDO: P = 0.16), plasma free hemoglobin (ECP: P = 0.36, PDO: P = 0.24), white blood cell count (ECP: P = 0.21, PDO: P = 0.66), and hematocrit (ECP: P = 0.06, PDO: P = 0.51). No difference was demonstrated for postoperative blood loss (P = 0.65) or red blood cell transfusion (P = 0.71). Intensive care unit length of stay (P = 0.30), hospital length of stay (P = 0.33), and mortality (P = 0.91) were similar between the CP and RP groups. Neurologic outcomes were not amenable to pooled analysis; nevertheless, the results were inconclusive. There was no reported pump-related malfunction or mishap. The meta-analysis of RCTs comparing CP and RP in adult cardiac surgery suggests no significant difference for hematological variables, postoperative blood loss, transfusions, neurological outcomes, or mortality.

  17. A cardiac-specific health-related quality of life module for young adults with congenital heart disease: development and validation.

    PubMed

    Kamphuis, M; Zwinderman, K H; Vogels, T; Vliegen, H W; Kamphuis, R P; Ottenkamp, J; Verloove-Vanhorick, S P; Bruil, J

    2004-05-01

    This study represents the development and validation of a cardiac-specific module of the generic health-related quality of life (HRQoL) instrument, the TAAQOL (TNO/AZL Adult Quality Of Life), for young adults with congenital heart disease (CHD). Items were selected based on literature, an explorative previous study in CHD patients, interviews with patients, and the advice of experts. The newly developed Congenital Heart Disease-TNO/AZL Adult Quality of Life (CHD-TAAQOL) was tested in 156 patients with mild or complex CHD and consisted of three hypothesised subject scales: 'Symptoms' (9 items), 'Impact Cardiac Surveillance' (7 items), and 'Worries' (10 items). Cronbach's alpha for the three scales were 0.77, 0.78, and 0.82, respectively. Scale structure was confirmed by Principal Component Analysis, corrected item-scale and interscale correlations. Overall, 55% of reported health status problems were associated with negative emotions, which is an argument for assessing HRQoL as a concept distinct from health status. Convergent validity with validated generic instruments (TAAQOL and Short Form-36, SF-36) showed satisfactory coefficients. Discriminant validity was proven by significantly higher scores for mild CHD patients compared with those with complex CHD. In conclusion, the CHD-TAAQOL module together with the generic TAAQOL can be used to assess group differences for cardiac-specific HRQoL in young adults with CHD. Testing psychometric properties of the CHD-TAAQOL shows satisfactory results. However, to detect changes in HRQoL over time, further research is needed.

  18. Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease

    PubMed Central

    Ounzain, Samir; Pezzuto, Iole; Micheletti, Rudi; Burdet, Frédéric; Sheta, Razan; Nemir, Mohamed; Gonzales, Christine; Sarre, Alexandre; Alexanian, Michael; Blow, Matthew J.; May, Dalit; Johnson, Rory; Dauvillier, Jérôme; Pennacchio, Len A.; Pedrazzini, Thierry

    2015-01-01

    The key information processing units within gene regulatory networks are enhancers. Enhancer activity is associated with the production of tissue-specific noncoding RNAs, yet the existence of such transcripts during cardiac development has not been established. Using an integrated genomic approach, we demonstrate that fetal cardiac enhancers generate long noncoding RNAs (IncRNAs) during cardiac differentiation and morphogenesis. Enhancer expression correlates with the emergence of active enhancer chromatin states, the initiation of RNA polymerase II at enhancer loci and expression of target genes. Orthologous human sequences are also transcribed in fetal human hearts and cardiac progenitor cells. Through a systematic bioinformatic analysis, we identified and characterized, for the first time, a catalog of IncRNAs that are expressed during embryonic stem cell differentiation into cardiomyocytes and associated with active cardiac enhancer sequences. RNA-sequencing demonstrates that many of these transcripts are polyadenylated, multi-exonic long noncoding RNAs. Moreover, knockdown of two enhancer-associated IncRNAs resulted in the specific downregulation of their predicted target genes. Interestingly, the reactivation of the fetal gene program, a hallmark of the stress response in the adult heart, is accompanied by increased expression of fetal cardiac enhancer transcripts. Altogether, these findings demonstrate that the activity of cardiac enhancers and expression of their target genes are associated with the production of enhancer-derived IncRNAs. PMID:25149110

  19. Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease

    DOE PAGES

    Ounzain, Samir; Pezzuto, Iole; Micheletti, Rudi; Burdet, Frédéric; Sheta, Razan; Nemir, Mohamed; Gonzales, Christine; Sarre, Alexandre; Alexanian, Michael; Blow, Matthew J.; et al

    2014-08-19

    We report here that the key information processing units within gene regulatory networks are enhancers. Enhancer activity is associated with the production of tissue-specific noncoding RNAs, yet the existence of such transcripts during cardiac development has not been established. Using an integrated genomic approach, we demonstrate that fetal cardiac enhancers generate long noncoding RNAs (lncRNAs) during cardiac differentiation and morphogenesis. Enhancer expression correlates with the emergence of active enhancer chromatin states, the initiation of RNA polymerase II at enhancer loci and expression of target genes. Orthologous human sequences are also transcribed in fetal human hearts and cardiac progenitor cells. Throughmore » a systematic bioinformatic analysis, we identified and characterized, for the first time, a catalog of lncRNAs that are expressed during embryonic stem cell differentiation into cardiomyocytes and associated with active cardiac enhancer sequences. RNA-sequencing demonstrates that many of these transcripts are polyadenylated, multi-exonic long noncoding RNAs. Moreover, knockdown of two enhancer-associated lncRNAs resulted in the specific downregulation of their predicted target genes. Interestingly, the reactivation of the fetal gene program, a hallmark of the stress response in the adult heart, is accompanied by increased expression of fetal cardiac enhancer transcripts. Altogether, these findings demonstrate that the activity of cardiac enhancers and expression of their target genes are associated with the production of enhancer-derived lncRNAs.« less

  20. Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease

    SciTech Connect

    Ounzain, Samir; Pezzuto, Iole; Micheletti, Rudi; Burdet, Frédéric; Sheta, Razan; Nemir, Mohamed; Gonzales, Christine; Sarre, Alexandre; Alexanian, Michael; Blow, Matthew J.; May, Dalit; Johnson, Rory; Dauvillier, Jérôme; Pennacchio, Len A.; Pedrazzini, Thierry

    2014-08-19

    We report here that the key information processing units within gene regulatory networks are enhancers. Enhancer activity is associated with the production of tissue-specific noncoding RNAs, yet the existence of such transcripts during cardiac development has not been established. Using an integrated genomic approach, we demonstrate that fetal cardiac enhancers generate long noncoding RNAs (lncRNAs) during cardiac differentiation and morphogenesis. Enhancer expression correlates with the emergence of active enhancer chromatin states, the initiation of RNA polymerase II at enhancer loci and expression of target genes. Orthologous human sequences are also transcribed in fetal human hearts and cardiac progenitor cells. Through a systematic bioinformatic analysis, we identified and characterized, for the first time, a catalog of lncRNAs that are expressed during embryonic stem cell differentiation into cardiomyocytes and associated with active cardiac enhancer sequences. RNA-sequencing demonstrates that many of these transcripts are polyadenylated, multi-exonic long noncoding RNAs. Moreover, knockdown of two enhancer-associated lncRNAs resulted in the specific downregulation of their predicted target genes. Interestingly, the reactivation of the fetal gene program, a hallmark of the stress response in the adult heart, is accompanied by increased expression of fetal cardiac enhancer transcripts. Altogether, these findings demonstrate that the activity of cardiac enhancers and expression of their target genes are associated with the production of enhancer-derived lncRNAs.

  1. The LIM Protein Ajuba Restricts the Second Heart Field Progenitor Pool by Regulating Isl1 Activity

    PubMed Central

    Witzel, Hagen R.; Jungblut, Benno; Choe, Chong Pyo; Crump, J. Gage; Braun, Thomas; Dobreva, Gergana

    2013-01-01

    SUMMARY Morphogenesis of the heart requires tight control of cardiac progenitor cell specification, expansion, and differentiation. Retinoic acid (RA) signaling restricts expansion of the second heart field (SHF), serving as an important morphogen in heart development. Here, we identify the LIM domain protein Ajuba as a crucial regulator of the SHF progenitor cell specification and expansion. Ajuba-deficient zebra-fish embryos show an increased pool of Isl1+ cardiac progenitors and, subsequently, dramatically increased numbers of cardiomyocytes at the arterial and venous poles. Furthermore, we show that Ajuba binds Isl1, represses its transcriptional activity, and is also required for autorepression of Isl1 expression in an RA-dependent manner. Lack of Ajuba abrogates the RA-dependent restriction of Isl1+ cardiac cells. We conclude that Ajuba plays a central role in regulating the SHF during heart development by linking RA signaling to the function of Isl1, a key transcription factor in cardiac progenitor cells. PMID:22771034

  2. The role of biosimilar granulocyte colony stimulating factor (GCSF) Zarzio for progenitor cell mobilization and the treatment of therapy-induced neutropenia in adult hematopoietic stem cell transplantation.

    PubMed

    Severson, Cherie C

    2015-01-01

    Originator GCSF (Neupogen) has been used to mobilize progenitor stem cells and treat therapy-induced neutropenia in Canadian stem cell transplant settings for years. Although its benefit is not in question, viable alternatives are available. Biosimilar GCSF (Zarzio) is widely in use in Europe since 2009 and was recently approved in the U.S.for the same five indications as Neupogen. Zarzio is reported as safe, equally efficacious, more accessible and cost effective without negatively impacting patient outcomes. This paper summarizes the supporting evidence. PMID:26897866

  3. Cardiac arrhythmias as the initial manifestation of adult primary Sjögren's syndrome: a case report and literature review.

    PubMed

    Liang, Minrui; Bao, Liwen; Xiong, Nanqing; Jin, Bo; Ni, Huanchun; Zhang, Jinjin; Zou, Hejian; Luo, Xinping; Li, Jian

    2015-09-01

    Two middle-aged female patients presenting with heart palpitation and electrocardiogram revealed complex cardiac arrhythmias. A review of systems was positive for dry mouth and transient arthralgia, while laboratory and instrumental tests enabled us to make the diagnosis of primary Sjögren's syndrome (pSS). Cardiac electrophysiology revealed atrioventricular node dysfunction and impaired intraventricular conduction. Prednisone therapy induced a significant improvement in symptoms and electrocardiographic readings. The diagnosis of pSS should be considered in a patient presenting with complex cardiac arrhythmias.

  4. Telocytes in exercise-induced cardiac growth.

    PubMed

    Xiao, Junjie; Chen, Ping; Qu, Yi; Yu, Pujiao; Yao, Jianhua; Wang, Hongbao; Fu, Siyi; Bei, Yihua; Chen, Yan; Che, Lin; Xu, Jiahong

    2016-05-01

    Exercise can induce physiological cardiac growth, which is featured by enlarged cardiomyocyte cell size and formation of new cardiomyocytes. Telocytes (TCs) are a recently identified distinct interstitial cell type, existing in many tissues and organs including heart. TCs have been shown to form a tandem with cardiac stem/progenitor cells in cardiac stem cell niches, participating in cardiac regeneration and repair. Although exercise-induced cardiac growth has been confirmed as an important way to promote cardiac regeneration and repair, the response of cardiac TCs to exercise is still unclear. In this study, 4 weeks of swimming training was used to induce robust healthy cardiac growth. Exercise can induce an increase in cardiomyocyte cell size and formation of new cardiomyocytes as determined by Wheat Germ Lectin and EdU staining respectively. TCs were identified by three immunofluorescence stainings including double labelling for CD34/vimentin, CD34/platelet-derived growth factor (PDGF) receptor-α and CD34/PDGF receptor-β. We found that cardiac TCs were significantly increased in exercised heart, suggesting that TCs might help control the activity of cardiac stem/progenitor cells, cardiomyocytes or endothelial cells. Adding cardiac TCs might help promote cardiac regeneration and renewal. PMID:26987685

  5. Novel all-extremity high-intensity interval training improves aerobic fitness, cardiac function and insulin resistance in healthy older adults.

    PubMed

    Hwang, Chueh-Lung; Yoo, Jeung-Ki; Kim, Han-Kyul; Hwang, Moon-Hyon; Handberg, Eileen M; Petersen, John W; Christou, Demetra D

    2016-09-01

    Aging is associated with decreased aerobic fitness and cardiac remodeling leading to increased risk for cardiovascular disease. High-intensity interval training (HIIT) on the treadmill has been reported to be more effective in ameliorating these risk factors compared with moderate-intensity continuous training (MICT) in patients with cardiometabolic disease. In older adults, however, weight-bearing activities are frequently limited due to musculoskeletal and balance problems. The purpose of this study was to examine the feasibility and safety of non-weight-bearing all-extremity HIIT in older adults. In addition, we tested the hypothesis that all-extremity HIIT will be more effective in improving aerobic fitness, cardiac function, and metabolic risk factors compared with all-extremity MICT. Fifty-one healthy sedentary older adults (age: 65±1years) were randomized to HIIT (n=17), MICT (n=18) or non-exercise control (CONT; n=16). HIIT (4×4min 90% of peak heart rate; HRpeak) and isocaloric MICT (70% of HRpeak) were performed on a non-weight-bearing all-extremity ergometer, 4×/week for 8weeks under supervision. All-extremity HIIT was feasible in older adults and resulted in no adverse events. Aerobic fitness (peak oxygen consumption; VO2peak) and ejection fraction (echocardiography) improved by 11% (P<0.0001) and 4% (P=0.001), respectively in HIIT, while no changes were observed in MICT and CONT (P≥0.1). Greater improvements in ejection fraction were associated with greater improvements in VO2peak (r=0.57; P<0.0001). Insulin resistance (homeostatic model assessment) decreased only in HIIT by 26% (P=0.016). Diastolic function, body composition, glucose and lipids were unaffected (P≥0.1). In conclusion, all-extremity HIIT is feasible and safe in older adults. HIIT, but not MICT, improved aerobic fitness, ejection fraction, and insulin resistance. PMID:27346646

  6. Novel all-extremity high-intensity interval training improves aerobic fitness, cardiac function and insulin resistance in healthy older adults.

    PubMed

    Hwang, Chueh-Lung; Yoo, Jeung-Ki; Kim, Han-Kyul; Hwang, Moon-Hyon; Handberg, Eileen M; Petersen, John W; Christou, Demetra D

    2016-09-01

    Aging is associated with decreased aerobic fitness and cardiac remodeling leading to increased risk for cardiovascular disease. High-intensity interval training (HIIT) on the treadmill has been reported to be more effective in ameliorating these risk factors compared with moderate-intensity continuous training (MICT) in patients with cardiometabolic disease. In older adults, however, weight-bearing activities are frequently limited due to musculoskeletal and balance problems. The purpose of this study was to examine the feasibility and safety of non-weight-bearing all-extremity HIIT in older adults. In addition, we tested the hypothesis that all-extremity HIIT will be more effective in improving aerobic fitness, cardiac function, and metabolic risk factors compared with all-extremity MICT. Fifty-one healthy sedentary older adults (age: 65±1years) were randomized to HIIT (n=17), MICT (n=18) or non-exercise control (CONT; n=16). HIIT (4×4min 90% of peak heart rate; HRpeak) and isocaloric MICT (70% of HRpeak) were performed on a non-weight-bearing all-extremity ergometer, 4×/week for 8weeks under supervision. All-extremity HIIT was feasible in older adults and resulted in no adverse events. Aerobic fitness (peak oxygen consumption; VO2peak) and ejection fraction (echocardiography) improved by 11% (P<0.0001) and 4% (P=0.001), respectively in HIIT, while no changes were observed in MICT and CONT (P≥0.1). Greater improvements in ejection fraction were associated with greater improvements in VO2peak (r=0.57; P<0.0001). Insulin resistance (homeostatic model assessment) decreased only in HIIT by 26% (P=0.016). Diastolic function, body composition, glucose and lipids were unaffected (P≥0.1). In conclusion, all-extremity HIIT is feasible and safe in older adults. HIIT, but not MICT, improved aerobic fitness, ejection fraction, and insulin resistance.

  7. Cardiac Rehabilitation

    MedlinePlus

    ... from the NHLBI on Twitter. What Is Cardiac Rehabilitation? Cardiac rehabilitation (rehab) is a medically supervised program ... be designed to meet your needs. The Cardiac Rehabilitation Team Cardiac rehab involves a long-term commitment ...

  8. Translational research of adult stem cell therapy.

    PubMed

    Suzuki, Gen

    2015-11-26

    Congestive heart failure (CHF) secondary to chronic coronary artery disease is a major cause of morbidity and mortality world-wide. Its prevalence is increasing despite advances in medical and device therapies. Cell based therapies generating new cardiomyocytes and vessels have emerged as a promising treatment to reverse functional deterioration and prevent the progression to CHF. Functional efficacy of progenitor cells isolated from the bone marrow and the heart have been evaluated in preclinical large animal models. Furthermore, several clinical trials using autologous and allogeneic stem cells and progenitor cells have demonstrated their safety in humans yet their clinical relevance is inconclusive. This review will discuss the clinical therapeutic applications of three specific adult stem cells that have shown particularly promising regenerative effects in preclinical studies, bone marrow derived mesenchymal stem cell, heart derived cardiosphere-derived cell and cardiac stem cell. We will also discuss future therapeutic approaches.

  9. Cardiac Outcomes in Adult Survivors of Childhood Cancer Exposed to Cardiotoxic Therapy: A Cross-Sectional Study from the St. Jude Lifetime Cohort

    PubMed Central

    Mulrooney, Daniel A.; Armstrong, Gregory T.; Huang, Sujuan; Ness, Kirsten K.; Ehrhardt, Matthew J.; Joshi, Vijaya M.; Plana, Juan Carlos; Soliman, Elsayed Z.; Green, Daniel M.; Srivastava, Deokumar; Santucci, Aimee; Krasin, Matthew J.; Robison, Leslie L.; Hudson, Melissa M.

    2016-01-01

    Background Studies of cardiac disease among adult survivors of childhood cancer have generally relied upon self-reported or registry-based data. Objective Systematically assess cardiac outcomes among childhood cancer survivors Design Cross-sectional Setting St. Jude Children's Research Hospital Patients 1,853 adult survivors of childhood cancer, ≥18 years old, and ≥10 years from treatment with cardiotoxic therapy for childhood cancer. Measurements History/physical examination, fasting metabolic and lipid panels, echocardiogram, electrocardiogram (ECG), 6-minute walk test (6MWT) all collected at baseline evaluation. Results Half (52.3%) of the survivors were male, median age 8.0 years (range: 0-24) at cancer diagnosis, 31.0 years (18-60) at evaluation. Cardiomyopathy was present in 7.4% (newly identified at the time of evaluation in 4.7%), coronary artery disease (CAD) in 3.8% (newly identified in 2.2%), valvular regurgitation/stenosis in 28.0% (newly identified in 24.8%), and conduction/rhythm abnormalities in 4.6% (newly identified in 1.4%). Nearly all (99.7%) were asymptomatic. The prevalences of cardiac conditions increased with age at evaluation, ranging from 3-24% among those 30-39 years to 10-37% among those ≥40 years. On multivariable analysis, anthracycline exposure ≥250 mg/m2 increased the odds of cardiomyopathy (odds ratio [OR] 2.7, 95% CI 1.1-6.9) compared to anthracycline unexposed survivors. Radiation to the heart increased the odds of cardiomyopathy (OR 1.9 95% CI 1.1-3.7) compared to radiation unexposed survivors. Radiation >1500 cGy with any anthracycline exposure conferred the greatest odds for valve findings. Limitations 61% participation rate of survivors exposed to cardiotoxic therapies, which were limited to anthracyclines and cardiac-directed radiation. A comparison group and longitudinal assessments are not available. Conclusions Cardiovascular screening identified considerable subclinical disease among adult survivors of childhood

  10. Trophic effect of human pericardial fluid on adult cardiac myocytes. Differential role of fibroblast growth factor-2 and factors related to ventricular hypertrophy.

    PubMed

    Corda, S; Mebazaa, A; Gandolfini, M P; Fitting, C; Marotte, F; Peynet, J; Charlemagne, D; Cavaillon, J M; Payen, D; Rappaport, L; Samuel, J L

    1997-11-01

    Pericardial fluid (PF) may contain myocardial growth factors that exert paracrine actions on cardiac myocytes. The aims of this study were (1) to investigate the effects of human PF and serum, collected from patients undergoing cardiac surgery, on the growth of cultured adult rat cardiac myocytes and (2) to relate the growth activity of both fluids to the adaptive changes in overloaded human hearts. Both PF and serum increased the rate of protein synthesis, measured by [14C]phenylalanine incorporation in adult rat cardiomyocytes (PF, +71.9 +/- 8.2% [n = 17]; serum, +14.9 +/- 6.5% [n = 13]; both P < .01 versus control medium). The effects of both PF and serum on cardiomyocyte growth correlated positively with the respective left ventricular (LV) mass. However, the magnitude of change with PF was 3-fold greater than with serum (P < .01). These trophic effects of PF were mimicked by exogenous basic fibroblast growth factor (FGF2) and inhibited by anti-FGF2 antibodies and transforming growth factor-beta (TGF-beta), suggesting a relationship to FGF2. In addition, FGF2 concentration in PF was 20 times greater than in serum. On the other hand, the LV mass-dependent trophic effect, present in both fluids, was independent of FGF2 concentration or other factors, such as angiotensin II, atrial natriuretic factor, and TGF-beta. These data suggest that FGF2 in human PF is a major determining factor in normal myocyte growth, whereas unidentified LV mass-dependent factor(s), present in both PF and serum, participates in the development of ventricular hypertrophy. PMID:9351441

  11. Stem and progenitor cell dysfunction in human trisomies

    PubMed Central

    Liu, Binbin; Filippi, Sarah; Roy, Anindita; Roberts, Irene

    2015-01-01

    Trisomy 21, the commonest constitutional aneuploidy in humans, causes profound perturbation of stem and progenitor cell growth, which is both cell context dependent and developmental stage specific and mediated by complex genetic mechanisms beyond increased Hsa21 gene dosage. While proliferation of fetal hematopoietic and testicular stem/progenitors is increased and may underlie increased susceptibility to childhood leukemia and testicular cancer, fetal stem/progenitor proliferation in other tissues is markedly impaired leading to the characteristic craniofacial, neurocognitive and cardiac features in individuals with Down syndrome. After birth, trisomy 21-mediated premature aging of stem/progenitor cells may contribute to the progressive multi-system deterioration, including development of Alzheimer's disease. PMID:25520324

  12. Endothelial progenitor cells in cardiovascular diseases.

    PubMed

    Lee, Poay Sian Sabrina; Poh, Kian Keong

    2014-07-26

    Endothelial dysfunction has been associated with the development of atherosclerosis and cardiovascular diseases. Adult endothelial progenitor cells (EPCs) are derived from hematopoietic stem cells and are capable of forming new blood vessels through a process of vasculogenesis. There are studies which report correlations between circulating EPCs and cardiovascular risk factors. There are also studies on how pharmacotherapies may influence levels of circulating EPCs. In this review, we discuss the potential role of endothelial progenitor cells as both diagnostic and prognostic biomarkers. In addition, we look at the interaction between cardiovascular pharmacotherapies and endothelial progenitor cells. We also discuss how EPCs can be used directly and indirectly as a therapeutic agent. Finally, we evaluate the challenges facing EPC research and how these may be overcome.

  13. Matrix adhesion polarizes heart progenitor induction in the invertebrate chordate Ciona intestinalis.

    PubMed

    Norton, Jennifer; Cooley, James; Islam, A F M Tariqul; Cota, Christina D; Davidson, Brad

    2013-03-01

    Cell-matrix adhesion strongly influences developmental signaling. Resulting impacts on cell migration and tissue morphogenesis are well characterized. However, the in vivo impact of adhesion on fate induction remains ambiguous. Here, we employ the invertebrate chordate Ciona intestinalis to delineate an essential in vivo role for matrix adhesion in heart progenitor induction. In Ciona pre-cardiac founder cells, invasion of the underlying epidermis promotes localized induction of the heart progenitor lineage. We found that these epidermal invasions are associated with matrix adhesion along the pre-cardiac cell/epidermal boundary. Through targeted manipulations of RAP GTPase activity, we were able to manipulate pre-cardiac cell-matrix adhesion. Targeted disruption of pre-cardiac cell-matrix adhesion blocked heart progenitor induction. Conversely, increased matrix adhesion generated expanded induction. We were also able to selectively restore cell-matrix adhesion and heart progenitor induction through targeted expression of Ci-Integrin β2. These results indicate that matrix adhesion functions as a necessary and sufficient extrinsic cue for regional heart progenitor induction. Furthermore, time-lapse imaging suggests that cytokinesis acts as an intrinsic temporal regulator of heart progenitor adhesion and induction. Our findings highlight a potentially conserved role for matrix adhesion in early steps of vertebrate heart progenitor specification.

  14. Lifelong exposure to bisphenol a alters cardiac structure/function, protein expression, and DNA methylation in adult mice.

    PubMed

    Patel, Bhavini B; Raad, Mohamad; Sebag, Igal A; Chalifour, Lorraine E

    2013-05-01

    Bisphenol A (BPA) is an estrogenizing endocrine disruptor compound of concern. Our objective was to test whether lifelong BPA would impact cardiac structure/function, calcium homeostasis protein expression, and the DNA methylation of cardiac genes. We delivered 0.5 and 5.0 µg/kg/day BPA lifelong from gestation day 11 or 200 µg/kg/day from gestation day 11 to postnatal day 21 via the drinking water to C57bl/6n mice. BPA 5.0 males and females had increased body weight, body mass index, body surface area, and adiposity. Echocardiography identified concentric remodeling in all BPA-treated males. Systolic and diastolic cardiac functions were essentially similar, but lifelong BPA enhanced male and reduced female sex-specific differences in velocity of circumferential shortening and ascending aorta velocity time integral. Diastolic blood pressure was increased in all BPA females. The calcium homeostasis proteins sarcoendoplasmic reticulum ATPase 2a (SERCA2a), sodium calcium exchanger-1, phospholamban (PLB), phospho-PLB, and calsequestrin 2 are important for contraction and relaxation. Changes in their expression suggest increased calcium mobility in males and reduced calcium mobility in females supporting the cardiac function changes. DNA methyltransferase 3a expression was increased in all BPA males and BPA 0.5 females and reduced in BPA 200 females. Global DNA methylation was increased in BPA 0.5 males and reduced in BPA 0.5 females. BPA induced sex-specific altered DNA methylation in specific CpG pairs in the calsequestrin 2 CpG island. These results suggest that continual exposure to BPA impacts cardiac structure/function, protein expression, and epigenetic DNA methylation marks in males and females.

  15. Caspase-1 mediates hyperlipidemia-weakened progenitor cell vessel repair

    PubMed Central

    Li, Ya-Feng; Huang, Xiao; Li, Xinyuan; Gong, Ren; Yin, Ying; Nelson, Jun; Gao, Erhe; Zhang, Hongyu; Hoffman, Nicholas E.; Houser, Steven R.; Madesh, Muniswamy; Tilley, Douglas G.; Choi, Eric T.; Jiang, Xiaohua; Huang, Cong-Xin; Wang, Hong; Yang, Xiao-Feng

    2015-01-01

    Caspase-1 activation senses metabolic danger-associated molecular patterns (DAMPs) and mediates the initiation of inflammation in endothelial cells. Here, we examined whether the caspase-1 pathway is responsible for sensing hyperlipidemia as a DAMP in bone marrow (BM)-derived Stem cell antigen-1 positive (Sca-1+) stem/progenitor cells and weakening their angiogenic ability. Using biochemical methods, gene knockout, cell therapy and myocardial infarction (MI) models, we had the following findings: 1) Hyperlipidemia induces caspase-1 activity in mouse Sca-1+ progenitor cells in vivo; 2) Caspase-1 contributes to hyperlipidemia-induced modulation of vascular cell death-related gene expression in vivo; 3) Injection of Sca-1+ progenitor cells from caspase-1−/− mice improves endothelial capillary density in heart and decreases cardiomyocyte death in a mouse model of MI; and 4) Caspase-1−/− Sca-1+ progenitor cell therapy improves mouse cardiac function after MI. Our results provide insight on how hyperlipidemia activates caspase-1 in Sca-1+ progenitor cells, which subsequently weakens Sca-1+ progenitor cell repair of vasculature injury. These results demonstrate the therapeutic potential of caspase-1 inhibition in improving progenitor cell therapy for MI. PMID:26709768

  16. Cardiac outflow tract anomalies

    PubMed Central

    Neeb, Zachary; Lajiness, Jacquelyn D.; Bolanis, Esther; Conway, Simon J

    2014-01-01

    The mature outflow tract (OFT) is, in basic terms, a short conduit. It is a simple, although vital, connection situated between contracting muscular heart chambers and a vast embryonic vascular network. Unfortunately, it is also a focal point underlying many multifactorial congenital heart defects (CHDs). Through the use of various animal models combined with human genetic investigations, we are beginning to comprehend the molecular and cellular framework that controls OFT morphogenesis. Clear roles of neural crest cells (NCC) and second heart field (SHF) derivatives have been established during OFT formation and remodeling. The challenge now is to determine how the SHF and cardiac NCC interact, the complex reciprocal signaling that appears to be occurring at various stages of OFT morphogenesis, and finally how endocardial progenitors and primary heart field (PHF) communicate with both these colonizing extra-cardiac lineages. Although we are beginning to understand that this dance of progenitor populations is wonderfully intricate, the underlying pathogenesis and the spatiotemporal cell lineage interactions remain to be fully elucidated. What is now clear is that OFT alignment and septation are independent processes, invested via separate SHF and cardiac neural crest (CNC) lineages. This review will focus on our current understanding of the respective contributions of the SHF and CNC lineage during OFT development and pathogenesis. PMID:24014420

  17. Synergistic effects of transplanted adult neural stem/progenitor cells, chondroitinase, and growth factors promote functional repair and plasticity of the chronically injured spinal cord.

    PubMed

    Karimi-Abdolrezaee, Soheila; Eftekharpour, Eftekhar; Wang, Jian; Schut, Desiree; Fehlings, Michael G

    2010-02-01

    The transplantation of neural stem/progenitor cells (NPCs) is a promising therapeutic strategy for spinal cord injury (SCI). However, to date NPC transplantation has exhibited only limited success in the treatment of chronic SCI. Here, we show that chondroitin sulfate proteoglycans (CSPGs) in the glial scar around the site of chronic SCI negatively influence the long-term survival and integration of transplanted NPCs and their therapeutic potential for promoting functional repair and plasticity. We targeted CSPGs in the chronically injured spinal cord by sustained infusion of chondroitinase ABC (ChABC). One week later, the same rats were treated with transplants of NPCs and transient infusion of growth factors, EGF, bFGF, and PDGF-AA. We demonstrate that perturbing CSPGs dramatically optimizes NPC transplantation in chronic SCI. Engrafted NPCs successfully integrate and extensively migrate within the host spinal cord and principally differentiate into oligodendrocytes. Furthermore, this combined strategy promoted the axonal integrity and plasticity of the corticospinal tract and enhanced the plasticity of descending serotonergic pathways. These neuroanatomical changes were also associated with significantly improved neurobehavioral recovery after chronic SCI. Importantly, this strategy did not enhance the aberrant synaptic connectivity of pain afferents, nor did it exacerbate posttraumatic neuropathic pain. For the first time, we demonstrate key biological and functional benefits for the combined use of ChABC, growth factors, and NPCs to repair the chronically injured spinal cord. These findings could potentially bring us closer to the application of NPCs for patients suffering from chronic SCI or other conditions characterized by the formation of a glial scar.

  18. Cardiac rehabilitation

    MedlinePlus

    ... Coronary artery disease - cardiac rehab; Angina - cardiac rehab; Heart failure - cardiac rehab ... have had: Heart attack Coronary heart disease (CHD) Heart failure Angina (chest pain) Heart or heart valve surgery ...

  19. "String theory" of c-kit(pos) cardiac cells: a new paradigm regarding the nature of these cells that may reconcile apparently discrepant results.

    PubMed

    Keith, Matthew C L; Bolli, Roberto

    2015-03-27

    Although numerous preclinical investigations have consistently demonstrated salubrious effects of c-kit(pos) cardiac cells administered after myocardial infarction, the mechanism of action remains highly controversial. We and others have found little or no evidence that these cells differentiate into mature functional cardiomyocytes, suggesting paracrine effects. In this review, we propose a new paradigm predicated on a comprehensive analysis of the literature, including studies of cardiac development; we have (facetiously) dubbed this conceptual construct "string theory" of c-kit(pos) cardiac cells because it reconciles multifarious and sometimes apparently discrepant results. There is strong evidence that, during development, the c-kit receptor is expressed in different pools of cardiac progenitors (some capable of robust cardiomyogenesis and others with little or no contribution to myocytes). Accordingly, c-kit positivity, in itself, does not define the embryonic origins, lineage capabilities, or differentiation capacities of specific cardiac progenitors. C-kit(pos) cells derived from the first heart field exhibit cardiomyogenic potential during development, but these cells are likely depleted shortly before or after birth. The residual c-kit(pos) cells found in the adult heart are probably of proepicardial origin, possess a mesenchymal phenotype (resembling bone marrow mesenchymal stem/stromal cells), and are capable of contributing significantly only to nonmyocytic lineages (fibroblasts, smooth muscle cells, and endothelial cells). If these 2 populations (first heart field and proepicardium) express different levels of c-kit, the cardiomyogenic potential of first heart field progenitors might be reconciled with recent results of c-kit(pos) cell lineage tracing studies. The concept that c-kit expression in the adult heart identifies epicardium-derived, noncardiomyogenic precursors with a mesenchymal phenotype helps to explain the beneficial effects of c

  20. "String theory" of c-kit(pos) cardiac cells: a new paradigm regarding the nature of these cells that may reconcile apparently discrepant results.

    PubMed

    Keith, Matthew C L; Bolli, Roberto

    2015-03-27

    Although numerous preclinical investigations have consistently demonstrated salubrious effects of c-kit(pos) cardiac cells administered after myocardial infarction, the mechanism of action remains highly controversial. We and others have found little or no evidence that these cells differentiate into mature functional cardiomyocytes, suggesting paracrine effects. In this review, we propose a new paradigm predicated on a comprehensive analysis of the literature, including studies of cardiac development; we have (facetiously) dubbed this conceptual construct "string theory" of c-kit(pos) cardiac cells because it reconciles multifarious and sometimes apparently discrepant results. There is strong evidence that, during development, the c-kit receptor is expressed in different pools of cardiac progenitors (some capable of robust cardiomyogenesis and others with little or no contribution to myocytes). Accordingly, c-kit positivity, in itself, does not define the embryonic origins, lineage capabilities, or differentiation capacities of specific cardiac progenitors. C-kit(pos) cells derived from the first heart field exhibit cardiomyogenic potential during development, but these cells are likely depleted shortly before or after birth. The residual c-kit(pos) cells found in the adult heart are probably of proepicardial origin, possess a mesenchymal phenotype (resembling bone marrow mesenchymal stem/stromal cells), and are capable of contributing significantly only to nonmyocytic lineages (fibroblasts, smooth muscle cells, and endothelial cells). If these 2 populations (first heart field and proepicardium) express different levels of c-kit, the cardiomyogenic potential of first heart field progenitors might be reconciled with recent results of c-kit(pos) cell lineage tracing studies. The concept that c-kit expression in the adult heart identifies epicardium-derived, noncardiomyogenic precursors with a mesenchymal phenotype helps to explain the beneficial effects of c

  1. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain.

    PubMed

    Elmore, Monica R P; Najafi, Allison R; Koike, Maya A; Dagher, Nabil N; Spangenberg, Elizabeth E; Rice, Rachel A; Kitazawa, Masashi; Matusow, Bernice; Nguyen, Hoa; West, Brian L; Green, Kim N

    2014-04-16

    The colony-stimulating factor 1 receptor (CSF1R) is a key regulator of myeloid lineage cells. Genetic loss of the CSF1R blocks the normal population of resident microglia in the brain that originates from the yolk sac during early development. However, the role of CSF1R signaling in microglial homeostasis in the adult brain is largely unknown. To this end, we tested the effects of selective CSF1R inhibitors on microglia in adult mice. Surprisingly, extensive treatment results in elimination of ∼99% of all microglia brain-wide, showing that microglia in the adult brain are physiologically dependent upon CSF1R signaling. Mice depleted of microglia show no behavioral or cognitive abnormalities, revealing that microglia are not necessary for these tasks. Finally, we discovered that the microglia-depleted brain completely repopulates with new microglia within 1 week of inhibitor cessation. Microglial repopulation throughout the CNS occurs through proliferation of nestin-positive cells that then differentiate into microglia.

  2. The endocannabinoid system drives neural progenitor proliferation.

    PubMed

    Aguado, Tania; Monory, Krisztina; Palazuelos, Javier; Stella, Nephi; Cravatt, Benjamin; Lutz, Beat; Marsicano, Giovanni; Kokaia, Zaal; Guzmán, Manuel; Galve-Roperh, Ismael

    2005-10-01

    The discovery of multipotent neural progenitor (NP) cells has provided strong support for the existence of neurogenesis in the adult brain. However, the signals controlling NP proliferation remain elusive. Endocannabinoids, the endogenous counterparts of marijuana-derived cannabinoids, act as neuromodulators via presynaptic CB1 receptors and also control neural cell death and survival. Here we show that progenitor cells express a functional endocannabinoid system that actively regulates cell proliferation both in vitro and in vivo. Specifically, NPs produce endocannabinoids and express the CB1 receptor and the endocannabinoid-inactivating enzyme fatty acid amide hydrolase (FAAH). CB1 receptor activation promotes cell proliferation and neurosphere generation, an action that is abrogated in CB1-deficient NPs. Accordingly, proliferation of hippocampal NPs is increased in FAAH-deficient mice. Our results demonstrate that endocannabinoids constitute a new group of signaling cues that regulate NP proliferation and thus open novel therapeutic avenues for manipulation of NP cell fate in the adult brain.

  3. Glutamate Increases In Vitro Survival and Proliferation and Attenuates Oxidative Stress-Induced Cell Death in Adult Spinal Cord-Derived Neural Stem/Progenitor Cells via Non-NMDA Ionotropic Glutamate Receptors.

    PubMed

    Hachem, Laureen D; Mothe, Andrea J; Tator, Charles H

    2016-08-15

    Traumatic spinal cord injury (SCI) leads to a cascade of secondary chemical insults, including oxidative stress and glutamate excitotoxicity, which damage host neurons and glia. Transplantation of exogenous neural stem/progenitor cells (NSPCs) has shown promise in enhancing regeneration after SCI, although survival of transplanted cells remains poor. Understanding the response of NSPCs to the chemical mediators of secondary injury is essential in finding therapies to enhance survival. We examined the in vitro effects of glutamate and glutamate receptor agonists on adult rat spinal cord-derived NSPCs. NSPCs isolated from the periventricular region of the adult rat spinal cord were exposed to various concentrations of glutamate for 96 h. We found that glutamate treatment (500 μM) for 96 h significantly increased live cell numbers, reduced cell death, and increased proliferation, but did not significantly alter cell phenotype. Concurrent glutamate treatment (500 μM) in the setting of H2O2 exposure (500 μM) for 10 h increased NSPC survival compared to H2O2 exposure alone. The effects of glutamate on NSPCs were blocked by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonist GYKI-52466, but not by the N-methyl-D-aspartic acid receptor antagonist MK-801 or DL-AP5, or the mGluR3 antagonist LY-341495. Furthermore, treatment of NSPCs with AMPA, kainic acid, or the kainate receptor-specific agonist (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid mimicked the responses seen with glutamate both alone and in the setting of oxidative stress. These findings offer important insights into potential mechanisms to enhance NSPC survival and implicate a potential role for glutamate in promoting NSPC survival and proliferation after traumatic SCI.

  4. Relationship between left ventricular mass and coronary artery disease in young adults: a single-center study using cardiac computed tomography.

    PubMed

    Cho, Jae Yong; Sun, Joo Sung; Sur, Young Keun; Park, Jin Sun; Kang, Doo Kyoung

    2015-12-01

    We evaluated the relationship between coronary artery disease (CAD) and left ventricular mass (LVM) as measured by cardiac computed tomography (CT) in young adults ≤40 years of age. We retrospectively enrolled 490 consecutive individuals (383 males; mean age, 35.2 ± 4.4 years) who underwent cardiac CT. CAD was defined by the presence of any plaque detected by coronary CT angiography. Left ventricular (LV) function, including LVM, was automatically measured by a dedicated workstation. LVM and LVM index (LVMi) in patients with CT-detected CAD were compared to those of patients without CT-detected CAD. Logistic regression analysis was used to evaluate the relationship between cardiovascular risk factors and CAD. Fifty-five individuals had CT-detected CAD (11.2 %, 53 males). LVM measured by cardiac CT was 126.9 ± 30.0 g for males and 93.6 ± 20.9 g for females. LVM was higher (117.8 ± 30.8 vs. 133.6 ± 33.1 g, P < 0.001) in patients with CT-detected CAD compared with patients without CT-detected CAD. Obesity, hypertension, smoking, hypercholesterolemia, LVM and LVMi were predictors of CT-detected CAD. Body mass index (r = 0.237, P < 0.001) and systolic blood pressure (r = 0.281, P < 0.001) were positively correlated with LVM. In the multivariate analysis, LVM [odds ratio (OR) = 1.016] and LVMi (OR = 1.026) remained independent predictors of CAD. LVM and LVMi in patients with CT-detected CAD were higher than that of patients without CT-detected CAD. LVM and LVMi measured by cardiac CT were independent predictors of CAD.

  5. Cerebral Near-Infrared Spectroscopy (NIRS) Monitoring and Neurologic Outcomes in Adult Cardiac Surgery Patients and Neurologic Outcomes: A Systematic Review

    PubMed Central

    Zheng, Fei; Sheinberg, Rosanne; Yee, May Sann; Ono, Masa; Zheng, Yueyging; Hogue, Charles W.

    2013-01-01

    Background Near-infrared spectroscopy is used during cardiac surgery to monitor the adequacy of cerebral perfusion. In this systematic review, we evaluated available data for adult patients to determine (1) whether decrements in cerebral oximetry during cardiac surgery are associated with stroke, postoperative cognitive dysfunction (POCD), or delirium and (2) whether interventions aimed at correcting cerebral oximetry decrements improve neurologic outcomes. Methods We searched PubMed, Cochrane, and Embase databases from inception until January 31, 2012, without restriction on languages. Each article was examined for additional references. A publication was excluded if it did not include original data (e.g., review, commentary) or if it was not published as a full-length article in a peer-reviewed journal (e.g., abstract only). The identified abstracts were screened first, and full texts of eligible papers were reviewed independently by two investigators. For eligible publications, we recorded the number of subjects, type of surgery, and criteria for diagnosis of neurologic endpoints. Results We identified 13 case reports, 27 observational studies, and two prospectively randomized intervention trials that met our inclusion criteria. Case reports and two observational studies contained anecdotal evidence suggesting that regional cerebral O2 saturation (rScO2) monitoring could be used to identify cardiopulmonary bypass (CPB) cannula malposition. Six of nine observational studies reported an association between acute rScO2 desaturation and POCD based on the Mini-Mental Status Examination (n=3 studies) or more detailed cognitive testing (n=6 studies). Two retrospective studies reported a relationship between rScO2 desaturation and stroke or type I and II neurologic injury after surgery. The observational studies had many limitations, including small sample size, assessments only during the immediate postoperative period, and failure to perform risk adjustments. Two

  6. Disturbance of cardiac gene expression and cardiomyocyte structure predisposes Mecp2-null mice to arrhythmias

    PubMed Central

    Hara, Munetsugu; Takahashi, Tomoyuki; Mitsumasu, Chiaki; Igata, Sachiyo; Takano, Makoto; Minami, Tomoko; Yasukawa, Hideo; Okayama, Satoko; Nakamura, Keiichiro; Okabe, Yasunori; Tanaka, Eiichiro; Takemura, Genzou; Kosai, Ken-ichiro; Yamashita, Yushiro; Matsuishi, Toyojiro

    2015-01-01

    Methyl-CpG-binding protein 2 (MeCP2) is an epigenetic regulator of gene expression that is essential for normal brain development. Mutations in MeCP2 lead to disrupted neuronal function and can cause Rett syndrome (RTT), a neurodevelopmental disorder. Previous studies reported cardiac dysfunction, including arrhythmias in both RTT patients and animal models of RTT. In addition, recent studies indicate that MeCP2 may be involved in cardiac development and dysfunction, but its role in the developing and adult heart remains unknown. In this study, we found that Mecp2-null ESCs could differentiate into cardiomyocytes, but the development and further differentiation of cardiovascular progenitors were significantly affected in MeCP2 deficiency. In addition, we revealed that loss of MeCP2 led to dysregulation of endogenous cardiac genes and myocardial structural alterations, although Mecp2-null mice did not exhibit obvious cardiac functional abnormalities. Furthermore, we detected methylation of the CpG islands in the Tbx5 locus, and showed that MeCP2 could target these sequences. Taken together, these results suggest that MeCP2 is an important regulator of the gene-expression program responsible for maintaining normal cardiac development and cardiomyocyte structure. PMID:26073556

  7. Disturbance of cardiac gene expression and cardiomyocyte structure predisposes Mecp2-null mice to arrhythmias.

    PubMed

    Hara, Munetsugu; Takahashi, Tomoyuki; Mitsumasu, Chiaki; Igata, Sachiyo; Takano, Makoto; Minami, Tomoko; Yasukawa, Hideo; Okayama, Satoko; Nakamura, Keiichiro; Okabe, Yasunori; Tanaka, Eiichiro; Takemura, Genzou; Kosai, Ken-ichiro; Yamashita, Yushiro; Matsuishi, Toyojiro

    2015-06-15

    Methyl-CpG-binding protein 2 (MeCP2) is an epigenetic regulator of gene expression that is essential for normal brain development. Mutations in MeCP2 lead to disrupted neuronal function and can cause Rett syndrome (RTT), a neurodevelopmental disorder. Previous studies reported cardiac dysfunction, including arrhythmias in both RTT patients and animal models of RTT. In addition, recent studies indicate that MeCP2 may be involved in cardiac development and dysfunction, but its role in the developing and adult heart remains unknown. In this study, we found that Mecp2-null ESCs could differentiate into cardiomyocytes, but the development and further differentiation of cardiovascular progenitors were significantly affected in MeCP2 deficiency. In addition, we revealed that loss of MeCP2 led to dysregulation of endogenous cardiac genes and myocardial structural alterations, although Mecp2-null mice did not exhibit obvious cardiac functional abnormalities. Furthermore, we detected methylation of the CpG islands in the Tbx5 locus, and showed that MeCP2 could target these sequences. Taken together, these results suggest that MeCP2 is an important regulator of the gene-expression program responsible for maintaining normal cardiac development and cardiomyocyte structure.

  8. The alpha1 isoform of the Na+/K+ ATPase is up-regulated in dedifferentiated progenitor cells that mediate lens and retina regeneration in adult newts.

    PubMed

    Vergara, M Natalia; Smiley, Laura K; Del Rio-Tsonis, Katia; Tsonis, Panagiotis A

    2009-02-01

    Adult newts are able to regenerate their retina and lens after injury or complete removal through transdifferentiation of the pigmented epithelial tissues of the eye. This process needs to be tightly controlled, and several different mechanisms are likely to be recruited for this function. The Na(+)/K(+) ATPase is a transmembrane protein that establishes electrochemical gradients through the transport of Na(+) and K(+) and has been implicated in the modulation of key cellular processes such as cell division, migration and adhesion. Even though it is expressed in all cells, its isoform composition varies with cell type and is tightly controlled during development and regeneration. In the present study we characterize the expression pattern of Na(+)/K(+) ATPase alpha1 in the adult newt eye and during the process of lens and retina regeneration. We show that this isoform is up-regulated in undifferentiated cells during transdifferentiation. Such change in composition could be one of the mechanisms that newt cells utilize to modulate this process.

  9. Cell Sorting of Neural Stem and Progenitor Cells from the Adult Mouse Subventricular Zone and Live-imaging of their Cell Cycle Dynamics.

    PubMed

    Daynac, Mathieu; Morizur, Lise; Kortulewski, Thierry; Gauthier, Laurent R; Ruat, Martial; Mouthon, Marc-André; Boussin, François D

    2015-01-01

    Neural stem cells (NSCs) in the subventricular zone of the lateral ventricles (SVZ) sustain olfactory neurogenesis throughout life in the mammalian brain. They successively generate transit amplifying cells (TACs) and neuroblasts that differentiate into neurons once they integrate the olfactory bulbs. Emerging fluorescent activated cell sorting (FACS) techniques have allowed the isolation of NSCs as well as their progeny and have started to shed light on gene regulatory networks in adult neurogenic niches. We report here a cell sorting technique that allows to follow and distinguish the cell cycle dynamics of the above-mentioned cell populations from the adult SVZ with a LeX/EGFR/CD24 triple staining. Isolated cells are then plated as adherent cells to explore in details their cell cycle progression by time-lapse video microscopy. To this end, we use transgenic Fluorescence Ubiquitination Cell Cycle Indicator (FUCCI) mice in which cells are red-fluorescent during G1 phase due to a G1 specific red-Cdt1 reporter. This method has recently revealed that proliferating NSCs progressively lengthen their G1 phase during aging, leading to neurogenesis impairment. This method is easily transposable to other systems and could be of great interest for the study of the cell cycle dynamics of brain cells in the context of brain pathologies. PMID:26436641

  10. The Crab Nebula's progenitor

    NASA Technical Reports Server (NTRS)

    Nomoto, K.; Sugimoto, D.; Sparks, W. M.; Fesen, R. A.; Gull, T. R.; Miyaji, S.

    1982-01-01

    The initial mass of the Crab Nebula's progenitor star is estimated by comparing the observed nebular chemical abundances with detailed evolutionary calculations for 2.4- and 2.6-solar-mass helium cores of stars with masses of 8 to 10 solar masses. The results indicate that the mass of the Crab's progenitor was between the upper limit of about 8 solar masses for carbon deflagration and the lower limit of about 9.5 solar masses set by the dredge-up of the helium layer before the development of the helium-burning convective region. A scenario is outlined for the evolution of the progenitor star. It is suggested that the Crab Nebula was probably the product of an electron-capture supernova.

  11. Heart fields and cardiac morphogenesis.

    PubMed

    Kelly, Robert G; Buckingham, Margaret E; Moorman, Antoon F

    2014-10-01

    In this review, we focus on two important steps in the formation of the embryonic heart: (i) the progressive addition of late differentiating progenitor cells from the second heart field that drives heart tube extension during looping morphogenesis, and (ii) the emergence of patterned proliferation within the embryonic myocardium that generates distinct cardiac chambers. During the transition between these steps, the major site of proliferation switches from progenitor cells outside the early heart to proliferation within the embryonic myocardium. The second heart field and ballooning morphogenesis concepts have major repercussions on our understanding of human heart development and disease. In particular, they provide a framework to dissect the origin of congenital heart defects and the regulation of myocardial proliferation and differentiation of relevance for cardiac repair.

  12. Effects of an 18 week walking programme on cardiac function in previously sedentary or relatively inactive adults.

    PubMed Central

    Woolf-May, K; Bird, S; Owen, A

    1997-01-01

    OBJECTIVE: To investigate the effects of an 18 week walking programme upon cardiac function. METHODS: 29 sedentary or relatively inactive but otherwise healthy subjects (15 walkers and 14 controls, aged 40-68 years) completed the study. The walkers completed a progressive 18 week walking programme which required an estimated average energy expenditure of 900 kcal week-1 for the total duration of the study and 1161 kcal week-1 during the final six weeks. Walking was carried out at an intensity of 67.8 (SD 4.99)% of maximum oxygen consumption and 73.8(6.99%) of maximum heart rate. Before and after the intervention all subjects underwent an M mode echocardiogram, graded treadmill walking test, and step test for the assessment of aerobic fitness. RESULTS: After 18 weeks the results of the control group showed no change in any of the variables measured while the walkers showed a statistically significant increase in the velocity of relaxation of the longitudinal myocardial fibres of the left ventricle and a decrease in heart rate measured during the step tests, indicating an improvement in aerobic capacity. CONCLUSIONS: Walking promotes improvements in cardiovascular fitness. Moderate forms of exercise may improve cardiac function. Images p50-a PMID:9132212

  13. Executive functions improvement following a 5-month aquaerobics program in older adults: Role of cardiac vagal control in inhibition performance.

    PubMed

    Albinet, Cédric T; Abou-Dest, Amira; André, Nathalie; Audiffren, Michel

    2016-03-01

    The aims of this study were to examine the effects of aerobic exercise on measures of executive performance and their relationships with changes in cardiorespiratory fitness, cardiac vagal control (heart rate variability) and psychological variables. Thirty-six sedentary seniors aged 60-75 years were randomly assigned to a swimming and aquaerobics program or a stretching program two times a week for 21 weeks. Executive functions (inhibition, updating of working memory and cognitive flexibility) and cardiorespiratory fitness (estimated VO2max) were assessed at the start, after 10 weeks of program and at the end of the program. Resting HRV and measures of psychological outcomes (depression, self-efficacy, decisional balance) were obtained at the start and at the end of the program. Participants of both groups significantly improved their VO2max level, their psychological state and their performance for the 2-back task. Only the participants in the aquaerobics group significantly improved their vagally-mediated HRV and their performance for the Stroop test and the verbal running-span test at the end of the program. Only improvements in cardiac vagal control and in inhibition were shown to be functionally related. These results are discussed in line with the model of neurovisceral integration. PMID:26812613

  14. Executive functions improvement following a 5-month aquaerobics program in older adults: Role of cardiac vagal control in inhibition performance.

    PubMed

    Albinet, Cédric T; Abou-Dest, Amira; André, Nathalie; Audiffren, Michel

    2016-03-01

    The aims of this study were to examine the effects of aerobic exercise on measures of executive performance and their relationships with changes in cardiorespiratory fitness, cardiac vagal control (heart rate variability) and psychological variables. Thirty-six sedentary seniors aged 60-75 years were randomly assigned to a swimming and aquaerobics program or a stretching program two times a week for 21 weeks. Executive functions (inhibition, updating of working memory and cognitive flexibility) and cardiorespiratory fitness (estimated VO2max) were assessed at the start, after 10 weeks of program and at the end of the program. Resting HRV and measures of psychological outcomes (depression, self-efficacy, decisional balance) were obtained at the start and at the end of the program. Participants of both groups significantly improved their VO2max level, their psychological state and their performance for the 2-back task. Only the participants in the aquaerobics group significantly improved their vagally-mediated HRV and their performance for the Stroop test and the verbal running-span test at the end of the program. Only improvements in cardiac vagal control and in inhibition were shown to be functionally related. These results are discussed in line with the model of neurovisceral integration.

  15. A molecular and genetic outline of cardiac morphogenesis.

    PubMed

    Rana, M S; Christoffels, V M; Moorman, A F M

    2013-04-01

    Perturbations in cardiac development result in congenital heart disease, the leading cause of birth defect-related infant morbidity and mortality. Advances in cardiac developmental biology have significantly augmented our understanding of signalling pathways and transcriptional networks underlying heart formation. Cardiogenesis is initiated with the formation of mesodermal multipotent cardiac progenitor cells and is governed by cross-talk between developmental cues emanating from endodermal, mesodermal and ectodermal cells. The molecular and transcriptional machineries that direct the specification and differentiation of these cardiac precursors are part of an evolutionarily conserved programme that includes the Nkx-, Gata-, Hand-, T-box- and Mef2 family of transcription factors. Unravelling the hierarchical networks governing the fate and differentiation of cardiac precursors is crucial for our understanding of congenital heart disease and future stem cell-based and gene therapies. Recent molecular and genetic lineage analyses have revealed that subpopulations of cardiac progenitor cells follow distinctive specification and differentiation paths, which determine their final contribution to the heart. In the last decade, progenitor cells that contribute to the arterial pole and right ventricle have received much attention, as abnormal development of these cells frequently results in congenital defects of the aortic and pulmonary outlets, representing the most commonly occurring congenital cardiac defects. In this review, we provide an overview of the building plan of the vertebrate four-chambered heart, with a special focus on cardiac progenitor cell specification, differentiation and deployment during arterial pole development. PMID:23297764

  16. Optimizing cardiac repair and regeneration through activation of the endogenous cardiac stem cell compartment.

    PubMed

    Ellison, Georgina M; Nadal-Ginard, Bernardo; Torella, Daniele

    2012-10-01

    Given the aging of the Western World and declining death rates due to acute coronary syndromes, the increasing trends in the magnitude and morbidity of heart failure (HF) are predicted to continue for the foreseeable future. It is imperative to develop effective therapies for the amelioration and prevention of HF. The search for the best cell type to be used in clinical protocols of cardiac regeneration is still on. That the adult mammalian heart harbors endogenous, multipotent cardiac stem/progenitor cells (eCSCs) and that cardiomyocytes are replaced throughout adulthood represent a paradigm shift in cardiovascular biology. The presence of eCSCs supports the view that the heart can repair itself if the eCSCs can be properly stimulated. Pending a better understanding of eCSC biology, it should be possible to replace autologous cell transplantation-based myocardial regeneration protocols with an "off-the-shelf," readily available, and effective regenerative/reparative therapy based on activation of the eCSCs in situ. PMID:22688972

  17. Clinical practice guide for the choice of perioperative volume-restoring fluid in adult patients undergoing non-cardiac surgery.

    PubMed

    Basora, M; Colomina, M J; Moral, V; Asuero de Lis, M S; Boix, E; Jover, J L; Llau, J V; Rodrigo, M P; Ripollés, J; Calvo Vecino, J M

    2016-01-01

    The present Clinical practice guide responds to the clinical questions about security in the choice of fluid (crystalloid, colloid or hydroxyethyl starch 130) in patients who require volume replacement during perioperative period of non-cardiac surgeries. From the evidence summary, recommendations were made following the GRADE methodology. In this population fluid therapy based on crystalloids is suggested (weak recommendation, low quality evidence). In the events where volume replacement is not reached with crystalloids, the use of synthetic colloids (hydroxyethyl starch 130 or modified fluid gelatin) is suggested instead of 5% albumin (weak recommendation, low quality evidence). The choice and dosage of the colloid should be based in the product characteristics, patient comorbidity and anesthesiologist's experience.

  18. Clinical practice guide for the choice of perioperative volume-restoring fluid in adult patients undergoing non-cardiac surgery.

    PubMed

    Basora, M; Colomina, M J; Moral, V; Asuero de Lis, M S; Boix, E; Jover, J L; Llau, J V; Rodrigo, M P; Ripollés, J; Calvo Vecino, J M

    2016-01-01

    The present Clinical practice guide responds to the clinical questions about security in the choice of fluid (crystalloid, colloid or hydroxyethyl starch 130) in patients who require volume replacement during perioperative period of non-cardiac surgeries. From the evidence summary, recommendations were made following the GRADE methodology. In this population fluid therapy based on crystalloids is suggested (weak recommendation, low quality evidence). In the events where volume replacement is not reached with crystalloids, the use of synthetic colloids (hydroxyethyl starch 130 or modified fluid gelatin) is suggested instead of 5% albumin (weak recommendation, low quality evidence). The choice and dosage of the colloid should be based in the product characteristics, patient comorbidity and anesthesiologist's experience. PMID:26343809

  19. Hyperlactatemia in patients undergoing adult cardiac surgery under cardiopulmonary bypass: Causative factors and its effect on surgical outcome

    PubMed Central

    Naik, Rakesh; George, Gladdy; Karuppiah, Sathappan; Philip, Madhu Andrew

    2016-01-01

    Objectives of the Study: To identify the factors causing high lactate levels in patients undergoing cardiac surgery under cardiopulmonary bypass (CPB) and to assess the association between high blood lactate levels and postoperative morbidity and mortality. Methods: A retrospective observational study including 370 patients who underwent cardiac surgeries under cardiopulmonary bypass. The patients were divided into 2 groups based on serum lactate levels; those with serum lactate levels greater than or equal to 4 mmol/L considered as hyperlactatemia and those with serum lactate levels less than 4 mmol/L. Blood lactate samples were collected intraoperatively and postoperatively in the ICU. Preoperative and intraoperative risk factors for hyperlactatemia were identified using the highest intraoperative value of lactate. The postoperative morbidity and mortality associated with hyperlactatemia was studied using the overall (intraoperative and postoperative values) peak lactate levels. Preoperative clinical data, perioperative events and postoperative morbidity and mortality were recorded. Results: Intraoperative peak blood lactate levels of 4.0 mmol/L or more were present in 158 patients (42.7%). Females had higher peak intra operative lactate levels (P = 0.011). There was significant correlation between CPB time (Pearson correlation coefficient r = 0.024; P = 0.003) and aortic cross clamp time (r = 0.02, P = 0.007) with peak intraoperative blood lactate levels. Patients with hyperlactatemia had significantly higher rate of postoperative morbidity like atrial fibrillation (19.9% vs. 5.3%; P = 0.004), prolonged requirement of inotropes (34% vs. 11.8%; P = 0.001), longer stay in the ICU (P = 0.013) and hospital (P = 0.001). Conclusions: Hyperlactatemia had significant association with post-operative morbidity. Detection of hyperlactatemia in the perioperative period should be considered as an indicator of inadequate tissue oxygen delivery and must be aggressively

  20. Noninvasive Imaging of Administered Progenitor Cells

    SciTech Connect

    Steven R Bergmann, M.D., Ph.D.

    2012-12-03

    The objective of this research grant was to develop an approach for labeling progenitor cells, specifically those that we had identified as being able to replace ischemic heart cells, so that the distribution could be followed non-invasively. In addition, the research was aimed at determining whether administration of progenitor cells resulted in improved myocardial perfusion and function. The efficiency and toxicity of radiolabeling of progenitor cells was to be evaluated. For the proposed clinical protocol, subjects with end-stage ischemic coronary artery disease were to undergo a screening cardiac positron emission tomography (PET) scan using N-13 ammonia to delineate myocardial perfusion and function. If they qualified based on their PET scan, they would undergo an in-hospital protocol whereby CD34+ cells were stimulated by the administration of granulocytes-colony stimulating factor (G-CSF). CD34+ cells would then be isolated by apharesis, and labeled with indium-111 oxine. Cells were to be re-infused and subjects were to undergo single photon emission computed tomography (SPECT) scanning to evaluate uptake and distribution of labeled progenitor cells. Three months after administration of progenitor cells, a cardiac PET scan was to be repeated to evaluate changes in myocardial perfusion and/or function. Indium oxine is a radiopharmaceutical for labeling of autologous lymphocytes. Indium-111 (In-111) decays by electron capture with a t{sub ½} of 67.2 hours (2.8 days). Indium forms a saturated complex that is neutral, lipid soluble, and permeates the cell membrane. Within the cell, the indium-oxyquinolone complex labels via indium intracellular chelation. Following leukocyte labeling, ~77% of the In-111 is incorporated in the cell pellet. The presence of red cells and /or plasma reduces the labeling efficacy. Therefore, the product needed to be washed to eliminate plasma proteins. This repeated washing can damage cells. The CD34 selected product was a 90

  1. In vitro analysis of the origin and maintenance of O-2Aadult progenitor cells

    PubMed Central

    1992-01-01

    We have been studying the differing characteristics of oligodendrocyte- type-2 astrocyte (O-2A) progenitors isolated from optic nerves of perinatal and adult rats. These two cell types display striking differences in their in vitro phenotypes. In addition, the O- 2Aperinatal progenitor population appears to have a limited life-span in vivo, while O-2Aadult progenitors appear to be maintained throughout life. O-2Aperinatal progenitors seem to have largely disappeared from the optic nerve by 1 mo after birth, and are not detectable in cultures derived from optic nerves of adult rats. In contrast, O-2Aadult progenitors can first be isolated from optic nerves of 7-d-old rats and are still present in optic nerves of 1-yr-old rats. These observations raise two questions: (a) From what source do O-2Aadult progenitors originate; and (b) how is the O-2Aadult progenitor population maintained in the nerve throughout life? We now provide in vitro evidence indicating that O-2Aadult progenitors are derived directly from a subpopulation of O-2Aperinatal progenitors. We also provide evidence indicating that O-2Aadult progenitors are capable of prolonged self renewal in vitro. In addition, our data suggests that the in vitro generation of oligodendrocytes from O-2Aadult progenitors occurs primarily through asymmetric division and differentiation, in contrast with the self-extinguishing pattern of symmetric division and differentiation displayed by O-2Aperinatal progenitors in vitro. We suggest that O-2Aadult progenitors express at least some properties of stem cells and thus may be able to support the generation of both differentiated progeny cells as well as their own continued replenishment throughout adult life. PMID:1730741

  2. Functional Assessment of Cardiac Responses of Adult Zebrafish (Danio rerio) to Acute and Chronic Temperature Change Using High-Resolution Echocardiography.

    PubMed

    Lee, Ling; Genge, Christine E; Cua, Michelle; Sheng, Xiaoye; Rayani, Kaveh; Beg, Mirza F; Sarunic, Marinko V; Tibbits, Glen F

    2016-01-01

    The zebrafish (Danio rerio) is an important organism as a model for understanding vertebrate cardiovascular development. However, little is known about adult ZF cardiac function and how contractile function changes to cope with fluctuations in ambient temperature. The goals of this study were to: 1) determine if high resolution echocardiography (HRE) in the presence of reduced cardiodepressant anesthetics could be used to accurately investigate the structural and functional properties of the ZF heart and 2) if the effect of ambient temperature changes both acutely and chronically could be determined non-invasively using HRE in vivo. Heart rate (HR) appears to be the critical factor in modifying cardiac output (CO) with ambient temperature fluctuation as it increases from 78 ± 5.9 bpm at 18°C to 162 ± 9.7 bpm at 28°C regardless of acclimation state (cold acclimated CA- 18°C; warm acclimated WA- 28°C). Stroke volume (SV) is highest when the ambient temperature matches the acclimation temperature, though this difference did not constitute a significant effect (CA 1.17 ± 0.15 μL at 18°C vs 1.06 ± 0.14 μl at 28°C; WA 1.10 ± 0.13 μL at 18°C vs 1.12 ± 0.12 μl at 28°C). The isovolumetric contraction time (IVCT) was significantly shorter in CA fish at 18°C. The CA group showed improved systolic function at 18°C in comparison to the WA group with significant increases in both ejection fraction and fractional shortening and decreases in IVCT. The decreased early peak (E) velocity and early peak velocity / atrial peak velocity (E/A) ratio in the CA group are likely associated with increased reliance on atrial contraction for ventricular filling. PMID:26730947

  3. Functional Assessment of Cardiac Responses of Adult Zebrafish (Danio rerio) to Acute and Chronic Temperature Change Using High-Resolution Echocardiography

    PubMed Central

    Cua, Michelle; Sheng, Xiaoye; Rayani, Kaveh; Beg, Mirza F.; Sarunic, Marinko V.; Tibbits, Glen F.

    2016-01-01

    The zebrafish (Danio rerio) is an important organism as a model for understanding vertebrate cardiovascular development. However, little is known about adult ZF cardiac function and how contractile function changes to cope with fluctuations in ambient temperature. The goals of this study were to: 1) determine if high resolution echocardiography (HRE) in the presence of reduced cardiodepressant anesthetics could be used to accurately investigate the structural and functional properties of the ZF heart and 2) if the effect of ambient temperature changes both acutely and chronically could be determined non-invasively using HRE in vivo. Heart rate (HR) appears to be the critical factor in modifying cardiac output (CO) with ambient temperature fluctuation as it increases from 78 ± 5.9 bpm at 18°C to 162 ± 9.7 bpm at 28°C regardless of acclimation state (cold acclimated CA– 18°C; warm acclimated WA– 28°C). Stroke volume (SV) is highest when the ambient temperature matches the acclimation temperature, though this difference did not constitute a significant effect (CA 1.17 ± 0.15 μL at 18°C vs 1.06 ± 0.14 μl at 28°C; WA 1.10 ± 0.13 μL at 18°C vs 1.12 ± 0.12 μl at 28°C). The isovolumetric contraction time (IVCT) was significantly shorter in CA fish at 18°C. The CA group showed improved systolic function at 18°C in comparison to the WA group with significant increases in both ejection fraction and fractional shortening and decreases in IVCT. The decreased early peak (E) velocity and early peak velocity / atrial peak velocity (E/A) ratio in the CA group are likely associated with increased reliance on atrial contraction for ventricular filling. PMID:26730947

  4. Acquisition of multiple nuclei and the activity of DNA polymerase alpha and reinitiation of DNA replication in terminally differentiated adult cardiac muscle cells in culture

    SciTech Connect

    Claycomb, W.C.; Bradshaw, H.D. Jr.

    1983-10-01

    Terminally differentiated ventricular cardiac muscle cells isolated from the adult rat and maintained in cell culture have been observed to acquire multiple nuclei. In one cultured myocyte as many as 10 nuclei have been counted. Apparently, these multiple nuclei are formed by DNA replication followed by karyokinesis; the cells must then fail to complete mitosis and divide. To investigate whether DNA synthesis was occurring, the cells were cultured in the presence of (3H)thymidine and then processed for autoradiography. Mononucleated, binucleated, and multinucleated cells incorporate (3H)thymidine into DNA as evidenced by the high concentration of silver grains over their nuclei. Peak periods of incorporation were observed to occur at 10- to 12-day intervals; at 11, 23, and 33 days after initially placing the cells in culture. When the cells were maintained in the presence of (3H)thymidine continuously from Day 7 to Day 17 of culture, 23% of the cells became labeled. If the cells were cultured continuously for 30 days in the presence of (3H)thymidine, from Day 10 to Day 40, 56% of the cells were labeled. Isopycnic gradient analysis indicates that this thymidine incorporation was into DNA that was being replicated semiconservatively; these experiments did not eliminate the possibility, however, that this incorporation was due to amplification of specific genes, such as those coding for the contractile proteins. The activity of DNA polymerase alpha also returns to these cells. These studies demonstrate that the terminally differentiated mammalian ventricular cardiac muscle cell, previously thought to have permanently lost the capacity to replicate DNA during early development, is able to reinitiate semiconservative DNA replication when grown in culture.

  5. The dynamics of murine mammary stem/progenitor cells

    PubMed Central

    DONG, Qiaoxiang; SUN, Lu-Zhe

    2014-01-01

    The stem/progenitor cells in the murine mammary gland are a highly dynamic population of cells that are responsible for ductal elongation in puberty, homeostasis maintenance in adult, and lobulo-alveolar genesis during pregnancy. In recent years understanding the epithelial cell hierarchy within the mammary gland is becoming particularly important as these different stem/progenitor cells were perceived to be the cells of origin for various subtypes of breast cancer. Although significant advances have been made in enrichment and isolation of stem/progenitor cells by combinations of antibodies against cell surface proteins together with flow cytometry, and in identification of stem/progenitor cells with multi-lineage differentiation and self-renewal using mammary fat pad reconstitution assay and in vivo genetic labeling technique, a clear understanding of how these different stem/progenitors are orchestrated in the mammary gland is still lacking. Here we discuss the different in vivo and in vitro methods currently available for stem/progenitor identification, their associated caveats, and a possible new hierarchy model to reconcile various putative stem/progenitor cell populations identified by different research groups. PMID:25580105

  6. Cardiovascular Development and the Colonizing Cardiac Neural Crest Lineage

    PubMed Central

    Snider, Paige; Olaopa, Michael; Firulli, Anthony B.

    2008-01-01

    Although it is well established that transgenic manipulation of mammalian neural crest-related gene expression and microsurgical removal of premigratory chicken and Xenopus embryonic cardiac neural crest progenitors results in a wide spectrum of both structural and functional congenital heart defects, the actual functional mechanism of the cardiac neural crest cells within the heart is poorly understood. Neural crest cell migration and appropriate colonization of the pharyngeal arches and outflow tract septum is thought to be highly dependent on genes that regulate cell-autonomous polarized movement (i.e., gap junctions, cadherins, and noncanonical Wnt1 pathway regulators). Once the migratory cardiac neural crest subpopulation finally reaches the heart, they have traditionally been thought to participate in septation of the common outflow tract into separate aortic and pulmonary arteries. However, several studies have suggested these colonizing neural crest cells may also play additional unexpected roles during cardiovascular development and may even contribute to a crest-derived stem cell population. Studies in both mice and chick suggest they can also enter the heart from the venous inflow as well as the usual arterial outflow region, and may contribute to the adult semilunar and atrioventricular valves as well as part of the cardiac conduction system. Furthermore, although they are not usually thought to give rise to the cardiomyocyte lineage, neural crest cells in the zebrafish (Danio rerio) can contribute to the myocardium and may have different functions in a species-dependent context. Intriguingly, both ablation of chick and Xenopus premigratory neural crest cells, and a transgenic deletion of mouse neural crest cell migration or disruption of the normal mammalian neural crest gene expression profiles, disrupts ventral myocardial function and/or cardiomyocyte proliferation. Combined, this suggests that either the cardiac neural crest secrete factor/s that

  7. Identification and characterization of an injury-induced skeletal progenitor

    PubMed Central

    Marecic, Owen; Tevlin, Ruth; McArdle, Adrian; Seo, Eun Young; Wearda, Taylor; Duldulao, Christopher; Walmsley, Graham G.; Nguyen, Allison; Weissman, Irving L.; Chan, Charles K. F.; Longaker, Michael T.

    2015-01-01

    The postnatal skeleton undergoes growth, remodeling, and repair. We hypothesized that skeletal progenitor cells active during these disparate phases are genetically and phenotypically distinct. We identified a highly potent regenerative cell type that we term the fracture-induced bone, cartilage, stromal progenitor (f-BCSP) in the fracture callus of adult mice. The f-BCSP possesses significantly enhanced skeletogenic potential compared with BCSPs harvested from uninjured bone. It also recapitulates many gene expression patterns involved in perinatal skeletogenesis. Our results indicate that the skeletal progenitor population is functionally stratified, containing distinct subsets responsible for growth, regeneration, and repair. Furthermore, our findings suggest that injury-induced changes to the skeletal stem and progenitor microenvironments could activate these cells and enhance their regenerative potential. PMID:26216955

  8. Identification and characterization of an injury-induced skeletal progenitor.

    PubMed

    Marecic, Owen; Tevlin, Ruth; McArdle, Adrian; Seo, Eun Young; Wearda, Taylor; Duldulao, Christopher; Walmsley, Graham G; Nguyen, Allison; Weissman, Irving L; Chan, Charles K F; Longaker, Michael T

    2015-08-11

    The postnatal skeleton undergoes growth, remodeling, and repair. We hypothesized that skeletal progenitor cells active during these disparate phases are genetically and phenotypically distinct. We identified a highly potent regenerative cell type that we term the fracture-induced bone, cartilage, stromal progenitor (f-BCSP) in the fracture callus of adult mice. The f-BCSP possesses significantly enhanced skeletogenic potential compared with BCSPs harvested from uninjured bone. It also recapitulates many gene expression patterns involved in perinatal skeletogenesis. Our results indicate that the skeletal progenitor population is functionally stratified, containing distinct subsets responsible for growth, regeneration, and repair. Furthermore, our findings suggest that injury-induced changes to the skeletal stem and progenitor microenvironments could activate these cells and enhance their regenerative potential.

  9. Activated c-Kit receptor in the heart promotes cardiac repair and regeneration after injury

    PubMed Central

    Di Siena, S; Gimmelli, R; Nori, S L; Barbagallo, F; Campolo, F; Dolci, S; Rossi, P; Venneri, M A; Giannetta, E; Gianfrilli, D; Feigenbaum, L; Lenzi, A; Naro, F; Cianflone, E; Mancuso, T; Torella, D; Isidori, A M; Pellegrini, M

    2016-01-01

    The role of endogenous c-Kit receptor activation on cardiac cell homeostasis and repair remains largely unexplored. Transgenic mice carrying an activating point mutation (TgD814Y) in the kinase domain of the c-Kit gene were generated. c-KitTgD814Y receptor was expressed in the heart during embryonic development and postnatal life, in a similar timing and expression pattern to that of the endogenous gene, but not in the hematopoietic compartment allowing the study of a cardiac-specific phenotype. c-KitTgD814Y mutation produced a constitutive active c-Kit receptor in cardiac tissue and cells from transgenic mice as demonstrated by the increased phosphorylation of ERK1/2 and AKT, which are the main downstream molecular effectors of c-Kit receptor signaling. In adult transgenic hearts, cardiac morphology, size and total c-Kit+ cardiac cell number was not different compared with wt mice. However, when c-KitTgD814Y mice were subjected to transmural necrotic heart damage by cryoinjury (CI), all transgenic survived, compared with half of wt mice. In the sub-acute phase after CI, transgenic and wt mice showed similar heart damage. However, 9 days after CI, transgenic mice exhibited an increased number of c-Kit+CD31+ endothelial progenitor cells surrounding the necrotic area. At later follow-up, a consistent reduction of fibrotic area, increased capillary density and increased cardiomyocyte replenishment rate (as established by BrdU incorporation) were observed in transgenic compared with wt mice. Consistently, CD45−c-Kit+ cardiac stem cells isolated from transgenic c-KitTgD814Y mice showed an enhanced endothelial and cardiomyocyte differentiation potential compared with cells isolated from the wt. Constitutive activation of c-Kit receptor in mice is associated with an increased cardiac myogenic and vasculogenic reparative potential after injury, with a significant improvement of survival. PMID:27468693

  10. Activated c-Kit receptor in the heart promotes cardiac repair and regeneration after injury.

    PubMed

    Di Siena, S; Gimmelli, R; Nori, S L; Barbagallo, F; Campolo, F; Dolci, S; Rossi, P; Venneri, M A; Giannetta, E; Gianfrilli, D; Feigenbaum, L; Lenzi, A; Naro, F; Cianflone, E; Mancuso, T; Torella, D; Isidori, A M; Pellegrini, M

    2016-01-01

    The role of endogenous c-Kit receptor activation on cardiac cell homeostasis and repair remains largely unexplored. Transgenic mice carrying an activating point mutation (TgD814Y) in the kinase domain of the c-Kit gene were generated. c-Kit(TgD814Y) receptor was expressed in the heart during embryonic development and postnatal life, in a similar timing and expression pattern to that of the endogenous gene, but not in the hematopoietic compartment allowing the study of a cardiac-specific phenotype. c-Kit(TgD814Y) mutation produced a constitutive active c-Kit receptor in cardiac tissue and cells from transgenic mice as demonstrated by the increased phosphorylation of ERK1/2 and AKT, which are the main downstream molecular effectors of c-Kit receptor signaling. In adult transgenic hearts, cardiac morphology, size and total c-Kit(+) cardiac cell number was not different compared with wt mice. However, when c-Kit(TgD814Y) mice were subjected to transmural necrotic heart damage by cryoinjury (CI), all transgenic survived, compared with half of wt mice. In the sub-acute phase after CI, transgenic and wt mice showed similar heart damage. However, 9 days after CI, transgenic mice exhibited an increased number of c-Kit(+)CD31(+) endothelial progenitor cells surrounding the necrotic area. At later follow-up, a consistent reduction of fibrotic area, increased capillary density and increased cardiomyocyte replenishment rate (as established by BrdU incorporation) were observed in transgenic compared with wt mice. Consistently, CD45(-)c-Kit(+) cardiac stem cells isolated from transgenic c-Kit(TgD814Y) mice showed an enhanced endothelial and cardiomyocyte differentiation potential compared with cells isolated from the wt. Constitutive activation of c-Kit receptor in mice is associated with an increased cardiac myogenic and vasculogenic reparative potential after injury, with a significant improvement of survival. PMID:27468693

  11. Interneuron Progenitor Transplantation to Treat CNS Dysfunction

    PubMed Central

    Chohan, Muhammad O.; Moore, Holly

    2016-01-01

    Due to the inadequacy of endogenous repair mechanisms diseases of the nervous system remain a major challenge to scientists and clinicians. Stem cell based therapy is an exciting and viable strategy that has been shown to ameliorate or even reverse symptoms of CNS dysfunction in preclinical animal models. Of particular importance has been the use of GABAergic interneuron progenitors as a therapeutic strategy. Born in the neurogenic niches of the ventral telencephalon, interneuron progenitors retain their unique capacity to disperse, integrate and induce plasticity in adult host circuitries following transplantation. Here we discuss the potential of interneuron based transplantation strategies as it relates to CNS disease therapeutics. We also discuss mechanisms underlying their therapeutic efficacy and some of the challenges that face the field. PMID:27582692

  12. Progenitor cells for ocular surface regenerative therapy.

    PubMed

    Casaroli-Marano, Ricardo P; Nieto-Nicolau, Nuria; Martínez-Conesa, Eva M

    2013-01-01

    The integrity and normal function of the corneal epithelium are essential for maintaining the cornea's transparency and vision. The existence of a cell population with progenitor characteristics in the limbus maintains a dynamic of constant epithelial repair and renewal. Currently, cell-based therapies for bio-replacement, such as cultured limbal epithelial transplantation and cultured oral mucosal epithelial transplantation, present very encouraging clinical results for treating limbal stem cell deficiencies. Another emerging therapeutic strategy consists of obtaining and implementing human progenitor cells of different origins using tissue engineering methods. The development of cell-based therapies using stem cells, such as human adult mesenchymal stromal cells, represents a significant breakthrough in the treatment of certain eye diseases and also offers a more rational, less invasive and more physiological approach to ocular surface regeneration. PMID:23257987

  13. Progenitor cells for ocular surface regenerative therapy.

    PubMed

    Casaroli-Marano, Ricardo P; Nieto-Nicolau, Nuria; Martínez-Conesa, Eva M

    2013-01-01

    The integrity and normal function of the corneal epithelium are essential for maintaining the cornea's transparency and vision. The existence of a cell population with progenitor characteristics in the limbus maintains a dynamic of constant epithelial repair and renewal. Currently, cell-based therapies for bio-replacement, such as cultured limbal epithelial transplantation and cultured oral mucosal epithelial transplantation, present very encouraging clinical results for treating limbal stem cell deficiencies. Another emerging therapeutic strategy consists of obtaining and implementing human progenitor cells of different origins using tissue engineering methods. The development of cell-based therapies using stem cells, such as human adult mesenchymal stromal cells, represents a significant breakthrough in the treatment of certain eye diseases and also offers a more rational, less invasive and more physiological approach to ocular surface regeneration.

  14. Human progenitor cells for bone engineering applications.

    PubMed

    de Peppo, G M; Thomsen, P; Karlsson, C; Strehl, R; Lindahl, A; Hyllner, J

    2013-06-01

    In this report, the authors review the human skeleton and the increasing burden of bone deficiencies, the limitations encountered with the current treatments and the opportunities provided by the emerging field of cell-based bone engineering. Special emphasis is placed on different sources of human progenitor cells, as well as their pros and cons in relation to their utilization for the large-scale construction of functional bone-engineered substitutes for clinical applications. It is concluded that, human pluripotent stem cells represent a valuable source for the derivation of progenitor cells, which combine the advantages of both embryonic and adult stem cells, and indeed display high potential for the construction of functional substitutes for bone replacement therapies.

  15. Myoplasmic free calcium concentration reached during the twitch of an intact isolated cardiac cell and during calcium-induced release of calcium from the sarcoplasmic reticulum of a skinned cardiac cell from the adult rat or rabbit ventricle

    PubMed Central

    1981-01-01

    Intact cardiac cells from the adult rat or rabbit ventricle were isolated by enzymatic digestion with a progressive increase of the [free Ca2+] in the solution. These cells were electrically stimulated in the presence of 2.50 mM free Ca2+, and a twitch of maximum amplitude was elicited by the positive inotropic interventions that were found to be optimum. Then the cells were chemically skinned, and the maximum tension induced by a saturating [free Ca2+] was used as a reference to express the tension developed during the twitch of the intact cells. The myoplasmic [free Ca2+] reached during the twitch was inferred from the tension-pCa curve. In mechanically skinned cells of the same animal species, the myoplasmic [free Ca2+] reached during Ca2+-induced release of Ca2+ from the sarcoplasmic reticulum (SR) was inferred by two methods using (a) the tension-pCa curve and (b) a direct calibration of the transients of aequorin bioluminescence. The induction of a maximum Ca2+ release from the SR required a larger Ca2+ preload of the SR and a higher [free Ca2+] trigger in the rabbit than in the rat skinned cells. However, the results obtained with the two methods of inference of the myoplasmic [free Ca2+] suggest that in both animal species a maximum myoplasmic [free Ca2+] of pCa approximately 5.40 was reached during both the optimum Ca2+-induced release of Ca2+ from the SR of the skinned cells and the optimum twitch of the intact cells. This was much lower than the [free Ca2+] necessary for the full activation of the myofilaments (pCa approximately 4.90). PMID:6796647

  16. Cardiac arrest

    MedlinePlus

    ... Article.jsp. Accessed June 16, 2014. Myerburg RJ, Castellanos A. Approach to cardiac arrest and life-threatening ... PA: Elsevier Saunders; 2011:chap 63. Myerburg RJ, Castellanos A. Cardiac arrest and audden aardiac death. In: ...

  17. [Congenital heart disease in adults: residua, sequelae, and complications of cardiac defects repaired at an early age].

    PubMed

    Oliver Ruiz, José María

    2003-01-01

    Nowadays, it is estimated that 85% of the infants born with congenital heart disease (CHD) will survive to adulthood, thanks mainly to surgical or therapeutic procedures performed during infancy or childhood. The clinical profile and disease pattern of adults with CHD is changing. The prevalence of certain adult CHDs, such as tetralogy of Fallot, transposition of the great arteries or univentricular heart, is rising, but these conditions have practically become new diseases as a result of therapy. Most surviving patients present residua, sequelae, or complications, which can progress during adult life. These disorders can present electrophysiological disturbances, valvular disease, persistent shunts, myocardial dysfunction, pulmonary or systemic vascular disease, problems caused by prosthetic materials, infectious complications, thromboembolic events, or extravascular disorders involving multiple organs or systems. In tetralogy of Fallot, the most striking problems that affect long-term prognosis are pulmonary valve regurgitation, right ventricle dysfunction, and atrial or ventricular arrhythmias. The main problems appearing after physiological atrial repair of transposition of the great arteries are related to right ventricular function, since it is structurally unprepared for systemic circulation, and atrial arrhythmias. Surgical repair of univentricular heart using Fontan techniques should be considered a palliative procedure that does not modify the underlying structural disorder and exposes the postoperative patient to severe complications and problems. The increase in the number of patients with CHD who will reach adulthood in the coming decades makes it necessary to carefully consider the new healthcare demands that are being generated, who should be responsible for them, and how and where solutions can be found.

  18. Cardiac contraction, calcium transients, and myofilament calcium sensitivity fluctuate with the estrous cycle in young adult female mice.

    PubMed

    MacDonald, Jennifer K; Pyle, W Glen; Reitz, Cristine J; Howlett, Susan E

    2014-04-01

    This study established conditions to induce regular estrous cycles in female C57BL/6J mice and investigated the impact of the estrous cycle on contractions, Ca2+ transients, and underlying cardiac excitation-contraction (EC)-coupling mechanisms. Daily vaginal smears from group-housed virgin female mice were stained to distinguish estrous stage (proestrus, estrus, metestrus, diestrus). Ventricular myocytes were isolated from anesthetized mice. Contractions and Ca2+ transients were measured simultaneously (4 Hz, 37 °C). Interestingly, mice did not exhibit regular cycles unless they were exposed to male pheromones in bedding added to their cages. Field-stimulated myocytes from mice in estrus had larger contractions (∼2-fold increase), larger Ca2+ transients (∼1.11-fold increase), and longer action potentials (>2-fold increase) compared with other stages. Larger contractions and Ca2+ transients were not observed in estrus myocytes voltage-clamped with shorter action potentials. Voltage-clamp experiments also demonstrated that estrous stage had no effect on Ca2+ current, EC-coupling gain, diastolic Ca2+, sarcoplasmic reticulum (SR) Ca2+ content, or fractional release. Although contractions were largest in estrus, myofilament Ca2+ sensitivity was lowest (EC50 values ∼1.15-fold higher) in conjunction with increased phosphorylation of myosin binding protein C in estrus. Contractions were enhanced in ventricular myocytes from mice in estrus because action potential prolongation increased SR Ca2+ release. These findings demonstrate that cyclical changes in reproductive hormones associated with the estrous cycle can influence myocardial electrical and contractile function and modify Ca2+ homeostasis. However, such changes are unlikely to occur in female mice housed in groups under conventional conditions, since these mice do not exhibit regular estrous cycles.

  19. Walnut ingestion in adults at risk for diabetes: effects on body composition, diet quality, and cardiac risk measures

    PubMed Central

    Njike, Valentine Yanchou; Ayettey, Rockiy; Petraro, Paul; Treu, Judith A; Katz, David L

    2015-01-01

    Background Despite their energy density, walnuts can be included in the diet without adverse effects on weight or body composition. The effect of habitual walnut intake on total calorie intake is not well studied. Effects on overall diet quality have not been reported. Methods Randomized, controlled, modified Latin square parallel design study with 2 treatment arms. The 112 participants were randomly assigned to a diet with or without dietary counseling to adjust calorie intake. Within each treatment arm, participants were further randomized to 1 of the 2 possible sequence permutations to receive a walnut-included diet with 56 g (providing 366 kcal) of walnuts per day and a walnut-excluded diet. Participants were assessed for diet quality, body composition, and cardiac risk measures. Results When compared with a walnut-excluded diet, a walnut-included diet for 6 months, with or without dietary counseling to adjust caloric intake, significantly improved diet quality as measured by the Healthy Eating Index 2010 (9.14±17.71 vs 0.40±15.13; p=0.02 and 7.02±15.89 vs -5.92±21.84; p=0.001, respectively). Endothelial function, total and low-density lipoprotein (LDL) cholesterol improved significantly from baseline in the walnut-included diet. Body mass index, percent body fat, visceral fat, fasting glucose, glycated hemoglobin, and blood pressure did not change significantly. Conclusions The inclusion of walnuts in an ad libitum diet for 6 months, with or without dietary counseling to adjust calorie intake, significantly improved diet quality, endothelial function, total and LDL cholesterol, but had no effects on anthropometric measures, blood glucose level, and blood pressure. Trial registration number: NCT02330848 PMID:26688734

  20. Relation of fragmented QRS complex to right ventricular fibrosis detected by late gadolinium enhancement cardiac magnetic resonance in adults with repaired tetralogy of fallot.

    PubMed

    Park, Seung-Jung; On, Young Keun; Kim, June Soo; Park, Seung Woo; Yang, Ji-Hyuk; Jun, Tae-Gook; Kang, I-Seok; Lee, Heung Jae; Choe, Yeon Hyeon; Huh, June

    2012-01-01

    Fragmented QRS (fQRS) on 12-lead electrocardiography reflects conduction delay caused by myocardial fibrosis and dysfunction. Ventricular fibrosis detected by late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) is reportedly correlated with worse clinical outcomes in adults with repaired tetralogy of Fallot (TOF). The aim of this study was to assess whether the presence of fQRS is associated with right ventricular (RV) fibrosis or dysfunction in this patient group. In 37 consecutive patients (median age 30 years, median age at repair 6.6 years), the number of leads showing fQRS, defined as the presence of >2 notches on the R/S wave in ≥2 contiguous leads, was counted. RV systolic function, dilatation, and LGE score were measured using LGE CMR. Ventricular LGE was observed mainly at the previous surgical sites: the RV outflow tract (33 of 37), ventricular septal defect patch region (15 of 37), and RV anterior wall (11 of 37). Fragmented QRS was found mostly in the right and mid precordial leads. The fQRS group (n = 20) demonstrated higher RV LGE scores (p <0.001) and lower RV ejection fractions (p = 0.02) and a trend toward larger RV end-diastolic and end-systolic volumes (p = 0.12 and p = 0.06, respectively) compared to the non-fQRS group (n = 17). The number of electrocardiographic leads showing fQRS was positively correlated with RV LGE score (r = 0.75, p <0.001). The presence of fQRS remained independently associated with the presence of supramedian RV LGE score, even after adjusting for relevant parameters. In conclusion, fQRS was closely associated with more extensive RV fibrosis and dysfunction in adults with repaired tetralogy of Fallot.

  1. Coagulation Parameter Thresholds Associated with Non-Bleeding in the Eighth Hour of Adult Cardiac Surgical Post-Cardiotomy Extracorporeal Membrane Oxygenation.

    PubMed

    Riley, Jeffrey B; Schears, Gregory J; Nuttall, Gregory A; Oliver, William C; Ereth, Mark H; Dearani, Joseph A

    2016-06-01

    Excessive bleeding and allogeneic transfusion during adult post-cardiotomy venoarterial extracorporeal membrane oxygenation (ECMO) are potentially harmful and expensive. Balancing the inhibition of clotting and distinguishing surgical from non-surgical bleeding in post-operative period is difficult. The sensitivity of coagulation tests including Thromboelastography(®) (TEG) to predict chest tube drainage in the early hours of ECMO was examined with the use of receiver-operating characteristics (ROC). The results are useful to incorporate in clinical evidence-based algorithms to guide management decisions. In the eighth hour of ECMO, 26 of the 53 adult patients (49%) studied were identified as non-bleeders (less than 2.0 mL/kg/h). All had experienced various types of cardiac surgical procedures. Fifty-two percent were female and the group was 54 ± 19 (mean ± 1 SD) years old. The coagulation parameter threshold with the maximum sensitivity and specificity to predict non-bleeding at 8 hours on ECMO was the kaolin plus heparinase TEG maximum amplitude (KH-TEG MA) at a significant ROC threshold (t) > 50 mm. The activated partial thromboplastin time (aPTT) t < 49 seconds, KH-TEG alpha-angle t > 51°, and the kaolin activated clotting time (ACT) t < 148 seconds were sensitive predictors of non-bleeders. The whole-blood KH-TEG MA was superior to the plasma-based aPTT or International Normalization Ratio (INR) to predict bleeding in the eighth hour of ECMO. Using coagulation laboratory thresholds that predict non-bleeding can begin a process of identifying patients earlier that are likely to bleed. Awareness of these parameter thresholds may improve care through patient protection from unnecessary transfusion and prolonging the life of the ECMO circuit. An algorithm incorporating the ROC thresholds was created to help recognize surgical bleeding to minimize unnecessary transfusions. PMID:27578897

  2. Association of interatrial septal abnormalities with cardiac impulse conduction disorders in adult patients: experience from a tertiary center in Kosovo

    PubMed Central

    Bakalli, Aurora; Pllana, Ejup; Koçinaj, Dardan; Bekteshi, Tefik; Dragusha, Gani; Gashi, Masar; Musliu, Nebih; Gashi, Zaim

    2011-01-01

    Interatrial septal disorders, which include: atrial septal defect, patent foramen ovale and atrial septal aneurysm, are frequent congenital anomalies found in adult patients. Early detection of these anomalies is important to prevent their hemodynamic and/or thromboembolic consequences. The aims of this study were: to assess the association between impulse conduction disorders and anomalies of interatrial septum; to determine the prevalence of different types of interatrial septum abnormalities; to assess anatomic, hemodynamic, and clinical consequences of interatrial septal pathologies. Fifty-three adult patients with impulse conduction disorders and patients without ECG changes but with signs of interatrial septal abnormalities, who were referred to our center for echocardiography, were included in a prospective transesophageal echocardiography study. Interatrial septal anomalies were detected in around 85% of the examined patients. Patent foramen ovale was encountered in 32% of the patients, and in combination with atrial septal aneurysm in an additional 11.3% of cases. Atrial septal aneurysm and atrial septal defect were diagnosed with equal frequency in 20.7% of our study population. Impulse conduction disorders were significantly more suggestive of interatrial septal anomalies than clinical signs and symptoms observed in our patients (84.91% vs 30.19%, P=0.002). Right bundle branch block was the most frequent impulse conduction disorder, found in 41 (77.36%) cases. We conclude that interatrial septal anomalies are highly associated with impulse conduction disorders, particularly with right bundle branch block. Impulse conduction disorders are more indicative of interatrial septal abnormalities in earlier stages than can be understood from the patient’s clinical condition. PMID:21977304

  3. Prevalence of coronary artery ectasia in older adults and the relationship with epicardial fat volume by cardiac computed tomography angiography

    PubMed Central

    Yang, Jun-Jie; Yang, Xia; Chen, Zhi-Ye; Wang, Qi; He, Bai; Du, Luo-Shan; Chen, Yun-Dai

    2013-01-01

    Objective Coronary artery ectasia (CAE) refers to abnormal dilation of coronary artery segments to 1.5 times of adjacent normal ones. Epicardial fat is associated with cardiovascular risk factors. The relationship between CAE and epicardial fat has not yet been investigated. This study aimed to assess the relationship between CAE and epicardial fat volume (EFV) in older people by dual-source computed tomography coronary angiography (CTCA). Methods We prospectively enrolled 1400 older adults who were scheduled for dual-source CTCA. Under reconstruction protocols, patients with abnormal segments 1.5 times larger than the adjacent segments were accepted as CAE. EFV was measured by semi-automated software. Traditional risk factors in CAE patients, as well as the extent of EFV, were analyzed and compared to non-CAE group. Results A total of 885 male and 515 female older patients were enrolled. CAE was identified by univariable analysis in 131 patients and significantly correlated to hypertension, smoking, hyperlipidemia, prior percutaneous coronary intervention and ascending aorta aneurysm. EFV was shown to be significantly higher in CAE patients than patients without ectasia. In multivariable analyses, EFV (P = 0.018), hypertension (P < 0.001) and hyperlipidemia (P < 0.001) were significantly correlated to CAE. There was a significant negative correlation between EFV and Markis classification. Conclusions CAE can be reliably recognized by dual-source CTCA. Epicardial fat might play a role in etiopathogenesis and progression of CAE, providing a new target for treating ectasia. PMID:23610568

  4. Endothelial progenitor cells in hematologic malignancies

    PubMed Central

    Saulle, Ernestina; Castelli, Germana; Pelosi, Elvira

    2016-01-01

    Studies carried out in the last years have improved the understanding of the cellular and molecular mechanisms controlling angiogenesis during adult life in normal and pathological conditions. Some of these studies have led to the identification of some progenitor cells that sustain angiogenesis through indirect, paracrine mechanisms (hematopoietic angiogenic cells) and through direct mechanisms, i.e., through their capacity to generate a progeny of phenotypically and functionally competent endothelial cells [endothelial colony forming cells (ECFCs)]. The contribution of these progenitors to angiogenetic processes under physiological and pathological conditions is intensively investigated. Angiogenetic mechanisms are stimulated in various hematological malignancies, including chronic myeloid leukemia (CML), acute myeloid leukemia (AML), myelodysplastic syndromes and multiple myeloma, resulting in an increased angiogenesis that contributes to disease progression. In some of these conditions there is preliminary evidence that some endothelial cells could derive from the malignant clone, thus leading to the speculation that the leukemic cell derives from the malignant transformation of a hemangioblastic progenitor, i.e., of a cell capable of differentiation to the hematopoietic and to the endothelial cell lineages. Our understanding of the mechanisms underlying increased angiogenesis in these malignancies not only contributed to a better knowledge of the mechanisms responsible for tumor progression, but also offered the way for the discovery of new therapeutic targets. PMID:27583252

  5. Endothelial progenitor cells in hematologic malignancies.

    PubMed

    Testa, Ugo; Saulle, Ernestina; Castelli, Germana; Pelosi, Elvira

    2016-01-01

    Studies carried out in the last years have improved the understanding of the cellular and molecular mechanisms controlling angiogenesis during adult life in normal and pathological conditions. Some of these studies have led to the identification of some progenitor cells that sustain angiogenesis through indirect, paracrine mechanisms (hematopoietic angiogenic cells) and through direct mechanisms, i.e., through their capacity to generate a progeny of phenotypically and functionally competent endothelial cells [endothelial colony forming cells (ECFCs)]. The contribution of these progenitors to angiogenetic processes under physiological and pathological conditions is intensively investigated. Angiogenetic mechanisms are stimulated in various hematological malignancies, including chronic myeloid leukemia (CML), acute myeloid leukemia (AML), myelodysplastic syndromes and multiple myeloma, resulting in an increased angiogenesis that contributes to disease progression. In some of these conditions there is preliminary evidence that some endothelial cells could derive from the malignant clone, thus leading to the speculation that the leukemic cell derives from the malignant transformation of a hemangioblastic progenitor, i.e., of a cell capable of differentiation to the hematopoietic and to the endothelial cell lineages. Our understanding of the mechanisms underlying increased angiogenesis in these malignancies not only contributed to a better knowledge of the mechanisms responsible for tumor progression, but also offered the way for the discovery of new therapeutic targets. PMID:27583252

  6. Rigid microenvironments promote cardiac differentiation of mouse and human embryonic stem cells

    NASA Astrophysics Data System (ADS)

    Arshi, Armin; Nakashima, Yasuhiro; Nakano, Haruko; Eaimkhong, Sarayoot; Evseenko, Denis; Reed, Jason; Stieg, Adam Z.; Gimzewski, James K.; Nakano, Atsushi

    2013-04-01

    While adult heart muscle is the least regenerative of tissues, embryonic cardiomyocytes are proliferative, with embryonic stem (ES) cells providing an endless reservoir. In addition to secreted factors and cell-cell interactions, the extracellular microenvironment has been shown to play an important role in stem cell lineage specification, and understanding how scaffold elasticity influences cardiac differentiation is crucial to cardiac tissue engineering. Though previous studies have analyzed the role of matrix elasticity on the function of differentiated cardiomyocytes, whether it affects the induction of cardiomyocytes from pluripotent stem cells is poorly understood. Here, we examine the role of matrix rigidity on cardiac differentiation using mouse and human ES cells. Culture on polydimethylsiloxane (PDMS) substrates of varied monomer-to-crosslinker ratios revealed that rigid extracellular matrices promote a higher yield of de novo cardiomyocytes from undifferentiated ES cells. Using a genetically modified ES system that allows us to purify differentiated cardiomyocytes by drug selection, we demonstrate that rigid environments induce higher cardiac troponin T expression, beating rate of foci, and expression ratio of adult α- to fetal β- myosin heavy chain in a purified cardiac population. M-mode and mechanical interferometry image analyses demonstrate that these ES-derived cardiomyocytes display functional maturity and synchronization of beating when co-cultured with neonatal cardiomyocytes harvested from a developing embryo. Together, these data identify matrix stiffness as an independent factor that instructs not only the maturation of already differentiated cardiomyocytes but also the induction and proliferation of cardiomyocytes from undifferentiated progenitors. Manipulation of the stiffness will help direct the production of functional cardiomyocytes en masse from stem cells for regenerative medicine purposes.

  7. Rigid microenvironments promote cardiac differentiation of mouse and human embryonic stem cells

    PubMed Central

    Arshi, Armin; Nakashima, Yasuhiro; Nakano, Haruko; Eaimkhong, Sarayoot; Evseenko, Denis; Reed, Jason; Stieg, Adam Z.; Gimzewski, James K.; Nakano, Atsushi

    2013-01-01

    While adult heart muscle is the least regenerative of tissues, embryonic cardiomyocytes are proliferative, with embryonic stem (ES) cells providing an endless reservoir. In addition to secreted factors and cell-cell interactions, the extracellular microenvironment has been shown to play an important role in stem cell lineage specification, and understanding how scaffold elasticity influences cardiac differentiation is crucial to cardiac tissue engineering. Though previous studies have analyzed the role of the matrix elasticity on the function of differentiated cardiomyocytes, whether it affects the induction of cardiomyocytes from pluripotent stem cells is poorly understood. Here, we examined the role of matrix rigidity on the cardiac differentiation using mouse and human ES cells. Culture on polydimethylsiloxane (PDMS) substrates of varied monomer-to-crosslinker ratios revealed that rigid extracellular matrices promote a higher yield of de novo cardiomyocytes from undifferentiated ES cells. Using an genetically modified ES system that allows us to purify differentiated cardiomyocytes by drug selection, we demonstrate that rigid environments induce higher cardiac troponin T expression, beating rate of foci, and expression ratio of adult α- to fetal β- myosin heavy chain in a purified cardiac population. M-mode and mechanical interferometry image analyses demonstrate that these ES-derived cardiomyocytes display functional maturity and synchronization of beating when co-cultured with neonatal cardiomyocytes harvested from a developing embryo. Together, these data identify matrix stiffness as an independent factor that instructs not only the maturation of the already differentiated cardiomyocytes but also the induction and proliferation of cardiomyocytes from undifferentiated progenitors. Manipulation of the stiffness will help direct the production of functional cardiomyocytes en masse from stem cells for regenerative medicine purposes. PMID:24311969

  8. The effect of head up tilting on bioreactance cardiac output and stroke volume readings using suprasternal transcutaneous Doppler as a control in healthy young adults.

    PubMed

    Zhang, Jie; Critchley, Lester A H; Lee, Daniel C W; Khaw, Kim S; Lee, Shara W Y

    2016-10-01

    To compare the performance of a bioreactance cardiac output (CO) monitor (NICOM) and transcutaneous Doppler (USCOM) during head up tilting (HUT). Healthy young adult subjects, age 22 ± 1 years, 7 male and 7 female, were tilted over 3-5 s from supine to 70° HUT, 30° HUT and back to supine. Positions were held for 3 min. Simultaneous readings of NICOM and USCOM were performed 30 s into each new position. Mean blood pressure (MBP), heart rate (HR), CO and stroke volume (SV), and thoracic fluid content (TFC) were recorded. Bland-Altman, percentage changes and analysis of variance for repeated measures were used for statistical analysis. Pre-tilt NICOM CO and SV readings (6.1 ± 1.0 L/min and 113 ± 25 ml) were higher than those from USCOM (4.1 ± 0.6 L/min and 77 ± 9 ml) (P < 0.001). Bland-Altman limits of agreement for CO were wide with a percentage error of 38 %. HUT increased MBP and HR (P < 0.001). CO and SV readings decreased with HUT. However, the percentage changes in USCOM and NICOM readings did not concur (P < 0.001). Whereas USCOM provided gravitational effect proportional changes in SV readings of 23 ± 15 % (30° half tilt) and 44 ± 11 % (70° near full tilt), NICOM changes did not being 28 ± 10 and 33 ± 11 %. TFC decreased linearly with HUT. The NICOM does not provide linear changes in SV as predicted by physiology when patients are tilted. Furthermore there is a lack of agreement with USCOM measurements at baseline and during tilting.

  9. Investigating the regulation of stem and progenitor cell mitotic progression by in situ imaging.

    PubMed

    Gerhold, Abigail R; Ryan, Joël; Vallée-Trudeau, Julie-Nathalie; Dorn, Jonas F; Labbé, Jean-Claude; Maddox, Paul S

    2015-05-01

    Genome stability relies upon efficacious chromosome congression and regulation by the spindle assembly checkpoint (SAC). The study of these fundamental mitotic processes in adult stem and progenitor cells has been limited by the technical challenge of imaging mitosis in these cells in situ. Notably, how broader physiological changes, such as dietary intake or age, affect mitotic progression in stem and/or progenitor cells is largely unknown. Using in situ imaging of C. elegans adult germlines, we describe the mitotic parameters of an adult stem and progenitor cell population in an intact animal. We find that SAC regulation in germline stem and progenitor cells is distinct from that found in early embryonic divisions and is more similar to that of classical tissue culture models. We further show that changes in organismal physiology affect mitotic progression in germline stem and progenitor cells. Reducing dietary intake produces a checkpoint-dependent delay in anaphase onset, and inducing dietary restriction when the checkpoint is impaired increases the incidence of segregation errors in mitotic and meiotic cells. Similarly, developmental aging of the germline stem and progenitor cell population correlates with a decline in the rate of several mitotic processes. These results provide the first in vivo validation of models for SAC regulation developed in tissue culture systems and demonstrate that several fundamental features of mitotic progression in adult stem and progenitor cells are highly sensitive to organismal physiological changes.

  10. Cardiac Sarcoidosis.

    PubMed

    Birnie, David; Ha, Andrew C T; Gula, Lorne J; Chakrabarti, Santabhanu; Beanlands, Rob S B; Nery, Pablo

    2015-12-01

    Studies suggest clinically manifest cardiac involvement occurs in 5% of patients with pulmonary/systemic sarcoidosis. The principal manifestations of cardiac sarcoidosis (CS) are conduction abnormalities, ventricular arrhythmias, and heart failure. Data indicate that an 20% to 25% of patients with pulmonary/systemic sarcoidosis have asymptomatic (clinically silent) cardiac involvement. An international guideline for the diagnosis and management of CS recommends that patients be screened for cardiac involvement. Most studies suggest a benign prognosis for patients with clinically silent CS. Immunosuppression therapy is advocated for clinically manifest CS. Device therapy, with implantable cardioverter defibrillators, is recommended for some patients.

  11. Subventricular zone progenitors in time and space: generating neuronal diversity

    PubMed Central

    Sequerra, Eduardo B.

    2014-01-01

    The adult mammalian brain harbors a population of cells around their lateral ventricles capable of giving rise to new neurons throughout life. The so-called subventricular zone (SVZ) is a heterogeneous germinative niche in regard to the neuronal types it generates. SVZ progenitors give rise to different olfactory bulb (OB) interneuron types in accordance to their position along the ventricles. Here, I review data showing the difference between progenitors located along different parts of the SVZ axes and ages. I also discuss possible mechanisms for the origin of this diversity. PMID:25565967

  12. The neurogenic competence of progenitors from the postnatal rat retina in vitro.

    PubMed

    Engelhardt, Maren; Wachs, Frank-Peter; Couillard-Despres, Sebastien; Aigner, Ludwig

    2004-05-01

    The mammalian retina develops from stem or progenitor cells that are of neuroectodermal origin and derive from bilateral invaginations of the neuroepithelium, the optic vesicles. Shortly after birth, around 12 days postnatal in rats, the retina is fully developed in its cellular parts. Even though different cell types in the adult might be potential sources for retinal stem cells or progenitor cells, the retina is a non-neurogenic region and the diseased retina is devoid of any spontaneous regeneration. In an attempt to link late developmental processes to the adult situation, we analyzed the presence and the neurogenic potential of retinal progenitors during the postnatal period and compared it to adult ciliary body (CB) derived retinal progenitors and subventricular zone (SVZ) derived neural stem cells. Retinal progenitor properties were identified by the capacity to proliferate and by the expression of the progenitor markers Nestin, Flk-1, Chx10, Pax6 and the radial glia marker BLBP. The neurogenic potential was assayed by the expression of the neuronal markers doublecortin, betaIII Tubulin, Map2 and NSE, the glial makers A2B5, NG2, GalC and GFAP, and by incorporation of BrdU. The number of Flk-1 positive cells and concomitantly the number of newly born betaIII Tubulin-positive cells decreased within the first postnatal week in retinal progenitor cultures and no newly generated betaIII Tubulin, but GFAP positive cells were detected thereafter. In contrast to neural stem cells derived from the adult SVZ, postnatal and adult CB derived progenitors had a lower and a restricted proliferation potential and did not generate oligodendrocytes. The work demonstrates, however, that the existence of retinal progenitor cells is not restricted to embryonic development. In the sensory retina the differentiation potential of late retinal progenitors becomes restricted to the glial lineage, whereas neurogenic progenitor cells are still present in the CB. In addition, major

  13. Gene Transfer into Cardiac Myocytes

    PubMed Central

    Lang, Sarah E.; Westfall, Margaret V.

    2016-01-01

    Traditional methods for DNA transfection are often inefficient and toxic for terminally differentiated cells, such as cardiac myocytes. Vector-based gene transfer is an efficient approach for introducing exogenous cDNA into these types of primary cell cultures. In this chapter, separate protocols for adult rat cardiac myocyte isolation and gene transfer with recombinant adenovirus are provided and are routinely utilized for studying the effects of sarcomeric proteins on myofilament function. PMID:25836585

  14. Cardiac metastases

    PubMed Central

    Bussani, R; De‐Giorgio, F; Abbate, A; Silvestri, F

    2007-01-01

    Tumours metastatic to the heart (cardiac metastases) are among the least known and highly debated issues in oncology, and few systematic studies are devoted to this topic. Although primary cardiac tumours are extremely uncommon (various postmortem studies report rates between 0.001% and 0.28%), secondary tumours are not, and at least in theory, the heart can be metastasised by any malignant neoplasm able to spread to distant sites. In general, cardiac metastases are considered to be rare; however, when sought for, the incidence seems to be not as low as expected, ranging from 2.3% and 18.3%. Although no malignant tumours are known that diffuse preferentially to the heart, some do involve the heart more often than others—for example, melanoma and mediastinal primary tumours. This paper attempts to review the pathophysiology of cardiac metastatic disease, epidemiology and clinical presentation of cardiac metastases, and pathological characterisation of the lesions. PMID:17098886

  15. Drosophila Models of Cardiac Disease

    PubMed Central

    Piazza, Nicole; Wessells, R.J.

    2013-01-01

    The fruit fly Drosophila melanogaster has emerged as a useful model for cardiac diseases, both developmental abnormalities and adult functional impairment. Using the tools of both classical and molecular genetics, the study of the developing fly heart has been instrumental in identifying the major signaling events of cardiac field formation, cardiomyocyte specification, and the formation of the functioning heart tube. The larval stage of fly cardiac development has become an important model system for testing isolated preparations of living hearts for the effects of biological and pharmacological compounds on cardiac activity. Meanwhile, the recent development of effective techniques to study adult cardiac performance in the fly has opened new uses for the Drosophila model system. The fly system is now being used to study long-term alterations in adult performance caused by factors such as diet, exercise, and normal aging. The fly is a unique and valuable system for the study of such complex, long-term interactions, as it is the only invertebrate genetic model system with a working heart developmentally homologous to the vertebrate heart. Thus, the fly model combines the advantages of invertebrate genetics (such as large populations, facile molecular genetic techniques, and short lifespan) with physiological measurement techniques that allow meaningful comparisons with data from vertebrate model systems. As such, the fly model is well situated to make important contributions to the understanding of complicated interactions between environmental factors and genetics in the long-term regulation of cardiac performance. PMID:21377627

  16. Omega-3 Fatty Acid Supplementation Appears to Attenuate Particulate Air Pollution-induced Cardiac Effects and Lipid Changes in Healthy Middle-aged Adults.

    EPA Science Inventory

    Context: Air pollution exposure has been associated with adverse cardiovascular effects. A recent epidemiologic study reported that omega-3 fatty acid (fish oil) supplementation blunted the cardiac responses to air pollution exposure. Objective: To evaluate in a randomized contro...

  17. MicroRNAs and cardiac regeneration

    PubMed Central

    Hodgkinson, Conrad P.; Kang, Martin H.; Dal-Pra, Sophie; Mirotsou, Maria; Dzau, Victor J.

    2015-01-01

    The human heart has a very limited capacity to regenerate lost or damaged cardiomyocytes following cardiac insult. Instead, myocardial injury is characterized by extensive cardiac remodeling by fibroblasts, resulting in the eventual deterioration of cardiac structure and function. Cardiac function would be improved if these fibroblasts could be converted into cardiomyocytes. MicroRNAs (miRNAs), small non-coding RNAs that promote mRNA degradation and inhibit mRNA translation, have been shown to be important in cardiac development. Using this information various researchers have utilized miRNAs to promote the formation of cardiomyocytes through a number of approaches. Several miRNAs acting in combination promote the direct conversion of cardiac fibroblasts into cardiomyocytes. Moreover, a number of miRNAs have been identified that aid the formation of iPS cells and miRNAs also induce these cells to adopt a cardiac fate. MiRNAs have also been implicated in resident cardiac progenitor cell differentiation. In this review we will discuss the current literature as it pertains to these processes as well as discussing the therapeutic implications of these findings. PMID:25953925

  18. The endocannabinoid system promotes astroglial differentiation by acting on neural progenitor cells.

    PubMed

    Aguado, Tania; Palazuelos, Javier; Monory, Krisztina; Stella, Nephi; Cravatt, Benjamin; Lutz, Beat; Marsicano, Giovanni; Kokaia, Zaal; Guzmán, Manuel; Galve-Roperh, Ismael

    2006-02-01

    Endocannabinoids exert an important neuromodulatory role via presynaptic cannabinoid CB1 receptors and may also participate in the control of neural cell death and survival. The function of the endocannabinoid system has been extensively studied in differentiated neurons, but its potential role in neural progenitor cells remains to be elucidated. Here we show that the CB1 receptor and the endocannabinoid-inactivating enzyme fatty acid amide hydrolase are expressed, both in vitro and in vivo, in postnatal radial glia (RC2+ cells) and in adult nestin type I (nestin(+)GFAP+) neural progenitor cells. Cell culture experiments show that CB1 receptor activation increases progenitor proliferation and differentiation into astroglial cells in vitro. In vivo analysis evidences that, in postnatal CB1(-/-) mouse brain, progenitor proliferation and astrogliogenesis are impaired. Likewise, in adult CB1-deficient mice, neural progenitor proliferation is decreased but is increased in fatty acid amide hydrolase-deficient mice. In addition, endocannabinoid signaling controls neural progenitor differentiation in the adult brain by promoting astroglial differentiation of newly born cells. These results show a novel physiological role of endocannabinoids, which constitute a new family of signaling cues involved in the regulation of neural progenitor cell function.

  19. Hepatic progenitor cells express SerpinB3

    PubMed Central

    2014-01-01

    Background In the setting of liver injury hepatic progenitor cells are activated, counterbalancing the inhibited regenerative capacity of mature hepatocytes. Chronic activation of this compartment may give rise to a subset of liver tumours with poor prognosis. SerpinB3, a serpin over-expressed in injured liver and in primary liver cancer, has been shown to induce apoptosis resistance, epithelial to mesenchymal transition and to increase TGF-beta and Myc expression. Aim of the present study was to explore the presence of SerpinB3 in hepatic progenitor cells in human livers and in a mouse model of liver stem/progenitor cell activation. Hepatic progenitor cells were analysed in foetal and adult livers at protein and transcriptional levels. To induce experimental activation of the liver stem/progenitor compartment, C57BL/6J mice were injected with lipopolysaccharide plus D-galactosamine and were sacrificed at different time points. Liver cDNA was amplified using specific primers for mouse-homologous SerpinB3 isoforms and automatically sequenced. Results The presence of SerpinB3 in the progenitor cell compartment was detected in sorted human foetal and adult epithelial cell adhesion molecule (EpCAM) positive liver cells. By immunohistochemistry SerpinB3 was found in human cirrhotic livers in portal areas with progenitor cell activation showing ductular proliferation. CK-7, CK-19, EpCAM and CD-90 positive cell were also positive for SerpinB3. In the animal model, time course analysis in liver specimens revealed a progressive increase of SerpinB3 and a parallel decrease of activated caspase 3, which was barely detectable at 20 hours. Transcription analysis confirmed the presence of SerpinB3-homologous only in the liver of injured mice and sequence analysis proved its belonging to mouse Serpinb3b. Conclusion SerpinB3 is highly expressed in hepatic stem/progenitor cell compartment of both foetal and adult livers. PMID:24517394

  20. Single adult rabbit and rat cardiac myocytes retain the Ca2+- and species-dependent systolic and diastolic contractile properties of intact muscle

    PubMed Central

    1986-01-01

    The systolic and diastolic properties of single myocytes and intact papillary muscles isolated from hearts of adult rats and rabbits were examined at 37 degrees C over a range of stimulation frequencies and bathing [Ca2+]o (Cao). In both rabbit myocytes and intact muscles bathed in 1 mM Cao, increasing the frequency of stimulation from 6 to 120 min-1 resulted in a positive staircase of twitch performance. During stimulation at 2 min-1, twitch performance also increased with increases in Cao up to 20 mM. In the absence of stimulation, both rabbit myocytes and muscles were completely quiescent in less than 15 mM Cao. Further increases in Cao caused the appearance of spontaneous asynchronous contractile waves in myocytes and in intact muscles caused scattered light intensity fluctuations (SLIF), which were previously demonstrated to be caused by Ca2+-dependent spontaneous contractile waves. In contrast to rabbit preparations, intact rat papillary muscles exhibited SLIF in 1.0 mM Cao. Two populations of rat myocytes were observed in 1 mM Cao: approximately 85% of unstimulated cells exhibited low-frequency (3-4 min-1) spontaneous contractile waves, whereas 15%, during a 1-min observation period, were quiescent. In a given Cao, the contractile wave frequency in myocytes and SLIF in intact muscles were constant for long periods of time. In both intact rat muscles and myocytes with spontaneous waves, in 1 mM Cao, increasing the frequency of stimulation from 6 to 120 min-1 resulted, on the average, in a 65% reduction in steady state twitch amplitude. Of the rat myocytes that did not manifest waves, some had a positive, some had a flat, and some had a negative staircase; the average steady state twitch amplitude of these cells during stimulation at 120 min-1 was 30% greater than that at 6 min-1. In contrast to rabbit preparations, twitch performance during stimulation at 2 min-1 saturated at 1.5 mM Cao in both intact rat muscles and in the myocytes with spontaneous waves. We

  1. Myostatin promotes the terminal differentiation of embryonic muscle progenitors

    PubMed Central

    Manceau, Marie; Gros, Jérôme; Savage, Kathleen; Thomé, Virginie; McPherron, Alexandra; Paterson, Bruce; Marcelle, Christophe

    2008-01-01

    Myostatin, a TGF-β family member, is an important regulator of adult muscle size. While extensively studied in vitro, the mechanisms by which this molecule mediates its effect in vivo are poorly understood. We addressed this question using chick and mouse embryos. We show that while myostatin overexpression in chick leads to an exhaustion of the muscle progenitor population that ultimately results in muscle hypotrophy, myostatin loss of function in chick and mouse provokes an expansion of this population. Our data demonstrate that myostatin acts in vivo to regulate the balance between proliferation and differentiation of embryonic muscle progenitors by promoting their terminal differentiation through the activation of p21 and MyoD. Previous studies have suggested that myostatin imposes quiescence on muscle progenitors. Our data suggest that myostatin’s effect on muscle progenitors is more complex than previously realized and is likely to be context-dependent. We propose a novel model for myostatin mode of action in vivo, in which myostatin affects the balance between proliferation and differentiation of embryonic muscle progenitors by enhancing their differentiation. PMID:18316481

  2. Progenitors of type Ia supernovae

    NASA Astrophysics Data System (ADS)

    Maeda, Keiichi; Terada, Yukikatsu

    2016-07-01

    Natures of progenitors of type Ia Supernovae (SNe Ia) have not yet been clarified. There has been long and intensive discussion on whether the so-called single degenerate (SD) scenario or the double degenerate (DD) scenario, or anything else, could explain a major population of SNe Ia, but the conclusion has not yet been reached. With rapidly increasing observational data and new theoretical ideas, the field of studying the SN Ia progenitors has been quickly developing, and various new insights have been obtained in recent years. This paper aims at providing a summary of the current situation regarding the SN Ia progenitors<