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Sample records for adult liver progenitor

  1. Simultaneous characterization of progenitor cell compartments in adult human liver.

    PubMed

    Porretti, Laura; Cattaneo, Alessandra; Colombo, Federico; Lopa, Raffaella; Rossi, Giorgio; Mazzaferro, Vincenzo; Battiston, Carlo; Svegliati-Baroni, Gianluca; Bertolini, Francesco; Rebulla, Paolo; Prati, Daniele

    2010-01-01

    The human liver is a complex tissue consisting of epithelial, endothelial, hematopoietic, and mesenchymal elements that probably derive from multiple lineage-committed progenitors, but no comprehensive study aimed at identifying and characterizing intrahepatic precursors has yet been published. Cell suspensions for this study were obtained by enzymatic digestion of liver specimens taken from 20 patients with chronic liver disease and 13 multiorgan donors. Stem and progenitor cells were first isolated, amplified, and characterized ex vivo according to previously validated methods, and then optimized flow cytometry was used to assess their relative frequencies and characterize their immunophenotypes in the clinical specimens. Stem and progenitor cells committed to hematopoietic, endothelial, epithelial, and mesenchymal lineages were clearly identifiable in livers from both healthy and diseased subjects. Within the mononuclear liver cell compartment, epithelial progenitors [epithelial cell adhesion molecule (EpCAM)(+)/CD49f(+)/CD29(+)/CD45(-)] accounted for 2.7-3.5% whereas hematopoietic (CD34(+)/CD45(+)), endothelial [vascular endothelial growth factor-2 (KDR)(+)/CD146(+)/CD45(-)], and mesenchymal [CD73(+)/CD105(+)/CD90 (Thy-1)(+)/CD45 (-)] stem cells and progenitors accounted for smaller fractions (0.02-0.6%). The patients' livers had higher percentages of hematopoietic and endothelial precursors than those of the donors. In conclusion, we identified and characterized precursors committed to four different lineages in adult human liver. We also optimized a flow cytometry approach that will be useful in exploring the contribution of these cells to the pathogenesis of liver disease. PMID:19960544

  2. Perivascular mesenchymal progenitors in human fetal and adult liver.

    PubMed

    Gerlach, Jörg C; Over, Patrick; Turner, Morris E; Thompson, Robert L; Foka, Hubert G; Chen, William C W; Péault, Bruno; Gridelli, Bruno; Schmelzer, Eva

    2012-12-10

    The presence of mesenchymal stem cells (MSCs) has been described in various organs. Pericytes possess a multilineage differentiation potential and have been suggested to be one of the developmental sources for MSCs. In human liver, pericytes have not been defined. Here, we describe the identification, purification, and characterization of pericytes in human adult and fetal liver. Flow cytometry sorting revealed that human adult and fetal liver contains 0.56%±0.81% and 0.45%±0.39% of CD146(+)CD45(-)CD56(-)CD34(-) pericytes, respectively. Of these, 41% (adult) and 30% (fetal) were alkaline phosphatase-positive (ALP(+)). In situ, pericytes were localized around periportal blood vessels and were positive for NG2 and vimentin. Purified pericytes could be cultured extensively and had low population doubling times. Immunofluorescence of cultures demonstrated that cells were positive for pericyte and mesenchymal cell markers CD146, NG2, CD90, CD140b, and vimentin, and negative for endothelial, hematopoietic, stellate, muscle, or liver epithelial cell markers von Willebrand factor, CD31, CD34, CD45, CD144, CD326, CK19, albumin, α-fetoprotein, CYP3A7, glial fibrillary acid protein, MYF5, and Pax7 by gene expression; myogenin and alpha-smooth muscle actin expression were variable. Fluorescence-activated cell sorting analysis of cultures confirmed surface expression of CD146, CD73, CD90, CD10, CD13, CD44, CD105, and ALP and absence of human leukocyte antigen-DR. In vitro differentiation assays demonstrated that cells possessed robust osteogenic and myogenic, but low adipogenic and low chondrogenic differentiation potentials. In functional in vitro assays, cells had typical mesenchymal strong migratory and invasive activity. In conclusion, human adult and fetal livers harbor pericytes that are similar to those found in other organs and are distinct from hepatic stellate cells. PMID:22931482

  3. 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

  4. 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

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

    PubMed

    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 × 10(6) 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

  6. 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

  7. Human Liver Progenitor Cells for Liver Repair

    PubMed Central

    Lombard, Catherine A.; Prigent, Julie; Sokal, Etienne M.

    2013-01-01

    Because of their high proliferative capacity, resistance to cryopreservation, and ability to differentiate into hepatocyte-like cells, stem and progenitor cells have recently emerged as attractive cell sources for liver cell therapy, a technique used as an alternative to orthotopic liver transplantation in the treatment of various hepatic ailments ranging from metabolic disorders to end-stage liver disease. Although stem and progenitor cells have been isolated from various tissues, obtaining them from the liver could be an advantage for the treatment of hepatic disorders. However, the techniques available to isolate these stem/progenitor cells are numerous and give rise to cell populations with different morphological and functional characteristics. In addition, there is currently no established consensus on the tests that need to be performed to ensure the quality and safety of these cells when used clinically. The purpose of this review is to describe the different types of liver stem/progenitor cells currently reported in the literature, discuss their suitability and limitations in terms of clinical applications, and examine how the culture and transplantation techniques can potentially be improved to achieve a better clinical outcome. PMID:26858860

  8. Role of liver progenitors in liver regeneration

    PubMed Central

    Best, Jan; Manka, Paul; Syn, Wing-Kin; Dollé, Laurent; van Grunsven, Leo A.

    2015-01-01

    During massive liver injury and hepatocyte loss, the intrinsic regenerative capacity of the liver by replication of resident hepatocytes is overwhelmed. Treatment of this condition depends on the cause of liver injury, though in many cases liver transplantation (LT) remains the only curative option. LT for end stage chronic and acute liver diseases is hampered by shortage of donor organs and requires immunosuppression. Hepatocyte transplantation is limited by yet unresolved technical difficulties. Since currently no treatment is available to facilitate liver regeneration directly, therapies involving the use of resident liver stem or progenitor cells (LPCs) or non-liver stem cells are coming to fore. LPCs are quiescent in the healthy liver, but may be activated under conditions where the regenerative capacity of mature hepatocytes is severely impaired. Non-liver stem cells include embryonic stem cells (ES cells) and mesenchymal stem cells (MSCs). In the first section, we aim to provide an overview of the role of putative cytokines, growth factors, mitogens and hormones in regulating LPC response and briefly discuss the prognostic value of the LPC response in clinical practice. In the latter section, we will highlight the role of other (non-liver) stem cells in transplantation and discuss advantages and disadvantages of ES cells, induced pluripotent stem cells (iPS), as well as MSCs. PMID:25713804

  9. TWEAK induces liver progenitor cell proliferation.

    PubMed

    Jakubowski, Aniela; Ambrose, Christine; Parr, Michael; Lincecum, John M; Wang, Monica Z; Zheng, Timothy S; Browning, Beth; Michaelson, Jennifer S; Baetscher, Manfred; Baestcher, Manfred; Wang, Bruce; Bissell, D Montgomery; Burkly, Linda C

    2005-09-01

    Progenitor ("oval") cell expansion accompanies many forms of liver injury, including alcohol toxicity and submassive parenchymal necrosis as well as experimental injury models featuring blocked hepatocyte replication. Oval cells can potentially become either hepatocytes or biliary epithelial cells and may be critical to liver regeneration, particularly when hepatocyte replication is impaired. The regulation of oval cell proliferation is incompletely understood. Herein we present evidence that a TNF family member called TWEAK (TNF-like weak inducer of apoptosis) stimulates oval cell proliferation in mouse liver through its receptor Fn14. TWEAK has no effect on mature hepatocytes and thus appears to be selective for oval cells. Transgenic mice overexpressing TWEAK in hepatocytes exhibit periportal oval cell hyperplasia. A similar phenotype was obtained in adult wild-type mice, but not Fn14-null mice, by administering TWEAK-expressing adenovirus. Oval cell expansion induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) was significantly reduced in Fn14-null mice as well as in adult wild-type mice with a blocking anti-TWEAK mAb. Importantly, TWEAK stimulated the proliferation of an oval cell culture model. Finally, we show increased Fn14 expression in chronic hepatitis C and other human liver diseases relative to its expression in normal liver, which suggests a role for the TWEAK/Fn14 pathway in human liver injury. We conclude that TWEAK has a selective mitogenic effect for liver oval cells that distinguishes it from other previously described growth factors. PMID:16110324

  10. Functional Blood Progenitor Markers in Developing Human Liver Progenitors.

    PubMed

    Goldman, Orit; Cohen, Idan; Gouon-Evans, Valerie

    2016-08-01

    In the early fetal liver, hematopoietic progenitors expand and mature together with hepatoblasts, the liver progenitors of hepatocytes and cholangiocytes. Previous analyses of human fetal livers indicated that both progenitors support each other's lineage maturation and curiously share some cell surface markers including CD34 and CD133. Using the human embryonic stem cell (hESC) system, we demonstrate that virtually all hESC-derived hepatoblast-like cells (Hep cells) transition through a progenitor stage expressing CD34 and CD133 as well as GATA2, an additional hematopoietic marker that has not previously been associated with human hepatoblast development. Dynamic expression patterns for CD34, CD133, and GATA2 in hepatoblasts were validated in human fetal livers collected from the first and second trimesters of gestation. Knockdown experiments demonstrate that each gene also functions to regulate hepatic fate mostly in a cell-autonomous fashion, revealing unprecedented roles of fetal hematopoietic progenitor markers in human liver progenitors. PMID:27509132

  11. Effect of AGM and fetal liver-derived stromal cell lines on globin expression in adult baboon (P. anubis) bone marrow-derived erythroid progenitors.

    PubMed

    Lavelle, Donald; Vaitkus, Kestutis; Ruiz, Maria Armila; Ibanez, Vinzon; Kouznetsova, Tatiana; Saunthararajah, Yogen; Mahmud, Nadim; DeSimone, Joseph

    2012-01-01

    This study was performed to investigate the hypothesis that the erythroid micro-environment plays a role in regulation of globin gene expression during adult erythroid differentiation. Adult baboon bone marrow and human cord blood CD34+ progenitors were grown in methylcellulose, liquid media, and in co-culture with stromal cell lines derived from different developmental stages in identical media supporting erythroid differentiation to examine the effect of the micro-environment on globin gene expression. Adult progenitors express high levels of γ-globin in liquid and methylcellulose media but low, physiological levels in stromal cell co-cultures. In contrast, γ-globin expression remained high in cord blood progenitors in stromal cell line co-cultures. Differences in γ-globin gene expression between adult progenitors in stromal cell line co-cultures and liquid media required cell-cell contact and were associated with differences in rate of differentiation and γ-globin promoter DNA methylation. We conclude that γ-globin expression in adult-derived erythroid cells can be influenced by the micro-environment, suggesting new potential targets for HbF induction. PMID:22693559

  12. Effect of AGM and Fetal Liver-Derived Stromal Cell Lines on Globin Expression in Adult Baboon (P. anubis) Bone Marrow-Derived Erythroid Progenitors

    PubMed Central

    Lavelle, Donald; Vaitkus, Kestutis; Ruiz, Maria Armila; Ibanez, Vinzon; Kouznetsova, Tatiana; Saunthararajah, Yogen; Mahmud, Nadim; DeSimone, Joseph

    2012-01-01

    This study was performed to investigate the hypothesis that the erythroid micro-environment plays a role in regulation of globin gene expression during adult erythroid differentiation. Adult baboon bone marrow and human cord blood CD34+ progenitors were grown in methylcellulose, liquid media, and in co-culture with stromal cell lines derived from different developmental stages in identical media supporting erythroid differentiation to examine the effect of the micro-environment on globin gene expression. Adult progenitors express high levels of γ-globin in liquid and methylcellulose media but low, physiological levels in stromal cell co-cultures. In contrast, γ-globin expression remained high in cord blood progenitors in stromal cell line co-cultures. Differences in γ-globin gene expression between adult progenitors in stromal cell line co-cultures and liquid media required cell-cell contact and were associated with differences in rate of differentiation and γ-globin promoter DNA methylation. We conclude that γ-globin expression in adult-derived erythroid cells can be influenced by the micro-environment, suggesting new potential targets for HbF induction. PMID:22693559

  13. Role of liver progenitors in acute liver injury

    PubMed Central

    Best, Jan; Dollé, Laurent; Manka, Paul; Coombes, Jason; van Grunsven, Leo A.; Syn, Wing-Kin

    2013-01-01

    Acute liver failure (ALF) results from the acute and rapid loss of hepatocyte function and frequently exhibits a fulminant course, characterized by high mortality in the absence of immediate state-of-the-art intensive care and/or emergency liver transplantation (ELT). The role of hepatocyte-mediated liver regeneration during acute and chronic liver injury has been extensively investigated, and recent studies suggest that hepatocytes are not exclusively responsible for the regeneration of the injured liver during fulminant liver injury. Liver progenitor cells (LPC) (or resident liver stem cells) are quiescent in the healthy liver, but may be activated under conditions where the regenerative capacity of mature hepatocytes is severely impaired. This review aims to provide an overview of the role of the LPC population during ALF, and the role of putative cytokines, growth factors, mitogens, and hormones in the LPC response. We will highlight the potential interaction among cellular compartments during ALF, and discuss the possible prognostic value of the LPC response on ALF outcomes. PMID:24133449

  14. Transcriptional Profiling of Bipotential Embryonic Liver Cells to Identify Liver Progenitor Cell Surface Markers

    PubMed Central

    Ochsner, Scott A.; Strick-Marchand, Hélène; Qiu, Qiong; Venable, Susan; Dean, Adam; Wilde, Margaret; Weiss, Mary C.; Darlington, Gretchen J.

    2010-01-01

    The ability to purify to homogeneity a population of hepatic progenitor cells from adult liver is critical for their characterization prior to any therapeutic application. As a step in this direction, we have used a bipotential liver cell line from 14 days postcoitum mouse embryonic liver to compile a list of cell surface markers expressed specifically by liver progenitor cells. These cells, known as bipotential mouse embryonic liver (BMEL) cells, proliferate in an undifferentiated state and are capable of differentiating into hepatocyte-like and cholangiocyte-like cells in vitro. Upon transplantation, BMEL cells are capable of differentiating into hepatocytes and cholangiocytes in vivo. Microarray and Gene Ontology (GO) analysis of gene expression in the 9A1 and 14B3 BMEL cell lines grown under proliferating and differentiating conditions was used to identify cell surface markers preferentially expressed in the bipotential undifferentiated state. This analysis revealed that proliferating BMEL cells express many genes involved in cell cycle regulation, whereas differentiation of BMEL cells by cell aggregation causes a switch in gene expression to functions characteristic of mature hepatocytes. In addition, microarray data and protein analysis indicated that the Notch signaling pathway could be involved in maintaining BMEL cells in an undifferentiated stem cell state. Using GO annotation, a list of cell surface markers preferentially expressed on undifferentiated BMEL cells was generated. One marker, Cd24a, is specifically expressed on progenitor oval cells in livers of diethyl 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate-treated animals. We therefore consider Cd24a expression a candidate molecule for purification of hepatic progenitor cells. PMID:17641245

  15. 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

  16. Advances in Liver Regeneration: Revisiting Hepatic Stem/Progenitor Cells and Their Origin.

    PubMed

    Sadri, Ali-Reza; Jeschke, Marc G; Amini-Nik, Saeid

    2016-01-01

    The liver has evolved to become a highly plastic organ with extraordinary regenerative capabilities. What drives liver regeneration is still being debated. Adult liver stem/progenitor cells have been characterized and used to produce functional hepatocytes and biliary cells in vitro. However, in vivo, numerous studies have questioned whether hepatic progenitor cells have a significant role in liver regeneration. Mature hepatocytes have recently been shown to be more plastic than previously believed and give rise to new hepatocytes after acute and chronic injury. In this review, we discuss current knowledge in the field of liver regeneration and the importance of the serotonin pathway as a clinical target for patients with liver dysfunction. PMID:26798363

  17. Advances in Liver Regeneration: Revisiting Hepatic Stem/Progenitor Cells and Their Origin

    PubMed Central

    Jeschke, Marc G.; Amini-Nik, Saeid

    2016-01-01

    The liver has evolved to become a highly plastic organ with extraordinary regenerative capabilities. What drives liver regeneration is still being debated. Adult liver stem/progenitor cells have been characterized and used to produce functional hepatocytes and biliary cells in vitro. However, in vivo, numerous studies have questioned whether hepatic progenitor cells have a significant role in liver regeneration. Mature hepatocytes have recently been shown to be more plastic than previously believed and give rise to new hepatocytes after acute and chronic injury. In this review, we discuss current knowledge in the field of liver regeneration and the importance of the serotonin pathway as a clinical target for patients with liver dysfunction. PMID:26798363

  18. 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.

  19. Alcohol Increases Liver Progenitor Populations and Induces Disease Phenotypes in Human IPSC-Derived Mature Stage Hepatic Cells

    PubMed Central

    Tian, Lipeng; Deshmukh, Abhijeet; Prasad, Neha; Jang, Yoon-Young

    2016-01-01

    Alcohol consumption has long been a global problem affecting human health, and has been found to influence both fetal and adult liver functions. However, how alcohol affects human liver development and liver progenitor cells remains largely unknown. Here, we used human induced pluripotent stem cells (iPSCs) as a model to examine the effects of alcohol, on multi-stage hepatic cells including hepatic progenitors, early and mature hepatocyte-like cells derived from human iPSCs. While alcohol has little effect on endoderm development from iPSCs, it reduces formation of hepatic progenitor cells during early hepatic specification. The proliferative activities of early and mature hepatocyte-like cells are significantly decreased after alcohol exposure. Importantly, at a mature stage of hepatocyte-like cells, alcohol treatment increases two liver progenitor subsets, causes oxidative mitochondrial injury and results in liver disease phenotypes (i.e., steatosis and hepatocellular carcinoma associated markers) in a dose dependent manner. Some of the phenotypes were significantly improved by antioxidant treatment. This report suggests that fetal alcohol exposure may impair generation of hepatic progenitors at early stage of hepatic specification and decrease proliferation of fetal hepatocytes; meanwhile alcohol injury in post-natal or mature stage human liver may contribute to disease phenotypes. This human iPSC model of alcohol-induced liver injury can be highly valuable for investigating alcoholic injury in the fetus as well as understanding the pathogenesis and ultimately developing effective treatment for alcoholic liver disease in adults. PMID:27570479

  20. Alcohol Increases Liver Progenitor Populations and Induces Disease Phenotypes in Human IPSC-Derived Mature Stage Hepatic Cells.

    PubMed

    Tian, Lipeng; Deshmukh, Abhijeet; Prasad, Neha; Jang, Yoon-Young

    2016-01-01

    Alcohol consumption has long been a global problem affecting human health, and has been found to influence both fetal and adult liver functions. However, how alcohol affects human liver development and liver progenitor cells remains largely unknown. Here, we used human induced pluripotent stem cells (iPSCs) as a model to examine the effects of alcohol, on multi-stage hepatic cells including hepatic progenitors, early and mature hepatocyte-like cells derived from human iPSCs. While alcohol has little effect on endoderm development from iPSCs, it reduces formation of hepatic progenitor cells during early hepatic specification. The proliferative activities of early and mature hepatocyte-like cells are significantly decreased after alcohol exposure. Importantly, at a mature stage of hepatocyte-like cells, alcohol treatment increases two liver progenitor subsets, causes oxidative mitochondrial injury and results in liver disease phenotypes (i.e., steatosis and hepatocellular carcinoma associated markers) in a dose dependent manner. Some of the phenotypes were significantly improved by antioxidant treatment. This report suggests that fetal alcohol exposure may impair generation of hepatic progenitors at early stage of hepatic specification and decrease proliferation of fetal hepatocytes; meanwhile alcohol injury in post-natal or mature stage human liver may contribute to disease phenotypes. This human iPSC model of alcohol-induced liver injury can be highly valuable for investigating alcoholic injury in the fetus as well as understanding the pathogenesis and ultimately developing effective treatment for alcoholic liver disease in adults. PMID:27570479

  1. A novel method of mouse ex utero transplantation of hepatic progenitor cells into the fetal liver

    SciTech Connect

    Shikanai, Mima; Asahina, Kinji; Iseki, Sachiko Teramoto, Kenichi; Nishida, Tomohiro; Shimizu-Saito, Keiko; Ota, Masato; Eto, Kazuhiro; Teraoka, Hirobumi

    2009-04-03

    Avoiding the limitations of the adult liver niche, transplantation of hepatic stem/progenitor cells into fetal liver is desirable to analyze immature cells in a hepatic developmental environment. Here, we established a new monitor tool for cell fate of hepatic progenitor cells transplanted into the mouse fetal liver by using ex utero surgery. When embryonic day (ED) 14.5 hepatoblasts were injected into the ED14.5 fetal liver, the transplanted cells expressed albumin abundantly or {alpha}-fetoprotein weakly, and contained glycogen in the neonatal liver, indicating that transplanted hepatoblasts can proliferate and differentiate in concord with surrounding recipient parenchymal cells. The transplanted cells became mature in the liver of 6-week-old mice. Furthermore, this method was applicable to transplantation of hepatoblast-like cells derived from mouse embryonic stem cells. These data indicate that this unique technique will provide a new in vivo experimental system for studying cell fate of hepatic stem/progenitor cells and liver organogenesis.

  2. Liver Disease and Adult Vaccination

    MedlinePlus

    ... Resources for Healthcare Professionals Liver Disease and Adult Vaccination Recommend on Facebook Tweet Share Compartir Vaccines are ... have immunity to this disease Learn about adult vaccination and other health conditions Asplenia Diabetes Type 1 ...

  3. Osteopontin Neutralization Abrogates the Liver Progenitor Cell Response and Fibrogenesis in Mice

    PubMed Central

    Coombes, J; Swiderska-Syn, M; Dollé, L; Reid, D; Eksteen, B; Claridge, L; Briones-Orta, MA; Shetty, S; Oo, YH; Riva, A; Chokshi, S; Papa, S; Mi, Z; Kuo, PC; Williams, R; Canbay, A; Adams, DH; Diehl, AM; van Grunsven, LA; Choi, SS; Syn, WK

    2015-01-01

    Background Chronic liver injury triggers a progenitor-cell repair-response, and liver fibrosis occurs when repair becomes de-regulated. Previously, we reported that reactivation of the Hedgehog (Hh) pathway promotes fibrogenic liver-repair. Osteopontin (OPN) is a Hh-target, and a cytokine that is highly upregulated in fibrotic tissues, and regulates stem-cell fate. Thus, we hypothesized that OPN may modulate liver progenitor-cell response, and thereby, modulate fibrotic outcomes. We further evaluated the impact of OPN-neutralization on murine liver fibrosis. Methods Liver progenitors (603B and BMOL) were treated with OPN-neutralizing aptamers in the presence or absence of TGF–β, to determine if (and how) OPN modulates liver progenitor function. Effects of OPN-neutralization (using OPN-aptamers or OPN-neutralizing antibodies) on liver progenitor-cell response and fibrogenesis were assessed in three models of liver fibrosis (carbon tetrachloride, methionine-choline deficient diet, 3, 5,-diethoxycarbonyl-1,4-dihydrocollidine diet) by qRTPCR, Sirius-Red staining, hydroxyproline assay, and semi-quantitative double-immunohistochemistry. Finally, OPN expression and liver progenitor response were corroborated in liver tissues obtained from patients with chronic liver disease. Results OPN is over-expressed by liver progenitors in humans and mice. In cultured progenitors, OPN enhances viability and wound-healing by modulating TGF-β signaling. In vivo, OPN-neutralization attenuates the liver progenitor-cell response, reverses epithelial-mesenchymal-transition in Sox9+ cells, and abrogates liver fibrogenesis. Conclusions OPN upregulation during liver injury is a conserved repair-response, and influences liver progenitor-cell function. OPN-neutralization abrogates the liver progenitor-cell response and fibrogenesis in mouse models of liver fibrosis. PMID:24902765

  4. Hepatic progenitor cells, stem cells, and AFP expression in models of liver injury

    PubMed Central

    Kuhlmann, Wolf D; Peschke, Peter

    2006-01-01

    Adult hepatocytes and liver-cell progenitors play a role in restoring liver tissue after injury. For the study of progenitor cells in liver repair, experimental models included (a) surgical removal of liver tissue by partial hepatectomy; (b) acute injury by carbontetrachloride; (c) acute injury by d-galactosamine (GalN) and N-nitrosomorpholine (NNM); and (d) chemical hepatocarcinogenesis by feeding NNM in low and high doses. Serological and immunohistological detection of alpha-fetoprotein gene expression served to follow pathways of cellular differentiation. Stem cells were not required in models of surgical removal of parenchyma and in carbon tetrachloride intoxication of adult hepatocytes. In contrast, regeneration of liver occurred through biliary epithelial cells in injuries induced by GalN and NNM. These biliary epithelial cells, collectively called oval cells, are most probably derived from the canals of Hering. Proliferating bile duct cells reached a level of differentiation with reactivation of foetal genes and significant alpha-1-fetoprotein (AFP) synthesis signalling a certain degree of retrodifferentiation with potential stemness. Due to the same embryonic origin of bile ducts and hepatocytes, biliary epithelium and its proliferating progeny (oval cells) have a defined role in liver regeneration as a transit and amplification compartment. In their early proliferation stage, oval cells were heavily engaged in DNA synthesis ([3H]thymidine labelling). Pulse-chase experiments during experimental hepatocarcinogenesis exhibited their development into hepatocytes with high risk for transformation and leading to foci of altered hepatocytes. Hepatocellular carcinomas may arise either from proliferating/differentiating oval cells or from adult hepatocytes; both cell types have stem-like properties. AFP-positive and AFP-negative carcinomas occurred in the same liver. They may represent random clonal origin. The heterogeneity of phenotypic marker (AFP) correlated

  5. Bmi1 Is Required for Hepatic Progenitor Cell Expansion and Liver Tumor Development

    PubMed Central

    Wang, Chunmei; Tao, Junyan; Ho, Coral; Jiang, Lijie; Gui, Bing; Huang, Shiang; Evert, Matthias; Calvisi, Diego F.; Chen, Xin

    2012-01-01

    Bmi1 is a polycomb group transcriptional repressor and it has been implicated in regulating self-renewal and proliferation of many types of stem or progenitor cells. In addition, Bmi1 has been shown to function as an oncogene in multiple tumor types. In this study, we investigated the functional significance of Bmi1 in regulating hepatic oval cells, the major type of bipotential progenitor cells in adult liver, as well as the role of Bmi1 during hepatocarcinogenesis using Bmi1 knockout mice. We found that loss of Bmi1 significantly restricted chemically induced oval cell expansion in the mouse liver. Concomitant deletion of Ink4a/Arf in Bmi1 deficient mice completely rescued the oval cell expansion phenotype. Furthermore, ablation of Bmi1 delayed hepatocarcinogenesis induced by AKT and Ras co-expression. This antineoplastic effect was accompanied by the loss of hepatic oval cell marker expression in the liver tumor samples. In summary, our data demonstrated that Bmi1 is required for hepatic oval cell expansion via deregulating the Ink4a/Arf locus in mice. Our study also provides the evidence, for the first time, that Bmi1 expression is required for liver cancer development in vivo, thus representing a promising target for innovative treatments against human liver cancer. PMID:23029524

  6. Thyroid hormone accelerates the differentiation of adult hippocampal progenitors.

    PubMed

    Kapoor, R; Desouza, L A; Nanavaty, I N; Kernie, S G; Vaidya, V A

    2012-09-01

    Disrupted thyroid hormone function evokes severe physiological consequences in the immature brain. In adulthood, although clinical reports document an effect of thyroid hormone status on mood and cognition, the molecular and cellular changes underlying these behavioural effects are poorly understood. More recently, the subtle effects of thyroid hormone on structural plasticity in the mature brain, in particular on adult hippocampal neurogenesis, have come to be appreciated. However, the specific stages of adult hippocampal progenitor development that are sensitive to thyroid hormone are not defined. Using nestin-green fluorescent protein reporter mice, we demonstrate that thyroid hormone mediates its effects on hippocampal neurogenesis by influencing Type 2b and Type 3 progenitors, although it does not alter proliferation of either the Type 1 quiescent progenitor or the Type 2a amplifying neural progenitor. Thyroid hormone increases the number of doublecortin (DCX)-positive Type 3 progenitors, and accelerates neuronal differentiation into both DCX-positive immature neurones and neuronal nuclei-positive granule cell neurones. Furthermore, we show that this increase in neuronal differentiation is accompanied by a significant induction of specific transcription factors involved in hippocampal progenitor differentiation. In vitro studies using the neurosphere assay support a direct effect of thyroid hormone on progenitor development because neurospheres treated with thyroid hormone are shifted to a more differentiated state. Taken together, our results indicate that thyroid hormone mediates its neurogenic effects via targeting Type 2b and Type 3 hippocampal progenitors, and suggests a role for proneural transcription factors in contributing to the effects of thyroid hormone on neuronal differentiation of adult hippocampal progenitors. PMID:22497336

  7. Hedgehog signal activation coordinates proliferation and differentiation of fetal liver progenitor cells

    SciTech Connect

    Hirose, Yoshikazu; Itoh, Tohru; Miyajima, Atsushi

    2009-09-10

    Hedgehog (Hh) signaling plays crucial roles in development and homeostasis of various organs. In the adult liver, it regulates proliferation and/or viability of several types of cells, particularly under injured conditions, and is also implicated in stem/progenitor cell maintenance. However, the role of this signaling pathway during the normal developmental process of the liver remains elusive. Although Sonic hedgehog (Shh) is expressed in the ventral foregut endoderm from which the liver derives, the expression disappears at the onset of the liver bud formation, and its possible recurrence at the later stages has not been investigated. Here we analyzed the activation and functional relevance of Hh signaling during the mouse fetal liver development. At E11.5, Shh and an activation marker gene for Hh signaling, Gli1, were expressed in Dlk{sup +} hepatoblasts, the fetal liver progenitor cells, and the expression was rapidly decreased thereafter as the development proceeded. In the culture of Dlk{sup +} hepatoblasts isolated from the E11.5 liver, activation of Hh signaling stimulated their proliferation and this effect was cancelled by a chemical Hh signaling inhibitor, cyclopamine. In contrast, hepatocyte differentiation of Dlk{sup +} hepatoblasts in vitro as manifested by the marker gene expression and acquisition of ammonia clearance activity was significantly inhibited by forced activation of Hh signaling. Taken together, these results demonstrate the temporally restricted manner of Hh signal activation and its role in promoting the hepatoblast proliferation, and further suggest that the pathway needs to be shut off for the subsequent hepatic differentiation of hepatoblasts to proceed normally.

  8. Differential Apoptosis Radiosensitivity of Neural Progenitors in Adult Mouse Hippocampus.

    PubMed

    Li, Yu-Qing; Cheng, Zoey; Wong, Shun

    2016-01-01

    Mammalian tissue-specific stem cells and progenitors demonstrate differential DNA damage response. Neural progenitors in dentate gyrus of the hippocampus are known to undergo apoptosis after irradiation. Using a mouse model of hippocampal neuronal development, we characterized the apoptosis sensitivity of the different neural progenitor subpopulations in adult mouse dentate gyrus after irradiation. Two different bromodeoxyuridine incorporation paradigms were used for cell fate mapping. We identified two apoptosis sensitive neural progenitor subpopulations after irradiation. The first represented non-proliferative and non-newborn neuroblasts and immature neurons that expressed doublecortin, calretinin or both. The second consisted of proliferative intermediate neural progenitors. The putative radial glia-like neural stem cells or type-1 cells, regardless of proliferation status, were apoptosis resistant after irradiation. There was no evidence of radiation-induced apoptosis in the absence of the Trp53 (p53) gene but absence of Cdkn1a (p21) did not alter the apoptotic response. Upregulation of nuclear p53 was observed in neuroblasts after irradiation. We conclude that adult hippocampal neural progenitors may demonstrate differential p53-dependent apoptosis sensitivity after irradiation. PMID:27331809

  9. Differential Apoptosis Radiosensitivity of Neural Progenitors in Adult Mouse Hippocampus

    PubMed Central

    Li, Yu-Qing; Cheng, Zoey; Wong, Shun

    2016-01-01

    Mammalian tissue-specific stem cells and progenitors demonstrate differential DNA damage response. Neural progenitors in dentate gyrus of the hippocampus are known to undergo apoptosis after irradiation. Using a mouse model of hippocampal neuronal development, we characterized the apoptosis sensitivity of the different neural progenitor subpopulations in adult mouse dentate gyrus after irradiation. Two different bromodeoxyuridine incorporation paradigms were used for cell fate mapping. We identified two apoptosis sensitive neural progenitor subpopulations after irradiation. The first represented non-proliferative and non-newborn neuroblasts and immature neurons that expressed doublecortin, calretinin or both. The second consisted of proliferative intermediate neural progenitors. The putative radial glia-like neural stem cells or type-1 cells, regardless of proliferation status, were apoptosis resistant after irradiation. There was no evidence of radiation-induced apoptosis in the absence of the Trp53 (p53) gene but absence of Cdkn1a (p21) did not alter the apoptotic response. Upregulation of nuclear p53 was observed in neuroblasts after irradiation. We conclude that adult hippocampal neural progenitors may demonstrate differential p53-dependent apoptosis sensitivity after irradiation. PMID:27331809

  10. General Information about Adult Primary Liver Cancer

    MedlinePlus

    ... Primary Liver Cancer Treatment (PDQ®)–Patient Version General Information About Adult Primary Liver Cancer Go to Health ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  11. Hepatic cancer stem cells may arise from adult ductal progenitors

    PubMed Central

    Nikolaou, Kostas C; Talianidis, Iannis

    2016-01-01

    Cancer stem cells (CSCs) are defined as cells within tumors that can self-renew and differentiate into heterogeneous lineages of cancerous cells. The origin of CSCs is not well understood. Recent evidence suggests that CSCs in hepatocellular carcinoma could be generated via oncogenic transformation and partial differentiation of adult hepatic ductal progenitor cells.

  12. The progenitor cell compartment in the feline liver: an (immuno)histochemical investigation.

    PubMed

    Ijzer, J; Kisjes, J R; Penning, L C; Rothuizen, J; van den Ingh, T S G A M

    2009-07-01

    The hepatic progenitor compartment is of vital importance in liver regeneration when hepatocellular replication is impaired, as it occurs in acute fulminant hepatitis or severe liver fibrosis. It consists of resident progenitor cells in the normal liver, and ductular reaction and intermediate hepatobiliary cells in diseased livers. An histologic and immunohistochemical study was conducted to demonstrate putative hepatic progenitor cells in the normal liver (n = 5) and in a range of hepatic diseases (n = 13) in the cat. Formalin-fixed, paraffin-embedded specimens were stained with HE, the van Gieson stain, and the reticulin stain according to Gordon and Sweet, and immunohistochemically stained for cytokeratin-7 (CK7), human hepatocyte marker 1 (Hepar1), and multidrug resistance-binding protein-2/ATP binding cassette C2 (MRP2). The normal feline liver contains a liver progenitor cell morphologically similar to humans and dogs, which resides in the canal of Hering. In acute and chronic feline liver diseases a ductular reaction is present, whether in the parenchyma or in a portal or septal location. The putative progenitor cells could easily be demonstrated by staining for CK7, whereas they were generally negative for Hepar1 and MRP2. In a parenchymal ductular reaction mitotic figures and cells with an intermediate hepatobiliary phenotype could be demonstrated. This is the first account of hepatic progenitor cells in feline liver. PMID:19329493

  13. Adult living donor liver imaging

    PubMed Central

    Cai, Larry; Yeh, Benjamin M.; Westphalen, Antonio C.; Roberts, John P.; Wang, Zhen J.

    2016-01-01

    Adult living donor liver transplantation (LDLT) is increasingly used for the treatment of end-stage liver disease. The three most commonly harvested grafts for LDLT are left lateral segment, left lobe, and right lobe grafts. The left lateral segment graft, which includes Couinaud’s segments II and III, is usually used for pediatric recipients or small size recipients. Most of the adult recipients need either a left or a right lobe graft. Whether a left or right lobe graft should be harvested from the donors depends on estimated graft and donor remnant liver volume, as well as biliary and vascular anatomy. Detailed preoperative assessment of the potential donor liver volumetrics, biliary and vascular anatomy, and liver parenchyma is vital to minimize risks to the donors and maximize benefits to the recipients. Computed tomography (CT) and magnetic resonance imaging (MRI) are currently the imaging modalities of choice in the preoperative evaluation of potential donors. This review provides an overview of key surgical considerations in LDLT that the radiologists must be aware of, and imaging findings on CT and MRI that the radiologists must convey to the surgeons when evaluating potential donors for LDLT. PMID:26912106

  14. Adult living donor liver imaging.

    PubMed

    Cai, Larry; Yeh, Benjamin M; Westphalen, Antonio C; Roberts, John P; Wang, Zhen J

    2016-01-01

    Adult living donor liver transplantation (LDLT) is increasingly used for the treatment of end-stage liver disease. The three most commonly harvested grafts for LDLT are left lateral segment, left lobe, and right lobe grafts. The left lateral segment graft, which includes Couinaud's segments II and III, is usually used for pediatric recipients or small size recipients. Most of the adult recipients need either a left or a right lobe graft. Whether a left or right lobe graft should be harvested from the donors depends on estimated graft and donor remnant liver volume, as well as biliary and vascular anatomy. Detailed preoperative assessment of the potential donor liver volumetrics, biliary and vascular anatomy, and liver parenchyma is vital to minimize risks to the donors and maximize benefits to the recipients. Computed tomography (CT) and magnetic resonance imaging (MRI) are currently the imaging modalities of choice in the preoperative evaluation of potential donors. This review provides an overview of key surgical considerations in LDLT that the radiologists must be aware of, and imaging findings on CT and MRI that the radiologists must convey to the surgeons when evaluating potential donors for LDLT. PMID:26912106

  15. Properties of Adult Lung Stem and Progenitor Cells.

    PubMed

    Bertoncello, Ivan

    2016-12-01

    The last decade has seen significant progress in understanding the organisation of regenerative cells in the adult lung. Cell-lineage tracing and in vitro clonogenic assays have enabled the identification and characterisation of endogenous lung epithelial stem and progenitor cells. Selective lung injury models, and genetically engineered mice have revealed highly conserved gene networks, factors, signalling pathways, and cellular interactions important in maintaining lung homeostasis and regulating lung regeneration and repair following injury. This review describes the current models of lung epithelial stem and progenitor cell organisation in adult mice, and the impediments encountered in translational studies aiming to identify and characterise their human homologs. J. Cell. Physiol. 231: 2582-2589, 2016. © 2016 Wiley Periodicals, Inc. PMID:27062064

  16. The role of liver progenitor cells during liver regeneration, fibrogenesis, and carcinogenesis.

    PubMed

    Köhn-Gaone, Julia; Gogoi-Tiwari, Jully; Ramm, Grant A; Olynyk, John K; Tirnitz-Parker, Janina E E

    2016-02-01

    The growing worldwide challenge of cirrhosis and hepatocellular carcinoma due to increasing prevalence of excessive alcohol consumption, viral hepatitis, obesity, and the metabolic syndrome has sparked interest in stem cell-like liver progenitor cells (LPCs) as potential candidates for cell therapy and tissue engineering, as an alternative approach to whole organ transplantation. However, LPCs always proliferate in chronic liver diseases with a predisposition to cancer; they have been suggested to play major roles in driving fibrosis, disease progression, and may even represent tumor-initiating cells. Hence, a greater understanding of the factors that govern their activation, communication with other hepatic cell types, and bipotential differentiation as opposed to their potential transformation is needed before their therapeutic potential can be harnessed. PMID:26608186

  17. 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

  18. The Involving Roles of Intrahepatic and Extrahepatic Stem/Progenitor Cells (SPCs) to Liver Regeneration

    PubMed Central

    Liu, Wei-hui; Ren, Li-na; Wang, Tao; Navarro-Alvarez, Nalu; Tang, Li-jun

    2016-01-01

    Liver regeneration is usually attributed to mature hepatocytes, which possess a remarkable potential to proliferate under mild to moderate injury. However, when the liver is severely damaged or hepatocyte proliferation is greatly inhibited, liver stem/progenitor cells (LSPCs) will contribute to the liver regeneration process. LSPCs in the developing liver have been extensively characterized, however, their contributing role to liver regeneration has not been completely understood. In addition to the restoration of the liver parenchymal tissue by hepatocytes or/and LSPCs, or in some cases bone marrow (BM) derived cells, such as hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs), the wound healing after injury in terms of angiopoiesis by liver sinusoidal endothelial cells (LSECs) or/and sinusoidal endothelial progenitor cells (SEPCs) is another important aspect taking place during regeneration. To conclude, liver regeneration can be mainly divided into three distinct restoring levels according to the cause and severity of injury: hepatocyte dominant regeneration, LSPCs mediated regeneration, extrahepatic stem cells participative regeneration. In this review, we focus on the recent findings of liver regeneration, especially on those related to stem/progenitor cells (SPCs)-mediated regeneration and their potential clinical applications and challenges. PMID:27489499

  19. Combinatorial microenvironmental regulation of liver progenitor differentiation by Notch ligands, TGFβ, and extracellular matrix

    PubMed Central

    Kaylan, Kerim B.; Ermilova, Viktoriya; Yada, Ravi Chandra; Underhill, Gregory H.

    2016-01-01

    The bipotential differentiation of liver progenitor cells underlies liver development and bile duct formation as well as liver regeneration and disease. TGFβ and Notch signaling are known to play important roles in the liver progenitor specification process and tissue morphogenesis. However, the complexity of these signaling pathways and their currently undefined interactions with other microenvironmental factors, including extracellular matrix (ECM), remain barriers to complete mechanistic understanding. Utilizing a series of strategies, including co-cultures and cellular microarrays, we identified distinct contributions of different Notch ligands and ECM proteins in the fate decisions of bipotential mouse embryonic liver (BMEL) progenitor cells. In particular, we demonstrated a cooperative influence of Jagged-1 and TGFβ1 on cholangiocytic differentiation. We established ECM-specific effects using cellular microarrays consisting of 32 distinct combinations of collagen I, collagen III, collagen IV, fibronectin, and laminin. In addition, we demonstrated that exogenous Jagged-1, Delta-like 1, and Delta-like 4 within the cellular microarray format was sufficient for enhancing cholangiocytic differentiation. Further, by combining Notch ligand microarrays with shRNA-based knockdown of Notch ligands, we systematically examined the effects of both cell-extrinsic and cell-intrinsic ligand. Our results highlight the importance of divergent Notch ligand function and combinatorial microenvironmental regulation in liver progenitor fate specification. PMID:27025873

  20. 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

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

    PubMed

    Cuvertino, Sara; Lacaud, Georges; Kouskoff, Valerie

    2016-07-01

    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

  2. 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

  3. 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

  4. Activin A-Smad Signaling Mediates Connective Tissue Growth Factor Synthesis in Liver Progenitor Cells

    PubMed Central

    Ding, Ze-Yang; Jin, Guan-Nan; Wang, Wei; Sun, Yi-Min; Chen, Wei-Xun; Chen, Lin; Liang, Hui-Fang; Datta, Pran K.; Zhang, Ming-Zhi; Zhang, Bixiang; Chen, Xiao-Ping

    2016-01-01

    Liver progenitor cells (LPCs) are activated in chronic liver damage and may contribute to liver fibrosis. Our previous investigation reported that LPCs produced connective tissue growth factor (CTGF/CCN2), an inducer of liver fibrosis, yet the regulatory mechanism of the production of CTGF/CCN2 in LPCs remains elusive. In this study, we report that Activin A is an inducer of CTGF/CCN2 in LPCs. Here we show that expression of both Activin A and CTGF/CCN2 were upregulated in the cirrhotic liver, and the expression of Activin A positively correlates with that of CTGF/CCN2 in liver tissues. We go on to show that Activin A induced de novo synthesis of CTGF/CCN2 in LPC cell lines LE/6 and WB-F344. Furthermore, Activin A contributed to autonomous production of CTGF/CCN2 in liver progenitor cells (LPCs) via activation of the Smad signaling pathway. Smad2, 3 and 4 were all required for this induction. Collectively, these results provide evidence for the fibrotic role of LPCs in the liver and suggest that the Activin A-Smad-CTGF/CCN2 signaling in LPCs may be a therapeutic target of liver fibrosis. PMID:27011166

  5. Liver involvement in adults with measles.

    PubMed

    Dinh, Aurélien; Fleuret, Victoire; Hanslik, Thomas

    2013-12-01

    We retrospectively collected the characteristics of 80 consecutive adult patients with biologically confirmed measles during a recent epidemic in France. We report on the frequency and severity of liver involvement in adult patients with measles. In our experience, measles in adults was not severe and hepatitis was not correlated with severe cases or bacterial infection. Therefore, hepatitis should be regarded as a usual symptom rather than a complication of measles infection in adults. PMID:23938044

  6. Identification of a T lineage committed progenitor in adult blood

    PubMed Central

    Krueger, Andreas; von Boehmer, Harald

    2007-01-01

    With help of a hCD25 reporter controlled by Ptcra regulatory elements T cell precursors were identified in peripheral blood. Sca-1+, IL-7Rα+, Flt3− precursors that were c-kitlo and Thy-1hi generated T lineage cells when cultured on OP9-DL1 stromal cells and upon transfer into Rag−/−γc−/− mice. No B cells were generated in vivo and only few in vitro. The circulating T cell progenitors (CTP) were found at the same frequency in Foxn1nu/nu thymus deficient mice and wt mice indicating that they were pre- rather than post-thymic, consistent with the observation that inhibition of Notch signaling in vivo did reduce the frequency of intrathymic ETP, but not CTP. Thus, extrathymic T cell commitment is Notch-independent even in adult mice. PMID:17222572

  7. Divergent Inflammatory, Fibrogenic, and Liver Progenitor Cell Dynamics in Two Common Mouse Models of Chronic Liver Injury.

    PubMed

    Köhn-Gaone, Julia; Dwyer, Benjamin J; Grzelak, Candice A; Miller, Gregory; Shackel, Nicholas A; Ramm, Grant A; McCaughan, Geoffrey W; Elsegood, Caryn L; Olynyk, John K; Tirnitz-Parker, Janina E E

    2016-07-01

    Complications of end-stage chronic liver disease signify a major cause of mortality worldwide. Irrespective of the underlying cause, most chronic liver diseases are characterized by hepatocellular necrosis, inflammation, fibrosis, and proliferation of liver progenitor cells or ductular reactions. Vast differences exist between experimental models that mimic these processes, and their identification is fundamental for translational research. We compared two common murine models of chronic liver disease: the choline-deficient, ethionine-supplemented (CDE) diet versus thioacetamide (TAA) supplementation. Markers of liver injury, including serum alanine transaminase levels, apoptosis, hepatic fat loading, and oxidative stress, as well as inflammatory, fibrogenic and liver progenitor cell responses, were assessed at days 3, 7, 14, 21, and 42. This study revealed remarkable differences between the models. It identified periportal injury and fibrosis with an early peak and slow normalization of all parameters in the CDE regimen, whereas TAA-treated mice had pericentral patterns of progressive injury and fibrosis, resulting in a more severe hepatic injury phenotype. This study is the first to resolve two different patterns of injury and fibrosis in the CDE and TAA model and to indisputably identify the fibrosis pattern in the TAA model as driven from the pericentral vein region. Our data provide a valuable foundation for future work using the CDE and TAA regimens to model a variety of human chronic liver diseases. PMID:27181403

  8. Phagocytic activity of neuronal progenitors regulates adult neurogenesis.

    PubMed

    Lu, Zhenjie; Elliott, Michael R; Chen, Yubo; Walsh, James T; Klibanov, Alexander L; Ravichandran, Kodi S; Kipnis, Jonathan

    2011-09-01

    Whereas thousands of new neurons are generated daily during adult life, only a fraction of them survive and become part of neural circuits; the rest die, and their corpses are presumably cleared by resident phagocytes. How the dying neurons are removed and how such clearance influences neurogenesis are not well understood. Here, we identify an unexpected phagocytic role for the doublecortin (DCX)-positive neuronal progenitor cells during adult neurogenesis. Our in vivo and ex vivo studies demonstrate that DCX(+) cells comprise a significant phagocytic population within the neurogenic zones. Intracellular engulfment protein ELMO1, which promotes Rac activation downstream of phagocytic receptors, was required for phagocytosis by DCX(+) cells. Disruption of engulfment in vivo genetically (in Elmo1-null mice) or pharmacologically (in wild-type mice) led to reduced uptake by DCX(+) cells, accumulation of apoptotic nuclei in the neurogenic niches and impaired neurogenesis. Collectively, these findings indicate a paradigm wherein DCX(+) neuronal precursors also serve as phagocytes, and that their phagocytic activity critically contributes to neurogenesis in the adult brain. PMID:21804544

  9. Expression of nestin-GFP transgene marks oval cells in the adult liver

    PubMed Central

    Gleiberman, Anatoli S.; Encinas, Juan M.; Mignone, John L.; Michurina, Tatyana; Rosenfeld, Michael G.; Enikolopov, Grigori

    2009-01-01

    Oval cells which become apparent in the liver after chronic injury, serve as bi-potent progenitors for differentiated hepatocytes and cholangiocytes. We found that in the liver of adult transgenic mice in which expression of green fluorescent protein (GFP) is driven by regulatory elements of the nestin gene, the GFP signal marks a subpopulation of small epithelial cells which meet the criteria for oval cells, including morphology, localization, antigenic profile, and reactivity in response to injury. In the regenerating and developing liver we also found nestin-GFP-positive cells which express hepatocyte markers; such cells may correspond to transiently appearing differentiating progeny of oval cells. During development, GFP-expressing cells in the liver emerge relatively late, after the appearance of differentiated hepatocytes and cholangiocytes. Our results suggest that nestin-GFP cells in the liver correspond to a specialized cell type whose primary function may be to serve as a reserve for adult liver epithelial cell types. PMID:16127706

  10. Two sides of one coin: massive hepatic necrosis and progenitor cell-mediated regeneration in acute liver failure

    PubMed Central

    Weng, Hong-Lei; Cai, Xiaobo; Yuan, Xiaodong; Liebe, Roman; Dooley, Steven; Li, Hai; Wang, Tai-Ling

    2015-01-01

    Massive hepatic necrosis is a key event underlying acute liver failure, a serious clinical syndrome with high mortality. Massive hepatic necrosis in acute liver failure has unique pathophysiological characteristics including extremely rapid parenchymal cell death and removal. On the other hand, massive necrosis rapidly induces the activation of liver progenitor cells, the so-called “second pathway of liver regeneration.” The final clinical outcome of acute liver failure depends on whether liver progenitor cell-mediated regeneration can efficiently restore parenchymal mass and function within a short time. This review summarizes the current knowledge regarding massive hepatic necrosis and liver progenitor cell-mediated regeneration in patients with acute liver failure, the two sides of one coin. PMID:26136687

  11. Two sides of one coin: massive hepatic necrosis and progenitor cell-mediated regeneration in acute liver failure.

    PubMed

    Weng, Hong-Lei; Cai, Xiaobo; Yuan, Xiaodong; Liebe, Roman; Dooley, Steven; Li, Hai; Wang, Tai-Ling

    2015-01-01

    Massive hepatic necrosis is a key event underlying acute liver failure, a serious clinical syndrome with high mortality. Massive hepatic necrosis in acute liver failure has unique pathophysiological characteristics including extremely rapid parenchymal cell death and removal. On the other hand, massive necrosis rapidly induces the activation of liver progenitor cells, the so-called "second pathway of liver regeneration." The final clinical outcome of acute liver failure depends on whether liver progenitor cell-mediated regeneration can efficiently restore parenchymal mass and function within a short time. This review summarizes the current knowledge regarding massive hepatic necrosis and liver progenitor cell-mediated regeneration in patients with acute liver failure, the two sides of one coin. PMID:26136687

  12. Recruitment of Host Progenitor Cells in Rat Liver Transplants

    PubMed Central

    Sun, Zhaoli; Zhang, Xiuying; Locke, Jayme E.; Zheng, Qizhi; Tachibana, Shingo; Diehl, Anna Mae; Williams, George Melville

    2015-01-01

    Despite MHC incompatibility, Lewis to DA rat liver transplants survive indefinitely without immunosuppression, and the studies we report sought the mechanism(s) responsible for this. At one year most of the liver reacted positively to host anti-DA antibody. When small (50%) grafts were transplanted, recruitment was more rapid as most of the organ assumed the host phenotype at 3 months. After transplantation the Y-chromosome was detected in the hepatocytes of XX to XY grafts by both in-situ hybridization and PCR. Further, livers from transgenic Lewis rats carrying strong GFP markers lost the marker with time after transplantation to DA, GFP− hosts. Few liver cells contained the Y chromosome in syngeneic XX to XY liver grafts or when the hosts of Lewis XX to DA XY allografts were treated with cyclosporine A (CsA) 10mgs/kg/day. This dosage also impeded enlargement of the liver at ten days. Using GFP+ XX Lewis donors transplanted to GFP− XY DA hosts, we found little Y DNA in GFP+ cells at 10 days. Host derived OV-6 and c-kit positive, albumen positive cells were present at 3-10 days, but cells with the CD34 marker were less common and some clearly still had the donor phenotype at ten days. CXCR-4 positive cells increased with time and were abundant at 1 month after transplantation. We conclude: 1. extra-hepatic cells can differentiate into liver tissues; 2. regenerative stimuli accelerate stem cell recruitment; 3. both regeneration and recruitment are impeded by CsA immunosuppression, and 4. donor GFP positive cells contained little host Y-chromosome after transplantation suggesting that cell fusion was uncommon and, therefore, unlikely to be the mechanism leading to the changes in genotype and phenotype we observed. PMID:18972402

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

    PubMed

    Zhang, Yiqiang; Zhong, Jiang F; Qiu, Hongyu; MacLellan, W Robb; 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

  14. 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

  15. Dnmt3a Regulates Myeloproliferation and Liver-Specific Expansion of Hematopoietic Stem and Progenitor Cells

    PubMed Central

    Guryanova, Olga A.; Lieu, Yen K.; Garrett-Bakelman, Francine E.; Spitzer, Barbara; Glass, Jacob L.; Shank, Kaitlyn; Valencia Martinez, Ana Belen; Rivera, Sharon A.; Durham, Benjamin H.; Rapaport, Franck; Keller, Matthew D.; Pandey, Suveg; Bastian, Lennart; Tovbin, Daniel; Weinstein, Abby R.; Teruya-Feldstein, Julie; Abdel-Wahab, Omar; Santini, Valeria; Mason, Christopher E.; Melnick, Ari M.; Mukherjee, Siddhartha; Levine, Ross L.

    2015-01-01

    DNMT3A mutations are observed in myeloid malignancies, including myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). Transplantation studies have elucidated an important role for Dnmt3a in stem cell self-renewal and in myeloid differentiation. Here we investigated the impact of conditional hematopoietic Dnmt3a loss on disease phenotype in primary mice. Mx1-Cre-mediated Dnmt3a ablation led to the development of a lethal, fully penetrant myeloproliferative neoplasm with myelodysplasia (MDS/MPN) characterized by peripheral cytopenias and by marked, progressive hepatomegaly. We detected expanded stem/progenitor populations in the liver of Dnmt3a-ablated mice. The MDS/MPN induced by Dnmt3a ablation was transplantable, including the marked hepatomegaly. Homing studies showed that Dnmt3a-deleted bone marrow cells preferentially migrated to the liver. Gene expression and DNA methylation analyses of progenitor cell populations identified differential regulation of hematopoietic regulatory pathways, including fetal liver hematopoiesis transcriptional programs. These data demonstrate that Dnmt3a ablation in the hematopoietic system leads to myeloid transformation in vivo, with cell autonomous aberrant tissue tropism and marked extramedullary hematopoiesis (EMH) with liver involvement. Hence, in addition to the established role of Dnmt3a in regulating self-renewal, Dnmt3a regulates tissue tropism and limits myeloid progenitor expansion in vivo. PMID:26710888

  16. Characterization of two distinct liver progenitor cell subpopulations of hematopoietic and hepatic origins

    SciTech Connect

    Corcelle, V.; Stieger, B.; Gjinovci, A.; Wollheim, C.B.; Gauthier, B.R. . E-mail: Benoit.Gauthier@medecine.unige.ch

    2006-09-10

    Despite extensive studies, the hematopoietic versus hepatic origin of liver progenitor oval cells remains controversial. The aim of this study was to determine the origin of such cells after liver injury and to establish an oval cell line. Rat liver injury was induced by subcutaneous insertion of 2-AAF pellets for 7 days with subsequent injection of CCl{sub 4}. Livers were removed 9 to 13 days post-CCl{sub 4} treatment. Immunohistochemistry was performed using anti-c-kit, OV6, Thy1, CK19, AFP, vWF and Rab3b. Isolated non-parenchymal cells were grown on mouse embryonic fibroblast, and their gene expression profile was characterized by RT-PCR. We identified a subpopulation of OV6/CK19/Rab3b-expressing cells that was activated in the periportal region of traumatized livers. We also characterized a second subpopulation that expressed the HSCs marker c-kit but not Thy1. Although we successfully isolated both cell types, OV6/CK19/Rab3b{sup +} cells fail to propagate while c-kit {sup +}-HSCs appeared to proliferate for up to 7 weeks. Cells formed clusters which expressed c-kit, Thy1 and albumin. Our results indicate that a bona fide oval progenitor cell population resides within the liver and is distinct from c-kit {sup +}-HSCs. Oval cells require the hepatic niche to proliferate, while cells mobilized from the circulation proliferate and transdifferentiate into hepatocytes without evidence of cell fusion.

  17. ATP binding cassette transporter gene expression in rat liver progenitor cells

    PubMed Central

    Ros, J E; Roskams, T A D; Geuken, M; Havinga, R; Splinter, P L; Petersen, B E; LaRusso, N F; van der Kolk, D M; Kuipers, F; Faber, K N; Müller, M; Jansen, P L M

    2003-01-01

    Background and aim: Liver regeneration after severe liver damage depends in part on proliferation and differentiation of hepatic progenitor cells (HPCs). Under these conditions they must be able to withstand the toxic milieu of the damaged liver. ATP binding cassette (ABC) transporters are cytoprotective efflux pumps that may contribute to the preservation of these cells. The aim of this study was to determine the ABC transporter phenotype of HPCs. Methods: HPC activation was studied in rats treated with 2- acetylaminofluorene (2-AAF) followed by partial hepatectomy (PHx). ABC transporter gene expression was determined by real time detection reverse transcription-polymerase chain reaction in isolated HPCs, hepatocytes, cholangiocytes, and cultured progenitor cell-like RLF φ 13 cells and by immunohistochemistry of total liver samples. ABC transporter efflux activity was studied in RLF φ 13 cells by flow cytometry. Results: 2-AAF/PHx treated animals showed increased hepatic mRNA levels of the genes encoding multidrug resistance proteins Mdr1b, Mrp1, and Mrp3. Immunohistochemistry demonstrated expression of Mrp1 and Mrp3 proteins in periportal progenitor cells and of the Mdr1b protein in periportal hepatocytes. Freshly isolated Thy-1 positive cells and cultured RLF φ 13 progenitor cells highly expressed Mrp1 and Mrp3 mRNA while the hepatocyte specific transporters Mdr2, Bsep, Mrp2, and Mrp6 were only minimally expressed. Blocking Mrp activity by MK-571 resulted in accumulation of the Mrp specific substrate carboxyfluorescein in RLF φ 13 cells. Conclusion: HPCs express high levels of active Mrp1 and Mrp3. These may have a cytoprotective role in conditions of severe hepatotoxicity. PMID:12801967

  18. Decellularized liver scaffolds effectively support the proliferation and differentiation of mouse fetal hepatic progenitors

    PubMed Central

    Wang, Xiaojun; Cui, Jing; Zhang, Bing-Qiang; Zhang, Hongyu; Bi, Yang; Kang, Quan; Wang, Ning; Bie, Ping; Yang, Zhanyu; Wang, Huaizhi; Liu, Xiangde; Haydon, Rex C; Luu, Hue H; Tang, Ni; Dong, Jiahong; He, Tong-Chuan

    2014-01-01

    Decellularized whole organs represent ideal scaffolds for engineering new organs and/or cell transplantation. Here, we investigate whether decellularized liver scaffolds provide cell-friendly biocompatible three-dimensional environment to support the proliferation and differentiation of hepatic progenitor cells. Mouse liver tissues are efficiently decellularized through portal vein perfusion. Using the reversibly immortalized mouse fetal hepatic progenitor cells (iHPCs), we are able to effectively recellularize the decellularized liver scaffolds. The perfused iHPCs survive and proliferate in the three-dimensional scaffolds in vitro for 2 weeks. When the recellularized scaffolds are implanted into the kidney capsule of athymic nude mice, cell survival and proliferation of the implanted scaffolds are readily detected by whole body imaging for 10 days. Furthermore, EGF is shown to significantly promote the proliferation and differentiation of the implanted iHPCs. Histologic and immunochemical analyses indicate that iHPCs are able to proliferate and differentiate to mature hepatocytes upon EGF stimulation in the scaffolds. The recellularization of the biomaterial scaffolds is accompanied with vascularization. Taken together, these results indicate that decullarized liver scaffolds effectively support the proliferation and differentiation of iHPCs, suggesting that decellularized liver matrix may be used as ideal biocompatible scaffolds for hepatocyte transplantation. PMID:23625886

  19. Decellularized liver scaffolds effectively support the proliferation and differentiation of mouse fetal hepatic progenitors.

    PubMed

    Wang, Xiaojun; Cui, Jing; Zhang, Bing-Qiang; Zhang, Hongyu; Bi, Yang; Kang, Quan; Wang, Ning; Bie, Ping; Yang, Zhanyu; Wang, Huaizhi; Liu, Xiangde; Haydon, Rex C; Luu, Hue H; Tang, Ni; Dong, Jiahong; He, Tong-Chuan

    2014-04-01

    Decellularized whole organs represent ideal scaffolds for engineering new organs and/or cell transplantation. Here, we investigate whether decellularized liver scaffolds provide cell-friendly biocompatible three-dimensional (3-D) environment to support the proliferation and differentiation of hepatic progenitor cells. Mouse liver tissues are efficiently decellularized through portal vein perfusion. Using the reversibly immortalized mouse fetal hepatic progenitor cells (iHPCs), we are able to effectively recellularize the decellularized liver scaffolds. The perfused iHPCs survive and proliferate in the 3-D scaffolds in vitro for 2 weeks. When the recellularized scaffolds are implanted into the kidney capsule of athymic nude mice, cell survival and proliferation of the implanted scaffolds are readily detected by whole body imaging for 10 days. Furthermore, epidermal growth factor (EGF) is shown to significantly promote the proliferation and differentiation of the implanted iHPCs. Histologic and immunochemical analyzes indicate that iHPCs are able to proliferate and differentiate to mature hepatocytes upon EGF stimulation in the scaffolds. The recellularization of the biomaterial scaffolds is accompanied with vascularization. Taken together, these results indicate that decullarized liver scaffolds effectively support the proliferation and differentiation of iHPCs, suggesting that decellularized liver matrix may be used as ideal biocompatible scaffolds for hepatocyte transplantation. PMID:23625886

  20. Evidence of progenitor cells of glandular and myoepithelial cell lineages in the human adult female breast epithelium: a new progenitor (adult stem) cell concept.

    PubMed

    Boecker, Werner; Buerger, Horst

    2003-10-01

    Although experimental data clearly confirm the existence of self-renewing mammary stem cells, the characteristics of such progenitor cells have never been satisfactorily defined. Using a double immunofluorescence technique for simultaneous detection of the basal cytokeratin 5, the glandular cytokeratins 8/18 and the myoepithelial differentiation marker smooth muscle actin (SMA), we were able to demonstrate the presence of CK5+ cells in human adult breast epithelium. These cells have the potential to differentiate to either glandular (CK8/18+) or myoepithelial cells (SMA+) through intermediary cells (CK5+ and CK8/18+ or SMA+). We therefore proceeded on the assumption that the CK5+ cells are phenotypically and behaviourally progenitor (committed adult stem) cells of human breast epithelium. Furthermore, we furnish evidence that most of these progenitor cells are located in the luminal epithelium of the ductal lobular tree. Based on data obtained in extensive analyses of proliferative breast disease lesions, we have come to regard usual ductal hyperplasia as a progenitor cell-derived lesion, whereas most breast cancers seem to evolve from differentiated glandular cells. Double immunofluorescence experiments provide a new tool to characterize phenotypically progenitor (adult stem) cells and their progenies. This model has been shown to be of great value for a better understanding not only of normal tissue regeneration but also of proliferative breast disease. Furthermore, this model provides a new tool for unravelling further the regulatory mechanisms that govern normal and pathological cell growth. PMID:14521517

  1. Clonal tracing of Sox9+ liver progenitors in oval cell injury

    PubMed Central

    Tarlow, Branden D.; Finegold, Milton J.; Grompe, Markus

    2014-01-01

    Proliferating ducts, termed “oval cells”, have long thought to be bipotential, i.e. produce both biliary ducts and hepatocytes during chronic liver injury. The precursor to oval cells is considered to be a facultative liver stem cell (LSC). Recent lineage tracing experiments indicated that the LSC is Sox9+ and can replace the bulk of hepatocyte mass in several settings. However, no clonal relationship between Sox9+ cells and the two epithelial liver lineages was established. We labeled Sox9+ mouse liver cells at low density with a multicolor fluorescent confetti reporter. Organoid formation validated the progenitor activity of the labeled population. Sox9+ cells were traced in multiple oval cell injury models using both histology and FACS. Surprisingly, only rare clones containing both hepatocytes and oval cells were found in any experiment. Quantitative analysis showed that Sox9+ cells contributed only minimally (<1%) to the hepatocyte pool, even in classic oval cell injury models. In contrast, clonally marked mature hepatocytes demonstrated the ability to self-renew in all classic mouse oval cell activation injuries. A hepatocyte chimera model to trace hepatocytes and non-parenchymal cells also demonstrated the prevalence of hepatocyte-driven regeneration in mouse oval cell injury models. Conclusion Sox9+ ductal progenitor cells give rise to clonal oval cell proliferation and bipotential organoids but rarely produce hepatocytes in vivo. Hepatocytes themselves are the predominant source of new parenchyma cells in prototypical mouse models of oval cell activation. PMID:24700457

  2. Substrate stiffness and matrix composition coordinately control the differentiation of liver progenitor cells.

    PubMed

    Kourouklis, Andreas P; Kaylan, Kerim B; Underhill, Gregory H

    2016-08-01

    Recent approaches have utilized microfabricated platforms to examine combinations of microenvironmental signals that regulate stem and progenitor cell differentiation. However, the majority of these efforts have focused on the biochemical properties of extracellular matrix (ECM) or soluble factors without simultaneously exploring the biomechanical effects of cell-substrate interactions. To address this need, we combined a high-throughput approach for the analysis of combinatorial ECM cues with substrates of modular stiffness and traction force microscopy. This integrated approach enabled the characterization of cell-generated traction stress and phenotypic expression in response to ECM cues. We investigated the impact of substrate stiffness and ECM composition on the differentiation of bipotential mouse embryonic liver (BMEL) progenitor cells. We observed that hepatocyte differentiation was primarily regulated by ECM composition, and cholangiocyte differentiation was cooperatively influenced by ECM proteins and stiffness properties. In particular, stiffness-mediated cholangiocyte differentiation was observed for cells cultured on fibronectin, while collagen IV promoted differentiation independent of substrate stiffness. We demonstrated the influence of cell contractility and traction stress in early cholangiocyte specification and further uncovered the roles of ERK and ROCK in this differentiation process. Overall, these findings illustrate the involvement of biomechanical signals in liver progenitor differentiation. Further, this approach could enable investigations for a broad range of cell types and ECM proteins, providing an integrated platform for evaluating the combinatorial effects of biochemical and biophysical signals in cell differentiation. PMID:27235994

  3. Embryonic----Fetal Hb switch in humans: studies on erythroid bursts generated by embryonic progenitors from yolk sac and liver.

    PubMed

    Peschle, C; Migliaccio, A R; Migliaccio, G; Petrini, M; Calandrini, M; Russo, G; Mastroberardino, G; Presta, M; Gianni, A M; Comi, P

    1984-04-01

    The synthesis of embryonic (zeta, epsilon), fetal (alpha, gamma), and adult (beta) globin was evaluated in human yolk sacs (YS) and livers at different ontogenic stages (i.e., from 6 through 10-12 wk of age) by means of analytical isoelectric focusing. Globin production was comparatively evaluated in vivo (i.e., in directly labeled erythroblasts from YS and liver) and in vitro [i.e., in erythroid bursts generated in culture by erythroid burst-forming units (BFU-E) from the same erythropoietic tissues]. Erythroid bursts generated in vitro by BFU-E from 6-wk livers and YS show essentially a "fetal" globin synthetic pattern: this is in sharp contrast to the "embryonic" pattern in corresponding liver and YS erythroblasts directly labeled in vivo. The invitro phenomenon suggests that (i) 6-wk BFU-E constitute a new generation of progenitors, which have already switched from an embryonic to a fetal program, and/or (ii) expression of their fetal program is induced by unknown in vitro factor(s), which may underlie the in vivo switch at later ontogenic stages. It is emphasized that 6- to 7-wk BFU-E are endowed with the potential for in vitro synthesis of not only epsilon- and gamma-chains but also some beta-globin. In general, we observed an inverse correlation between the levels of epsilon- and beta-chain synthesis. These results, together with previous studies on fetal, perinatal, and adult BFU-E, are compatible with models suggesting that in ontogeny the chromatin configuration is gradually modified at the level of the non-alpha gene cluster, thus leading to a 5'----3' activation of globin genes in a balanced fashion. PMID:6201856

  4. 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

  5. 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

  6. 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

  7. Hematopoietic Progenitors from Early Murine Fetal Liver Possess Hepatic Differentiation Potential

    PubMed Central

    Khurana, Satish; Mukhopadhyay, Asok

    2008-01-01

    Bipotential hepatoblasts differentiate into hepatocytes and cholangiocytes during liver development. It is believed that hepatoblasts originate from endodermal tissue. Here, we provide evidence for the presence of hepatic progenitor cells in the hematopoietic compartment at an early stage of liver development. Flow cytometric analysis showed that at early stages of liver development, approximately 13% of CD45+ cells express Δ-like protein-1, a marker of hepatoblasts. Furthermore, reverse transcriptase-PCR data suggest that many hepatic genes are expressed in these cells. Cell culture experiments confirmed the hepatic differentiation potential of these cells with the loss of the CD45 marker. We observed that both hematopoietic activity in Δ-like protein-1+ cells and hepatic activity in CD45+ cells were high at embryonic day 10.5 and declined thereafter. Clonal analysis revealed that the hematopoietic fraction of fetal liver cells at embryonic day 10.5 gave rise to both hepatic and hematopoietic colonies. The above results suggest a common source of these two functionally distinct cell lineages. In utero transplantation experiments confirmed these results, as green fluorescent protein-expressing CD45+ cells at the same stage of development yielded functional hepatocytes and hematopoietic reconstitution. Since these cells were unable to differentiate into cytokeratin-19-expressing cholangiocytes, we distinguished them from hepatoblasts. This preliminary study provides hope to correct many liver diseases during prenatal development via transplantation of fetal liver hematopoietic cells. PMID:18988804

  8. Endothelial Progenitor Cells Combined with Cytosine Deaminase-Endostatin for Suppression of Liver Carcinoma.

    PubMed

    Chen, Rong; Yu, Hui; An, Yan-Li; Chen, Hua-Jun; Jia, ZhenYu; Teng, Gao-Jun

    2016-06-01

    Transplantation of gene transfected endothelial progenitor cells (EPCs) provides a novel method for treatment of human tumors. To study treatment of hepatocellular carcinoma using cytosine deaminase (CD)- and endostatin (ES)-transfected endothelial progenitor cells (EPCs), mouse bone marrow-derived EPCs were cultured and transfected with Lenti6.3-CD-EGFP and Lenti6.3-ES-Monomer-DsRed labeled with superparamagnetic iron oxide (SPIO) nanoparticles. DiD (lipophilic fluorescent dye)-labeled EPCs were injected into normal mice and mice with liver carcinoma. The EPCs loaded with CD-ES were infused into the mice through caudal veins and tumor volumes were measured. The tumor volumes in the EPC + SPIO + CD/5-Fc + ES group were found to be smaller as a result and grew more slowly than those from the EPC + SPIO + LV (lentivirus, empty vector control) group. Survival times were also measured after infusion of the cells into the mice. The median survival time was found to be longer in the EPC + SPIO + CD/5-Fc + ES group than in the others. In conclusion, the EPCs transfected with CD-ES suppressed the liver carcinoma cells in vitro, migrated primarily to the carcinoma, inhibited tumor growth, and also extended the median survival time for the mice with liver carcinoma. PMID:27319212

  9. Direct Differentiation of Adult Ocular Progenitors into Striatal Dopaminergic Neurons

    PubMed Central

    Ahmad, Iqbal; Zhao, Xing; Parameswaran, Sowmya; Destache, Christopher J.; Rodriguez-Sierra, Jorge; Thoreson, Wallace B.; Ahmad, Hiba; Sorrentino, John; Balasubramanian, Sudha

    2015-01-01

    Parkinson’s disease, characterized by motor dysfunction due to the loss of nigrostriatal dopaminergic neurons, is one of the most prevalent age-related neurodegenerative disorders. Given there is no current cure, the stem cell approach has emerged as a viable therapeutic option to replace the dopaminergic neurons that are progressively lost to the disease. The success of the approach is likely to depend upon accessible, renewable, immune compatible, and non-tumorigenic sources of neural progenitors from which stable dopaminergic neurons can be generated efficaciously. Here, we demonstrate that neural progenitors derived from limbus, a regenerative and accessible ocular tissue, represent a safe source of dopaminergic neurons. When the limbus-derived neural progenitors were subjected to a well-established protocol of directed differentiation under the influence of Shh and FGF8, they acquired the biochemical and functional phenotype of dopaminergic neurons that included the ability to synthesize dopamine. Their intrastriatal transplantation in the rat model of hemi-Parkinsonism was associated with a reduction in the amphetamine-induced rotation. No tumor formation was observed 6 weeks post-transplantation. Together, these observations posit limbus-derived neural progenitors as an accessible and safe source of dopaminergic neurons for a potential autologous ex-vivo stem cell approach to Parkinson’s disease. PMID:26019760

  10. Direct differentiation of adult ocular progenitors into striatal dopaminergic neurons.

    PubMed

    Ahmad, Iqbal; Zhao, Xing; Parameswaran, Sowmya; Destache, Christopher J; Rodriguez-Sierra, Jorge; Thoreson, Wallace B; Ahmad, Hiba; Sorrentino, John; Balasubramanian, Sudha

    2015-05-01

    Parkinson's disease, characterized by motor dysfunction due to the loss of nigrostriatal dopaminergic neurons, is one of the most prevalent age-related neurodegenerative disorders. Given there is no current cure, the stem cell approach has emerged as a viable therapeutic option to replace the dopaminergic neurons that are progressively lost to the disease. The success of the approach is likely to depend upon accessible, renewable, immune compatible, and non-tumorigenic sources of neural progenitors from which stable dopaminergic neurons can be generated efficaciously. Here, we demonstrate that neural progenitors derived from limbus, a regenerative and accessible ocular tissue, represent a safe source of dopaminergic neurons. When the limbus-derived neural progenitors were subjected to a well-established protocol of directed differentiation under the influence of Shh and FGF8, they acquired the biochemical and functional phenotype of dopaminergic neurons that included the ability to synthesize dopamine. Their intrastriatal transplantation in the rat model of hemi-Parkinsonism was associated with a reduction in the amphetamine-induced rotation. No tumor formation was observed 6 weeks post-transplantation. Together, these observations posit limbus-derived neural progenitors as an accessible and safe source of dopaminergic neurons for a potential autologous ex-vivo stem cell approach to Parkinson's disease. PMID:26019760

  11. Macrophage Activation in Pediatric Nonalcoholic Fatty Liver Disease (NAFLD) Correlates with Hepatic Progenitor Cell Response via Wnt3a Pathway

    PubMed Central

    Renzi, Anastasia; De Stefanis, Cristiano; Stronati, Laura; Franchitto, Antonio; Alisi, Anna; Onori, Paolo; De Vito, Rita; Alpini, Gianfranco; Gaudio, Eugenio

    2016-01-01

    Non-alcoholic fatty liver disease is one of the most important causes of liver-related morbidity in children. In non-alcoholic fatty liver disease, the activation of liver resident macrophage pool is a central event in the progression of liver injury. The aims of the present study were to evaluate the polarization of liver macrophages and the possible role of Wnt3a production by macrophages in hepatic progenitor cell response in the progression of pediatric non-alcoholic fatty liver disease. 32 children with biopsy-proven non-alcoholic fatty liver disease were included. 20 out of 32 patients were treated with docosahexaenoic acid for 18 months and biopsies at the baseline and after 18 months were included. Hepatic progenitor cell activation, macrophage subsets and Wnt/β-catenin pathway were evaluated by immunohistochemistry and immunofluorescence. Our results indicated that in pediatric non-alcoholic fatty liver disease, pro-inflammatory macrophages were the predominant subset. Macrophage polarization was correlated with Non-alcoholic fatty liver disease Activity Score, ductular reaction, and portal fibrosis; docosahexaenoic acid treatment determined a macrophage polarization towards an anti-inflammatory phenotype in correlation with the reduction of serum inflammatory cytokines, with increased macrophage apoptosis, and with the up-regulation of macrophage Wnt3a expression; macrophage Wnt3a expression was correlated with β-catenin phosphorylation in hepatic progenitor cells and signs of commitment towards hepatocyte fate. In conclusion, macrophage polarization seems to have a key role in the progression of pediatric non-alcoholic fatty liver disease; the modulation of macrophage polarization could drive hepatic progenitor cell response by Wnt3a production. PMID:27310371

  12. DJ-1 deficiency attenuates expansion of liver progenitor cells through modulating the inflammatory and fibrogenic niches.

    PubMed

    Chen, L; Luo, M; Sun, X; Qin, J; Yu, C; Wen, Y; Zhang, Q; Gu, J; Xia, Q; Kong, X

    2016-01-01

    Our previous study suggested that DJ-1 has a critical role in initiating an inflammatory response, but its role in the liver progenitor cell (LPC) expansion, a process highly dependent on the inflammatory niche, remains elusive. The objective of this study is to determine the role of DJ-1 in LPC expansion. The correlation of DJ-1 expression with LPC markers was examined in the liver of patients with hepatitis B or hepatitis C virus (HBV and HCV, respectively) infection, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), nonalcoholic fatty liver disease (NAFLD), cirrhosis or hepatocellular carcinoma (HCC), respectively. The role of DJ-1 in LPC expansion and the formation of LPC-associated fibrosis and inflammation was examined in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet-induced liver injury murine model. We also determined the ability of hepatic stellate cells (HSCs) in recruiting macrophages in DJ-1 knockout (KO) mice. The expression levels of DJ-1 were upregulated in the liver of HBV, HCV, PBC and PSC patients and DDC-fed mice. Additionally, DJ-1 expression was positively correlated with LPC proliferation in patients with liver injury and mice with DDC exposure. DJ-1 has no direct effect on LPC proliferation. Reduced activation of HSCs and collagen deposition were observed in DJ-1 KO mice. Furthermore, infiltrated CD11b(+)Gr-1(low) macrophages and pro-inflammatory factors (IL-6, TNF-α) were attenuated in DJ-1 KO mice. Mechanistically, we found that HSCs isolated from DJ-1 KO mice had decreased secretion of macrophage-mobilizing chemokines, such as CCL2 and CX3CL1, resulting in impaired macrophage infiltration. DJ-1 positively correlates with LPC expansion during liver injury. DJ-1 deficiency negatively regulates LPC proliferation by impairing the formation of LPC-associated fibrosis and inflammatory niches. PMID:27277679

  13. Identification of a Bipotent Epithelial Progenitor Population in the Adult Thymus

    PubMed Central

    Ulyanchenko, Svetlana; O’Neill, Kathy E.; Medley, Tanya; Farley, Alison M.; Vaidya, Harsh J.; Cook, Alistair M.; Blair, Natalie F.; Blackburn, C. Clare

    2016-01-01

    Summary Thymic epithelial cells (TECs) are critically required for T cell development, but the cellular mechanisms that maintain adult TECs are poorly understood. Here, we show that a previously unidentified subpopulation, EpCam+UEA1−Ly-51+PLET1+MHC class IIhi, which comprises <0.5% of adult TECs, contains bipotent TEC progenitors that can efficiently generate both cortical (c) TECs and medullary (m) TECs. No other adult TEC population tested in this study contains this activity. We demonstrate persistence of PLET1+Ly-51+ TEC-derived cells for 9 months in vivo, suggesting the presence of thymic epithelial stem cells. Additionally, we identify cTEC-restricted short-term progenitor activity but fail to detect high efficiency mTEC-restricted progenitors in the adult thymus. Our data provide a phenotypically defined adult thymic epithelial progenitor/stem cell that is able to generate both cTECs and mTECs, opening avenues for improving thymus function in patients. PMID:26997270

  14. Identification of a Bipotent Epithelial Progenitor Population in the Adult Thymus.

    PubMed

    Ulyanchenko, Svetlana; O'Neill, Kathy E; Medley, Tanya; Farley, Alison M; Vaidya, Harsh J; Cook, Alistair M; Blair, Natalie F; Blackburn, C Clare

    2016-03-29

    Thymic epithelial cells (TECs) are critically required for T cell development, but the cellular mechanisms that maintain adult TECs are poorly understood. Here, we show that a previously unidentified subpopulation, EpCam(+)UEA1(-)Ly-51(+)PLET1(+)MHC class II(hi), which comprises <0.5% of adult TECs, contains bipotent TEC progenitors that can efficiently generate both cortical (c) TECs and medullary (m) TECs. No other adult TEC population tested in this study contains this activity. We demonstrate persistence of PLET1(+)Ly-51(+) TEC-derived cells for 9 months in vivo, suggesting the presence of thymic epithelial stem cells. Additionally, we identify cTEC-restricted short-term progenitor activity but fail to detect high efficiency mTEC-restricted progenitors in the adult thymus. Our data provide a phenotypically defined adult thymic epithelial progenitor/stem cell that is able to generate both cTECs and mTECs, opening avenues for improving thymus function in patients. PMID:26997270

  15. 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

  16. Adult liver transplantation at UCL: update 2002.

    PubMed

    Lerut, J; Matthys, J; Lemaire, J; Van Thuyne, V; Ciccarelli, O; Goffette, P; Peeters, A; Aunac, S; Boddeus, M; Carlier, M A; Danse, E; De Kock, M; De Reyck, Ch; Donataccio, M; Geubel, A; Gonze, D; Goubau, P; Latinne, D; Laterre, P F; Luts, A; Cool, G; Otte, J B; Horsmans, Y; Martinez, J; Orlando, G; Rahier, J; Reding, R; Reynaert, M; Starkel, P; Sempoux, Ch; Talpe, St; Van Obbergh, L; Veyckemans, F; Wallemacq, P; Wittebolle, X; Roggen, F

    2004-01-01

    The authors present the results of a single centre study of 587 liver transplants performed in 522 adults during the period 1984-2002. Results have improved significantly over time due to better pre-, peri- and post-transplant care. One, five, ten and fifteen year actuarial survivals for the whole patient group are 81.2; 69.8; 58.9 and 51.2%. The high incidence of de novo tumors (12.3%), of cardiovascular diseases (7.5%) and of end-stage renal function (3.6%) should be further incentives to tailor the immunosuppression to the individual patient and to direct the attention of the transplant physician to the long-term quality of life of the liver recipient. PMID:15285577

  17. Prospective heterotopic ossification progenitors in adult human skeletal muscle.

    PubMed

    Downey, Jennifer; Lauzier, Dominique; Kloen, Peter; Klarskov, Klaus; Richter, Martin; Hamdy, Reggie; Faucheux, Nathalie; Scimè, Anthony; Balg, Frédéric; Grenier, Guillaume

    2015-02-01

    Skeletal muscle has strong regenerative capabilities. However, failed regeneration can lead to complications where aberrant tissue forms as is the case with heterotopic ossification (HO), in which chondrocytes, osteoblasts and white and brown adipocytes can arise following severe trauma. In humans, the various HO cell types likely originate from multipotent mesenchymal stromal cells (MSCs) in skeletal muscle, which have not been identified in humans until now. In the present study, adherent cells from freshly digested skeletal muscle tissue were expanded in defined culture medium and were FACS-enriched for the CD73(+)CD105(+)CD90(-) population, which displayed robust multilineage potential. Clonal differentiation assays confirmed that all three lineages originated from a single multipotent progenitor. In addition to differentiating into typical HO lineages, human muscle resident MSCs (hmrMSCs) also differentiated into brown adipocytes expressing uncoupling protein 1 (UCP1). Characterizing this novel multipotent hmrMSC population with a brown adipocyte differentiation capacity has enhanced our understanding of the contribution of non-myogenic progenitor cells to regeneration and aberrant tissue formation in human skeletal muscle. PMID:25445454

  18. Characterisation of the hepatic progenitor cell compartment in normal liver and in hepatitis: an immunohistochemical comparison between dog and man.

    PubMed

    Ijzer, J; Schotanus, B A; Vander Borght, S; Roskams, T A D; Kisjes, R; Penning, L C; Rothuizen, J; van den Ingh, T S G A M

    2010-06-01

    The liver progenitor cell compartment in the normal canine liver and in spontaneous canine acute (AH) and chronic hepatitis (CH) was morphologically characterised and compared to its human equivalents. Immunohistochemistry was performed for cytokeratin-7 (CK7), human hepatocyte marker (Hep Par 1), multidrug resistance-associated protein-2 (MRP2), and breast cancer resistance protein (BCRP) on paraffin and frozen sections from canine and human tissues. Normal liver showed similar morphology and immunohistochemical reaction of the progenitor cell compartment/canal of Hering in man and dog. In addition, a ductular reaction, comparable in terms of severity, location and immunohistochemical characteristics, was observed in canine and human AH and CH. CK7 was a good marker for canine progenitor cells, including intermediate cells, which were positively identified in cases of AH and CH. In both species, BCRP was expressed in both hepatocytes and bile ducts of the normal liver, and in ductular reaction in AH and CH. MRP2 detected bile canalicular membranes in man and dog. These findings underline the similarities between canine and human liver reaction patterns and may offer mutual advantage for comparative research in human and canine spontaneous liver diseases. PMID:19369099

  19. Liver Transplantation for Cholestatic Liver Diseases in Adults.

    PubMed

    Khungar, Vandana; Goldberg, David Seth

    2016-02-01

    Liver transplantation (LT) is an established lifesaving therapy for patients with cholestatic liver diseases, including primary cholestatic diseases, namely primary sclerosing cholangitis and primary biliary cirrhosis, as well as secondary forms of cholestatic liver disease, including those with cholestatic complications of LT needing a retransplant. Patients with cholestatic liver diseases can be transplanted for complications of end-stage liver disease or for disease-specific symptoms before the onset of end-stage liver disease. These patients should be regularly assessed. Patient survival after LT for cholestatic liver diseases is generally better than for other indications. PMID:26593299

  20. Alcohol Disrupts Human Liver Stem/Progenitor Cell Proliferation and Differentiation

    PubMed Central

    Shi, Xin; Chang, Chia-Cheng; Basson, Marc D; Upham, Brad L; Wei, Lixin; Zhang, Ping

    2016-01-01

    Objective Excessive alcohol consumption injures the liver resulting in various liver diseases including liver cirrhosis. Advanced liver disease continues to be a major challenge to human health. Liver stem/progenitor cells (LSPCs) are tissue specific precursors with a distinct capacity of multi-lineage differentiation. These precursor cells may play an important role in the process of tissue injury repair and pathological transition of liver structures. At the present time, knowledge about the effect of alcohol on LSPC function during the development of alcoholic liver disease remains absent. This study was conducted to investigate changes in LSPC activity of proliferation and differentiation following alcohol exposure. The disruption of cell signaling mechanisms underlying alcohol-induced alteration of LSPC activities was also examined. Methods Primary and immortalized human liver stem cells (HL1-1 cells and HL1-hT1 cells, respectively) were cultured in media optimized for cell proliferation and hepatocyte differentiation in the absence and presence of ethanol. Changes in cell morphology, proliferation and differentiation were determined. Functional disruption of cell signaling components following alcohol exposure was examined. Results Ethanol exposure suppressed HL1-1 cell growth [as measured by cell 5-bromo-2-deoxyuridine (BrdU) incorporation] mediated by epidermal growth factor (EGF) or EGF plus interleukin-6 (IL-6) in an ethanol dose-dependent manner. Similarly, ethanol inhibited BrdU incorporation into HL1-hT1 cells. Cyclin D1 mRNA expression by HL1-hT1 cells was suppressed when cells were cultured with 50 and 100 mM ethanol. Ethanol exposure induced morphological change of HL1-1 cells toward a myofibroblast-like phenotype. Furthermore, ethanol down-regulated E-cadherin expression while increasing collagen I expression by HL1-1 cells. Ethanol also stimulated Snail transcriptional repressor (Snail) and α-smooth muscle actin (α-SMA) gene expression by HL1

  1. Stromal vascular progenitors in adult human adipose tissue

    PubMed Central

    Zimmerlin, Ludovic; Donnenberg, Vera S.; Pfeifer, Melanie E.; Meyer, E. Michael; Péault, Bruno; Rubin, J. Peter; Donnenberg, Albert D.

    2014-01-01

    Background The in vivo progenitor of culture-expanded mesenchymal-like adipose-derived stem cells (ADSC) remains elusive, owing in part to the complex organization of stromal cells surrounding the small vessels, and the rapidity with which adipose stromal vascular cells adopt a mesenchymal phenotype in vitro. Methods Immunohistostaining of intact adipose tissue was used to identify 3 markers (CD31, CD34, CD146) which together unambiguously discriminate histologically distinct inner and outer rings of vessel-associated stromal cells, as well as capillary and small vessel endothelial cells. These markers were used in multiparameter flow cytometry in conjunction with stem/progenitor markers (CD90, CD117) to further characterize stromal vascular fraction (SVF) subpopulations. Two mesenchymal and two endothelial populations were isolated by high speed flow cytometric sorting, expanded in short term culture and tested for adipogenesis. Results The inner layer of stromal cells in contact with small vessel endothelium (pericytes) was CD146+/α-SMA+/CD90±/CD34−/CD31−; the outer adventitial stromal ring (designated supra adventitial-adipose stromal cells, SA-ASC) was CD146−/α-SMA−/CD90+/CD34+/CD31−. Capillary endothelial cells were CD31+/CD34+/CD90+ (endothelial progenitor), while small vessel endothelium was CD31+/CD34−/CD90− (endothelial mature). Flow cytometry confirmed these expression patterns and revealed a CD146+/CD90+/CD34+/CD31− pericyte subset that may be transitional between pericytes and SA-ASC. Pericytes had the most potent adipogenic potential, followed by the more numerous SA-ASC. Endothelial populations had significantly reduced adipogenic potential compared to unsorted expanded SVF cells. Conclusions In adipose tissue perivascular stromal cells are organized in two discrete layers, the innermost consisting of CD146+/CD34− pericytes, and the outermost of CD146−/CD34+ SA-ASC, both of which have adipogenic potential in culture. A CD146+/CD

  2. Development and specification of cerebellar stem and progenitor cells in zebrafish: from embryo to adult

    PubMed Central

    2013-01-01

    Background Teleost fish display widespread post-embryonic neurogenesis originating from many different proliferative niches that are distributed along the brain axis. During the development of the central nervous system (CNS) different cell types are produced in a strict temporal order from increasingly committed progenitors. However, it is not known whether diverse neural stem and progenitor cell types with restricted potential or stem cells with broad potential are maintained in the teleost fish brain. Results To study the diversity and output of neural stem and progenitor cell populations in the zebrafish brain the cerebellum was used as a model brain region, because of its well-known architecture and development. Transgenic zebrafish lines, in vivo imaging and molecular markers were used to follow and quantify how the proliferative activity and output of cerebellar progenitor populations progress. This analysis revealed that the proliferative activity and progenitor marker expression declines in juvenile zebrafish before they reach sexual maturity. Furthermore, this correlated with the diminished repertoire of cell types produced in the adult. The stem and progenitor cells derived from the upper rhombic lip were maintained into adulthood and they actively produced granule cells. Ventricular zone derived progenitor cells were largely quiescent in the adult cerebellum and produced a very limited number of glia and inhibitory inter-neurons. No Purkinje or Eurydendroid cells were produced in fish older than 3 months. This suggests that cerebellar cell types are produced in a strict temporal order from distinct pools of increasingly committed stem and progenitor cells. Conclusions Our results in the zebrafish cerebellum show that neural stem and progenitor cell types are specified and they produce distinct cell lineages and sub-types of brain cells. We propose that only specific subtypes of brain cells are continuously produced throughout life in the teleost fish

  3. 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

  4. 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

  5. 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

  6. From progenitors to integrated neurons: role of neurotransmitters in adult olfactory neurogenesis.

    PubMed

    Bovetti, Serena; Gribaudo, Simona; Puche, Adam C; De Marchis, Silvia; Fasolo, Aldo

    2011-12-01

    Adult neurogenesis is due to the persistence of pools of constitutive stem cells able to give rise to a progeny of proliferating progenitors. In rodents, adult neurogenic niches have been found in the subventricular zone (SVZ) along the lateral ventricles and in the subgranular zone of the dentate gyrus in the hippocampus. SVZ progenitors undergo a unique process of tangential migration from the lateral ventricle to the olfactory bulb (OB) where they differentiate mainly into GABAergic interneurons in the granule and glomerular layers. SVZ progenitor proliferation, migration and differentiation into fully integrated neurons, are strictly related processes regulated by complex interactions between cell intrinsic and extrinsic influences. Numerous observations demonstrate that neurotrasmitters are involved in all steps of the adult neurogenic process, but the understanding of their role is hampered by their intricate mechanism of action and by the highly complex network in which neurotransmitters work. By considering the three main steps of olfactory adult neurogenesis (proliferation, migration and integration), this review will discuss recent advances in the study of neurotransmitters, highlighting the regulatory mechanisms upstream and downstream their action. PMID:21641990

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

    PubMed

    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

  8. 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

  9. Neurite formation by neurons derived from adult rat hippocampal progenitor cells is susceptible to myelin inhibition.

    PubMed

    Mellough, Carla B; Cho, Seongeun; Wood, Andrew; Przyborski, Stefan

    2011-09-01

    Myelin-associated inhibitors expressed following injury to the adult central nervous system (CNS) induce growth cone collapse and retraction of the axonal cytoskeleton. Myelin-associated glycoprotein (MAG) is a bi-functional molecule that promotes neuritogenesis in some immature neurons during development then becomes inhibitory to neurite outgrowth as neurons mature. Progress is being made towards the elucidation of the downstream events that regulate myelin inhibition of regeneration in neuronal populations. However it is not known how adult-derived neural stem cells or progenitors respond to myelin during neuronal differentiation and neuritogenesis. Here we examine the effect of MAG on neurons derived from an adult rat hippocampal progenitor cell line (AHPCs). We show that, unlike their developmental counterparts, AHPC-derived neurons are susceptible to MAG inhibition of neuritogenesis during differentiation and display a 57% reduction in neurite outgrowth when compared with controls. We demonstrate that this effect can be overcome (by up to 69%) by activation of the neurotrophin, cyclic AMP and protein kinase A pathways or by Rho-kinase suppression. We also demonstrate that combination of these factors enhanced neurite outgrowth from differentiating neurons in the presence of MAG. This work provides important information for the successful generation of new neurons from adult neural stem cell populations within compromised adult circuitry and is thus directly relevant to endogenous repair and regeneration of the adult CNS. PMID:21256909

  10. TRIM32-dependent transcription in adult neural progenitor cells regulates neuronal differentiation.

    PubMed

    Hillje, A-L; Pavlou, M A S; Beckmann, E; Worlitzer, M M A; Bahnassawy, L; Lewejohann, L; Palm, T; Schwamborn, J C

    2013-01-01

    In the adult mammalian brain, neural stem cells in the subventricular zone continuously generate new neurons for the olfactory bulb. Cell fate commitment in these adult neural stem cells is regulated by cell fate-determining proteins. Here, we show that the cell fate-determinant TRIM32 is upregulated during differentiation of adult neural stem cells into olfactory bulb neurons. We further demonstrate that TRIM32 is necessary for the correct induction of neuronal differentiation in these cells. In the absence of TRIM32, neuroblasts differentiate slower and show gene expression profiles that are characteristic of immature cells. Interestingly, TRIM32 deficiency induces more neural progenitor cell proliferation and less cell death. Both effects accumulate in an overproduction of adult-generated olfactory bulb neurons of TRIM32 knockout mice. These results highlight the function of the cell fate-determinant TRIM32 for a balanced activity of the adult neurogenesis process. PMID:24357807

  11. 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

  12. Human-derived neural progenitors functionally replace astrocytes in adult mice

    PubMed Central

    Chen, Hong; Qian, Kun; Chen, Wei; Hu, Baoyang; Blackbourn, Lisle W.; Du, Zhongwei; Ma, Lixiang; Liu, Huisheng; Knobel, Karla M.; Ayala, Melvin; Zhang, Su-Chun

    2015-01-01

    Astrocytes are integral components of the homeostatic neural network as well as active participants in pathogenesis of and recovery from nearly all neurological conditions. Evolutionarily, compared with lower vertebrates and nonhuman primates, humans have an increased astrocyte-to-neuron ratio; however, a lack of effective models has hindered the study of the complex roles of human astrocytes in intact adult animals. Here, we demonstrated that after transplantation into the cervical spinal cords of adult mice with severe combined immunodeficiency (SCID), human pluripotent stem cell–derived (PSC-derived) neural progenitors migrate a long distance and differentiate to astrocytes that nearly replace their mouse counterparts over a 9-month period. The human PSC-derived astrocytes formed networks through their processes, encircled endogenous neurons, and extended end feet that wrapped around blood vessels without altering locomotion behaviors, suggesting structural, and potentially functional, integration into the adult mouse spinal cord. Furthermore, in SCID mice transplanted with neural progenitors derived from induced PSCs from patients with ALS, astrocytes were generated and distributed to a similar degree as that seen in mice transplanted with healthy progenitors; however, these mice exhibited motor deficit, highlighting functional integration of the human-derived astrocytes. Together, these results indicate that this chimeric animal model has potential for further investigating the roles of human astrocytes in disease pathogenesis and repair. PMID:25642771

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

    PubMed

    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

  14. 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

  15. 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.

  16. 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

  17. 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

  18. Fate Analysis of Adult Hippocampal Progenitors in a Murine Model of Fetal Alcohol Spectrum Disorder (FASD)

    PubMed Central

    Kajimoto, Kenta; Allan, Andrea; Cunningham, Lee Anna

    2013-01-01

    Prenatal alcohol exposure can lead to fetal alcohol spectrum disorder (FASD) and associated behavioral impairments that may be linked to disruptions in adult hippocampal neurogenesis. Social and physical enrichment has been proposed as a potential therapeutic approach toward reversing behavioral deficits associated with FASD and is also a potent stimulator of adult hippocampal neurogenesis. In the present study, we utilized a genetic fate mapping approach in nestin-CreERT2/YFP bitransgenic mice to identify the stage-specific impact of prenatal alcohol exposure on the stepwise maturation of adult hippocampal progenitors. Using a limited alcohol access “drinking-in-the-dark” model of FASD, we confirm previous findings that moderate prenatal alcohol exposure has no effect on adult neurogenesis under standard housing conditions, but abolishes the neurogenic response to enriched environment (EE). Furthermore, we demonstrate that this effect is primarily due to failed EE-mediated survival of postmitotic neurons. Finally, we demonstrate that the neurogenic deficit is associated with impaired spatial pattern recognition, as demonstrated by delayed learning of FASD-EE mice in an A–B contextual discrimination task. These results identify a potential maturational stage-specific mechanism(s) underlying impaired neurogenic function in a preclinical model of FASD, and provide a basis for testing regulatory pathways in this model through conditional and inducible manipulation of gene expression in the adult hippocampal progenitor population. PMID:24040071

  19. Fate analysis of adult hippocampal progenitors in a murine model of fetal alcohol spectrum disorder (FASD).

    PubMed

    Kajimoto, Kenta; Allan, Andrea; Cunningham, Lee Anna

    2013-01-01

    Prenatal alcohol exposure can lead to fetal alcohol spectrum disorder (FASD) and associated behavioral impairments that may be linked to disruptions in adult hippocampal neurogenesis. Social and physical enrichment has been proposed as a potential therapeutic approach toward reversing behavioral deficits associated with FASD and is also a potent stimulator of adult hippocampal neurogenesis. In the present study, we utilized a genetic fate mapping approach in nestin-CreER(T2)/YFP bitransgenic mice to identify the stage-specific impact of prenatal alcohol exposure on the stepwise maturation of adult hippocampal progenitors. Using a limited alcohol access "drinking-in-the-dark" model of FASD, we confirm previous findings that moderate prenatal alcohol exposure has no effect on adult neurogenesis under standard housing conditions, but abolishes the neurogenic response to enriched environment (EE). Furthermore, we demonstrate that this effect is primarily due to failed EE-mediated survival of postmitotic neurons. Finally, we demonstrate that the neurogenic deficit is associated with impaired spatial pattern recognition, as demonstrated by delayed learning of FASD-EE mice in an A-B contextual discrimination task. These results identify a potential maturational stage-specific mechanism(s) underlying impaired neurogenic function in a preclinical model of FASD, and provide a basis for testing regulatory pathways in this model through conditional and inducible manipulation of gene expression in the adult hippocampal progenitor population. PMID:24040071

  20. Quantitative analysis of signaling mechanisms controlling adult neural progenitor cell proliferation.

    PubMed

    Schaffer, David V; O'Neill, Analeah; Hochrein, Lisa; McGranahan, Tresa

    2004-01-01

    Tools of systems engineering and signal dynamics were employed to develop a quantitative model of the intracellular signaling systems involved in adult neural stem cell proliferation, based on pathways elucidated in our experimental systems. Neural progenitors isolated from the adult rat hippocampus are dependent on the basic fibroblast growth factor (FGF-2) and extracellular matrix (ECM) proteins. However, the intracellular effects of these stimuli were previously undetermined. We employed chemical inhibitors of known signal transduction molecules to identify important players in the FGF-2/ECM signal cascade, such as the cyclic AMP responsive element binding protein (CREB), protein kinase B/Akt, and several related molecules. Genetic mutants of these proteins were used to confirm their role in adult neural progenitor proliferation. Proliferation was assayed using the incorporation of a thymidine analog to determine cell doubling rate under various stimuli. Such assays have also uncovered novel synergistic signaling between FGF-2 and ECM components. This research is, to our knowledge, the first to elucidate intracellular signaling pathways for adult neural stem cell proliferation. Upon determination of the pertinent intracellular signaling pathways, quantitative immunoblots were employed to examine the dynamics of these systems. These data, as well as enzyme kinetics information from the literature, are being used to parameterize a dynamic mathematical model of progenitor proliferation events induced by FGF-2. This computational model will be used to predict the biochemical and mechanical signaling inputs necessary to achieve a desired proliferative output from the cells, based on specific extracellular stimuli. It is our hope that this essential quantitative understanding will facilitate the use of adult neural stem cells in medical applications. PMID:17271428

  1. 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

  2. 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

  3. Impaired Survival of Neural Progenitor Cells in Dentate Gyrus of Adult Mice Lacking FMRP

    PubMed Central

    Lazarov, Orly; Demars, Michael P.; Zhao, Kai Da Tommy; Ali, Haroon M.; Grauzas, Vanessa; Kney, Adam; Larson, John

    2011-01-01

    Fragile X syndrome (FXS) is the most common form of inherited intellectual disability in humans. Individuals affected with the disorder exhibit a deficiency of the fragile X mental retardation protein (FMRP), due to transcriptional silencing of the Fmr1 gene. It is widely accepted that learning deficits in FXS result from impaired synaptic function and/or plasticity in the brain. Interestingly, recent evidence suggests that conditional knockout of Fmr1 in neural progenitor cells in mice impairs hippocampal neurogenesis, which in turn contributes to learning impairments. To examine the nature of the neurogenic impairments and determine whether they impact the morphology of the dentate gyrus, we assessed the extent of neural progenitor cell proliferation, survival, and differentiation in older adult Fmr1 knockout mice. Here we show that the number of fast- proliferating cells in the subgranule layer of the dentate gyrus, as well as the subsequent survival of these cells, are dramatically reduced in Fmr1 knockout mice. In addition, the number of mature neurons in the granule layer of the dentate gyrus of these mice is significantly smaller than in WT littermate controls, suggesting that impaired proliferation and survival of neural progenitor cells compromises the structure of the dentate gyrus. Impaired adult neurogenesis may underlie, at least in part, the learning deficits that characterize fragile X syndrome. PMID:22128095

  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

    2015-01-01

    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

  5. Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver

    PubMed Central

    Huch, Meritxell; Gehart, Helmuth; van Boxtel, Ruben; Hamer, Karien; Blokzijl, Francis; Verstegen, Monique M.A.; Ellis, Ewa; van Wenum, Martien; Fuchs, Sabine A.; de Ligt, Joep; van de Wetering, Marc; Sasaki, Nobuo; Boers, Susanne J.; Kemperman, Hans; de Jonge, Jeroen; Ijzermans, Jan N.M.; Nieuwenhuis, Edward E.S.; Hoekstra, Ruurdtje; Strom, Stephen; Vries, Robert R.G.; van der Laan, Luc J.W.; Cuppen, Edwin; Clevers, Hans

    2015-01-01

    Summary Despite the enormous replication potential of the human liver, there are currently no culture systems available that sustain hepatocyte replication and/or function in vitro. We have shown previously that single mouse Lgr5+ liver stem cells can be expanded as epithelial organoids in vitro and can be differentiated into functional hepatocytes in vitro and in vivo. We now describe conditions allowing long-term expansion of adult bile duct-derived bipotent progenitor cells from human liver. The expanded cells are highly stable at the chromosome and structural level, while single base changes occur at very low rates. The cells can readily be converted into functional hepatocytes in vitro and upon transplantation in vivo. Organoids from α1-antitrypsin deficiency and Alagille syndrome patients mirror the in vivo pathology. Clonal long-term expansion of primary adult liver stem cells opens up experimental avenues for disease modeling, toxicology studies, regenerative medicine, and gene therapy. PMID:25533785

  6. Osteogenic Potential of Multipotent Adult Progenitor Cells for Calvaria Bone Regeneration

    PubMed Central

    Lee, Dong Joon; Park, Yonsil; Hu, Wei-Shou; Ko, Ching-Chang

    2016-01-01

    Osteogenic cells derived from rat multipotent adult progenitor cells (rMAPCs) were investigated for their potential use in bone regeneration. rMAPCs are adult stem cells derived from bone marrow that have a high proliferation capacity and the differentiation potential to multiple lineages. They may also offer immunomodulatory properties favorable for applications for regenerative medicine. rMAPCs were cultivated as single cells or as 3D aggregates in osteogenic media for up to 38 days, and their differentiation to bone lineage was then assessed by immunostaining of osteocalcin and collagen type I and by mineralization assays. The capability of rMAPCs in facilitating bone regeneration was evaluated in vivo by the direct implantation of multipotent adult progenitor cell (MAPC) aggregates in rat calvarial defects. Bone regeneration was examined radiographically, histologically, and histomorphometrically. Results showed that rMAPCs successfully differentiated into osteogenic lineage by demonstrating mineralized extracellular matrix formation in vitro and induced new bone formation by the effect of rMAPC aggregates in vivo. These outcomes confirm that rMAPCs have a good osteogenic potential and provide insights into rMAPCs as a novel adult stem cell source for bone regeneration. PMID:27239552

  7. 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. PMID:25902481

  8. 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

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

    PubMed

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

    2015-08-15

    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

  10. Translational control plays a prominent role in the hepatocytic differentiation of HepaRG liver progenitor cells

    PubMed Central

    Parent, Romain; Beretta, Laura

    2008-01-01

    Background We investigated the molecular events associated with the differentiation of liver progenitor cells into functional and polarized hepatocytes, using human HepaRG cells that display potent hepatocytic differentiation-inducible properties and share some features with liver progenitor cells. Results Profiling of total and of polysome-bound transcripts isolated from HepaRG cells undergoing hepatocytic differentiation was performed. A group of 3,071 probe sets was reproducibly regulated by at least 2-fold in total or in polysome-bound RNA populations, upon differentiation. The fold changes in the total and the polysome-bound RNA populations for these 3,071 probe sets were poorly correlated (R = 0.38). Moreover, while the majority of the regulated polysome-bound RNA probe sets were up-regulated upon differentiation, the majority of the regulated probe sets selected from the total RNA population was down-regulated. Genes translationally up-regulated were associated with cell cycle inhibition, increased susceptibility to apoptosis and innate immunity. In contrast, genes transcriptionally up-regulated during differentiation corresponded in the majority to liver-enriched transcripts involved in lipid homeostasis and drug metabolism. Finally, several epithelial and hepato-specific transcripts were strongly induced in the total RNA population but were translationally repressed. Conclusion Translational regulation is the main genomic event associated with hepatocytic differentiation of liver progenitor cells in vitro and targets genes critical for moderating hepatocellular growth, cell death and susceptibility to pathogens. Transcriptional regulation targets specifically liver-enriched transcripts vital for establishing normal hepatic energy homeostasis, cell morphology and polarization. The hepatocytic differentiation is also accompanied by a reduction of the transcript content complexity. PMID:18221535

  11. Liver lobe torsion in three adult rabbits.

    PubMed

    Wenger, S; Barrett, E L; Pearson, G R; Sayers, I; Blakey, C; Redrobe, S

    2009-06-01

    This paper describes three cases of liver lobe torsion in rabbits presenting with anorexia, lethargy, jaundice and abdominal pain. This condition was associated with anaemia and elevation of alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase. Abnormal radiological findings included hepatomegaly, gas-filled intestinal loops consistent with gastrointestinal ileus and ascites. Ultrasonographic findings included heterogeneous liver parenchyma, free abdominal fluid and reduced bowel motility. Diagnosis was confirmed by histopathological examination of the liver in all three cases. PMID:19527423

  12. 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

  13. 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

  14. Immunological characteristics of human mesenchymal stem cells and multipotent adult progenitor cells.

    PubMed

    Jacobs, Sandra A; Roobrouck, Valerie D; Verfaillie, Catherine M; Van Gool, Stefaan W

    2013-01-01

    Somatic, also termed adult, stem cells are highly attractive biomedical cell candidates because of their extensive replication potential and functional multilineage differentiation capacity. They can be used for drug and toxicity screenings in preclinical studies, as in vitro model to study differentiation or for regenerative medicine to aid in the repair of tissues or replace tissues that are lost upon disease, injury or ageing. Multipotent adult progenitor cells (MAPCs) and mesenchymal stem cells (MSCs) are two types of adult stem cells derived from bone marrow that are currently being used clinically for tissue regeneration and for their immunomodulatory and trophic effects. This review will give an overview of the phenotypic and functional differences between human MAPCs and MSCs, with a strong emphasis on their immunological characteristics. Finally, we will discuss the clinical studies in which MSCs and MAPCs are already used. PMID:23295415

  15. 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

  16. Characterization of TLX Expression in Neural Stem Cells and Progenitor Cells in Adult Brains

    PubMed Central

    Li, Shengxiu; Sun, Guoqiang; Murai, Kiyohito; Ye, Peng; Shi, Yanhong

    2012-01-01

    TLX has been shown to play an important role in regulating the self-renewal and proliferation of neural stem cells in adult brains. However, the cellular distribution of endogenous TLX protein in adult brains remains to be elucidated. In this study, we used immunostaining with a TLX-specific antibody to show that TLX is expressed in both neural stem cells and transit-amplifying neural progenitor cells in the subventricular zone (SVZ) of adult mouse brains. Then, using a double thymidine analog labeling approach, we showed that almost all of the self-renewing neural stem cells expressed TLX. Interestingly, most of the TLX-positive cells in the SVZ represented the thymidine analog-negative, relatively quiescent neural stem cell population. Using cell type markers and short-term BrdU labeling, we demonstrated that TLX was also expressed in the Mash1+ rapidly dividing type C cells. Furthermore, loss of TLX expression dramatically reduced BrdU label-retaining neural stem cells and the actively dividing neural progenitor cells in the SVZ, but substantially increased GFAP staining and extended GFAP processes. These results suggest that TLX is essential to maintain the self-renewing neural stem cells in the SVZ and that the GFAP+ cells in the SVZ lose neural stem cell property upon loss of TLX expression.Understanding the cellular distribution of TLX and its function in specific cell types may provide insights into the development of therapeutic tools for neurodegenerative diseases by targeting TLX in neural stem/progenitors cells. PMID:22952666

  17. 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

  18. Adult-to-adult living donor liver transplantation for acute liver failure in China

    PubMed Central

    Yuan, Ding; Liu, Fei; Wei, Yong-Gang; Li, Bo; Yan, Lv-Nan; Wen, Tian-Fu; Zhao, Ji-Chun; Zeng, Yong; Chen, Ke-Fei

    2012-01-01

    AIM: To investigate the long-term outcome of recipients and donors of adult-to-adult living-donor liver transplantation (AALDLT) for acute liver failure (ALF). METHODS: Between January 2005 and March 2010, 170 living donor liver transplantations were performed at West China Hospital of Sichuan University. All living liver donor was voluntary and provided informed consent. Twenty ALF patients underwent AALDLT for rapid deterioration of liver function. ALF was defined based on the criteria of the American Association for the Study of Liver Diseases, including evidence of coagulation abnormality [international normalized ratio (INR) ≥ 1.5] and degree of mental alteration without pre-existing cirrhosis and with an illness of < 26 wk duration. We reviewed the clinical indications, operative procedure and prognosis of AALDTL performed on patients with ALF and corresponding living donors. The potential factors of recipient with ALF and corresponding donor outcome were respectively investigated using multivariate analysis. Survival rates after operation were analyzed using the Kaplan-Meier method. Receiver operator characteristic (ROC) curve analysis was undertaken to identify the threshold of potential risk factors. RESULTS: The causes of ALF were hepatitis B (n = 18), drug-induced (n = 1) and indeterminate (n = 1). The score of the model for end-stage liver disease was 37.1 ± 8.6, and the waiting duration of recipients was 5 ± 4 d. The graft types included right lobe (n = 17) and dual graft (n = 3). The mean graft weight was 623.3 ± 111.3 g, which corresponded to graft-to-recipient weight ratio of 0.95% ± 0.14%. The segment Vor VIII hepatic vein was reconstructed in 11 right-lobe grafts. The 1-year and 3-year recipient’s survival and graft survival rates were 65% (13 of 20). Postoperative results of total bilirubin, INR and creatinine showed obvious improvements in the survived patients. However, the creatinine level of the deaths was increased postoperatively

  19. 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

  20. Legacy Effect of Foxo1 in Pancreatic Endocrine Progenitors on Adult β-Cell Mass and Function.

    PubMed

    Talchai, Shivatra Chutima; Accili, Domenico

    2015-08-01

    β-Cell dysfunction in diabetes results from abnormalities of insulin production, secretion, and cell number. These abnormalities may partly arise from altered developmental programming of β-cells. Foxo1 is important to maintain adult β-cells, but little is known about its role in pancreatic progenitor cells as determinants of future β-cell function. We addressed this question by generating an allelic series of somatic Foxo1 knockouts at different stages of pancreatic development in mice. Surprisingly, ablation of Foxo1 in pancreatic progenitors resulted in delayed appearance of Neurogenin3(+) progenitors and their persistence into adulthood as a self-replicating pool, causing a fourfold increase of β-cell mass. Similarly, Foxo1 ablation in endocrine progenitors increased their numbers, extended their survival, and expanded β-cell mass. In contrast, ablation of Foxo1 in terminally differentiated β-cells did not increase β-cell mass nor did it affect Neurogenin3 expression. Despite the increased β-cell mass, islets from mice lacking Foxo1 in pancreatic or endocrine progenitors responded poorly to glucose, resulting in glucose intolerance. We conclude that Foxo1 integrates cues that determine developmental timing, pool size, and functional features of endocrine progenitor cells, resulting in a legacy effect on adult β-cell mass and function. Our results illustrate how developmental programming predisposes to β-cell dysfunction in adults and raise questions on the desirability of increasing β-cell mass for therapeutic purposes in type 2 diabetes. PMID:25784544

  1. Genetic variants in adult liver diseases.

    PubMed

    Dröge, C; Häussinger, D; Keitel, V

    2015-12-01

    In the last decades, understanding of genetic variants contributing to liver disease development has considerably improved through novel genotyping techniques. Genetic variants of single genes are known to be decisive for the development of monogenetic liver diseases of varying severity. Identification of genetic variants is an important part of the diagnostic process, e. g. the majority of patients with high iron [Fe] (HFE)-associated hemochromatosis carry the homozygous mutation p.C282Y. Detection of mutations in genes encoding hepatobiliary transport proteins like familial intrahepatic cholestasis 1 (FIC1), bile salt export pump (BSEP), or multidrug resistance protein 3 (MDR3) is the basis to differentiate various forms of intrahepatic cholestasis. Moreover, genetic variants in a variety of genes are known to act as disease modifiers and represent risk factors for disease progression and the development of cirrhosis or even hepatocellular carcinoma. Success of drug treatment or appearance of severe side effects can also be influenced by specific genetic variants. All these aspects underscore the increasing importance of genetic variants, which in the future may help to identify patients at risk for disease progression or help to guide treatment decisions. In the present overview, specific frequent genetic variants are summarized that play roles in monogenetic liver diseases, forms of intrahepatic cholestasis, gallstone development, fatty liver disease, drug-induced liver injury, and liver disease progression as well as hepatocellular carcinoma development. PMID:26666282

  2. Outcomes of liver transplantation with liver grafts from pediatric donors used in adult recipients.

    PubMed

    Croome, Kristopher P; Lee, David D; Burns, Justin M; Saucedo-Crespo, Hector; Perry, Dana K; Nguyen, Justin H; Taner, C Burcin

    2016-08-01

    Although there is an agreement that liver grafts from pediatric donors (PDs) should ideally be used for pediatric patients, there remain situations when these grafts are turned down for pediatric recipients and are then offered to adult recipients. The present study aimed to investigate the outcomes of using these grafts for liver transplantation (LT) in adult patients. Data from all patients undergoing LT between 2002 and 2014 were obtained from the United Network for Organ Sharing Standard Analysis and Research file. Adult recipients undergoing LT were divided into 2 groups: those receiving a pediatric liver graft (pediatric-to-adult group) and those receiving a liver graft from adult donors (adult-to-adult group). A separate subgroup analysis comparing the PDs used for adult recipients and those used for pediatric recipients was also performed. Patient and graft survival were not significantly different between pediatric-to-adult and adult-to-adult groups (P = 0.08 and P = 0.21, respectively). Hepatic artery thrombosis as the cause for graft loss was higher in the pediatric-to-adult group (3.6%) than the adult-to-adult group (1.9%; P < 0.001). A subanalysis looking at the pediatric-to-adult group found that patients with a predicted graft-to-recipient weight ratio (GRWR) < 0.8 had a higher 90-day graft loss rate than those with a GRWR ≥ 0.8 (39% versus 9%; P < 0.001). PDs used for adult recipients had a higher proportion of donors with elevated aspartate aminotransferase/alanine aminotransferase (20% vs. 12%; P < 0.001), elevated creatinine (11% vs. 4%; P < 0.001), donation after cardiac death donors (12% vs. 0.9%; P < 0.001), and were hepatitis B virus core positive (1% vs. 0.3%; P = 0.002) than PDs used for pediatric recipients. In conclusion, acceptable patient and graft survival can be achieved with the use of pediatric liver grafts in adult recipients, when these grafts have been determined to be inappropriate for

  3. Fragile X Mental Retardation Protein Regulates Proliferation and Differentiation of Adult Neural Stem/Progenitor Cells

    PubMed Central

    Smrt, Richard D.; Johnson, Eric B.; Li, Xuekun; Pfeiffer, Rebecca L.; Szulwach, Keith E.; Duan, Ranhui; Barkho, Basam Z.; Li, Wendi; Liu, Changmei; Jin, Peng; Zhao, Xinyu

    2010-01-01

    Fragile X syndrome (FXS), the most common form of inherited mental retardation, is caused by the loss of functional fragile X mental retardation protein (FMRP). FMRP is an RNA–binding protein that can regulate the translation of specific mRNAs. Adult neurogenesis, a process considered important for neuroplasticity and memory, is regulated at multiple molecular levels. In this study, we investigated whether Fmrp deficiency affects adult neurogenesis. We show that in a mouse model of fragile X syndrome, adult neurogenesis is indeed altered. The loss of Fmrp increases the proliferation and alters the fate specification of adult neural progenitor/stem cells (aNPCs). We demonstrate that Fmrp regulates the protein expression of several components critical for aNPC function, including CDK4 and GSK3β. Dysregulation of GSK3β led to reduced Wnt signaling pathway activity, which altered the expression of neurogenin1 and the fate specification of aNPCs. These data unveil a novel regulatory role for Fmrp and translational regulation in adult neurogenesis. PMID:20386739

  4. Tuberculosis as an Etiological Factor in Liver Abscess in Adults.

    PubMed

    Dey, Jaideep; Gautam, Hitender; Venugopal, Shwetha; Porwal, Chhavi; Mirdha, Bijay Ranjan; Gupta, Naresh; Singh, Urvashi B

    2016-01-01

    Background. Tuberculosis of the liver without active pulmonary or miliary tuberculosis is considered as an uncommon diagnosis. The aim of the present study was to determine the etiological role of tuberculosis in adult patients presenting with features of liver abscess. Methods. A total of 40 patients with liver abscess were included in the study. The liver abscess aspirate was subjected to microscopy, culture, and polymerase chain reaction to determine the role of tuberculosis as an etiological factor in liver abscess. Results. Of the 40 patients enrolled, 25% (10/40) were diagnosed with having tubercular liver abscess. In a total of 40 specimens, 2.5% (1/40) were positive for acid fast bacilli by Ziehl-Neelsen method, while 10% (4/40) were positive for M. tuberculosis by culture using BACTEC 460 and the yield increased to 25% (10/40) by polymerase chain reaction for M. tuberculosis. Conclusion. 25% of the patients presenting with liver abscess had tubercular etiology without features of active pulmonary or miliary tuberculosis. Liver can act as the primary site of involvement in the absence of activity elsewhere in the body. Tuberculosis should be considered as an important differential diagnosis of liver abscess irrespective of evidence of active tuberculosis elsewhere in the body. PMID:27595021

  5. Tuberculosis as an Etiological Factor in Liver Abscess in Adults

    PubMed Central

    Dey, Jaideep; Venugopal, Shwetha; Mirdha, Bijay Ranjan

    2016-01-01

    Background. Tuberculosis of the liver without active pulmonary or miliary tuberculosis is considered as an uncommon diagnosis. The aim of the present study was to determine the etiological role of tuberculosis in adult patients presenting with features of liver abscess. Methods. A total of 40 patients with liver abscess were included in the study. The liver abscess aspirate was subjected to microscopy, culture, and polymerase chain reaction to determine the role of tuberculosis as an etiological factor in liver abscess. Results. Of the 40 patients enrolled, 25% (10/40) were diagnosed with having tubercular liver abscess. In a total of 40 specimens, 2.5% (1/40) were positive for acid fast bacilli by Ziehl-Neelsen method, while 10% (4/40) were positive for M. tuberculosis by culture using BACTEC 460 and the yield increased to 25% (10/40) by polymerase chain reaction for M. tuberculosis. Conclusion. 25% of the patients presenting with liver abscess had tubercular etiology without features of active pulmonary or miliary tuberculosis. Liver can act as the primary site of involvement in the absence of activity elsewhere in the body. Tuberculosis should be considered as an important differential diagnosis of liver abscess irrespective of evidence of active tuberculosis elsewhere in the body. PMID:27595021

  6. 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

  7. Function of GATA Factors in the Adult Mouse Liver

    PubMed Central

    Zheng, Rena; Rebolledo-Jaramillo, Boris; Zong, Yiwei; Wang, Liqing; Russo, Pierre; Hancock, Wayne; Stanger, Ben Z.; Hardison, Ross C.; Blobel, Gerd A.

    2013-01-01

    GATA transcription factors and their Friend of Gata (FOG) cofactors control the development of diverse tissues. GATA4 and GATA6 are essential for the expansion of the embryonic liver bud, but their expression patterns and functions in the adult liver are unclear. We characterized the expression of GATA and FOG factors in whole mouse liver and purified hepatocytes. GATA4, GATA6, and FOG1 are the most prominently expressed family members in whole liver and hepatocytes. GATA4 chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq) identified 4409 occupied sites, associated with genes enriched in ontologies related to liver function, including lipid and glucose metabolism. However, hepatocyte-specific excision of Gata4 had little impact on gross liver architecture and function, even under conditions of regenerative stress, and, despite the large number of GATA4 occupied genes, resulted in relatively few changes in gene expression. To address possible redundancy between GATA4 and GATA6, both factors were conditionally excised. Surprisingly, combined Gata4,6 loss did not exacerbate the phenotype resulting from Gata4 loss alone. This points to the presence of an unusually robust transcriptional network in adult hepatocytes that ensures the maintenance of liver function. PMID:24367609

  8. 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

  9. 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

  10. Fetal and adult liver stem cells for liver regeneration and tissue engineering.

    PubMed

    Fiegel, H C; Lange, Claudia; Kneser, U; Lambrecht, W; Zander, A R; Rogiers, X; Kluth, D

    2006-01-01

    For the development of innovative cell-based liver directed therapies, e.g. liver tissue engineering, the use of stem cells might be very attractive to overcome the limitation of donor liver tissue. Liver specific differentiation of embryonic, fetal or adult stem cells is currently under investigation. Different types of fetal liver (stem) cells during development were identified, and their advantageous growth potential and bipotential differentiation capacity were shown. However, ethical and legal issues have to be addressed before using fetal cells. Use of adult stem cells is clinically established, e.g. transplantation of hematopoietic stem cells. Other bone marrow derived liver stem cells might be mesenchymal stem cells (MSC). However, the transdifferentiation potential is still in question due to the observation of cellular fusion in several in vivo experiments. In vitro experiments revealed a crucial role of the environment (e.g. growth factors and extracellular matrix) for specific differentiation of stem cells. Co-cultured liver cells also seemed to be important for hepatic gene expression of MSC. For successful liver cell transplantation, a novel approach of tissue engineering by orthotopic transplantation of gel-immobilized cells could be promising, providing optimal environment for the injected cells. Moreover, an orthotopic tissue engineering approach using bipotential stem cells could lead to a repopulation of the recipients liver with healthy liver and biliary cells, thus providing both hepatic functions and biliary excretion. Future studies have to investigate, which stem cell and environmental conditions would be most suitable for the use of stem cells for liver regeneration or tissue engineering approaches. PMID:16989722

  11. Hippocampal adult neurogenesis is maintained by Neil3-dependent repair of oxidative DNA lesions in neural progenitor cells.

    PubMed

    Regnell, Christine Elisabeth; Hildrestrand, Gunn Annette; Sejersted, Yngve; Medin, Tirill; Moldestad, Olve; Rolseth, Veslemøy; Krokeide, Silje Zandstra; Suganthan, Rajikala; Luna, Luisa; Bjørås, Magnar; Bergersen, Linda H

    2012-09-27

    Accumulation of oxidative DNA damage has been proposed as a potential cause of age-related cognitive decline. The major pathway for removal of oxidative DNA base lesions is base excision repair, which is initiated by DNA glycosylases. In mice, Neil3 is the main DNA glycosylase for repair of hydantoin lesions in single-stranded DNA of neural stem/progenitor cells, promoting neurogenesis. Adult neurogenesis is crucial for maintenance of hippocampus-dependent functions involved in behavior. Herein, behavioral studies reveal learning and memory deficits and reduced anxiety-like behavior in Neil3(-/-) mice. Neural stem/progenitor cells from aged Neil3(-/-) mice show impaired proliferative capacity and reduced DNA repair activity. Furthermore, hippocampal neurons in Neil3(-/-) mice display synaptic irregularities. It appears that Neil3-dependent repair of oxidative DNA damage in neural stem/progenitor cells is required for maintenance of adult neurogenesis to counteract the age-associated deterioration of cognitive performance. PMID:22959434

  12. 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

  13. 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

  14. Assessment of adult patients with chronic liver failure for liver transplantation in 2015: who and when?

    PubMed

    McCaughan, G W; Crawford, M; Sandroussi, C; Koorey, D J; Bowen, D G; Shackel, N A; Strasser, S I

    2016-04-01

    In 2015, there are a few absolute contraindications to liver transplantation. In adult patients, survival post-liver transplant is excellent, with 1-year survival rate >90% and 5-year survival rates >80% and predicted median allograft survival beyond 20 years. Patients with a Child-Turcotte Pugh score ≥9 or a model for end-stage liver disease (MELD) score >15 should be referred for liver transplantation, with patients who have a MELD score >17 showing a 1-year survival benefit with liver transplantation. A careful selection of hepatocellular cancer patients results in excellent outcomes, while consideration of extra-hepatic disease (reversible vs irreversible) and social support structures are crucial to patient assessment. Alcoholic liver disease remains a challenge, and the potential to cure hepatitis C virus infection together with the emerging issue of non-alcoholic fatty liver disease-associated chronic liver failure will change the landscape of the who in the years ahead. The when will continue to be determined largely by the severity of liver disease based on the MELD score for the foreseeable future. PMID:27062203

  15. Expression of tissue polypeptide antigen (TPA) in fetal and adult liver: changes in liver disease.

    PubMed Central

    Burt, A D; Stewart, J A; Aitchison, M; MacSween, R N

    1987-01-01

    The distribution of tissue polypeptide antigen (40 kD molecular weight) in normal adult and fetal liver, and in liver disease was investigated and compared with the distribution of low and high molecular weight cytokeratins. In normal liver tissue polypeptide antigen was found only in bile duct epithelium; this distribution is similar to that of high molecular weight cytokeratin, but differs from that of low molecular weight cytokeratins. In liver disease it was found in areas of ductular transformation; in Mallory's bodies; and in alcoholic liver disease and primary biliary cirrhosis in some hepatocytes that did not contain Mallory's bodies. Images Fig 1 Fig 2 Fig 3 Fig 4 Fig 5 Fig 6 PMID:2442199

  16. NTPDase2 and Purinergic Signaling Control Progenitor Cell Proliferation in Neurogenic Niches of the Adult Mouse Brain

    PubMed Central

    Gampe, Kristine; Stefani, Jennifer; Hammer, Klaus; Brendel, Peter; Pötzsch, Alexandra; Enikolopov, Grigori; Enjyoji, Keiichi; Acker-Palmer, Amparo; Robson, Simon C.; Zimmermann, Herbert

    2014-01-01

    Nerve cells are continuously generated from stem cells in the adult mammalian subventricular zone (SVZ) and hippocampal dentate gyrus. We have previously noted that stem/progenitor cells in the SVZ and the subgranular layer (SGL) of the dentate gyrus express high levels of plasma membrane-bound nucleoside triphosphate diphosphohydrolase 2 (NTPDase2), an ectoenzyme that hydrolyzes extracellular nucleoside di- and triphosphates. We inferred that deletion of NTPDase2 would increase local extracellular nucleoside triphosphate concentrations perturbing purinergic signaling and boosting progenitor cell proliferation and neurogenesis. Using newly generated mice globally null for Entpd2, we demonstrate that NTPDase2 is the major ectonucleotidase in these progenitor cell rich areas. Using BrdU-labeling protocols, we have measured stem cell proliferation and determined long term survival of cell progeny under basal conditions. Brains of Entpd2 null mice revealed increased progenitor cell proliferation in both the SVZ and the SGL. However, this occurred without noteworthy alterations in long-term progeny survival. The hippocampal stem cell pool and the pool of the intermediate progenitor type-2 cells clearly expanded. However, substantive proportions of these proliferating cells were lost during expansion at around type-3 stage. Cell loss was paralleled by decreases in CREB phosphorylation in the doublecortin-positive progenitor cell population and by an increase in labeling for activated caspase-3 levels. We propose that NTPDase2 has functionality in scavenging mitogenic extracellular nucleoside triphosphates in neurogenic niches of the adult brain, thereby acting as a homeostatic regulator of nucleotide-mediated neural progenitor cell proliferation and expansion. PMID:25205248

  17. Smad3 is required for the survival of proliferative intermediate progenitor cells in the dentate gyrus of adult mice

    PubMed Central

    2013-01-01

    Background New neurons are continuously being generated in the adult hippocampus, a phenomenon that is regulated by external stimuli, such as learning, memory, exercise, environment or stress. However, the molecular mechanisms underlying neuron production and how they are integrated into existing circuits under such physiological conditions remain unclear. Indeed, the intracellular modulators that transduce the extracellular signals are not yet fully understood. Results We show that Smad3, an intracellular molecule involved in the transforming growth factor (TGF)-β signaling cascade, is strongly expressed by granule cells in the dentate gyrus (DG) of adult mice, although the loss of Smad3 in null mutant mice does not affect their survival. Smad3 is also expressed by adult progenitor cells in the subgranular zone (SGZ) and more specifically, it is first expressed by Type 2 cells (intermediate progenitor cells). Its expression persists through the distinct cell stages towards that of the mature neuron. Interestingly, proliferative intermediate progenitor cells die in Smad3 deficiency, which is associated with a large decrease in the production of newborn neurons in Smad3 deficient mice. Smad3 signaling appears to influence adult neurogenesis fulfilling distinct roles in the rostral and mid-caudal regions of the DG. In rostral areas, Smad3 deficiency increases proliferation and promotes the cell cycle exit of undifferentiated progenitor cells. By contrast, Smad3 deficiency impairs the survival of newborn neurons in the mid-caudal region of the DG at early proliferative stages, activating apoptosis of intermediate progenitor cells. Furthermore, long-term potentiation (LTP) after high frequency stimulation (HFS) to the medial perforant path (MPP) was abolished in the DG of Smad3-deficient mice. Conclusions These data show that endogenous Smad3 signaling is central to neurogenesis and LTP induction in the adult DG, these being two forms of hippocampal brain plasticity

  18. Nuclear β-Catenin Induces an Early Liver Progenitor Phenotype in Hepatocellular Carcinoma and Promotes Tumor Recurrence

    PubMed Central

    Zulehner, Gudrun; Mikula, Mario; Schneller, Doris; van Zijl, Franziska; Huber, Heidemarie; Sieghart, Wolfgang; Grasl-Kraupp, Bettina; Waldhör, Thomas; Peck-Radosavljevic, Markus; Beug, Hartmut; Mikulits, Wolfgang

    2010-01-01

    Transforming growth factor-β cooperates with oncogenic Ras to activate nuclear β-catenin during the epithelial to mesenchymal transition of hepatocytes, a process relevant in the progression of hepatocellular carcinoma (HCC). In this study we investigated the role of β-catenin in the differentiation of murine, oncogene-targeted hepatocytes and in 133 human HCC patients scheduled for orthotopic liver transplantation. Transforming growth factor-β caused dissociation of plasma membrane E-cadherin/β-catenin complexes and accumulation of nuclear β-catenin in Ras-transformed, but otherwise normal hepatocytes in p19ARF−/− mice. Both processes were inhibited by Smad7-mediated disruption of transforming growth factor-β signaling. Overexpression of constitutively active β-catenin resulted in high levels of CK19 and M2-PK, whereas ablation of β-catenin by axin overexpression caused strong expression of CK8 and CK18. Therefore, nuclear β-catenin resulted in dedifferentiation of neoplastic hepatocytes to immature progenitor cells, whereas loss of nuclear β-catenin led to a differentiated HCC phenotype. Poorly differentiated human HCC showed cytoplasmic redistribution or even loss of E-cadherin, suggesting epithelial to mesenchymal transition. Analysis of 133 HCC patient samples revealed that 58.6% of human HCC exhibited strong nuclear β-catenin accumulation, which correlated with clinical features such as vascular invasion and recurrence of disease after orthotopic liver transplantation. These data suggest that activation of β-catenin signaling causes dedifferentiation to malignant, immature hepatocyte progenitors and facilitates recurrence of human HCC after orthotopic liver transplantation. PMID:20008139

  19. 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

  20. 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

  1. The frequency of multipotent CD133(+)CD45RA(-)CD34(+) hematopoietic stem cells is not increased in fetal liver compared with adult stem cell sources.

    PubMed

    Radtke, Stefan; Haworth, Kevin G; Kiem, Hans-Peter

    2016-06-01

    The cell surface marker CD133 has been used to describe a revised model of adult human hematopoiesis, with hematopoietic stem cells and multipotent progenitors (HSCs/MPPs: CD133(+)CD45RA(-)CD34(+)) giving rise to lymphomyeloid-primed progenitors (LMPPs: CD133(+)CD45RA(+)CD34(+)) and erythromyeloid progenitors (EMPs: CD133(low)CD45RA(-)CD34(+)). Because adult and fetal hematopoietic stem and progenitor cells (HSPCs) differ in their gene expression profile, differentiation capabilities, and cell surface marker expression, we were interested in whether the reported segregation of lineage potentials in adult human hematopoiesis would also apply to human fetal liver. CD133 expression was easily detected in human fetal liver cells, and the defined hematopoietic subpopulations were similar to those found for adult HSPCs. Fetal HSPCs were enriched for EMPs and HSCs/MPPs, which were primed toward erythromyeloid differentiation. However, the frequency of multipotent CD133(+)CD45RA(-)CD34(+) HSPCs was much lower than previously reported and comparable to that of umbilical cord blood. We noted that engraftment in NSG (NOD scid gamma [NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ]) mice was driven mostly by LMPPs, confirming recent findings that repopulation in mice is not a unique feature of multipotent HSCs/MPPs. Thus, our data challenge the general assumption that human fetal liver contains a greater percentage of multipotent HSCs/MPPs than any adult HSC source, and the mouse model may have to be re-evaluated with respect to the type of readout it provides. PMID:27016273

  2. Embryonal Sarcoma of the Liver in an Adult Patient

    PubMed Central

    Lightfoot, Nicole; Nikfarjam, Mehrdad

    2012-01-01

    Undifferentiated embryonal sarcomas (UESs) are uncommon tumours that are seen predominantly in late childhood. Cases in adults are rare and generally present once a large mass develops and may be mistaken for other tumours. A case of an UES of the liver with an isolated peritoneal metastasis is described. The patient presented with a palpable mass with imaging findings suggestive of a cystic tumour. She had complete surgical resection of the liver mass and isolated peritoneal metastasis. She was tumour-free on imaging at 6 months without adjuvant chemotherapy. An UES should be considered in the differential of large cystic hepatic lesions, with aggressive surgical resection considered when possible. PMID:22690347

  3. Interleukin-22 Promotes Proliferation of Liver Stem/Progenitor Cells in Mice and Patients with Chronic HBV Infection

    PubMed Central

    Feng, Dechun; Kong, Xiaoni; Weng, Honglei; Park, Ogyi; Wang, Hua; Dooley, Steven; Gershwin, M. Eric; Gao, Bin

    2012-01-01

    Background & Aims Proliferation of liver stem/progenitor cells (LPCs), which can differentiate into hepatocytes or biliary epithelial cells, is often observed in chronically inflamed regions of liver in patients. We investigated how inflammation might promote proliferation of LPCs. Methods We examined the role of interleukin (IL)-22, a survival factor for hepatocytes, on proliferation of LPCs in patients with chronic hepatitis B virus (HBV) infection and in mice. Proliferation of LPCs in mice was induced by feeding a diet that contained 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Results Hepatic expression of IL-22 was increased in patients with HBV and correlated with the grade of inflammation and proliferation of LPCs. Mice on the DDC diet that overexpressed an IL-22 transgene specifically in liver (IL-22TG), or that were infected with an IL-22–expressing adenovirus, had increased proliferation of LPCs. Signal transducer and activator of transcription (STAT) 3, a component of the IL-22 signaling pathway, was activated in LPCs isolated from DDC-fed IL-22TG mice. Deletion of STAT3 from livers of IL-22TG mice reduced proliferation of LPCs. Moreover, the receptors IL-22R1 and IL-10R2 were detected on EpCAM+CD45– LPCs isolated from DDC-fed wild-type mice. Culture of these cells with IL-22 activated STAT3 and led to cell proliferation, but IL-22 had no effect on proliferation of STAT3-deficient EpCAM+CD45– LPCs. IL-22 also activated STAT3 and promoted proliferation of cultured BMOL cells (a mouse LPC line). Conclusion In livers of mice and patients with chronic HBV infection, inflammatory cells produce IL-22, which promotes proliferation of LPCs via STAT3. These findings link inflammation with proliferation of LPCs in patients with HBV infection. PMID:22484119

  4. Development and verification of a hydrostatic pressure chamber for determining the efffect of pressure on liver progenitor cells.

    PubMed

    McMullen, Sarah; Maggio, Emily; Millard, Nathan; Dennis, Alyssa; Landrum, Barry; Alexander, Jayson; Weeks, Michael; Sparks, Jessica L

    2014-01-01

    Hepatic progenitor cells (HPCs) have regenerative properties that could aid the development of treatments for severe liver disease. To study how pressure influences HPC fate, a hydrostatic pressure-controlled cell culture chamber was developed. The design incorporates custom LabView scripting for enhanced pressure regulation and data acquisition. Pressure can be controlled within ±0.2mmHg. Continuous airflow permits gas exchange, and CO2 is maintained at 5%±0.2%. Applied pressures range from 5 to 20 mmHg, reflecting interstitial pressure conditions in healthy and diseased livers, respectively. Bipotential Murine Oval Liver (BMOL) cells, an HPC-like cell line, were cultured in the chamber to test for maintenance of cell viability, adequate CO2 regulation, and maintenance of adequate media volume over 24 hours. Cultured cells were exposed to 5 or 19 mmHg. After 24 hours, media pH was measured, viable cells were counted (Trypan Blue, n=3), and plates were weighed to assess fluid loss. The number of live cells cultured under pressure vs. control conditions was not statistically different (p>.05). The pH remained constant at 7.0 for all conditions, suggesting adequate gas exchange. Evaporation of media was minimal at 3.97%. Results indicate that the pressure chamber provides appropriate environmental conditions for future studies on HPC pressure sensitivity. PMID:25405406

  5. 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

  6. Dissection of the Human Multipotent Adult Progenitor Cell Secretome by Proteomic Analysis

    PubMed Central

    van't Hof, Wouter; Newell, Laura F.; Reddy, Ashok; Wilmarth, Phillip A.; David, Larry L.; Raber, Amy; Bogaerts, Annelies; Pinxteren, Jef; Deans, Robert J.; Maziarz, Richard T.

    2013-01-01

    Multipotent adult progenitor cells (MAPCs) are adult adherent stromal stem cells currently being assessed in acute graft versus host disease clinical trials with demonstrated immunomodulatory capabilities and the potential to ameliorate detrimental autoimmune and inflammation-related processes. Our previous studies documented that MAPCs secrete factors that play a role in regulating T-cell activity. Here we expand our studies using a proteomics approach to characterize and quantify MAPC secretome components secreted over 72 hours in vitro under steady-state conditions and in the presence of the inflammatory triggers interferon-γ and lipopolysaccharide, or a tolerogenic CD74 ligand, RTL1000. MAPCs differentially responded to each of the tested stimuli, secreting molecules that regulate the biological activity of the extracellular matrix (ECM), including proteins that make up the ECM itself, proteins that regulate its construction/deconstruction, and proteins that serve to attach and detach growth factors from ECM components for redistribution upon appropriate stimulation. MAPCs secreted a wide array of proteases, some detectable in their zymogen forms. MAPCs also secreted protease inhibitors that would regulate protease activity. MAPCs secreted chemokines and cytokines that could provide molecular guidance cues to various cell types, including neutrophils, macrophages, and T cells. In addition, MAPCs secreted factors involved in maintenance of a homeostatic environment, regulating such diverse programs as innate immunity, angiogenesis/angiostasis, targeted delivery of growth factors, and the matrix-metalloprotease cascade. PMID:23981727

  7. Comparative Analysis of the Hematopoietic Progenitor Cells from Placenta, Cord Blood, and Fetal Liver, Based on Their Immunophenotype

    PubMed Central

    Kuchma, Maria D.; Kyryk, Vitaliy M.; Svitina, Hanna M.; Shablii, Yulia M.; Lukash, Lubov L.; Lobyntseva, Galina S.; Shablii, Volodymyr A.

    2015-01-01

    We have investigated the characteristics of human hematopoietic progenitor cells (HPCs) with the CD34+CD45lowSSClow phenotype from full-term placental tissue (FTPT) as compared to cord blood (CB) and fetal liver (FL) cells. We demonstrated the presence of cell subpopulations at various stages of the differentiation with such immunophenotypes as CD34+/lowCD45low/−, CD34++CD45low/−, CD34+++CD45low/−, CD34+/lowCD45hi, and CD34++CD45hi in both first trimester placental tissue (FiTPT) and FTPT which implies their higher phenotypic heterogeneity compared to CB. HPCs of the FTPT origin expressed the CD90 antigen at a higher level compared to its expression by the CB HPCs and the CD133 antigen expression being at the same level in both cases. The HPCs compartment of FTPT versus CB contained higher number of myeloid and erythroid committed cells but lower number of myeloid and lymphoid ones compared to FL HPCs. HPCs of the FTPT and CB origin possess similar potentials for the multilineage differentiation in vitro and similar ratios of myeloid and erythroid progenitors among the committed cells. This observation suggests that the active hematopoiesis occurs in the FTPT. We obtained viable HPCs from cryopreserved placental tissue fragments allowing us to develop procedures for banking and testing of placenta-derived HPCs for clinical use. PMID:26347038

  8. Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells.

    PubMed

    Zalzman, Michal; Gupta, Sanjeev; Giri, Ranjit K; Berkovich, Irina; Sappal, Baljit S; Karnieli, Ohad; Zern, Mark A; Fleischer, Norman; Efrat, Shimon

    2003-06-10

    Beta-cell replacement is considered to be the most promising approach for treatment of type 1 diabetes. Its application on a large scale is hindered by a shortage of cells for transplantation. Activation of insulin expression, storage, and regulated secretion in stem/progenitor cells offers novel ways to overcome this shortage. We explored whether fetal human progenitor liver cells (FH) could be induced to differentiate into insulin-producing cells after expression of the pancreatic duodenal homeobox 1 (Pdx1) gene, which is a key regulator of pancreatic development and insulin expression in beta cells. FH cells possess a considerable replication capacity, and this was further extended by introduction of the gene for the catalytic subunit of human telomerase. Immortalized FH cells expressing Pdx1 activated multiple beta-cell genes, produced and stored considerable amounts of insulin, and released insulin in a regulated manner in response to glucose. When transplanted into hyperglycemic immunodeficient mice, the cells restored and maintained euglycemia for prolonged periods. Quantitation of human C-peptide in the mouse serum confirmed that the glycemia was normalized by the transplanted human cells. This approach offers the potential of a novel source of cells for transplantation into patients with type 1 diabetes. PMID:12756298

  9. Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells

    NASA Astrophysics Data System (ADS)

    Zalzman, Michal; Gupta, Sanjeev; Giri, Ranjit K.; Berkovich, Irina; Sappal, Baljit S.; Karnieli, Ohad; Zern, Mark A.; Fleischer, Norman; Efrat, Shimon

    2003-06-01

    Beta-cell replacement is considered to be the most promising approach for treatment of type 1 diabetes. Its application on a large scale is hindered by a shortage of cells for transplantation. Activation of insulin expression, storage, and regulated secretion in stem/progenitor cells offers novel ways to overcome this shortage. We explored whether fetal human progenitor liver cells (FH) could be induced to differentiate into insulin-producing cells after expression of the pancreatic duodenal homeobox 1 (Pdx1) gene, which is a key regulator of pancreatic development and insulin expression in beta cells. FH cells possess a considerable replication capacity, and this was further extended by introduction of the gene for the catalytic subunit of human telomerase. Immortalized FH cells expressing Pdx1 activated multiple beta-cell genes, produced and stored considerable amounts of insulin, and released insulin in a regulated manner in response to glucose. When transplanted into hyperglycemic immunodeficient mice, the cells restored and maintained euglycemia for prolonged periods. Quantitation of human C-peptide in the mouse serum confirmed that the glycemia was normalized by the transplanted human cells. This approach offers the potential of a novel source of cells for transplantation into patients with type 1 diabetes.

  10. Hepatic haemangioendothelioma in adults: excellent outcome following liver transplantation.

    PubMed

    Lerut, Jan P; Orlando, Giuseppe; Sempoux, Christine; Ciccarelli, Olga; Van Beers, Bernard E; Danse, Etienne; Horsmans, Yves; Rahier, Jacques; Roggen, Francine

    2004-05-01

    Hepatic epithelioid haemangioendotheliomas (HEHEs) are rare, low-grade vascular tumours. Five adults with HEHEs and one adult with a vascular tumour showing combined features of haemangioma and haemangioendothelioma underwent liver transplantation. Two HEHE patients had extrahepatic metastases at the time of transplantation. Median survival time following diagnosis was 10.7 years (range 40 months to 195 months). One patient needed resection of a HEHE in the breast 13 years post-transplantation. All six patients are surviving free from disease 22 to 166 months after transplantation (median 77 months). One HEHE-patient who had been treated for 8 years for vertebral and cerebral localisations is free of disease without immunosuppression 56 months after transplantation. We can conclude that liver transplantation is a valuable treatment for hepatic haemangioendothelioma, even in cases of extrahepatic localisation of the disease. PMID:15114438

  11. 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

  12. 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. PMID:26679864

  13. Multiple Functions of MSCA-1/TNAP in Adult Mesenchymal Progenitor/Stromal Cells

    PubMed Central

    Estève, David; Galitzky, Jean; Bouloumié, Anne; Fonta, Caroline; Buchet, René; Magne, David

    2016-01-01

    Our knowledge about mesenchymal stem cells has considerably grown in the last years. Since the proof of concept of the existence of such cells in the 70s by Friedenstein et al., a growing mass of reports were conducted for a better definition of these cells and for the reevaluation from the term “mesenchymal stem cells” to the term “mesenchymal stromal cells (MSCs).” Being more than a semantic shift, concepts behind this new terminology reveal the complexity and the heterogeneity of the cells grouped in MSC family especially as these cells are present in nearly all adult tissues. Recently, mesenchymal stromal cell antigen-1 (MSCA-1)/tissue nonspecific alkaline phosphatase (TNAP) was described as a new cell surface marker of MSCs from different tissues. The alkaline phosphatase activity of this protein could be involved in wide range of MSC features described below from cell differentiation to immunomodulatory properties, as well as occurrence of pathologies. The present review aims to decipher and summarize the role of TNAP in progenitor cells from different tissues focusing preferentially on brain, bone marrow, and adipose tissue. PMID:26839555

  14. 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. PMID:26107416

  15. A modified choline-deficient, ethionine-supplemented diet reduces morbidity and retains a liver progenitor cell response in mice

    PubMed Central

    Passman, Adam M.; Strauss, Robyn P.; McSpadden, Sarah B.; Finch-Edmondson, Megan L.; Woo, Ken H.; Diepeveen, Luke A.; London, Roslyn; Callus, Bernard A.; Yeoh, George C.

    2015-01-01

    ABSTRACT The choline-deficient, ethionine-supplemented (CDE) dietary model induces chronic liver damage, and stimulates liver progenitor cell (LPC)-mediated repair. Long-term CDE administration leads to hepatocellular carcinoma in rodents and lineage-tracing studies show that LPCs differentiate into functional hepatocytes in this model. The CDE diet was first modified for mice by our laboratory by separately administering choline-deficient chow and ethionine in the drinking water (CD+E diet). Although this CD+E diet is widely used, concerns with variability in weight loss, morbidity, mortality and LPC response have been raised by researchers who have adopted this model. We propose that these inconsistencies are due to differential consumption of chow and ethionine in the drinking water, and that incorporating ethionine in the choline-deficient chow, and altering the strength, will achieve better outcomes. Therefore, C57Bl/6 mice, 5 and 6 weeks of age, were fed an all-inclusive CDE diet of various strengths (67% to 100%) for 3 weeks. The LPC response was quantitated and cell lines were derived. We found that animal survival, LPC response and liver damage are correlated with CDE diet strength. The 67% and 75% CDE diet administered to mice older than 5 weeks and greater than 18 g provides a consistent and acceptable level of animal welfare and induces a substantial LPC response, permitting their isolation and establishment of cell lines. This study shows that an all-inclusive CDE diet for mice reproducibly induces an LPC response conducive to in vivo studies and isolation, whilst minimizing morbidity and mortality. PMID:26496771

  16. In vivo formation of unstable heterokaryons after liver damage and hematopoietic stem cell/progenitor transplantation.

    PubMed

    Kashofer, Karl; Siapati, Elena K; Bonnet, Dominique

    2006-04-01

    Following reports of lineage plasticity in human hematopoietic stem cells (HSCs), we investigated the potential of human cord blood HSC-enriched cells to create hepatocytes in hosts after inducing liver damage. Carbon tetrachloride induces severe liver damage and subsequent repair via mitosis of resident hepatocytes. It additionally leads to a threefold increase in homing of human mononuclear cells to bone marrow and liver and subsequently to a substantial enhancement of bone marrow engraftment. Eight weeks after liver damage and infusion of an enhanced green fluorescent protein (eGFP) lentivirus-transduced human HSC-enriched cell population, we observed eGFP-positive cells with clear hepatocyte morphology in the livers of animals. These eGFP-positive cells co-expressed human albumin, and reverse-transcription polymerase chain reaction (PCR) analysis demonstrated the presence of human albumin and alpha-anti-trypsin mRNA. However, two antibodies against human mitochondria and human nuclei failed to mark eGFP-positive hepatocyte-like cells but did give clear staining of donor-derived hematopoietic cells. Subsequent fluorescent in situ hybridization (FISH) analysis revealed the presence of mouse Y chromosome in eGFP-positive hepatocyte-like cells. To resolve this discrepancy, we performed single-cell PCR analysis of microdissected eGFP-positive hepatocyte-like cells and found that they contained mostly mouse and little human genomic material. FISH analysis highlighting the centromeres of all human chromosomes revealed only few human chromosomes in these cells. From these results, we conclude that similar to their murine counterparts, human hematopoietic cells have the potential to fuse with resident host hepatocytes. Because no selective pressure is applied to retain the human genomic material, it is gradually lost over time, leading to a variable phenotype of the chimeric cells and making their detection difficult. PMID:16282440

  17. Identification of A2B5-positive putative oligodendrocyte progenitor cells and A2B5-positive astrocytes in adult human white matter.

    PubMed

    Scolding, N J; Rayner, P J; Compston, D A

    1999-03-01

    Spontaneous remyelination of previously demyelinated axons is found in a substantial minority of acute and chronic lesions in multiple sclerosis. In the rodent, central remyelination restores saltatory conduction and helps restore limb function, and it seems likely that endogenous myelin repair contributes to neurological recovery in multiple sclerosis. However, the identity of the remyelinating cell remains enigmatic. Fully differentiated oligodendrocytes have very limited capacity for recapitulating their developmental activities and re-engaging myelination pathways. Proliferative oligodendrocyte progenitors--often known as O-2A cells because of their ability to differentiate in vitro into either oligodendrocytes or ("type 2") astrocytes--are, in contrast, extremely efficient at myelin repair either spontaneously, or after transplantation into the de- or dysmyelinated CNS. Oligodendrocyte progenitors are present in both developing and adult rodent CNS. We have previously demonstrated that proliferative oligodendrocyte progenitors are present in cultures prepared from the adult human CNS. Here, using fresh tissue print preparations, we report that cells with processes and the A2B5-positive immunophenotype of proliferative oligodendrocyte progenitors are present in situ in adult human white matter. This technique also reveals the occurrence of A2B5-positive astrocytes, a cell also not previously identified in the normal adult human CNS. In the light of the rodent data showing the importance of oligodendrocyte progenitors in myelin repair, our findings suggesting the presence of progenitors in the adult human brain may have significant implications for spontaneous remyelination in multiple sclerosis and other demyelinating conditions. PMID:10051212

  18. Wnt1 and BMP2: two factors recruiting multipotent neural crest progenitors isolated from adult bone marrow.

    PubMed

    Glejzer, A; Laudet, E; Leprince, P; Hennuy, B; Poulet, C; Shakhova, O; Sommer, L; Rogister, B; Wislet-Gendebien, S

    2011-06-01

    Recent studies have shown that neural crest-derived progenitor cells can be found in diverse mammalian tissues including tissues that were not previously shown to contain neural crest derivatives, such as bone marrow. The identification of those "new" neural crest-derived progenitor cells opens new strategies for developing autologous cell replacement therapies in regenerative medicine. However, their potential use is still a challenge as only few neural crest-derived progenitor cells were found in those new accessible locations. In this study, we developed a protocol, based on wnt1 and BMP2 effects, to enrich neural crest-derived cells from adult bone marrow. Those two factors are known to maintain and stimulate the proliferation of embryonic neural crest stem cells, however, their effects have never been characterized on neural crest cells isolated from adult tissues. Using multiple strategies from microarray to 2D-DIGE proteomic analyses, we characterized those recruited neural crest-derived cells, defining their identity and their differentiating abilities. PMID:20976520

  19. 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

  20. p300/β-Catenin Interactions Regulate Adult Progenitor Cell Differentiation Downstream of WNT5a/Protein Kinase C (PKC).

    PubMed

    Rieger, Megan E; Zhou, Beiyun; Solomon, Nicola; Sunohara, Mitsuhiro; Li, Changgong; Nguyen, Cu; Liu, Yixin; Pan, Jie-Hong; Minoo, Parviz; Crandall, Edward D; Brody, Steven L; Kahn, Michael; Borok, Zea

    2016-03-18

    Maintenance of stem/progenitor cell-progeny relationships is required for tissue homeostasis during normal turnover and repair. Wnt signaling is implicated in both maintenance and differentiation of adult stem/progenitor cells, yet how this pathway serves these dichotomous roles remains enigmatic. We previously proposed a model suggesting that specific interaction of β-catenin with either of the homologous Kat3 co-activators, p300 or CREB-binding protein, differentially regulates maintenance versus differentiation of embryonic stem cells. Limited knowledge of endogenous mechanisms driving differential β-catenin/co-activator interactions and their role in adult somatic stem/progenitor cell maintenance versus differentiation led us to explore this process in defined models of adult progenitor cell differentiation. We focused primarily on alveolar epithelial type II (AT2) cells, progenitors of distal lung epithelium, and identified a novel axis whereby WNT5a/protein kinase C (PKC) signaling regulates specific β-catenin/co-activator interactions to promote adult progenitor cell differentiation. p300/β-catenin but not CBP/β-catenin interaction increases as AT2 cells differentiate to a type I (AT1) cell-like phenotype. Additionally, p300 transcriptionally activates AT1 cell-specific gene Aqp-5. IQ-1, a specific inhibitor of p300/β-catenin interaction, prevents differentiation of not only primary AT2 cells, but also tracheal epithelial cells, and C2C12 myoblasts. p300 phosphorylation at Ser-89 enhances p300/β-catenin interaction, concurrent with alveolar epithelial cell differentiation. WNT5a, a traditionally non-canonical WNT ligand regulates Ser-89 phosphorylation and p300/β-catenin interactions in a PKC-dependent manner, likely involving PKCζ. These studies identify a novel intersection of canonical and non-canonical Wnt signaling in adult progenitor cell differentiation that has important implications for targeting β-catenin to modulate adult progenitor cell

  1. Adult Living Donor Liver Transplantation Across ABO-Incompatibility

    PubMed Central

    Lee, Chen-Fang; Cheng, Chih-Hsien; Wang, Yu-Chao; Soong, Ruey-Shyang; Wu, Tsung-Han; Chou, Hong-Shiue; Wu, Ting-Jung; Chan, Kun-Ming; Lee, Ching-Song; Lee, Wei-Chen

    2015-01-01

    Abstract The objective of this study was to evaluate the results of adult ABO-incompatible living donor liver transplantation (LDLT). ABO-incompatible LDLT is an aggressive treatment that crosses the blood-typing barrier for saving lives from liver diseases. Although graft and patient survival have been improved recently by various treatments, the results of adult ABO-incompatible LDLT require further evaluation. Two regimens were designed based on isoagglutinin IgG and IgM titers and the time course of immunological reactions at this institute. When isoagglutinin IgG and IgM titers were ≤64, liver transplantation was directly performed and rituximab (375 mg/m2) was administrated on postoperative day 1 (regimen I). When isoagglutinin titers were >64, rituximab (375 mg/m2) was administered preoperatively with or without plasmapheresis and boosted on postoperative day 1 (regimen II). Immunosuppression was achieved by administration of mycophenolate mofetil, tacrolimus, and steroids. Forty-six adult ABO-incompatible and 340 ABO-compatible LDLTs were performed from 2006 to 2013. The Model for End-Stage Liver Disease scores for ABO-incompatible recipients ranged from 7 to 40, with a median of 14. The graft-to-recipient weight ratio ranged from 0.61% to 1.61% with a median of 0.91%. The 1-, 3-, and 5-year survival rates were 81.7%, 75.7%, and 71.0%, respectively, for ABO-incompatible LDLT recipients, compared to 81.0%, 75.2%, and 71.5% for ABO-C recipients (P = 0.912). The biliary complication rate was higher in ABO-incompatible LDLT recipients than in the ABO-compatible recipients (50.0% vs 29.7%, P = 0.009). In the rituximab era, the blood type barrier can be crossed to achieve adult ABO-incompatible LDLT with survival rates comparable to those of ABO-compatible LDLT, but with more biliary complications. PMID:26496313

  2. Adult Living Donor Liver Transplantation Across ABO-Incompatibility.

    PubMed

    Lee, Chen-Fang; Cheng, Chih-Hsien; Wang, Yu-Chao; Soong, Ruey-Shyang; Wu, Tsung-Han; Chou, Hong-Shiue; Wu, Ting-Jung; Chan, Kun-Ming; Lee, Ching-Song; Lee, Wei-Chen

    2015-10-01

    The objective of this study was to evaluate the results of adult ABO-incompatible living donor liver transplantation (LDLT).ABO-incompatible LDLT is an aggressive treatment that crosses the blood-typing barrier for saving lives from liver diseases. Although graft and patient survival have been improved recently by various treatments, the results of adult ABO-incompatible LDLT require further evaluation.Two regimens were designed based on isoagglutinin IgG and IgM titers and the time course of immunological reactions at this institute. When isoagglutinin IgG and IgM titers were ≤64, liver transplantation was directly performed and rituximab (375 mg/m) was administrated on postoperative day 1 (regimen I). When isoagglutinin titers were >64, rituximab (375 mg/m) was administered preoperatively with or without plasmapheresis and boosted on postoperative day 1 (regimen II). Immunosuppression was achieved by administration of mycophenolate mofetil, tacrolimus, and steroids.Forty-six adult ABO-incompatible and 340 ABO-compatible LDLTs were performed from 2006 to 2013. The Model for End-Stage Liver Disease scores for ABO-incompatible recipients ranged from 7 to 40, with a median of 14. The graft-to-recipient weight ratio ranged from 0.61% to 1.61% with a median of 0.91%. The 1-, 3-, and 5-year survival rates were 81.7%, 75.7%, and 71.0%, respectively, for ABO-incompatible LDLT recipients, compared to 81.0%, 75.2%, and 71.5% for ABO-C recipients (P = 0.912). The biliary complication rate was higher in ABO-incompatible LDLT recipients than in the ABO-compatible recipients (50.0% vs 29.7%, P = 0.009).In the rituximab era, the blood type barrier can be crossed to achieve adult ABO-incompatible LDLT with survival rates comparable to those of ABO-compatible LDLT, but with more biliary complications. PMID:26496313

  3. Remyelination after chronic spinal cord injury is associated with proliferation of endogenous adult progenitor cells after systemic administration of guanosine.

    PubMed

    Jiang, Shucui; Ballerini, Patrizia; Buccella, Silvana; Giuliani, Patricia; Jiang, Cai; Huang, Xinjie; Rathbone, Michel P

    2008-03-01

    Axonal demyelination is a consistent pathological sequel to chronic brain and spinal cord injuries and disorders that slows or disrupts impulse conduction, causing further functional loss. Since oligodendroglial progenitors are present in the demyelinated areas, failure of remyelination may be due to lack of sufficient proliferation and differentiation of oligodendroglial progenitors. Guanosine stimulates proliferation and differentiation of many types of cells in vitro and exerts neuroprotective effects in the central nervous system (CNS). Five weeks after chronic traumatic spinal cord injury (SCI), when there is no ongoing recovery of function, intraperitoneal administration of guanosine daily for 2 weeks enhanced functional improvement correlated with the increase in myelination in the injured cord. Emphasis was placed on analysis of oligodendrocytes and NG2-positive (NG2+) cells, an endogenous cell population that may be involved in oligodendrocyte replacement. There was an increase in cell proliferation (measured by bromodeoxyuridine staining) that was attributable to an intensification in progenitor cells (NG2+ cells) associated with an increase in mature oligodendrocytes (determined by Rip+ staining). The numbers of astroglia increased at all test times after administration of guanosine whereas microglia only increased in the later stages (14 days). Injected guanosine and its breakdown product guanine accumulated in the spinal cords; there was more guanine than guanosine detected. We conclude that functional improvement and remyelination after systemic administration of guanosine is due to the effect of guanosine/guanine on the proliferation of adult progenitor cells and their maturation into myelin-forming cells. This raises the possibility that administration of guanosine may be useful in the treatment of spinal cord injury or demyelinating diseases such as multiple sclerosis where quiescent oligodendroglial progenitors exist in demyelinated plaques. PMID

  4. Remyelination after chronic spinal cord injury is associated with proliferation of endogenous adult progenitor cells after systemic administration of guanosine

    PubMed Central

    Ballerini, Patrizia; Buccella, Silvana; Giuliani, Patricia; Jiang, Cai; Huang, Xinjie; Rathbone, Michel P.

    2008-01-01

    Axonal demyelination is a consistent pathological sequel to chronic brain and spinal cord injuries and disorders that slows or disrupts impulse conduction, causing further functional loss. Since oligodendroglial progenitors are present in the demyelinated areas, failure of remyelination may be due to lack of sufficient proliferation and differentiation of oligodendroglial progenitors. Guanosine stimulates proliferation and differentiation of many types of cells in vitro and exerts neuroprotective effects in the central nervous system (CNS). Five weeks after chronic traumatic spinal cord injury (SCI), when there is no ongoing recovery of function, intraperitoneal administration of guanosine daily for 2 weeks enhanced functional improvement correlated with the increase in myelination in the injured cord. Emphasis was placed on analysis of oligodendrocytes and NG2-positive (NG2+) cells, an endogenous cell population that may be involved in oligodendrocyte replacement. There was an increase in cell proliferation (measured by bromodeoxyuridine staining) that was attributable to an intensification in progenitor cells (NG2+ cells) associated with an increase in mature oligodendrocytes (determined by Rip+ staining). The numbers of astroglia increased at all test times after administration of guanosine whereas microglia only increased in the later stages (14 days). Injected guanosine and its breakdown product guanine accumulated in the spinal cords; there was more guanine than guanosine detected. We conclude that functional improvement and remyelination after systemic administration of guanosine is due to the effect of guanosine/guanine on the proliferation of adult progenitor cells and their maturation into myelin-forming cells. This raises the possibility that administration of guanosine may be useful in the treatment of spinal cord injury or demyelinating diseases such as multiple sclerosis where quiescent oligodendroglial progenitors exist in demyelinated plaques

  5. Differentiation of adult rat bone marrow stem cells into epithelial progenitor cells in culture.

    PubMed

    Shu, Chang; Li, Ting Yu; Tsang, Lai Ling; Fok, Kin Lam; Lo, Pui Shan; Zhu, Jin Xia; Ho, Lo Sze; Chung, Yiu Wa; Chan, Hsiao Chang

    2006-10-01

    We have previously obtained monoclonal bone marrow stem cells from adult rats (rMSCs) and induced them into phenotypic neurons. In the present study, we aimed to induce rMSCs into epithelial cells by culturing them onto compartmentalized permeable supports, which have been used for growing a variety of polarized epithelia in culture. Hematoxylin staining showed that after 4 days grown on permeable supports, rMSCs formed an epithelial-like monolayer. Immunofluorescence of the permeably-supported monolayers, but not the rMSCs grown in culture flasks, showed positive signals for epithelial markers, cytokeratin 5 & 8. RT-PCR results also showed the mRNA expression of epithelial sodium channel (ENaC) and cystic fibrosis transmembrane conductance regulator (CFTR) as well as tight junction protein ZO-1 in the rMSC-derived monolayers grown on permeable supports but absent from those grown in culture flasks. However, western blot only detected protein expression of ZO-1 but not ENaC nor CFTR. The short-circuit current measurements showed that the rMSC-derived monolayers grown on permeable supports exhibited a trans-monolayer resistance of 30-50 Omega cm(2); however, the monolayers did not respond to activators or blockers of CFTR or ENaC. The results suggest that compartmentalized or polarized culture conditions provide a suitable environment for rMSCs to differentiate into epithelial progenitor cells with tight junction formation; however, this condition is not sufficient for functional expression of epithelial ion channels associated with well-differentiated epithelia. PMID:16877014

  6. [Comparison of serum trace element spectrum of liver cancer patients and healthy adults].

    PubMed

    Yin, D Z

    1990-05-01

    The contents of 15 trace elements in the sera of 30 liver cancer patients and 30 healthy adults were assayed by ICP-AES method. The data obtained were analysed by routine statistical tests, multi-variate discrimination analysis, multi-variate stepwise regression analysis and non-linear mapping algorithm. The results showed that the contents of copper, vanadium, cadmium, stannum, cobalt, nickel in liver cancer patients were significantly higher than those in healthy adults. The serum trace element spectrum of liver cancer patients was different from that of healthy adults. Hence, the liver cancer patients could be differentiated from healthy adults by serum trace element spectrum. PMID:2249593

  7. Biphasic change of progenitor proliferation in dentate gyrus after single dose of isoflurane in young adult rats

    PubMed Central

    Lin, Nan; Moon, Tiffany Sun; Stratmann, Greg; Sall, Jeffrey W.

    2013-01-01

    Background Isoflurane exposure causes improvement in long-term neurocognitive function in young adult rats, this is associated with an increase in dentate gyrus progenitor proliferation 4 days after anesthesia. However, the number of new neurons, that were born from cells that incorporated bromodeoxyuridine 4 days after anesthesia is not affected by anesthesia. We tested the hypothesis that progenitor proliferation continues to increase past 4 days, which would imply the possibility that the number of new neurons after anesthesia could be increased if bromodeoxyuridine labeling occurred at a later time point. Methods Bromodeoxyuridine was injected at 0, 1, 2, 4, 9, 16 days after 4 hours of isoflurane exposure to 60-day old rats. Brains were harvested 2 hours later, immunohistochemically stained, and the number of bromodeoxyuridine-positive cells in the dentate gyrus was assessed microscopically. Results After 4 hours of exposure to isoflurane in 60-day old rats, the number of bromodeoxyuridine-positive cells decreased on days 0–2, then increased on day 4 significantly, and regressed toward the control level on day 9 and 16. Conclusions Anesthesia-induced progenitor proliferation in the dentate gyrus was not sustained 9 days after anesthesia. We interpret these results to signify that an anesthetic effect on neurogenesis likely does not play a critical role in the previously observed isoflurane-induced long-term improvement in neurocognitive function in 60-day old rats and that the transient increase in progenitor proliferation serves to replenish the pool of neural stem cells. The mechanism of anesthesia-induced improvement in cognition of young adult rats remains elusive. PMID:23752046

  8. Hedgehog Signaling in the Liver

    PubMed Central

    Omenetti, Alessia; Choi, Steve; Michelotti, Gregory; Diehl, Anna Mae

    2010-01-01

    Reactivation of Hedgehog (Hh), a morphogenic signaling pathway that controls progenitor cell fate and tissue construction during embryogenesis occurs during many types of liver injury in adult. The net effects of activating the Hedgehog pathway include expansion of liver progenitor populations to promote liver regeneration, but also hepatic accumulation of inflammatory cells, liver fibrogenesis, and vascular remodeling. All of these latter responses are known to be involved in the pathogenesis of cirrhosis. In addition, Hh signaling may play a role in primary liver cancers, such as cholangiocarcinoma and hepatocellular carcinoma. Study of Hedgehog signaling in liver cells is in its infancy. Additional research in this area is justified given growing experimental and clinical data supporting a role for the pathway in regulating outcomes of liver injury. PMID:21093090

  9. Reproducible expansion and characterization of mouse neural stem/progenitor cells in adherent cultures derived from the adult subventricular zone

    PubMed Central

    Theus, Michelle H.; Ricard, Jerome; Liebl, Daniel J.

    2012-01-01

    Endogenous neural stem/progenitor cells (NSPCs) residing in the subventricular zone (SVZ) of the adult mouse forebrain have been shown to enhance their neurogenic potential in response to CNS injury. Mechanisms involved in regulating adult neurogenesis under naïve or stressed conditions can be studied using a monolayer cell-culture system of the nestin-expressing NSPC lineage to analyze proliferation, survival and differentiation. Here, we describe a protocol for the expansion of NSPCs for studies aimed at understanding the functional role of NSPCs in maintaining adult neurogenic processes. In this unit, we outline in detail the procedures for: (1) isolation, maintenance and culture of the NSPC component of the SVZ niche from the lateral wall of the lateral ventricle; (2) characterization of NSPC functions by examining proliferation, survival and differentiation; and (3) efficient siRNA transfection methods in 96-well format. PMID:22415840

  10. Adult to adult living related liver transplantation: Where do we currently stand?

    PubMed Central

    Carlisle, Erica M; Testa, Giuliano

    2012-01-01

    Adult to adult living donor liver transplantation (AALDLT) was first preformed in the United States in 1997. The procedure was rapidly integrated into clinical practice, but in 2002, possibly due to the first widely publicized donor death, the number of living liver donors plummeted. The number of donors has since reached a steady plateau far below its initial peak. In this review we evaluate the current climate of AALDLT. Specifically, we focus on several issues key to the success of AALDLT: determining the optimal indications for AALDLT, balancing graft size and donor safety, assuring adequate outflow, minimizing biliary complications, and maintaining ethical practices. We conclude by offering suggestions for the future of AALDLT in United States transplantation centers. PMID:23239910

  11. Adult to adult living related liver transplantation: where do we currently stand?

    PubMed

    Carlisle, Erica M; Testa, Giuliano

    2012-12-14

    Adult to adult living donor liver transplantation (AALDLT) was first preformed in the United States in 1997. The procedure was rapidly integrated into clinical practice, but in 2002, possibly due to the first widely publicized donor death, the number of living liver donors plummeted. The number of donors has since reached a steady plateau far below its initial peak. In this review we evaluate the current climate of AALDLT. Specifically, we focus on several issues key to the success of AALDLT: determining the optimal indications for AALDLT, balancing graft size and donor safety, assuring adequate outflow, minimizing biliary complications, and maintaining ethical practices. We conclude by offering suggestions for the future of AALDLT in United States transplantation centers. PMID:23239910

  12. 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

  13. Adult thymic epithelial cell (TEC) progenitors and TEC stem cells: Models and mechanisms for TEC development and maintenance.

    PubMed

    Hamazaki, Yoko

    2015-11-01

    The thymus is the primary lymphoid organ for generating self-restricted and self-tolerant functional T cells. Its two distinct anatomical regions, the cortex and the medulla, are involved in positive and negative selection, respectively. Thymic epithelial cells (TECs) constitute the framework of this tissue and function as major stromal components. Extensive studies for more than a decade have revealed how TECs are generated during organogenesis; progenitors specific for medullary TECs (mTECs) and cortical TECs (cTECs) as well as bipotent progenitors for both lineages have been identified, and the signaling pathways required for the development and maturation of mTECs have been elucidated. However, little is known about the initial commitment of mTECs and cTECs during ontogeny, and how regeneration of both lineages is sustained in the postnatal/adult thymus. Recently, stem cell activities in TECs have been demonstrated, and TEC progenitors have been identified in the postnatal thymus. In this review, recent advances in studying the development and maintenance of TECs are summarized, and the possible mechanisms of thymic regeneration and involution are discussed. PMID:26362014

  14. Diabetes enhances the proliferation of adult pancreatic multipotent progenitor cells and biases their differentiation to more β-cell production.

    PubMed

    Razavi, Rozita; Najafabadi, Hamed S; Abdullah, Sarah; Smukler, Simon; Arntfield, Margot; van der Kooy, Derek

    2015-04-01

    Endogenous pancreatic multipotent progenitors (PMPs) are ideal candidates for regenerative approaches to compensate for β-cell loss since their β-cell-producing capacities as well as strategic location would eliminate unnecessary invasive manipulations. However, little is known about the status and potentials of PMPs under diabetic conditions. Here we show that β-cell metabolic stress and hyperglycemia enhance the proliferation capacities of adult PMP cells and bias their production of progeny toward β-cells in mouse and human. These effects are dynamic and correlate with functional β-cell regeneration when conditions allow. PMID:25392245

  15. 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. PMID:24656820

  16. Adult mice transplanted with embryonic retinal progenitor cells: New approach for repairing damaged optic nerves

    PubMed Central

    Cho, Jang-Hyeon; Mao, Chai-An

    2012-01-01

    Purpose Retinal ganglion cell (RGC) death and optic nerve degeneration are complex processes whose underlying molecular mechanisms are only vaguely understood. Treatments commonly used for optic nerve degeneration have little long-term value and only prolong degeneration. Recent advances in stem cell replacement therapy offer new ways to overcome RGC loss by transferring healthy cells into eyes of afflicted individuals. However, studies on stem cell replacement for optic nerve degeneration are hampered by limitations of the available animal models, especially genetic models. We have developed a mouse model in which RGCs are genetically ablated in adult mice with subsequent degeneration of the optic nerve. In the study reported here, we used this model to determine whether embryonic retinal progenitor cells (RPCs) removed from donor retinas when RPCs are committing to an RGC fate could restore lost RGCs. Methods We used the RGC-depleted model as a host for transplanting donor green fluorescent protein (GFP)–labeled RPCs from embryonic retinas that are maximally expressing Atoh7, a basic helix–loop–helix gene essential for RGC specification. Dissociated GFP-labeled RPCs were characterized in situ by immunolabeling with antibodies against proteins known to be expressed in RPCs at embryonic day (E)14.5. Dissociated retinal cells were injected into the vitreous of one eye of RGC-depleted mice at two to six months of age. The injected and non-injected retinas were analyzed for gene expression using immunolabeling, and the morphology of optic nerves was assessed visually and with histological staining at different times up to four months after injection. Results We demonstrate the successful transfer of embryonic GFP-labeled RPCs into the eyes of RGC-depleted mice. Many transplanted RPCs invaded the ganglion cell layer, but the efficiency of the invasion was low. GFP-labeled cells within the ganglion cell layer expressed genes associated with early and late stages

  17. Accessory liver lobe of the gallbladder in adults.

    PubMed

    Handra-Luca, Adriana

    2016-09-01

    The accessory liver lobe (ALL) of the gallbladder wall is rare, mentioned by Meckel since 1822. We present two cases of ALL occurring in two adult women. The ALLs were diagnosed at microscopic examination of cholecystectomy specimens for lithiasic cholecystitis and were located at the gallbladder body level. They measured 0.5 and 1.1 cm and were pediculated from the gallbladder serosa. Luschka duct complexes were seen in the adjacent subserosa in one of the cases. The main clinical relevance of ALL of the gallbladder resides in the differential diagnosis with a lymph node and in the risk of peroperative hemorragia or bile leakage by sectioning of the connecting blood vessels and/or bile duct. Intraparietal ALL may interfere with dysmotility, possibly resulting in bile stagnation and stone formation. PMID:27147442

  18. Sequential and simultaneous revascularization in adult orthotopic piggyback liver transplantation.

    PubMed

    Polak, Wojciech G; Miyamoto, Shungo; Nemes, Balazs A; Peeters, Paul M J G; de Jong, Koert P; Porte, Robert J; Slooff, Maarten J H

    2005-08-01

    The aim of the study was to assess whether there is a difference in outcome after sequential or simultaneous revascularization during orthotopic liver transplantation (OLT) in terms of patient and graft survival, mortality, morbidity, and liver function. The study population consisted of 102 adult patients with primary full-size piggyback OLT transplanted between January 1998 and December 2001. In 71 patients (70%) the grafts were sequentially reperfused after completion of the portal vein anastomosis and subsequent arterial reconstruction was performed (sequential reperfusion [SeqR] group). In 31 patients (30%) the graft was reperfused simultaneously via the portal vein and hepatic artery (simultaneous reperfusion [SimR] group). Patient and graft survival at 1, 3, and 6 months and at 1 year did not differ between the SeqR group and the SimR group. The red blood cell (RBC) requirements were significantly higher in the SimR group (5.5 units; range 0-20) in comparison to the SeqR group (2 units; range 0-19) (P = 0.02). Apart from a higher number of biliary anastomotic complications and abdominal bleeding complications in the SimR group in comparison to the SeqR group (13% vs. 2% and 19% vs. 6%, respectively; P = 0.06), morbidity was not different between the groups. No differences between the groups were observed regarding the incidence of primary nonfunction (PNF), intensive care unit stay, and acute rejection. This was also true for the severity of rejections. Postoperative recuperation of liver function was not different between the groups. In conclusion, no advantage of either of the 2 reperfusion protocols could be observed in this analysis, especially with respect to the incidence of ischemic type biliary lesions (ITBL). PMID:16035059

  19. Metabolic aspects of adult patients with nonalcoholic fatty liver disease.

    PubMed

    Abenavoli, Ludovico; Milic, Natasa; Di Renzo, Laura; Preveden, Tomislav; Medić-Stojanoska, Milica; De Lorenzo, Antonino

    2016-08-21

    Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease and it encompasses a spectrum from simple steatosis to steatohepatitis, fibrosis, or cirrhosis. The mechanisms involved in the occurrence of NAFLD and its progression are probably due to a metabolic profile expressed within the context of a genetic predisposition and is associated with a higher energy intake. The metabolic syndrome (MS) is a cluster of metabolic alterations associated with an increased risk for the development of cardiovascular diseases and diabetes. NAFLD patients have more than one feature of the MS, and now they are considered the hepatic components of the MS. Several scientific advances in understanding the association between NAFLD and MS have identified insulin resistance (IR) as the key aspect in the pathophysiology of both diseases. In the multi parallel hits theory of NAFLD pathogenesis, IR was described to be central in the predisposition of hepatocytes to be susceptible to other multiple pathogenetic factors. The recent knowledge gained from these advances can be applied clinically in the prevention and management of NAFLD and its associated metabolic changes. The present review analyses the current literature and highlights the new evidence on the metabolic aspects in the adult patients with NAFLD. PMID:27610012

  20. Metabolic aspects of adult patients with nonalcoholic fatty liver disease

    PubMed Central

    Abenavoli, Ludovico; Milic, Natasa; Di Renzo, Laura; Preveden, Tomislav; Medić-Stojanoska, Milica; De Lorenzo, Antonino

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease and it encompasses a spectrum from simple steatosis to steatohepatitis, fibrosis, or cirrhosis. The mechanisms involved in the occurrence of NAFLD and its progression are probably due to a metabolic profile expressed within the context of a genetic predisposition and is associated with a higher energy intake. The metabolic syndrome (MS) is a cluster of metabolic alterations associated with an increased risk for the development of cardiovascular diseases and diabetes. NAFLD patients have more than one feature of the MS, and now they are considered the hepatic components of the MS. Several scientific advances in understanding the association between NAFLD and MS have identified insulin resistance (IR) as the key aspect in the pathophysiology of both diseases. In the multi parallel hits theory of NAFLD pathogenesis, IR was described to be central in the predisposition of hepatocytes to be susceptible to other multiple pathogenetic factors. The recent knowledge gained from these advances can be applied clinically in the prevention and management of NAFLD and its associated metabolic changes. The present review analyses the current literature and highlights the new evidence on the metabolic aspects in the adult patients with NAFLD. PMID:27610012

  1. Nonviral in situ green fluorescent protein labeling and culture of primary, adult human hair follicle epithelial progenitor cells.

    PubMed

    Tiede, Stephan; Koop, Norbert; Kloepper, Jennifer E; Fässler, Reinhard; Paus, Ralf

    2009-11-01

    In this article we show that cloning of the human K15 promoter before a green fluorescence protein (GFP)/geneticin-resistance cassette and transfection of microdissected, organ-cultured adult human scalp hair follicles generates specific K15 promoter-driven GFP expression in their stem cell-rich bulge region. K15-GFP+ cells can be visualized in situ by GFP fluorescence and 2-photon laser scanning microscopy. Vital K15-GFP+ progenitor cells can then be selected by using the criteria of their green fluorescence, adhesion to collagen type IV and fibronectin, and geneticin resistance. Propagated K15-GFP+ cells express epithelial progenitor markers, show the expected differential gene expression profile of human bulge epithelium, and form holoclones. This application of nonretroviral, K15 promoter-driven, GFP labeling to adult human hair follicles facilitates the characterization and manipulation of human epithelial stem cells, both in situ and in vitro, and should be transferable to other complex human tissues. PMID:19750535

  2. 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. PMID:26074082

  3. Differences in Liver Impairment Between Adults and Children with Dengue Infection.

    PubMed

    Martínez Vega, Rosario; Phumratanaprapin, Weerapong; Phonrat, Benjaluck; Dhitavat, Jittima; Sutherat, Maleerat; Choovichian, Vorada

    2016-05-01

    Dengue infection (DI) is a major vector-borne disease in southeast Asia and an important cause of morbidity. The complications such as hepatic impairment are common, and because the physiology of the liver differs between children and adults, the DI-associated liver impairments might be expected to differ as well. This study aims to compare the differences in liver impairment between adults and children with DI. We retrospectively studied 158 adults and 79 children with serologically confirmed DI admitted to the Bangkok Hospital for Tropical Diseases from 2008 to 2012. In total, 93% of adults and 87% of children exhibited abnormal liver enzyme levels during hospitalization. Overall, 76 (42.4%) adults and 16 (20.3%) children had dengue hemorrhagic fever (DHF). Compared with children, adults with dengue fever (DF) presented a significantly higher incidence of liver function impairment (alanine transaminase [ALT] > 2 × upper limit of normal [ULN]) (47.1% versus 25.5%), hepatitis (ALT > 4 × ULN) (29.4% versus 12.8%), and severe hepatitis (aspartate transaminase [AST]/ALT > 10 × ULN) (16.5% versus 4.3%). Children with DHF showed a significantly higher incidence of liver function impairment due to AST derangement than did adults (100% versus 73%). There were no differences in the total bilirubin, albumin, or total protein levels between adults and children. Liver enzymes normalized significantly more slowly in adults, and AST recovery was faster than ALT. In conclusion, liver function impairment was more common among adults than children with DF. As the severity progressed to DHF, liver injury became more common in children. PMID:26976884

  4. 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.

  5. Patterns and predictors of sexual function after liver donation: The Adult-to-Adult Living Donor Liver Transplantation Cohort study.

    PubMed

    DiMartini, Andrea F; Dew, Mary Amanda; Butt, Zeeshan; Simpson, Mary Ann; Ladner, Daniela P; Smith, Abigail R; Hill-Callahan, Peg; Gillespie, Brenda W

    2015-05-01

    Although sexual functioning is an important facet of a living donor's quality of life, it has not received an extensive evaluation in this population. Using data from the Adult-to-Adult Living Donor Liver Transplantation Cohort Study, we examined donor sexual functioning across the donation process from the predonation evaluation to 3 months and 1 year after donation. Donors (n = 208) and a comparison group of nondonors (n = 155) completed self-reported surveys with specific questions on sexual desire, satisfaction, orgasm, and (for men) erectile function. Across the 3 time points, donor sexual functioning was lower at the evaluation phase and 3 months after donation versus 1 year after donation. In the early recovery period, abdominal pain was associated with difficulty reaching orgasm [odds ratio (OR), 3.98; 95% confidence interval (CI), 1.30-12.16], concerns over appearance were associated with lower sexual desire (OR, 4.14; 95% CI, 1.02-16.79), and not feeling back to normal was associated with dissatisfaction with sexual life (OR, 3.58; 95% CI, 1.43-8.99). Efforts to educate donors before the surgery and prepare them for the early recovery phase may improve recovery and reduce distress regarding sexual functioning. PMID:25779554

  6. Brain Derived Neurotrophic Factor Contributes to the Cardiogenic Potential of Adult Resident Progenitor Cells in Failing Murine Heart

    PubMed Central

    Samal, Rasmita; Ameling, Sabine; Dhople, Vishnu; Sappa, Praveen Kumar; Wenzel, Kristin; Völker, Uwe; Felix, Stephan B.; Hammer, Elke; Könemann, Stephanie

    2015-01-01

    Aims Resident cardiac progenitor cells show homing properties when injected into the injured but not to the healthy myocardium. The molecular background behind this difference in behavior needs to be studied to elucidate how adult progenitor cells can restore cardiac function of the damaged myocardium. Since the brain derived neurotrophic factor (BDNF) moderates cardioprotection in injured hearts, we focused on delineating its regulatory role in the damaged myocardium. Methods and Results Comparative gene expression profiling of freshly isolated undifferentiated Sca-1 progenitor cells derived either from heart failure transgenic αMHC-CyclinT1/Gαq overexpressing mice or wildtype littermates revealed transcriptional variations. Bdnf expression was up regulated 5-fold during heart failure which was verified by qRT-PCR and confirmed at protein level. The migratory capacity of Sca-1 cells from transgenic hearts was improved by 15% in the presence of 25ng/ml BDNF. Furthermore, BDNF-mediated effects on Sca-1 cells were studied via pulsed Stable Isotope Labeling of Amino acids in Cell Culture (pSILAC) proteomics approach. After BDNF treatment significant differences between newly synthesized proteins in Sca-1 cells from control and transgenic hearts were observed for CDK1, SRRT, HDGF, and MAP2K3 which are known to regulate cell cycle, survival and differentiation. Moreover BDNF repressed the proliferation of Sca-1 cells from transgenic hearts. Conclusion Comparative profiling of resident Sca-1 cells revealed elevated BDNF levels in the failing heart. Exogenous BDNF (i) stimulated migration, which might improve the homing ability of Sca-1 cells derived from the failing heart and (ii) repressed the cell cycle progression suggesting its potency to ameliorate heart failure. PMID:25799225

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

    PubMed

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

    2011-02-01

    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

  8. 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

  9. Feelings of living donors about adult-to-adult living donor liver transplantation.

    PubMed

    Kusakabe, Tomoko; Irie, Shinji; Ito, Naomi; Kazuma, Keiko

    2008-01-01

    This study investigated the feelings of living donors about adult-to-adult liver transplantation. We interviewed 18 donors about their feelings before and after transplantation using semistructured interviews and then conducted a content analysis of their responses. Before transplantation, many donors reported that they wanted recipients to live for the donor or his or her family, and there was no one else to donate. Many donors were not anxious, did not feel coerced, and did not consider donation dangerous. Some reported being excited at facing a new experience. Some said they would not mind whatever happens. Others were anxious or unsure about the operation. Diagnostic testing and preoperative blood banking were painful. Donors experienced increasing stress just before the operation. After transplantation, some donors verbalized feeling more grateful to others and that they gained maturity. Throughout the process, donors were concerned about their recipients. Our results suggest that donors might act for themselves or their family. It is important to recognize the varied responses of donors' feelings toward liver transplant recipients. PMID:18708830

  10. Reinduction of ErbB2 in astrocytes promotes radial glial progenitor identity in adult cerebral cortex

    PubMed Central

    Ghashghaei, H.T.; Weimer, Jill M.; Schmid, Ralf S.; Yokota, Yukako; McCarthy, Ken D.; Popko, Brian; Anton, E.S.

    2007-01-01

    Radial glial cells play a critical role in the construction of mammalian brain by functioning as a source of new neurons and by providing a scaffold for radial migration of new neurons to their target locations. Radial glia transform into astrocytes at the end of embryonic development. Strategies to promote functional recovery in the injured adult brain depend on the generation of new neurons and the appropriate guidance of these neurons to where they are needed, two critical functions of radial glia. Thus, the competence to regain radial glial identity in the adult brain is of significance for the ability to promote functional repair via neurogenesis and targeted neuronal migration in the mature brain. Here we show that the in vivo induction of the tyrosine kinase receptor, ErbB2, in mature astrocytes enables a subset of them to regain radial glial identity in the mature cerebral cortex. These new radial glial progenitors are capable of giving rise to new neurons and can support neuronal migration. These studies indicate that ErbB2 signaling critically modulates the functional state of radial glia, and induction of ErbB2 in distinct adult astrocytes can promote radial glial identity in the mature cerebral cortex. PMID:18079173

  11. Functional Electrical Stimulation Helps Replenish Progenitor Cells in the Injured Spinal Cord of Adult Rats

    PubMed Central

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

    2010-01-01

    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. PMID:20059998

  12. 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

  13. Development and molecular composition of the hepatic progenitor cell niche.

    PubMed

    Vestentoft, Peter Siig

    2013-05-01

    End-stage liver diseases represent major health problems that are currently treated by liver transplantation. However, given the world-wide shortage of donor livers novel strategies are needed for therapeutic treatment. Adult stem cells have the ability to self-renew and differentiate into the more specialized cell types of a given organ and are found in tissues throughout the body. These cells, whose progeny are termed progenitor cells in human liver and oval cells in rodents, have the potential to treat patients through the generation of hepatic parenchymal cells, even from the patient's own tissue. Little is known regarding the nature of the hepatic progenitor cells. Though they are suggested to reside in the most distal part of the biliary tree, the canal of Hering, the lack of unique surface markers for these cells has hindered their isolation and characterization. Upon activation, they proliferate and form ductular structures, termed "ductular reactions", which radiate into the hepatic parenchyma. The ductular reactions contain activated progenitor cells that not only acquire a phenotype resembling that observed in developing liver but also display markers of differentiation shared with the cholangiocytic or hepatocytic lineages, the two parenchymal hepatic cell types. Interactions between the putative progenitor cells, the surrounding support cells and the extracellular matrix scaffold, all constituting the progenitor cell niche, are likely to be important for regulating progenitor cell activity and differentiation. Therefore, identifying novel progenitor cell markers and deciphering their microenvironment could facilitate clinical use. The aims of the present PhD thesis were to expand knowledge of the hepatic progenitor cell niche and characterize it both during development and in disease. Several animal models of hepatic injury are known to induce activation of the progenitor cells. In order to identify possible progenitor cell markers and niche components

  14. Undifferentiated embryonal sarcoma of the liver in an adult patient.

    PubMed

    Lee, Kyu Ho; Maratovich, Mussin Nadiar; Lee, Kyoung-Bun

    2016-06-01

    Undifferentiated embryonal sarcoma of the liver (UESL) is rare primary hepatic sarcoma and is known to occur in pediatric patients. This case is the UESL occurred in a 51-year old male patient. Multilocular cystic lesion was composed of primitive spindle cells without specific differentiation. This rare case would help to review differential diagnosis of primary sarcoma in liver and cystic neoplasm of the liver. PMID:27377912

  15. Undifferentiated embryonal sarcoma of the liver in an adult patient

    PubMed Central

    Lee, Kyu Ho; Maratovich, Mussin Nadiar; Lee, Kyoung-Bun

    2016-01-01

    Undifferentiated embryonal sarcoma of the liver (UESL) is rare primary hepatic sarcoma and is known to occur in pediatric patients. This case is the UESL occurred in a 51-year old male patient. Multilocular cystic lesion was composed of primitive spindle cells without specific differentiation. This rare case would help to review differential diagnosis of primary sarcoma in liver and cystic neoplasm of the liver. PMID:27377912

  16. 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

  17. Deceased Donor Split Liver Transplantation In Adult Recipients: Is The Learning Curve Over?

    PubMed Central

    Cauley, Ryan P.; Vakili, Khashayar; Fullington, Nora; Potanos, Kristina; Graham, Dionne A.; Finkelstein, Jonathan A.; Kim, Heung Bae

    2016-01-01

    Background Infants have the highest waitlist mortality of all liver transplant candidates. Deceased-donor split liver transplantation, a technique that provides both an adult and pediatric graft, may be the best way to decrease this disproportionate mortality. Yet concern for an increased risk to adult split recipients has discouraged its widespread adoption. We aimed to determine the current risk of graft failure in adult recipients following split liver transplantation. Study Design United Network for Organ Sharing (UNOS) data from 62,190 first-time adult recipients of deceased-donor liver transplants (1995–2010) were analyzed (889 split grafts). Bivariate risk factors (p<0.2) were included in cox proportional hazards models of the effect of transplant type on graft failure. Results Split liver recipients had an over-all hazard-ratio (HR) of graft failure of 1.26 (p<.001) compared to whole liver recipients. The split liver HR was 1.45 (p<.001) in the pre-MELD era (1995–2002), and 1.10 (p=.28) in the MELD era (2002–2010). Interaction analyses suggested an increased risk of split graft failure in Status 1 recipients and those given an exception for hepatocellular carcinoma (HCC). Excluding higher-risk recipients, split and whole grafts had similar outcomes (HR .94, p=.59). Conclusions The risk of graft failure is now similar between split and whole liver recipients in the vast majority of cases – demonstrating that the expansion of split liver allocation may be possible without increasing the overall risk of long-term graft failure in adult recipients. Further prospective analysis should examine if selection bias may account for the possible increase in risk for recipients with HCC or designated Status 1. PMID:23978530

  18. Methylglyoxal Causes Cell Death in Neural Progenitor Cells and Impairs Adult Hippocampal Neurogenesis.

    PubMed

    Chun, Hye Jeong; Lee, Yujeong; Kim, Ah Hyun; Lee, Jaewon

    2016-04-01

    Methylglyoxal (MG) is formed during normal metabolism by processes like glycolysis, lipid peroxidation, and threonine catabolism, and its accumulation is associated with various degenerative diseases, such as diabetes and arterial atherogenesis. Furthermore, MG has also been reported to have toxic effects on hippocampal neurons. However, these effects have not been studied in the context of neurogenesis. Here, we report that MG adversely affects hippocampal neurogenesis and induces neural progenitor cell (NPC) death. MG significantly reduced C17.2 NPC proliferation, and high concentration of MG (500 μM) induced cell death and elevated oxidative stress. Further, MG was found to activate the ERK signaling pathway, indicating elevated stress response. To determine the effects of MG in vivo, mice were administrated with vehicle or MG (0.5 or 1 % in drinking water) for 4 weeks. The numbers of BrdU-positive cells in hippocampi were significantly lower in MG-treated mice, indicating impaired neurogenesis, but MG did not induce neuronal damage or glial activations. Interestingly, MG reduced memory retention when administered to mice at 1 % but not at 0.5 %. In addition, the levels of hippocampal BDNF and synaptophysin were significantly lower in the hippocampi of mice treated with MG at 1 %. Collectively, our findings suggest MG could be harmful to NPCs and to hippocampal neurogenesis. PMID:26690780

  19. Temporal Response of Endogenous Neural Progenitor Cells Following Injury to the Adult Rat Spinal Cord

    PubMed Central

    Mao, Yilin; Mathews, Kathryn; Gorrie, Catherine A.

    2016-01-01

    A pool of endogenous neural progenitor cells (NPCs) found in the ependymal layer and the sub-ependymal area of the spinal cord are reported to upregulate Nestin in response to traumatic spinal cord injury (SCI). These cells could potentially be manipulated within a critical time period offering an innovative approach to the repair of SCI. However, little is known about the temporal response of endogenous NPCs following SCI. This study used a mild contusion injury in rat spinal cord and immunohistochemistry to determine the temporal response of ependymal NPCs following injury and their correlation to astrocyte activation at the lesion edge. The results from the study demonstrated that Nestin staining intensity at the central canal peaked at 24 h post-injury and then gradually declined over time. Reactive astrocytes double labeled by Nestin and glial fibrillary acidic protein (GFAP) were found at the lesion edge and commenced to form the glial scar from 1 week after injury. We conclude that the critical time period for manipulating endogenous NPCs following a spinal cod injury in rats is between 24 h when Nestin expression in ependymal cells is increased and 1 week when astrocytes are activated in large numbers. PMID:27013972

  20. Ring1b bookmarks genes in pancreatic embryonic progenitors for repression in adult β cells.

    PubMed

    van Arensbergen, Joris; García-Hurtado, Javier; Maestro, Miguel Angel; Correa-Tapia, Miguel; Rutter, Guy A; Vidal, Miguel; Ferrer, Jorge

    2013-01-01

    Polycomb-mediated gene repression is essential for embryonic development, yet its precise role in lineage-specific programming is poorly understood. Here we inactivated Ring1b, encoding a polycomb-repressive complex 1 subunit, in pancreatic multipotent progenitors (Ring1b(progKO)). This caused transcriptional derepression of a subset of direct Ring1b target genes in differentiated pancreatic islet cells. Unexpectedly, Ring1b inactivation in differentiated islet β cells (Ring1b(βKO)) did not cause derepression, even after multiple rounds of cell division, suggesting a role for Ring1b in the establishment but not the maintenance of repression. Consistent with this notion, derepression in Ring1b(progKO) islets occurred preferentially in genes that were targeted de novo by Ring1b during pancreas development. The results support a model in which Ring1b bookmarks its target genes during embryonic development, and these genes are maintained in a repressed state through Ring1b-independent mechanisms in terminally differentiated cells. This work provides novel insights into how epigenetic mechanisms contribute to shaping the transcriptional identity of differentiated lineages. PMID:23271347

  1. Promoting the selection and maintenance of fetal liver stem/progenitor cell colonies by layer-by-layer polypeptide tethered supported lipid bilayer.

    PubMed

    Lee, I-Chi; Liu, Yung-Chiang; Tsai, Hsuan-Ang; Shen, Chia-Ning; Chang, Ying-Chih

    2014-12-10

    In this study, we designed and constructed a series of layer-by-layer polypeptide adsorbed supported lipid bilayer (SLB) films as a novel and label-free platform for the isolation and maintenance of rare populated stem cells. In particular, four alternative layers of anionic poly-l-glutamic acid and cationic poly-l-lysine were sequentially deposited on an anionic SLB. We found that the fetal liver stem/progenitor cells from the primary culture were selected and formed colonies on all layer-by-layer polypeptide adsorbed SLB surfaces, regardless of the number of alternative layers and the net charges on those layers. Interestingly, these isolated stem/progenitor cells formed colonies which were maintained for an 8 day observation period. Quartz crystal microbalance with dissipation measurements showed that all SLB-polypeptide films were protein resistant with serum levels significantly lower than those on the polypeptide multilayer films without an underlying SLB. We suggest the fluidic SLB promotes selective binding while minimizing the cell-surface interaction due to its nonfouling nature, thus limiting stem cell colonies from spreading. PMID:25243588

  2. Tg737 inhibition results in malignant transformation in fetal liver stem/progenitor cells by promoting cell-cycle progression and differentiation arrest.

    PubMed

    You, Nan; Liu, Weihui; Zhong, Xiao; Ji, Ru; Zhang, Ming; You, Houcheng; Dou, Kefeng; Tao, Kaishan

    2012-08-01

    Cancer stem/progenitor cells (CSPCs) may originate from the malignant transformation of normal stem cells. However, the mechanism by which normal stem cells undergo such transformation is not understood. Our previous studies provided evidence that Tg737 may play an important role in carcinogenesis of liver stem cells. In this study, we investigated the role of Tg737 in the malignant transformation of fetal liver stem/progenitor cells (FLSPCs). We inhibited Tg737 in FLSPCs using short hairpin RNA (shRNA). The microscopic observations of freshly purified Tg737 normal FLSPCs (nFLSPCs) and Tg737-silent FLSPCs (sFLSPCs), which showed high expression levels of stem cell markers, revealed no significant morphological changes in sFLSPCs. Following RNAi of Tg737, the mRNA and protein levels of sFLSPCs decreased by 81.81% and 80.10% as shown by PCR, Western blot and immunocytochemistry analyses. Excluding apoptosis-related effects, we found that silencing of Tg737 resulted in enhanced cell proliferation through promoting cell-cycle progression via upregulation of cyclin D1 and cyclin B expression (P < 0.05). Silencing of Tg737 also resulted in significant arrest of cell differentiation (P < 0.05), stable expression of both albumin (ALB) and alpha fetoprotein (AFP) (P > 0.05) and quiescent ultrastructure. Assessment of cell malignant traits by transwell migration assays and by growth of xenograft tumors in athymic mice showed that reduced expression of Tg737 greatly promoted cell invasion and hepatocarcinogenesis of FLSPCs (P < 0.05). This work shows that inactivation of Tg737 may play an important role in malignant transformation of FLSPCs. PMID:21837759

  3. Scar formation and lack of regeneration in adult and neonatal liver after stromal injury.

    PubMed

    Masuzaki, Ryota; Zhao, Sophia R; Csizmadia, Eva; Yannas, Ioannis; Karp, Seth J

    2013-01-01

    Known as a uniquely regenerative tissue, the liver shows a remarkable capacity to heal without scarring after many types of acute injury. In contrast, during chronic liver disease, the liver responds with fibrosis, which can progress to cirrhosis and ultimately liver failure. The cause of this shift from a nonfibrotic to a fibrotic response is unknown. We hypothesized that stromal injury is a key event that prevents restoration of normal liver architecture. To test this, we developed a model of stromal injury using a surgical incision through the normal liver in adult and neonatal mice. This injury produces minimal cell death but locally complete stromal (extracellular matrix) disruption. The adult liver responds with inflammation and stellate cell activation, culminating in fibrosis characterized by collagen deposition. This sequence of events is remarkably similar to the fibrotic response leading to cirrhosis. Studies in neonates reveal a similar fibrotic response to a stromal injury. These findings suggest that extracellular matrix disruption leads not to regeneration but rather to scar, similar to other mammalian organs. These findings may shed light on the pathogenesis of chronic liver disease, and suggest therapeutic strategies. PMID:23228176

  4. Liver transplantation for a giant mesenchymal hamartoma of the liver in an adult: Case report and review of the literature

    PubMed Central

    Li, Jiang; Cai, Jin-Zhen; Guo, Qing-Jun; Li, Jun-Jie; Sun, Xiao-Ye; Hu, Zhan-Dong; Cooper, David KC; Shen, Zhong-Yang

    2015-01-01

    Mesenchymal hamartomas of the liver (MHLs) in adults are rare and potentially premalignant lesions, which present as solid/cystic neoplasms. We report a rare case of orthotopic liver transplantation in a patient with a giant MHL. In 2013, a 34-year-old female sought medical advice after a 2-year history of progressive abdominal distention and respiratory distress. Physical examination revealed an extensive mass in the abdomen. Computed tomography (CT) of her abdomen revealed multiple liver cysts, with the diameter of largest cyst being 16 cm × 14 cm. The liver hilar structures were not clearly displayed. The adjacent organs were compressed and displaced. Initial laboratory tests, including biochemical investigations and coagulation profile, were unremarkable. Tumor markers, including levels of AFP, CEA and CA19-9, were within the normal ranges. The patient underwent orthotopic liver transplantation in November 2013, the liver being procured from a 40-year-old man after cardiac death following traumatic brain injury. Warm ischemic time was 7.5 min and cold ischemic time was 3 h. The recipient underwent classical orthotopic liver transplantation. The recipient operative procedure took 8.5 h, the anhepatic phase lasting for 1 h without the use of venovenous bypass. The immunosuppressive regimen included intraoperative induction with basiliximab and high-dose methylprednisolone, and postoperative maintenance with tacrolimus, mycophenolate mofetil, and prednisone. The recipient’s diseased liver weighed 21 kg (dry weight) and measured 41 cm × 32 cm × 31 cm. Histopathological examination confirmed the diagnosis of an MHL. The patient did not experience any acute rejection episode or other complication. All the laboratory tests returned to normal within one month after surgery. Three months after transplantation, the immunosuppressive therapy was reduced to tacrolimus monotherapy, and the T-tube was removed after cholangiography showed no abnormalities. Twelve months

  5. Liver transplantation for a giant mesenchymal hamartoma of the liver in an adult: Case report and review of the literature.

    PubMed

    Li, Jiang; Cai, Jin-Zhen; Guo, Qing-Jun; Li, Jun-Jie; Sun, Xiao-Ye; Hu, Zhan-Dong; Cooper, David K C; Shen, Zhong-Yang

    2015-05-28

    Mesenchymal hamartomas of the liver (MHLs) in adults are rare and potentially premalignant lesions, which present as solid/cystic neoplasms. We report a rare case of orthotopic liver transplantation in a patient with a giant MHL. In 2013, a 34-year-old female sought medical advice after a 2-year history of progressive abdominal distention and respiratory distress. Physical examination revealed an extensive mass in the abdomen. Computed tomography (CT) of her abdomen revealed multiple liver cysts, with the diameter of largest cyst being 16 cm × 14 cm. The liver hilar structures were not clearly displayed. The adjacent organs were compressed and displaced. Initial laboratory tests, including biochemical investigations and coagulation profile, were unremarkable. Tumor markers, including levels of AFP, CEA and CA19-9, were within the normal ranges. The patient underwent orthotopic liver transplantation in November 2013, the liver being procured from a 40-year-old man after cardiac death following traumatic brain injury. Warm ischemic time was 7.5 min and cold ischemic time was 3 h. The recipient underwent classical orthotopic liver transplantation. The recipient operative procedure took 8.5 h, the anhepatic phase lasting for 1 h without the use of venovenous bypass. The immunosuppressive regimen included intraoperative induction with basiliximab and high-dose methylprednisolone, and postoperative maintenance with tacrolimus, mycophenolate mofetil, and prednisone. The recipient's diseased liver weighed 21 kg (dry weight) and measured 41 cm × 32 cm × 31 cm. Histopathological examination confirmed the diagnosis of an MHL. The patient did not experience any acute rejection episode or other complication. All the laboratory tests returned to normal within one month after surgery. Three months after transplantation, the immunosuppressive therapy was reduced to tacrolimus monotherapy, and the T-tube was removed after cholangiography showed no abnormalities. Twelve months

  6. Characterization of a unique technique for culturing primary adult human epithelial progenitor/“stem cells”

    PubMed Central

    2012-01-01

    be generated without the use of the enzyme trypsin to split the cultures. The cells are small in diameter and have basal cell progenitor/”stem” (P/SC) cell characteristics induced by daily feeding with larger than normal medium volumes. The ePUK epithelial cells have the potential to be used in regenerative medicine and for basic studies of epithelia P/SC phenotype. PMID:22726819

  7. Adult mouse model of early hepatocellular carcinoma promoted by alcoholic liver disease

    PubMed Central

    Ambade, Aditya; Satishchandran, Abhishek; Gyongyosi, Benedek; Lowe, Patrick; Szabo, Gyongyi

    2016-01-01

    AIM: To establish a mouse model of alcohol-driven hepatocellular carcinoma (HCC) that develops in livers with alcoholic liver disease (ALD). METHODS: Adult C57BL/6 male mice received multiple doses of chemical carcinogen diethyl nitrosamine (DEN) followed by 7 wk of 4% Lieber-DeCarli diet. Serum alanine aminotransferase (ALT), alpha fetoprotein (AFP) and liver Cyp2e1 were assessed. Expression of F4/80, CD68 for macrophages and Ly6G, MPO, E-selectin for neutrophils was measured. Macrophage polarization was determined by IL-1β/iNOS (M1) and Arg-1/IL-10/CD163/CD206 (M2) expression. Liver steatosis and fibrosis were measured by oil-red-O and Sirius red staining respectively. HCC development was monitored by magnetic resonance imaging, confirmed by histology. Cellular proliferation was assessed by proliferating cell nuclear antigen (PCNA). RESULTS: Alcohol-DEN mice showed higher ALTs than pair fed-DEN mice throughout the alcohol feeding without weight gain. Alcohol feeding resulted in increased ALT, liver steatosis and inflammation compared to pair-fed controls. Alcohol-DEN mice had reduced steatosis and increased fibrosis indicating advanced liver disease. Molecular characterization showed highest levels of both neutrophil and macrophage markers in alcohol-DEN livers. Importantly, M2 macrophages were predominantly higher in alcohol-DEN livers. Magnetic resonance imaging revealed increased numbers of intrahepatic cysts and liver histology confirmed the presence of early HCC in alcohol-DEN mice compared to all other groups. This correlated with increased serum alpha-fetoprotein, a marker of HCC, in alcohol-DEN mice. PCNA immunostaining revealed significantly increased hepatocyte proliferation in livers from alcohol-DEN compared to pair fed-DEN or alcohol-fed mice. CONCLUSION: We describe a new 12-wk HCC model in adult mice that develops in livers with alcoholic hepatitis and defines ALD as co-factor in HCC. PMID:27122661

  8. A study of the awareness of chronic liver diseases among Korean adults

    PubMed Central

    Jun, Dae Won; Cho, Yong Kyun; Lee, Chang Hyeong; Kim, Seok Hyun; Eun, Jong Ryul

    2011-01-01

    Background/Aims Chronic liver disease is closely associated with lifestyle, and public enlightenment of the lifestyle factors is important in reducing prevalence of chronic liver disease. The KASL (Korean Association for the Study of the Liver) conducted a survey of basic information and epidemiological data regarding chronic liver diseases. Methods A survey of chronic liver disease involving a total of 2,794 respondents was conducted. The respondents included patients and their guardians, visitors for health check-ups, and online pollees who completed a questionnaire on the awareness of fatty liver or chronic liver disease. Results Of the entire cohort, 854 (39.7%) said they have had or still have fatty liver or an elevated transaminase level (>40 IU/L), but only 23.4% of the respondents had visited a hospital. It was found that 35% of healthy subjects and 45% of patients and their guardians misunderstood hepatitis B as the hereditary disesase. Furthermore, 26% of the subjects responded that patients with inactive hepatitis B do not require regular follow-up. While 17.9% answered that it is not too late to test for liver cancer when symptoms arise, 38.8% believed that liver transplant in liver cancer patients has a low success rate and is thus not recommended. Conclusions Despite the inundation of information and widespread media advertising, the awareness of chronic liver disease is unsatisfactory among Korean adults. Systematic nationwide studies are needed to obtain data and information regarding the prevalence of chronic liver disease and patterns of use of the health-care system. PMID:21757980

  9. Foetal hepatic progenitor cells assume a cholangiocytic cell phenotype during two-dimensional pre-culture

    PubMed Central

    Anzai, Kazuya; Chikada, Hiromi; Tsuruya, Kota; Ida, Kinuyo; Kagawa, Tatehiro; Inagaki, Yutaka; Mine, Tesuya; Kamiya, Akihide

    2016-01-01

    Liver consists of parenchymal hepatocytes and other cells. Liver progenitor cell (LPC) is the origin of both hepatocytes and cholangiocytic cells. The analyses of mechanism regulating differentiation of LPCs into these functional cells are important for liver regenerative therapy using progenitor cells. LPCs in adult livers were found to form cysts with cholangiocytic characteristics in 3D culture. In contrast, foetal LPCs cannot form these cholangiocytic cysts in the same culture. Thus, the transition of foetal LPCs into cholangiocytic progenitor cells might occur during liver development. Primary CD45−Ter119−Dlk1+ LPCs derived from murine foetal livers formed ALBUMIN (ALB)+CYTOKERATIN (CK)19− non-cholangiocytic cysts within 3D culture. In contrast, when foetal LPCs were pre-cultured on gelatine-coated dishes, they formed ALB−CK19+ cholangiocytic cysts. When hepatocyte growth factor or oncostatin M, which are inducers of hepatocytic differentiation, was added to pre-culture, LPCs did not form cholangiocytic cysts. These results suggest that the pre-culture on gelatine-coated dishes changed the characteristics of foetal LPCs into cholangiocytic cells. Furthermore, neonatal liver progenitor cells were able to form cholangiocytic cysts in 3D culture without pre-culture. It is therefore possible that the pre-culture of mid-foetal LPCs in vitro functioned as a substitute for the late-foetal maturation step in vivo. PMID:27335264

  10. Liver transplantation with preservation of the inferior vena cava in case of symptomatic adult polycystic disease.

    PubMed

    Lerut, Jan; Ciccarelli, Olga; Rutgers, Matthieu; Orlando, Giuseppe; Mathijs, Jules; Danse, Etienne; Goffin, Eric; Gigot, Jean-François; Goffette, Pierre

    2005-05-01

    Adult polycystic liver disease (APLD) is a rare disorder of the liver parenchyma, the treatment of which is still controversial. Conservative surgery may have a significant morbidity and is often ineffective in the long run. Liver replacement may be indicated in case of incapacitating hepatomegaly. Patients (one male, five females) undergoing liver transplantation for symptomatic APLD is presented in this study. The particular nature of this series is the fact that successful transplantation was performed in all cases with preservation of the recipient's inferior vena cava and without use of veno-venous bypass despite massive hepatomegaly and previous extensive liver surgery (in three cases). There was minimal morbidity and no mortality. All patients have excellent quality of life with a median follow-up of 41 months (range: 12-58) as testified by a median Karnofsky score of 90% (range: 80-100%). PMID:15819798

  11. 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

  12. Outcomes of adult living donor liver transplantation: comparison of the Adult-to-adult Living Donor Liver Transplantation Cohort Study and the national experience.

    PubMed

    Olthoff, Kim M; Abecassis, Michael M; Emond, Jean C; Kam, Igal; Merion, Robert M; Gillespie, Brenda W; Tong, Lan

    2011-07-01

    The study objectives were to determine whether the findings of the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) reflect the U.S. national experience and to define risk factors for patient mortality and graft loss in living donor liver transplantation (LDLT). A2ALL previously identified risk factors for mortality after LDLT, which included early center experience, older recipient age, and longer cold ischemia time. LDLT procedures at 9 A2ALL centers (n = 702) and 67 non-A2ALL centers (n = 1664) from January 1998 through December 2007 in the Scientific Registry of Transplant Recipients database were analyzed. Potential predictors of time from transplantation to death or graft failure were tested using Cox regression. No significant difference in overall mortality between A2ALL and non-A2ALL centers was found. Higher hazard ratios (HRs) were associated with donor age (HR = 1.13 per 10 years, P = 0.0002), recipient age (HR = 1.20 per 10 years, P = 0.0003), serum creatinine levels (HR = 1.52 per loge unit increase, P < 0.0001), hepatocellular carcinoma (HR = 2.12, P<0.0001) or hepatitis C virus (HR = 1.18, P = 0.026), intensive care unit stay (HR = 2.52, P< 0.0001) or hospitalization (HR = 1.62, P < 0.0001) versus home, earlier center experience (LDLT case number 15: HR = 1.61, P < 0.0001, and a cold ischemia time >4.5 hours (HR = 1.79, P = 0.0006). Except for center experience, risk factor effects between A2ALL and non-A2ALL centers were not significantly different. Variables associated with graft loss were identified and showed similar trends. In conclusion, mortality and graft loss risk factors were similar in A2ALL and non-A2ALL centers. These analyses demonstrate that findings from the A2ALL consortium are relevant to other centers in the U.S. performing LDLT, and conclusions and recommendations from A2ALL may help to guide clinical decision making. PMID:21360649

  13. The usefulness of hepatobiliary scintigraphy in the diagnosis of complications after adult-to-adult living donor liver transplantation.

    PubMed

    Kim, Jae Seung; Moon, Dae Hyuk; Lee, Sung Gyu; Lee, Young Joo; Park, Kwang Min; Hwang, Shin; Lee, Hee Kyung

    2002-04-01

    Living donor liver transplantation has become an accepted procedure to overcome the shortage of adult donor organs. The aim of this study was to evaluate the usefulness of hepatobiliary scintigraphy in the diagnosis of complications after adult-to-adult living donor liver transplantation. We analysed 82 hepatobiliary scintigraphy studies performed using technetium-99m DISIDA in 60 adult patients (44 males, 16 females) who had been transplanted with a living donor's hepatic lobe (right lobe, 32; left lobe, 28). Indications for hepatobiliary scintigraphy were abnormal symptoms and/or liver function tests ( n=54) or suspected bile leak or biloma ( n=28). Median interval between transplantation and scintigraphy was 69 days (9 days to 23 months). Scintigraphic findings were classified into hepatic parenchymal dysfunction, total biliary obstruction, segmental biliary obstruction, bile leak and normal graft. Scintigraphic findings were confirmed by liver biopsy in 17 cases, and by radiological and clinical follow-up in 65 cases. There were 29 events relating to biliary complications (six total biliary obstructions, eight segmental biliary obstructions and 15 bile leaks) and 19 relating to non-biliary complications (15 cases of rejection, two of infection and two of vascular compromise) in 38 patients. Hepatobiliary scintigraphy provided the correct diagnosis in all eight segmental and five of six total biliary obstructions, and in all 15 cases of bile leak. Of the 19 non-biliary complications, 16 showed parenchymal dysfunction regardless of the aetiology and three showed total biliary obstruction on scintigraphy. All but three of 34 normally functioning grafts were normal on scintigraphy. The diagnostic sensitivity and specificity of scintigraphy for biliary obstruction in the 54 patients with abnormal symptoms or liver function tests were 93% (100% for segmental, 83% for total) and 88% (35/40), respectively. The sensitivity and specificity were each 100% (15/15, 13

  14. 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

  15. Hepatic progenitor cells in canine and feline medicine: potential for regenerative strategies

    PubMed Central

    2014-01-01

    New curative therapies for severe liver disease are urgently needed in both the human and veterinary clinic. It is important to find new treatment modalities which aim to compensate for the loss of parenchymal tissue and to repopulate the liver with healthy hepatocytes. A prime focus in regenerative medicine of the liver is the use of adult liver stem cells, or hepatic progenitor cells (HPCs), for functional recovery of liver disease. This review describes recent developments in HPC research in dog and cat and compares these findings to experimental rodent studies and human pathology. Specifically, the role of HPCs in liver regeneration, key components of the HPC niche, and HPC activation in specific types of canine and feline liver disease will be reviewed. Finally, the potential applications of HPCs in regenerative medicine of the liver are discussed and a potential role is suggested for dogs as first target species for HPC-based trials. PMID:24946932

  16. Hepatic progenitor cells in canine and feline medicine: potential for regenerative strategies.

    PubMed

    Kruitwagen, Hedwig S; Spee, Bart; Schotanus, Baukje A

    2014-01-01

    New curative therapies for severe liver disease are urgently needed in both the human and veterinary clinic. It is important to find new treatment modalities which aim to compensate for the loss of parenchymal tissue and to repopulate the liver with healthy hepatocytes. A prime focus in regenerative medicine of the liver is the use of adult liver stem cells, or hepatic progenitor cells (HPCs), for functional recovery of liver disease. This review describes recent developments in HPC research in dog and cat and compares these findings to experimental rodent studies and human pathology. Specifically, the role of HPCs in liver regeneration, key components of the HPC niche, and HPC activation in specific types of canine and feline liver disease will be reviewed. Finally, the potential applications of HPCs in regenerative medicine of the liver are discussed and a potential role is suggested for dogs as first target species for HPC-based trials. PMID:24946932

  17. Intravenous Multipotent Adult Progenitor Cell Therapy Attenuates Activated Microglial/Macrophage Response and Improves Spatial Learning After Traumatic Brain Injury

    PubMed Central

    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.

    2013-01-01

    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. PMID:24191266

  18. Chromatin Remodeling Factor Brg1 Supports the Early Maintenance and Late Responsiveness of Nestin-Lineage Adult Neural Stem and Progenitor Cells.

    PubMed

    Petrik, David; Latchney, Sarah E; Masiulis, Irene; Yun, Sanghee; Zhang, Zilai; Wu, Jiang I; Eisch, Amelia J

    2015-12-01

    Insights from embryonic development suggest chromatin remodeling is important in adult neural stem cells (aNSCs) maintenance and self-renewal, but this concept has not been fully explored in the adult brain. To assess the role of chromatin remodeling in adult neurogenesis, we inducibly deleted Brg1--the core subunit of SWI/SNF-like Brg1/Brm-associated factor chromatin remodeling complexes--in nestin-expressing aNSCs and their progeny in vivo and in culture. This resulted in abnormal adult neurogenesis in the hippocampus, which initially reduced hippocampal aNSCs and progenitor maintenance, and later reduced its responsiveness to physiological stimulation. Mechanistically, deletion of Brg1 appeared to impair cell cycle progression, which is partially due to elevated p53 pathway and p21 expression. Knockdown of p53 rescued the neurosphere growth defects caused by Brg1 deletion. Our results show that epigenetic chromatin remodeling (via a Brg1 and p53/p21-dependent process) determines the aNSCs and progenitor maintenance and responsiveness of neurogenesis. PMID:26418130

  19. BCRP protein levels do not differ regionally in adult human livers, but decline in the elderly.

    PubMed

    Riches, Zoe; Abanda, Ngu; Collier, Abby C

    2015-12-01

    The aim of this study was to characterize the ontogeny and variability of the BCRP (ABCG2) transporter in healthy human liver. Levels of BCRP mRNA and protein were determined with q-RT-PCR and western blot in a cohort of 87 human livers aged from 7 days to 87 years. A study of the regional expression of BCRP within adult livers was also performed in a nested cohort of 14 individuals with multiple samples per person collected from pre-selected sites. Levels of BCRP mRNA were not significantly different at any age, but protein levels for BCRP were lower in the elderly compared with adults (p < 0.001) and children (p < 0.05). The intra-liver levels of BCRP protein ranged approximately 6.5-fold and inter-liver BCRP protein varied 8.5-fold in the cohort. No differences in BCRP mRNA or protein were observed with sex or ethnicity, although higher levels of BCRP mRNA were observed in livers from overweight individuals (Body Mass Index ≥ 25-29.9) as compared to underweight or ideal weight individuals. There were no differences in the levels of BCRP mRNA or protein in different regions of the large lobe (n = 3 regions), small lobe (n = 3 regions), directly adjacent to the portal vein or directly adjacent to the common bile duct. This indicates that BCRP researchers can source tissue from all parts of the adult liver without artificial bias in their results. Lower BCRP protein expression in the elderly may be associated with compromised xeno- and endobiotic transport. PMID:26462791

  20. Is severe progressive liver disease caused by alpha-1-antitrypsin deficiency more common in children or adults?

    PubMed

    Chu, Andrew S; Chopra, Kapil B; Perlmutter, David H

    2016-07-01

    The classical form of alpha-1-antitrypsin deficiency (A1ATD) is known to cause liver disease in children and adults, but there is relatively little information about the risk of severe, progressive liver disease and the need for liver transplantation. To better understand how newly evolving pharmacological, genetic, and cellular therapies may be targeted according to risk for progressive liver disease, we sought to determine the age distribution of A1ATD as a cause of severe liver disease, as defined by the need for liver transplantation. Using 3 US liver transplantation databases for the period 1991-2012, we found 77.2% of 1677 liver transplants with a reported diagnosis of A1ATD were adults. The peak age range was 50-64 years. Using 2 of the databases which included specific A1AT phenotypes, we found that many of these adults who undergo liver transplantation with A1ATD as the diagnosis are heterozygotes and have other potential causes of liver disease, most notably obesity and ethanol abuse. However, even when these cases are excluded and only ZZ and SZ phenotypes are considered, severe liver disease requiring transplantation is more than 2.5 times as likely in adults. The analysis also showed a markedly increased risk for males. In the pediatric group, almost all of the transplants are done in children less than 5 years of age. In conclusion, A1ATD causes progressive liver disease most commonly in adults with males in the highest risk category. In the pediatric group, children less than 5 years of age are highest in risk. These results suggest that A1ATD most commonly causes liver disease by mechanisms similar to age-dependent degenerative diseases and more rarely in children by powerful modifiers. Liver Transplantation 22 886-894 2016 AASLD. PMID:26946192

  1. Disruption of polyubiquitin gene Ubc leads to defective proliferation of hepatocytes and bipotent fetal liver epithelial progenitor cells

    SciTech Connect

    Park, Hyejin; Yoon, Min-Sik; Ryu, Kwon-Yul

    2013-06-07

    Highlights: •Proliferation capacity of Ubc{sup −/−} FLCs was reduced during culture in vitro. •Ubc is required for proliferation of both hepatocytes and bipotent FLEPCs. •Bipotent FLEPCs exhibit highest Ubc transcription and proliferation capacity. •Cell types responsible for Ubc{sup −/−} fetal liver developmental defect were identified. -- Abstract: We have previously demonstrated that disruption of polyubiquitin gene Ubc leads to mid-gestation embryonic lethality most likely due to a defect in fetal liver development, which can be partially rescued by ectopic expression of Ub. In a previous study, we assessed the cause of embryonic lethality with respect to the fetal liver hematopoietic system. We confirmed that Ubc{sup −/−} embryonic lethality could not be attributed to impaired function of hematopoietic stem cells, which raises the question of whether or not FLECs such as hepatocytes and bile duct cells, the most abundant cell types in the liver, are affected by disruption of Ubc and contribute to embryonic lethality. To answer this, we isolated FLCs from E13.5 embryos and cultured them in vitro. We found that proliferation capacity of Ubc{sup −/−} cells was significantly reduced compared to that of control cells, especially during the early culture period, however we did not observe the increased number of apoptotic cells. Furthermore, levels of Ub conjugate, but not free Ub, decreased upon disruption of Ubc expression in FLCs, and this could not be compensated for by upregulation of other poly- or mono-ubiquitin genes. Intriguingly, the highest Ubc expression levels throughout the entire culture period were observed in bipotent FLEPCs. Hepatocytes and bipotent FLEPCs were most affected by disruption of Ubc, resulting in defective proliferation as well as reduced cell numbers in vitro. These results suggest that defective proliferation of these cell types may contribute to severe reduction of fetal liver size and potentially mid

  2. Differences in DNA damage and repair produced by systemic, hepatocarcinogenic and sarcomagenic dibenzocarbazole derivatives in a model of rat liver progenitor cells.

    PubMed

    Valovicová, Zuzana; Marvanová, Sona; Mészárosová, Monika; Srancíková, Annamária; Trilecová, Lenka; Milcová, Alena; Líbalová, Helena; Vondrácek, Jan; Machala, Miroslav; Topinka, Jan; Gábelová, Alena

    2009-06-01

    Liver progenitor (oval) cells are a potential target cell population for hepatocarcinogens. Our recent study showed that the liver carcinogens 7H-dibenzo[c,g]carbazole (DBC) and 5,9-dimethyldibenzo[c,g]carbazole (DiMeDBC), but not the sarcomagen N-methyldibenzo[c,g]carbazole (N-MeDBC), induced several cellular events associated with tumor promotion in WB-F344 cells, an in vitro model of liver oval cells [J. Vondracek, L. Svihalkova-Sindlerova, K. Pencikova, P. Krcmar, Z. Andrysik, K. Chramostova, S. Marvanova, Z. Valovicova, A. Kozubik, A. Gabelova, M. Machala, 7H-Dibenzo[c,g]carbazole and 5,9-dimethyldibenzo[c,g]carbazole exert multiple toxic events contributing to tumor promotion in rat liver epithelial 'stem-like' cells, Mutat. Res. Fundam. Mol. Mech. Mutagen. 596 (2006) 43-56]. In this study, we focused on the genotoxic effects generated by these dibenzocarbazoles in WB-F344 cells to better understand the cellular and molecular mechanisms involved in hepatocarcinogenesis. Lower IC(50) values determined for DBC and DiMeDBC, as compared with N-MeDBC, indicated a higher sensitivity of WB-F344 cells towards hepatocarcinogens. Accordingly, DBC produced a dose-dependent DNA-adduct formation resulting in substantial inhibition of DNA replication and transcription. In contrast, DNA-adduct number detected in DiMeDBC-exposed cells was almost negligible, whereas N-MeDBC produced a low level of DNA adducts. Although all dibenzocarbazoles significantly increased the level of strand breaks (p<0.05) and micronuclei (p<0.001) after 2-h treatment, differences in the kinetics of strand break rejoining were found. The strand break level in DiMeDBC- and N-MeDBC-exposed cells returned to near the background level within 24h after treatment, whereas a relatively high DNA damage level was detected in DBC-treated cells up to 48h after exposure. Additional breaks detected after incubation of DiMeDBC-exposed WB-F344 cells with a repair-specific endonuclease, along with a nearly 3-fold

  3. Adult DRG Stem/Progenitor Cells Generate Pericytes in the Presence of Central Nervous System (CNS) Developmental Cues, and Schwann Cells in Response to CNS Demyelination.

    PubMed

    Vidal, Marie; Maniglier, Madlyne; Deboux, Cyrille; Bachelin, Corinne; Zujovic, Violetta; Baron-Van Evercooren, Anne

    2015-06-01

    It has been proposed that the adult dorsal root ganglia (DRG) harbor neural stem/progenitor cells (NPCs) derived from the neural crest. However, the thorough characterization of their stemness and differentiation plasticity was not addressed. In this study, we investigated adult DRG-NPC stem cell properties overtime, and their fate when ectopically grafted in the central nervous system. We compared them in vitro and in vivo to the well-characterized adult spinal cord-NPCs derived from the same donors. Using micro-dissection and neurosphere cultures, we demonstrate that adult DRG-NPCs have quasi unlimited self-expansion capacities without compromising their tissue specific molecular signature. Moreover, they differentiate into multiple peripheral lineages in vitro. After transplantation, adult DRG-NPCs generate pericytes in the developing forebrain but remyelinating Schwann cells in response to spinal cord demyelination. In addition, we show that axonal and endothelial/astrocytic factors as well astrocytes regulate the fate of adult DRG-NPCs in culture. Although the adult DRG-NPC multipotency is restricted to the neural crest lineage, their dual responsiveness to developmental and lesion cues highlights their impressive adaptive and repair potentials making them valuable targets for regenerative medicine. PMID:25786382

  4. Changes in liver and spleen volumes after living liver donation: A report from the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL)

    PubMed Central

    Emond, Jean C.; Fisher, Robert A.; Everson, Gregory; Samstein, Benjamin; Pomposelli, James J.; Zhao, Binsheng; Forney, Sarah; Olthoff, Kim M.; Baker, Talia B.; Gillespie, Brenda W.; Merion, Robert M.

    2014-01-01

    Previous reports have drawn attention to persistently decreased platelet counts among liver donors. We hypothesized an etiologic association between altered platelet counts and post-donation splenomegaly and sought to explore this relationship. This study analyzed de-identified CT/MR scans of 388 donors from 9 A2ALL centers read at a central computational image analysis lab. Resulting liver and spleen volumes were correlated with time-matched clinical lab values. Pre-donation liver volumes varied twofold in healthy subjects, even when normalized by body surface area (BSA) (range: 522 – 1887cc/m2, N=346). At 3 months post-donation liver volumes were, on average, 79% of pre-donation volumes (IQR: 73-86%, N=165) and approached 88% at 1 year (IQR: 80-93%, N=75). The mean spleen volume pre-donation was 245 cc (N=346). Spleen volumes greater than 100% of pre-donation volume occurred in 92% of donors at 3 months (N=165) and 88% at 1 year post-donation (N=75). We sought to develop a standard spleen volume (SSV) model to predict “normal” spleen volumes in donors pre-donation and found that decreased platelet counts, younger age, higher pre-donation liver volume, higher hemoglobin and higher BSA predicted a larger spleen volume (N=344, R2=0.52). When applied to post-donation values some large volumes were under predicted by the SSV model. Models developed on the reduced sample of post-donation volumes yielded smaller under-predictions. These findings confirm previous observations of thrombocytopenia associated with splenomegaly post-donation. The results of the SSV model suggest the biology of this phenomenon is complex. This merits further long term mechanistic studies of liver donors with investigation into the role of other factors such as thrombopoietin, and exposure to viral infections to better understand the evolution of spleen volume after liver donation. PMID:25488878

  5. Mesangiogenic Progenitor Cells Derived from One Novel CD64brightCD31brightCD14neg Population in Human Adult Bone Marrow

    PubMed Central

    Barachini, Serena; Montali, Marina; Carnicelli, Vittoria; Fazzi, Rita; Parchi, Paolo; Petrini, Mario

    2016-01-01

    Mesenchymal stromal cells (MSCs) have been the object of extensive research for decades, due to their intrinsic clinical value. Nonetheless, the unambiguous identification of a unique in vivo MSC progenitor is still lacking, and the hypothesis that these multipotent cells could possibly arise from different in vivo precursors has been gaining consensus in the last years. We identified a novel multipotent cell population in human adult bone marrow that we first named Mesodermal Progenitor Cells (MPCs) for the ability to differentiate toward the mesenchymal lineage, while still retaining angiogenic potential. Despite extensive characterization, MPCs positioning within the differentiation pathway and whether they can be ascribed as possible distinctive progenitor of the MSC lineage is still unclear. In this study, we describe the ex vivo isolation of one novel bone marrow subpopulation (Pop#8) with the ability to generate MPCs. Multicolor flow cytometry in combination with either fluorescence-activated cell sorting or magnetic-activated cell sorting were applied to characterize Pop#8 as CD64brightCD31brightCD14neg. We defined Pop#8 properties in culture, including the potential of Pop#8-derived MPCs to differentiate into MSCs. Gene expression data were suggestive of Pop#8 in vivo involvement in hematopoietic stem cell niche constitution/maintenance. Pop#8 resulted over three logs more frequent than other putative MSC progenitors, corroborating the idea that most of the controversies regarding culture-expanded MSCs could be the consequence of different culture conditions that select or promote particular subpopulations of precursors. PMID:26975798

  6. Mesangiogenic Progenitor Cells Derived from One Novel CD64(bright)CD31(bright)CD14(neg) Population in Human Adult Bone Marrow.

    PubMed

    Pacini, Simone; Barachini, Serena; Montali, Marina; Carnicelli, Vittoria; Fazzi, Rita; Parchi, Paolo; Petrini, Mario

    2016-05-01

    Mesenchymal stromal cells (MSCs) have been the object of extensive research for decades, due to their intrinsic clinical value. Nonetheless, the unambiguous identification of a unique in vivo MSC progenitor is still lacking, and the hypothesis that these multipotent cells could possibly arise from different in vivo precursors has been gaining consensus in the last years. We identified a novel multipotent cell population in human adult bone marrow that we first named Mesodermal Progenitor Cells (MPCs) for the ability to differentiate toward the mesenchymal lineage, while still retaining angiogenic potential. Despite extensive characterization, MPCs positioning within the differentiation pathway and whether they can be ascribed as possible distinctive progenitor of the MSC lineage is still unclear. In this study, we describe the ex vivo isolation of one novel bone marrow subpopulation (Pop#8) with the ability to generate MPCs. Multicolor flow cytometry in combination with either fluorescence-activated cell sorting or magnetic-activated cell sorting were applied to characterize Pop#8 as CD64(bright)CD31(bright)CD14(neg). We defined Pop#8 properties in culture, including the potential of Pop#8-derived MPCs to differentiate into MSCs. Gene expression data were suggestive of Pop#8 in vivo involvement in hematopoietic stem cell niche constitution/maintenance. Pop#8 resulted over three logs more frequent than other putative MSC progenitors, corroborating the idea that most of the controversies regarding culture-expanded MSCs could be the consequence of different culture conditions that select or promote particular subpopulations of precursors. PMID:26975798

  7. Open-Porous Hydroxyapatite Scaffolds for Three-Dimensional Culture of Human Adult Liver Cells

    PubMed Central

    Schmelzer, Eva; Over, Patrick; Nettleship, Ian; Gerlach, Joerg C.

    2016-01-01

    Liver cell culture within three-dimensional structures provides an improved culture system for various applications in basic research, pharmacological screening, and implantable or extracorporeal liver support. Biodegradable calcium-based scaffolds in such systems could enhance liver cell functionality by providing endothelial and hepatic cell support through locally elevated calcium levels, increased surface area for cell attachment, and allowing three-dimensional tissue restructuring. Open-porous hydroxyapatite scaffolds were fabricated and seeded with primary adult human liver cells, which were embedded within or without gels of extracellular matrix protein collagen-1 or hyaluronan. Metabolic functions were assessed after 5, 15, and 28 days. Longer-term cultures exhibited highest cell numbers and liver specific gene expression when cultured on hydroxyapatite scaffolds in collagen-1. Endothelial gene expression was induced in cells cultured on scaffolds without extracellular matrix proteins. Hydroxyapatite induced gene expression for cytokeratin-19 when cells were cultured in collagen-1 gel while culture in hyaluronan increased cytokeratin-19 gene expression independent of the use of scaffold in long-term culture. The implementation of hydroxyapatite composites with extracellular matrices affected liver cell cultures and cell differentiation depending on the type of matrix protein and the presence of a scaffold. The hydroxyapatite scaffolds enable scale-up of hepatic three-dimensional culture models for regenerative medicine applications. PMID:27403430

  8. Serial volumetric assessment of large for size liver grafts after whole cadaveric liver transplant in adults: do large liver grafts shrink in size?

    PubMed Central

    Bekheit, Mohamed; Rajakannu, Muthukumarassamy; Bucur, Petru; Adam, Rene; SaCunha, Antonio; Castaing, Denis; Cherqui, Daniel; Vibert, Eric

    2015-01-01

    Background After whole graft orthotopic liver transplantation (OLT), adaptation of the large grafts' volume to recipient weight is widely accepted despite the paucity of evidence on this subject. Methods Thirty nine patients with GRWR > 2.5% were included in this study and subsequently divided into two groups with 3 ≥ GRWR > 3%. Patients had CT scans at three predetermined time points after OLT used for measuring the liver volume. The objective of this study is to evaluate the volumetric changes of whole large liver grafts after adult OLT. Results At LT, the mean graft recipient body weight ratio (GRWR) was 3.1 ± 0.4%. The mean liver weight was 1881 ± 68 g at LT, 2014 ± 99 ml at one week, 1725 ± 126 ml at 3 months, and 1632 ± 117 (ml) at >6 months. There is an initial increase at 1 week after LT and a subsequent decrease of liver volume on later measurements. None of the late volume measurements were significantly different from the initial graft volume at liver transplant in pair wise comparisons ANOVA repeated measures (p > 0.05). Similarly, the mean GRWR did not change significantly between the initial calculation at transplantation date and the subsequent measurements during the different study time points (F = 0.04, p = 0.96) with a mean of 3.1% (95% CI = 2.2–4.2). AUC ROC discriminated a cutoff of 3% for the initial GRWR above which grafts tend to decrease in size over time (c statistics = 0.74, p = 0.036). In a Clustered ANOVA repeated measures, there was no significant difference in the changes of liver volume between both groups. However, patients with GRWR > 3 showed a trend towards a latent reduction in volume over the tracing period. There was a tendency, but none significant; towards a higher bilirubin, AST, ALT levels over the first postoperative days in recipients with GRWR > 3. Conclusion Large grafts do not significantly decrease in size. Nonetheless, grafts weighing >3% of the GRWR show a different trend

  9. Comparison of tetrodotoxin uptake and gene expression in the liver between juvenile and adult tiger pufferfish, Takifugu rubripes.

    PubMed

    Kiriake, Aya; Ohta, Akira; Suga, Emi; Matsumoto, Takuya; Ishizaki, Shoichiro; Nagashima, Yuji

    2016-03-01

    Marine pufferfish of the family Tetraodontidae accumulate high levels of tetrodotoxin (TTX). The profile of TTX accumulation is reported to differ between tiger pufferfish Takifugu rubripes juveniles and adults administered TTX. Adults mainly accumulate TTX in liver, while juveniles transfer TTX from the liver to the skin. In the present study, we investigated TTX uptake into liver tissue slices of T. rubripes juveniles (4-month-old) and adults (18-month-old) in an in vitro incubation experiment, and compared their differential gene expression profiles in the liver by suppression subtracted hybridization (SSH). The tissue culture experiment revealed that TTX uptake in the liver itself was indistinguishable between the juveniles and the adults. In SSH analysis, a total of 176 clones were upregulated in the juvenile liver, the majority of which comprised hemoglobin subunit alpha-2-like gene (53 clones), hemoglobin subunit beta-like gene (40 clones), and type-4 ice-structuring protein LS-12-like gene (20 clones). A total of 211 clones were upregulated in the adult liver, including serotransferrin-like gene (84 clones), fibrinogen beta chain-like gene (15 clones), and 14 kDa apolipoprotein gene (10 clones). Based on these and previous findings on genes related to TTX intoxication in pufferfish, serotransferrin-like gene, complement C3-like gene, water-temperature-acclimation-related-65 kDa-protein-like gene, and chymotrypsin elastase family member 2A-like gene appear to be involved in TTX toxification of the T. rubripes liver. PMID:26708657

  10. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors.

    PubMed

    Gomez Perdiguero, Elisa; Klapproth, Kay; Schulz, Christian; Busch, Katrin; Azzoni, Emanuele; Crozet, Lucile; Garner, Hannah; Trouillet, Celine; de Bruijn, Marella F; Geissmann, Frederic; Rodewald, Hans-Reimer

    2015-02-26

    Most haematopoietic cells renew from adult haematopoietic stem cells (HSCs), however, macrophages in adult tissues can self-maintain independently of HSCs. Progenitors with macrophage potential in vitro have been described in the yolk sac before emergence of HSCs, and fetal macrophages can develop independently of Myb, a transcription factor required for HSC, and can persist in adult tissues. Nevertheless, the origin of adult macrophages and the qualitative and quantitative contributions of HSC and putative non-HSC-derived progenitors are still unclear. Here we show in mice that the vast majority of adult tissue-resident macrophages in liver (Kupffer cells), brain (microglia), epidermis (Langerhans cells) and lung (alveolar macrophages) originate from a Tie2(+) (also known as Tek) cellular pathway generating Csf1r(+) erythro-myeloid progenitors (EMPs) distinct from HSCs. EMPs develop in the yolk sac at embryonic day (E) 8.5, migrate and colonize the nascent fetal liver before E10.5, and give rise to fetal erythrocytes, macrophages, granulocytes and monocytes until at least E16.5. Subsequently, HSC-derived cells replace erythrocytes, granulocytes and monocytes. Kupffer cells, microglia and Langerhans cells are only marginally replaced in one-year-old mice, whereas alveolar macrophages may be progressively replaced in ageing mice. Our fate-mapping experiments identify, in the fetal liver, a sequence of yolk sac EMP-derived and HSC-derived haematopoiesis, and identify yolk sac EMPs as a common origin for tissue macrophages. PMID:25470051

  11. Comparison of the Phenotype and Approach to Pediatric vs Adult Patients With Nonalcoholic Fatty Liver Disease.

    PubMed

    Nobili, Valerio; Alisi, Anna; Newton, Kimberly P; Schwimmer, Jeffrey B

    2016-06-01

    Nonalcoholic fatty liver disease (NAFLD) is one of the main chronic noncommunicable diseases in Westernized societies; its worldwide prevalence has doubled during the last 20 years. NAFLD has serious health implications not only for adults, but also for children. However, pediatric NAFLD is not only an important global problem in itself, but it is likely to be associated with increases in comorbidities, such as metabolic syndrome and cardiovascular diseases. There are several differences between NAFLD in children and adults, and it is not clear whether the disease observed in children is the initial phase of a process that progresses with age. The increasing prevalence of pediatric NAFLD has serious implications for the future adult population requiring appropriate action. Studies of NAFLD progression, pathogenesis, and management should evaluate disease phenotypes in children and follow these over the patient's lifetime. We review the similarities and differences of NAFLD between children and adults. PMID:27003600

  12. The 14-day repeated dose liver micronucleus test with methapyrilene hydrochloride using young adult rats.

    PubMed

    Inoue, Kenji; Ochi, Akimu; Koda, Akira; Wako, Yumi; Kawasako, Kazufumi; Doi, Takaaki

    2015-03-01

    The repeated dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect genotoxic hepatocarcinogens that can be integrated into a general toxicity study. The assay methods were thoroughly validated by 19 Japanese facilities. Methapyrilene hydrochloride (MP), known to be a non-genotoxic hepatocarcinogen, was examined in the present study. MP was dosed orally at 10, 30 and 100mg/kg/day to 6-week-old male Crl:CD (SD) rats daily for 14 days. Treatment with MP resulted in an increase in micronucleated hepatocytes (MNHEPs) with a dosage of only 100mg/kg/day. At this dose level, cytotoxicity followed by regenerative cell growth was noted in the liver. These findings suggest that MP may induce clastogenic effects indirectly on the liver or hepatotoxicity of MP followed by regeneration may cause increase in spontaneous incidence of MNHEPs. PMID:24768639

  13. 3-Tesla MRI Response to TACE in HCC (Liver Cancer)

    ClinicalTrials.gov

    2016-08-22

    Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Localized Resectable Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Stage A Adult Primary Liver Cancer (BCLC); Stage B Adult Primary Liver Cancer (BCLC)

  14. 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

  15. Different sensitivity of PPARalpha gene expression to nutritional changes in liver of suckling and adult rats.

    PubMed

    Panadero, Maribel; Herrera, Emilio; Bocos, Carlos

    2005-01-14

    The amount of peroxisome proliferator-activated receptor-alpha (PPARalpha) protein was markedly augmented in the liver of suckling rats compared to adult rats. This different PPARalpha abundance was used to study the sensitivity to nutritional changes in the expression and activity of this receptor. Thus, 10-day-old and adult rats were orally given either glucose, Intralipid or a combination of both diets, and liver mRNA levels of PPARalpha and the PPAR related genes, acyl-CoA oxidase (ACO) and phosphoenolpyruvate carboxykinase (PEPCK), and plasma metabolites were measured. In neonates, the expression of PPARalpha and ACO was seen to increase when the level of FFA in plasma was also high, unless an elevated level of insulin was also present. However, this fatty acid-induced effect was not detected in adult rats. On the contrary, the hepatic expression of PEPCK was modulated by the nutritional changes similarly in both neonates and adult rats. Thus, it may be concluded that the expression of the PPARalpha gene in adult rats seems to be less sensitive to nutritional changes than in neonates. PMID:15607334

  16. 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

  17. Concealed expansion of immature precursors underpins acute burst of adult HSC activity in foetal liver.

    PubMed

    Rybtsov, Stanislav; Ivanovs, Andrejs; Zhao, Suling; Medvinsky, Alexander

    2016-04-15

    One day prior to mass emergence of haematopoietic stem cells (HSCs) in the foetal liver at E12.5, the embryo contains only a few definitive HSCs. It is thought that the burst of HSC activity in the foetal liver is underpinned by rapid maturation of immature embryonic precursors of definitive HSCs, termed pre-HSCs. However, because pre-HSCs are not detectable by direct transplantations into adult irradiated recipients, the size and growth of this population, which represents the embryonic rudiment of the adult haematopoietic system, remains uncertain. Using a novel quantitative assay, we demonstrate that from E9.5 the pre-HSC pool undergoes dramatic growth in the aorta-gonad-mesonephros region and by E11.5 reaches the size that matches the number of definitive HSCs in the E12.5 foetal liver. Thus, this study provides for the first time a quantitative basis for our understanding of how the large population of definitive HSCs emerges in the foetal liver. PMID:27095492

  18. Concealed expansion of immature precursors underpins acute burst of adult HSC activity in foetal liver

    PubMed Central

    Ivanovs, Andrejs; Zhao, Suling; Medvinsky, Alexander

    2016-01-01

    One day prior to mass emergence of haematopoietic stem cells (HSCs) in the foetal liver at E12.5, the embryo contains only a few definitive HSCs. It is thought that the burst of HSC activity in the foetal liver is underpinned by rapid maturation of immature embryonic precursors of definitive HSCs, termed pre-HSCs. However, because pre-HSCs are not detectable by direct transplantations into adult irradiated recipients, the size and growth of this population, which represents the embryonic rudiment of the adult haematopoietic system, remains uncertain. Using a novel quantitative assay, we demonstrate that from E9.5 the pre-HSC pool undergoes dramatic growth in the aorta-gonad-mesonephros region and by E11.5 reaches the size that matches the number of definitive HSCs in the E12.5 foetal liver. Thus, this study provides for the first time a quantitative basis for our understanding of how the large population of definitive HSCs emerges in the foetal liver. PMID:27095492

  19. A Monte Carlo approach to assessing 147Pm in the liver of the adult phantom.

    PubMed

    Bhati, S

    1993-06-01

    A low-background phoswich detector is used to detect small amounts of 147Pm--a pure beta-emitting nuclide--present in the liver of an occupational worker. The assessment was based on the measurement of bremsstrahlung radiation produced by the beta particles in the tissue. Computer programs based on Monte Carlo techniques for photon transport have been developed to calculate the response of an external phoswich detector to 1) a 147Pm point source embedded in tissue-equivalent slabs of various thicknesses; and 2) various source distributions of 147Pm in the liver of an adult phantom. The goal is to theoretically calibrate the phoswich detector for each source distribution and to study the variation of maxima of the spectra with the depth of the source in the adult phantom liver and tissue-equivalent slabs. The initial bremsstrahlung photon distribution of 147Pm in water has been computed using Wyard's and Pratt's methods. These calculations have been compared with experimental measurements using Perspex acrylic sheet slabs. Good agreements have been noted when the initial bremsstrahlung spectrum is obtained by using Wyard's method. These results find applications in monitoring the liver burdens in occupational workers handling 147Pm-based radioluminous paints. PMID:8491620

  20. Deep sexual dimorphism in adult medaka fish liver highlighted by multi-omic approach

    PubMed Central

    Qiao, Qin; Le Manach, Séverine; Sotton, Benoit; Huet, Hélène; Duvernois-Berthet, Evelyne; Paris, Alain; Duval, Charlotte; Ponger, Loïc; Marie, Arul; Blond, Alain; Mathéron, Lucrèce; Vinh, Joelle; Bolbach, Gérard; Djediat, Chakib; Bernard, Cécile; Edery, Marc; Marie, Benjamin

    2016-01-01

    Sexual dimorphism describes the features that discriminate between the two sexes at various biological levels. Especially, during the reproductive phase, the liver is one of the most sexually dimorphic organs, because of different metabolic demands between the two sexes. The liver is a key organ that plays fundamental roles in various physiological processes, including digestion, energetic metabolism, xenobiotic detoxification, biosynthesis of serum proteins, and also in endocrine or immune response. The sex-dimorphism of the liver is particularly obvious in oviparous animals, as the female liver is the main organ for the synthesis of oocyte constituents. In this work, we are interested in identifying molecular sexual dimorphism in the liver of adult medaka fish and their sex-variation in response to hepatotoxic exposures. By developing an integrative approach combining histology and different high-throughput omic investigations (metabolomics, proteomics and transcriptomics), we were able to globally depict the strong sexual dimorphism that concerns various cellular and molecular processes of hepatocytes comprising protein synthesis, amino acid, lipid and polysaccharide metabolism, along with steroidogenesis and detoxification. The results of this work imply noticeable repercussions on the biology of oviparous organisms environmentally exposed to chemical or toxin issues. PMID:27561897

  1. Deep sexual dimorphism in adult medaka fish liver highlighted by multi-omic approach.

    PubMed

    Qiao, Qin; Le Manach, Séverine; Sotton, Benoit; Huet, Hélène; Duvernois-Berthet, Evelyne; Paris, Alain; Duval, Charlotte; Ponger, Loïc; Marie, Arul; Blond, Alain; Mathéron, Lucrèce; Vinh, Joelle; Bolbach, Gérard; Djediat, Chakib; Bernard, Cécile; Edery, Marc; Marie, Benjamin

    2016-01-01

    Sexual dimorphism describes the features that discriminate between the two sexes at various biological levels. Especially, during the reproductive phase, the liver is one of the most sexually dimorphic organs, because of different metabolic demands between the two sexes. The liver is a key organ that plays fundamental roles in various physiological processes, including digestion, energetic metabolism, xenobiotic detoxification, biosynthesis of serum proteins, and also in endocrine or immune response. The sex-dimorphism of the liver is particularly obvious in oviparous animals, as the female liver is the main organ for the synthesis of oocyte constituents. In this work, we are interested in identifying molecular sexual dimorphism in the liver of adult medaka fish and their sex-variation in response to hepatotoxic exposures. By developing an integrative approach combining histology and different high-throughput omic investigations (metabolomics, proteomics and transcriptomics), we were able to globally depict the strong sexual dimorphism that concerns various cellular and molecular processes of hepatocytes comprising protein synthesis, amino acid, lipid and polysaccharide metabolism, along with steroidogenesis and detoxification. The results of this work imply noticeable repercussions on the biology of oviparous organisms environmentally exposed to chemical or toxin issues. PMID:27561897

  2. 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

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

    PubMed

    Djabrayan, Nareg J-V; Casanova, Jordi

    2016-03-01

    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

  4. Percutaneous Endovascular Treatment of Hepatic Artery Stenosis in Adult and Pediatric Patients After Liver Transplantation

    SciTech Connect

    Maruzzelli, Luigi; Miraglia, Roberto Caruso, Settimo; Milazzo, Mariapina; Mamone, Giuseppe; Gruttadauria, Salvatore; Spada, Marco; Luca, Angelo; Gridelli, Bruno

    2010-12-15

    The purpose of this study was to evaluate the efficacy of percutaneous endovascular techniques for the treatment of hepatic artery stenosis (HAS) occurring after liver transplantation (LT) in adult and pediatrics patients. From February 2003 to March 2009, 25 patients (15 adults and 10 children) whose developed HAS after LT were referred to our interventional radiology unit. Technical success was achieved in 96% (24 of 25) of patients. Percutaneous transluminal angioplasty (PTA) was performed in 13 patients (7 children), and stenting was performed in 11 patients (2 children). After the procedure, all patients were followed-up with liver function tests, Doppler ultrasound, and/or computed tomography. Mean follow-up was 15.8 months (range 5 days to 58 months). Acute hepatic artery thrombosis occurred immediately after stent deployment in 2 patients and was successfully treated with local thrombolysis. One patient developed severe HA spasm, which reverted after 24 h. After the procedure, mean trans-stenotic pressure gradient decreased from 30.5 to 6.2 mmHg. Kaplan-Meyer curve of HA primary patency was 77% at 1 and 2 years. During the follow-up period, 5 patients (20%) had recurrent stenosis, and 2 patients (8.3%) had late thrombosis. Two of 7 patients with stenosis/thrombosis underwent surgical revascularization (n = 1) and liver retransplantation (n = 1). Six (25%) patients died during follow-up, but overall mortality was not significantly different when comparing patients having patent hepatic arteries with those having recurrent stenosis/thrombosis. There were no significant differences in recurrent stenosis/thrombosis and mortality comparing patients treated by PTA versus stenting and comparing adult versus pediatric status. Percutaneous interventional treatment of HAS in LT recipients is safe and effective and decreases the need for surgical revascularization and liver retransplantation. However, the beneficial effects for survival are not clear, probably because

  5. Quality of Life in Adults with Nonalcoholic Fatty Liver Disease: Baseline Data from the NASH CRN

    PubMed Central

    David, Kristin; Kowdley, Kris V.; Unalp, Aynur; Kanwal, Fasiha; Brunt, Elizabeth M.; Schwimmer, Jeffrey B.

    2009-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States. The association between NAFLD and quality of life (QOL) remains unclear. These data are important to estimate the burden of illness in NAFLD. The aim was to report QOL scores of adults with NAFLD, and examine the association between NAFLD severity and QOL. QOL data were collected from adults with NAFLD enrolled in the NASH Clinical Research Network using the SF-36 survey and scores were compared to normative U.S. population scores. Liver biopsy histology was reviewed by a central pathology committee. A total of 713 subjects with NAFLD (M=269, F=444) were included. Mean age of subjects was 48.3 years; 61% had definite NASH, and 28% had bridging fibrosis or cirrhosis. Diabetes was present in 27% of subjects. Subjects with NAFLD had worse physical (mean=45.2) and mental health scores (mean=47.6) compared to the U.S. population with (mean=50) and without (physical: 55.8, mental: 52.5) chronic illness. Subjects with NASH reported lower physical health compared to subjects with fatty liver disease without NASH (44.5 vs. 47.1, p=.02). Subjects with cirrhosis had significantly (P<0.001) poorer physical health scores (38.4) vs. subjects with no (47.6), mild (46.2), moderate (44.6) or bridging fibrosis (44.6). Cirrhosis was associated with poorer physical health after adjusting for potential confounders. Mental health scores did not differ between participants with and without NASH or by degree of fibrosis. Conclusion Adults with NAFLD have a significant decrement in QOL. Treatment of NAFLD should incorporate strategies to improve QOL, especially physical health. PMID:19434741

  6. Donor Safety in Adult-Adult Living Donor Liver Transplantation: A Single-Center Experience of 356 Cases

    PubMed Central

    Meng, Haipeng; Yang, Jiayin; Yan, Lunan

    2016-01-01

    Background As an important means to tackle the worldwide shortage of liver grafts, adult-adult living donor liver transplantation (A-ALDLT) is the most massive operation a healthy person could undergo, so donor safety is of prime importance. However, most previous research focused on recipients, while complications in donors have not been fully described or investigated. Material/Methods To investigate donor safety in terms of postoperative complications, the clinical data of 356 A-ALDLT donors in our center from January 2002 to September 2015 were retrospectively analyzed. These patients were divided into a pre-2008 group (before January 2008) and a post-2008 group (after January 2008). Donor safety was evaluated with regard to the type, frequency, and severity of postoperative complications. Results There were no donor deaths in our center during this period. The overall complication rate was 23.0% (82/356). The proportion of Clavien I, II, III, and IV complications was 51.2% (42/82), 25.6% (21/82), 22.0% (18/82), and 1.2% (1/82), respectively. In all the donors, the incidence of Clavien I, II, III, and IV complications was 11.8% (42/356), 5.9% (21/356), 5.1% (18/356), and 0.3% (1/356), respectively. The overall complication rate in the post-2008 group was significantly lower than that in the pre-2008 group (18.1% (41/227) vs. 32.6% (42/129), P<0.01). Biliary complications were the most common, with an incidence of 8.4% (30/356). Conclusions The risk to A-ALDLT donors is controllable and acceptable with improvement in preoperative assessment and liver surgery. PMID:27178367

  7. Donor Safety in Adult-Adult Living Donor Liver Transplantation: A Single-Center Experience of 356 Cases.

    PubMed

    Meng, Haipeng; Yang, Jiayin; Yan, Lunan

    2016-01-01

    BACKGROUND As an important means to tackle the worldwide shortage of liver grafts, adult-adult living donor liver transplantation (A-ALDLT) is the most massive operation a healthy person could undergo, so donor safety is of prime importance. However, most previous research focused on recipients, while complications in donors have not been fully described or investigated. MATERIAL AND METHODS To investigate donor safety in terms of postoperative complications, the clinical data of 356 A-ALDLT donors in our center from January 2002 to September 2015 were retrospectively analyzed. These patients were divided into a pre-2008 group (before January 2008) and a post-2008 group (after January 2008). Donor safety was evaluated with regard to the type, frequency, and severity of postoperative complications. RESULTS There were no donor deaths in our center during this period. The overall complication rate was 23.0% (82/356). The proportion of Clavien I, II, III, and IV complications was 51.2% (42/82), 25.6% (21/82), 22.0% (18/82), and 1.2% (1/82), respectively. In all the donors, the incidence of Clavien I, II, III, and IV complications was 11.8% (42/356), 5.9% (21/356), 5.1% (18/356), and 0.3% (1/356), respectively. The overall complication rate in the post-2008 group was significantly lower than that in the pre-2008 group (18.1% (41/227) vs. 32.6% (42/129), P<0.01). Biliary complications were the most common, with an incidence of 8.4% (30/356). CONCLUSIONS The risk to A-ALDLT donors is controllable and acceptable with improvement in preoperative assessment and liver surgery. PMID:27178367

  8. ESRP2 controls an adult splicing programme in hepatocytes to support postnatal liver maturation.

    PubMed

    Bhate, Amruta; Parker, Darren J; Bebee, Thomas W; Ahn, Jaegyoon; Arif, Waqar; Rashan, Edrees H; Chorghade, Sandip; Chau, Anthony; Lee, Jae-Hyung; Anakk, Sayeepriyadarshini; Carstens, Russ P; Xiao, Xinshu; Kalsotra, Auinash

    2015-01-01

    Although major genetic networks controlling early liver specification and morphogenesis are known, the mechanisms responsible for postnatal hepatic maturation are poorly understood. Here we employ global analyses of the mouse liver transcriptome to demonstrate that postnatal remodelling of the liver is accompanied by large-scale transcriptional and post-transcriptional transitions that are cell-type-specific and temporally coordinated. Combining detailed expression analyses with gain- and loss-of-function studies, we identify epithelial splicing regulatory protein 2 (ESRP2) as a conserved regulatory factor that controls the neonatal-to-adult switch of ∼20% of splice isoforms in mouse and human hepatocytes. The normal shift in splicing coincides tightly with dramatic postnatal induction of ESRP2 in hepatocytes. We further demonstrate that forced expression of ESRP2 in immature mouse and human hepatocytes is sufficient to drive a reciprocal shift in splicing and causes various physiological abnormalities. These findings define a direct role for ESRP2 in the generation of conserved repertoires of adult splice isoforms that facilitate terminal differentiation and maturation of hepatocytes. PMID:26531099

  9. Combined Detection of Serum IL-10, IL-17, and CXCL10 Predicts Acute Rejection Following Adult Liver Transplantation

    PubMed Central

    Kim, Nayoung; Yoon, Young-In; Yoo, Hyun Ju; Tak, Eunyoung; Ahn, Chul-Soo; Song, Gi-Won; Lee, Sung-Gyu; Hwang, Shin

    2016-01-01

    Discovery of non-invasive diagnostic and predictive biomarkers for acute rejection in liver transplant patients would help to ensure the preservation of liver function in the graft, eventually contributing to improved graft and patient survival. We evaluated selected cytokines and chemokines in the sera from liver transplant patients as potential biomarkers for acute rejection, and found that the combined detection of IL-10, IL-17, and CXCL10 at 1-2 weeks post-operation could predict acute rejection following adult liver transplantation with 97% specificity and 94% sensitivity. PMID:27498551

  10. From the Cover: Cell-replacement therapy for diabetes: Generating functional insulin-producing tissue from adult human liver cells

    NASA Astrophysics Data System (ADS)

    Sapir, Tamar; Shternhall, Keren; Meivar-Levy, Irit; Blumenfeld, Tamar; Cohen, Hamutal; Skutelsky, Ehud; Eventov-Friedman, Smadar; Barshack, Iris; Goldberg, Iris; Pri-Chen, Sarah; Ben-Dor, Lya; Polak-Charcon, Sylvie; Karasik, Avraham; Shimon, Ilan; Mor, Eytan; Ferber, Sarah

    2005-05-01

    Shortage in tissue availability from cadaver donors and the need for life-long immunosuppression severely restrict the large-scale application of cell-replacement therapy for diabetic patients. This study suggests the potential use of adult human liver as alternate tissue for autologous beta-cell-replacement therapy. By using pancreatic and duodenal homeobox gene 1 (PDX-1) and soluble factors, we induced a comprehensive developmental shift of adult human liver cells into functional insulin-producing cells. PDX-1-treated human liver cells express insulin, store it in defined granules, and secrete the hormone in a glucose-regulated manner. When transplanted under the renal capsule of diabetic, immunodeficient mice, the cells ameliorated hyperglycemia for prolonged periods of time. Inducing developmental redirection of adult liver offers the potential of a cell-replacement therapy for diabetics by allowing the patient to be the donor of his own insulin-producing tissue. pancreas | transdifferentiation

  11. 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

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

    PubMed

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

    2015-08-15

    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

  13. Similarities and differences between pediatric and adult nonalcoholic fatty liver disease.

    PubMed

    Crespo, Maricruz; Lappe, Sara; Feldstein, Ariel E; Alkhouri, Naim

    2016-08-01

    Nonalcoholic fatty liver disease (NAFLD) is highly common and potentially serious in children and adolescents. The term NAFLD refers to a spectrum of diseases ranging from accumulation of fat in the liver (simple steatosis or nonalcoholic fatty liver "NAFL") to the potentially progressive form of nonalcoholic steatohepatitis (NASH) characterized by hepatocyte ballooning, inflammation, and often associated with fibrosis. While large prospective longitudinal studies in pediatric NAFLD are still lacking, growing evidence suggests that children with NAFL are at increased risk for cardiometabolic complications, while those with NASH and advance fibrosis are also at risk for significant liver-related morbidity including cirrhosis and its complications. Pediatric NAFLD shares features of adult NAFLD but also shows many different characteristics in terms of prevalence, histology, diagnosis and management. Translational studies suggest that NAFLD is a highly heritable disease in which genetic variations and environment closely interact to determine the disease phenotype and the progression to the more advanced forms of the disease. Changes in lifestyle, targeting gradual weight reduction, and physical exercise continue to be the mainstay of treatment for NAFLD in children. Recent advances in development of noninvasive diagnostic modalities and the potential for identifying effective pharmacological interventions may result in significant progress in the management of NAFLD in the pediatric population. PMID:26961580

  14. Patterns and Predictors of Sexual Function After Liver Donation: the Adult to Adult Living Donor Liver Transplantation Cohort Study (A2ALL)

    PubMed Central

    DiMartini, AF.; Dew, MA.; Butt, Z.; Simpson, MA.; Ladner, DP.; Smith, AR.; Hill-Callahan, P.; Gillespie, BW.

    2015-01-01

    Although sexual functioning is an important facet of living donor quality of life, it has not received extensive evaluation in this population. Using data from the Adult-to-Adult Living Donor Liver Transplantation Cohort Study, we examined donor sexual functioning across the donation process from the predonation evaluation to 3 months and 1 year postdonation. Donors (n=208) and a comparison group of non-donors (n=155) completed self-reported surveys with specific questions on sexual desire, satisfaction, orgasm, and (for men) erectile function. Across the three time points, donor sexual functioning was lower at the evaluation phase and 3 months postdonation than at one year postdonation. In the early recovery period, abdominal pain was associated with difficulty reaching orgasm (OR = 3.98, 95% CI 1.30–12.16), concerns over appearance with lower sexual desire (OR = 4.14, 95% CI 1.02–16.79), and not feeling back to normal was associated with dissatisfaction with sexual life (OR 3.58, 95% CI 1.43–8.99). Efforts to educate donors before the surgery and prepare them for the early recovery phase may improve recovery and reduce distress regarding sexual functioning. PMID:25779554

  15. Evolution of anterior segment reconstruction after live donor adult liver transplantation: a single-center experience.

    PubMed

    Pomposelli, James J; Akoad, Mohamed; Khwaja, Khalid; Lewis, W D; Cheah, Yee L; Verbesey, Jennifer; Jenkins, Roger L; Pomfret, Elizabeth A

    2012-01-01

    Controversy exists regarding the best method for venous outflow reconstruction after live donor liver transplantation using right lobe grafts. Some authors advocate routine inclusion of the middle hepatic vein with the graft, whereas others favor a more selective approach. In this report, we examine the evolution of our decision making and technique of selective anterior venous segment reconstruction during live donor adult liver transplantation performed in 226 recipients. We have developed a simplified back-bench procedure using sequential-composite anastomosis using various vascular conduits with syndactylization to the right hepatic vein creating a single large-outflow anastomosis in the recipient. Conduits used include iliac artery or vein allograft, recanalized umbilical vein, cryopreserved iliac artery allograft, and 6-mm synthetic expanded polytetrafluoroethylene vascular graft. This technique can be performed quickly, safely, and under cold storage conditions and results in excellent outcome while minimizing donor risk. PMID:21980936

  16. Cyclophilin D-Sensitive Mitochondrial Permeability Transition in Adult Human Brain and Liver Mitochondria

    PubMed Central

    Morota, Saori; Chen, Li; Matsuyama, Nagahisa; Suzuki, Yoshiaki; Nakajima, Satoshi; Tanoue, Tadashi; Omi, Akibumi; Shibasaki, Futoshi; Shimazu, Motohide; Ikeda, Yukio; Uchino, Hiroyuki; Elmér, Eskil

    2011-01-01

    Abstract The mitochondrial permeability transition (mPT) is considered to be a major cause of cell death under a variety of pathophysiological conditions of the central nervous system (CNS) and other organs. Pharmacological inhibition or genetic knockout of the matrix protein cyclophilin D (CypD) prevents mPT and cell degeneration in several models of brain injury. If these findings in animal models are translatable to human disease, pharmacological inhibition of mPT offers a promising therapeutic target. The objective of this study was to validate the presence of a CypD-sensitive mPT in adult human brain and liver mitochondria. In order to perform functional characterization of human mitochondria, fresh tissue samples were obtained during hemorrhage or tumor surgery and mitochondria were rapidly isolated. Mitochondrial calcium retention capacity, a quantitative assay for mPT, was significantly increased by the CypD inhibitor cyclosporin A in both human brain and liver mitochondria, whereas thiol-reactive compounds and oxidants sensitized mitochondria to calcium-induced mPT. Brain mitochondria underwent swelling upon calcium overload, which was reversible upon calcium removal. To further explore mPT of human mitochondria, liver mitochondria were demonstrated to exhibit several classical features of the mPT phenomenon, such as calcium-induced loss of membrane potential and respiratory coupling, as well as release of the pro-apoptotic protein cytochrome c. We concluded that adult viable human brain and liver mitochondria possess an active CypD-sensitive mPT. Our findings support the rationale of CypD and mPT inhibition as pharmacological targets in acute and chronic neurodegeneration. PMID:21121808

  17. Activation, isolation, identification and in vitro proliferation of oval cells from adult rat livers.

    PubMed

    He, Z P; Tan, W Q; Tang, Y F; Zhang, H J; Feng, M F

    2004-04-01

    Oval cells, putative hepatic stem cells, could potentially provide a novel solution to the severe shortage of donor livers, because of their ability to proliferate and differentiate into functional hepatocytes. We have previously demonstrated that oval cells can be induced to differentiate into cells with morphologic, phenotypic, and functional characteristics of mature hepatocytes. In this study, we have established a new model combining ethionine treatment with partial hepatectomy to activate oval cells, then developed a procedure utilizing selective enzymatic digestion and density gradient centrifugation to isolate and purify such cells from heterogeneous liver cell population. We identified oval cells by their morphological characteristics and phenotypic properties, thereby providing definitive evidence of the presence of hepatic stem-like cells in adult rat livers. Viewed by transmission electron microscopy, they were small cells with ovoid nuclei, a high nucleus/cytoplasm ratio and few organelles, including mitochondria and endoplasmic reticulum. Flow cytometric assay showed that these cells highly expressed OV-6, cytokeratin-19 (CK-19) and albumin. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis displayed that the freshly isolated cells co-expressed albumin, cytokeratin-7 (CK-7) and CK-19 mRNA, indicating that they were essentially bipotential hepatic stem-like cells. Furthermore, we set up a culture system containing growth factors and a fibroblast feeder layer, to provide nourishment to these cells. Thus, we were able to culture them in vitro for more than 3 months, with the number of cells doubling 100 times. Gene expressions of albumin, CK-7 and CK-19 in the cells derived from the expanding colonies at day 95 were confirmed by RT-PCR analysis. These data suggested that the hepatic oval cells derived from adult rat livers possess a high potential to proliferate in vitro with a large increase in number, while maintaining the bipotential

  18. Protease-activated receptor-1 negatively regulates proliferation of neural stem/progenitor cells derived from the hippocampal dentate gyrus of the adult mouse.

    PubMed

    Tanaka, Masayuki; Yoneyama, Masanori; Shiba, Tatsuo; Yamaguchi, Taro; Ogita, Kiyokazu

    2016-07-01

    Thrombin-activated protease-activated receptor (PAR)-1 regulates the proliferation of neural cells following brain injury. To elucidate the involvement of PAR-1 in the neurogenesis that occurs in the adult hippocampus, we examined whether PAR-1 regulated the proliferation of neural stem/progenitor cells (NPCs) derived from the murine hippocampal dentate gyrus. NPC cultures expressed PAR-1 protein and mRNA encoding all subtypes of PAR. Direct exposure of the cells to thrombin dramatically attenuated the cell proliferation without causing cell damage. This thrombin-induced attenuation was almost completely abolished by the PAR antagonist RWJ 56110, as well as by dabigatran and 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF), which are selective and non-selective thrombin inhibitors, respectively. Expectedly, the PAR-1 agonist peptide (AP) SFLLR-NH2 also attenuated the cell proliferation. The cell proliferation was not affected by the PAR-1 negative control peptide RLLFT-NH2, which is an inactive peptide for PAR-1. Independently, we determined the effect of in vivo treatment with AEBSF or AP on hippocampal neurogenesis in the adult mouse. The administration of AEBSF, but not that of AP, significantly increased the number of newly-generated cells in the hippocampal subgranular zone. These data suggest that PAR-1 negatively regulated adult neurogenesis in the hippocampus by inhibiting the proliferative activity of the NPCs. PMID:27426918

  19. 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. PMID:24140724

  20. Sexually dimorphic effect of in vitro fertilization (IVF) on adult mouse fat and liver metabolomes.

    PubMed

    Feuer, Sky K; Donjacour, Annemarie; Simbulan, Rhodel K; Lin, Wingka; Liu, Xiaowei; Maltepe, Emin; Rinaudo, Paolo F

    2014-11-01

    The preimplantation embryo is particularly vulnerable to environmental perturbation, such that nutritional and in vitro stresses restricted exclusively to this stage may alter growth and affect long-term metabolic health. This is particularly relevant to the over 5 million children conceived by in vitro fertilization (IVF). We previously reported that even optimized IVF conditions reprogram mouse postnatal growth, fat deposition, and glucose homeostasis in a sexually dimorphic fashion. To more clearly interrogate the metabolic changes associated with IVF in adulthood, we used nontargeted mass spectrometry to globally profile adult IVF- and in vivo-conceived liver and gonadal adipose tissues. There was a sex- and tissue-specific effect of IVF on adult metabolite signatures indicative of metabolic reprogramming and oxidative stress and reflective of the observed phenotypes. Additionally, we observed a striking effect of IVF on adult sexual dimorphism. Male-female differences in metabolite concentration were exaggerated in hepatic IVF tissue and significantly reduced in IVF adipose tissue, with the majority of changes affecting amino acid and lipid metabolites. We also observed female-specific changes in markers of oxidative stress and adipogenesis, including reduced glutathione, cysteine glutathione disulfide, ophthalmate, urate, and corticosterone. In summary, embryo manipulation and early developmental experiences can affect adult patterns of sexual dimorphism and metabolic physiology. PMID:25211591

  1. Liver.

    PubMed

    Kim, W R; Lake, J R; Smith, J M; Skeans, M A; Schladt, D P; Edwards, E B; Harper, A M; Wainright, J L; Snyder, J J; Israni, A K; Kasiske, B L

    2016-01-01

    The median waiting time for patients with MELD ≥ 35 decreased from 18 days in 2012 to 9 days in 2014, after implementation of the Share 35 policy in June 2013. Similarly, mortality among candidates listed with MELD ≥ 35 decreased from 366 per 100 waitlist years in 2012 to 315 in 2014. The number of new active candidates added to the pediatric liver transplant waiting list in 2014 was 655, down from a peak of 826 in 2005. The number of prevalent candidates (on the list on December 31 of the given year) continued to decline, 401 active and 173 inactive. The number of deceased donor pediatric liver transplants peaked at 542 in 2008 and was 478 in 2014. The number of living donor liver pediatric transplants was 52 in 2014; most were from donors closely related to the recipients. Graft survival continued to improve among pediatric recipients of deceased donor and living donor livers. PMID:26755264

  2. Metabolic alterations in liver and testes of adult and newborn rats following cadmium administration

    SciTech Connect

    Agarwal, A.K.

    1988-04-01

    A large number of studies have been conducted to understand the effect of cadmium on cellular intermediary metabolism. Although, most of the metal is stored in liver and kidney, the organ affected most in acute toxicity is testis. Increased lipid peroxidation and decreased mitochondrial respiration along with other cellular enzyme activities have been reported to take place due to cadmium administration. The present experiment was designed to study the effect of acute cadmium administration on the activities of some of the tissue enzyme systems that provide the reducing equivalent NADPH. The levels of NADH and NADPH were also measured. All the measurements were conducted in two tissues: liver and testes. The effect of simultaneous administration of zinc on cadmium induced changes was also determined. Newborn animals have been found to be resistant to many effects of cadmium. The present studies were also conducted in newborn rat liver and testes. The purpose of the study is to compare the effects of cadmium on adult and new born rats.

  3. Undifferentiated embryonal sarcoma of the liver in a middle-aged adult with systemic lupus erythematosus

    PubMed Central

    2013-01-01

    Adult primary undifferentiated embryonal sarcoma of the liver (UESL) is a rare disease. While the etiology of UESL remains largely unknown, association with systemic inflammatory disorders has been observed. Here, we report a case of UESL in a 46-year-old woman with systemic lupus erythematosus (SLE) and without chronic hepatitis or liver cirrhosis. Systematic review of the publicly available English language medical literature identified only 27 cases of UESL in patients aged >45 years and none with SLE. Our patient presented with abdominal pain and had a 2-year history of SLE. Abdominal ultrasonography and enhanced computed tomography revealed a solid mass in the right lobe of the liver. Presumptive diagnosis of atypical hepatocellular carcinoma was made and the patient was treated with segmentectomy of S5 and S4a and cholecystectomy. The final diagnosis of UESL was made according to the pathology results. Since SLE patients may be at increased risk of malignancy, it is possible that the SLE pathogenesis may have contributed to the development of UESL in our patient. According to this case, UESL should be considered when SLE patients present with hepatic space-occupying lesions. PMID:24073982

  4. Hepatoprotective activity of bacoside A against N-nitrosodiethylamine-induced liver toxicity in adult rats.

    PubMed

    Janani, Panneerselvam; Sivakumari, Kanakarajan; Parthasarathy, Chandrakesan

    2009-10-01

    N-Nitrosodiethylamine (DEN) is a notorious carcinogen, present in many environmental factors. DEN induces oxidative stress and cellular injury due to enhanced generation of reactive oxygen species; free radical scavengers protect the membranes from DEN-induced damage. The present study was designed to evaluate the protective effect of bacoside A (the active principle isolated from Bacopa monniera Linn.) on carcinogen-induced damage in rat liver. Adult male albino rats were pretreated with 15 mg/kg body weight/day of bacoside A orally (for 14 days) and then intoxicated with single necrogenic dose of N-nitrosodiethylamine (200 mg/kg bodyweight, intraperitonially) and maintained for 7 days. The liver weight, lipid peroxidation (LPO), and activity of serum marker enzymes (aspartate transaminases, alanine transaminases, lactate dehydrogenase, alkaline phosphatase, and gamma-glutamyl transpeptidase) were markedly increased in carcinogen-administered rats, whereas the activities of marker enzymes were near normal in bacoside A-pretreated rats. Activities of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutatione-S-transferase, and reduced glutathione) in liver also decreased in carcinogen-administered rats, which were significantly elevated in bacoside A-pretreated rats. It is concluded that pretreatment of bacoside A prevents the elevation of LPO and activity of serum marker enzymes and maintains the antioxidant system and thus protects the rats from DEN-induced hepatotoxicity. PMID:18679812

  5. Vascular complications after adult living donor liver transplantation: Evaluation with ultrasonography

    PubMed Central

    Ma, Lin; Lu, Qiang; Luo, Yan

    2016-01-01

    Living donor liver transplantation (LDLT) has been widely used to treat end-stage liver disease with improvement in surgical technology and the application of new immunosuppressants. Vascular complications after liver transplantation remain a major threat to the survival of recipients. LDLT recipients are more likely to develop vascular complications because of their complex vascular reconstruction and the slender vessels. Early diagnosis and treatment are critical for the survival of graft and recipients. As a non-invasive, cost-effective and non-radioactive method with bedside availability, conventional gray-scale and Doppler ultrasonography play important roles in identifying vascular complications in the early postoperative period and during the follow-up. Recently, with the detailed vascular tracing and perfusion visualization, contrast-enhanced ultrasound (CEUS) has significantly improved the diagnosis of postoperative vascular complications. This review focuses on the role of conventional gray-scale ultrasound, Doppler ultrasound and CEUS for early diagnosis of vascular complications after adult LDLT. PMID:26819527

  6. Bioreactance Is Not Interchangeable with Thermodilution for Measuring Cardiac Output during Adult Liver Transplantation

    PubMed Central

    Han, Sangbin; Lee, Jong Hwan; Kim, Gaabsoo; Ko, Justin Sangwook; Choi, Soo Joo; Kwon, Ji Hae; Heo, Burn Young; Gwak, Mi Sook

    2015-01-01

    Background Thermodilution technique using a pulmonary artery catheter is widely used for the assessment of cardiac output (CO) in patients undergoing liver transplantation. However, the unclearness of the risk-benefit ratio of this method has led to an interest in less invasive modalities. Thus, we evaluated whether noninvasive bioreactance CO monitoring is interchangeable with thermodilution technique. Methods Nineteen recipients undergoing adult-to-adult living donor liver transplantation were enrolled in this prospective observational study. COs were recorded automatically by the two devices and compared simultaneously at 3-minute intervals. The Bland–Altman plot was used to evaluate the agreement between bioreactance and thermodilution. Clinically acceptable agreement was defined as a percentage error of limits of agreement <30%. The four quadrant plot was used to evaluate concordance between bioreactance and thermodilution. Clinically acceptable concordance was defined as a concordance rate >92%. Results A total of 2640 datasets were collected. The mean CO difference between the two techniques was 0.9 l/min, and the 95% limits of agreement were -3.5 l/min and 5.4 l/min with a percentage error of 53.9%. The percentage errors in the dissection, anhepatic, and reperfusion phase were 50.6%, 56.1%, and 53.5%, respectively. The concordance rate between the two techniques was 54.8%. Conclusion Bioreactance and thermodilution failed to show acceptable interchangeability in terms of both estimating CO and tracking CO changes in patients undergoing liver transplantation. Thus, the use of bioreactance as an alternative CO monitoring to thermodilution, in spite of its noninvasiveness, would be hard to recommend in these surgical patients. PMID:26017364

  7. Parenteral nutrition-associated liver disease in adult and pediatric patients.

    PubMed

    Kumpf, Vanessa J

    2006-06-01

    There are essentially 3 types of hepatobiliary disorders associated with parenteral nutrition (PN) therapy: steatosis, cholestasis, and gallbladder sludge/stones. Reported prevalence rates of PN-associated liver disease (PNALD) vary greatly, and there are distinct differences between adult and pediatric patients. Various etiologic factors have been evaluated for significance in contributing to PNALD, including enteral feeding history, septic events, bacterial overgrowth, length of intestinal resection, and prematurity/low birth weight. Etiologic factors specifically related to the PN formulation or nutrient intake have also been evaluated, including excessive calorie intake, dextrose-to-lipid ratio, amino acid dose, taurine deficiency, IV fat emulsion (IVFE) dose, carnitine deficiency, choline deficiency, and continuous vs cyclic infusion. Minor increases in serum aminotransferase concentrations are relatively common in patients receiving PN therapy and generally require no intervention. The primary indicator of cholestasis is a serum conjugated bilirubin >2 mg/dL. When a patient receiving PN develops liver complications, it is necessary to rule out all treatable causes and minimize other risk factors. All potential hepatotoxic medications and herbal supplements should be eliminated. Modifications to the PN regimen that may be helpful include reduction of calories, reduction of IVFE dose to <1 g/kg/d, supplementation of taurine in the infant, and use of cyclic infusion. Initiation of even small amounts of enteral nutrition and use of ursodiol may be beneficial in stimulating bile flow. In the long-term PN patient with severe and progressive liver disease, intestinal or liver transplantation may be the only remaining treatment option. PMID:16772545

  8. 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

  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. PMID:27302752

  10. The canine hepatic progenitor cell niche: molecular characterisation in health and disease.

    PubMed

    Kruitwagen, H S; Spee, B; Viebahn, C S; Venema, H B; Penning, L C; Grinwis, G C M; Favier, R P; van den Ingh, T S G A M; Rothuizen, J; Schotanus, B A

    2014-09-01

    Hepatic progenitor cells (HPCs) are an adult stem cell compartment in the liver that contributes to liver regeneration when replication of mature hepatocytes is insufficient. In this study, laser microdissection was used to isolate HPC niches from the livers of healthy dogs and dogs with lobular dissecting hepatitis (LDH), in which HPCs are massively activated. Gene expression of HPC, hepatocyte and biliary markers was determined by quantitative reverse transcriptase PCR. Expression and localisation of selected markers were further studied at the protein level by immunohistochemistry and immunofluorescent double staining in samples of normal liver and liver from dogs with LDH, acute and chronic hepatitis, and extrahepatic cholestasis. Activated HPC niches had higher gene expression of the hepatic progenitor markers OPN, FN14, CD29, CD44, CD133, LIF, LIFR and BMI1 compared to HPCs from normal liver. There was lower expression of albumin, but activated HPC niches were positive for the biliary markers SOX9, HNF1β and keratin 19 by immunohistochemistry and immunofluorescence. Laminin, activated stellate cells and macrophages are abundant extracellular matrix and cellular components of the canine HPC niche. This study demonstrates that the molecular and cellular characteristics of canine HPCs are similar to rodent and human HPCs, and that canine HPCs are distinctively activated in different types of liver disease. PMID:24923752

  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. Noninvasive methods, including transient elastography, for the detection of liver disease in adults with cystic fibrosis

    PubMed Central

    Sadler, Matthew D; Crotty, Pam; Fatovich, Linda; Wilson, Stephanie; Rabin, Harvey R; Myers, Robert P

    2015-01-01

    BACKGROUND: Liver disease is the third leading cause of mortality in patients with cystic fibrosis (CF). However, detection of CF-associated liver disease (CFLD) is challenging. OBJECTIVE: To evaluate the diagnostic performance of noninvasive methods for the detection of CFLD with a focus on transient elastography (TE). METHODS: Patients at the Adult CF Clinic of Calgary and Southern Alberta (n=127) underwent liver stiffness measurement (LSM) by TE using the FibroScan (FS, Ecosens, France) M probe; aspartate amino-transferase to platelet ratio index (APRI) and FibroTest (FT) scores were also calculated. The diagnostic performance of these tools for the detection of CFLD (defined as two or more the following criteria: abnormal liver biochemistry, hepatomegaly or sonographic abnormalities other than steatosis) were compared using the area under ROC curves. RESULTS: Forty-seven percent of the cohort was male. The median age was 27 years (interquartile range [IQR] 22 to 37 years) and body mass index 21 kg/m2 (IQR 19 kg/m2 to 23 kg/m2); 25% of patients were on ursodeoxycholic acid and 12% had undergone lung transplantation. The prevalence of CFLD was 14% (n=18). FS was successful in all patients; one (0.8%) patient had poorly reliable results (IQR/M >30% and LSM ≥7.1kPa). Compared with patients without CFLD (n=109), individuals with CFLD had higher median LSM according to FS (3.9 kPa [IQR 3.4 to 4.9 kPa] versus 6.4 kPa [IQR 4.4 to 8.0 kPa]), APRI (0.24 [IQR 0.17 to 0.31] versus 0.50 [IQR 0.22 to 1.18]) and FT scores (0.08 [IQR 0.05 to 1.5] versus 0.18 [IQR 0.11 to 0.35]; all P<0.05). Area under ROC curve for FS, APRI and FT for the detection of CFLD were 0.78 (95% CI 0.65 to 0.92), 0.72 (95% CI 0.56 to 0.87) and 0.76 (95% CI 0.62 to 0.90) (P not significant). At a threshold of >5.2 kPa, the sensitivity, specificity, positive and negative predictive values of LSM according to FS for detecting CFLD were 67%, 83%, 40% and 94%, respectively. CONCLUSIONS: FS, APRI and FT

  13. In Vivo 4-Dimensional Tracking of Hematopoietic Stem and Progenitor Cells in Adult Mouse Calvarial Bone Marrow

    PubMed Central

    Scott, Mark K.; Akinduro, Olufolake; Lo Celso, Cristina

    2014-01-01

    Through a delicate balance between quiescence and proliferation, self renewal and production of differentiated progeny, hematopoietic stem cells (HSCs) maintain the turnover of all mature blood cell lineages. The coordination of the complex signals leading to specific HSC fates relies upon the interaction between HSCs and the intricate bone marrow microenvironment, which is still poorly understood[1-2]. We describe how by combining a newly developed specimen holder for stable animal positioning with multi-step confocal and two-photon in vivo imaging techniques, it is possible to obtain high-resolution 3D stacks containing HSPCs and their surrounding niches and to monitor them over time through multi-point time-lapse imaging. High definition imaging allows detecting ex vivo labeled hematopoietic stem and progenitor cells (HSPCs) residing within the bone marrow. Moreover, multi-point time-lapse 3D imaging, obtained with faster acquisition settings, provides accurate information about HSPC movement and the reciprocal interactions between HSPCs and stroma cells. Tracking of HSPCs in relation to GFP positive osteoblastic cells is shown as an exemplary application of this method. This technique can be utilized to track any appropriately labeled hematopoietic or stromal cell of interest within the mouse calvarium bone marrow space. PMID:25225854

  14. Direct Stimulation of Adult Neural Stem/Progenitor Cells In Vitro and Neurogenesis In Vivo by Salvianolic Acid B

    PubMed Central

    Zhuang, Pengwei; Zhang, Yanjun; Cui, Guangzhi; Bian, Yuhong; Zhang, Mixia; Zhang, Jinbao; Liu, Yang; Yang, Xinpeng; Isaiah, Adejobi Oluwaniyi; Lin, Yingxue; Jiang, Yongbo

    2012-01-01

    Background Small molecules have been shown to modulate the neurogenesis processes. In search for new therapeutic drugs, the herbs used in traditional medicines for neurogenesis are promising candidates. Methodology and Principal Findings We selected a total of 45 natural compounds from Traditional Chinese herbal medicines which are extensively used in China to treat stroke clinically, and tested their proliferation-inducing activities on neural stem/progenitor cells (NSPCs). The screening results showed that salvianolic acid B (Sal B) displayed marked effects on the induction of proliferation of NSPCs. We further demonstrated that Sal B promoted NSPCs proliferation in dose- and time-dependent manners. To explore the molecular mechanism, PI3K/Akt, MEK/ERK and Notch signaling pathways were investigated. Cell proliferation assay demonstrated that Ly294002 (PI3K/Akt inhibitor), but neither U0126 (ERK inhibitor) nor DAPT (Notch inhibitor) inhibited the Sal B-induced proliferation of cells. Western Blotting results showed that stimulation of NSPCs with Sal B enhanced the phosphorylation of Akt, and Ly294002 abolished this effect, confirming the role of Akt in Sal B mediated proliferation of NSPCs. Rats exposed to transient cerebral ischemia were treated for 4 weeks with Sal B from the 7th day after stroke. BrdU incorporation assay results showed that exposure Sal B could maintain the proliferation of NSPCs after cerebral ischemia. Morris water maze test showed that delayed post-ischemic treatment with Sal B improved cognitive impairment after stroke in rats. Significance Sal B could maintain the NSPCs self-renew and promote proliferation, which was mediated by PI3K/Akt signal pathway. And delayed post-ischemic treatment with Sal B improved cognitive impairment after stroke in rats. These findings suggested that Sal B may act as a potential drug in treatment of brain injury or neurodegenerative diseases. PMID:22545124

  15. 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

  16. Isolation and expansion of adult cardiac stem/progenitor cells in the form of cardiospheres from human cardiac biopsies and murine hearts.

    PubMed

    Chimenti, Isotta; Gaetani, Roberto; Barile, Lucio; Forte, Elvira; Ionta, Vittoria; Angelini, Francesco; Frati, Giacomo; Messina, Elisa; Giacomello, Alessandro

    2012-01-01

    The successful isolation and ex vivo expansion of resident cardiac stem/progenitor cells from human heart biopsies has allowed us to study their biological characteristics and their applications in therapeutic approaches for the repair of ischemic/infarcted heart, the preparation of tissue-engineered cardiac grafts and, possibly, the design of cellular kits for drug screening applications. From the first publication of the original method in 2004, several adjustments and slight changes have been introduced to optimize and adjust the procedure to the evolving experimental and translational needs. Moreover, due to the wide applicability of such a method (which is based on the exploitation of intrinsic functional properties of cells with regenerative properties that are present in most tissues), the key steps of this procedure have been used to derive several kinds of tissue-specific adult stem cells for preclinical or clinical purposes.In order to define the original procedure, complete with the up-to-date modifications introduced through the years, an exhaustive description of the current protocol is performed in this chapter, with particular attention in highlighting critical steps and troubleshoots. The procedure described here consists of modular steps, that could be employed to derive cells from any kind of tissue biopsy, and needs to be considered the gold standard of all the so-called "explant methods" or "cardiosphere methods," and it represents a milestone in the clinical translation of autologous cell therapy. PMID:22610568

  17. 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

  18. 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

  19. Urinary enterolactone associated with liver enzyme levels in US adults: National Health and Nutrition Examination Survey (NHANES).

    PubMed

    Xu, Cheng; Liu, Qian; Zhang, Qunwei; Jiang, Zhao-Yan; Gu, Aihua

    2015-07-14

    Phyto-oestrogens are a family of plant-derived xeno-oestrogens that appear to have beneficial effects on human health. To date, no data are available about phyto-oestrogen consumption affecting liver health in a population. The present study aimed to explore the relationship of urinary phyto-oestrogen metabolites with serum liver enzymes in US adults. A nationally representative sample of US adults in the National Health and Nutrition Examination Survey (NHANES) 2003-10 was analysed. The cross-sectional study sample consisted of 6438 adults with data on urinary phyto-oestrogen levels, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and γ-glutamyl transaminase (GGT) concentrations and data on other potential confounders. Multivariate logistic regression and linear regression were applied to assess associations between urinary phyto-oestrogen levels and ALT, AST, ALP and GGT concentrations. We found a remarkable association between urinary enterolactone and GGT in both adult males (OR 0.37, 95 % CI 0.22, 0.61; P= 0.003) and females (OR 0.37, 95 % CI 0.26, 0.54; P= 0.009). Moreover, elevated enterolactone levels were inversely associated with ALT and AST levels in adult males. However, no association was present between levels of urinary daidzein, O-desmethylangolensin, equol, enterodiol or genistein with liver enzyme levels in this population. The present study results provide epidemiological evidence that urinary enterolactone levels are associated with liver GGT levels in humans. This suggests a potential protective effect of enterolactone on human liver function. However, the underlying mechanisms still need further investigation. PMID:25990984

  20. Engraftment and Lineage Potential of Adult Hematopoietic Stem and Progenitor Cells Is Compromised Following Short-Term Culture in the Presence of an Aryl Hydrocarbon Receptor Antagonist

    PubMed Central

    Gu, Angel; Torres-Coronado, Monica; Tran, Chy-Anh; Vu, Hieu; Epps, Elizabeth W.; Chung, Janet; Gonzalez, Nancy; Blanchard, Suzette

    2014-01-01

    Abstract Hematopoietic stem cell gene therapy for HIV/AIDS is a promising alternative to lifelong antiretroviral therapy. One of the limitations of this approach is the number and quality of stem cells available for transplant following in vitro manipulations associated with stem cell isolation and genetic modification. The development of methods to increase the number of autologous, gene-modified stem cells available for transplantation would overcome this barrier. Hematopoietic stem and progenitor cells (HSPC) from adult growth factor-mobilized peripheral blood were cultured in the presence of an aryl hydrocarbon receptor antagonist (AhRA) previously shown to expand HSPC from umbilical cord blood. Qualitative and quantitative assessment of the hematopoietic potential of minimally cultured (MC-HSPC) or expanded HSPC (Exp-HSPC) was performed using an immunodeficient mouse model of transplantation. Our results demonstrate robust, multilineage engraftment of both MC-HSPC and Exp-HSPC although estimates of expansion based on stem cell phenotype were not supported by a corresponding increase in in vivo engrafting units. Bone marrow of animals transplanted with either MC-HSPC or Exp-HSPC contained secondary engrafting cells verifying the presence of primitive stem cells in both populations. However, the frequency of in vivo engrafting units among the more primitive CD34+/CD90+ HSPC population was significantly lower in Exp-HSPC compared with MC-HSPC. Exp-HSPC also produced fewer lymphoid progeny and more myeloid progeny than MC-HSPC. These results reveal that in vitro culture of adult HSPC in AhRA maintains but does not increase the number of in vivo engrafting cells and that HSPC expanded in vitro contain defects in lymphopoiesis as assessed in this model system. Further investigation is required before implementation of this approach in the clinical setting. PMID:25003230

  1. Electroacupuncture upregulates ERK signaling pathways and promotes adult hippocampal neural progenitors proliferation in a rat model of depression

    PubMed Central

    2013-01-01

    Background In this study, we investigate the proliferation of adult neural stem cells (NSCs) in a chronic unpredictable stress (CUS) rat model of depression, the effects of electroacupunture (EA) on depressive-like symptoms and the corresponding signaling pathways. Methods SD rats were subjected to 4 weeks of CUS to induce depressive-like behaviors. EA was performed at the Du-20 (Bai-Hui) and GB-34 (Yang-Ling-Quan) acupoints. Rats were injected with BrdU and the brains were cut into sections. Double-labeling with BrdU/Sox2 and p-ERK/Nestin was performed to demonstrate the in vivo proliferation of adult NSCs in hippocampus and ERK activation in NSCs. Hippocampal microdialysates of different groups were collected to observe the in vitro effects on NSCs. Results After 8 treatments, EA generated a clear antidepressant effect on the stressed rats and promoted the NSC proliferation. ERK activation might be involved in the antidepressant-like effects of EA treatment. Hippocampal microdialysates from EA-treated stressed rats influenced NSCs to form larger neural spheres and exhibit higher p-ERK level in vitro, compared to the untreated stressed rats. Meanwhile, the antidepressant-like effects of EA involved contribution from both acupoint specificity and electrical stimulus. Conclusions EA might interfere with the hippocampal microenvironment and enhance the activation of ERK signaling pathways. This could mediate, at least in part, the beneficial effects of EA on NSC proliferation and depressive-like behaviors. PMID:24165147

  2. Laminin alpha 5, a major transcript of normal and malignant rat liver epithelial cells, is differentially expressed in developing and adult liver.

    PubMed

    Seebacher, T; Medina, J L; Bade, E G

    1997-11-25

    The laminin family of extracellular matrix glycoproteins plays a major role in cell migration and differentiation and in tumor cell invasion. As previously shown, the laminin deposited by normal and malignant rat liver epithelial cells in their extracellular matrix (ECM) and into their ECM migration tracks does not contain a typical (EHS-like) alpha 1 heavy chain. By RT-PCR screening we have now identified two alpha chains among a total of five additional laminin chains produced by these cells. Three of the newly identified chains were not previously known for the rat. Their sequences have been deposited in the EMBL nucleotide sequence data bank. The alpha 5 chain now identified is expressed at comparably high levels by both the normal and the malignant liver epithelial cells. The chain is also expressed in fetal liver together with the alpha 2 and beta 2 chains, but it is only vestigially expressed in the mature organ as shown by RT-PCR. These results suggest for alpha 5 a role in development and production of the chain by only a small subset of cells in adult liver. At the level of detection used, no changes were observed in regenerating liver after partial hepatectomy. In addition to the alpha 5 chain, the cultured cells express the beta 1 and beta 2 light chains, indicating the expression of more than one laminin isoform by the same cell line. The expression of the alpha 5 chain and of the other new non-EHS isoform chains was also analyzed in various tissues. The malignant liver epithelial cells, but not their nontumorigenic parental cells, also express, in addition to the alpha 5 chain the alpha 2 chain, which is expressed at high level by the NBT II bladder carcinoma cell line, suggesting a relationship with malignancy. PMID:9417868

  3. S-Nitrosoglutathione Reductase Deficiency Enhances the Proliferative Expansion of Adult Heart Progenitors and Myocytes Post Myocardial Infarction

    PubMed Central

    Hatzistergos, Konstantinos E; Paulino, Ellena C; Dulce, Raul A; Takeuchi, Lauro M; Bellio, Michael A; Kulandavelu, Shathiyah; Cao, Yenong; Balkan, Wayne; Kanashiro-Takeuchi, Rosemeire M; Hare, Joshua M

    2015-01-01

    Background Mammalian heart regenerative activity is lost before adulthood but increases after cardiac injury. Cardiac repair mechanisms, which involve both endogenous cardiac stem cells (CSCs) and cardiomyocyte cell-cycle reentry, are inadequate to achieve full recovery after myocardial infarction (MI). Mice deficient in S-nitrosoglutathione reductase (GSNOR−⁄−), an enzyme regulating S-nitrosothiol turnover, have preserved cardiac function after MI. Here, we tested the hypothesis that GSNOR activity modulates cardiac cell proliferation in the post-MI adult heart. Methods and Results GSNOR−⁄− and C57Bl6/J (wild-type [WT]) mice were subjected to sham operation (n=3 GSNOR−⁄−; n=3 WT) or MI (n=41 GSNOR−⁄−; n=65 WT). Compared with WT,GSNOR−⁄− mice exhibited improved survival, cardiac performance, and architecture after MI, as demonstrated by higher ejection fraction (P<0.05), lower endocardial volumes (P<0.001), and diminished scar size (P<0.05). In addition, cardiomyocytes from post-MI GSNOR−⁄− hearts exhibited faster calcium decay and sarcomeric relaxation times (P<0.001). Immunophenotypic analysis illustrated that post-MI GSNOR−⁄− hearts demonstrated enhanced neovascularization (P<0.001), c-kit+ CSC abundance (P=0.013), and a ≈3-fold increase in proliferation of adult cardiomyocytes and c-kit+/CD45− CSCs (P<0.0001 and P=0.023, respectively) as measured by using 5-bromodeoxyuridine. Conclusions Loss of GSNOR confers enhanced post-MI cardiac regenerative activity, characterized by enhanced turnover of cardiomyocytes and CSCs. Endogenous denitrosylases exert an inhibitory effect over cardiac repair mechanisms and therefore represents a potential novel therapeutic target. PMID:26178404

  4. Epidermal growth factor receptor plays a role in the regulation of liver and plasma lipid levels in adult male mice

    PubMed Central

    Zhang, Xiuqi; Garcia, Oscar A.; Wang, Rebecca F.; Stevenson, Mary C.; Threadgill, David W.; Russell, William E.

    2014-01-01

    Dsk5 mice have a gain of function in the epidermal growth factor receptor (EGFR), caused by a point mutation in the kinase domain. We analyzed the effect of this mutation on liver size, histology, and composition. We found that the livers of 12-wk-old male Dsk5 heterozygotes (+/Dsk5) were 62% heavier compared with those of wild-type controls (+/+). The livers of the +/Dsk5 mice compared with +/+ mice had larger hepatocytes with prominent, polyploid nuclei and showed modestly increased cell proliferation indices in both hepatocytes and nonparenchymal cells. An analysis of total protein, DNA, and RNA (expressed relative to liver weight) revealed no differences between the mutant and wild-type mice. However, the livers of the +/Dsk5 mice had more cholesterol but less phospholipid and fatty acid. Circulating cholesterol levels were twice as high in adult male +/Dsk5 mice but not in postweaned young male or female mice. The elevated total plasma cholesterol resulted mainly from an increase in low-density lipoprotein (LDL). The +/Dsk5 adult mouse liver expressed markedly reduced protein levels of LDL receptor, no change in proprotein convertase subtilisin/kexin type 9, and a markedly increased fatty acid synthase and 3-hydroxy-3-methyl-glutaryl-CoA reductase. Increased expression of transcription factors associated with enhanced cholesterol synthesis was also observed. Together, these findings suggest that the EGFR may play a regulatory role in hepatocyte proliferation and lipid metabolism in adult male mice, explaining why elevated levels of EGF or EGF-like peptides have been positively correlated to increased cholesterol levels in human studies. PMID:24407590

  5. JAK-STAT and AKT pathway-coupled genes in erythroid progenitor cells through ontogeny

    PubMed Central

    2012-01-01

    Background It has been reported that the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway regulates erythropoietin (EPO)-induced survival, proliferation, and maturation of early erythroid progenitors. Erythroid cell proliferation and survival have also been related to activation of the JAK-STAT pathway. The goal of this study was to observe the function of EPO activation of JAK-STAT and PI3K/AKT pathways in the development of erythroid progenitors from hematopoietic CD34+ progenitor cells, as well as to distinguish early EPO target genes in human erythroid progenitors during ontogeny. Methods Hematopoietic CD34+ progenitor cells, isolated from fetal and adult hematopoietic tissues, were differentiated into erythroid progenitor cells. We have used microarray analysis to examine JAK-STAT and PI3K/AKT related genes, as well as broad gene expression modulation in these human erythroid progenitor cells. Results In microarray studies, a total of 1755 genes were expressed in fetal liver, 3844 in cord blood, 1770 in adult bone marrow, and 1325 genes in peripheral blood-derived erythroid progenitor cells. The erythroid progenitor cells shared 1011 common genes. Using the Ingenuity Pathways Analysis software, we evaluated the network pathways of genes linked to hematological system development, cellular growth and proliferation. The KITLG, EPO, GATA1, PIM1 and STAT3 genes represent the major connection points in the hematological system development linked genes. Some JAK-STAT signaling pathway-linked genes were steadily upregulated throughout ontogeny (PIM1, SOCS2, MYC, PTPN11), while others were downregulated (PTPN6, PIAS, SPRED2). In addition, some JAK-STAT pathway related genes are differentially expressed only in some stages of ontogeny (STATs, GRB2, CREBB). Beside the continuously upregulated (AKT1, PPP2CA, CHUK, NFKB1) and downregulated (FOXO1, PDPK1, PIK3CG) genes in the PI3K-AKT signaling pathway, we also observed intermittently regulated gene expression

  6. Acute lethal graft-versus-host disease stimulates cellular proliferation in the adult rat liver.

    PubMed

    Klein, R M; Clancy, J; Stuart, S

    1982-11-01

    The present investigation was designed to analyse the effects of acute lethal graft-versus-host disease (GVHD) in adult (DA x LEW)F1 rats on cellular proliferation within the liver. The influence of the host thymus on GVHD-induced proliferation was also assessed. From 1-28 days after initiation of GVHD [3H]thymidine ([3H]-TdR) was injected i.v. and rats were killed one hour later. Percentage labelled cells (LI) of periportal infiltrating cells (PIC), hepatocytes (H), and sinusoidal lining cells (SC) were counted. Mean values for control rats were 0.3 +/- 0.1% (H), 0.4 +/- 0.1% (SC) and 0.2 +/- 0.1% (PIC). GVHD rats demonstrated a significant increase in LI of PIC (days 1-21), SC (days 2-17) and H (days 2-17). Most labelled cells in PIC were large lymphocytes. Peak LI values were 7.0 +/- 1.0% PIC (day 17), 6.8 +/- 0.9% SC (day 17), and 5.2 +/- 0.9% H (day 7), with all cellular compartments returning to near normal LI values by day 28. Stimulation of cellular proliferation occurred in all three liver cell compartments in neonatally thymectomized (TXM) rats. The intensity of GVHD-induced cell proliferation was significantly decreased at day 7 in all compartments and PIC was dramatically decreased at day 21 in TXM-GVHD rats as compared to non-TXM-GVHD rats. It is hypothesized that the general stimulation of hepatocyte cell proliferation in GVHD is related to the secretion of lymphokines by primarily donor and secondarily host T cells in the periportal infiltrate. PMID:7172201

  7. Neonatal Androgenization Exacerbates Alcohol-Induced Liver Injury in Adult Rats, an Effect Abrogated by Estrogen

    PubMed Central

    Ellefson, Whitney M.; Lakner, Ashley M.; Hamilton, Alicia; McKillop, Iain H.; Bonkovsky, Herbert L.; Steuerwald, Nury M.; Huet, Yvette M.; Schrum, Laura W.

    2011-01-01

    Alcoholic liver disease (ALD) affects millions of people worldwide and is a major cause of morbidity and mortality. However, fewer than 10% of heavy drinkers progress to later stages of injury, suggesting other factors in ALD development, including environmental exposures and genetics. Females display greater susceptibility to the early damaging effects of ethanol. Estrogen (E2) and ethanol metabolizing enzymes (cytochrome P450, CYP450) are implicated in sex differences of ALD. Sex steroid hormones are developmentally regulated by the hypothalamic-pituitary-gonadal (HPG) axis, which controls sex-specific cycling of gonadal steroid production and expression of hepatic enzymes. The aim of this study was to determine if early postnatal inhibition of adult cyclic E2 alters ethanol metabolizing enzyme expression contributing to the development of ALD in adulthood. An androgenized rat model was used to inhibit cyclic E2 production. Control females (Ctrl), androgenized females (Andro) and Andro females with E2 implants were administered either an ethanol or isocalorically-matched control Lieber-DeCarli diet for four weeks and liver injury and CYP450 expression assessed. Androgenization exacerbated the deleterious effects of ethanol demonstrated by increased steatosis, lipid peroxidation, profibrotic gene expression and decreased antioxidant defenses compared to Ctrl. Additionally, CYP2E1 expression was down-regulated in Andro animals on both diets. No change was observed in CYP1A2 protein expression. Further, continuous exogenous administration of E2 to Andro in adulthood attenuated these effects, suggesting that E2 has protective effects in the androgenized animal. Therefore, early postnatal inhibition of cyclic E2 modulates development and progression of ALD in adulthood. PMID:22206017

  8. Liver and lung transplantation in cystic fibrosis: an adult cystic fibrosis centre's experience.

    PubMed

    Sivam, S; Al-Hindawi, Y; Di Michiel, J; Moriarty, C; Spratt, P; Jansz, P; Malouf, M; Plit, M; Pleass, H; Havryk, A; Bowen, D; Haber, P; Glanville, A R; Bye, P T P

    2016-07-01

    Liver disease develops in one-third of patients with cystic fibrosis (CF). It is rare for liver disease to have its onset after 20 years of age. Lung disease, however, is usually more severe in adulthood. A retrospective analysis was performed on nine patients. Three patients required lung transplantation approximately a decade after liver transplant, and another underwent combined liver and lung transplants. Four additional patients with liver transplants are awaiting assessment for lung transplants. One patient is awaiting combined liver and lung transplants. With increased survival in CF, several patients may require more than single organ transplantation. PMID:27405894

  9. Progenitor Cells and Podocyte Regeneration

    PubMed Central

    Shankland, Stuart J.; Pippin, Jeffrey W.; Duffield, Jeremy S.

    2014-01-01

    The very limited ability of adult podocytes to proliferate in vivo is clinically significant because: podocytes form a vascular barrier which is functionally critical to the nephron; podocyte hypoplasia is a characteristic of disease; and inadequate regeneration of podocytes is a major cause of persistent podocyte hypoplasia. Excessive podocyte loss or inadequate replacement leads to glomerulosclerosis in many progressive kidney diseases. Thus, restoration of podocyte cell density is almost certainly reliant on regeneration by podocyte progenitors. However such putative progenitors have remained elusive until recently. In this review we describe the developmental processes leading to podocyte and parietal epithelial cell (PEC) formation during glomerulogenesis. We compare evidence that in normal human kidneys PECs expressing ‘progenitor’ markers CD133 and CD24 can differentiate into podocytes in vitro and in vivo with evidence from animal models suggesting a more limited role of PEC-capacity to serve as podocyte progenitors in adults. We will highlight tantalizing new evidence that specialized vascular wall cells of afferent arterioles including those which produce renin in healthy kidney, provide a novel local progenitor source of new PECs and podocytes in response to podocyte hypoplasia in the adult, and draw comparisons with glomerulogenesis. PMID:25217270

  10. Notch Signaling Coordinates Progenitor Cell-Mediated Biliary Regeneration Following Partial Hepatectomy

    PubMed Central

    Lu, Jie; Zhou, Yingqun; Hu, Tianyuan; Zhang, Hui; Shen, Miao; Cheng, Ping; Dai, Weiqi; Wang, Fan; Chen, Kan; Zhang, Yan; Wang, Chengfeng; Li, Jingjing; Zheng, Yuanyuan; Yang, Jing; Zhu, Rong; Wang, Jianrong; Lu, Wenxia; Zhang, Huawei; Wang, Junshan; Xia, Yujing; De Assuncao, Thiago M.; Jalan-Sakrikar, Nidhi; Huebert, Robert C.; Bin Zhou; Guo, Chuanyong

    2016-01-01

    Aberrant transcriptional regulation contributes to the pathogenesis of both congenital and adult forms of liver disease. Although the transcription factor RBPJ is essential for liver morphogenesis and biliary development, its specific function in the differentiation of hepatic progenitor cells (HPC) has not been investigated, and little is known about its role in adult liver regeneration. HPCs are bipotent liver stem cells that can self-replicate and differentiate into hepatocytes or cholangiocytes in vitro. HPCs are thought to play an important role in liver regeneration and repair responses. While the coordinated repopulation of both hepatocyte and cholangiocyte compartment is pivotal to the structure and function of the liver after regeneration, the mechanisms coordinating biliary regeneration remain vastly understudied. Here, we utilized complex genetic manipulations to drive liver-specific deletion of the Rbpj gene in conjunction with lineage tracing techniques to delineate the precise functions of RBPJ during biliary development and HPC-associated biliary regeneration after hepatectomy. Furthermore, we demonstrate that RBPJ promotes HPC differentiation toward cholangiocytes in vitro and blocks hepatocyte differentiation through mechanisms involving Hippo-Notch crosstalk. Overall, this study demonstrates that the Notch-RBPJ signaling axis critically regulates biliary regeneration by coordinating the fate decision of HPC and clarifies the molecular mechanisms involved. PMID:26951801

  11. Chronic cocaine exposure impairs progenitor proliferation but spares survival and maturation of neural precursors in adult rat dentate gyrus.

    PubMed

    Domínguez-Escribà, L; Hernández-Rabaza, V; Soriano-Navarro, M; Barcia, J A; Romero, F J; García-Verdugo, J M; Canales, J J

    2006-07-01

    Recent observations indicate that drugs of abuse, including alcohol and opiates, impair adult neurogenesis in the hippocampus. We have studied in rats the impact of cocaine treatment (20 mg/kg, daily, i.p.) on cell proliferation, survival and maturation following short-term (8-day) and long-term (24-day) exposure. Using 5'-bromo-2-deoxyuridine (BrdU) and Ki-67 as mitotic markers at the end of the drug treatments, we found that both short- and long-term cocaine exposures significantly reduced cell proliferation in the dentate gyrus (DG) of the hippocampus. By labelling mitotic cells with BrdU pulses before or during the early stages of the drug treatment, we determined that long-term cocaine exposure did not affect the survival of newly generated cells. In register with this finding, cocaine chronic exposure did not increase the number of apoptotic cells labelled by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling). Using doublecortin (DCX) immunocytochemistry and electron microscopy, we next examined the effects of cocaine exposure on the maturation of the neural precursors and on synaptic output to CA3. DCX immunocytochemistry showed that immature hippocampal cells of rats exposed to cocaine displayed normal arborization patterns and similar degrees of colocalization with BrdU at two different developmental stages. Moreover, cocaine did not produce significant morphological alterations of the mossy fibre projection system to stratum lucidum in the CA3 area of the hippocampus. The results presented demonstrate that chronic cocaine exposure impairs proliferation dynamics in the DG without significantly altering either the survival and growth of immature cells or the structural features of terminal projections to CA3. PMID:16903860

  12. A Milestone: Approval of CEUS for Diagnostic Liver Imaging in Adults and Children in the USA.

    PubMed

    Seitz, K; Strobel, D

    2016-06-01

    The approval of microbubbles with the inert gas sulfur hexafluoride (SF6) and a palmitic acid shell (SonoVue(®), Bracco Geneva, CH) for the diagnostic imaging of liver tumors in adults and children by the FDA in the United States represents a milestone for contrast-enhanced ultrasound (CEUS).This warrants a look back at the history of the development of CEUS. The first publications based on echocardiographic observations of right ventricular contrast phenomena caused by tiny air bubbles following i. v. injection of indocyanine green appeared around 1970 1 2 3. A longer period of sporadic publications but no real progress then followed since, in contrast to X-ray methods, ultrasound works quite well without a contrast agent.It is noteworthy that the foundations for further development were primarily laid in Europe. The development and approval (1991) of the contrast agent Echovist(®) by a German contrast manufacturer for echocardiography unsuitable for passing through lungcapillaries 4 5 resulted in the first extracardiac indications, e. g. for detecting retrovesical reflux and tubal patency, in the mid-1980 s 6 7 8. The sensitivity of color Doppler was not able to compensate for the lack of an ultrasound contrast agent compared to CT with its obligatory contrast administration.Studies of SHU 508 - microbubbles of air moderately stabilized with galactose and palmitic acid - began in 1990 9 10 11 12 13 14 15 and the contrast agent was then introduced in 1995 in Germany as Levovist(®). The most important publications by Blomley, Cosgrove, Leen, and Albrecht are named here on a representative basis 16 17 18 19 20.SHU 508 along with other US contrast agents provided impressive proof of the superiority of CEUS for the diagnosis of liver metastases. However, practical application remained complicated and required skill and technical know-how because of a lack of suitable software on US units 21 22 23 24 25. The monograph regarding the use of contrast agent in

  13. 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

  14. Cell culture: Progenitor cells from human brain after death

    NASA Astrophysics Data System (ADS)

    Palmer, Theo D.; Schwartz, Philip H.; Taupin, Philippe; Kaspar, Brian; Stein, Stuart A.; Gage, Fred H.

    2001-05-01

    Culturing neural progenitor cells from the adult rodent brain has become routine and is also possible from human fetal tissue, but expansion of these cells from postnatal and adult human tissue, although preferred for ethical reasons, has encountered problems. Here we describe the isolation and successful propagation of neural progenitor cells from human postmortem tissues and surgical specimens. Although the relative therapeutic merits of adult and fetal progenitor cells still need to be assessed, our results may extend the application of these progenitor cells in the treatment of neurodegenerative diseases.

  15. Overall Quality of Life in Adult Biliary Atresia Survivors with or without Liver Transplantation: Results from a National Cohort.

    PubMed

    de Vries, Willemien; Lind, Robert C; Sze, Yuk-Kueng; van der Steeg, Alida F W; Sieders, Egbert; Porte, Robert Jack; Verkade, Henkjan J; Hulscher, Jan B F; Hoekstra-Weebers, Josette E H M

    2016-08-01

    Background Biliary atresia (BA) is a rare cholestatic disease of infancy. Kasai portoenterostomy and liver transplantation (LT) are the two sequential treatment options. An increasing number of patients survive into adulthood. Little is known about their health-related quality of life (HRQOL). This study aims to compare HRQOL of transplanted and nontransplanted patients in a cohort of young adult BA survivors. Patients and Methods RAND-36 and Liver Disease Index Score (LDSI) questionnaires were sent to eligible adult patients with BA. Clinical characteristics were obtained from the NeSBAR (Netherlands Study group on Biliary Atresia Registry) and the national pediatric LT database. RAND-36 domain and summary scores were compared with those of an age-matched Dutch reference group. The correlations between several clinical variables and HRQOL were analyzed. Results Mean RAND-36 domain and summary scores of transplanted (n = 15) and nontransplanted (n = 25) patients with BA (response 74%) were similar to the reference scores, with the exception of a decreased general health perception in nontransplanted patients (63 ± 21 vs. 75 ± 17; [p < 0.001], particularly in females. RAND-36 domain and summary scores were not significantly correlated to age at LT, time since LT, serum bilirubin, aspartate amino transferase or albumin levels, but were moderately to strongly correlated to LDSI total scores (r values 0.35-0.77). Conclusions Overall, young adult patients with BA have a HRQOL similar to an age-matched reference group. However, general health perception of nontransplanted patients, particularly of females, was decreased. HRQOL is correlated to liver disease symptoms but not to liver biochemistry parameters. Nontransplanted females and patients suffering from liver disease-associated symptoms may be a target for tailored supportive interventions. PMID:26018212

  16. Blood flow to and the metabolism of glucose and lactate by the liver in vivo in fetal, newborn and adult sheep.

    PubMed Central

    Apatu, R S; Barnes, R J

    1991-01-01

    1. The blood flow to the liver in fetuses near to term, in newborn and in adult sheep was measured in vivo by the Fick principle using radionuclide-labelled plastic microspheres and timed withdrawal of reference organ blood samples. 2. There is a rapid flow of blood, 410.1 +/- 41.8 ml min-1 (100 g liver)-1, mean +/- S.E.M., to the liver in the fetus. Immediately after birth the blood flow is significantly less (172.5 +/- 27.5 ml min-1 (100 g liver)-1), reflecting the loss of the umbilical venous return to the liver following delivery and separation from the placenta. Arterial blood flow to the liver per unit weight of liver was small in the fetus (9.5 +/- 1.2 ml min-1 (100 g liver)-1), significantly greater in the immediate newborn (27.9 +/- 7.9 ml min-1 (100 g)-1) but appeared to decline with age after birth to 12.2 +/- 6.6 ml min-1 (100 g)-1 in lambs at 16 weeks of age. Portal blood flow to the liver, on a weight basis, changed little with age being 126 +/- 20.9 ml min-1 (100 g liver)-1 in the fetus, 144.7 +/- 21.1 ml min-1 (100 g liver)-1 in the immediate newborn and 203.2 +/- 27.8 ml min-1 (100 g liver)-1 in the adult. 3. Oxygen consumption and glucose and lactate fluxes across the sheep liver were determined from 132 days of gestation into adulthood. 4. The oxygen consumption by the fetal liver was 0.11 +/- 0.02 mmol min-1 (100 g)-1 which represents about 6% of the total fetal oxygen metabolism. Immediately after birth there was an apparent increase in liver oxygen consumption but the wide variation in the values recorded means that the change is not statistically significant. There were no significant changes in liver oxygen consumption with age after delivery, oxygen consumption by the adult liver was 0.16 +/- 0.05 mmol min-1 (100 g)-1. 5. The liver at all ages studied consumed lactate. Lactate consumption was particularly high in the fetus (0.13 +/- 0.04 mmol min-1 (100 g)-1 and could account for three times the oxygen consumed by the fetal liver, but the

  17. Decreased liver triglyceride content in adult rats exposed to protein restriction during gestation and lactation: role of hepatic triglyceride utilization.

    PubMed

    Qasem, Rani J; Li, Jing; Tang, Hee Man; Browne, Veron; Mendez-Garcia, Claudia; Yablonski, Elizabeth; Pontiggia, Laura; D'Mello, Anil P

    2015-04-01

    We have previously demonstrated that protein restriction throughout gestation and lactation reduces liver triglyceride content in adult rat offspring. However, the mechanisms mediating the decrease in liver triglyceride content are not understood. The aim of the current study was to use a new group of pregnant animals and their offspring and determine the contribution of increased triglyceride utilization via the hepatic fatty-acid oxidation and triglyceride secretory pathways to the reduction in liver triglyceride content. Pregnant Sprague-Dawley rats received either a control or a low protein diet throughout pregnancy and lactation. Pups were weaned onto laboratory chow on day 28 and killed on day 65. Liver triglyceride content was reduced in male, but not female, low-protein offspring, both in the fed and fasted states. The reduction was accompanied by a trend towards higher liver carnitine palmitoyltransferase-1a activity, suggesting increased fatty-acid transport into the mitochondrial matrix. However, medium-chain acyl coenzyme A dehydrogenase activity within the mitochondrial matrix, expression of nuclear peroxisome proliferator activated receptor-α, and plasma levels of β-hydroxybutyrate were similar between low protein and control offspring, indicating a lack of change in fatty-acid oxidation. Hepatic triglyceride secretion, assessed by blocking peripheral triglyceride utilization and measuring serum triglyceride accumulation rate, and the activity of microsomal transfer protein, were similar between low protein and control offspring. Because enhanced triglyceride utilization is not a significant contributor, the decrease in liver triglyceride content in male low-protein offspring is likely due to alterations in liver fatty-acid transport or triglyceride biosynthesis. PMID:25641378

  18. Decreased liver triglyceride content in adult rats exposed to protein restriction during gestation and lactation: role of hepatic triglyceride utilization

    PubMed Central

    Qasem, Rani J.; Li, Jing; Tang, Hee Man; Browne, Veron; Mendez, Claudia; Yablonski, Elizabeth; Pontiggia, Laura; D’mello, Anil P.

    2015-01-01

    We have previously demonstrated that protein restriction throughout gestation and lactation reduced liver triglyceride content in adult rat offspring. The mechanism(s) mediating the decrease in liver triglyceride content are not understood. The objective of the current study was to use a new group of pregnant animals and their offspring and determine the contribution of increased triglyceride utilization via the hepatic fatty acid oxidation and triglyceride secretory pathways to the reduction in liver triglyceride content. Pregnant Sprague-Dawley rats received either a control or a low protein diet throughout pregnancy and lactation. Pups were weaned onto laboratory chow on day 28 and sacrificed on day 65. Liver triglyceride content was reduced in male, but not female, low protein offspring both in the fed and fasted states. The reduction was accompanied by a trend towards higher liver carnitine palmitoyltransferase-1a activity suggesting increased fatty acid transport into the mitochondrial matrix. However, medium chain acyl CoA dehydrogenase activity within the mitochondrial matrix, expression of nuclear peroxisome proliferator activated receptor-α, and plasma levels of β-hydroxybutyrate were similar between low protein and control offspring indicating a lack of change in fatty acid oxidation. Hepatic triglyceride secretion, assessed by blocking peripheral triglyceride utilization and measuring serum triglyceride accumulation rate, and the activity of microsomal transfer protein were similar between low protein and control offspring. Since enhanced triglyceride utilization is not a significant contributor, the decrease in liver triglyceride content in male low protein offspring is likely due to alterations in liver fatty acid transport or triglyceride biosynthesis. PMID:25641378

  19. Survey of adult liver transplantation techniques (SALT): an international study of current practices in deceased donor liver transplantation

    PubMed Central

    Kluger, Michael D; Memeo, Riccardo; Laurent, Alexis; Tayar, Claude; Cherqui, Daniel

    2011-01-01

    Background There has been little focus lately on operative techniques for full graft liver transplantation, and the standard technique is unclear. Methods An internet survey addressing the key technical issues was e-mailed to programme directors. Results Responses were obtained from 93 out of 128 (73%) directors contacted. Programmes performed a median of 60 (8–240) transplants per year. Maximum mean cold time of 13 ± 3 h and maximum median steatosis of 40% (15–90%) were tolerated. The inferior vena cava was preserved by 48% of centres all the time and 43% selectively. European centres used temporary portacaval shunting (42%) four times more often than USA programmes. Venous bypass was always used when not preserving the inferior vena cava by less than 25%, and used selectively by approximately 40% of centres. Portal vein anastomosis with room for expansion (88%), graft hepatic artery to native gastroduodenal/common hepatic artery bifurcation (57%) and bile duct-to-duct (47%) were the favoured techniques. Discussion A standard international operative technique for deceased donor liver transplantation does not exist, although there is a trend towards inferior vena cava preservation. Donor selection criteria were more homogenous across programmes. As suggested by the high response rate, there likely exists interest to investigate technical variations on an international scale. PMID:21929669

  20. Repeated dose liver micronucleus assay using adult mice with multiple genotoxicity assays concurrently performed as a combination test.

    PubMed

    Hagio, Soichiro; Furukawa, Satoshi; Abe, Masayoshi; Kuroda, Yusuke; Hayashi, Seigo; Ogawa, Izumi

    2014-06-01

    Recently, the liver micronucleus (MN) assay using young adult rats with repeated administrations has been investigated by employing a new method without partial hepatectomy or in situcollagenase perfusion as the repeated dose liver MN (RDLMN) assay by Narumi et al. (2012). In our study, in order to investigate the possibility of the RDLMN assay using young adult mice instead of rats and the feasibility of employing some genotoxicity assays along with the RDLMN assay as a combination test, two genotoxic carcinogens (N,N-diethylnitrosoamine (DEN) and cisplatin (CIS)) and a nongenotoxic carcinogen (phenobarbital sodium (PHE)) were administered to mice for 15 or 29 days. Then, the liver MN assay, peripheral blood (PB) MN assay and comet assay using the liver and kidney were concurrently performed as a combination test. DEN showed positive responses to all endpoints except MN induction in PB after 15 days of repeat administration. A cross-linking agent, CIS, showed MN induction in liver after 29 days of repeat administration, and in PB after 15 and 29 days of repeat administration, although the comet assay yielded negative responses for both organs at both sampling times. PHE yielded negative responses for all endpoints. In conclusion, it is suggested that the RDLMN assay using mice is a feasible method to be integrated into the general repeated toxicity test along with the combination assays, i.e., comet assay or PB MN assay, which would help in risk assessment for carcinogenicity by comparing the results of combination assays with each other. PMID:24849678

  1. Human Fetal Brain-Derived Neural Stem/Progenitor Cells Grafted into the Adult Epileptic Brain Restrain Seizures in Rat Models of Temporal Lobe Epilepsy

    PubMed Central

    Lee, Haejin; Yun, Seokhwan; Kim, Il-Sun; Lee, Il-Shin; Shin, Jeong Eun; Park, Soo Chul; Kim, Won-Joo; Park, Kook In

    2014-01-01

    Cell transplantation has been suggested as an alternative therapy for temporal lobe epilepsy (TLE) because this can suppress spontaneous recurrent seizures in animal models. To evaluate the therapeutic potential of human neural stem/progenitor cells (huNSPCs) for treating TLE, we transplanted huNSPCs, derived from an aborted fetal telencephalon at 13 weeks of gestation and expanded in culture as neurospheres over a long time period, into the epileptic hippocampus of fully kindled and pilocarpine-treated adult rats exhibiting TLE. In vitro, huNSPCs not only produced all three central nervous system neural cell types, but also differentiated into ganglionic eminences-derived γ-aminobutyric acid (GABA)-ergic interneurons and released GABA in response to the depolarization induced by a high K+ medium. NSPC grafting reduced behavioral seizure duration, afterdischarge duration on electroencephalograms, and seizure stage in the kindling model, as well as the frequency and the duration of spontaneous recurrent motor seizures in pilocarpine-induced animals. However, NSPC grafting neither improved spatial learning or memory function in pilocarpine-treated animals. Following transplantation, grafted cells showed extensive migration around the injection site, robust engraftment, and long-term survival, along with differentiation into β-tubulin III+ neurons (∼34%), APC-CC1+ oligodendrocytes (∼28%), and GFAP+ astrocytes (∼8%). Furthermore, among donor-derived cells, ∼24% produced GABA. Additionally, to explain the effect of seizure suppression after NSPC grafting, we examined the anticonvulsant glial cell-derived neurotrophic factor (GDNF) levels in host hippocampal astrocytes and mossy fiber sprouting into the supragranular layer of the dentate gyrus in the epileptic brain. Grafted cells restored the expression of GDNF in host astrocytes but did not reverse the mossy fiber sprouting, eliminating the latter as potential mechanism. These results suggest that human fetal

  2. Recurrent primary sclerosing cholangitis in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study: Comparison of risk factors between living and deceased donor recipients.

    PubMed

    Gordon, Fredric D; Goldberg, David S; Goodrich, Nathan P; Lok, Anna S F; Verna, Elizabeth C; Selzner, Nazia; Stravitz, R Todd; Merion, Robert M

    2016-09-01

    Primary sclerosing cholangitis (PSC) recurs in 15%-25% of patients transplanted for PSC. In the United States, PSC transplant patients are more likely to receive an organ from a living donor (LD) than patients without PSC. Our aims were to (1) compare risk of PSC recurrence in LD versus deceased donor recipients and (2) identify risk factors for PSC recurrence. There were 241 living donor liver transplantations (LDLTs) and 65 deceased donor liver transplantation (DDLT) patients transplanted between 1998 and 2013 enrolled in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study who were evaluated. PSC recurrence risk for LDLT and DDLT recipients was compared using Kaplan-Meier survival curves and log-rank tests. Cox models were used to evaluate PSC risk factors. Overall PSC recurrence probabilities were 8.7% and 22.4% at 5 and 10 years after liver transplantation (LT), respectively. The risk of PSC recurrence was not significantly different for DDLT versus LDLT recipients (P = 0.36). For DDLT versus LDLT recipients, unadjusted 5- and 10-year PSC recurrence was 9.4% versus 9.5% and 36.9% versus 21.1%. Higher laboratory Model for End-Stage Liver Disease (MELD) score at LT, onset of a biliary complication, cholangiocarcinoma, and higher donor age were associated with increased risks of PSC recurrence: for MELD (hazard ratio [HR] = 1.06; 95% confidence interval [CI] 1.02-1.10 per MELD point, P = 0.002); for biliary complication (HR, 2.82; 95% CI, 1.28-6.25; P = 0.01); for cholangiocarcinoma (HR, 3.98; 95% CI, 1.43-11.09; P = 0.008); for donor age (per 5-years donor age; HR, 1.17; 95% CI, 1.02-1.35; P = 0.02). Factors not significantly associated with PSC recurrence included the following: first-degree relative donor (P = 0.11), post-LT cytomegalovirus infection (P = 0.38), and acute rejection (P = 0.22). Risk of recurrent PSC was not significantly different for DDLT and LDLT recipients. Biliary complications

  3. Pericentral activity of AFP enhancer E3 and glutamine synthetase upstream enhancer in the adult liver are regulated by β-catenin

    PubMed Central

    Clinkenbeard, Erica L.; Butler, James E.; Spear, Brett T.

    2015-01-01

    We previously showed that mouse alpha-fetoprotein enhancer E3 activity is highly restricted to pericentral hepatocytes in the adult liver. Here, using transgenic mice, we show that the upstream enhancer of the rat glutamine synthetase gene is also active specifically in pericentral regions. Activity of both enhancers is lost in the absence of β-catenin, a key regulator of zonal gene expression in the adult liver. Both enhancers contain a single highly conserved TCF/LEF binding site that is required for responsiveness to β-catenin. We also show that endogenous AFP mRNA levels in the perinatal liver are lower when β-catenin is reduced. These data identify the first distinct zonally-active regulatory regions required for β-catenin responsiveness in the adult liver and suggest that postnatal AFP repression and the establishment of zonal regulation are controlled, at least in part, by the same factors. PMID:22544812

  4. PET-CT in Determining the Radioembolization Dose Delivered to Patients With Liver Metastasis, Primary Liver Cancer, or Biliary Cancer

    ClinicalTrials.gov

    2016-03-01

    Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Metastatic Extrahepatic Bile Duct Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Stage D Adult Primary Liver Cancer (BCLC); Unspecified Adult Solid Tumor, Protocol Specific

  5. Repeated-dose liver and gastrointestinal tract micronucleus assays with CI Solvent Yellow 14 (Sudan I) using young adult rats.

    PubMed

    Matsumura, Shoji; Ikeda, Naohiro; Hamada, Shuichi; Ohyama, Wakako; Wako, Yumi; Kawasako, Kazufumi; Kasamatsu, Toshio; Nishiyama, Naohiro

    2015-03-01

    The in vivo genotoxicity of CI Solvent Yellow 14 (Sudan I) was examined using repeated-dose liver and gastrointestinal tract micronucleus (MN) assays in young adult rats. Sudan I is a mono-azo dye based on aniline and 1-amino-2-hydroxynaphthalene. This dye was demonstrated as a rat liver carcinogen in a National Toxicology Program (NTP) bioassay, and genotoxicity was noted in a rat bone marrow micronucleus (BMMN) assay. In the present study, Sudan I was administered orally to rats for 14-days, and the MN frequency in the liver, stomach, colon, and bone marrow were analyzed. The frequency of micronucleated hepatocytes (MNHEPs) was not significantly increased by the administration of the Sudan I. Gastrointestinal tract MNs were also not induced. However, in the BMMN assay, a significant increase in micronucleated immature erythrocytes (MNIMEs) was observed in a dose-dependent manner. While Sudan I has been reported to lack hepatic genotoxicity, it has also exhibited tumor-promoting activities. These results are consistent with the lack of induction of MN in the hepatocytes. The lack of MN induction in cells of the gastrointestinal tract was also logical because azo-compounds are reported to be unlikely to induce DNA damage in the rat gut. The repeated-dose rat liver and gastrointestinal tract MN assays have the potential to be used in the evaluation of the genotoxicity of a chemical in each organ in accordance with its mode of action. PMID:25892626

  6. Preoperative single-dose methylprednisolone versus placebo after major liver resection in adults: protocol for a randomised controlled trial

    PubMed Central

    Bressan, Alexsander K; Roberts, Derek J; Bhatti, Sana U; Dixon, Elijah; Sutherland, Francis R; Bathe, Oliver F; Ball, Chad G

    2015-01-01

    Introduction Although randomised controlled trials have demonstrated that preoperative glucocorticoids may improve postoperative surrogate outcomes among patients undergoing major liver resection, evidence supporting improved patient-important outcomes is lacking. This superiority trial aims to evaluate the effect of administration of a bolus of the glucocorticoid methylprednisolone versus placebo during induction of anaesthesia on postoperative morbidity among adults undergoing elective major liver resection. Methods and analysis This will be a randomised, dual-arm, parallel-group, superiority trial. All consecutive adults presenting to a large Canadian tertiary care hospital who consent to undergo major liver resection will be included. Patients aged <18 years and those currently receiving systemic corticosteroid therapy will be excluded. We will randomly allocate participants to a preoperative 500 mg intravenous bolus of methylprednisolone versus placebo. Surgical team members and outcome assessors will be blinded to treatment allocation status. The primary outcome measure will be postoperative complications. Secondary outcome measures will include mortality, the incidence of several specific postoperative complications, and blood levels of select proinflammatory cytokines, acute-phase proteins, and laboratory liver enzymes or function tests on postoperative days 0, 1, 2 and 5. The incidence of postoperative complications and mortality will be compared using Fisher's exact test, while the above laboratory measures will be compared using mixed-effects models with a subject-specific random intercept. Ethics and dissemination This trial will evaluate the protective effect of a single preoperative dose of methylprednisolone on the hazard of postoperative complications. A report releasing study results will be submitted for publication in an appropriate journal, approximately 3 months after finishing the data collection. Trial registration number NCT01997658

  7. Dietary Patterns Modulate the Risk of Non-Alcoholic Fatty Liver Disease in Chinese Adults

    PubMed Central

    Yang, Chao-Qun; Shu, Long; Wang, Shuai; Wang, Jia-Jia; Zhou, Yu; Xuan, Yu-Jie; Wang, Su-Fang

    2015-01-01

    Although previous studies reported the associations between the intakes of individual foods or nutrients and the risk of non-alcoholic fatty liver disease (NAFLD), the relationship between dietary patterns and NAFLD in the Chinese population has been rarely studied to date. This study aimed to investigate the associations between dietary patterns and the risk of NAFLD in a middle-aged Chinese population. The Study subjects were 999 Chinese adults aged 45–60 years in the Anhui province who participated in the Hefei Nutrition and Health Study. Dietary intake was collected by a semi-quantitative food frequency questionnaire. NAFLD was defined as the presence of moderate-severe hepatic steatosis (by B-ultrasonic examination); the absence of excessive alcohol use (>20 g day−1 in men and 10 g day−1 in women); no use of steatogenic medications within the past six months; no exposure to hepatotoxins; and no history of bariatric surgery. Log-binomial regression analysis was used to examine the association between dietary patterns and NAFLD with adjustment of potential confounding variables. Out of 999 participants, 345 (34.5%) were classified as having NAFLD. Four major dietary patterns were identified: “Traditional Chinese”, “Animal food”, “Grains-vegetables” and “High-salt” dietary patterns. After adjusting for potential confounders, subjects in the highest quartile of the “Animal food” pattern scores had greater prevalence ratio for NAFLD (prevalence ratio (PR) = 1.354; 95% confidence interval (CI): 1.063–1.724; p < 0.05) than did those in the lowest quartile. After adjustment for body mass index (BMI), compared with the lowest quartile of the “Grains-vegetables” pattern, the highest quartile had a lower prevalence ratio for NAFLD (PR = 0.777; 95% CI: 0.618–0.977, p < 0.05). However, the “traditional Chinese” and “high-salt” dietary patterns showed no association with the risk of NAFLD. Our findings indicated that the

  8. Histology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis in Adults and Children.

    PubMed

    Kleiner, David E; Makhlouf, Hala R

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) is the liver disease associated with obesity, diabetes, and the metabolic syndrome. Although steatosis is a key histologic feature, liver biopsies of patients with NAFLD can show a wide range of findings. Nonalcoholic steatohepatitis (NASH) is a progressive subtype of NAFLD first defined by analogy to alcoholic hepatitis. Young children may have an alternate pattern of progressive NAFLD characterized by a zone 1 distribution of steatosis, inflammation, and fibrosis. Several grading and staging systems exist, but all require adequate biopsies. Although NASH generally shows fibrosis progression over time, some patients show regression of disease. PMID:27063270

  9. Graft selection strategy in adult-to-adult living donor liver transplantation: When both hemiliver grafts meet volumetric criteria.

    PubMed

    Kurihara, Takeshi; Yoshizumi, Tomoharu; Yoshida, Yoshihiro; Ikegami, Toru; Itoh, Shinji; Harimoto, Norifumi; Ninomiya, Mizuki; Uchiyama, Hideaki; Okabe, Hirohisa; Kimura, Koichi; Kawanaka, Hirofumi; Shirabe, Ken; Maehara, Yoshihiko

    2016-07-01

    To ensure donor safety in living donor liver transplantation (LDLT), the left and caudate lobe (LL) is the preferred graft choice. However, patient prognosis may still be poor even if graft volume (GV) selection criteria are met. Our aim was to evaluate the effects of right lobe (RL) donation when the LL graft selection criteria are met. Consecutive donors (n = 135) with preoperative LL graft volumetric GV/standard liver volume (SLV) of ≥35% and RL remnant of ≥35% were retrospectively studied. Patients were divided into 2 groups: LL graft and RL graft. Recipient's body surface area (BSA), Model for End-Stage Liver Disease (MELD) score, and the donor's age were higher in the RL group. The donor's BSA and preoperative volumetric GV/SLV of the LL graft were smaller in the RL group. The predicted score (calculated using data for graft size, donor age, MELD score, and the presence of portosystemic shunt, which correlated well with graft function and with 6-month graft survival) of the RL group, was significantly lower if the LL graft were used, but using the actual RL graft improved the score equal to that of the LL group. Six-month and 12-month graft survival rates did not differ between the 2 groups. In patients with a poor prognosis, a larger RL graft improved the predicted score and survival was equal to that of patients who received LL grafts. In conclusion, graft selection by GV, donor age, and recipient MELD score improves outcomes in LDLT. Liver Transplantation 22 914-922 2016 AASLD. PMID:26953726

  10. Effect of selenium on methimazole-induced liver damage and oxidative stress in adult rats and their offspring.

    PubMed

    Sefi, Mediha; Ben Amara, Ibtissem; Troudi, Afef; Soudani, Nejla; Hakim, Ahmed; Zeghal, Khaled Mounir; Boudawara, Tahia; Zeghal, Najiba

    2014-08-01

    This study aimed to investigate the protective effect of selenium (Se) on methimazole (MMI; an antithyroid drug)-induced hepatotoxicity in adult rats and their progeny. Female Wistar rats were randomly divided into four groups of six rats in each group: group I served as controls that received standard diet; group II received MMI in drinking water as 250 mg L(-1) and standard diet; group III received both MMI (250 mg L(-1), orally) and Se (0.5 mg kg(-1) of diet); group IV received Se (0.5 mg kg(-1) of diet) as sodium selenite. Treatments were started from the 14th day of pregnancy until day 14 after delivery. Exposure of rats to MMI promoted oxidative stress with an increase in liver malondialdehyde levels, advanced oxidation protein products and protein carbonyl contents and a decrease in the levels of glutathione, nonprotein thiols and vitamin C. A decrease in the activities of liver glutathione peroxidase, superoxide dismutase, catalase and lactate dehydrogenase and in the levels of plasma total protein and albumin was also observed. Plasma transaminase activities and total, direct and indirect bilirubin levels increased. Coadministration of Se through diet improved all biochemical parameters. The histopathological changes confirmed the biochemical results. Therefore, our investigation revealed that Se, a trace element with antioxidant properties, was effective in preventing MMI-induced liver damage. PMID:23047615

  11. Sexually Dimorphic Patterns of Episomal rAAV Genome Persistence in the Adult Mouse Liver and Correlation With Hepatocellular Proliferation

    PubMed Central

    Dane, Allison P; Cunningham, Sharon C; Graf, Nicole S; Alexander, Ian E

    2009-01-01

    Recombinant adeno-associated virus vectors (rAAVs) show exceptional promise for liver-targeted gene therapy, with phenotype correction in small and large animal disease models being reported with increasing frequency. Success in humans, however, remains a considerable challenge that demands greater understanding of host–vector interactions, notably those governing the efficiency of initial gene transfer and subsequent long-term persistence of gene expression. In this study, we examined long-term enhanced green fluorescent protein (eGFP) expression and vector genome persistence in the mouse liver after rAAV2/8-mediated gene transfer in early adulthood. Two intriguing findings emerged of considerable scientific and clinical interest. First, adult female and male mice showed distinctly different patterns of persistence of eGFP expression across the hepatic lobule after exhibiting similar patterns initially. Female mice retained a predominantly perivenous pattern of expression, whereas male mice underwent inversion of this pattern with preferential loss of perivenous expression and relative retention of periportal expression. Second, these changing patterns of expression correlated with sexually dimorphic patterns of genome persistence that appear linked both spatially and temporally to underlying hepatocellular proliferation. Observation of the equivalent phenomenon in man could have significant implications for the long-term therapeutic efficacy of rAAV-mediated gene transfer, particularly in the context of correction of liver functions showing metabolic zonation. PMID:19568224

  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. PMID:26866353

  13. A novel isolation method for macrophage-like cells from mixed primary cultures of adult rat liver cells.

    PubMed

    Kitani, Hiroshi; Takenouchi, Takato; Sato, Mitsuru; Yoshioka, Miyako; Yamanaka, Noriko

    2010-08-31

    We report a simple and efficient method to obtain macrophage-like cells from the mixed primary cultures of adult rat liver cells. A parenchymal hepatocyte enriched fraction was prepared from adult rat livers and seeded into culture flasks. After 7 to 10 days of culture, when most hepatocytes were degenerated or transformed into fibroblastic cells, macrophage-like cells vigorously proliferated on the cell sheet. By shaking the flasks, macrophage-like cells were readily detached. Subsequent transfer and incubation in plastic dishes resulted in quick and selective adhesion of macrophage-like cells, while other contaminating cells remained suspended in the medium. After rinsing with saline, attached macrophage-like cells were harvested with 95 to 99% purity, as evaluated by flow cytometry or immunocytochemistry. These cells showed typical macrophage morphology and were strongly positive for markers of rat macrophages, such as ED-1, ED-3, and OX-41, but negative for cytokeratins and alpha-smooth muscle actin. They possessed functional properties of typical macrophages, including active phagocytosis of latex beads, proliferative response to recombinant GM-CSF, secretion of inflammatory and anti-inflammatory cytokines upon stimulation with LPS, and formation of multinucleated giant cells. As more than 10(6) cells can be recovered repeatedly from a T75 culture flask at two to three day intervals for more than two weeks, our procedure might implicate a novel alternative to obtain Kupffer cells in sufficient number and purity without complex equipment and skills. PMID:20600081

  14. Isolated intestinal transplants vs. liver-intestinal transplants in adult patients in the United States: 22 yr of OPTN data.

    PubMed

    Desai, Chirag S; Gruessner, Angelika C; Khan, Khalid M; Fishbein, Thomas M; Jie, Tun; Rodriguez Rilo, Horacio L; Gruessner, Rainer W G

    2012-01-01

    We examined the outcomes of adult intestinal transplants (ITx); isolated ITx vs. liver-intestinal transplants (L-ITx) were compared using the UNOS database (1987-2009). Of 759 ITx transplants in 687 patients, 463 (61%) were isolated and 296 (39%) were L-ITx. Patient survival for primary isolated ITx at one, three, and five yr was 84%, 66.7%, and 54.2%; and primary L-ITx was, 67%, 53.3%, and 46% (p = 0.0005). Primary isolated ITx graft survival at one, three, and five yr was 80.7%, 57.6%, 42.8%; primary L-ITx was 64.1%, 51%, 44.1% (p = 0.0003 at one, three yr, Wilcoxon test). For retransplants (n = 72), patient and graft survival for isolated ITx (n = 41) at five yr was 40% in era 1 (1987-2000) and 16% in era 2 (p = 0.47); for retransplanted L-ITx (n = 31), it improved from 14% to 64% in era 2 (p = 0.01). Cox regression: creatinine >1.3 mg/dL and pre-transplant hospitalization were negative predictors for outcome of both; bilirubin >1.3 mg/dL was a negative predictor for isolated ITx and donor age >40 yr for L-ITx. Isolated ITx should be considered prior to liver disease for adults with intestinal failure; L-ITx is preferable for retransplantation. PMID:22192061

  15. Molecular Changes in Opisthorchis viverrini (Southeast Asian Liver Fluke) during the Transition from the Juvenile to the Adult Stage

    PubMed Central

    Sripa, Jittiyawadee; Hall, Ross S.; Scheerlinck, Jean-Pierre; Laha, Thewarach; Sripa, Banchob; Gasser, Robin B.

    2012-01-01

    Background The Southeast Asian liver fluke (Opisthorchis viverrini) chronically infects and affects tens of millions of people in regions of Asia, leading to chronic illness and, importantly, inducing malignant cancer ( = cholangiocarcinoma). In spite of this, little is known, at the molecular level, about the parasite itself, its interplay with its hosts or the mechanisms of disease and/or carcinogenesis. Methodology/Principal Findings Here, we generated extensive RNA-Seq data (Illumina) representing adult and juvenile stages of O. viverrini, and combined these sequences with previously published transcriptomic data (454 technology) for this species, yielding a combined assembly of significantly increased quality and allowing quantitative assessment of transcription in the juvenile and adult stage. Conclusions This enhanced assembly reveals that, despite the substantial biological similarities between the human liver flukes, O. viverinni and Clonorchis sinensis, there are previously unrecognized differences in major aspects of their molecular biology. Most notable are differences among the C13 and cathepsin L-like cysteine peptidases, which play key roles in tissue migration, immune evasion and feeding, and, thus, represent potential drug and/or vaccine targets. Furthermore, these data indicate that major lineages of cysteine peptidases of socioeconomically important trematodes have evolved through a process of gene loss rather than independent radiation, contrasting previous proposals. PMID:23209858

  16. Sex-specific associations between birth weight and adult primary liver cancer in a large cohort of Danish children.

    PubMed

    Zimmermann, Esther; Berentzen, Tina L; Gamborg, Michael; Sørensen, Thorkild I A; Baker, Jennifer L

    2016-03-15

    Whether the prenatal period is critical for the development of adult primary liver cancer (PLC) is sparsely investigated. Recently, attention has been drawn to potential sex-differences in the early origins of adult disease. The association between birth weight and adult PLC, separately in men and women was investigated, using a large cohort of 217,227 children (51% boys), born from 1936 to 1980, from the Copenhagen School Health Records Register, and followed them until 2010 in national registers. Hazard ratios (95% confidence intervals) of PLC (30 years or older) were estimated by Cox regression models stratified by birth cohort. During 5.1 million person-years of follow-up, 185 men and 65 women developed PLC. Sex modified the association between birth weight and adult PLC (p values for interaction = 0.0005). Compared with a sex-specific reference group of birth weights between 3.25 and 3.75 kg, men with birth weights between 2.00 and 3.25 kg and 3.75-5.50 kg, had HRs of 1.48 (1.06-2.05) and 0.85 (0.56-1.28), respectively. Among women the corresponding HRs were 1.71 (0.90-3.29) and 3.43 (1.73-6.82). Associations were similar for hepatocellular carcinoma only, across year of birth, and after accounting for diagnoses of alcohol-related disorders, viral hepatitis and biliary cirrhosis. Prenatal exposures influenced the risk of adult PLC, and the effects at the high birth weight levels appeared to be sex-specific. These findings underscore the importance of considering sex-specific mechanisms in the early origins of adult PLC. PMID:26506514

  17. Flt3 Ligand Regulates the Development of Innate Lymphoid Cells in Fetal and Adult Mice.

    PubMed

    Baerenwaldt, Anne; von Burg, Nicole; Kreuzaler, Matthias; Sitte, Selina; Horvath, Edit; Peter, Annick; Voehringer, David; Rolink, Antonius G; Finke, Daniela

    2016-03-15

    Flt3 ligand (Flt3L) promotes survival of lymphoid progenitors in the bone marrow and differentiation of dendritic cells (DCs), but its role in regulating innate lymphoid cells (ILCs) during fetal and adult life is not understood. By using Flt3L knockout and transgenic mice, we demonstrate that Flt3L controls ILC numbers by regulating the pool of α4β7(-) and α4β7(+) lymphoid tissue inducer cell progenitors in the fetal liver and common lymphoid progenitors in the bone marrow. Deletion of flt3l severely reduced the number of fetal liver progenitors and lymphoid tissue inducer cells in the neonatal intestine, resulting in impaired development of Peyer's patches. In the adult intestine, NK cells and group 2 and 3 ILCs were severely reduced. This effect occurred independently of DCs as ILC numbers were normal in mice in which DCs were constitutively deleted. Finally, we could show that administration of Flt3L increased the number of NKp46(-) group 3 ILCs in wild-type and even in Il7(-/-) mice, which generally have reduced numbers of ILCs. Taken together, Flt3L significantly contributes to ILC and Peyer's patches development by targeting lymphoid progenitor cells during fetal and adult life. PMID:26851220

  18. Prenatal ethanol exposure programs an increased susceptibility of non-alcoholic fatty liver disease in female adult offspring rats

    SciTech Connect

    Shen, Lang; Liu, Zhongfen; Gong, Jun; Zhang, Li; Wang, Linlong; Magdalou, Jacques; Chen, Liaobin; Wang, Hui

    2014-01-15

    Prenatal ethanol exposure (PEE) induces dyslipidemia and hyperglycemia in fetus and adult offspring. However, whether PEE increases the susceptibility to non-alcoholic fatty liver disease (NAFLD) in offspring and its underlying mechanism remain unknown. This study aimed to demonstrate an increased susceptibility to high-fat diet (HFD)-induced NAFLD and its intrauterine programming mechanisms in female rat offspring with PEE. Rat model of intrauterine growth retardation (IUGR) was established by PEE, the female fetus and adult offspring that fed normal diet (ND) or HFD were sacrificed. The results showed that, in PEE + ND group, serum corticosterone (CORT) slightly decreased and insulin-like growth factor-1 (IGF-1) and glucose increased with partial catch-up growth; In PEE + HFD group, serum CORT decreased, while serum IGF-1, glucose and triglyceride (TG) increased, with notable catch-up growth, higher metabolic status and NAFLD formation. Enhanced liver expression of the IGF-1 pathway, gluconeogenesis, and lipid synthesis as well as reduced expression of lipid output were accompanied in PEE + HFD group. In PEE fetus, serum CORT increased while IGF-1 decreased, with low body weight, hyperglycemia, and hepatocyte ultrastructural changes. Hepatic IGF-1 expression as well as lipid output was down-regulated, while lipid synthesis significantly increased. Based on these findings, we propose a “two-programming” hypothesis for an increased susceptibility to HFD-induced NAFLD in female offspring of PEE. That is, the intrauterine programming of liver glucose and lipid metabolic function is “the first programming”, and postnatal adaptive catch-up growth triggered by intrauterine programming of GC-IGF1 axis acts as “the second programming”. - Highlights: • Prenatal ethanol exposure increase the susceptibility of NAFLD in female offspring. • Prenatal ethanol exposure reprograms fetal liver’s glucose and lipid metabolism . • Prenatal ethanol exposure cause

  19. Prenatal ethanol exposure programs an increased susceptibility of non-alcoholic fatty liver disease in female adult offspring rats.

    PubMed

    Shen, Lang; Liu, Zhongfen; Gong, Jun; Zhang, Li; Wang, Linlong; Magdalou, Jacques; Chen, Liaobin; Wang, Hui

    2014-01-15

    Prenatal ethanol exposure (PEE) induces dyslipidemia and hyperglycemia in fetus and adult offspring. However, whether PEE increases the susceptibility to non-alcoholic fatty liver disease (NAFLD) in offspring and its underlying mechanism remain unknown. This study aimed to demonstrate an increased susceptibility to high-fat diet (HFD)-induced NAFLD and its intrauterine programming mechanisms in female rat offspring with PEE. Rat model of intrauterine growth retardation (IUGR) was established by PEE, the female fetus and adult offspring that fed normal diet (ND) or HFD were sacrificed. The results showed that, in PEE+ND group, serum corticosterone (CORT) slightly decreased and insulin-like growth factor-1 (IGF-1) and glucose increased with partial catch-up growth; In PEE+HFD group, serum CORT decreased, while serum IGF-1, glucose and triglyceride (TG) increased, with notable catch-up growth, higher metabolic status and NAFLD formation. Enhanced liver expression of the IGF-1 pathway, gluconeogenesis, and lipid synthesis as well as reduced expression of lipid output were accompanied in PEE+HFD group. In PEE fetus, serum CORT increased while IGF-1 decreased, with low body weight, hyperglycemia, and hepatocyte ultrastructural changes. Hepatic IGF-1 expression as well as lipid output was down-regulated, while lipid synthesis significantly increased. Based on these findings, we propose a "two-programming" hypothesis for an increased susceptibility to HFD-induced NAFLD in female offspring of PEE. That is, the intrauterine programming of liver glucose and lipid metabolic function is "the first programming", and postnatal adaptive catch-up growth triggered by intrauterine programming of GC-IGF1 axis acts as "the second programming". PMID:24275070

  20. Informed consent and decision-making about adult-to-adult living donor liver transplantation: a systematic review of empirical research.

    PubMed

    Gordon, Elisa J; Daud, Amna; Caicedo, Juan Carlos; Cameron, Kenzie A; Jay, Colleen; Fryer, Jonathan; Beauvais, Nicole; Skaro, Anton; Baker, Talia

    2011-12-27

    Adult-to-adult living donor liver transplantation (LDLT) is a complex procedure that poses serious health risks to and provides no direct health benefit for the donor. Because of this uneven risk-benefit ratio, ensuring donor autonomy through informed consent is critical. To assess the current knowledge pertaining to informed consent for LDLT, we conducted a systematic review of the empirical literature on donors' decision-making process, comprehension about risks and outcomes, and information needs for LDLT. Of the 1423 identified articles, 24 met final review criteria, representing the perspective of approximately 2789 potential and actual donors. As donors' decisions to donate often occur before evaluation, they often make uninformed decisions. The review found that 88% to 95% of donors reported understanding information clinicians disclosed about risks and benefits. However, donors reported unmet information needs, knowledge gaps regarding risks, and unanticipated complications. Few donors reported feeling pressure to donate. Most studies were limited by cultural differences, small sample sizes, inconsistent measures, and poor methodological approaches. This systematic review suggests that informed consent for LDLT is sub-optimal as donors do not adequately appreciate disclosed information during the informed consent process, despite United Network for Organ Sharing/CMS regulations requiring formal psychological evaluation of donor candidates. Interventions are needed to improve donor-clinician communication during the LDLT informed consent process such as through the use of comprehension assessment tools and e-health educational tools that leverage adult learning theory to effectively convey LDLT outcome data. PMID:22143436

  1. Accessory lobe of the right liver mocking a pulmonary tumor in an adult woman.

    PubMed

    Kitamura, Yuka; Sakakura, Noriaki; Uchida, Tatsuo; Suyama, Motokazu

    2012-08-01

    We report a rare case of an accessory lobe of the liver in the right thoracic cavity with the past history of breast cancer. A 66-year-old woman underwent thoracotomy owing to a slowly growing suspected lung tumor identified by computed tomography. The intraoperative findings revealed an accessory lobe of the liver. If this possibility had been considered, the correct diagnosis could have been achieved using computed tomography with multi-directional scanning, so that an unnecessary operation could have been avoided. PMID:22618988

  2. Standardized surgical techniques for adult living donor liver transplantation using a modified right lobe graft: a video presentation from bench to reperfusion.

    PubMed

    Hwang, Shin; Ha, Tae-Yong; Ahn, Chul-Soo; Moon, Deok-Bog; Kim, Ki-Hun; Song, Gi-Won; Jung, Dong-Hwan; Park, Gil-Chun; Lee, Sung-Gyu

    2016-08-01

    After having experienced more than 2,000 cases of adult living donor liver transplantation (LDLT), we established the concepts of right liver graft standardization. Right liver graft standardization intends to provide hemodynamics-based and regeneration-compliant reconstruction of vascular inflow and outflow. Right liver graft standardization consists of the following components: Right hepatic vein reconstruction includes a combination of caudal-side deep incision and patch venoplasty of the graft right hepatic vein to remove the acute angle between the graft right hepatic vein and the inferior vena cava; middle hepatic vein reconstruction includes interposition of a uniform-shaped conduit with large-sized homologous or prosthetic grafts; if the inferior right hepatic vein is present, its reconstruction includes funneling and unification venoplasty for multiple short hepatic veins; if donor portal vein anomaly is present, its reconstruction includes conjoined unification venoplasty for two or more portal vein orifices. This video clip that shows the surgical technique from bench to reperfusion was a case presentation of adult LDLT using a modified right liver graft from the patient's son. Our intention behind proposing the concept of right liver graft standardization is that it can be universally applicable and may guarantee nearly the same outcomes regardless of the surgeon's experience. We believe that this reconstruction model would be primarily applied to a majority of adult LDLT cases. PMID:27621745

  3. Standardized surgical techniques for adult living donor liver transplantation using a modified right lobe graft: a video presentation from bench to reperfusion

    PubMed Central

    Ha, Tae-Yong; Ahn, Chul-Soo; Moon, Deok-Bog; Kim, Ki-Hun; Song, Gi-Won; Jung, Dong-Hwan; Park, Gil-Chun; Lee, Sung-Gyu

    2016-01-01

    After having experienced more than 2,000 cases of adult living donor liver transplantation (LDLT), we established the concepts of right liver graft standardization. Right liver graft standardization intends to provide hemodynamics-based and regeneration-compliant reconstruction of vascular inflow and outflow. Right liver graft standardization consists of the following components: Right hepatic vein reconstruction includes a combination of caudal-side deep incision and patch venoplasty of the graft right hepatic vein to remove the acute angle between the graft right hepatic vein and the inferior vena cava; middle hepatic vein reconstruction includes interposition of a uniform-shaped conduit with large-sized homologous or prosthetic grafts; if the inferior right hepatic vein is present, its reconstruction includes funneling and unification venoplasty for multiple short hepatic veins; if donor portal vein anomaly is present, its reconstruction includes conjoined unification venoplasty for two or more portal vein orifices. This video clip that shows the surgical technique from bench to reperfusion was a case presentation of adult LDLT using a modified right liver graft from the patient's son. Our intention behind proposing the concept of right liver graft standardization is that it can be universally applicable and may guarantee nearly the same outcomes regardless of the surgeon's experience. We believe that this reconstruction model would be primarily applied to a majority of adult LDLT cases. PMID:27621745

  4. Retinoid Homeostatic Gene Expression in Liver, Lung and Kidney: Ontogeny and Response to Vitamin A-Retinoic Acid (VARA) Supplementation from Birth to Adult Age

    PubMed Central

    Owusu, Sarah A.; Ross, A. Catharine

    2016-01-01

    Vitamin A (VA, retinol) metabolism is homeostatically controlled, but little is known of its regulation in the postnatal period. Here, we determined the postnatal trajectory of VA storage and metabolism in major compartments of VA metabolism–plasma, liver, lung, and kidney from postnatal (P) day 1 to adulthood. We also investigated the response to supplementation with VARA, a combination of VA and 10% all-trans-retinoic acid that previously was shown to synergistically increase retinol uptake and storage in lung. Nursling pups of dams fed a VA-marginal diet received an oral dose of oil (placebo) or VARA on each of four neonatal days: P1, P4, P7, and P10; and again as adults. Tissues were collected 6 h after the final dosing on P1, P4, P10, and at adult age. Gene transcripts for Lrat and Rbp4 in liver and Raldh-1 and Raldh-3 in lung, did not differ in the neonatal period but were higher, P<0.05, in adults, while Cyp26B1, Stra6, megalin, and Raldh-2 in lung did not differ from perinatal to adult ages. VARA supplementation increased total retinol in plasma, liver and lung, with a dose-by-dose accumulation in neonatal liver and lung, while transcripts for Lrat in liver, megalin in kidney, Cyp26A1/B1 in liver and lung, respectively, and Stra6 in lung, were all increased, suggesting pathways of VA uptake, storage and RA oxidation were each augmented after VARA. VARA decreased hepatic expression of Rbp4, responsible for VA trafficking from liver to plasma, and, in lung, of Raldh-1 and Raldh-2, which function in RA production. Our results define retinoid homeostatic gene expression from neonatal and adult age and show that while supplementation with VARA acutely alters retinol content and retinoid homeostatic gene expression in neonatal and adult lung, liver and kidney, VARA supplementation of neonates increased adult-age VA content only in the liver. PMID:26731668

  5. Retinoid Homeostatic Gene Expression in Liver, Lung and Kidney: Ontogeny and Response to Vitamin A-Retinoic Acid (VARA) Supplementation from Birth to Adult Age.

    PubMed

    Owusu, Sarah A; Ross, A Catharine

    2016-01-01

    Vitamin A (VA, retinol) metabolism is homeostatically controlled, but little is known of its regulation in the postnatal period. Here, we determined the postnatal trajectory of VA storage and metabolism in major compartments of VA metabolism-plasma, liver, lung, and kidney from postnatal (P) day 1 to adulthood. We also investigated the response to supplementation with VARA, a combination of VA and 10% all-trans-retinoic acid that previously was shown to synergistically increase retinol uptake and storage in lung. Nursling pups of dams fed a VA-marginal diet received an oral dose of oil (placebo) or VARA on each of four neonatal days: P1, P4, P7, and P10; and again as adults. Tissues were collected 6 h after the final dosing on P1, P4, P10, and at adult age. Gene transcripts for Lrat and Rbp4 in liver and Raldh-1 and Raldh-3 in lung, did not differ in the neonatal period but were higher, P<0.05, in adults, while Cyp26B1, Stra6, megalin, and Raldh-2 in lung did not differ from perinatal to adult ages. VARA supplementation increased total retinol in plasma, liver and lung, with a dose-by-dose accumulation in neonatal liver and lung, while transcripts for Lrat in liver, megalin in kidney, Cyp26A1/B1 in liver and lung, respectively, and Stra6 in lung, were all increased, suggesting pathways of VA uptake, storage and RA oxidation were each augmented after VARA. VARA decreased hepatic expression of Rbp4, responsible for VA trafficking from liver to plasma, and, in lung, of Raldh-1 and Raldh-2, which function in RA production. Our results define retinoid homeostatic gene expression from neonatal and adult age and show that while supplementation with VARA acutely alters retinol content and retinoid homeostatic gene expression in neonatal and adult lung, liver and kidney, VARA supplementation of neonates increased adult-age VA content only in the liver. PMID:26731668

  6. Left lobe graft poses a potential risk of hepatic venous outflow obstruction in adult living donor liver transplantation.

    PubMed

    Kitajima, Toshihiro; Kaido, Toshimi; Iida, Taku; Yagi, Shintaro; Fujimoto, Yasuhiro; Ogawa, Kohei; Mori, Akira; Okajima, Hideaki; Imamine, Rinpei; Shibata, Toshiya; Uemoto, Shinji

    2016-06-01

    Hepatic venous outflow obstruction (HVOO) is a critical complication after living donor liver transplantation (LDLT). This study aimed to evaluate the incidence of HVOO and the risk factors for HVOO in adults. From 2005 to 2015, 430 adult LDLT patients (right lobe [RL] graft, 270 patients; left lobe [LL] graft, 160 patients) were enrolled and divided into no HVOO (n = 413) and HVOO (n = 17) groups. Patient demographics and surgical data were compared, and risk factors for HVOO were analyzed. Furthermore, the longterm outcomes of percutaneous interventions as treatment for HVOO were assessed. HVOO occurred in 17 (4.0%) patients. The incidence of HVOO in patients receiving a LL graft was significantly higher than in those receiving a RL graft (8.1% versus 1.5%; P = 0.001). The body weight and caliber of hepatic vein anastomosis in the HVOO group were significantly lower compared with the no HVOO group (P = 0.02 and P = 0.008, respectively). Multivariate analysis revealed that only LL graft was an independent risk factor for HVOO (OR, 4.782; 95% CI, 1.387-16.488; P = 0.01). Among 17 patients with HVOO, 7 patients were treated with single balloon angioplasty, and 9 patients who developed recurrence were treated with repeated interventions. Overall, 6 patients underwent stent placement: 1 at the initial procedure, 3 at the second procedure for early recurrence, and 2 following repeated balloon angioplasty (≥3 interventions). These 6 patients experienced no recurrence. Overall graft survival was not significantly different between the HVOO and no HVOO groups (P = 0.99). In conclusion, the use of a LL graft was associated with HVOO, and percutaneous interventions were effective for treating adult HVOO after LDLT. Liver Transplantation 22 785-795 2016 AASLD. PMID:26785423

  7. The Medication Level Variability Index (MLVI) predicts rejection, possibly due to nonadherence, in adult liver transplant recipients

    PubMed Central

    Supelana, Christina; Annunziato, Rachel; Schiano, Thomas; Anand, Ravinder; Vaidya, Swapna; Chuang, Kelley; Zack, Yelena; Florman, Sander; Shneider, Benjamin L.; Shemesh, Eyal

    2014-01-01

    Nonadherence to immunosuppressants may play a role in late rejection in liver transplant recipients. In children, emerging data suggest that adherence can be measured by computing the standard deviation (SD) of consecutive blood levels of tacrolimus, resulting in a number that reflects the degree of variability between individual measures (the Medication Level Variability Index, MLVI). A higher MLVI value means erratic immunosuppression, likely due to less adherence. Data on this method in adults are limited. We obtained data from the medical charts of 150 randomly selected adult recipients. The MLVI was significantly higher in patients who had biopsy-confirmed rejection (mean MLVI=3.8, SD=3.2) as compared with the rest of the cohort (mean MLVI=2.3, SD=1.5; p<0.01), and it was significantly higher in patients who had a rejection as compared with patients who had a biopsy that was not read as a rejection (mean MLVI=2.6, SD=1.6; p<0.01). The MLVI was both associated with rejection and predicted its occurrence. A threshold MLVI of 2.0 resulted in 77% sensitivity and 60% specificity in predicting rejection; a threshold of 1.8 resulted in a sensitivity of 92% and specificity of 48%. The Area Under the Curve (AUC) in a Receiver Operating Characteristic (ROC) curve analysis was 0.71 (95% CI: 0.61–0.81). The MLVI is associated with and can predict rejection, possibly related to nonadherence, in adult liver transplant recipients. PMID:24931127

  8. Local allograft irradiation as an adjunct for treating severe resistant rejection after liver transplantation in adults.

    PubMed

    Ramanathan, Rajesh; Sharma, Amit; Kaspar, Matthew; Behnke, Martha; Song, Shiyu; Stravitz, R Todd; Cotterell, Adrian; Posner, Marc; Fisher, Robert A

    2015-01-01

    Acute rejection after liver transplantation occurs in one-third of all recipients and can be managed with conventional rejection therapy in the majority of cases. In rare instances, patients with severe acute rejection may be refractory to or have contraindications for conventional therapies. This case series evaluates the role of local allograft irradiation (LAI) as an adjunct for patients with rejection that is refractory to or contraindicated for conventional therapies. Additionally, the literature on the use of radiation therapy for reversing rejection in solid organ transplantation is reviewed. Five patients underwent 9 LAI treatments: 2 had refractory rejection, and 1 each had a malignancy, a concurrent life-threatening infection, and serum sickness with antibody therapy. Conventional rejection therapies included steroids, calcineurin inhibitors, and antithymocyte globulin. LAI consisted of 3 cycles of 1.5 Gy directed toward the liver allograft. Two of the 5 patients remained alive with excellent graft function. Six of the 9 treatments were successful in rescuing the liver allograft (reversing the rejection episode). Treatment success was associated with lower pretreatment serum bilirubin levels and higher pretreatment alanine aminotransferase levels. Compared with patients with immunosuppression-responsive severe acute rejection, those requiring LAI trended toward a later onset of first rejection. In conclusion, local irradiation of liver allografts can be a useful adjunct in patients for whom conventional options have been exhausted or cannot be used. The ability of LAI to reverse allograft dysfunction and promote patient survival appears to be greatest before the onset of severe cholestatic injury. PMID:25287272

  9. Liver bioengineering

    PubMed Central

    Caralt, Mireia; Velasco, Enrique; Lanas, Angel; Baptista, Pedro M

    2014-01-01

    Liver bioengineering has been a field of intense research and popular excitement in the past decades. It experiences great interest since the introduction of whole liver acellular scaffolds generated by perfusion decellularization1–3. Nevertheless, the different strategies developed so far have failed to generate hepatic tissue in vitro bioequivalent to native liver tissue. Even notable novel strategies that rely on iPSC-derived liver progenitor cells potential to self-organize in association with endothelial cells in hepatic organoids are lacking critical components of the native tissue (e.g., bile ducts, functional vascular network, hepatic microarchitecture, etc)4. Hence, it is vital to understand the strengths and short comes of our current strategies in this quest to re-create liver organogenesis in vitro. To shed some light into these issues, this review describes the different actors that play crucial roles in liver organogenesis and highlights the steps still missing to successfully generate whole livers and hepatic organoids in vitro for multiple applications. PMID:25102189

  10. Stem cell-based regenerative opportunities for the liver: State of the art and beyond

    PubMed Central

    Tsolaki, Eleftheria; Yannaki, Evangelia

    2015-01-01

    The existing mismatch between the great demand for liver transplants and the number of available donor organs highlights the urgent need for alternative therapeutic strategies in patients with acute or chronic liver failure. The rapidly growing knowledge on stem cell biology and the intrinsic repair processes of the liver has opened new avenues for using stem cells as a cell therapy platform in regenerative medicine for hepatic diseases. An impressive number of cell types have been investigated as sources of liver regeneration: adult and fetal liver hepatocytes, intrahepatic stem cell populations, annex stem cells, adult bone marrow-derived hematopoietic stem cells, endothelial progenitor cells, mesenchymal stromal cells, embryonic stem cells, and induced pluripotent stem cells. All these highly different cell types, used either as cell suspensions or, in combination with biomaterials as implantable liver tissue constructs, have generated great promise for liver regeneration. However, fundamental questions still need to be addressed and critical hurdles to be overcome before liver cell therapy emerges. In this review, we summarize the state-of-the-art in the field of stem cell-based therapies for the liver along with existing challenges and future perspectives towards a successful liver cell therapy that will ultimately deliver its demanding goals. PMID:26604641

  11. 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

  12. The organoid-initiating cells in mouse pancreas and liver are phenotypically and functionally similar

    PubMed Central

    Dorrell, Craig; Tarlow, Branden; Wang, Yuhan; Canaday, Pamela S; Haft, Annelise; Schug, Jonathan; Streeter, Philip R; Finegold, Milton J; Shenje, Lincoln T; Kaestner, Klaus H; Grompe, Markus

    2014-01-01

    Pancreatic Lgr5 expression has been associated with organoid-forming epithelial progenitor populations but the identity of the organoid-initiating epithelial cell subpopulation has remained elusive. Injury causes the emergence of an Lgr5+ organoid-forming epithelial progenitor population in the adult mouse liver and pancreas. Here, we define the origin of organoid-initiating cells from mouse pancreas and liver prior to Lgr5 activation. This clonogenic population was defined as MIC1-1C3+/CD133+/CD26− in both tissues and the frequency of organoid initiation within this population was approximately 5% in each case. The transcriptomes of these populations overlapped extensively and showed enrichment of epithelial progenitor-associated regulatory genes such as Sox9 and FoxJ1. Surprisingly, pancreatic organoid cells also had the capacity to generate hepatocyte-like cells upon transplantation to Fah-/- mice, indicating a differentiation capacity similar to hepatic organoids. Although spontaneous endocrine differentiation of pancreatic progenitors was not observed in culture, adenoviral delivery of fate-specifying factors Pdx1, Neurog3 and MafA induced insulin expression without glucagon or somatostatin. Pancreatic organoid cultures therefore preserve many key attributes of progenitor cells while allowing unlimited expansion, facilitating the study of fate determination. PMID:25151611

  13. The organoid-initiating cells in mouse pancreas and liver are phenotypically and functionally similar.

    PubMed

    Dorrell, Craig; Tarlow, Branden; Wang, Yuhan; Canaday, Pamela S; Haft, Annelise; Schug, Jonathan; Streeter, Philip R; Finegold, Milton J; Shenje, Lincoln T; Kaestner, Klaus H; Grompe, Markus

    2014-09-01

    Pancreatic Lgr5 expression has been associated with organoid-forming epithelial progenitor populations but the identity of the organoid-initiating epithelial cell subpopulation has remained elusive. Injury causes the emergence of an Lgr5(+) organoid-forming epithelial progenitor population in the adult mouse liver and pancreas. Here, we define the origin of organoid-initiating cells from mouse pancreas and liver prior to Lgr5 activation. This clonogenic population was defined as MIC1-1C3(+)/CD133(+)/CD26(-) in both tissues and the frequency of organoid initiation within this population was approximately 5% in each case. The transcriptomes of these populations overlapped extensively and showed enrichment of epithelial progenitor-associated regulatory genes such as Sox9 and FoxJ1. Surprisingly, pancreatic organoid cells also had the capacity to generate hepatocyte-like cells upon transplantation to Fah(-/-) mice, indicating a differentiation capacity similar to hepatic organoids. Although spontaneous endocrine differentiation of pancreatic progenitors was not observed in culture, adenoviral delivery of fate-specifying factors Pdx1, Neurog3 and MafA induced insulin expression without glucagon or somatostatin. Pancreatic organoid cultures therefore preserve many key attributes of progenitor cells while allowing unlimited expansion, facilitating the study of fate determination. PMID:25151611

  14. Serum prolactin in patients with liver disease in comparison with healthy adults: A preliminary cross-sectional study

    PubMed Central

    Jha, Sumit Kant; Kannan, Sridharan

    2016-01-01

    Introduction: Studies from the west have shown raised prolactin levels in patients with liver disease. Considering the lacunae on Indian context, we conducted the present study with an objective to assess the prolactin levels in patients with cirrhosis and viral hepatitis with or without features of encephalopathy. The data presented here are the results of the preliminary analysis. Materials and Methods: The present study was a prospective, cohort study among patients diagnosed as either viral hepatitis or cirrhosis liver. A cohort of normal healthy adults was selected based on history and laboratory investigations (complete blood count, liver and renal function tests). Serum prolactin was measured for all the study participants, and Kruskal–Wallis H-test with post-hoc Dunn's test was used to analyze the significance of the differences in the levels between various groups. Tests of diagnostic accuracy were used to assess the prediction capability of serum prolactin with a cut-off level of 50 ng/ml. Results: A total of 70 patients (10 - normal healthy; 25 - acute viral hepatitis; 35 - cirrhosis liver) were recruited in the present study with the median (range) age in years of 56 (34–68) and male: female ratio of 2:1. A statistically significant (P < 0.05) increase in the serum prolactin was observed in patients with cirrhosis with or without encephalopathy. But, among the patients with viral hepatitis, a significant elevation was observed only in patients with encephalopathy. Additionally, a statistically significant association was observed between serum prolactin levels with serum bilirubin (ρ =0.67, P = 0.04) and aspartate aminotransferase (ρ =0.72, P = 0.05). A cut-off value of 50 ng/ml of serum prolactin was found to predict the mortality. A total of 4/12 (33.3%) with prolactin value of <50 ng/ml died while 11/23 (47.8%) died with values >50 ng/ml (P < 0.05). Similarly, in patients with viral hepatitis with encephalopathy features, 1/4 (25%) with

  15. In Vitro and In Vivo Hepatic Differentiation of Adult Somatic Stem Cells and Extraembryonic Stem Cells for Treating End Stage Liver Diseases

    PubMed Central

    Hu, Chenxia; Li, Lanjuan

    2015-01-01

    The shortage of liver donors is a major handicap that prevents most patients from receiving liver transplantation and places them on a waiting list for donated liver tissue. Then, primary hepatocyte transplantation and bioartificial livers have emerged as two alternative treatments for these often fatal diseases. However, another problem has emerged. Functional hepatocytes for liver regeneration are in short supply, and they will dedifferentiate immediately in vitro after they are isolated from liver tissue. Alternative stem-cell-based therapeutic strategies, including hepatic stem cells (HSCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and mesenchymal stem cells (MSCs), are more promising, and more attention has been devoted to these approaches because of the high potency and proliferation ability of the cells. This review will focus on the general characteristics and the progress in hepatic differentiation of adult somatic stem cells and extraembryonic stem cells in vitro and in vivo for the treatment of end stage liver diseases. The hepatic differentiation of stem cells would offer an ideal and promising source for cell therapy and tissue engineering for treating liver diseases. PMID:26347063

  16. Herpes Simplex Virus Hepatitis in an Immunocompetent Adult: A Fatal Outcome due to Liver Failure

    PubMed Central

    Poley, Rachel A.; Snowdon, Jaime F.; Howes, Daniel W.

    2011-01-01

    Objective. To present a case of a healthy 41-year-old female who developed fulminant hepatic failure leading to death. The cause of hepatic failure identified on postmortem exam was herpes simplex virus hepatitis. Design. Observation of a single patient. Setting. Intensive care unit of a tertiary care university teaching hospital in Canada. Patient. 41-year-old previously healthy female presenting with a nonspecific viral illness and systemic inflammatory response syndrome. Intervention. The patient was treated with intravenous fluids and broad-spectrum antibiotics. On the second day of admission, she was found to have elevated transaminases, and, over 48 hours, she progressed to fulminant liver failure with disseminated intravascular coagulopathy, refractory lactic acidosis, and shock. She progressed to respiratory failure requiring intubation and mechanical ventilation. She was started on N-acetylcysteine, a bicarbonate infusion, hemodialysis, and multiple vasopressors and inotropes. Measurements and Main Results. Despite treatment, the patient died roughly 70 hours after her initial presentation to hospital. Her postmortem liver biopsy revealed herpes simplex virus hepatitis as her cause of death. Conclusions. Herpes simplex virus must be considered in all patients presenting with liver failure of unknown cause. If suspected, prompt treatment with acyclovir should be initiated. PMID:24826316

  17. Oral exposure of pubertal male mice to endocrine-disrupting chemicals alters fat metabolism in adult livers.

    PubMed

    Jin, Yuanxiang; Lin, Xiaojian; Miao, Wenyu; Wang, Linggang; Wu, Yan; Fu, Zhengwei

    2015-12-01

    The potential for the exposure of humans and wildlife to environmental endocrine-disrupting chemicals (EDCs) has been increasing. Risk assessment for such EDCs is primarily based on detecting the main endpoints related to the endocrine and reproductive systems, while the effects on glucose and fat metabolism have only received limited attention. In this study, pubertal male C57BL/6J mice were orally administered 10 mg/kg body weight cypermethrin (CYP), 100 mg/kg body weight atrazine (ATZ), and 0.1 mg/kg body weight 17α-ethynyestradiol (EE2) for 4 weeks and then switched to a high-energy diet (HD) for 8 weeks. The body weight gain in the EDC-treated groups was lower than that in the control group during exposure and then tended to show values similar to the HD group. The epididymal fat weight, cell size and serum triacylglycerol (TG) and total cholesterol (TCH) levels in the EDC-HD groups were lower than those in the HD group. The transcription of genes related to glycolytic and gluconeogenic processes in the liver was affected by EDC exposure. Furthermore, the expression levels of transcriptional factors including PPARα, PPARγ, and SREBP1C and their target genes related to fatty acid synthesis and oxidation in the liver were also influenced by early life EDC administration. The results showed that early-life-stage exposure to high doses of various environmental EDCs affected the homeostasis of glucose and fatty acid metabolism in the livers of adult male mice. PMID:24916741

  18. Reliability and validity of the Chronic Liver Disease Questionnaire (CLDQ) in adults with non-alcoholic steatohepatitis (NASH)

    PubMed Central

    Chawla, Kashmira S; Talwalkar, Jayant A; Keach, Jill C; Malinchoc, Michael; Lindor, Keith D; Jorgensen, Roberta

    2016-01-01

    Introduction Significant impairments in health-related quality of life (HRQL) in patients with non-alcoholic fatty liver disease have been previously described. The disease-specific HRQL among patients with non-alcoholic steatohepatitis (NASH), however, remains unknown. Aim To determine the degree of construct validity of the Chronic Liver Disease Questionnaire (CLDQ) in adults with NASH. Methods Participants referred for the evaluation of histology-proven NASH at Mayo Clinic, Rochester, between 1996 and 2000, were evaluated. HRQL assessment by the Short-Form 36 (SF-36) Health Survey and CLD) was performed. The primary outcome was to determine the level of correlation between overall and subscale scores for the CLDQ and SF-36 instruments. Results Among 79 participants (70%) with NASH completing both questionnaires (mean age, 51.2 years with 64% female gender), excellent reliability was noted for the CLDQ instrument. Significant reductions in all SF-36 domains (p<0.05 for all) including PCS and MCS scores (p<0.02 for both) among participants with NASH compared with normative data from an age-matched and sex-matched US general population sample was observed. Highly significant correlations were observed between overall CLDQ score with SF-36 PCS (r=0.82, p<0.0001) and SF-36 MCS (r=0.67, p<0.0001) scores. Similar degrees of correlation were observed between relevant subscales of the CLDQ and SF-36 as well. Discussion The CLDQ has excellent reliability and validity of construct for HRQL assessment in adults with NASH when compared with the SF-36. Future investigations among participants with NASH require assessing the responsiveness of the CLDQ to medical therapies and disease progression. PMID:27110379

  19. EFFECT OF SINGLE VERSUS SPLIT DOSES OF DIETHYINITROSAMINE ON THE INDUCTION OF GAMMA-GLUTAMYLTRANSPEPTIDASE-FOCI IN THE LIVERS OF ADULT AND JUVENILE RATS

    EPA Science Inventory

    The induction of gamma-glutamyltranspeptidase (GGT)-foci by single and by split doses of diethylnitrosamine (DENA) was evaluated in the livers of juvenile and young adult male, Sprague-Dawley rats. A single dose of DENA was administered at either 32, 41 or 52 days of age and foll...

  20. Constitutive expression of cytochrome P450 in foetal and adult porcine livers-Effects of body weight.

    PubMed

    Rasmussen, Martin Krøyer; Theil, Peter Kappel; Oksbjerg, Niels

    2016-09-01

    The liver hosts a great number of enzymatically driven processes, including detoxification. The super-family of enzymes named cytochrome P450 (CYP) is the major participant in that process. The expression of CYPs is affected by several factors including life-stage (foetal vs. adult). In the present study we investigated the impact of birth-weight (high or low birth weight) and life-stage on constitutive expression of porcine hepatic CYP1A1, CYP1A2, CYP2A19, CYP2B22, CYP2C33, CYP2D25, CYP2E1 and CYP3A29, as well as the transcription factors controlling their expression; aryl hydrocarbon receptor, constitutive androstane receptor, pregnane X receptor, C/EBP and hepatocyte nuclear factors 1 and 4. Both RT-PCR and western blotting showed a marked increase in the expression of the adult pigs compared with prenatal pigs. Moreover, CYP2E1 mRNA expression was 7.5 fold higher in foetuses with low birth weight compared with foetuses with high birth weight. Gender did not affect the mRNA expression within the different life-stages. These results indicate a similarity to what is observed in humans and porcine foetuses may therefore be a model for humans when studying expression of CYPs. PMID:27320961

  1. Culture and establishment of self-renewing human and mouse adult liver and pancreas 3D organoids and their genetic manipulation.

    PubMed

    Broutier, Laura; Andersson-Rolf, Amanda; Hindley, Christopher J; Boj, Sylvia F; Clevers, Hans; Koo, Bon-Kyoung; Huch, Meritxell

    2016-09-01

    Adult somatic tissues have proven difficult to expand in vitro, largely because of the complexity of recreating appropriate environmental signals in culture. We have overcome this problem recently and developed culture conditions for adult stem cells that allow the long-term expansion of adult primary tissues from small intestine, stomach, liver and pancreas into self-assembling 3D structures that we have termed 'organoids'. We provide a detailed protocol that describes how to grow adult mouse and human liver and pancreas organoids, from cell isolation and long-term expansion to genetic manipulation in vitro. Liver and pancreas cells grow in a gel-based extracellular matrix (ECM) and a defined medium. The cells can self-organize into organoids that self-renew in vitro while retaining their tissue-of-origin commitment, genetic stability and potential to differentiate into functional cells in vitro (hepatocytes) and in vivo (hepatocytes and endocrine cells). Genetic modification of these organoids opens up avenues for the manipulation of adult stem cells in vitro, which could facilitate the study of human biology and allow gene correction for regenerative medicine purposes. The complete protocol takes 1-4 weeks to generate self-renewing 3D organoids and to perform genetic manipulation experiments. Personnel with basic scientific training can conduct this protocol. PMID:27560176

  2. Association between sleep condition and arterial stiffness in Chinese adult with nonalcoholic fatty liver disease.

    PubMed

    Cao, Xia; Zhou, Jiansong; Yuan, Hong; Chen, Zhiheng

    2016-07-01

    Nonalcoholic fatty liver (NAFLD) usually has worse cardiovascular risk factors. Given the potential association between deterioration of sleep and arterial stiffness, we aim to investigate the association between deterioration of sleep and arterial stiffness in a middle-aged Chinese population with NAFLD. In this cross-sectional study, 15,372 Chinese aged 40-60 years who participated in periodic health checkups in central south China, were included. Self-reported sleep duration and sleep quality, anthropometric, biochemical, and liver ultrasound scan were analyzed and brachial-ankle pulse wave velocity (baPWV) was used as the indicator of arterial stiffness. Poor sleep quality was found to be associated with increased arterial stiffness, with odds ratios and 95 % confidence intervals (CIs) of 2.28 (95 % CI, 1.53-3.38) compared with good sleep quality. Using sleep duration ≥ 8 h as the reference, there was no significant association between sleep duration of ≤ 6 or 6-8 h and arterial stiffness after multivariable-adjusted. In additional analyses, further investigation of the association of different combinations of sleep duration and quality in relation to arterial stiffness indicated participants with poor sleep quality and sleep duration ≤ 6 h were more likely to have arterial stiffness than those with good quality sleep who sleep for ≥ 8 h (OR 2.59, 95 % CI 1.58-4.24). The present study indicates that short sleep duration, poor sleep quality in individuals with NAFLD correlate with increased arterial stiffness. PMID:27034174

  3. Role of basiliximab in the prevention of acute cellular rejection in adult to adult living-related liver transplantation: a single center experience

    PubMed Central

    Gruttadauria, S; Mandalà, L; Biondo, D; Spampinato, M; Lamonaca, V; Volpes, R; Vizzini, G; Marsh, JW; Marcos, A; Gridelli, B

    2007-01-01

    We report our single center experience with the use of basiliximab, a chimeric monoclonal antibody directed against the alpha chain of the interleukin-2 (IL-2) receptor (CD25), in combination with a steroid- and tacrolimus-based regimen in adult to adult living-related liver transplantation (ALRLT). Sixty consecutive ALRLTs were analyzed. All patients received two 20-mg doses of basiliximab (days 0 and 4 after transplantation) followed by tacrolimus (0.15 mg/kg/day; 10–15 ng/mL target trough levels) and a dose regimen of steroids (starting with 20 mg iv, switched to po as soon as the patient was able to eat, and weaned off within 1–2 months). Follow-up ranged from 6 to 1699.4 days after transplantation (mean 517.5 days, SD ± 413.4; median 424 days). Of the recipients, 95% remained rejection-free during follow-up, with an actuarial rejection-free probability of 96.61% within 3 months. Three patients had episodes of biopsy-proven acute cellular rejection (ACR). Actuarial patient and graft survival rates at 3 years were 82.09% and 75.61%. Six patients (10%) experienced sepsis. There was no evidence of cytomegalovirus infections or side-effects related to the basiliximab. We found zero de novo malignancy, although we observed 5 patients with metastatic spread of their primary malignancy during the follow-up. Basiliximab in association with tacrolimus and steroids is effective in reducing episodes of ACR and increasing ACR-free survival after ALRLT. PMID:19707350

  4. Relationship between grip strength and newly diagnosed nonalcoholic fatty liver disease in a large-scale adult population.

    PubMed

    Meng, Ge; Wu, Hongmei; Fang, Liyun; Li, Chunlei; Yu, Fei; Zhang, Qing; Liu, Li; Du, Huanmin; Shi, Hongbin; Xia, Yang; Guo, Xiaoyan; Liu, Xing; Bao, Xue; Su, Qian; Gu, Yeqing; Yang, Huijun; Bin Yu; Wu, Yuntang; Sun, Zhong; Niu, Kaijun

    2016-01-01

    Enhanced muscle strength is often related to improved insulin sensitivity and secretion, control of lipid metabolism, and increased secretion of myokines. These factors have emerged as important mechanisms involved in the development and progression of nonalcoholic fatty liver disease (NAFLD), implying that muscle strength may be a useful predictor for NAFLD. We aimed to assess the relationship between grip strength (GS) and NAFLD in a large-scale adult population. GS was assessed using an electronic hand-grip dynamometer, and NAFLD was diagnosed by the liver ultrasonography. Multiple logistic regression analysis was used to assess the relationship between the quartiles of GS per body weight and the prevalence of NAFLD. After adjusting for potentially confounding factors, the odds ratios (95% confidence interval) for overall NAFLD, NAFLD with normal alanine aminotransferase levels, and NAFLD with elevated alanine aminotransferase levels across the quartiles of GS were 1.00 (reference), 0.89 (0.78, 1.01), 0.77 (0.67, 0.89), and 0.67 (0.57, 0.79); 1.00 (reference), 0.91 (0.80, 1.04), 0.79 (0.68, 0.92), and 0.72 (0.61, 0.85); 1.00 (reference), 0.77 (0.61, 0.98), 0.67 (0.51, 0.86), and 0.53 (0.40, 0.71) (all P for trend < 0.01), respectively. This is the first study shows that increased GS is independently associated with lower prevalence of NAFLD. PMID:27616599

  5. Impact of e-cigarette refill liquid with or without nicotine on liver function in adult rats.

    PubMed

    El Golli, Narges; Jrad-Lamine, Aicha; Neffati, Hajira; Rahali, Dalila; Dallagi, Yosra; Dkhili, Houssem; Ba, Nathalie; El May, Michele V; El Fazaa, Saloua

    2016-07-01

    This study was conducted to evaluate the effects of e-cigarette refill liquid administration alone or with nicotine on the antioxidant defense status, functional and histopathological changes in adult rat liver tissue. For this purpose, 32 rats were treated for 28 days as follows: control group was injected intra-peritoneally with physiological saline; e-cigarette 0% treated group received an intra-peritoneal injection of e-liquid without nicotine diluted in physiological saline, e-cigarette-treated group received an intra-peritoneal injection of e-liquid containing 0.5 mg of nicotine/kg of body weight/day diluted in physiological saline and nicotine-treated group received an intra-peritoneal injection of 0.5 mg of nicotine/kg of body weight/day diluted in physiological saline. In e-liquid without nicotine-exposed group, activities of the liver biomarkers aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and lactate dehydrogenase increase. Interestingly, oxidative stress indicators showed decreased total protein content, associated with a reduction in the antioxidant enzymes activities superoxide dismutase, catalase and glutathione-S-transferase, and an elevation in malondialdehyde content, highlighting the promotion of lipid peroxidation and oxidative stress. Histological studies identified inflammatory cells infiltration and cell death. Thus, e-liquid seems to promote oxidative tissue injuries, which in turn lead to the observed histopathological finding. In comparison, nicotine alone induced less oxidative stress and less histopathological disorders, whereas e-liquid with nicotine gave rise to more histopathological injuries. Thereby, e-liquid, per se, is able to induce hepatotoxicity and supplementation with nicotine worsens this state. PMID:27484987

  6. Repeated dose liver and gastrointestinal tract micronucleus assays using N-methyl-N'-nitro-N-nitrosoguanidine in young adult rats.

    PubMed

    Takayanagi, Tomomi; Wako, Yumi; Kawasako, Kazufumi; Hori, Hisako; Fujii, Wataru; Ohyama, Wakako

    2015-03-01

    N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG) is a direct-acting mutagen that induces tumors in the glandular stomach, but not in the liver or colon, of rats after oral administration. To evaluate the performance of repeated dose liver and gastrointestinal tract micronucleus (MN) assays in young adult rats, MNNG was administered by oral gavage to male CD (SD) rats aged 6 weeks at doses of 0 (vehicle; 2.5% DMSO aqueous solution), 3.125, 6.25, 12.5, and 25mg/kg/day once daily for 14 and 28 days, and the MN frequencies were examined in the hepatocytes, glandular stomach cells, and colonic cells. The MN induction in immature erythrocytes in the bone marrow of these animals was also simultaneously evaluated. The frequencies of micronucleated (MNed) glandular stomach cells were significantly increased in all MNNG treatment groups in a dose-dependent manner in both repeated dose studies. In contrast, the frequencies of MNed hepatocytes and colonic cells were not significantly increased compared to the vehicle control. In the bone marrow, a small but significant increase in the frequency of MNed immature erythrocytes was observed only at the highest dose in the 28-day study. Since a clear positive result in the glandular stomach agrees with the tissue specificity of tumor induction by this chemical, the MN assay with the glandular stomach, which is a direct contact site with high concentrations of test substances administered by oral gavage, may be useful for detecting genotoxic compounds that are short-lived in vivo, such as MNNG. PMID:25892628

  7. The functional role of some tomato products on lipid profile and liver function in adult rats.

    PubMed

    Ibrahim, Hoda Salama; Ahmed, Lamiaa Ali; El-din, Maha Mohamed Essam

    2008-09-01

    This study was carried out to investigate the functional role of lycopene obtained from powder prepared from fresh tomato, tomato paste, and ketchup that contained equal amounts of lycopene based on levels of intake on body weight gain (BWG), feed intake, feed efficiency ratio (FER), lipid profiles, atherogenic index, and liver enzymes of hyperlipidemic rats. Forty-eight male albino rats were divided into two main groups: the first group (n = 6 rats) was kept on the basal diet as a normal control, while the second group (n = 42 rats) was fed a hyperlipidemic diet for 5 weeks to induce hyperlipidemia. The latter group was divided into seven subgroups: the first subgroup was the positive control group, while the others were supplemented with one of the tomato products at one of two levels (10 or 20 mg of lycopene/kg of diet). BWG, feed intake, and FER were calculated, and blood samples were collected to determine total lipids, total cholesterol, triglycerides, lipoprotein fractions, atherogenic index, and liver function in sera. Relative organ weights were also calculated. Results revealed that administration of various tomato products produced a significant reduction in feed intake except for the hyperlipidemic group that supplemented with the lower lycopene level from tomato paste. In addition, BWG and FER were not influenced by addition of tomato products at any level of intake. Hyperlipidemic rats supplemented with tomato powder, tomato paste, or ketchup showed significant improvement in almost all the parameters studied compared to the positive control group. Results showed that the higher lycopene level from tomato paste produced significant improvement in all lipid parameters, followed by 10 mg of lycopene/kg from tomato paste, which caused significant elevation in high-density lipoprotein cholesterol comparable to that of the negative control group. The lowest atherogenic index was achieved by addition of the lower lycopene level from tomato paste followed by

  8. Variations in Practice to Therapeutic Monitoring of Tacrolimus following Primary Adult Liver Transplantation

    PubMed Central

    Dasari, B. V. M.; Hodson, J.; Nassir, A.; Widmer, J.; Isaac, J.; Mergentel, H.; Muiesan, P.; Mirza, D. F.; Perera, M. T. P. R.

    2016-01-01

    Background: There is limited clinical evidence evaluating the correlation between immunosuppressant monitoring practice and transplant outcomes. Objective: To assess current practice of tacrolimus trough monitoring in early post-operative period following liver transplantation (LT), and its impact on outcomes. Methods: The duration to trough levels (DTT) were calculated in patients undergoing primary LT. The impact of variability in DTT on graft rejection episodes, serum tacrolimus level and renal function was assessed. These results were converted into a drug level estimation tool, which was validated in a prospective cohort of patients. Results: 2946 events in 274 patients were evaluated. The median DTT was 7:19 hrs (range: 27 min to 19:38 hrs). In 72% (2140 events) of the occasions, DTT was <8 hrs. There was a significant (p=0.022) correlation between DTT and tacrolimus level. Despite clinical decisions were taken to modify the dose of tacrolimus based on trough level, neither did DTT affect the average creatinine levels (p=0.923), nor the variability in DTT did affect acute rejection (p=0.914, and 0.712, respectively). A dose estimation tool was developed and applied to validation cohort (n=612), and returned a moderate R2 value of 0.50. Conclusion: There is a significant variation in the “real world” monitoring of tacrolimus with DTT in majority of measurements falling below recommendations; reassuringly, this did not lead to adverse transplant sequelae. PMID:26889368

  9. Transcriptional Ontogeny of the Developing Liver

    EPA Science Inventory

    During embryogenesis the liver is derived from endodermal cells lining the digestive tract. These endodermal progenitor cells contribute to forming the parenchyma of a number of organs including the liver and pancreas. Early in organogenesis the fetal liver is populated by hemato...

  10. 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. PMID:20130176

  11. Post-stroke transplantation of adult subventricular zone derived neural progenitor cells--A comprehensive analysis of cell delivery routes and their underlying mechanisms.

    PubMed

    Doeppner, Thorsten R; Kaltwasser, Britta; Teli, Mahesh K; Sanchez-Mendoza, Eduardo H; Kilic, Ertugrul; Bähr, Mathias; Hermann, Dirk M

    2015-11-01

    With neuroprotective approaches having failed until recently, current focus on experimental stroke research has switched towards manipulation of post-ischemic neuroregeneration. Transplantation of subventricular zone (SVZ) derived neural progenitor cells (NPCs) is a promising strategy for promotion of neurological recovery. Yet, fundamental questions including the optimal cell delivery route still have to be addressed. Consequently, male C57BL6 mice were exposed to transient focal cerebral ischemia and allowed to survive for as long as 84 days post-stroke. At 6h post-stroke, NPCs were grafted using six different cell delivery routes, i.e., intravenous, intraarterial, ipsilateral intrastriatal, contralateral intrastriatal, ipsilateral intraventricular and ipsilateral intracortical injection. Control mice received PBS only using the aforementioned delivery routes. Intralesional numbers of GFP(+) NPCs were high only after ipsilateral intrastriatal transplantation, whereas other injection paradigms only yielded comparatively small numbers of grafted cells. However, acute neuroprotection and improved functional outcome were observed after both systemic (i.e., intraarterial and intravenous) and ipsilateral intrastriatal transplantation only. Whereas systemic cell delivery induced acute and long-term neuroprotection, reduction of brain injury after ipsilateral intrastriatal cell grafting was only temporary, in line with the loss of transplanted NPCs in the brain. Both systemic and ipsilateral intrastriatal NPC delivery reduced microglial activation and leukocyte invasion, thus reducing free radical formation within the ischemic brain. On the contrary, only systemic NPC administration stabilized the blood-brain-barrier and reduced leukocytosis in the blood. Although intraarterial NPC transplantation was as effective as intravenous cell grafting, mortality of stroke mice was high using the intraarterial delivery route. Consequently, intravenous delivery of native NPCs in

  12. Simulated Microgravity Exerts an Age-Dependent Effect on the Differentiation of Cardiovascular Progenitors Isolated from the Human Heart.

    PubMed

    Fuentes, Tania I; Appleby, Nancy; Raya, Michael; Bailey, Leonard; Hasaniya, Nahidh; Stodieck, Louis; Kearns-Jonker, Mary

    2015-01-01

    Microgravity has a profound effect on cardiovascular function, however, little is known about the impact of microgravity on progenitors that reside within the heart. We investigated the effect of simulated microgravity exposure on progenitors isolated from the neonatal and adult human heart by quantifying changes in functional parameters, gene expression and protein levels after 6-7 days of 2D clinorotation. Utilization of neonatal and adult cardiovascular progenitors in ground-based studies has provided novel insight into how microgravity may affect cells differently depending on age. Simulated microgravity exposure did not impact AKT or ERK phosphorylation levels and did not influence cell migration, but elevated transcripts for paracrine factors were identified in neonatal and adult cardiovascular progenitors. Age-dependent responses surfaced when comparing the impact of microgravity on differentiation. Endothelial cell tube formation was unchanged or increased in progenitors from adults whereas neonatal cardiovascular progenitors showed a decline in tube formation (p<0.05). Von Willebrand Factor, an endothelial differentiation marker, and MLC2v and Troponin T, markers for cardiomyogenic differentiation, were elevated in expression in adult progenitors after simulated microgravity. DNA repair genes and telomerase reverse transcriptase which are highly expressed in early stem cells were increased in expression in neonatal but not adult cardiac progenitors after growth under simulated microgravity conditions. Neonatal cardiac progenitors demonstrated higher levels of MESP1, OCT4, and brachyury, markers for early stem cells. MicroRNA profiling was used to further investigate the impact of simulated microgravity on cardiovascular progenitors. Fifteen microRNAs were significantly altered in expression, including microRNAs-99a and 100 (which play a critical role in cell dedifferentiation). These microRNAs were unchanged in adult cardiac progenitors. The effect of

  13. Two distinct genes for ADP/ATP translocase are expressed at the mRNA level in adult human liver

    SciTech Connect

    Houldsworth, J.; Attardi, G.

    1988-01-01

    Several clones hybridizing with a bovine ADP/ATP translocase cDNA were isolated from an adult human liver cDNA library in the vector pEX1. DNA sequence analysis revealed that these clones encode two distinct forms of translocase. In particular, two clones specifying the COOH-end-proximal five-sixths of the protein exhibit a 9% amino acid sequence divergence and totally dissimilar 3' untranslated regions. One of these cDNAs is nearly identical in sequence to an ADP/ATP translocase clone (hp2F1) recently isolated from a human fibroblast cDNA library with three amino acid changes and a few differences in the 3' untranslated region. Another clone isolated from the pEX1 library contains a reading frame encoding the remaining, NH/sub 2/-end-proximal, 37 amino acids of the translocase. This sequence differs significantly (14% amino acid sequence divergence) from the corresponding segment of hp2F1, and the 5' untranslated regions of the two clones are totally dissimilar. RNA transfer hybridization experiments utilizing the clones isolated from the pEX1 library revealed the presence in HeLa cells of three distinct mRNA species. The pattern of hybridization and the sizes of these mRNAs suggest a greater complexity of organization and expression of the ADP/ATP translocase genes in human cells than indicated by the analysis of the cDNA clones.

  14. Genetic Delineation of the Pathways Mediated by Bid and JNK in Tumor Necrosis Factor-α-induced Liver Injury in Adult and Embryonic Mice*S⃞

    PubMed Central

    Ni, Hong-Min; Chen, Xiaoyun; Shi, Ying-Hong; Liao, Yong; Beg, Amer A.; Fan, Jia; Yin, Xiao-Ming

    2009-01-01

    Tumor necrosis factor-α (TNFα)-induced hepatocyte death and liver injury can be mediated by multiple mechanisms, which could be evaluated by different animal models. Previous studies have defined the importance of Bid in mitochondrial apoptosis activation in adult mice treated with lipopolysaccharides in the presence of galactosamine (GalN), which suppresses NF-κB activation, but not in embryonic mice in which NF-κB activation is suppressed by genetic deletion of p65RelA. JNK has also been found important in TNFα-induced mitochondria activation and liver injury in the lipopolysaccharide/GalN and concanavalin A (ConA)/GalN models, but not in a ConA-only model in which NF-κB activation was not suppressed. To determine the mechanistic relationship of pathways mediated by Bid and JNK, we investigated these two molecules in TNFα injury models that had not been previously examined. Most importantly, we created and studied mice deficient in both Bid and JNK. We found that, like JNK, Bid was also required for TNFα-induced injury induced by concanavalin A/GalN but not by ConA alone. Furthermore, our results indicate that these two molecules function in a largely overlapped manner, with Bid being downstream of JNK in the adult livers. However, JNK, but not Bid, was able to contribute to the TNFα-induced liver apoptosis in RelA-deficient embryos. The Bid-independent role of JNK was also observed in the adult mice, mainly in the promotion of the lethal progression of the TNFα injury. This work defined both linear and parallel relationships of Bid and JNK in TNFα-induced hepatocyte apoptosis and liver injury. PMID:19060338

  15. Growing Up: Not an Easy Transition—Perspectives of Patients and Parents regarding Transfer from a Pediatric Liver Transplant Center to Adult Care

    PubMed Central

    Chandra, Sona; Luetkemeyer, Shannon; Romero, Rene; Gupta, Nitika Arora

    2015-01-01

    The transition from pediatric to adult care is a critical time when children with chronic illness sustain high morbidity and mortality. Transition services need to be focused on the adolescents' needs, which may differ from those perceived by healthcare providers. In this study, a survey of 31 patients with chronic liver disease and/or liver transplant who were “transferred” to adult services within the last 3 years was conducted. Patients were asked about their current health status and their perceptions of the overall transfer process. The mean age at transfer was 19.81 (18–21) years. Almost half the patients (47%) were not seen at the adult facility until 2–6 months after leaving the Children's hospital and 20% were not seen until 6–12 months. About 20% had their first contact with adult services through an emergency room visit. About 19% reported being out of medication during transition. Of the transplanted patients, 19% were being evaluated for a retransplant. The majority (82%) felt that an increased emphasis on promoting independence and “letting go” both by parents and by pediatric care providers was critical in their transition to independence and adult care services. This study provides thought-provoking insights, which are critical in designing the ideal transition program for children with chronic diseases. PMID:26682071

  16. The influence of waist circumference on insulin resistance and nonalcoholic fatty liver disease in apparently healthy Korean adults

    PubMed Central

    Ju, Deok Yun; Choe, Young Gil; Shin, Dong Suk; Yoo, Su Hyeon; Yim, Seo Hyoung; Lee, Ji Yong; Park, Jung Ho; Kim, Hong Joo; Park, Dong Il; Sohn, Chong Il; Jeon, Woo Kyu; Kim, Byung Ik

    2013-01-01

    Background/Aims Waist circumference (WC) is a risk factor for metabolic syndrome and is related to insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD). The purpose of this study was to determine the association between WC and IR and NAFLD in apparently healthy Korean adults. Methods The volunteers included in this cross-sectional study comprised 9,159 adults (5,052 men, 4,107 women) who participated in a comprehensive health checkup program. IR was evaluated by the homeostasis model assessment of IR (HOMA-IR) and was considered to be present when the HOMA-IR score was >2. NAFLD was evaluated by ultrasound examination. Elevated alanine aminotransferase (ALT) was defined as >40 IU/L in men and >35 IU/L in women. Logistic regression was performed to determine the odds ratios (ORs) and 95% confidence intervals (95% CIs) for NAFLD, IR, and ALT according to categorized levels of WC. Results NAFLD was found in 2,553 (27.9%) of the participants (82.6% men, 17.4% women), while IR and elevated ALT were found in 17.2% (68.1% men, 31.9% women) and 10% (83% men, 17% women), respectively. After adjusting for confounding factors, the prevalence of NAFLD, IR, and elevated ALT was significantly associated with increases in WC quartile: highest quartile for NAFLD in men, OR=15.539, 95% CI=12.687-19.033; highest quartile for NAFLD in women, OR=48.732, 95% CI=23.918-99.288 (P<0.001); and highest quartile for IR in men, OR=17.576, 95% CI=13.283-23.255; highest quartile for IR in women, OR=11.078, 95% CI=7.813-15.708 (P<0.001); highest quartile for elevated ALT in men, OR=7.952, 95% CI=6.046-10.459; and highest quartile for elevated ALT in women, OR=8.487, 95% CI=4.679-15.395 (P<0.001). Conclusions WC contributes to IR and NAFLD in apparently healthy Korean adults, and thus may be an important factor in the development of IR and NAFLD. PMID:23837138

  17. The lack of protective effects of tea supplementation on liver and jejunal epithelium in adult rats exposed to cadmium and lead.

    PubMed

    Tomaszewska, Ewa; Winiarska-Mieczan, Anna; Dobrowolski, Piotr

    2015-11-01

    Adult rats at the age of 12 weeks were divided into the control group and groups supplemented with green (GT), black (BT), red (RT), or white (WT) tea extracts. The diet (except that for the control) was mixed with 7 mg Cd/kg and 50 mg Pb/kg. The experiment lasted 12 weeks. Basal haematology and plasma biochemical parameters as well as the histomorphometrical parameters of jejunal epithelium and liver were determined. The lowest body mass was found in the RT and WT groups. Some functional (increased plasma ALT and AST, and the de Ritis coefficient) and structural changes in the liver (slight fatty degenerative changes, an increase in the intercellular space) were evident irrespective of the type of tea in the Cd and Pb poisoned rats. This toxic effect was visible especially in rats drinking black or red tea. However, the rats had no elevated LDH and ALT activities. The highest content of Cd and Pb in the liver and blood plasma was found in rats drinking red tea. Based on the results obtained, it is clear that long-term exposure of adult rats with a mature intestinal barrier to Cd and Pb contamination, under higher exposure conditions than the current estimates of weekly exposure of the general population to Cd and Pb through diet, causes a toxic effect, especially in the liver, and can change the structure of intestinal mucosa, irrespective of tea administration. PMID:26410089

  18. Dose of Phenobarbital and Age of Treatment at Early Life are Two Key Factors for the Persistent Induction of Cytochrome P450 Enzymes in Adult Mouse Liver.

    PubMed

    Tien, Yun-Chen; Liu, Ke; Pope, Chad; Wang, Pengcheng; Ma, Xiaochao; Zhong, Xiao-bo

    2015-12-01

    Drug treatment of neonates and infants and its long-term consequences on drug responses have emerged in recent years as a major challenge for health care professionals. In the current study, we use phenobarbital as a model drug and mouse as an in vivo model to demonstrate that the dose of phenobarbital and age of treatment are two key factors for the persistent induction of gene expression and consequential increases of enzyme activities of Cyp2b, Cyp2c, and Cyp3a in adult livers. We show that phenobarbital treatment at early life of day 5 after birth with a low dose (<100 mg/kg) does not change expression and enzyme activities of Cyp2b, Cyp2c, and Cyp3a in adult mouse liver, whereas phenobarbital treatment with a high dose (>200 mg/kg) significantly increases expression and enzyme activities of these P450s in adult liver. We also demonstrate that phenobarbital treatment before day 10 after birth, but not at later ages, significantly increases mRNAs, proteins, and enzyme activities of the tested P450s. Such persistent induction of P450 gene expression and enzyme activities in adult livers by phenobarbital treatment only occurs within a sensitive age window early in life. The persistent induction in gene expression and enzyme activities is higher in female mice than in male mice for Cyp2b10 but not for Cyp2c29 and Cyp3a11. These results will stimulate studies to evaluate the long-term impacts of drug treatment with different doses at neonatal and infant ages on drug metabolism, therapeutic efficacy, and drug-induced toxicity throughout the rest of life. PMID:26400395

  19. Cardiac progenitor cells for heart repair

    PubMed Central

    Le, TYL; Chong, JJH

    2016-01-01

    Stem cell therapy is being investigated as an innovative and promising strategy to restore cardiac function in patients with heart failure. Several stem cell populations, including adult (multipotent) stem cells from developed organs and tissues, have been tested for cardiac repair with encouraging clinical and pre-clinical results. The heart has been traditionally considered a post-mitotic organ, however, this view has recently changed with the identification of stem/progenitor cells residing within the adult heart. Given their cardiac developmental origins, these endogenous cardiac progenitor cells (CPCs) may represent better candidates for cardiac cell therapy compared with stem cells from other organs such as the bone marrow and adipose tissue. This brief review will outline current research into CPC populations and their cardiac repair/regenerative potential. PMID:27551540

  20. 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. PMID:27316370

  1. Efficacy of the Omega-3 Index in predicting non-alcoholic fatty liver disease in overweight and obese adults: a pilot study.

    PubMed

    Parker, Helen M; O'Connor, Helen T; Keating, Shelley E; Cohn, Jeffrey S; Garg, Manohar L; Caterson, Ian D; George, Jacob; Johnson, Nathan A

    2015-09-14

    Non-alcoholic fatty liver disease (NAFLD) is an independent predictor of CVD in otherwise healthy individuals. Low n-3 PUFA intake has been associated with the presence of NAFLD; however, the relationship between a biomarker of n-3 status - the Omega-3 Index - and liver fat is yet to be elucidated. A total of eighty overweight adults (fifty-six men) completed the anthropometric and biochemical measurements, including the Omega-3 Index, and underwent proton magnetic resonance spectroscopy assessment of liver fat. Bivariate correlations and multiple regression analyses were performed with reference to prediction of liver fat percentage. The mean Omega-3 Index was high in both NAFLD (intrahepatic lipid concentration≥5·5 %) and non-NAFLD groups. The Omega-3 Index, BMI, waist circumference, glucose, insulin, TAG, high-sensitive C-reactive protein (hsCRP) and alanine aminotransferase (ALT) were positively correlated, and HDL and erythrocyte n-6:n-3 ratio negatively correlated with liver fat concentration. Regression analysis found that simple anthropometric and demographic variables (waist, age) accounted for 31 % of the variance in liver fat and the addition of traditional cardiometabolic blood markers (TAG, HDL, hsCRP and ALT) increased the predictive power to 43 %. The addition of the novel erythrocyte fatty acid variable (Omega-3 Index) to the model only accounted for a further 3 % of the variance (P=0·049). In conclusion, the Omega-3 Index was associated with liver fat concentration but did not improve the overall capacity of demographic, anthropometric and blood markers to predict NAFLD. PMID:26202539

  2. Liver metastases

    MedlinePlus

    Metastases to the liver; Metastatic liver cancer; Liver cancer - metastatic; Colorectal cancer - liver metastases; Colon cancer - liver metastases; Esophageal cancer - liver metastases; Lung cancer - liver metastases; Melanoma - liver metastases

  3. Lapatinib Ditosylate in Treating Patients With Unresectable Liver or Biliary Tract Cancer

    ClinicalTrials.gov

    2015-04-08

    Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

  4. The α1 isoform of the Na+/K+ ATPase is up-regulated in dedifferentiated progenitor cells that mediate lens and retina regeneration in adult newts*

    PubMed Central

    Vergara, M. Natalia; Smiley, Laura K.; Del Rio-Tsonis, Katia; Tsonis, Panagiotis A.

    2009-01-01

    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 α1 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. PMID:18755185

  5. 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

  6. Chinese Herbal Formulation PHY906 and Sorafenib Tosylate in Treating Patients With Advanced Liver Cancer

    ClinicalTrials.gov

    2016-06-17

    Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Advanced Adult Hepatocellular Carcinoma; BCLC Stage B Adult Hepatocellular Carcinoma; BCLC Stage C Adult Hepatocellular Carcinoma

  7. Long-term maintenance of taurocholate uptake by adult rat hepatocytes co-cultured with a liver epithelial cell line.

    PubMed

    Foliot, A; Glaise, D; Erlinger, S; Guguen-Guillouzo, C

    1985-01-01

    Taurocholate (TC) uptake by adult rat hepatocytes co-cultured with other rat liver epithelial cells (RLEC) was studied comparatively to hepatocytes in primary culture. Cells were cultured on Petri dishes for desired times prior to measuring their ability to transport TC. TC uptake was linear for 150 sec in both culture conditions. In hepatocytes cultured alone, the initial rate of TC uptake at an extracellular concentration of 100 microM was 0.19 +/- 0.02 nmole per min per 10(6) cells after 48 hr of culture and decreased by 75% after 4 to 6 days. In hepatocytes co-cultured with RLEC, the rate of uptake at 48 hr (0.31 +/- 0.01 nmole per min per 10(6) cells) was significantly higher than in hepatocytes cultured alone (p less than 0.01); in addition, TC uptake remained stable at an average rate of 0.17 +/- 0.01 nmole per min per 10(6) cells for up to 56 days. No detectable uptake was found in RLEC cultured alone. TC uptake exhibited both saturable (Vmax = 0.30 +/- 0.03 nmole per min per 10(6) cells and Km = 42.6 +/- 4.4 microM) and nonsaturable components. These kinetic parameters were similar to those previously reported in isolated hepatocytes and in short-term cultured hepatocytes. TC uptake exhibited sodium dependence and was significantly reduced when extracellular sodium was replaced by lithium and sucrose, or in the presence of 1 mM ouabain. After 18 days of co-culture, TC uptake had qualitatively the same characteristics as at 48 hr, with a saturable and a nonsaturable component.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3979952

  8. Prostaglandin E2 Regulates Liver versus Pancreas Cell Fate Decisions and Endodermal Outgrowth

    PubMed Central

    Nissim, Sahar; Sherwood, Richard I.; Wucherpfennig, Julia; Saunders, Diane; Harris, James M.; Esain, Virginie; Carroll, Kelli J.; Frechette, Gregory M.; Kim, Andrew J.; Hwang, Katie L.; Cutting, Claire C.; Elledge, Susanna; North, Trista E.; Goessling, Wolfram

    2014-01-01

    SUMMARY The liver and pancreas arise from common endodermal progenitors. How these distinct cell fates are specified is poorly understood. Here, we describe prostaglandin E2 (PGE2) as a regulator of endodermal fate specification during development. Modulating PGE2 activity has opposing effects on liver-versus-pancreas specification in zebrafish embryos as well as mouse endodermal progenitors. The PGE2 synthetic enzyme cox2a and receptor ep2a are patterned such that cells closest to PGE2 synthesis acquire a liver fate whereas more distant cells acquire a pancreas fate. PGE2 interacts with the bmp2b pathway to regulate fate specification. At later stages of development, PGE2 acting via the ep4a receptor promotes outgrowth of both the liver and pancreas. PGE2 remains important for adult organ growth, as it modulates liver regeneration. This work provides in vivo evidence that PGE2 may act as a morphogen to regulate cell fate decisions and outgrowth of the embryonic endodermal anlagen. PMID:24530296

  9. Analysing human neural stem cell ontogeny by consecutive isolation of Notch active neural progenitors

    PubMed Central

    Edri, Reuven; Yaffe, Yakey; Ziller, Michael J.; Mutukula, Naresh; Volkman, Rotem; David, Eyal; Jacob-Hirsch, Jasmine; Malcov, Hagar; Levy, Carmit; Rechavi, Gideon; Gat-Viks, Irit; Meissner, Alexander; Elkabetz, Yechiel

    2015-01-01

    Decoding heterogeneity of pluripotent stem cell (PSC)-derived neural progeny is fundamental for revealing the origin of diverse progenitors, for defining their lineages, and for identifying fate determinants driving transition through distinct potencies. Here we have prospectively isolated consecutively appearing PSC-derived primary progenitors based on their Notch activation state. We first isolate early neuroepithelial cells and show their broad Notch-dependent developmental and proliferative potential. Neuroepithelial cells further yield successive Notch-dependent functional primary progenitors, from early and midneurogenic radial glia and their derived basal progenitors, to gliogenic radial glia and adult-like neural progenitors, together recapitulating hallmarks of neural stem cell (NSC) ontogeny. Gene expression profiling reveals dynamic stage-specific transcriptional patterns that may link development of distinct progenitor identities through Notch activation. Our observations provide a platform for characterization and manipulation of distinct progenitor cell types amenable for developing streamlined neural lineage specification paradigms for modelling development in health and disease. PMID:25799239

  10. An Apo-14 Promoter-Driven Transgenic Zebrafish That Marks Liver Organogenesis

    PubMed Central

    Wang, Rui; Li, Zhi; Wang, Yang; Gui, Jian-Fang

    2011-01-01

    Several transgenic zebrafish lines for liver development studies had been obtained in the first decade of this century, but not any transgenic GFP zebrafish lines that mark the through liver development and organogenesis were reported. In this study, we analyzed expression pattern of endogenous Apo-14 in zebrafish embryogenesis by whole-mount in situ hybridization, and revealed its expression in liver primordium and in the following liver development. Subsequently, we isolated zebrafish Apo-14 promoter of 1763 bp 5′-flanking sequence, and developed an Apo-14 promoter-driven transgenic zebrafish Tg(Apo14: GFP). And, maternal expression and post-fertilization translocation of Apo-14 promoter-driven GFP were observed in the transgenic zebrafish line. Moreover, we traced onset expression of Apo-14 promoter-driven GFP and developmental behavior of the expressed cells in early heterozygous embryos by out-crossing the Tg(Apo14: GFP) male to the wild type female. Significantly, the Apo-14 promoter-driven GFP is initially expressed around YSL beneath the embryo body at 10 hpf when the embryos develop to tail bud prominence. In about 14-somite embryos at 16–17 hpf, a typical “salt-and-pepper” expression pattern is clearly observed in YSL around the yolk sac. Then, a green fluorescence dot begins to appear between the notochord and the yolk sac adjacent to otic vesicle at about 20 hpf, which is later demonstrated to be liver primordium that gives rise to liver. Furthermore, we investigated dynamic progression of liver organogenesis in the Tg(Apo14: GFP) zebrafish, because the Apo-14 promoter-driven GFP is sustainably expressed from hepatoblasts and liver progenitor cells in liver primordium to hepatocytes in the larval and adult liver. Additionally, we observed similar morphology between the liver progenitor cells and the GFP-positive nuclei on the YSL, suggesting that they might originate from the same progenitor cells in early embryos. Overall, the current study

  11. Effect of liver regeneration on malignant hepatic tumors

    PubMed Central

    Shi, Ji-Hua; Line, Pål-Dag

    2014-01-01

    Liver regeneration after major surgery may activate occult micrometastases and facilitate tumor growth, leading to liver tumor recurrence. Molecular changes during liver regeneration can provide a microenvironment that stimulates intrahepatic tumor propagation through alterations in cellular signaling pathways, where activation and proliferation of mature hepatocytes, hepatic progenitor cells, non-parenchymal liver cells might favor both liver regeneration and tumor growth. This review highlights recent advances of tumor growth and development in the regenerating liver, possible mechanisms and clinical implications. PMID:25473170

  12. Distinct cis-Regulatory Elements from the Dlx1/Dlx2 Locus Mark Different Progenitor Cell Populations in the Ganglionic Eminences and Different Subtypes of Adult Cortical Interneurons

    PubMed Central

    Ghanem, Noël; Yu, Man; Long, Jason; Hatch, Gary; Rubenstein, John L. R.; Ekker, Marc

    2016-01-01

    Distinct subtypes of cortical GABAergic interneurons provide inhibitory signals that are indispensable for neural network function. The Dlx homeobox genes have a central role in regulating their development and function. We have characterized the activity of three cis-regulatory sequences involved in forebrain expression of vertebrate Dlx genes: upstream regulatory element 2 (URE2), I12b, and I56i. The three regulatory elements display regional and temporal differences in their activities within the lateral ganglionic eminence (LGE), medial ganglionic eminence (MGE), and caudal ganglionic eminence (CGE) and label distinct populations of tangentially migrating neurons at embryonic day 12.5 (E12.5) and E13.5. We provide evidence that the dorsomedial and ventral MGE are distinct sources of tangentially migrating neurons during midgestation. In the adult cortex, URE2 and I12b/I56i are differentially expressed in parvalbumin-, calretinin-, neuropeptide Y-, and neuronal nitric oxide synthase-positive interneurons; I12b and I56i were specifically active in somatostatin-, vasoactive intestinal peptide-, and calbindin-positive interneurons. These data suggest that interneuron subtypes use distinct combinations of Dlx1/Dlx2 enhancers from the time they are specified through adulthood. PMID:17494687

  13. Perivascular support of human hematopoietic stem/progenitor cells

    PubMed Central

    Corselli, Mirko; Chin, Chee Jia; Parekh, Chintan; Sahaghian, Arineh; Wang, Wenyuan; Ge, Shundi; Evseenko, Denis; Wang, Xiaoyan; Montelatici, Elisa; Lazzari, Lorenza; Crooks, Gay M.

    2013-01-01

    Hematopoietic stem and progenitor cells (HSPCs) emerge and develop adjacent to blood vessel walls in the yolk sac, aorta-gonad-mesonephros region, embryonic liver, and fetal bone marrow. In adult mouse bone marrow, perivascular cells shape a “niche” for HSPCs. Mesenchymal stem/stromal cells (MSCs), which support hematopoiesis in culture, are themselves derived in part from perivascular cells. In order to define their direct role in hematopoiesis, we tested the ability of purified human CD146+ perivascular cells, as compared with unfractionated MSCs and CD146− cells, to sustain human HSPCs in coculture. CD146+ perivascular cells support the long-term persistence, through cell-to-cell contact and at least partly via Notch activation, of human myelolymphoid HSPCs able to engraft primary and secondary immunodeficient mice. Conversely, unfractionated MSCs and CD146− cells induce differentiation and compromise ex vivo maintenance of HSPCs. Moreover, CD146+ perivascular cells express, natively and in culture, molecular markers of the vascular hematopoietic niche. Unexpectedly, this dramatic, previously undocumented ability to support hematopoietic stem cells is present in CD146+ perivascular cells extracted from the nonhematopoietic adipose tissue. PMID:23412095

  14. 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

  15. Targeting the Achilles' heel of adult living donor liver transplant: Corner-sparing sutures with mucosal eversion technique of biliary anastomosis.

    PubMed

    Vij, Vivek; Makki, Kausar; Chorasiya, Vishal Kumar; Sood, Gaurav; Singhal, Ashish; Dargan, Puneet

    2016-01-01

    Biliary complications are regarded as the Achilles' heel of liver transplantation, especially for living donor liver transplantation (LDLT) due to smaller, multiple ducts and difficult ductal anatomy. Overall biliary complications reported in most series are between 10% and 30%. This study describes our modified technique of biliary anastomosis and its effects on incidence of biliary complications. This was a single-center retrospective study of 148 adult LDLT recipients between December 2011 and June 2014. Group 1 (n = 40) consisted of the first 40 patients for whom the standard technique of biliary anastomosis (minimal hilar dissection during donor duct division, high hilar division of the recipient bile duct, and preservation of the recipient duct periductal tissue) was used. Group 2 (n = 108) consisted of 108 patients for whom biliary anastomosis was done with the addition of corner-sparing sutures and mucosal eversion of the recipient duct to the standard technique. Primary outcome measures included biliary complications (biliary leaks and strictures). Biliary complications occurred in 7/40 patients in group 1 (17.5%) and in 4/108 patients in group 2 (3.7%). The technical factors mentioned above are aimed at preserving the blood supply of the donor and recipient ducts and hold the key for minimizing biliary complications in adult-to-adult LDLT. PMID:26390361

  16. Ischaemic preconditioning of the graft in adult living related right lobe liver transplantation: impact on ischaemia–reperfusion injury and clinical relevance

    PubMed Central

    Andreani, Paola; Hoti, Emir; de la Serna, Sofia; degli Esposti, Davide; Sebagh, Mylène; Lemoine, Antoinette; Ichai, Philippe; Saliba, Fauzi; Castaing, Denis; Azoulay, Daniel

    2010-01-01

    Background Ischaemic preconditioning (IPC) of the right liver graft in the donor has not been studied in adult-to-adult living related liver transplantation (LRLT). Objective To assess the IPC effect of the graft on ischaemia reperfusion injury in the recipient and compare recipient and donor outcomes with and without preconditioned grafts. Patients and methods Alternate patients were transplanted with right lobe grafts that were (n =22; Group Precond) or were not (n =22; Group Control) subjected to IPC in the living donor. Liver ischaemia–reperfusion injury, liver/kidney function, morbidity/mortality rates and outcomes were compared. Univariate and multivariate analyses were performed to identify factors predictive of the aspartate aminotransferase (AST) peak and minimum prothrombin time. Results Both groups had similar length of hospital stay, morbidity/mortality, primary non-function and acute rejection rates. Post-operative AST (P =0.8) and alanine aminotransferase (ALT) peaks (P =0.6) were similar in both groups (307 ± 189 and 437 ± 302 vs. 290 ± 146 and 496 ± 343, respectively). In univariate analysis, only pre-operative AST and warm ischemia time (WIT) were significantly associated with post-operative AST peak (in recipients). In multivariate analysis, the graft/recipient weight ratio (P =0.003) and pre-operative bilirubin concentration (P =0.004) were significantly predictive of minimum prothrombin time post-transplantation. Conclusions Graft IPC in the living related donor is not associated with any benefit for the recipient or the donor and its clinical value remains uncertain. PMID:20815852

  17. 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

  18. 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

  19. 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. PMID:23642054

  20. A liver abscess deprived a healthy adult of eyesight: endogenous endophthalmitis associated with a pyogenic liver abscess caused by serotype K1 Klebsiella pneumonia.

    PubMed

    Maruno, Takahisa; Ooiwa, Yoko; Takahashi, Ken; Kodama, Yuzo; Takakura, Shunji; Ichiyama, Satoshi; Chiba, Tsutomu

    2013-01-01

    Klebsiella pneumonia usually causes urinary tract infections, pneumonia, and other infectious diseases in hospitalized and immunocompromised patients. Among the types of Klebsiella pneumonia, serotype K1 is known to be a highly virulent pathogen. We herein report the case of a healthy 63-year-old man with a pyogenic liver abscess and bilateral endogenous endophthalmitis caused by serotype K1 Klebsiella pneumonia. Although the patient received percutaneous abscess drainage and antibiotic therapy, he lost his eyesight. To improve the poor prognoses of ocular complications, providing both an earlier diagnosis and treatment is critical. PMID:23583997

  1. Sorafenib Tosylate With or Without Doxorubicin Hydrochloride in Treating Patients With Locally Advanced or Metastatic Liver Cancer

    ClinicalTrials.gov

    2016-06-20

    Adult Hepatocellular Carcinoma; Advanced Adult Hepatocellular Carcinoma; BCLC Stage C Adult Hepatocellular Carcinoma; BCLC Stage D Adult Hepatocellular Carcinoma; Localized Non-Resectable Adult Liver Carcinoma; Recurrent Adult Liver Carcinoma

  2. Adult Neurogenesis in Fish.

    PubMed

    Ganz, Julia; Brand, Michael

    2016-01-01

    Teleost fish have a remarkable neurogenic and regenerative capacity in the adult throughout the rostrocaudal axis of the brain. The distribution of proliferation zones shows a remarkable conservation, even in distantly related teleost species, suggesting a common teleost ground plan of proliferation zones. There are different progenitor populations in the neurogenic niches-progenitors positive for radial glial markers (dorsal telencephalon, hypothalamus) and progenitors with neuroepithelial-like characteristics (ventral telencephalon, optic tectum, cerebellum). Definition of these progenitors has allowed studying their role in normal growth of the adult brain, but also when challenged following a lesion. From these studies, important roles have emerged for intrinsic mechanisms and extrinsic signals controlling the activation of adult neurogenesis that enable regeneration of the adult brain to occur, opening up new perspectives on rekindling regeneration also in the context of the mammalian brain. PMID:26747664

  3. Regenerative medicine: Hepatic progenitor cells up their game in the therapeutic stakes.

    PubMed

    Alison, Malcolm R; Lin, Wey-Ran

    2015-11-01

    Bipotential hepatic progenitor cells (HPCs) are recognized as making modest contributions to hepatocyte regeneration, though never credited with major liver repopulation. A new study in mice demonstrates HPCs can make a massive contribution to hepatocyte replacement, suggesting HPCs have the potential to be an effective cell therapy for liver failure. PMID:26441248

  4. Recent Progress on Tissue-Resident Adult Stem Cell Biology and Their Therapeutic Implications

    PubMed Central

    2013-01-01

    Recent progress in the field of the stem cell research has given new hopes to treat and even cure diverse degenerative disorders and incurable diseases in human. Particularly, the identification of a rare population of adult stem cells in the most tissues/organs in human has emerged as an attractive source of multipotent stem/progenitor cells for cell replacement-based therapies and tissue engineering in regenerative medicine. The tissue-resident adult stem/progenitor cells offer the possibility to stimulate their in vivo differentiation or to use their ex vivo expanded progenies for cell replacement-based therapies with multiple applications in human. Among the human diseases that could be treated by the stem cell-based therapies, there are hematopoietic and immune disorders, multiple degenerative disorders, such as Parkinson’s and Alzeimeher’s diseases, type 1 or 2 diabetes mellitus as well as eye, liver, lung, skin and cardiovascular disorders and aggressive and metastatic cancers. In addition, the genetically-modified adult stem/progenitor cells could also be used as delivery system for expressing the therapeutic molecules in specific damaged areas of different tissues. Recent advances in cancer stem/progenitor cell research also offer the possibility to targeting these undifferentiated and malignant cells that provide critical functions in cancer initiation and progression and disease relapse for treating the patients diagnosed with the advanced and metastatic cancers which remain incurable in the clinics with the current therapies. PMID:18288619

  5. Gamma-interferon alters globin gene expression in neonatal and adult erythroid cells

    SciTech Connect

    Miller, B.A.; Perrine, S.P.; Antognetti, G.; Perlmutter, D.H.; Emerson, S.G.; Sieff, C.; Faller, D.V.

    1987-06-01

    The effect of gamma-interferon on fetal hemoglobin synthesis by purified cord blood, fetal liver, and adult bone marrow erythroid progenitors was studied with a radioligand assay to measure hemoglobin production by BFU-E-derived erythroblasts. Coculture with recombinant gamma-interferon resulted in a significant and dose-dependent decrease in fetal hemoglobin production by neonatal and adult, but not fetal, BFU-E-derived erythroblasts. Accumulation of fetal hemoglobin by cord blood BFU-E-derived erythroblasts decreased up to 38.1% of control cultures (erythropoietin only). Synthesis of both G gamma/A gamma globin was decreased, since the G gamma/A gamma ratio was unchanged. Picograms fetal hemoglobin per cell was decreased by gamma-interferon addition, but picograms total hemoglobin was unchanged, demonstrating that a reciprocal increase in beta-globin production occurred in cultures treated with gamma-interferon. No toxic effect of gamma-interferon on colony growth was noted. The addition of gamma-interferon to cultures resulted in a decrease in the percentage of HbF produced by adult BFU-E-derived cells to 45.6% of control. Fetal hemoglobin production by cord blood, fetal liver, and adult bone marrow erythroid progenitors, was not significantly affected by the addition of recombinant GM-CSF, recombinant interleukin 1 (IL-1), recombinant IL-2, or recombinant alpha-interferon. Although fetal progenitor cells appear unable to alter their fetal hemoglobin program in response to any of the growth factors added here, the interaction of neonatal and adult erythroid progenitors with gamma-interferon results in an altered expression of globin genes.

  6. De novo generation of adipocytes from circulating progenitor cells in mouse and human adipose tissue.

    PubMed

    Gavin, Kathleen M; Gutman, Jonathan A; Kohrt, Wendy M; Wei, Qi; Shea, Karen L; Miller, Heidi L; Sullivan, Timothy M; Erickson, Paul F; Helm, Karen M; Acosta, Alistaire S; Childs, Christine R; Musselwhite, Evelyn; Varella-Garcia, Marileila; Kelly, Kimberly; Majka, Susan M; Klemm, Dwight J

    2016-03-01

    White adipocytes in adults are typically derived from tissue resident mesenchymal progenitors. The recent identification of de novo production of adipocytes from bone marrow progenitor-derived cells in mice challenges this paradigm and indicates an alternative lineage specification that adipocytes exist. We hypothesized that alternative lineage specification of white adipocytes is also present in human adipose tissue. Bone marrow from transgenic mice in which luciferase expression is governed by the adipocyte-restricted adiponectin gene promoter was adoptively transferred to wild-type recipient mice. Light emission was quantitated in recipients by in vivo imaging and direct enzyme assay. Adipocytes were also obtained from human recipients of hematopoietic stem cell transplantation. DNA was isolated, and microsatellite polymorphisms were exploited to quantify donor/recipient chimerism. Luciferase emission was detected from major fat depots of transplanted mice. No light emission was observed from intestines, liver, or lungs. Up to 35% of adipocytes in humans were generated from donor marrow cells in the absence of cell fusion. Nontransplanted mice and stromal-vascular fraction samples were used as negative and positive controls for the mouse and human experiments, respectively. This study provides evidence for a nontissue resident origin of an adipocyte subpopulation in both mice and humans. PMID:26581599

  7. Lapatinib in Treating Patients With Locally Advanced or Metastatic Biliary Tract or Liver Cancer That Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2014-12-18

    Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

  8. PPAR-α and glucocorticoid receptor synergize to promote erythroid progenitor self-renewal.

    PubMed

    Lee, Hsiang-Ying; Gao, Xiaofei; Barrasa, M Inmaculada; Li, Hu; Elmes, Russell R; Peters, Luanne L; Lodish, Harvey F

    2015-06-25

    Many acute and chronic anaemias, including haemolysis, sepsis and genetic bone marrow failure diseases such as Diamond-Blackfan anaemia, are not treatable with erythropoietin (Epo), because the colony-forming unit erythroid progenitors (CFU-Es) that respond to Epo are either too few in number or are not sensitive enough to Epo to maintain sufficient red blood cell production. Treatment of these anaemias requires a drug that acts at an earlier stage of red cell formation and enhances the formation of Epo-sensitive CFU-E progenitors. Recently, we showed that glucocorticoids specifically stimulate self-renewal of an early erythroid progenitor, burst-forming unit erythroid (BFU-E), and increase the production of terminally differentiated erythroid cells. Here we show that activation of the peroxisome proliferator-activated receptor α (PPAR-α) by the PPAR-α agonists GW7647 and fenofibrate synergizes with the glucocorticoid receptor (GR) to promote BFU-E self-renewal. Over time these agonists greatly increase production of mature red blood cells in cultures of both mouse fetal liver BFU-Es and mobilized human adult CD34(+) peripheral blood progenitors, with a new and effective culture system being used for the human cells that generates normal enucleated reticulocytes. Although Ppara(-/-) mice show no haematological difference from wild-type mice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPAR-α agonists facilitate recovery of wild-type but not Ppara(-/-) mice from PHZ-induced acute haemolytic anaemia. We also show that PPAR-α alleviates anaemia in a mouse model of chronic anaemia. Finally, both in control and corticosteroid-treated BFU-E cells, PPAR-α co-occupies many chromatin sites with GR; when activated by PPAR-α agonists, additional PPAR-α is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Our discovery of the role of PPAR-α agonists in stimulating self-renewal of early erythroid

  9. PPARα and glucocorticoid receptor synergize to promote erythroid progenitor self-renewal

    PubMed Central

    Lee, Hsiang-Ying; Gao, Xiaofei; Barrasa, M. Inmaculada; Li, Hu; Elmes, Russell R.; Peters, Luanne L.; Lodish, Harvey F.

    2015-01-01

    Summary Many acute and chronic anemias, including hemolysis, sepsis, and genetic bone marrow failure diseases such as Diamond-Blackfan Anemia (DBA), are not treatable with erythropoietin (Epo), because the colony-forming unit erythroid progenitors (CFU-Es) that respond to Epo are either too few in number or are not sensitive enough to Epo to maintain sufficient red blood cell production 1,2,3–5,6,7,8,9. Treatment of these anemias requires a drug that acts at an earlier stage of red cell formation and enhances the formation of Epo-sensitive CFU-E progenitors. Recently we showed that glucocorticoids specifically stimulate self-renewal of the early erythroid progenitor, the burst-forming unit erythroid (BFU-E), and increase the production of terminally differentiated erythroid cells 10,11. Here we demonstrate that activation of the peroxisome proliferator-activated receptor alpha (PPARα) by PPARα agonists, GW7647 and fenofibrate, synergizes with glucocorticoid receptor (GR) to promote BFU-E self-renewal. Over time these agonists greatly increase production of mature red blood cells in cultures both of mouse fetal liver BFU-Es and of mobilized human adult CD34+ peripheral blood progenitors, the latter employing a new and effective culture system that generates normal enucleated reticulocytes. While PPARα−/− mice show no hematological difference from wild-type mice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPARα agonists facilitate recovery of wild-type mice, but not PPARα−/− mice, from PHZ-induced acute hemolytic anemia. We also showed that PPARα alleviates anemia in a mouse model of chronic anemia. Finally, both in control and corticosteroid-treated BFU-E cells PPARα co-occupies many chromatin sites with GR; when activated by PPARα agonists, additional PPARα is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Our discovery of the role of PPARα agonists in stimulating self

  10. Gastrointestinal and liver disease in Adult Life After Childhood Cancer in Scandinavia: A population-based cohort study.

    PubMed

    Asdahl, Peter Haubjerg; Winther, Jeanette Falck; Bonnesen, Trine Gade; De Fine Licht, Sofie; Gudmundsdottir, Thorgerdur; Holmqvist, Anna Sällfors; Malila, Nea; Tryggvadottir, Laufey; Wesenberg, Finn; Dahlerup, Jens Frederik; Olsen, Jørgen Helge; Hasle, Henrik

    2016-10-01

    Survival after childhood cancer diagnosis has remarkably improved, but emerging evidence suggests that cancer-directed therapy may have adverse gastrointestinal late effects. We aimed to comprehensively assess the frequency of gastrointestinal and liver late effects among childhood cancer survivors and compare this frequency with the general population. Our population-based cohort study included all 1-year survivors of childhood and adolescent cancer in Denmark, Finland, Iceland, Norway and Sweden diagnosed from the 1940s and 1950s. Our outcomes of interest were hospitalization rates for gastrointestinal and liver diseases, which were ascertained from national patient registries. We calculated standardized hospitalization rate ratios (RRs) and absolute excess rates comparing hospitalizations of any gastrointestinal or liver disease and for specific disease entities between survivors and the general population. The study included 31,132 survivors and 207,041 comparison subjects. The median follow-up in the hospital registries were 10 years (range: 0-42) with 23% of the survivors being followed at least to the age of 40 years. Overall, survivors had a 60% relative excess of gastrointestinal or liver diseases [RR: 1.6, 95% confidence interval (CI): 1.6-1.7], which corresponds to an absolute excess of 360 (95% CI: 330-390) hospitalizations per 100,000 person-years. Survivors of hepatic tumors, neuroblastoma and leukemia had the highest excess of gastrointestinal and liver diseases. In addition, we observed a relative excess of several specific diseases such as esophageal stricture (RR: 13; 95% CI: 9.2-20) and liver cirrhosis (RR: 2.9; 95% CI: 2.0-4.1). Our findings provide useful information about the breadth and magnitude of late complications among childhood cancer survivors and can be used for generating hypotheses about potential exposures related to these gastrointestinal and liver late effects. PMID:27194488

  11. Comparative transcriptomic analysis by RNA-seq to discern differential expression of genes in liver and muscle tissues of adult Berkshire and Jeju Native Pig.

    PubMed

    Sodhi, Simrinder Singh; Song, Ki-Duk; Ghosh, Mrinmoy; Sharma, Neelesh; Lee, Sung Jin; Kim, Jeong Hyun; Kim, Nameun; Mongre, Raj Kumar; Adhikari, Pradeep; Kim, Jin Young; Hong, Sang Pyo; Oh, Sung Jong; Jeong, Dong Kee

    2014-08-10

    RNA-seq is being rapidly adopted for the profiling of the transcriptomes in different areas of biology, especially in the studies related to gene regulation. The discovery of differentially expressed genes (DEGs) between adult animals of Jeju Native Pig (JNP) and Berkshire breeds of Sus scrofa, is of particular interest for the current study. For the better understanding of the gene expression profiles of the liver and longissimus dorsi muscle, DEGs were identified via RNA-seq. Sequence reads were obtained from Illumina HiSeq2000 and mapped to the pig reference genome (Sscrofa10.2) using Tophat2. We identified 169 and 39 DEGs in the liver and muscle of JNP respectively, by comparison with Berkshire breed. Out of all identified genes, 41 genes in the liver and 9 genes in the muscle have given significant expression. Gene ontology (GO) terms of developmental process and KEGG pathway analysis showed that metabolic, immune response and protein binding were commonly enriched pathways in the two tissues. Further the heat map analysis by ArrayStar has shown the different levels of expression in JNP with respect to the Berkshire breed. The validation through real time PCR and western blotting also confirmed the differential expression of genes in both breeds. Genes pertaining to metabolic process and inflammatory and immune system are more enriched in Berkshire breed. This comparative transcriptome analysis of two tissues suggests a subset of novel marker genes which expressed differently between the JNP and Berkshire. PMID:24910116

  12. Successful treatment of small-for-size syndrome in adult-to-adult living-related liver transplantation: single center series.

    PubMed

    Gruttadauria, Salvatore; Mandala', Lucio; Miraglia, Roberto; Caruso, Settimo; Minervini, Marta Ida; Biondo, Domenico; Volpes, Riccardo; Vizzini, Giovanni; Marsh, J Wallis; Luca, Angelo; Marcos, Amadeo; Gridelli, Bruno

    2007-01-01

    The portal hyperperfusion, or small-for-size syndrome (SFSS), is a widely recognized clinical complication that may occur after segmental liver transplantation. Several surgical strategies have been proposed to reduce portal blood inflow and portal pressure after partial liver transplantation. In particular, splenic artery ligation and splenectomy have been used without a firm hemodynamic basis for these procedures. Our group recently demonstrated that, in patients with cirrhosis and portal hypertension, the occlusion of the splenic artery causes a significant reduction in the portal pressure gradient, which is directly related to the spleen volume and indirectly related to the liver volume. This concept is at the center of our strategy for performing early splenic artery embolization (SAE) for the treatment of SFSS after living-related liver transplantation (LRLT). Six patients developed small-for-size syndrome, defined as: onset within the first week after LRLT of progressive hyperbilirubinemia without mechanical cause; marked cholestasis; centrilobular sinusoidal dilatation and hepatocyte atrophy at liver biopsy; and refractory ascites in the absence of vascular complications. All six patients who underwent SAE rapidly improved their clinical condition, with an evident decrease in the value of bilirubin in the serum, in the production of ascites, and improvement in condition of pancytopenia. Coagulopathy expressed by the international normalized ratio value (INR) was not a reliable early marker of SFSS in this series; in fact a slight improvement in the result of this test was already present immediately after LRLT and before SAE. Because splenic flow clearly contributes to portal hyperperfusion, an early SAE can relieve the partial graft from the deleterious effect of this portal overflow. PMID:17988271

  13. ALDH1B1 is a potential stem / progenitor marker for multiple pancreas progenitor pools

    PubMed Central

    Ioannou, Marilia; Serafimidis, Ioannis; Arnes, Luis; Sussel, Lori; Singh, Surendra; Vasiliou, Vasilis; Gavalas, Anthony

    2013-01-01

    Aldehyde Dehydrogenase (ALDH) genes are increasingly associated with stem / progenitor cell status but their role in the maintenance of pluripotency remains uncertain. In a screen conducted for downstream Ngn3 target genes using ES derived pancreas progenitors we identified Aldh1b1, encoding a mitochondrial enzyme, as one of the genes strongly up regulated in response to Ngn3 expression. We found both by in situ hybridization and immunofluorescence using a specific antibody that ALDH1B1 is exclusively expressed in the emerging pancreatic buds of the early embryo (9.5 dpc) in a Pdx1 dependent manner. Around the time of secondary transition, ALDH1B1 expression was restricted in the tip tripotent progenitors of the branching epithelium and in a subset of the trunk epithelium. Expression in the latter was Ngn3 dependent. Subsequently, ALDH1B1 expression persisted only in the tip cells that become restricted to the exocrine lineage and declined rapidly as these cells mature. In the adult pancreas we identified rare ALDH1B1+ cells that become abundant following pancreas injury in either the caerulein or streptozotocin paradigms. Blocking ALDH catalytic activity in pancreas embryonic explants resulted in reduced size of the explants and accelerated differentiation suggesting for the first time that ALDH activity may be necessary in the developing pancreas for the maintenance and expansion of progenitor pools. PMID:23142317

  14. 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

  15. 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

  16. Neonatal Heart-Enriched miR-708 Promotes Differentiation of Cardiac Progenitor Cells in Rats

    PubMed Central

    Deng, Shengqiong; Zhao, Qian; Zhou, Xianjin; Zhang, Lin; Bao, Luer; Zhen, Lixiao; Zhang, Yuzhen; Fan, Huimin; Liu, Zhongmin; Yu, Zuoren

    2016-01-01

    Cardiovascular disease is becoming the leading cause of death throughout the world. However, adult hearts have limited potential for regeneration after pathological injury, partly due to the quiescent status of stem/progenitor cells. Reactivation of cardiac stem/progenitor cells to create more myocyte progeny is one of the key steps in the regeneration of a damaged heart. In this study, miR-708 was identified to be enriched in the neonatal cardiomyocytes of rats, but this has not yet been proven in adult humans. A lower level of miR-708 in c-kit(+) stem/progenitor cells was detected compared to non-progenitors. Overexpression of miR-708 induced cardiomyocyte differentiation of cardiac stem/progenitor cells. This finding strengthened the potential of applying miRNAs in the regeneration of injured hearts, and this indicates that miR-708 could be a novel candidate for treatment of heart diseases. PMID:27338347

  17. Neonatal Heart-Enriched miR-708 Promotes Differentiation of Cardiac Progenitor Cells in Rats.

    PubMed

    Deng, Shengqiong; Zhao, Qian; Zhou, Xianjin; Zhang, Lin; Bao, Luer; Zhen, Lixiao; Zhang, Yuzhen; Fan, Huimin; Liu, Zhongmin; Yu, Zuoren

    2016-01-01

    Cardiovascular disease is becoming the leading cause of death throughout the world. However, adult hearts have limited potential for regeneration after pathological injury, partly due to the quiescent status of stem/progenitor cells. Reactivation of cardiac stem/progenitor cells to create more myocyte progeny is one of the key steps in the regeneration of a damaged heart. In this study, miR-708 was identified to be enriched in the neonatal cardiomyocytes of rats, but this has not yet been proven in adult humans. A lower level of miR-708 in c-kit(+) stem/progenitor cells was detected compared to non-progenitors. Overexpression of miR-708 induced cardiomyocyte differentiation of cardiac stem/progenitor cells. This finding strengthened the potential of applying miRNAs in the regeneration of injured hearts, and this indicates that miR-708 could be a novel candidate for treatment of heart diseases. PMID:27338347

  18. Kras is Required for Adult Hematopoiesis.

    PubMed

    Damnernsawad, Alisa; Kong, Guangyao; Wen, Zhi; Liu, Yangang; Rajagopalan, Adhithi; You, Xiaona; Wang, Jinyong; Zhou, Yun; Ranheim, Erik A; Luo, Hongbo R; Chang, Qiang; Zhang, Jing

    2016-07-01

    Previous studies indicate that Kras is dispensable for fetal liver hematopoiesis, but its role in adult hematopoiesis remains unclear. Here, we generated a Kras conditional knockout allele to address this question. Deletion of Kras in adult bone marrow (BM) is mediated by Vav-Cre or inducible Mx1-Cre. We find that loss of Kras leads to greatly reduced thrombopoietin (TPO) signaling in hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs), while stem cell factor-evoked ERK1/2 activation is not affected. The compromised TPO signaling is associated with reduced long term- and intermediate-term HSC compartments and a bias toward myeloid differentiation in MPPs. Although granulocyte macrophage colony-stimulating factor (GM-CSF)-evoked ERK1/2 activation is only moderately decreased in Kras(-/-) myeloid progenitors, it is blunted in neutrophils and neutrophil survival is significantly reduced in vitro. At 9-12 months old, Kras conditional knockout mice develop profound hematopoietic defects, including splenomegaly, an expanded neutrophil compartment, and reduced B cell number. In a serial transplantation assay, the reconstitution potential of Kras(-/-) BM cells is greatly compromised, which is attributable to defects in the self-renewal of Kras(-/-) HSCs and defects in differentiated hematopoietic cells. Our results demonstrate that Kras is a major regulator of TPO and GM-CSF signaling in specific populations of hematopoietic cells and its function is required for adult hematopoiesis. Stem Cells 2016;34:1859-1871. PMID:26972179

  19. High calcium diet improves the liver oxidative stress and microsteatosis in adult obese rats that were overfed during lactation.

    PubMed

    Conceição, E P S; Moura, E G; Soares, P N; Ai, X X; Figueiredo, M S; Oliveira, E; Lisboa, P C

    2016-06-01

    Obesity is related to diabetes, higher oxidative stress and nonalcoholic fatty liver disease, and dietetic therapies, for instance calcium-rich diet, can improve these dysfunctions. Rats raised in small litters (SL) had increased fat depots and insulin resistance at adulthood associated with higher liver oxidative stress and microsteatosis. Thus, we evaluated if dietary calcium can improve these changes. In PN3, litter size was adjusted to 3 pups (SL group) to induce overfeeding, while controls had 10 pups until weaning. At PN120, SL group was randomly divided into: rats fed with standard chow or fed with calcium supplementation (SL-Ca group, 10 g/kg chow) for 60 days. At PN180, dietary calcium normalized food consumption, visceral fat, plasma aspartate aminotransferase (AST) and glycaemia. Concerning oxidative balance, calcium restored both higher hepatic lipid peroxidation and protein carbonylation as well as higher plasma lipid peroxidation. Higher fatty acid synthase (FAS) content, steatosis and lower protein kinase B (Akt) in SL group were normalized by dietary calcium and SL-Ca rats had lower hepatic cholesterol. Thus, calcium supplementation improved the insulin sensitivity, redox balance and steatosis in the liver. Therefore, dietary calcium can be a promising therapy for liver disease in the metabolic syndrome. PMID:27108106

  20. Endothelial progenitor cells: identity defined?

    PubMed Central

    Timmermans, Frank; Plum, Jean; Yöder, Mervin C; Ingram, David A; Vandekerckhove, Bart; Case, Jamie

    2009-01-01

    Abstract In the past decade, researchers have gained important insights on the role of bone marrow (BM)-derived cells in adult neovascularization. A subset of BM-derived cells, called endothelial progenitor cells (EPCs), has been of particular interest, as these cells were suggested to home to sites of neovascularization and neoendothelialization and differentiate into endothelial cells (ECs) in situ, a process referred to as postnatal vasculogenesis. Therefore, EPCs were proposed as a potential regenerative tool for treating human vascular disease and a possible target to restrict vessel growth in tumour pathology. However, conflicting results have been reported in the field, and the identification, characterization, and exact role of EPCs in vascular biology is still a subject of much discussion. The focus of this review is on the controversial issues in the field of EPCs which are related to the lack of a unique EPC marker, identification challenges related to the paucity of EPCs in the circulation, and the important phenotypical and functional overlap between EPCs, haematopoietic cells and mature ECs. We also discuss our recent findings on the origin of endothelial outgrowth cells (EOCs), showing that this in vitro defined EC population does not originate from circulating CD133+ cells or CD45+ haematopoietic cells. PMID:19067770

  1. Fibrosing Cholestatic Hepatitis in a Complicated Case of an Adult Recipient After Liver Transplantation: Diagnostic Findings and Therapeutic Dilemma

    PubMed Central

    Hori, Tomohide; Onishi, Yasuharu; Kamei, Hideya; Kurata, Nobuhiko; Ishigami, Masatoshi; Ishizu, Yoji; Ogura, Yasuhiro

    2016-01-01

    Patient: Male, 66 Final Diagnosis: Fibrosing cholestatic hepatitis Symptoms: Prolonged jaundice and intractable ascites Medication: Steroid pulse therapy and direct-acting antivirals Clinical Procedure: Liver transplantation Specialty: Transplantology Objective: Challenging differential diagnosis Background: Hepatitis C recurrence is a serious matter after liver transplantation (LT). Approximately 10% of hepatitis C virus (HCV) positive recipients develop fibrosing cholestatic hepatitis (FCH). FCH rapidly results in graft loss. Currently, direct-acting antivirals (DAAs) are effective and safe for hepatitis C, even after LT. However, only a few cases of successfully treated FCH after LT have been reported. We present FCH in a complicated case with sepsis and portal flow obstruction after LT. Case Report: A 66-year-old man underwent cadaveric LT. Liver function disorders were observed from post-operative day (POD) 22. Sepsis repeated on POD 38, 74, and 101. Steroid pulse therapy was given from POD 40 to 54. The infectious focus was surgically removed on POD 89. Interventional radiology for portal venous obstruction was completed on POD 96. To make a real-time diagnosis and to investigate the graft condition, repeat liver needle biopsies (LNBs) were taken. Although there was a combined impact of sepsis, portal flow decrease, and recurrent hepatitis C on graft failure, it was interesting that recurrent hepatitis C was consistently detectable from the first LNB. HCV-ribonucleic acid increased on POD 68. Liver function disorders peaked on POD 71 and 72. Jaundice peaked on POD 82. DAA induction was regrettably delayed because of a reluctance to introduce DAAs under conditions of graft dysfunction. DAAs were administered after hospital discharge. Conclusions: A real-time and precise diagnosis based on histopathological examination and viral measurement is important for FCH treatment. Well-considered therapy with DAAs should be aggressively introduced for potentially fatal

  2. Derivation of endodermal progenitors from pluripotent stem cells†

    PubMed Central

    Ikonomou, Laertis; Kotton, Darrell N.

    2014-01-01

    Stem and progenitor cells play important roles in organogenesis during development and in tissue homeostasis and response to injury postnatally. As the regenerative capacity of many human tissues is limited, cell replacement therapies hold great promise for human disease management. Pluripotent stem cells such as embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are prime candidates for the derivation of unlimited quantities of clinically relevant cell types through development of directed differentiation protocols, i.e. the recapitulation of developmental milestones in in vitro cell culture. Tissue-specific progenitors, including progenitors of endodermal origin, are important intermediates in such protocols since they give rise to all mature parenchymal cells. In this review, we focus on the in vivo biology of embryonic endodermal progenitors in terms of key transcription factors and signaling pathways. We critically review the emerging literature aiming to apply this basic knowledge to achieve the efficient and reproducible in vitro derivation of endodermal progenitors such as pancreas, liver and lung precursor cells. PMID:25160562

  3. HGF/c-Met signaling promotes liver progenitor cell migration and invasion by an epithelial-mesenchymal transition-independent, phosphatidyl inositol-3 kinase-dependent pathway in an in vitro model.

    PubMed

    Suárez-Causado, A; Caballero-Díaz, D; Bertrán, E; Roncero, C; Addante, A; García-Álvaro, M; Fernández, M; Herrera, B; Porras, A; Fabregat, I; Sánchez, A

    2015-10-01

    Oval cells constitute an interesting hepatic cell population. They contribute to sustain liver regeneration during chronic liver damage, but in doing this they can be target of malignant conversion and become tumor-initiating cells and drive hepatocarcinogenesis. The molecular mechanisms beneath either their pro-regenerative or pro-tumorigenic potential are still poorly understood. In this study, we have investigated the role of the HGF/c-Met pathway in regulation of oval cell migratory and invasive properties. Our results show that HGF induces c-Met-dependent oval cell migration both in normal culture conditions and after in vitro wounding. HGF-triggered migration involves F-actin cytoskeleton reorganization, which is also evidenced by activation of Rac1. Furthermore, HGF causes ZO-1 translocation from cell-cell contact sites to cytoplasm and its concomitant activation by phosphorylation. However, no loss of expression of cell-cell adhesion proteins, including E-cadherin, ZO-1 and Occludin-1, is observed. Additionally, migration does not lead to cell dispersal but to a characteristic organized pattern in rows, in turn associated with Golgi compaction, providing strong evidence of a morphogenic collective migration. Besides migration, HGF increases oval cell invasion through extracellular matrix, a process that requires PI3K activation and is at least partly mediated by expression and activation of metalloproteases. Altogether, our findings provide novel insights into the cellular and molecular mechanisms mediating the essential role of HGF/c-Met signaling during oval cell-mediated mouse liver regeneration. PMID:26001768

  4. Associations of gut-flora-dependent metabolite trimethylamine-N-oxide, betaine and choline with non-alcoholic fatty liver disease in adults

    PubMed Central

    Chen, Yu-ming; Liu, Yan; Zhou, Rui-fen; Chen, Xiao-ling; Wang, Cheng; Tan, Xu-ying; Wang, Li-jun; Zheng, Rui-dan; Zhang, Hong-wei; Ling, Wen-hua; Zhu, Hui-lian

    2016-01-01

    Many studies suggest that trimethylamine-N-oxide (TMAO), a gut-flora-dependent metabolite of choline, contributes to the risk of cardiovascular diseases, but little is known for non-alcoholic fatty liver disease (NAFLD). We examined the association of circulating TMAO, choline and betaine with the presence and severity of NAFLD in Chinese adults. We performed a hospital-based case-control study (CCS) and a cross-sectional study (CSS). In the CCS, we recruited 60 biopsy-proven NAFLD cases and 35 controls (18–60 years) and determined serum concentrations of TMAO, choline and betaine by HPLC-MS/MS. For the CSS, 1,628 community-based adults (40-75 years) completed the blood tests and ultrasonographic NAFLD evaluation. In the CCS, analyses of covariance showed adverse associations of ln-transformed serum levels of TMAO, choline and betaine/choline ratio with the scores of steatosis and total NAFLD activity (NAS) (all P-trend <0.05). The CSS revealed that a greater severity of NAFLD was independently correlated with higher TMAO but lower betaine and betaine/choline ratio (all P-trend <0.05). No significant choline-NAFLD association was observed. Our findings showed adverse associations between the circulating TMAO level and the presence and severity of NAFLD in hospital- and community-based Chinese adults, and a favorable betaine-NAFLD relationship in the community-based participants. PMID:26743949

  5. Evaluation of the comparative efficacy of a moxidectin plus triclabendazole pour-on solution against adult and immature liver fluke, Fasciola hepatica, in cattle.

    PubMed

    Geurden, Thomas; Bartram, David; Van Brussel, Leen; Bo, Liu; Scott-Baird, Emer; Rugg, Douglas

    2012-10-26

    The objective of this study was to evaluate the efficacy of a pour-on solution containing moxidectin plus triclabendazole (MOX plus TCBZ) against immature and adult stages of the liver fluke in cattle and compare the efficacy with other commercially available preparations. To this end, 104 male Holstein-Friesian calves aged between 3 and 4 months, were randomly allocated to 13 groups of eight animals each, and infected with approximately 500 Fasciola hepatica metacercariae. One group remained untreated, four groups were treated with MOX plus TCBZ at a dose rate of 0.1 mL/kg, four other groups were treated with ivermectin (IVM) plus clorsulon injectable at a dose rate of 0.02 mL/kg, and the remaining four groups were treated with IVM plus closantel pour-on at a dose rate of 0.1 mL/kg. Each treatment was applied to one of the groups at 4 weeks, 6 weeks, 8 weeks and 12 weeks after the experimental infection. At necropsy (99-102 days after infection), all untreated animals were infected with a minimum of 30 flukes. The MOX plus TCBZ treated animals had significantly (P<0.0001) lower fluke counts compared to the untreated control animals at all time points after treatment. Efficacy against 8-week old and adult flukes was >99.5%. For 6-week old immature fluke, the efficacy was 98.0% and for 4-week old immature fluke the efficacy was 90.9%. The IVM plus closantel pour-on treated animals had significantly lower fluke counts compared to the untreated control animals for adult and 8-week old flukes (P<0.0001), and for 6-week old flukes (P=0.002). The efficacy was 26.8%, 68.2%, 90.6% and 99.3% against 4-week, 6-week and 8-week old immature flukes, and adult flukes respectively. The IVM plus clorsulon treated animals had significantly lower fluke counts compared to the untreated control animals for adult (P<0.0001) and 8-week old (P<0.05) flukes. The efficacy was 29.7%, 43.4%, 53.2% and 99.2% against 4-week, 6-week and 8-week old immature flukes, and adult flukes respectively

  6. MicroRNA-194 Regulates Hepatocytic Differentiation of Progenitor Cells by Targeting YAP1

    PubMed Central

    Jung, Kwang Hwa; McCarthy, Ryan L.; Zhou, Chong; Uprety, Nadima; Barton, Michelle Craig; Beretta, Laura

    2015-01-01

    MicroRNA expression profiling in human liver progenitor cells following hepatocytic differentiation identified miR-122 and miR-194 as the microRNAs most strongly upregulated during hepatocytic differentiation of progenitor cells. MiR-194 was also highly upregulated following hepatocytic differentiation of human embryonic stem cells (hESCs). Overexpression of miR-194 in progenitor cells accelerated their differentiation into hepatocytes, as measured by morphological features such as canaliculi and expression of hepatocytic markers. Overexpression of miR-194 in hESCs induced their spontaneous differentiation, a phenotype accompanied with accelerated loss of the pluripotent factors OCT4 and NANOG and decrease in mesoderm marker HAND1 expression. We then identified YAP1 as a direct target of miR-194. Inhibition of YAP1 strongly induced hepatocytic differentiation of progenitor cells and YAP1 over expression reversed the miR-194-induced hepatocytic differentiation of progenitor cells. In conclusion, we identified miR-194 as a potent inducer of hepatocytic differentiation of progenitor cells and further identified YAP1 as a mediator of miR-194's effects on hepatocytic differentiation and liver progenitor cell fate. PMID:26731713

  7. Stem/Progenitor Cell Niches Involved in Hepatic and Biliary Regeneration

    PubMed Central

    Carpino, Guido; Renzi, Anastasia; Franchitto, Antonio; Cardinale, Vincenzo; Onori, Paolo; Reid, Lola; Alvaro, Domenico; Gaudio, Eugenio

    2016-01-01

    Niches containing stem/progenitor cells are present in different anatomical locations along the human biliary tree and within liver acini. The most primitive stem/progenitors, biliary tree stem/progenitor cells (BTSCs), reside within peribiliary glands located throughout large extrahepatic and intrahepatic bile ducts. BTSCs are multipotent and can differentiate towards hepatic and pancreatic cell fates. These niches' matrix chemistry and other characteristics are undefined. Canals of Hering (bile ductules) are found periportally and contain hepatic stem/progenitor cells (HpSCs), participating in the renewal of small intrahepatic bile ducts and being precursors to hepatocytes and cholangiocytes. The niches also contain precursors to hepatic stellate cells and endothelia, macrophages, and have a matrix chemistry rich in hyaluronans, minimally sulfated proteoglycans, fetal collagens, and laminin. The microenvironment furnishes key signals driving HpSC activation and differentiation. Newly discovered third niches are pericentral within hepatic acini, contain Axin2+ unipotent hepatocytic progenitors linked on their lateral borders to endothelia forming the central vein, and contribute to normal turnover of mature hepatocytes. Their relationship to the other stem/progenitors is undefined. Stem/progenitor niches have important implications in regenerative medicine for the liver and biliary tree and in pathogenic processes leading to diseases of these tissues. PMID:26880956

  8. Characterization of interstitial Cajal progenitors cells and their changes in Hirschsprung's disease.

    PubMed

    Chen, Zhi-Hua; Zhang, Yong-Chang; Jiang, Wei-Fang; Yang, Cissy; Zou, Gang-Ming; Kong, Yu; Cai, Wei

    2014-01-01

    Interstitial cells of Cajal (ICC) are critical to gastrointestinal motility. The phenotypes of ICC progenitors have been observed in the mouse gut, but whether they exist in the human colon and what abnormal changes in their quantity and ultrastructure are present in Hirschsprung's disease (HSCR) colon remains uncertain. In this study, we collected the surgical resection of colons, both proximal and narrow segments, from HSCR patients and normal controls. First, we identified the progenitor of ICC in normal adult colon using immunofluorescent localization techniques with laser confocal microscopy. Next, the progenitors were sorted to observe their morphology. We further applied flow cytometry to examine the content of ICC progenitors in these fresh samples. The ultrastructural changes in the narrow and proximal parts of the HSCR colon were observed using transmission electron microscopy (TEM) and were compared with the normal adult colon. The presumed early progenitor (c-Kit(low)CD34(+)Igf1r(+)) and committed progenitor (c-Kit(+)CD34(+)Igf1r(+)) of ICC exist in adult normal colon as well as in the narrow and proximal parts of the HSCR colon. However, the proportions of mature, early and committed progenitors of ICC were dramatically reduced in the narrow segment of the HSCR colon. The proportions of mature and committed progenitors of ICC in the proximal segment of the HSCR colon were lower than in the adult normal colon. Ultrastructurally, ICC, enteric nerves, and smooth muscle in the narrow segment of the HSCR colon showed severe injury, including swollen vacuola or ted mitochondria, disappearance of mitochondrial cristae, dilated rough endoplasmic reticulum, vesiculation and degranulation, and disappearance of the caveolae on the ICC membrane surface. The contents of ICC and its progenitors in the narrow part of the HSCR colon were significantly decreased than those of adult colon, which may be associated with HSCR pathogenesis. PMID:24475076

  9. 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

  10. Fibrosing Cholestatic Hepatitis in a Complicated Case of an Adult Recipient After Liver Transplantation: Diagnostic Findings and Therapeutic Dilemma.

    PubMed

    Hori, Tomohide; Onishi, Yasuharu; Kamei, Hideya; Kurata, Nobuhiko; Ishigami, Masatoshi; Ishizu, Yoji; Ogura, Yasuhiro

    2016-01-01

    BACKGROUND Hepatitis C recurrence is a serious matter after liver transplantation (LT). Approximately 10% of hepatitis C virus (HCV) positive recipients develop fibrosing cholestatic hepatitis (FCH). FCH rapidly results in graft loss. Currently, direct-acting antivirals (DAAs) are effective and safe for hepatitis C, even after LT. However, only a few cases of successfully treated FCH after LT have been reported. We present FCH in a complicated case with sepsis and portal flow obstruction after LT. CASE REPORT A 66-year-old man underwent cadaveric LT. Liver function disorders were observed from post-operative day (POD) 22. Sepsis repeated on POD 38, 74, and 101. Steroid pulse therapy was given from POD 40 to 54. The infectious focus was surgically removed on POD 89. Interventional radiology for portal venous obstruction was completed on POD 96. To make a real-time diagnosis and to investigate the graft condition, repeat liver needle biopsies (LNBs) were taken. Although there was a combined impact of sepsis, portal flow decrease, and recurrent hepatitis C on graft failure, it was interesting that recurrent hepatitis C was consistently detectable from the first LNB. HCV-ribonucleic acid increased on POD 68. Liver function disorders peaked on POD 71 and 72. Jaundice peaked on POD 82. DAA induction was regrettably delayed because of a reluctance to introduce DAAs under conditions of graft dysfunction. DAAs were administered after hospital discharge. CONCLUSIONS A real-time and precise diagnosis based on histopathological examination and viral measurement is important for FCH treatment. Well-considered therapy with DAAs should be aggressively introduced for potentially fatal FCH after LT. PMID:27545580

  11. Liver Cancer

    MedlinePlus

    ... body digest food, store energy, and remove poisons. Primary liver cancer starts in the liver. Metastatic liver ... and spreads to your liver. Risk factors for primary liver cancer include Having hepatitis B or C ...

  12. Liver scan

    MedlinePlus

    ... hyperplasia or adenoma of the liver Abscess Budd-Chiari syndrome Infection Liver disease (such as cirrhosis or ... Amebic liver abscess Cirrhosis Hepatic vein obstruction (Budd-Chiari) Hepatitis Liver cancer - hepatocellular carcinoma Liver disease Splenic ...

  13. The Pathology of Acute Liver Failure.

    PubMed

    Lefkowitch, Jay H

    2016-05-01

    Acute liver failure (ALF) is a rare and severe liver disease that usually develops in 8 weeks or less in individuals without preexisting liver disease. Its chief causes worldwide are hepatitis virus infections (hepatitis A, B, and E) and drug hepatotoxicity (particularly intentional or unintentional acetaminophen toxicity). Massive hepatic necrosis is often seen in liver specimens in ALF and features marked loss of hepatocytes, variable degrees of inflammation, and a stereotypic proliferation of bile ductular structures (neocholangioles) derived from activated periportal hepatic progenitor cells. This paper reviews the liver pathology in ALF, including forms of zonal necrosis and their etiologies. PMID:27058243

  14. Macrophage colony-stimulating factor receptor marks and regulates a fetal myeloid-primed B-cell progenitor in mice

    PubMed Central

    Zriwil, Alya; Böiers, Charlotta; Wittmann, Lilian; Green, Joanna C. A.; Woll, Petter S.; Jacobsen, Sten Eirik W.

    2016-01-01

    Although it is well established that unique B-cell lineages develop through distinct regulatory mechanisms during embryonic development, much less is understood about the differences between embryonic and adult B-cell progenitor cells, likely to underpin the genetics and biology of infant and childhood PreB acute lymphoblastic leukemia (PreB-ALL), initiated by distinct leukemia-initiating translocations during embryonic development. Herein, we establish that a distinct subset of the earliest CD19+ B-cell progenitors emerging in the E13.5 mouse fetal liver express the colony-stimulating factor-1 receptor (CSF1R), previously thought to be expressed, and play a lineage-restricted role in development of myeloid lineages, and macrophages in particular. These early embryonic CSF1R+CD19+ ProB cells also express multiple other myeloid genes and, in line with this, possess residual myeloid as well as B-cell, but not T-cell lineage potential. Notably, these CSF1R+ myeloid-primed ProB cells are uniquely present in a narrow window of embryonic fetal liver hematopoiesis and do not persist in adult bone marrow. Moreover, analysis of CSF1R-deficient mice establishes a distinct role of CSF1R in fetal B-lymphopoiesis. CSF1R+ myeloid-primed embryonic ProB cells are relevant for infant and childhood PreB-ALLs, which frequently have a bi-phenotypic B-myeloid phenotype, and in which CSF1R-rearrangements have recently been reported. PMID:27207794

  15. Macrophage colony-stimulating factor receptor marks and regulates a fetal myeloid-primed B-cell progenitor in mice.

    PubMed

    Zriwil, Alya; Böiers, Charlotta; Wittmann, Lilian; Green, Joanna C A; Woll, Petter S; Jacobsen, Sten Eirik W; Sitnicka, Ewa

    2016-07-14

    Although it is well established that unique B-cell lineages develop through distinct regulatory mechanisms during embryonic development, much less is understood about the differences between embryonic and adult B-cell progenitor cells, likely to underpin the genetics and biology of infant and childhood PreB acute lymphoblastic leukemia (PreB-ALL), initiated by distinct leukemia-initiating translocations during embryonic development. Herein, we establish that a distinct subset of the earliest CD19(+) B-cell progenitors emerging in the E13.5 mouse fetal liver express the colony-stimulating factor-1 receptor (CSF1R), previously thought to be expressed, and play a lineage-restricted role in development of myeloid lineages, and macrophages in particular. These early embryonic CSF1R(+)CD19(+) ProB cells also express multiple other myeloid genes and, in line with this, possess residual myeloid as well as B-cell, but not T-cell lineage potential. Notably, these CSF1R(+) myeloid-primed ProB cells are uniquely present in a narrow window of embryonic fetal liver hematopoiesis and do not persist in adult bone marrow. Moreover, analysis of CSF1R-deficient mice establishes a distinct role of CSF1R in fetal B-lymphopoiesis. CSF1R(+) myeloid-primed embryonic ProB cells are relevant for infant and childhood PreB-ALLs, which frequently have a bi-phenotypic B-myeloid phenotype, and in which CSF1R-rearrangements have recently been reported. PMID:27207794

  16. MRI With Gadoxetate Disodium in Measuring Tumors in Patients With Liver Cancer

    ClinicalTrials.gov

    2015-10-14

    Adult Hepatocellular Carcinoma; Advanced Adult Hepatocellular Carcinoma; BCLC Stage 0 Adult Hepatocellular Carcinoma; BCLC Stage A Adult Hepatocellular Carcinoma; BCLC Stage B Adult Hepatocellular Carcinoma; BCLC Stage C Adult Hepatocellular Carcinoma; BCLC Stage D Adult Hepatocellular Carcinoma; Localized Non-Resectable Adult Liver Carcinoma; Localized Resectable Adult Liver Carcinoma

  17. Identification of potential mechanisms of toxicity after di-(2-ethylhexyl)-phthalate (DEHP) adult exposure in the liver using a systems biology approach.

    PubMed

    Eveillard, Alexandre; Lasserre, Frédéric; de Tayrac, Marie; Polizzi, Arnaud; Claus, Sandrine; Canlet, Cécile; Mselli-Lakhal, Laïla; Gotardi, Gaëlle; Paris, Alain; Guillou, Hervé; Martin, Pascal G P; Pineau, Thierry

    2009-05-01

    Phthalates are industrial additives widely used as plasticizers. In addition to deleterious effects on male genital development, population studies have documented correlations between phthalates exposure and impacts on reproductive tract development and on the metabolic syndrome in male adults. In this work we investigated potential mechanisms underlying the impact of DEHP on adult mouse liver in vivo. A parallel analysis of hepatic transcript and metabolic profiles from adult mice exposed to varying DEHP doses was performed. Hepatic genes modulated by DEHP are predominantly PPARalpha targets. However, the induction of prototypic cytochrome P450 genes strongly supports the activation of additional NR pathways, including Constitutive Androstane Receptor (CAR). Integration of transcriptomic and metabonomic profiles revealed a correlation between the impacts of DEHP on genes and metabolites related to heme synthesis and to the Rev-erbalpha pathway that senses endogenous heme level. We further confirmed the combined impact of DEHP on the hepatic expression of Alas1, a critical enzyme in heme synthesis and on the expression of Rev-erbalpha target genes involved in the cellular clock and in energy metabolism. This work shows that DEHP interferes with hepatic CAR and Rev-erbalpha pathways which are both involved in the control of metabolism. The identification of these new hepatic pathways targeted by DEHP could contribute to metabolic and endocrine disruption associated with phthalate exposure. Gene expression profiles performed on microdissected testis territories displayed a differential responsiveness to DEHP. Altogether, this suggests that impacts of DEHP on adult organs, including testis, could be documented and deserve further investigations. PMID:19245819

  18. Identification of potential mechanisms of toxicity after di-(2-ethylhexyl)-phthalate (DEHP) adult exposure in the liver using a systems biology approach

    SciTech Connect

    Eveillard, Alexandre; Lasserre, Frederic; Tayrac, Marie de; Polizzi, Arnaud; Claus, Sandrine; Canlet, Cecile; Mselli-Lakhal, Laila; Gotardi, Gaelle; Paris, Alain; Guillou, Herve; Martin, Pascal G.P.; Pineau, Thierry

    2009-05-01

    Phthalates are industrial additives widely used as plasticizers. In addition to deleterious effects on male genital development, population studies have documented correlations between phthalates exposure and impacts on reproductive tract development and on the metabolic syndrome in male adults. In this work we investigated potential mechanisms underlying the impact of DEHP on adult mouse liver in vivo. A parallel analysis of hepatic transcript and metabolic profiles from adult mice exposed to varying DEHP doses was performed. Hepatic genes modulated by DEHP are predominantly PPAR{alpha} targets. However, the induction of prototypic cytochrome P450 genes strongly supports the activation of additional NR pathways, including Constitutive Androstane Receptor (CAR). Integration of transcriptomic and metabonomic profiles revealed a correlation between the impacts of DEHP on genes and metabolites related to heme synthesis and to the Rev-erb{alpha} pathway that senses endogenous heme level. We further confirmed the combined impact of DEHP on the hepatic expression of Alas1, a critical enzyme in heme synthesis and on the expression of Rev-erb{alpha} target genes involved in the cellular clock and in energy metabolism. This work shows that DEHP interferes with hepatic CAR and Rev-erb{alpha} pathways which are both involved in the control of metabolism. The identification of these new hepatic pathways targeted by DEHP could contribute to metabolic and endocrine disruption associated with phthalate exposure. Gene expression profiles performed on microdissected testis territories displayed a differential responsiveness to DEHP. Altogether, this suggests that impacts of DEHP on adult organs, including testis, could be documented and deserve further investigations.

  19. Effect of Potassium Bromate on the Liver of Adult Male Albino Rat and A Possible Protective Role of Vitamin C: Histological, Immunohistochemical, and Biochemical Study.

    PubMed

    Bayomy, Naglaa A; Soliman, Gehan M; Abdelaziz, Eman Z

    2016-09-01

    Potassium bromate (KBrO3 ) is a food additive which is used primarily as a maturing agent for flour. It is proved as a toxic agent with significant reduction in the activities of antioxidant capacity. The therapeutic efficacy of vitamin C as antioxidant may provide a possible solution to KBrO3 mediated oxidative damage. Twenty four adult male albino rats were used to evaluate the protective role of vitamin C against KBrO3 induced hepatotoxicity and divided into four groups; Group 1 (control), Group 2: received 30 mg/Kg/day vitamin C orally for 4 weeks, Group 3: received 20 mg/Kg/dose KBrO3 orally twice weekly for 4 weeks and Group 4: received both KBrO3 and vitamin C. Liver specimens were processed for histological study by light and electron microscopes and stained immunohistochemically to detect glial fibriller acidic protein (GFAP). Serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were estimated as well as the levels of malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD) activities in all dissected tissues were determined. KBrO3 induced histological alterations in the form of degeneration, cellular infiltration and significant increase in collagen deposition in portal tracts with a significant increase in immunoexpression of GFAP. Significant rise in serum levels of AST, ALT, and MDA in liver tissues were recorded. However, levels of GSH and SOD were significantly decreased. Most of these changes were improved by vitamin C treatment. In conclusion, vitamin C ameliorates the histological and biochemical alterations of the liver induced by KBrO3 . Anat Rec, 299:1256-1269, 2016. © 2016 Wiley Periodicals, Inc. PMID:27373450

  20. Yolk Sac Macrophages, Fetal Liver, and Adult Monocytes Can Colonize an Empty Niche and Develop into Functional Tissue-Resident Macrophages.

    PubMed

    van de Laar, Lianne; Saelens, Wouter; De Prijck, Sofie; Martens, Liesbet; Scott, Charlotte L; Van Isterdael, Gert; Hoffmann, Eik; Beyaert, Rudi; Saeys, Yvan; Lambrecht, Bart N; Guilliams, Martin

    2016-04-19

    Tissue-resident macrophages can derive from yolk sac macrophages (YS-Macs), fetal liver monocytes (FL-MOs), or adult bone-marrow monocytes (BM-MOs). The relative capacity of these precursors to colonize a niche, self-maintain, and perform tissue-specific functions is unknown. We simultaneously transferred traceable YS-Macs, FL-MOs, and BM-MOs into the empty alveolar macrophage (AM) niche of neonatal Csf2rb(-/-) mice. All subsets produced AMs, but in competition preferential outgrowth of FL-MOs was observed, correlating with their superior granulocyte macrophage-colony stimulating factor (GM-CSF) reactivity and proliferation capacity. When transferred separately, however, all precursors efficiently colonized the alveolar niche and generated AMs that were transcriptionally almost identical, self-maintained, and durably prevented alveolar proteinosis. Mature liver, peritoneal, or colon macrophages could not efficiently colonize the empty AM niche, whereas mature AMs could. Thus, precursor origin does not affect the development of functional self-maintaining tissue-resident macrophages and the plasticity of the mononuclear phagocyte system is largest at the precursor stage. PMID:26992565

  1. Maneb disturbs expression of superoxide dismutase and glutathione peroxidase, increases reactive oxygen species production, and induces genotoxicity in liver of adult mice.

    PubMed

    Ben Amara, Ibtissem; Ben Saad, Hajer; Hamdaoui, Latifa; Karray, Aida; Boudawara, Tahia; Ben Ali, Yassine; Zeghal, Najiba

    2015-08-01

    Maneb (MB), a fungicide largely used in agriculture throughout the world including Tunisia, protects many vegetables, fruits and field crops against a wide spectrum of fungal diseases. However there is a lack of informations regarding the risks arising from MB exposure on non target organisms, especially mammals. The aim of this study was to investigate the morphological, biochemical and molecular aspects of liver injury after exposure of mice to MB. Four doses of MB corresponding to 1/8 (group D1), 1/6 (group D2), 1/4 (group D3), and 1/2 (group D4) of lethal dose (DL50 = 1500 mg/kg body weight) were administered to adult mice. Oxidative stress parameters were also objectified by molecular and histological endpoints in the liver. Maneb caused hepatotoxicity as characterized by the significant increase in the levels of malondialdehyde and protein oxidation marker, advanced oxidation protein products (AOPP). The activities of catalase, glutathione peroxidase, superoxide dismutase and the levels of glutathione decreased significantly in all treated mice, while vitamin C levels decreased only in group D4. We also noted a significant decrease in gene expression of superoxide dismutase and glutathione peroxidase enzymes. Maneb caused nucleic acids degradation testifying its genotoxicity. Yet, biochemical markers in plasma showed a decrease in total protein and an increase in aspartate, alanine amino transferases and bilirubin levels in all treatment groups. Moreover, plasma levels of cholesterol, triglycerides and low density lipoprotein-cholesterol significantly increased, while those of high density lipoprotein-cholesterol decreased. These biochemical alterations were correlated with significantly histological changes. Our data showed, for the first time, that intraperitoneal injection of very high non environmentally relevant MB concentrations to adult mice resulted in oxidative stress leading to hepatotoxicity and the impairment of defense systems, confirming the

  2. Human Pluripotent Stem Cells for Modelling Human Liver Diseases and Cell Therapy

    PubMed Central

    Dianat, Noushin; Steichen, Clara; Vallier, Ludovic; Weber, Anne; Dubart-Kupperschmitt, Anne

    2013-01-01

    The liver is affected by many types of diseases, including metabolic disorders and acute liver failure. Orthotopic liver transplantation (OLT) is currently the only effective treatment for life-threatening liver diseases but transplantation of allogeneic hepatocytes has now become an alternative as it is less invasive than OLT and can be performed repeatedly. However, this approach is hampered by the shortage of organ donors, and the problems related to the isolation of high quality adult hepatocytes, their cryopreservation and their absence of proliferation in culture. Liver is also a key organ to assess the pharmacokinetics and toxicology of xenobiotics and for drug discovery, but appropriate cell culture systems are lacking. All these problems have highlighted the need to explore other sources of cells such as stem cells that could be isolated, expanded to yield sufficiently large populations and then induced to differentiate into functional hepatocytes. The presence of a niche of “facultative” progenitor and stem cells in the normal liver has recently been confirmed but they display no telomerase activity. The recent discovery that human induced pluripotent stem cells can be generated from somatic cells has renewed hopes for regenerative medicine and in vitro disease modelling, as these cells are easily accessible. We review here the present progresses, limits and challenges for the generation of functional hepatocytes from human pluripotent stem cells in view of their potential use in regenerative medicine and drug discovery. PMID:23444872

  3. Methanol exposure does not produce oxidatively damaged DNA in lung, liver or kidney of adult mice, rabbits or primates

    SciTech Connect

    McCallum, Gordon P.; Siu, Michelle; Sweeting, J. Nicole; Wells, Peter G.

    2011-01-15

    In vitro and in vivo genotoxicity tests indicate methanol (MeOH) is not mutagenic, but carcinogenic potential has been claimed in one controversial long-term rodent cancer bioassay that has not been replicated. To determine whether MeOH could indirectly damage DNA via reactive oxygen species (ROS)-mediated mechanisms, we treated male CD-1 mice, New Zealand white rabbits and cynomolgus monkeys with MeOH (2.0 g/kg ip) and 6 h later assessed oxidative damage to DNA, measured as 8-oxo-2'-deoxyguanosine (8-oxodG) by HPLC with electrochemical detection. We found no MeOH-dependent increases in 8-oxodG in lung, liver or kidney of any species. Chronic treatment of CD-1 mice with MeOH (2.0 g/kg ip) daily for 15 days also did not increase 8-oxodG levels in these organs. These results were corroborated in DNA repair-deficient oxoguanine glycosylase 1 (Ogg1) knockout (KO) mice, which accumulated 8-oxodG in lung, kidney and liver with age, but exhibited no increase following MeOH, despite a 2-fold increase in renal 8-oxodG in Ogg1 KO mice following treatment with a ROS-initiating positive control, the renal carcinogen potassium bromate (KBrO{sub 3}; 100 mg/kg ip). These observations suggest that MeOH exposure does not promote the accumulation of oxidatively damaged DNA in lung, kidney or liver, and that environmental exposure to MeOH is unlikely to initiate carcinogenesis in these organs by DNA oxidation.

  4. Isolation of adult human pluripotent stem cells from mesenchymal cell populations and their application to liver damages.

    PubMed

    Wakao, Shohei; Kitada, Masaaki; Kuroda, Yasumasa; Dezawa, Mari

    2012-01-01

    We have found a novel type of pluripotent stem cells, Multilineage-differentiating stress enduring (Muse) cells that can be isolated from mesenchymal cell populations. Muse cells are characterized by stress tolerance, expression of pluripotency markers, self-renewal, and the ability to differentiate into endodermal-, mesodermal-, and ectodermal-lineage cells from a single cell, demonstrating that they are pluripotent stem cells. They can be isolated as cells positive for stage-specific embryonic antigen-3, a human pluripotent stem cell marker. Here, we introduce the isolation method for Muse cells and the effect of transplantation of these cells on chronic liver diseases. PMID:22167642

  5. [Liver and artificial liver].

    PubMed

    Chamuleau, R A

    1998-06-01

    Despite good results of orthotopic liver transplantation in patients with fulminant hepatic failure the need still exists for an effective and safe artificial liver, able to temporarily take over the complex liver function so as to bridge the gap with transplantation or regeneration. Attempts to develop non-biological artificial livers have failed, mostly when controlled clinical trials were performed. In the last decade several different types of bioartificial livers have been devised, in which the biocomponent consists of freshly isolated porcine hepatocytes or a human hepatoblastoma cell line. The majority use semipermeable hollow fibers known from artificial kidney devices. The liver cells may lie either inside or outside the lumen of these fibers. In vitro analysis of liver function and animal experimental work showing that the bioartificial liver increases survival justify clinical application. Bioartificial livers are connected to patients extracorporeally by means of plasmapheresis circuit for periods of about 6 hours. In different trials about 40 patients with severe liver failure have been treated. No important adverse effects have not been reported in these phase I trials. Results of controlled studies are urgently needed. As long as no satisfactory immortalised human liver cell line with good function is available, porcine hepatocytes will remain the first choice, provided transmission of porcine pathogens to man is prevented. PMID:9752034

  6. Waist Gain Is Associated with a Higher Incidence of Nonalcoholic Fatty Liver Disease in Korean Adults: A Cohort Study

    PubMed Central

    Lim, Jisun; Park, Hye Soon; Chang, Yoosoo; Jung, Hyun-Suk; Kim, Chan-Won; Ko, Byung-Joon; Chung, Eun Chul; Shin, Hocheol; Ryu, Seungho

    2016-01-01

    Background We examined the relationship between changes in waist circumference (WC) and the incidence of nonalcoholic fatty liver disease (NAFLD). Methods A cohort study of 37,130 men and women were followed-up annually or biennially. Differences in WC between baseline and subsequent measurements were categorized in quartiles: first (WC loss), second (no change in WC as the reference), third and highest quartiles (WC gain). The presence of fatty liver was determined using ultrasound. Parametric Cox modeling was used to estimate the adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) of the incidence of NAFLD. Results During 127,324.4 person-years of follow-up, 6249 participants developed NAFLD. Despite adjusting for possible confounders, the risk of development of NAFLD increased with increasing quartiles of WC change in a dose-response manner (p for trend < 0.001). Compared with the reference, WC loss was associated with a lower risk of NAFLD (men: aHR 0.79 [95% CI: 0.73–0.87]; women: 0.72 [0.63–0.81]), and the highest quartile (WC gain) was associated with a higher risk of NAFLD (men: 1.30 [1.19–1.42]; women: 1.48 [1.31–1.67]). Conclusion Waist gain appears to increase the risk of developing NAFLD, independently of the baseline body mass index and WC. PMID:27420035

  7. Comparative effects of nodularin and microcystin-LR in zebrafish: 2. Uptake and molecular effects in eleuthero-embryos and adult liver with focus on endoplasmic reticulum stress.

    PubMed

    Faltermann, Susanne; Grundler, Verena; Gademann, Karl; Pernthaler, Jakob; Fent, Karl

    2016-02-01

    . In contrast to adult liver, MC-LR and nodularin did not result in detectable changes of mRNA levels of selected target genes involved in ER-stress in zebrafish eleuthero-embryos, nor was the abundance of transcripts belonging to the MAPK and pro-apoptosis pathways altered. In conclusion, our data indicate that MC-LR and nodularin have similar transcriptional effects. They lead to changes in mRNA levels of genes that suggest induction of ER-stress, and furthermore, lead to increased level of tnfα mRNA in the adult liver, which suggests a novel (transcriptional) mode of action in fish. However, although taken up by eleuthero-embryos, no transcriptional changes induced by these cyanobacterial toxins were detected. This is probably due to action to specific organs such as liver and kidneys that could not be identified by whole-embryo sampling. PMID:26748408

  8. DISTINCT PROGENITOR POPULATIONS IN SKELETAL MUSCLE ARE BONE MARROW DERIVED AND EXHIBIT DIFFERENT CELL FATES DURING VASCULAR REGENERATION

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Vascular progenitors were previously isolated from blood and bone marrow; herein, we define the presence, phenotype, potential, and origin of vascular progenitors resident within adult skeletal muscle. Two distinct populations of cells were simultaneously isolated from hindlimb muscle: the side popu...

  9. 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, both in theory and observations. It seems difficult to explain the emerging diversity seen in observations of SNe Ia by a single population, and we emphasize that it is important to clarify links between different progenitor scenarios and different sub-classes of SNe Ia.

  10. Diverse routes to liver regeneration.

    PubMed

    Alison, Malcolm R; Lin, Wey-Ran

    2016-02-01

    The liver's ability to regenerate is indisputable; for example, after a two-thirds partial hepatectomy in rats all residual hepatocytes can divide, questioning the need for a specific stem cell population. On the other hand, there is a potential stem cell compartment in the canals of Hering, giving rise to ductular reactions composed of hepatic progenitor cells (HPCs) when the liver's ability to regenerate is hindered by replicative senescence, but the functional relevance of this response has been questioned. Several papers have now clarified regenerative mechanisms operative in the mouse liver, suggesting that the liver is possibly unrivalled in its versatility to replace lost tissue. Under homeostatic conditions a perivenous population of clonogenic hepatocytes operates, whereas during chronic damage a minor population of periportal clonogenic hepatocytes come to the fore, while the ability of HPCs to completely replace the liver parenchyma has now been shown. PMID:26510495

  11. Differential Effects of Isoxazole-9 on Neural Stem/Progenitor Cells, Oligodendrocyte Precursor Cells, and Endothelial Progenitor Cells

    PubMed Central

    Maki, Takakuni; Shindo, Akihiro; Osumi, Noriko; Zhao, Jing; Lin, Hong; Holder, Julie C.; Chuang, Tsu Tshen; McNeish, John D.; Arai, Ken; Lo, Eng H.

    2015-01-01

    Adult mammalian brain can be plastic after injury and disease. Therefore, boosting endogenous repair mechanisms would be a useful therapeutic approach for neurological disorders. Isoxazole-9 (Isx-9) has been reported to enhance neurogenesis from neural stem/progenitor cells (NSPCs). However, the effects of Isx-9 on other types of progenitor/precursor cells remain mostly unknown. In this study, we investigated the effects of Isx-9 on the three major populations of progenitor/precursor cells in brain: NSPCs, oligodendrocyte precursor cells (OPCs), and endothelial progenitor cells (EPCs). Cultured primary NSPCs, OPCs, or EPCs were treated with various concentrations of Isx-9 (6.25, 12.5, 25, 50 μM), and their cell numbers were counted in a blinded manner. Isx-9 slightly increased the number of NSPCs and effectively induced neuronal differentiation of NSPCs. However, Isx-9 significantly decreased OPC number in a concentration-dependent manner, suggesting cytotoxicity. Isx-9 did not affect EPC cell number. But in a matrigel assay of angiogenesis, Isx-9 significantly inhibited tube formation in outgrowth endothelial cells derived from EPCs. This potential anti-tube-formation effect of Isx-9 was confirmed in a brain endothelial cell line. Taken together, our data suggest that mechanisms and targets for promoting stem/progenitor cells in the central nervous system may significantly differ between cell types. PMID:26407349

  12. Comparative Quantification of the Surfaceome of Human Multipotent Mesenchymal Progenitor Cells

    PubMed Central

    Holley, Rebecca J.; Tai, Guangping; Williamson, Andrew J.K.; Taylor, Samuel; Cain, Stuart A.; Richardson, Stephen M.; Merry, Catherine L.R.; Whetton, Anthony D.; Kielty, Cay M.; Canfield, Ann E.

    2015-01-01

    Summary Mesenchymal progenitor cells have great therapeutic potential, yet incomplete characterization of their cell-surface interface limits their clinical exploitation. We have employed subcellular fractionation with quantitative discovery proteomics to define the cell-surface interface proteome of human bone marrow mesenchymal stromal/stem cells (MSCs) and human umbilical cord perivascular cells (HUCPVCs). We compared cell-surface-enriched fractions from MSCs and HUCPVCs (three donors each) with adult mesenchymal fibroblasts using eight-channel isobaric-tagging mass spectrometry, yielding relative quantification on >6,000 proteins with high confidence. This approach identified 186 upregulated mesenchymal progenitor biomarkers. Validation of 10 of these markers, including ROR2, EPHA2, and PLXNA2, confirmed upregulated expression in mesenchymal progenitor populations and distinct roles in progenitor cell proliferation, migration, and differentiation. Our approach has delivered a cell-surface proteome repository that now enables improved selection and characterization of human mesenchymal progenitor populations. PMID:25684225

  13. Exploring the activated adipogenic niche: interactions of macrophages and adipocyte progenitors.

    PubMed

    Lee, Yun-Hee; Thacker, Robert I; Hall, Brian Eric; Kong, Raymond; Granneman, James G

    2014-01-01

    Adult adipose tissue contains a large supply of progenitors that can renew fat cells for homeostatic tissue maintenance and adaptive growth or regeneration in response to external challenges. However, the in vivo mechanisms that control adipocyte progenitor behavior are poorly characterized. We recently demonstrated that recruitment of adipocyte progenitors by macrophages is a central feature of adipose tissue remodeling under various adipogenic conditions. Catabolic remodeling of white adipose tissue by β3-adrenergic receptor stimulation requires anti-inflammatory M2-polarized macrophages to clear dying adipocytes and to recruit new brown adipocytes from progenitors. In this Extra Views article, we discuss in greater detail the cellular elements of adipogenic niches and report a strategy to isolate and characterize the subpopulations of macrophages and adipocyte progenitors that actively participate in adrenergic tissue remodeling. Further characterization of these subpopulations may facilitate identification of new cellular targets to improve metabolic and immune function of adipose tissue. PMID:24394850

  14. Progenitor Outgrowth from the Niche in Drosophila Trachea Is Guided by FGF from Decaying Branches

    PubMed Central

    Chen, Feng; Krasnow, Mark A.

    2014-01-01

    Although there has been progress identifying adult stem and progenitor cells and the signals that control their proliferation and differentiation, little is known about the substrates and signals that guide them out of their niche. By examining Drosophila tracheal outgrowth during metamorphosis, we show that progenitors follow a stereotyped path out of the niche, tracking along a subset of tracheal branches destined for destruction. The embryonic tracheal inducer branchless FGF (fibroblast growth factor) is expressed dynamically just ahead of progenitor outgrowth in decaying branches. Knockdown of branchless abrogates progenitor outgrowth, whereas misexpression redirects it. Thus, reactivation of an embryonic tracheal inducer in decaying branches directs outgrowth of progenitors that replace them. This explains how the structure of a newly generated tissue is coordinated with that of the old. PMID:24408434

  15. Generation and In Vitro Expansion of Hepatic Progenitor Cells from Human iPS Cells.

    PubMed

    Yanagida, Ayaka; Nakauchi, Hiromitsu; Kamiya, Akihide

    2016-01-01

    Stem cells have the unique properties of self-renewal and multipotency (producing progeny belonging to two or more lineages). Induced pluripotent stem (iPS) cells can be generated from somatic cells by simultaneous expression of pluripotent factors (Oct3/4, Klf4, Sox2, and c-Myc). They share the same properties as embryonic stem (ES) cells and can differentiate into several tissue cells, i.e., neurons, hematopoietic cells, and liver cells. Therefore, iPS cells are suitable candidate cells for regenerative medicine and analyses of disease mechanisms.The liver is the major organ that regulates a multitude of metabolic functions. Hepatocytes are the major cell type populating the liver parenchyma and express several metabolic enzymes that are necessary for liver functions. Although hepatocytes are essential for maintaining homeostasis, it is difficult to alter artificial and transplanted cells because of their multifunctionality, donor shortage, and immunorejection risk. During liver development, hepatic progenitor cells in the fetal liver differentiate into both mature hepatocytes and cholangiocytes. As hepatic progenitor cells have bipotency and high proliferation ability, they could present a potential source for generating transplantable cells or as a liver study model. Here we describe the induction and purification of hepatic progenitor cells derived from human iPS cells. These cells can proliferate for a long term under suitable culture conditions. PMID:25697415

  16. Fibrosis progression in human immunodeficiency virus/hepatitis C virus coinfected adults: Prospective analysis of 435 liver biopsy pairs

    PubMed Central

    Konerman, Monica A.; Mehta, Shruti H.; Sutcliffe, Catherine G.; Vu, Trang; Higgins, Yvonne; Torbenson, Michael S.; Moore, Richard D.; Thomas, David L.; Sulkowski, Mark S.

    2013-01-01

    Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection is associated with progressive liver disease. However, the rate of progression is variable and the ability to differentiate patients with stable versus progressive HCV disease is limited. The objective of this study was to assess the incidence of and risk factors for fibrosis progression in a prospective cohort of coinfected patients. Overall, 435 liver biopsy pairs from 282 non-cirrhotic patients were analyzed. Biopsies were scored according to the METAVIR system by a single pathologist blind to biopsy sequence. Fibrosis progression was defined as an increase of at least one METAVIR fibrosis stage between paired biopsies. The majority of patients were African American (84.8%), male (67.7%) and infected with HCV genotype 1 (93.4%). On initial biopsy, no or minimal fibrosis was identified in 243 patients (86%). The median interval between biopsies was 2.5 years. Fibrosis progression was observed in 97 of 282 (34%) patients and 149 of 435 (34%) biopsy pairs. After adjustment, greater body mass index (adjusted odds ratio [aOR]: 1.04 per 1 unit increase), diabetes (aOR: 1.56) and hepatic steatosis (aOR: 1.78) at time of initial biopsy were associated with subsequent fibrosis progression. Between biopsies, elevated serum aspartate and alanine aminotransferase (AST, ALT) (aOR AST: 3.34, ALT: 2.18 for >25% values >100 U/l vs. < 25% values >100 U/l) were strongly associated with fibrosis progression. Conclusion Fibrosis progression is common among HIV/HCV coinfected patients; these data suggest that progression can be rapid. Persistent elevations in serum transaminase levels may serve as important non-invasive markers to identify subsets of patients who are more likely to progress and thus warrant closer monitoring and consideration of HCV treatment. PMID:24436062

  17. Centroacinar Cells Are Progenitors That Contribute to Endocrine Pancreas Regeneration.

    PubMed

    Delaspre, Fabien; Beer, Rebecca L; Rovira, Meritxell; Huang, Wei; Wang, Guangliang; Gee, Stephen; Vitery, Maria del Carmen; Wheelan, Sarah J; Parsons, Michael J

    2015-10-01

    Diabetes is associated with a paucity of insulin-producing β-cells. With the goal of finding therapeutic routes to treat diabetes, we aim to find molecular and cellular mechanisms involved in β-cell neogenesis and regeneration. To facilitate discovery of such mechanisms, we use a vertebrate organism where pancreatic cells readily regenerate. The larval zebrafish pancreas contains Notch-responsive progenitors that during development give rise to adult ductal, endocrine, and centroacinar cells (CACs). Adult CACs are also Notch responsive and are morphologically similar to their larval predecessors. To test our hypothesis that adult CACs are also progenitors, we took two complementary approaches: 1) We established the transcriptome for adult CACs. Using gene ontology, transgenic lines, and in situ hybridization, we found that the CAC transcriptome is enriched for progenitor markers. 2) Using lineage tracing, we demonstrated that CACs do form new endocrine cells after β-cell ablation or partial pancreatectomy. We concluded that CACs and their larval predecessors are the same cell type and represent an opportune model to study both β-cell neogenesis and β-cell regeneration. Furthermore, we show that in cftr loss-of-function mutants, there is a deficiency of larval CACs, providing a possible explanation for pancreatic complications associated with cystic fibrosis. PMID:26153247

  18. Isolation and characterization of portal branch ligation-stimulated Hmga2-positive bipotent hepatic progenitor cells

    SciTech Connect

    Sakai, Hiroshi; Tagawa, Yoh-ichi; Tamai, Miho; Motoyama, Hiroaki; Ogawa, Shinichiro; Soeda, Junpei; Nakata, Takenari; Miyagawa, Shinichi

    2010-12-17

    Research highlights: {yields} Hepatic progenitor cells were isolated from the portal branch-ligated liver of mice. {yields} Portal branch ligation-stimulated hepatic progenitor cells (PBLHCs) express Hmga2. {yields} PBLHCs have bidirectional differentiation capability in vitro. -- Abstract: Hepatic stem/progenitor cells are one of several cell sources that show promise for restoration of liver mass and function. Although hepatic progenitor cells (HPCs), including oval cells, are induced by administration of certain hepatotoxins in experimental animals, such a strategy would be inappropriate in a clinical setting. Here, we investigated the possibility of isolating HPCs in a portal branch-ligated liver model without administration of any chemical agents. A non-parenchymal cell fraction was prepared from the portal branch-ligated or non-ligated lobe, and seeded onto plates coated with laminin. Most of the cells died, but a small number were able to proliferate. These proliferating cells were cloned as portal branch ligation-stimulated hepatic cells (PBLHCs) by the limiting dilution method. The PBLHCs expressed cytokeratin19, albumin, and Hmga2. The PBLHCs exhibited metabolic functions such as detoxification of ammonium ions and synthesis of urea on Matrigel-coated plates in the presence of oncostatin M. In Matrigel mixed with type I collagen, the PBLHCs became rearranged into cystic and tubular structures. Immunohistochemical staining demonstrated the presence of Hmga2-positive cells around the interlobular bile ducts in the portal branch-ligated liver lobes. In conclusion, successful isolation of bipotent hepatic progenitor cell clones, PBLHCs, from the portal branch-ligated liver lobes of mice provides the possibility of future clinical application of portal vein ligation to induce hepatic progenitor cells.

  19. Imaging in pediatric liver transplantation.

    PubMed

    Monti, L; Soglia, G; Tomà, P

    2016-05-01

    Liver transplantation has become an established curative treatment in adult patients with acute or chronic end-stage liver diseases. In pediatric cases the number of cadaveric donor livers is not sufficient and to overcome the shortage of appropriate-sized whole liver grafts, technical variants of liver transplantation have been practiced. Reduced-size cadaveric and split cadaveric allografts have become an important therapeutic option, expanding the availability of size-appropriate organs for pediatric recipients with terminal liver disease. The number of pediatric deaths awaiting liver transplantation has been reduced by the introduction of living-related liver transplantation, developed to overcome the shortage of suitable grafts for children. It is important for radiologists to know that children have distinct imaging of liver transplantation that distinguish them from adults. A multidisciplinary pediatric liver transplantation team should be skilled in pediatric conditions and in associated processes, risks and complications. Radiologists should know the common pediatric liver diseases that lead to liver transplantation, the anastomotic techniques and the expected postoperative imaging findings. The aim of this study is to illustrate the role of non-invasive imaging such us ultrasonography, color Doppler ultrasonography, multidetector computed tomography and magnetic resonance imaging in the evaluation of pediatric liver transplantation and in potential liver donors. PMID:26909515

  20. The effects of age and liver disease on the disposition and elimination of diazepam in adult man.

    PubMed Central

    Klotz, U; Avant, G R; Hoyumpa, A; Schenker, S; Wilkinson, G R

    1975-01-01

    This study investigates the separate effects of age and hepatocellular liver disease on the disposition and elimination of diazepam (Valium) in man. The drug was given either by rapid intravenous injection (0.1 mg/kg) or orally (10 mg) to 33 normal volunteers rnaging in age from 15 to 82 yr as well as to 9 individuals with alcoholic cirrhosis, 8 with acute viral hepatitis, and 4 with chronic active hepatitis. In the normal individuals, the terminal plasma half-life of diazepam, (t 1/2 (B)) exhibited a striking age-dependence; at 20 yr the t 1/2 (beta) was about 20 h, but it increased linearly with age to about 90 h at 80 yr. The plasma clearance of diazepam in the majority of the normal subjects was between 20 and 32 ml/min and showed no significant age-dependence. Cigarette smoking did not affect the half-life or the clearance. Additionally, neither the plasma binding (97.4 plus or minus 1.2%, mean plus or minus SD) nor the blood/plasma concentration ratio (0.58 plus or minus 0.16) of diazepam showed any age-related changes (P greater than 0.05). By contrast, analysis of the intravenous data according to a two-compartment open model indicated that both the initial distribution space (V1) and the volume of distribution at steady state [Vd(ss)] of diazepam increased linearly with age (P less than 0.005). The increase in Vd(ss) was secondary to the change in V1. It appears then that the prolongation of t 1/2 (beta) of diazepam with age is primarily dependent on an increase in the initial distribution volume of the drug. The plasma concentration/time course of the metabolite, desmethyldiazepam, was also affected by age. In older individuals, the initial presence and the peak values of desmethyldiazepam were observed later and the metabolite was present in lower concentrations. Despite the profound prolongation of t 1/2 (theta) with age, the constancy of diazepam clearance indicates that drug plasma concentrations will not accumulate any more in the old than the young

  1. Liver Facts

    MedlinePlus

    ... Home / Before The Transplant / Organ Facts / Liver Organ Facts Heart Lung Heart/Lung Kidney Pancreas Kidney/Pancreas Liver ... Receiving "the call" About the Operation Heart Lung Heart/Lung Kidney Pancreas Kidney/Pancreas Liver Intestine Liver Facts How the Liver Works The liver is one ...

  2. Hepatic stem cells: A viable approach for the treatment of liver cirrhosis

    PubMed Central

    Habeeb, Md Aejaz; Vishwakarma, Sandeep Kumar; Bardia, Avinash; Khan, Aleem Ahmed

    2015-01-01

    Liver cirrhosis is characterized by distortion of liver architecture, necrosis of hepatocytes and regenerative nodules formation leading to cirrhosis. Various types of cell sources have been used for the management and treatment of decompensated liver cirrhosis. Knowledge of stem cells has offered a new dimension for regenerative therapy and has been considered as one of the potential adjuvant treatment modality in patients with end stage liver diseases (ESLD). Human fetal hepatic progenitor cells are less immunogenic than adult ones. They are highly propagative and challenging to cryopreservation. In our earlier studies we have demonstrated that fetuses at 10-18 wk of gestation age contain a large number of actively dividing hepatic stem and progenitor cells which possess bi-potent nature having potential to differentiate into bile duct cells and mature hepatocytes. Hepatic stem cell therapy for the treatment of ESLD is in their early stage of the translation. The emerging technology of decellularization and recellularization might offer a significant platform for developing bioengineered personalized livers to come over the scarcity of desired number of donor organs for the treatment of ESLD. Despite these significant advancements long-term tracking of stem cells in human is the most important subject nowadays in order to answer several unsettles issues regarding the route of delivery, the choice of stem cell type(s), the cell number and the time-point of cell delivery for the treatment in a chronic setting. Answering to these questions will further contribute to the development of safer, noninvasive, and repeatable imaging modalities that could discover better cell therapeutic approaches from bench to bed-side. Combinatorial approach of decellularization and nanotechnology could pave a way towards the better understanding in determination of cell fate post-transplantation. PMID:26131316

  3. Hepatic stem cells: A viable approach for the treatment of liver cirrhosis.

    PubMed

    Habeeb, Md Aejaz; Vishwakarma, Sandeep Kumar; Bardia, Avinash; Khan, Aleem Ahmed

    2015-06-26

    Liver cirrhosis is characterized by distortion of liver architecture, necrosis of hepatocytes and regenerative nodules formation leading to cirrhosis. Various types of cell sources have been used for the management and treatment of decompensated liver cirrhosis. Knowledge of stem cells has offered a new dimension for regenerative therapy and has been considered as one of the potential adjuvant treatment modality in patients with end stage liver diseases (ESLD). Human fetal hepatic progenitor cells are less immunogenic than adult ones. They are highly propagative and challenging to cryopreservation. In our earlier studies we have demonstrated that fetuses at 10-18 wk of gestation age contain a large number of actively dividing hepatic stem and progenitor cells which possess bi-potent nature having potential to differentiate into bile duct cells and mature hepatocytes. Hepatic stem cell therapy for the treatment of ESLD is in their early stage of the translation. The emerging technology of decellularization and recellularization might offer a significant platform for developing bioengineered personalized livers to come over the scarcity of desired number of donor organs for the treatment of ESLD. Despite these significant advancements long-term tracking of stem cells in human is the most important subject nowadays in order to answer several unsettles issues regarding the route of delivery, the choice of stem cell type(s), the cell number and the time-point of cell delivery for the treatment in a chronic setting. Answering to these questions will further contribute to the development of safer, noninvasive, and repeatable imaging modalities that could discover better cell therapeutic approaches from bench to bed-side. Combinatorial approach of decellularization and nanotechnology could pave a way towards the better understanding in determination of cell fate post-transplantation. PMID:26131316

  4. Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment

    PubMed Central

    Mu, Xueru; Español-Suñer, Regina; Mederacke, Ingmar; Affò, Silvia; Manco, Rita; Sempoux, Christine; Lemaigre, Frédéric P.; Adili, Arlind; Yuan, Detian; Weber, Achim; Unger, Kristian; Heikenwälder, Mathias; Leclercq, Isabelle A.; Schwabe, Robert F.

    2015-01-01

    In many organs, including the intestine and skin, cancers originate from cells of the stem or progenitor compartment. Despite its nomenclature, the cellular origin of hepatocellular carcinoma (HCC) remains elusive. In contrast to most organs, the liver lacks a defined stem cell population for organ maintenance. Previous studies suggest that both hepatocytes and facultative progenitor cells within the biliary compartment are capable of generating HCC. As HCCs with a progenitor signature carry a worse prognosis, understanding the origin of HCC is of clinical relevance. Here, we used complementary fate-tracing approaches to label the progenitor/biliary compartment and hepatocytes in murine hepatocarcinogenesis. In genotoxic and genetic models, HCCs arose exclusively from hepatocytes but never from the progenitor/biliary compartment. Cytokeratin 19–, A6- and α-fetoprotein–positive cells within tumors were hepatocyte derived. In summary, hepatocytes represent the cell of origin for HCC in mice, and a progenitor signature does not reflect progenitor origin, but dedifferentiation of hepatocyte-derived tumor cells. PMID:26348897

  5. Comparative Analysis of AhR-Mediated TCDD-Elicited Gene Expression in Human Liver Adult Stem Cells

    PubMed Central

    Kim, Suntae; Dere, Edward; Burgoon, Lyle D.; Chang, Chia-Cheng; Zacharewski, Timothy R.

    2009-01-01

    Time course and dose-response studies were conducted in HL1-1 cells, a human liver cell line with stem cell–like characteristics, to assess the differential gene expression elicited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) compared with other established models. Cells were treated with 0.001, 0.01, 0.1, 1, 10, or 100nM TCDD or dimethyl sulfoxide vehicle control for 12 h for the dose-response study, or with 10nM TCDD or vehicle for 1, 2, 4, 8, 12, 24, or 48 h for the time course study. Elicited changes were monitored using a human cDNA microarray with 6995 represented genes. Empirical Bayes analysis identified 144 genes differentially expressed at one or more time points following treatment. Most genes exhibited dose-dependent responses including CYP1A1, CYP1B1, ALDH1A3, and SLC7A5 genes. Comparative analysis of HL1-1 differential gene expression to human HepG2 data id