Yu, Ling; Yan, Mingquan; Simkin, Jennifer; Ketcham, Paulina D.; Leininger, Eric; Han, Manjong
Abstract The regenerating mouse digit tip is a unique model for investigating blastema formation and epimorphic regeneration in mammals. The blastema is characteristically avascular and we previously reported that blastema expression of a known anti‐angiogenic factor gene, Pedf, correlated with a successful regenerative response (Yu, L., Han, M., Yan, M., Lee, E. C., Lee, J. & Muneoka, K. (2010). BMP signaling induces digit regeneration in neonatal mice. Development, 137, 551–559). Here we show that during regeneration Vegfa transcripts are not detected in the blastema but are expressed at the onset of differentiation. Treating the amputation wound with vascular endothelial growth factor enhances angiogenesis but inhibits regeneration. We next tested bone morphogenetic protein 9 (BMP9), another known mediator of angiogenesis, and found that BMP9 is also a potent inhibitor of digit tip regeneration. BMP9 induces Vegfa expression in the digit stump suggesting that regenerative failure is mediated by enhanced angiogenesis. Finally, we show that BMP9 inhibition of regeneration is completely rescued by treatment with pigment epithelium‐derived factor. These studies show that precocious angiogenesis is inhibitory for regeneration, and provide compelling evidence that the regulation of angiogenesis is a critical factor in designing therapies aimed at stimulating mammalian regeneration. PMID:27499862
Yu, Ling; Yan, Mingquan; Simkin, Jennifer; Ketcham, Paulina D; Leininger, Eric; Han, Manjong; Muneoka, Ken
The regenerating mouse digit tip is a unique model for investigating blastema formation and epimorphic regeneration in mammals. The blastema is characteristically avascular and we previously reported that blastema expression of a known anti-angiogenic factor gene, Pedf, correlated with a successful regenerative response (Yu, L., Han, M., Yan, M., Lee, E. C., Lee, J. & Muneoka, K. (2010). BMP signaling induces digit regeneration in neonatal mice. Development, 137, 551-559). Here we show that during regeneration Vegfa transcripts are not detected in the blastema but are expressed at the onset of differentiation. Treating the amputation wound with vascular endothelial growth factor enhances angiogenesis but inhibits regeneration. We next tested bone morphogenetic protein 9 (BMP9), another known mediator of angiogenesis, and found that BMP9 is also a potent inhibitor of digit tip regeneration. BMP9 induces Vegfa expression in the digit stump suggesting that regenerative failure is mediated by enhanced angiogenesis. Finally, we show that BMP9 inhibition of regeneration is completely rescued by treatment with pigment epithelium-derived factor. These studies show that precocious angiogenesis is inhibitory for regeneration, and provide compelling evidence that the regulation of angiogenesis is a critical factor in designing therapies aimed at stimulating mammalian regeneration.
Mu, Xiaodong; Bellayr, Ian; Pan, Haiying; Choi, Yohan; Li, Yong
The ratio of matrix metalloproteinases (MMPs) to the tissue inhibitors of metalloproteinases (TIMPs) in wounded tissues strictly control the protease activity of MMPs, and therefore regulate the progress of wound closure, tissue regeneration and scar formation. Some amphibians (i.e. axolotl/newt) demonstrate complete regeneration of missing or wounded digits and even limbs; MMPs play a critical role during amphibian regeneration. Conversely, mammalian wound healing re-establishes tissue integrity, but at the expense of scar tissue formation. The differences between amphibian regeneration and mammalian wound healing can be attributed to the greater ratio of MMPs to TIMPs in amphibian tissue. Previous studies have demonstrated the ability of MMP1 to effectively promote skeletal muscle regeneration by favoring extracellular matrix (ECM) remodeling to enhance cell proliferation and migration. In this study, MMP1 was administered to the digits amputated at the mid-second phalanx of adult mice to observe its effect on digit regeneration. Results indicated that the regeneration of soft tissue and the rate of wound closure were significantly improved by MMP1 administration, but the elongation of the skeletal tissue was insignificantly affected. During digit regeneration, more mutipotent progenitor cells, capillary vasculature and neuromuscular-related tissues were observed in MMP1 treated tissues; moreover, there was less fibrotic tissue formed in treated digits. In summary, MMP1 was found to be effective in promoting wound healing in amputated digits of adult mice.
Yu, Ling; Han, Manjong; Yan, Mingquan; Lee, Eun-Chee; Lee, Jangwoo; Muneoka, Ken
The regenerating digit tip of mice is a novel epimorphic response in mammals that is similar to fingertip regeneration in humans. Both display restricted regenerative capabilities that are amputation-level dependent. Using this endogenous regeneration model in neonatal mice, we have found that noggin treatment inhibits regeneration, thus suggesting a bone morphogenetic protein (BMP) requirement. Using non-regenerating amputation wounds, we show that BMP7 or BMP2 can induce a regenerative response. BMP-induced regeneration involves the formation of a mammalian digit blastema. Unlike the endogenous regeneration response that involves redifferentiation by direct ossification (evolved regeneration), the BMP-induced response involves endochondral ossification (redevelopment). Our evidence suggests that BMP treatment triggers a reprogramming event that re-initiates digit tip development at the amputation wound. These studies demonstrate for the first time that the postnatal mammalian digit has latent regenerative capabilities that can be induced by growth factor treatment.
Simkin, Jennifer; Han, Manjong; Yu, Ling; Yan, Mingquan; Muneoka, Ken
A challenge to the study of regeneration is determining at what point the processes of wound healing and regeneration diverge. The mouse displays level-specific regeneration responses. An amputation through the distal third of the terminal phalanx will prompt a regeneration response and result in a new digit tip that mimics the morphology of the lost digit tip. Conversely, an amputation through the distal third of the intermediate phalanx initiates a wound healing and scarring response. The mouse, therefore, provides a model for studying the transition between wound healing and regeneration in the same animal. This chapter details the methods used in the study of mammalian digit regeneration, including a method to introduce exogenous protein into the mouse digit amputation model via microcarrier beads and methods for analysis of bone regeneration.
Vlaskalin, Tatjana; Wong, Christine J; Tsilfidis, Catherine
Many of the genes involved in the initial development of the limb in higher vertebrates are also expressed during regeneration of the limb in urodeles such as Notophthalmus viridescens. These similarities have led researchers to conclude that the regeneration process is a recapitulation of development, and that patterning of the regenerate mimics pattern formation in development. However, the developing limb and the regenerating limb do not look similar. In developing urodele forelimbs, digits appear sequentially as outgrowths from the limb palette. In regeneration, all the digits appear at once. In this work, we address the issue of whether regeneration and development are similar by examining growth and apoptosis patterns. In contrast to higher vertebrates, forelimb development in the newt, N. viridescens, does not use interdigital apoptosis as the method of digit separation. During adult forelimb regeneration, apoptosis seems to play an important role in wound healing and again during cartilage to bone turnover in the advanced digits and radius/ulna. However, similar to forelimb development, demarcation of the digits in adult forelimb regeneration does not involve interdigital apoptosis. Outgrowth, rather than regression of the interdigital mesenchyme, leads to the individualization of forelimb digits in both newt development and regeneration.
Moss, Jennifer B.; Koustubhan, Punita; Greenman, Melanie; Parsons, Michael J.; Walter, Ingrid; Moss, Larry G.
OBJECTIVE Regenerating organs in diverse biological systems have provided clues to processes that can be harnessed to repair damaged tissue. Adult mammalian β-cells have a limited capacity to regenerate, resulting in diabetes and lifelong reliance on insulin. Zebrafish have been used as a model for the regeneration of many organs. We demonstrate the regeneration of adult zebrafish pancreatic β-cells. This nonmammalian model can be used to define pathways for islet-cell regeneration in humans. RESEARCH DESIGN AND METHODS Adult transgenic zebrafish were injected with a single high dose of streptozotocin or metronidazole and anesthetized at 3, 7, or 14 days or pancreatectomized. Blood glucose measurements were determined and gut sections were analyzed using specific endocrine, exocrine, and duct cell markers as well as markers for dividing cells. RESULTS Zebrafish recovered rapidly without the need for insulin injections, and normoglycemia was attained within 2 weeks. Although few proliferating cells were present in vehicles, ablation caused islet destruction and a striking increase of proliferating cells, some of which were Pdx1 positive. Dividing cells were primarily associated with affected islets and ducts but, with the exception of surgical partial pancreatectomy, were not extensively β-cells. CONCLUSIONS The ability of the zebrafish to regenerate a functional pancreas using chemical, genetic, and surgical approaches enabled us to identify patterns of cell proliferation in islets and ducts. Further study of the origin and contribution of proliferating cells in reestablishing islet function could provide strategies for treating human diseases. PMID:19491207
Sammarco, Mimi C.; Simkin, Jennifer; Cammack, Alexander J.; Fassler, Danielle; Gossmann, Alexej; Marrero, Luis; Lacey, Michelle; Van Meter, Keith; Muneoka, Ken
Oxygen is critical for optimal bone regeneration. While axolotls and salamanders have retained the ability to regenerate whole limbs, mammalian regeneration is restricted to the distal tip of the digit (P3) in mice, primates, and humans. Our previous study revealed the oxygen microenvironment during regeneration is dynamic and temporally influential in building and degrading bone. Given that regeneration is dependent on a dynamic and changing oxygen environment, a better understanding of the effects of oxygen during wounding, scarring, and regeneration, and better ways to artificially generate both hypoxic and oxygen replete microenvironments are essential to promote regeneration beyond wounding or scarring. To explore the influence of increased oxygen on digit regeneration in vivo daily treatments of hyperbaric oxygen were administered to mice during all phases of the entire regenerative process. Micro-Computed Tomography (μCT) and histological analysis showed that the daily application of hyperbaric oxygen elicited the same enhanced bone degradation response as two individual pulses of oxygen applied during the blastema phase. We expand past these findings to show histologically that the continuous application of hyperbaric oxygen during digit regeneration results in delayed blastema formation at a much more proximal location after amputation, and the deposition of better organized collagen fibers during bone formation. The application of sustained hyperbaric oxygen also delays wound closure and enhances bone degradation after digit amputation. Thus, hyperbaric oxygen shows the potential for positive influential control on the various phases of an epimorphic regenerative response. PMID:26452224
Sammarco, Mimi C; Simkin, Jennifer; Cammack, Alexander J; Fassler, Danielle; Gossmann, Alexej; Marrero, Luis; Lacey, Michelle; Van Meter, Keith; Muneoka, Ken
Oxygen is critical for optimal bone regeneration. While axolotls and salamanders have retained the ability to regenerate whole limbs, mammalian regeneration is restricted to the distal tip of the digit (P3) in mice, primates, and humans. Our previous study revealed the oxygen microenvironment during regeneration is dynamic and temporally influential in building and degrading bone. Given that regeneration is dependent on a dynamic and changing oxygen environment, a better understanding of the effects of oxygen during wounding, scarring, and regeneration, and better ways to artificially generate both hypoxic and oxygen replete microenvironments are essential to promote regeneration beyond wounding or scarring. To explore the influence of increased oxygen on digit regeneration in vivo daily treatments of hyperbaric oxygen were administered to mice during all phases of the entire regenerative process. Micro-Computed Tomography (μCT) and histological analysis showed that the daily application of hyperbaric oxygen elicited the same enhanced bone degradation response as two individual pulses of oxygen applied during the blastema phase. We expand past these findings to show histologically that the continuous application of hyperbaric oxygen during digit regeneration results in delayed blastema formation at a much more proximal location after amputation, and the deposition of better organized collagen fibers during bone formation. The application of sustained hyperbaric oxygen also delays wound closure and enhances bone degradation after digit amputation. Thus, hyperbaric oxygen shows the potential for positive influential control on the various phases of an epimorphic regenerative response.
Agrawal, Vineet; Johnson, Scott A; Reing, Janet; Zhang, Li; Tottey, Stephen; Wang, Gang; Hirschi, Karen K; Braunhut, Susan; Gudas, Lorraine J; Badylak, Stephen F
Urodeles and fetal mammals are capable of impressive epimorphic regeneration in a variety of tissues, whereas the typical default response to injury in adult mammals consists of inflammation and scar tissue formation. One component of epimorphic regeneration is the recruitment of resident progenitor and stem cells to a site of injury. Bioactive molecules resulting from degradation of extracellular matrix (ECM) have been shown to recruit a variety of progenitor and stem cells in vitro in adult mammals. The ability to recruit multipotential cells to the site of injury by in vivo administration of chemotactic ECM degradation products in a mammalian model of digit amputation was investigated in the present study. Adult, 6- to 8-week-old C57/BL6 mice were subjected to midsecond phalanx amputation of the third digit of the right hind foot and either treated with chemotactic ECM degradation products or left untreated. At 14 days after amputation, mice treated with ECM degradation products showed an accumulation of heterogeneous cells that expressed markers of multipotency, including Sox2, Sca1, and Rex1 (Zfp42). Cells isolated from the site of amputation were capable of differentiation along neuroectodermal and mesodermal lineages, whereas cells isolated from control mice were capable of differentiation along only mesodermal lineages. The present findings demonstrate the recruitment of endogenous stem cells to a site of injury, and/or their generation/proliferation therein, in response to ECM degradation products.
Nakada, Yuji; Canseco, Diana C; Thet, SuWannee; Abdisalaam, Salim; Asaithamby, Aroumougame; Santos, Celio X; Shah, Ajay M; Zhang, Hua; Faber, James E; Kinter, Michael T; Szweda, Luke I; Xing, Chao; Hu, Zeping; Deberardinis, Ralph J; Schiattarella, Gabriele; Hill, Joseph A; Oz, Orhan; Lu, Zhigang; Zhang, Cheng Cheng; Kimura, Wataru; Sadek, Hesham A
The adult mammalian heart is incapable of regeneration following cardiomyocyte loss, which underpins the lasting and severe effects of cardiomyopathy. Recently, it has become clear that the mammalian heart is not a post-mitotic organ. For example, the neonatal heart is capable of regenerating lost myocardium, and the adult heart is capable of modest self-renewal. In both of these scenarios, cardiomyocyte renewal occurs via the proliferation of pre-existing cardiomyocytes, and is regulated by aerobic-respiration-mediated oxidative DNA damage. Therefore, we reasoned that inhibiting aerobic respiration by inducing systemic hypoxaemia would alleviate oxidative DNA damage, thereby inducing cardiomyocyte proliferation in adult mammals. Here we report that, in mice, gradual exposure to severe systemic hypoxaemia, in which inspired oxygen is gradually decreased by 1% and maintained at 7% for 2 weeks, results in inhibition of oxidative metabolism, decreased reactive oxygen species production and oxidative DNA damage, and reactivation of cardiomyocyte mitosis. Notably, we find that exposure to hypoxaemia 1 week after induction of myocardial infarction induces a robust regenerative response with decreased myocardial fibrosis and improvement of left ventricular systolic function. Genetic fate-mapping analysis confirms that the newly formed myocardium is derived from pre-existing cardiomyocytes. These results demonstrate that the endogenous regenerative properties of the adult mammalian heart can be reactivated by exposure to gradual systemic hypoxaemia, and highlight the potential therapeutic role of hypoxia in regenerative medicine.
Ghosh, Sukla; Hui, Subhra Prakash
Regeneration in the animal kingdom is one of the most fascinating problems that have allowed scientists to address many issues of fundamental importance in basic biology. However, we came to know that the regenerative capability may vary across different species. Among vertebrates, fish and amphibians are capable of regenerating a variety of complex organs through epimorphosis. Zebrafish is an excellent animal model, which can repair several organs like damaged retina, severed spinal cord, injured brain and heart, and amputated fins. The focus of the present paper is on spinal cord regeneration in adult zebrafish. We intend to discuss our current understanding of the cellular and molecular mechanism(s) that allows formation of proliferating progenitors and controls neurogenesis, which involve changes in epigenetic and transcription programs. Unlike mammals, zebrafish retains radial glia, a nonneuronal cell type in their adult central nervous system. Injury induced proliferation involves radial glia which proliferate, transcribe embryonic genes, and can give rise to new neurons. Recent technological development of exquisite molecular tools in zebrafish, such as cell ablation, lineage analysis, and novel and substantial microarray, together with advancement in stem cell biology, allowed us to investigate how progenitor cells contribute to the generation of appropriate structures and various underlying mechanisms like reprogramming. PMID:27382491
Zhang, Yong; Strehin, Iossif; Bedelbaeva, Khamilia; Gourevitch, Dmitri; Clark, Lise; Leferovich, John; Messersmith, Phillip B.; Heber-Katz, Ellen
Whereas amphibians regenerate lost appendages spontaneously, mammals generally form scars over the injury site through the process of wound repair. The MRL mouse strain is an exception among mammals because it shows a spontaneous regenerative healing trait and so can be used to investigate proregenerative interventions in mammals. We report that hypoxia-inducible factor 1α (HIF-1α) is a central molecule in the process of regeneration in adult MRL mice. The degradation of HIF-1α protein, which occurs under normoxic conditions, is mediated by prolyl hydroxylases (PHDs). We used the drug 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (1,4-DPCA), a PHD inhibitor, to stabilize constitutive expression of HIF-1α protein. A locally injectable hydrogel containing 1,4-DPCA was designed to achieve controlled delivery of the drug over 4 to 10 days. Subcutaneous injection of the 1,4-DPCA/hydrogel into Swiss Webster mice that do not show a regenerative phenotype increased stable expression of HIF-1α protein over 5 days, providing a functional measure of drug release in vivo. Multiple peripheral subcutaneous injections of the 1,4-DPCA/hydrogel over a 10-day period led to regenerative wound healing in Swiss Webster mice after ear hole punch injury. Increased expression of the HIF-1α protein may provide a starting point for future studies on regeneration in mammals. PMID:26041709
Hillerkuss, D; Ellis, A; Zarris, G; Simeonidou, D; Leuthold, J; Cotter, D
We present the first experimental demonstration of an asynchronous digital optical regenerator at 42.67 Gbit/s. The system effectively retimes incoming asynchronous data bursts to a local clock without burst mode clock recovery and converts the signal to a desired wavelength and duty cycle.
Simkin, Jennifer; Sammarco, Mimi C.; Dawson, Lindsay A.; Tucker, Catherine; Taylor, Louis J.; Van Meter, Keith
Abstract Mammalian digit regeneration progresses through consistent stages: histolysis, inflammation, epidermal closure, blastema formation, and finally redifferentiation. What we do not yet know is how each stage can affect others. Questions of stage timing, tissue interactions, and microenvironmental states are becoming increasingly important as we look toward solutions for whole limb regeneration. This study focuses on the timing of epidermal closure which, in mammals, is delayed compared to more regenerative animals like the axolotl. We use a standard wound closure device, Dermabond (2‐octyl cyanoacrylate), to induce earlier epidermal closure, and we evaluate the effect of fast epidermal closure on histolysis, blastema formation, and redifferentiation. We find that fast epidermal closure is reliant upon a hypoxic microenvironment. Additionally, early epidermal closure eliminates the histolysis stage and results in a regenerate that more closely replicates the amputated structure. We show that tools like Dermabond and oxygen are able to independently influence the various stages of regeneration enabling us to uncouple histolysis, wound closure, and other regenerative events. With this study, we start to understand how each stage of mammalian digit regeneration is controlled. PMID:27499872
Wu, Yuanyuan; Wang, Karen; Karapetyan, Adrine; Fernando, Warnakulusuriya Akash; Simkin, Jennifer; Han, Manjong; Rugg, Elizabeth L; Muneoka, Ken
A key factor that contributes to the regenerative ability of regeneration-competent animals such as the salamander is their use of innate positional cues that guide the regeneration process. The limbs of mammals has severe regenerative limitations, however the distal most portion of the terminal phalange is regeneration competent. This regenerative ability of the adult mouse digit is level dependent: amputation through the distal half of the terminal phalanx (P3) leads to successful regeneration, whereas amputation through a more proximal location, e.g. the subterminal phalangeal element (P2), fails to regenerate. Do the connective tissue cells of the mammalian digit play a role similar to that of the salamander limb in controlling the regenerative response? To begin to address this question, we isolated and cultured cells of the connective tissue surrounding the phalangeal bones of regeneration competent (P3) and incompetent (P2) levels. Despite their close proximity and localization, these cells show very distinctive profiles when characterized in vitro and in vivo. In vitro studies comparing their proliferation and position-specific interactions reveal that cells isolated from the P3 and P2 are both capable of organizing and differentiating epithelial progenitors, but with different outcomes. The difference in interactions are further characterized with three-dimension cultures, in which P3 regenerative cells are shown to lack a contractile response that is seen in other fibroblast cultures, including the P2 cultures. In in vivo engraftment studies, the difference between these two cell lines is made more apparent. While both P2 and P3 cells participated in the regeneration of the terminal phalanx, their survival and proliferative indices were distinct, thus suggesting a key difference in their ability to interact within a regeneration permissive environment. These studies are the first to demonstrate distinct positional characteristics of connective tissue
Saera-Vila, Alfonso; Kish, Phillip E; Kahana, Alon
Fibroblast growth factors (Fgfs) regulate critical biological processes such as embryonic development, tissue homeostasis, wound healing, and tissue regeneration. In zebrafish, Fgf signaling plays an important role in the regeneration of the spinal cord, liver, heart, fin, and photoreceptors, although its exact mechanism of action is not fully understood. Utilizing an adult zebrafish extraocular muscle (EOM) regeneration model, we demonstrate that blocking Fgf receptor function using either a chemical inhibitor (SU5402) or a dominant-negative transgenic construct (dnFGFR1a:EGFP) impairs muscle regeneration. Adult zebrafish EOMs regenerate through a myocyte dedifferentiation process, which involves a muscle-to-mesenchyme transition and cell cycle reentry by differentiated myocytes. Blocking Fgf signaling reduced cell proliferation and active caspase 3 levels in the regenerating muscle with no detectable levels of apoptosis, supporting the hypothesis that Fgf signaling is involved in the early steps of dedifferentiation. Fgf signaling in regenerating myocytes involves the MAPK/ERK pathway: inhibition of MEK activity with U0126 mimicked the phenotype of the Fgf receptor inhibition on both muscle regeneration and cell proliferation, and activated ERK (p-ERK) was detected in injured muscles by immunofluorescence and western blot. Interestingly, following injury, ERK2 expression is specifically induced and activated by phosphorylation, suggesting a key role in muscle regeneration. We conclude that the critical early steps of myocyte dedifferentiation in EOM regeneration are dependent on Fgf signaling.
Urodeles and fetal mammals are capable of impressive epimorphic regeneration in a variety of tissues, whereas the typical default response to injury in adult mammals consists of inflammation and scar tissue formation. One component of epimorphic regeneration is the recruitment of resident progenitor...
Saera-Vila, Alfonso; Kasprick, Daniel S.; Junttila, Tyler L.; Grzegorski, Steven J.; Louie, Ke'ale W.; Chiari, Estelle F.; Kish, Phillip E.; Kahana, Alon
Purpose The purpose of this study was to characterize the injury response of extraocular muscles (EOMs) in adult zebrafish. Methods Adult zebrafish underwent lateral rectus (LR) muscle myectomy surgery to remove 50% of the muscle, followed by molecular and cellular characterization of the tissue response to the injury. Results Following myectomy, the LR muscle regenerated an anatomically correct and functional muscle within 7 to 10 days post injury (DPI). Following injury, the residual muscle stump was replaced by a mesenchymal cell population that lost cell polarity and expressed mesenchymal markers. Next, a robust proliferative burst repopulated the area of the regenerating muscle. Regenerating cells expressed myod, identifying them as myoblasts. However, both immunofluorescence and electron microscopy failed to identify classic Pax7-positive satellite cells in control or injured EOMs. Instead, some proliferating nuclei were noted to express mef2c at the very earliest point in the proliferative burst, suggesting myonuclear reprogramming and dedifferentiation. Bromodeoxyuridine (BrdU) labeling of regenerating cells followed by a second myectomy without repeat labeling resulted in a twice-regenerated muscle broadly populated by BrdU-labeled nuclei with minimal apparent dilution of the BrdU signal. A double-pulse experiment using BrdU and 5-ethynyl-2′-deoxyuridine (EdU) identified double-labeled nuclei, confirming the shared progenitor lineage. Rapid regeneration occurred despite a cell cycle length of 19.1 hours, whereas 72% of the regenerating muscle nuclei entered the cell cycle by 48 hours post injury (HPI). Dextran lineage tracing revealed that residual myocytes were responsible for muscle regeneration. Conclusions EOM regeneration in adult zebrafish occurs by dedifferentiation of residual myocytes involving a muscle-to-mesenchyme transition. A mechanistic understanding of myocyte reprogramming may facilitate novel approaches to the development of molecular
Xian, Wa; McKeon, Frank
Despite the massive toll in human suffering imparted by degenerative lung disease, including COPD, idiopathic pulmonary fibrosis and ARDS, the scientific community has been surprisingly agnostic regarding the potential of lung tissue, and in particular the alveoli, to regenerate. However, there is circumstantial evidence in humans and direct evidence in mice that ARDS triggers robust regeneration of lung tissue rather than irreversible fibrosis. The stem cells responsible for this remarkable regenerative process has garnered tremendous attention, most recently yielding a defined set of cloned human airway stem cells marked by p63 expression but with distinct commitment to differentiated cell types typical of the upper or lower airways, the latter of which include alveoli-like structures in vitro and in vivo. These recent advances in lung regeneration and distal airway stem cells and the potential of associated soluble factors in regeneration must be harnessed for therapeutic options in chronic lung disease.
Sun, Fang; He, Zhigang
A major reason for the devastating and permanent disabilities after spinal cord and other types of CNS injury is the failure of injured axons to regenerate and to re-build the functional circuits. Thus, a long-standing goal has been to develop strategies that could promote axon regeneration and restore functions. Recent studies revealed that simply removing extracellular inhibitory activities is insufficient for successful axon regeneration in the adult CNS. On the other side, evidence from different species and different models is accumulating to support the notion that diminished intrinsic regenerative ability of mature neurons is a major contributor to regeneration failure. This review will summarize the molecular mechanisms regulating intrinsic axon growth capacity in the adult CNS and discuss potential implications for therapeutic strategies. PMID:20418094
Acute or chronic injury of the adult mammalian brain is often associated with persistent functional deficits as its potential for regeneration and capacity to rebuild lost neural structures is limited. However, the discovery that neural stem cells (NSCs) persist throughout life in discrete regions of the brain, novel approaches to induce the formation of neuronal and glial cells, and recently developed strategies to generate tissue for exogenous cell replacement strategies opened novel perspectives how to regenerate the adult brain. Here, we will review recently developed approaches for brain repair and discuss future perspectives that may eventually allow for developing novel treatment strategies in acute and chronic brain injury. PMID:27781019
The pathway from the retina to the brain in mammals provides a well-defined model system for investigation of not only surviving axotomy but also axonal regeneration of injured neurons. Here I introduce our recent works on axonal regeneration in the optic nerve (OpN) of adult cats. Fibers of retinal ganglion cells (RGCs) extend beyond the crush site of OpN with injections of a macrophage stimulator (oxidized galectin-1) or a Rho kinase (ROCK) inhibitor (Y-39983 or Y-27632) while axonal extension is blocked with injection of saline. Elongation of crushed optic fibers, however, is slowed after 2 weeks. Transplantation of peripheral nerve makes RGCs regenerate their transected axons into a graft but regenerated fibers extend only a few mm in the brain. Effectiveness of combination of the drugs and treatments has to be verified in future.
Godwin, James W; Pinto, Alexander R; Rosenthal, Nadia A
The failure to replace damaged body parts in adult mammals results from a muted growth response and fibrotic scarring. Although infiltrating immune cells play a major role in determining the variable outcome of mammalian wound repair, little is known about the modulation of immune cell signaling in efficiently regenerating species such as the salamander, which can regrow complete body structures as adults. Here we present a comprehensive analysis of immune signaling during limb regeneration in axolotl, an aquatic salamander, and reveal a temporally defined requirement for macrophage infiltration in the regenerative process. Although many features of mammalian cytokine/chemokine signaling are retained in the axolotl, they are more dynamically deployed, with simultaneous induction of inflammatory and anti-inflammatory markers within the first 24 h after limb amputation. Systemic macrophage depletion during this period resulted in wound closure but permanent failure of limb regeneration, associated with extensive fibrosis and disregulation of extracellular matrix component gene expression. Full limb regenerative capacity of failed stumps was restored by reamputation once endogenous macrophage populations had been replenished. Promotion of a regeneration-permissive environment by identification of macrophage-derived therapeutic molecules may therefore aid in the regeneration of damaged body parts in adult mammals.
Leferovich, John M.; Bedelbaeva, Khamilia; Samulewicz, Stefan; Zhang, Xiang-Ming; Zwas, Donna; Lankford, Edward B.; Heber-Katz, Ellen
The reaction of cardiac tissue to acute injury involves interacting cascades of cellular and molecular responses that encompass inflammation, hormonal signaling, extracellular matrix remodeling, and compensatory adaptation of myocytes. Myocardial regeneration is observed in amphibians, whereas scar formation characterizes cardiac ventricular wound healing in a variety of mammalian injury models. We have previously shown that the MRL mouse strain has an extraordinary capacity to heal surgical wounds, a complex trait that maps to at least seven genetic loci. Here, we extend these studies to cardiac wounds and demonstrate that a severe transmural, cryogenically induced infarction of the right ventricle heals extensively within 60 days, with the restoration of normal myocardium and function. Scarring is markedly reduced in MRL mice compared with C57BL/6 mice, consistent with both the reduced hydroxyproline levels seen after injury and an elevated cardiomyocyte mitotic index of 10-20% for the MRL compared with 1-3% for the C57BL/6. The myocardial response to injury observed in these mice resembles the regenerative process seen in amphibians.
Kumar, Anoop; Gates, Phillip B; Brockes, Jeremy P
Limb regeneration in larval and adult salamanders proceeds from a mound of mesenchymal stem cells called the limb blastema. The blastema gives rise just to those structures distal to its level of origin, and this property of positional identity is reset to more proximal values by treatment with retinoic acid. We have identified a cell surface protein, called Prod1/CD59, which appears to be a determinant of proximodistal identity. Prod1 is expressed in an exponential gradient in an adult limb as determined by detection of both mRNA and immunoreactive protein. Prod1 protein is up-regulated after treatment of distal blastemas with RA and this is particularly marked in cells of the dermis. These cells have previously been implicated in pattern formation during limb regeneration.
McCampbell, Kristen K.; Springer, Kristin N.; Wingert, Rebecca A.
The zebrafish is a useful animal model to study the signaling pathways that orchestrate kidney regeneration, as its renal nephrons are simple, yet they maintain the biological complexity inherent to that of higher vertebrate organisms including mammals. Recent studies have suggested that administration of the aminoglycoside antibiotic gentamicin in zebrafish mimics human acute kidney injury (AKI) through the induction of nephron damage, but the timing and details of critical phenotypic events associated with the regeneration process, particularly in existing nephrons, have not been characterized. Here, we mapped the temporal progression of cellular and molecular changes that occur during renal epithelial regeneration of the proximal tubule in the adult zebrafish using a platform of histological and expression analysis techniques. This work establishes the timing of renal cell death after gentamicin injury, identifies proliferative compartments within the kidney, and documents gene expression changes associated with the regenerative response of proliferating cells. These data provide an important descriptive atlas that documents the series of events that ensue after damage in the zebrafish kidney, thus availing a valuable resource for the scientific community that can facilitate the implementation of zebrafish research to delineate the mechanisms that control renal regeneration. PMID:26089919
Abstract A variety of digit and limb repair and reconstruction methods have been used in different clinical settings, but regeneration remains an item on every plastic surgeon's “wish list.” Although surgical salvage techniques are continually being improved, unreplantable digits and limbs are still abundant. We comprehensively review the structural and functional salvage methods in clinical practice, from the peeling injuries of small distal fingertips to multisegmented amputated limbs, and the developmental and tissue engineering approaches for regenerating human digits and limbs in the laboratory. Although surgical techniques have forged ahead, there are still situations in which digits and limbs are unreplantable. Advances in the field are delineated, and the regeneration processes of salamander limbs, lizard tails, and mouse digits and each component of tissue engineering approaches for digit‐ and limb‐building are discussed. Although the current technology is promising, there are many challenges in human digit and limb regeneration. We hope this review inspires research on the critical gap between clinical and basic science, and leads to more sophisticated digit and limb loss rescue and regeneration innovations. PMID:27499873
Schwartz, M.; Belkin, M.; Harel, A.; Solomon, A.; Lavie, V.; Hadani, M.; Rachailovich, I.; Stein-Izsak, C.
Regeneration of fish optic nerve (representing regenerative central nervous system) was accompanied by increased activity of regeneration-triggering factors produced by nonneuronal cells. A graft of regenerating fish optic nerve, or a ``wrap-around'' implant containing medium conditioned by it, induced a response associated with regeneration in injured optic nerves of adult rabbits (representing a nonregenerative central nervous system). This response was manifested by an increase of general protein synthesis and of selective polypeptides in the retinas and by the ability of the retina to sprout in culture.
Quijano, Lina M; Lynch, Kristen M; Allan, Christopher H; Badylak, Stephen F; Ahsan, Tabassum
Approximately 2 million people have had limb amputations in the United States due to disease or injury, with more than 185,000 new amputations every year. The ability to promote epimorphic regeneration, or the regrowth of a biologically based digit or limb, would radically change the prognosis for amputees. This ambitious goal includes the regrowth of a large number of tissues that need to be properly assembled and patterned to create a fully functional structure. We have yet to even identify, let alone address, all the obstacles along the extended progression that limit epimorphic regeneration in humans. This review aims to present introductory fundamentals in epimorphic regeneration to facilitate design and conduct of research from a tissue engineering and regenerative medicine perspective. We describe the clinical scenario of human digit healing, featuring published reports of regenerative potential. We then broadly delineate the processes of epimorphic regeneration in nonmammalian systems and describe a few mammalian regeneration models. We give particular focus to the murine digit tip, which allows for comparative studies of regeneration-competent and regeneration-incompetent outcomes in the same animal. Finally, we describe a few forward-thinking opportunities for promoting epimorphic regeneration in humans.
Currie, Joshua D; Kawaguchi, Akane; Traspas, Ricardo Moreno; Schuez, Maritta; Chara, Osvaldo; Tanaka, Elly M
Connective tissues-skeleton, dermis, pericytes, fascia-are a key cell source for regenerating the patterned skeleton during axolotl appendage regeneration. This complexity has made it difficult to identify the cells that regenerate skeletal tissue. Inability to identify these cells has impeded a mechanistic understanding of blastema formation. By tracing cells during digit tip regeneration using brainbow transgenic axolotls, we show that cells from each connective tissue compartment have distinct spatial and temporal profiles of proliferation, migration, and differentiation. Chondrocytes proliferate but do not migrate into the regenerate. In contrast, pericytes proliferate, then migrate into the blastema and give rise solely to pericytes. Periskeletal cells and fibroblasts contribute the bulk of digit blastema cells and acquire diverse fates according to successive waves of migration that choreograph their proximal-distal and tissue contributions. We further show that platelet-derived growth factor signaling is a potent inducer of fibroblast migration, which is required to form the blastema.
Rinkevich, Yuval; Lindau, Paul; Ueno, Hiroo; Longaker, Michael T.; Weissman, Irving L.
Summary The regrowth of amputated limbs and the distal tips of digits represent models of tissue regeneration in amphibians, fish, and mice. For decades it had been assumed that limb regeneration derived from the blastema, an undifferentiated pluripotent cell population thought to be derived from mature cells via dedifferentiation. Here we show that a wide-range of tissue stem/progenitor cells contribute to restore the mouse distal digit. Genetic fate mapping and clonal analysis of individual cells revealed that these stem cells are lineage restricted, mimicking digit growth during development. Transplantation of CFP expressing hematopoietic stem cells, and parabiosis between genetically marked mice, confirmed that the stem/progenitors are tissue resident, including the cells involved in angiogenesis. These results, combined with those from appendage development/regeneration in lower vertebrates, collectively demonstrate that tissue stem cells rather than pluripotent blastema cells are an evolutionarily conserved cellular mode for limb regeneration after amputation. PMID:21866153
Strand, Nicholas S; Hoi, Kimberly K; Phan, Tien M T; Ray, Catherine A; Berndt, Jason D; Moon, Randall T
Unlike mammals, zebrafish can regenerate their injured spinal cord and regain control of caudal tissues. It was recently shown that Wnt/β-catenin signaling is necessary for spinal cord regeneration in the larval zebrafish. However, the molecular mechanisms of regeneration may or may not be conserved between larval and adult zebrafish. To test this, we assessed the role of Wnt/β-catenin signaling after spinal cord injury in the adult zebrafish. We show that Wnt/β-catenin signaling is increased after spinal cord injury in the adult zebrafish. Moreover, overexpression of Dkk1b inhibited Wnt/β-catenin signaling in the regenerating spinal cord of adult zebrafish. Dkk1b overexpression also inhibited locomotor recovery, axon regeneration, and glial bridge formation in the injured spinal cord. Thus, our data illustrate a conserved role for Wnt/β-catenin signaling in adult and larval zebrafish spinal cord regeneration.
Rutkowski, Joseph M; Boardman, Kendrick C; Swartz, Melody A
To date, adult lymphangiogenesis is not well understood. In this study we describe the evolution of lymphatic capillaries in regenerating skin and correlate lymphatic migration and organization with the expression of matrix metalloproteinases (MMPs), immune cells, the growth factors VEGF-A and VEGF-C, and the heparan sulfate proteogylcan perlecan, a key component of basement membrane. We show that while lymphatic endothelial cells (LECs) migrate and organize unidirectionally, in the direction of interstitial fluid flow, they do not sprout into the region but rather migrate as single cells that later join together into vessels. Furthermore, in a modified "shunted flow" version of the model, infiltrated LECs fail to organize into functional vessels, indicating that interstitial fluid flow is necessary for lymphatic organization. Perlecan expression on new lymphatic vessels was only observed after vessel organization was complete and also appeared first in the distal region, consistent with the directionality of lymphatic migration and organization. VEGF-C expression peaked at the initiation of lymphangiogenesis but was reduced to lower levels throughout organization and maturation. In mice lacking MMP-9, lymphatics regenerated normally, suggesting that MMP-9 is not required for lymphangiogenesis, at least in mouse skin. This study thus characterizes the process of adult lymphangiogenesis and differentiates it from sprouting blood angiogenesis, verifies its dependence on interstitial fluid flow for vessel organization, and correlates its temporal evolution with those of relevant environmental factors.
Lehoczky, Jessica A.; Tabin, Clifford J.
The tips of the digits of some mammals, including human infants and mice, are capable of complete regeneration after injury. This process is reliant on the presence of the overlaying nail organ and is mediated by a proliferative blastema. Epithelial Wnt/β-catenin signaling has been shown to be necessary for mouse digit tip regeneration. Here, we report on Lgr5 and Lgr6 (leucine-rich repeat-containing G protein-coupled receptor 5 and 6), two important agonists of the Wnt pathway that are known to be markers of several epithelial stem cell populations. We find that Lgr5 is expressed in a dermal population of cells adjacent to the specialized epithelia surrounding the keratinized nail plate. Moreover, Lgr5-expressing cells contribute to this dermis, but not the blastema, during digit tip regeneration. In contrast, we find that Lgr6 is expressed within cells of the nail matrix portion of the nail epithelium, as well as in a subset of cells in the bone and eccrine sweat glands. Genetic lineage analysis reveals that Lgr6-expressing cells give rise to the nail during homeostatic growth, demonstrating that Lgr6 is a marker of nail stem cells. Moreover, Lgr6-expressing cells contribute to the blastema, suggesting a potential direct role for Lgr6-expressing cells during digit tip regeneration. This role is confirmed by analysis of Lgr6-deficient mice, which have both a nail and bone regeneration defect. PMID:26460010
Lehoczky, Jessica A; Tabin, Clifford J
The tips of the digits of some mammals, including human infants and mice, are capable of complete regeneration after injury. This process is reliant on the presence of the overlaying nail organ and is mediated by a proliferative blastema. Epithelial Wnt/β-catenin signaling has been shown to be necessary for mouse digit tip regeneration. Here, we report on Lgr5 and Lgr6 (leucine-rich repeat-containing G protein-coupled receptor 5 and 6), two important agonists of the Wnt pathway that are known to be markers of several epithelial stem cell populations. We find that Lgr5 is expressed in a dermal population of cells adjacent to the specialized epithelia surrounding the keratinized nail plate. Moreover, Lgr5-expressing cells contribute to this dermis, but not the blastema, during digit tip regeneration. In contrast, we find that Lgr6 is expressed within cells of the nail matrix portion of the nail epithelium, as well as in a subset of cells in the bone and eccrine sweat glands. Genetic lineage analysis reveals that Lgr6-expressing cells give rise to the nail during homeostatic growth, demonstrating that Lgr6 is a marker of nail stem cells. Moreover, Lgr6-expressing cells contribute to the blastema, suggesting a potential direct role for Lgr6-expressing cells during digit tip regeneration. This role is confirmed by analysis of Lgr6-deficient mice, which have both a nail and bone regeneration defect.
Cresci, M Kay; Yarandi, Hossein N; Morrell, Roger W
Computers and the Internet offer older adults opportunities and resources for independent living. However, many urban older adults do not use computers. This study examined the demographic, health, and social activities of urban older adults to determine variables that might predict the use and nonuse of computers in this population. A secondary data analysis was performed using the 2001 Detroit City-Wide Needs Assessment of Older Adults (n = 1410) data set. Logistic regression was used to explore potential differences in predictor variables between computer users and nonusers. Overall, computer users were younger (27%), had a higher level of education, were more likely to be employed, had an annual income greater than $20,000, and were healthier and more active than nonusers. They also were more likely to have memberships in community organizations and do volunteer work. Preferred computer activities included conducting Internet searches, playing games, writing, and communicating with family members and friends. The results suggest significant differences in demographic and health-related characteristics between computer users and nonusers among urban older adults. Although about a quarter of participants in this study used computers, the Digital Divide continues to exist in urban settings for scores of others.
Ooto, Sotaro; Akagi, Tadamichi; Kageyama, Ryoichiro; Akita, Joe; Mandai, Michiko; Honda, Yoshihito; Takahashi, Masayo
It has long been believed that the retina of mature mammals is incapable of regeneration. In this study, using the N-methyl-D-aspartate neurotoxicity model of adult rat retina, we observed that some Müller glial cells were stimulated to proliferate in response to a toxic injury and produce bipolar cells and rod photoreceptors. Although these newly produced neurons were limited in number, retinoic acid treatment promoted the number of regenerated bipolar cells. Moreover, misexpression of basic helix-loop-helix and homeobox genes promoted the induction of amacrine, horizontal, and rod photoreceptor specific phenotypes. These findings demonstrated that retinal neurons regenerated even in adult mammalian retina after toxic injury. Furthermore, we could partially control the fate of the regenerated neurons with extrinsic factors or intrinsic genes. The Müller glial cells constitute a potential source for the regeneration of adult mammalian retina and can be a target for drug delivery and gene therapy in retinal degenerative diseases.
Graver, H T
Transverse amputations were carried out through one-third fully regenerated jaw segments and through normal tissue of the mandible on the same and opposite sides of the jaw in adults of Notophthalmus viridescens. Collectively the results suggest that, in adult urodeles, the mandible and the dental lamina can be replaced in an identical manner more than one time. Although the major histological events are the same in jaw regeneration and re-regeneration, regrowth is more rapid in re-regeneration. It appears that recently differentiated tissues of the regenerate have a higher capacity for regeneration than normal tissues amputated for the first time. Re-regeneration of the jaw occurs by growth of the original regenerate cartilage which has undergone reorganization. In re-regeneration, the skeletal elements exhibit no polarity and regrowth occurs in both directions, while the dental lamina possesses an anterior-posterior polarity and can regrow in an anterior direction only. Information concerning the mechanisms involved in the regenerative events remain to be determined.
Berg, Daniel A; Kirkham, Matthew; Beljajeva, Anna; Knapp, Dunja; Habermann, Bianca; Ryge, Jesper; Tanaka, Elly M; Simon, András
In contrast to mammals, salamanders and teleost fishes can efficiently repair the adult brain. It has been hypothesised that constitutively active neurogenic niches are a prerequisite for extensive neuronal regeneration capacity. Here, we show that the highly regenerative salamander, the red spotted newt, displays an unexpectedly similar distribution of active germinal niches with mammals under normal physiological conditions. Proliferation zones in the adult newt brain are restricted to the forebrain, whereas all other regions are essentially quiescent. However, ablation of midbrain dopamine neurons in newts induced ependymoglia cells in the normally quiescent midbrain to proliferate and to undertake full dopamine neuron regeneration. Using oligonucleotide microarrays, we have catalogued a set of differentially expressed genes in these activated ependymoglia cells. This strategy identified hedgehog signalling as a key component of adult dopamine neuron regeneration. These data show that brain regeneration can occur by activation of neurogenesis in quiescent brain regions.
Unguez, Graciela A
Biology is replete with examples of regeneration, the process that allows animals to replace or repair cells, tissues and organs. As on land, vertebrates in aquatic environments experience the occurrence of injury with varying frequency and to different degrees. Studies demonstrate that ray-finned fishes possess a very high capacity to regenerate different tissues and organs when they are adults. Among fishes that exhibit robust regenerative capacities are the neotropical electric fishes of South America (Teleostei: Gymnotiformes). Specifically, adult gymnotiform electric fishes can regenerate injured brain and spinal cord tissues and restore amputated body parts repeatedly. We have begun to identify some aspects of the cellular and molecular mechanisms of tail regeneration in the weakly electric fish Sternopygus macrurus (long-tailed knifefish) with a focus on regeneration of skeletal muscle and the muscle-derived electric organ. Application of in vivo microinjection techniques and generation of myogenic stem cell markers are beginning to overcome some of the challenges owing to the limitations of working with non-genetic animal models with extensive regenerative capacity. This review highlights some aspects of tail regeneration in S. macrurus and discusses the advantages of using gymnotiform electric fishes to investigate the cellular and molecular mechanisms that produce new cells during regeneration in adult vertebrates.
Unguez, Graciela A.
Summary Biology is replete with examples of regeneration, the process that allows animals to replace or repair cells, tissues and organs. As on land, vertebrates in aquatic environments experience the occurrence of injury with varying frequency and to different degrees. Studies demonstrate that ray-finned fishes possess a very high capacity to regenerate different tissues and organs when they are adults. Among fishes that exhibit robust regenerative capacities are the neotropical electric fishes of South America (Teleostei: Gymnotiformes). Specifically, adult gymnotiform electric fishes can regenerate injured brain and spinal cord tissues and restore amputated body parts repeatedly. We have begun to identify some aspects of the cellular and molecular mechanisms of tail regeneration in the weakly electric fish Sternopygus macrurus (long-tailed knifefish) with a focus on regeneration of skeletal muscle and the muscle-derived electric organ. Application of in vivo microinjection techniques and generation of myogenic stem cell markers are beginning to overcome some of the challenges owing to the limitations of working with non-genetic animal models with extensive regenerative capacity. This review highlights some aspects of tail regeneration in S. macrurus and discusses the advantages of using gymnotiform electric fishes to investigate the cellular and molecular mechanisms that produce new cells during regeneration in adult vertebrates. PMID:23761473
Marsh, D. R.; Criswell, D. S.; Carson, J. A.; Booth, F. W.
Myogenic factor mRNA expression was examined during muscle regeneration after bupivacaine injection in Fischer 344/Brown Norway F1 rats aged 3, 18, and 31 mo of age (young, adult, and old, respectively). Mass of the tibialis anterior muscle in the young rats had recovered to control values by 21 days postbupivacaine injection but in adult and old rats remained 40% less than that of contralateral controls at 21 and 28 days of recovery. During muscle regeneration, myogenin mRNA was significantly increased in muscles of young, adult, and old rats 5 days after bupivacaine injection. Subsequently, myogenin mRNA levels in young rat muscle decreased to postinjection control values by day 21 but did not return to control values in 28-day regenerating muscles of adult and old rats. The expression of MyoD mRNA was also increased in muscles at day 5 of regeneration in young, adult, and old rats, decreased to control levels by day 14 in young and adult rats, and remained elevated in the old rats for 28 days. In summary, either a diminished ability to downregulate myogenin and MyoD mRNAs in regenerating muscle occurs in old rat muscles, or the continuing myogenic effort includes elevated expression of these mRNAs.
Monteiro, Joana; Aires, Rita; Becker, Jörg D.; Jacinto, António; Certal, Ana C.; Rodríguez-León, Joaquín
The activity of ion channels and transporters generates ion-specific fluxes that encode electrical and/or chemical signals with biological significance. Even though it is long known that some of those signals are crucial for regeneration, only in recent years the corresponding molecular sources started to be identified using mainly invertebrate or larval vertebrate models. We used adult zebrafish caudal fin as a model to investigate which and how ion transporters affect regeneration in an adult vertebrate model. Through the combined use of biophysical and molecular approaches, we show that V-ATPase activity contributes to a regeneration-specific H+ ef`flux. The onset and intensity of both V-ATPase expression and H+ efflux correlate with the different regeneration rate along the proximal-distal axis. Moreover, we show that V-ATPase inhibition impairs regeneration in adult vertebrate. Notably, the activity of this H+ pump is necessary for aldh1a2 and mkp3 expression, blastema cell proliferation and fin innervation. To the best of our knowledge, this is the first report on the role of V-ATPase during adult vertebrate regeneration. PMID:24671205
Monteiro, Joana; Aires, Rita; Becker, Jörg D; Jacinto, António; Certal, Ana C; Rodríguez-León, Joaquín
The activity of ion channels and transporters generates ion-specific fluxes that encode electrical and/or chemical signals with biological significance. Even though it is long known that some of those signals are crucial for regeneration, only in recent years the corresponding molecular sources started to be identified using mainly invertebrate or larval vertebrate models. We used adult zebrafish caudal fin as a model to investigate which and how ion transporters affect regeneration in an adult vertebrate model. Through the combined use of biophysical and molecular approaches, we show that V-ATPase activity contributes to a regeneration-specific H+ ef`flux. The onset and intensity of both V-ATPase expression and H+ efflux correlate with the different regeneration rate along the proximal-distal axis. Moreover, we show that V-ATPase inhibition impairs regeneration in adult vertebrate. Notably, the activity of this H+ pump is necessary for aldh1a2 and mkp3 expression, blastema cell proliferation and fin innervation. To the best of our knowledge, this is the first report on the role of V-ATPase during adult vertebrate regeneration.
Chen, Chen-Hui; Durand, Ellen; Wang, Jinhu; Zon, Leonard I; Poss, Kenneth D
The zebrafish has become a standard model system for stem cell and tissue regeneration research, based on powerful genetics, high tissue regenerative capacity and low maintenance costs. Yet, these studies can be challenged by current limitations of tissue visualization techniques in adult animals. Here we describe new imaging methodology and present several ubiquitous and tissue-specific luciferase-based transgenic lines, which we have termed zebraflash, that facilitate the assessment of regeneration and engraftment in freely moving adult zebrafish. We show that luciferase-based live imaging reliably estimates muscle quantity in an internal organ, the heart, and can longitudinally follow cardiac regeneration in individual animals after major injury. Furthermore, luciferase-based detection enables visualization and quantification of engraftment in live recipients of transplanted hematopoietic stem cell progeny, with advantages in sensitivity and gross spatial resolution over fluorescence detection. Our findings present a versatile resource for monitoring and dissecting vertebrate stem cell and regeneration biology.
Martinez, Jose A; Kobayashi, Masaki; Krishnan, Anand; Webber, Christine; Christie, Kimberly; Guo, GuiFang; Singh, Vandana; Zochodne, Douglas W
Intrinsic molecular determinants of neurodevelopmental outcomes assume new, albeit related roles during adult neural regeneration. Here we studied and identified a facilitatory role for Sonic hedgehog protein (Shh), a morphogen that influences motor neuron floor plate architecture, during adult peripheral neuron regeneration. Shh and its receptors were expressed in adult dorsal root ganglia (DRG) neurons, axons and glia and trended toward higher levels following axotomy injury. Knockdown of Shh in adult sensory neurons resulted in decreased outgrowth and branching in vitro, identifying a role for Shh in facilitating outgrowth. The findings argued for an intrinsic action to support neuron regeneration. Support of advancement and turning however, were not identified in adult sensory neuron growth cones in response to local extrinsic gradients of Shh. That intrinsic Shh supported the regrowth of peripheral nerves after injury was confirmed by the analysis of axon regrowth from the proximal stumps of transected sciatic nerves. By exposing regenerating axons to local infusions of Shh siRNA in vivo within a conduit bridging the transected proximal and distal stumps, we achieved local knockdown of Shh. In response, there was attenuated axonal and Schwann cell outgrowth beyond the transection zone. Unlike its role during neurodevelopment, Shh facilitates but does not confer regenerative outgrowth properties to adult neurons alone. Exploring the differing properties of morphogens and related proteins in the adult nervous system identifies new and important roles for them.
Rumman, Mohammad; Dhawan, Jyotsna; Kassem, Moustapha
Adult stem cells (ASCs) are tissue resident stem cells responsible for tissue homeostasis and regeneration following injury. In uninjured tissues, ASCs exist in a nonproliferating, reversibly cell cycle-arrested state known as quiescence or G0. A key function of the quiescent state is to preserve stemness in ASCs by preventing precocious differentiation, and thus maintaining a pool of undifferentiated ASCs. Recent evidences suggest that quiescence is an actively maintained state and that excessive or defective quiescence may lead to compromised tissue regeneration or tumorigenesis. The aim of this review is to provide an update regarding the biological mechanisms of ASC quiescence and their role in tissue regeneration.
Dimou, Helen; Kameas, Achilles
Purpose: This paper aims to present a model for the quality assurance of digital educational material that is appropriate for adult education. The proposed model adopts the software quality standard ISO/IEC 9126 and takes into account adult learning theories, Bloom's taxonomy of learning objectives and two instructional design models: Kolb's model…
Cruz, Ivan A.; Kappedal, Ryan; Mackenzie, Scott M.; Hailey, Dale W.; Hoffman, Trevor L.; Schilling, Thomas F.; Raible, David W.
We have examined lateral line hair cell and support cell maintenance in adult zebrafish when growth is largely complete. We demonstrate that adult zebrafish not only replenish hair cells after a single instance of hair cell damage, but also maintain hair cells and support cells after multiple rounds of damage and regeneration. We find that hair cells undergo continuous turnover in adult zebrafish in the absence of damage. We identify mitotically-distinct support cell populations and show that hair cells regenerate from underlying support cells in a region-specific manner. Our results demonstrate that there are two distinct support cell populations in the lateral line, which may help explain why zebrafish hair cell regeneration is extremely robust, retained throughout life, and potentially unlimited in regenerative capacity. PMID:25869855
Fan, Tingjun; Fan, Xianyuan; Du, Yutang; Sun, Wenjie; Zhang, Shaofeng; Li, Jiaxin
To understand the mechanisms of starfish regeneration, the arms of adult starfish Asterias rollestoni Bell were amputated and their regeneration patterns and cellular mechanisms were studied. It was found that cells in the outer epidermis and inner parietal peritoneum near the end of the stump began to dedifferentiate 4 d after amputation. The dedifferentiated cells in the outer epidermis proliferated, migrated to the wound site and formed a thickened pre-epidermis which would then re-differentiate gradually into mature epidermis. The new parietal peritoneum formed on the coelomic side of wound might be from the curvely elongated parietal peritoneum, resulting from the dedifferentiated and proliferated cells by extension. Afterwards, the proliferated cells made the outer epidermis and inner parietal peritoneum invaginate into the interior dermis and formed blastema-like structures together with induced dedifferentiated dermal cells. Most interestingly, the arm regeneration in A. rollestoni was achieved synchronously by de novo arm-bud formation and growth, and arm-stump elongation. The crucial aspects of arm-bud formation included cell dedifferentiation, proliferation and migration, while those of arm-stump elongation included cell dedifferentiation, proliferation, invagination, and arm-wall-across blastema-like structure formation. The unique pattern and cellular mechanisms of amputated arm regeneration make it easier to understand the rapid regeneration process of adult starfish. This study may lay solid foundations for the research into molecular mechanisms of echinoderm regeneration.
Heiduschka, P; Romann, I; Stieglitz, T; Thanos, S
Adult mammalian optic nerve axons are able to regenerate, when provided with the permissive environment of an autologous peripheral nerve graft, which is usually the sciatic nerve. This study demonstrates the ability of adult rat optic nerve axons to regenerate through the preformed perforations of a polyimide electrode carrier implanted at the interface between the proximal stump of the cut optic nerve and the stump of the peripheral nerve piece used for grafting. Evidence that retinal ganglion cells regenerated their axons through the perforated electrode carrier was obtained by retrograde labeling with a fluorescent dye deposited into the sciatic nerve graft beyond the nerve-carrier-nerve junction. The number of regenerating cells could be enhanced by injecting neuroprotective drugs like aurintricarboxylic acid and cortisol intravitreally. A second line of evidence was obtained by immunohistochemical staining with antibodies to neurofilament. Third, electrical activity of the regenerating nerves was recorded after stimulating the retina with a flash of light. The results suggest that a regenerating central nerve tract may serve as an experimental model to implant artificial microdevices to monitor the physiological and topographical properties of neurites passing through the device or to stimulate them, thus interfering with their potential to grow. This study reports for the first time that the optic nerve has unique properties, which aids in the realization of these goals.
Olsen, Ansgar S.; Sarras, Michael P.; Intine, Robert V.
The zebrafish (Danio Rerio) is an established model organism for the study of developmental processes, human disease and tissue regeneration. We report that limb regeneration is severely impaired in our newly developed adult zebrafish model of type I diabetes. Intraperitoneal streptozocin injection of adult, wild type zebrafish results in a sustained hyperglycemic state as determined by elevated fasting blood glucose values and increased glycation of serum protein. Serum insulin levels are also decreased and pancreas immunohistochemisty revealed a lesser amount of insulin signal in hyperglycemic fish. Additionally, the diabetic complications of retinal thinning and glomerular basement membrane thickening (early signs of retinopathy and nephropathy) resulting from the hyperglycemic state were evident in streptozocin injected fish at three weeks. Most significantly, limb regeneration, following caudal fin amputation, is severely impaired in diabetic zebrafish. Nonspecific toxic effects outside the pancreas were not found to contribute to impaired limb regeneration. This experimental system using adult zebrafish facilitates a broad spectrum of genetic and molecular approaches to study regeneration in the diabetic background. PMID:20840523
Ooto, Sotaro; Akagi, Tadamichi; Kageyama, Ryoichiro; Akita, Joe; Mandai, Michiko; Honda, Yoshihito; Takahashi, Masayo
It has long been believed that the retina of mature mammals is incapable of regeneration. In this study, using the N-methyl-d-aspartate neurotoxicity model of adult rat retina, we observed that some Müller glial cells were stimulated to proliferate in response to a toxic injury and produce bipolar cells and rod photoreceptors. Although these newly produced neurons were limited in number, retinoic acid treatment promoted the number of regenerated bipolar cells. Moreover, misexpression of basic helix–loop–helix and homeobox genes promoted the induction of amacrine, horizontal, and rod photoreceptor specific phenotypes. These findings demonstrated that retinal neurons regenerated even in adult mammalian retina after toxic injury. Furthermore, we could partially control the fate of the regenerated neurons with extrinsic factors or intrinsic genes. The Müller glial cells constitute a potential source for the regeneration of adult mammalian retina and can be a target for drug delivery and gene therapy in retinal degenerative diseases. PMID:15353594
Kim, MiJung; Choi, Yu Suk; Yang, Seung Hye; Hong, Hea-Nam; Cho, Sung-Woo; Cha, Sang Myun; Pak, Jhang Ho; Kim, Chan Wha; Kwon, Seog Woon; Park, Chan Jeoung
The [corrected] use of adult stem cells for cell-based tissue engineering and regeneration strategies represents a promising approach for skeletal muscle repair. We have evaluated the combination of adipose tissue-derived adult stem cells (ADSCs) obtained from autologous liposuction and injectable poly(lactic-co-glycolic acid) (PLGA) spheres for muscle regeneration. ADSCs attached to PLGA spheres and PLGA spheres alone were cultured in myogenic medium for 21 days and injected subcutaneously into the necks of nude mice. After 30 and 60 days, the mice were sacrificed, and newly formed tissues were analyzed by immunostaining, H and E staining, and RT-PCR. We found that ADSCs attached to PLGA spheres, but not PLGA spheres alone, were able to generate muscle tissue. These findings suggest that ADSCs and PLGA spheres are useful materials for muscle tissue engineering and that their combination can be used in clinical settings for muscle regeneration.
Wagner, Daniel E; Wang, Irving E; Reddien, Peter W
Pluripotent cells in the embryo can generate all cell types, but lineage-restricted cells are generally thought to replenish adult tissues. Planarians are flatworms and regenerate from tiny body fragments, a process requiring a population of proliferating cells (neoblasts). Whether regeneration is accomplished by pluripotent cells or by the collective activity of multiple lineage-restricted cell types is unknown. We used ionizing radiation and single-cell transplantation to identify neoblasts that can form large descendant-cell colonies in vivo. These clonogenic neoblasts (cNeoblasts) produce cells that differentiate into neuronal, intestinal, and other known postmitotic cell types and are distributed throughout the body. Single transplanted cNeoblasts restored regeneration in lethally irradiated hosts. We conclude that broadly distributed, adult pluripotent stem cells underlie the remarkable regenerative abilities of planarians.
Olthoff, Kim M; Emond, Jean C; Shearon, Tempie H; Everson, Greg; Baker, Talia B; Fisher, Robert A; Freise, Chris E; Gillespie, Brenda W; Everhart, James E
Adult-to-adult living donors and recipients were studied to characterize patterns of liver growth and identify associated factors in a multicenter study. Three hundred and fifty donors and 353 recipients in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) receiving transplants between March 2003 and February 2010 were included. Potential predictors of 3-month liver volume included total and standard liver volumes (TLV and SLV), Model for End-Stage Liver Disease (MELD) score (in recipients), the remnant and graft size, remnant-to-donor and graft-to-recipient weight ratios (RDWR and GRWR), remnant/TLV, and graft/SLV. Among donors, 3-month absolute growth was 676 ± 251 g (mean ± SD), and percentage reconstitution was 80% ± 13%. Among recipients, GRWR was 1.3% ± 0.4% (8 < 0.8%). Graft weight was 60% ± 13% of SLV. Three-month absolute growth was 549 ± 267 g, and percentage reconstitution was 93% ± 18%. Predictors of greater 3-month liver volume included larger patient size (donors and recipients), larger graft volume (recipients), and larger TLV (donors). Donors with the smallest remnant/TLV ratios had larger than expected growth but also had higher postoperative bilirubin and international normalized ratio at 7 and 30 days. In a combined donor-recipient analysis, donors had smaller 3-month liver volumes than recipients adjusted for patient size, remnant or graft volume, and TLV or SLV (P = 0.004). Recipient graft failure in the first 90 days was predicted by poor graft function at day 7 (HR = 4.50, P = 0.001) but not by GRWR or graft fraction (P > 0.90 for each). Both donors and recipients had rapid yet incomplete restoration of tissue mass in the first 3 months, and this confirmed previous reports. Recipients achieved a greater percentage of expected total volume. Patient size and recipient graft volume significantly influenced 3-month volumes. Importantly, donor liver volume is a
Vasil'ev, A Iu; Bulanova, I M; Mal'ginov, N N; Kiseleva, E V; Cherniaev, S E; Nikulina, O M; Tarasenko, I V; Volozhin, A I
Digital microfocal x-ray study was experimentally studied in animals to examine the time course of changes in their bone regeneration. Sixteen Chinchila rabbits whose bone defect in the angle of the mandibular ramus had been closed with the osteoplastic material Gapcol with the applied allogeneic, autologous stem cells isolated from rabbit adipose tissue and human plasma enriched with thrombocytic growth factors were examined. The capabilities of digital microfocal x-ray study versus x-ray computed tomography were compared in the evaluation of reparative regeneration of bone tissue. The results of radiation studies were verified with the data of scanning electron microscopy.
Hindi, Sajedah M; Paul, Pradyut K; Dahiya, Saurabh; Mishra, Vivek; Bhatnagar, Shephali; Kuang, Shihuan; Choi, Yongwon; Kumar, Ashok
Skeletal muscle is a postmitotic tissue that repairs and regenerates through activation of a population of stem-cell-like satellite cells. However, signaling mechanisms governing adult skeletal muscle regeneration remain less understood. In the present study, we have investigated the role of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), an adaptor protein involved in receptor-mediated activation of multiple signaling pathways in regeneration of adult myofibers. Skeletal muscle-specific depletion of TRAF6 in mice (TRAF6(mko)) improved regeneration of myofibers upon injury with a concomitant increase in the number of satellite cells and activation of the Notch signaling pathway. Ex vivo cultures of TRAF6(mko) myofiber explants demonstrated an increase in the proliferative capacity of myofiber-associated satellite cells accompanied by an upregulation of Notch ligands. Deletion of TRAF6 also inhibited the activity of transcription factor NF-κB and the expression of inflammatory cytokines and augmented the M2c macrophage phenotype in injured muscle tissues. Collectively, our study demonstrates that specific inhibition of TRAF6 improves satellite cell activation and skeletal muscle regeneration through upregulation of Notch signaling and reducing the inflammatory repertoire.
Gorsuch, Ryne A.; Hyde, David R.
This article examines our current knowledge underlying the mechanisms involved in neuronal regeneration in the adult zebrafish retina. Zebrafish, which has the capacity to regenerate a wide variety of tissues and organs (including the fins, kidney, heart, brain, and spinal cord), has become the premier model system to study retinal regeneration due to the robustness and speed of the response and the variety of genetic tools that can be applied to study this question. It is now well documented that retinal damage induces the resident Müller glia to dedifferentiate and reenter the cell cycle to produce neuronal progenitor cells that continue to proliferate, migrate to the damaged retinal layer and differentiate into the missing neuronal cell types. Increasing our understanding of how these cellular events are regulated and occur in response to neuronal damage may provide critical information that can be applied to stimulating a regeneration response in the mammalian retina. In this review, we will focus on the genes/proteins that regulate zebrafish retinal regeneration and will attempt to critically evaluate how these factors may interact to correctly orchestrate the definitive cellular events that occur during regeneration. PMID:23880528
Gorsuch, Ryne A; Hyde, David R
This article examines our current knowledge underlying the mechanisms involved in neuronal regeneration in the adult zebrafish retina. Zebrafish, which has the capacity to regenerate a wide variety of tissues and organs (including the fins, kidney, heart, brain, and spinal cord), has become the premier model system to study retinal regeneration due to the robustness and speed of the response and the variety of genetic tools that can be applied to study this question. It is now well documented that retinal damage induces the resident Müller glia to dedifferentiate and reenter the cell cycle to produce neuronal progenitor cells that continue to proliferate, migrate to the damaged retinal layer and differentiate into the missing neuronal cell types. Increasing our understanding of how these cellular events are regulated and occur in response to neuronal damage may provide critical information that can be applied to stimulating a regeneration response in the mammalian retina. In this review, we will focus on the genes/proteins that regulate zebrafish retinal regeneration and will attempt to critically evaluate how these factors may interact to correctly orchestrate the definitive cellular events that occur during regeneration.
Amamoto, Ryoji; Huerta, Violeta Gisselle Lopez; Takahashi, Emi; Dai, Guangping; Grant, Aaron K; Fu, Zhanyan; Arlotta, Paola
The axolotl can regenerate multiple organs, including the brain. It remains, however, unclear whether neuronal diversity, intricate tissue architecture, and axonal connectivity can be regenerated; yet, this is critical for recovery of function and a central aim of cell replacement strategies in the mammalian central nervous system. Here, we demonstrate that, upon mechanical injury to the adult pallium, axolotls can regenerate several of the populations of neurons present before injury. Notably, regenerated neurons acquire functional electrophysiological traits and respond appropriately to afferent inputs. Despite the ability to regenerate specific, molecularly-defined neuronal subtypes, we also uncovered previously unappreciated limitations by showing that newborn neurons organize within altered tissue architecture and fail to re-establish the long-distance axonal tracts and circuit physiology present before injury. The data provide a direct demonstration that diverse, electrophysiologically functional neurons can be regenerated in axolotls, but challenge prior assumptions of functional brain repair in regenerative species. DOI: http://dx.doi.org/10.7554/eLife.13998.001 PMID:27156560
Moore, Alex C.; Mark, Tiffany E.; Hogan, Ann K.; Topczewski, Jacek; LeClair, Elizabeth E.
Myelination is a cellular adaptation allowing rapid conduction along axons. We have investigated peripheral axons of the zebrafish maxillary barbel (ZMB), an optically clear sensory appendage. Each barbel carries taste buds, solitary chemosensory cells, and epithelial nerve endings, all of which regenerate after amputation (LeClair and Topczewski  PLoS One 5:e8737). The ZMB contains axons from the facial nerve; however, myelination within the barbel itself has not been established. Transcripts of myelin basic protein (mbp) are expressed in normal and regenerating adult barbels, indicating activity in both maintenance and repair. Myelin was confirmed in situ by using toluidine blue, an anti-MBP antibody, and transmission electron microscopy (TEM). The adult ZMB contains ~180 small-diameter axons (<2 μm), approximately 60% of which are myelinated. Developmental myelination was observed via whole-mount immunohistochemistry 4-6 weeks postfertilization, showing myelin sheaths lagging behind growing axons. Early-regenerating axons (10 days postsurgery), having no or few myelin layers, were disorganized within a fibroblast-rich collagenous scar. Twenty-eight days postsurgery, barbel axons had grown out several millimeters and were organized with compact myelin sheaths. Fiber types and axon areas were similar between normal and regenerated tissue; within 4 weeks, regenerating axons restored ~85% of normal myelin thickness. Regenerating barbels express multiple promyelinating transcription factors (sox10, oct6 = pou3f1; krox20a/b = egr2a/b) typical of Schwann cells. These observations extend our understanding of the zebrafish peripheral nervous system within a little-studied sensory appendage. The accessible ZMB provides a novel context for studying axon regeneration, Schwann cell migration, and remyelination in a model vertebrate. PMID:22592645
Broughton, Kathleen; Sussman, Mark A.
Much has changed since our survey of the landscape for myocardial regeneration powered by adult stem cells four years ago (Mohsin et al., Empowering adult stem cells for myocardial regeneration. Circ Res. 2011; 109(12):1415–1428) . The intervening years since that first review has witnessed an explosive expansion of studies that advance both understanding and implementation of adult stem cells in promoting myocardial repair. Painstaking research from innumerable laboratories throughout the world is prying open doors that may lead to restoration of myocardial structure and function in the wake of pathologic injury. This global effort has produced deeper mechanistic comprehension coupled with an evolving appreciation for the complexity of myocardial regeneration in the adult context. Undaunted by both known and (as yet) unknown challenges, pursuit of myocardial regenerative medicine mediated by adult stem cell therapy has gathered momentum fueled by tantalizing clues and visionary goals. This concise review takes a somewhat different perspective than our initial treatise, taking stock of the business sector that has become an integral part of the field while concurrently updating “state of affairs” in cutting edge research. Looking retrospectively at advancement over the years as all reviews eventually must, the fundamental lesson to be learned is best explained by Jonatan Mårtensson: “Success will never be a big step in the future. Success is a small step taken just now.” PMID:26941423
Background Adult human fibroblasts grown in low oxygen and with FGF2 supplementation have the capacity to tip the healing outcome of skeletal muscle injury – by favoring regeneration response in vivo over scar formation. Here, we compare the transcriptomes of control adult human dermal fibroblasts and induced regeneration-competent (iRC) fibroblasts to identify transcriptional changes that may be related to their regeneration competence. Results We identified a unique gene-expression profile that characterizes FGF2-induced iRC fibroblast phenotype. Significantly differentially expressed genes due to FGF2 treatment were identified and analyzed to determine overrepresented Gene Ontology terms. Genes belonging to extracellular matrix components, adhesion molecules, matrix remodelling, cytoskeleton, and cytokines were determined to be affected by FGF2 treatment. Conclusions Transcriptome analysis comparing control adult human fibroblasts with FGF2-treated fibroblasts identified functional groups of genes that reflect transcriptional changes potentially contributing to their regeneration competence. This comparative transcriptome analysis should contribute new insights into genes that characterize cells with greater regenerative potential. PMID:24066673
Sattler, Susanne; Rosenthal, Nadia
The immune system is a crucial player in tissue homeostasis and wound healing. A sophisticated cascade of events triggered upon injury ensures protection from infection and initiates and orchestrates healing. While the neonatal mammal can readily regenerate damaged tissues, adult regenerative capacity is limited to specific tissue types, and in organs such as the heart, adult wound healing results in fibrotic repair and loss of function. Growing evidence suggests that the immune system greatly influences the balance between regeneration and fibrotic repair. The neonate mammalian immune system has impaired pro-inflammatory function, is prone to T-helper type 2 responses and has an immature adaptive immune system skewed towards regulatory T cells. While these characteristics make infants susceptible to infection and prone to allergies, it may also provide an immunological environment permissive of regeneration. In this review we will give a comprehensive overview of the immune cells involved in healing and regeneration of the heart and explore differences between the adult and neonate immune system that may explain differences in regenerative ability. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.
Gilliam, Brian K.
Purpose: The purpose of this study was to identify future trends and barriers that will either facilitate or impede the narrowing of the digital skills divide among older adults during the next 10 years. Methodology: To address the research questions, this study used a modified version of the Delphi process using a panel of experts who…
Ady, Kellie; Kinsella, Keli; Paynter, Amber
As a part of a professional learning team, educators are constantly looking for new approaches and designs that promote deeper adult learning. This article describes how educators at Cherry Creek School District in Colorado developed a digital badge system that recognizes the work teachers are doing, supports a culture and climate of celebration,…
Kumar, Sanjay; Voracek, Martin; Singh, Maharaj
Sexual dimorphism in ventrally measured digit ratios (2D:4D and other) has been related to prenatal sex-hormone levels. In the present series of three studies, we measured all digit lengths (excluding the thumb) on the dorsal, rather than the ventral, side of left and right hands and investigated the sexual dimorphism in digit ratios in three independent samples, two of them comprising adults (Study I, N = 104; Study II, N = 154), and one further, comprising kindergarten children (Study III, N = 64). Results show that men have lower digit-ratio values compared to women in digit ratios that include digit 5 as one of the constituents of the ratio (i.e., the 4D:5D, 3D:5D, and 2D:5D ratios). Boys have lower values compared to girls for the 4D:5D and 3D:5D ratios, and there is a similar trend of sexual dimorphism in the 2D:5D ratio. Thus, based on the evidence from dorsally measured digit ratios, the present findings from three samples are consistent with the idea that early sex-hormonal effects might be stronger for digit ratios involving digit 5, as compared to the classic, and frequently studied, ventrally measured 2D:4D ratio. PMID:28321205
Vascotto, Sandy G; Beug, Shawn; Liversage, Richard A; Tsilfidis, Catherine
Epimorphic limb regeneration in the adult newt involves the dedifferentiation of differentiated cells to yield a pluripotent blastemal cell. These mesenchymal-like cells proliferate and subsequently respond to patterning and differentiation cues to form a new limb. Understanding the dedifferentiation process requires the selective identification of dedifferentiating cells within the heterogeneous population of cells in the regenerate. In this study, representational differences analysis was used to produce an enriched population of dedifferentiation-associated cDNA fragments. Fifty-nine unique cDNA fragments were identified, sequenced, and analyzed using bioinformatics tools and databases. Some of these clones demonstrate significant similarity to known genes in other species. Other clones can be linked by homology to pathways previously implicated in the dedifferentiation process. These data will form the basis for further analyses to elucidate the role of candidate genes in the dedifferentiation process during newt forelimb regeneration.
Reimer, Michell M; Norris, Anneliese; Ohnmacht, Jochen; Patani, Rickie; Zhong, Zhen; Dias, Tatyana B; Kuscha, Veronika; Scott, Angela L; Chen, Yu-Chia; Rozov, Stanislav; Frazer, Sarah L; Wyatt, Cameron; Higashijima, Shin-ichi; Patton, E Elizabeth; Panula, Pertti; Chandran, Siddharthan; Becker, Thomas; Becker, Catherina G
Coordinated development of brain stem and spinal target neurons is pivotal for the emergence of a precisely functioning locomotor system. Signals that match the development of these far-apart regions of the central nervous system may be redeployed during spinal cord regeneration. Here we show that descending dopaminergic projections from the brain promote motor neuron generation at the expense of V2 interneurons in the developing zebrafish spinal cord by activating the D4a receptor, which acts on the hedgehog pathway. Inhibiting this essential signal during early neurogenesis leads to a long-lasting reduction of motor neuron numbers and impaired motor responses of free-swimming larvae. Importantly, during successful spinal cord regeneration in adult zebrafish, endogenous dopamine promotes generation of spinal motor neurons, and dopamine agonists augment this process. Hence, we describe a supraspinal control mechanism for the development and regeneration of specific spinal cell types that uses dopamine as a signal.
Fang, Yuan; Mo, Xiaofen; Guo, Wenyi; Zhang, Meng; Zhang, Peihua; Wang, Yan; Rong, Xianfang; Tian, Jie; Sun, Xinghuai
Like other parts of the central nervous system, the adult mammalian optic nerve is difficult to regenerate after injury. Transplantation of the peripheral nerve or a Schwann cell (SC) graft can promote injured axonal regrowth. We tried to develop a new type of tissue-engineered SC graft that consisted of SCs seeded onto a poly(lactic-co-glycolic acid)/chitosan conduit. Meanwhile, SCs were transfected along the ciliary neurotrophic factor (CNTF) gene in vitro by electroporation to increase their neurotrophic effect. Four weeks after transplantation, GAP-43 labelled regenerating axons were found in the SC grafts, and axons in the CNTF-SC graft were longer than those in the SC graft. Tissue-engineered SC grafts can provide a feasible environment for optic nerve regeneration and may become an alternative for bridging damaged nerves and repairing nerve defects in the future.
Chimenti, Isotta; Forte, Elvira; Angelini, Francesco; Giacomello, Alessandro; Messina, Elisa
Since the first observations over two centuries ago by Lazzaro Spallanzani on the extraordinary regenerative capacity of urodeles, many attempts have been made to understand the reasons why such ability has been largely lost in metazoa and whether or how it can be restored, even partially. In this context, important clues can be derived from the systematic analysis of the relevant distinctions among species and of the pathways involved in embryonic development, which might be induced and/or recapitulated in adult tissues. This chapter provides an overview on regeneration and its mechanisms, starting with the lesson learned from lower vertebrates, and will then focus on recent advancements and novel insights concerning regeneration in the adult mammalian heart, including the discovery of resident cardiac progenitor cells (CPCs). Subsequently, it explores all the important pathways involved in regulating differentiation during development and embryogenesis, and that might potentially provide important clues on how to activate and/or modulate regenerative processes in the adult myocardium, including the potential activation of endogenous CPCs. Furthermore the importance of the stem cell niche is discussed, and how it is possible to create in vitro a microenvironment and culture system to provide adult CPCs with the ideal conditions promoting their regenerative ability. Finally, the state of clinical translation of cardiac cell therapy is presented. Overall, this chapter provides a new perspective on how to approach cardiac regeneration, taking advantage of important lessons from development and optimizing biotechnological tools to obtain the ideal conditions for cell-based cardiac regenerative therapy.
Hyde, David R; Godwin, Alan R; Thummel, Ryan
Certain species of urodeles and teleost fish can regenerate their tissues. Zebrafish have become a widely used model to study the spontaneous regeneration of adult tissues, such as the heart, retina, spinal cord, optic nerve, sensory hair cells, and fins. The zebrafish fin is a relatively simple appendage that is easily manipulated to study multiple stages in epimorphic regeneration. Classically, fin regeneration was characterized by three distinct stages: wound healing, blastema formation, and fin outgrowth. After amputating part of the fin, the surrounding epithelium proliferates and migrates over the wound. At 33 °C, this process occurs within six hours post-amputation (hpa, Figure 1B). Next, underlying cells from different lineages (ex. bone, blood, glia, fibroblast) re-enter the cell cycle to form a proliferative blastema, while the overlying epidermis continues to proliferate (Figure 1D). Outgrowth occurs as cells proximal to the blastema re-differentiate into their respective lineages to form new tissue (Figure 1E). Depending on the level of the amputation, full regeneration is completed in a week to a month. The expression of a large number of gene families, including wnt, hox, fgf, msx, retinoic acid, shh, notch, bmp, and activin-betaA genes, is up-regulated during specific stages of fin regeneration. However, the roles of these genes and their encoded proteins during regeneration have been difficult to assess, unless a specific inhibitor for the protein exists, a temperature-sensitive mutant exists or a transgenic animal (either overexpressing the wild-type protein or a dominant-negative protein) was generated. We developed a reverse genetic technique to quickly and easily test the function of any gene during fin regeneration. Morpholino oligonucleotides are widely used to study loss of specific proteins during zebrafish, Xenopus, chick, and mouse development. Morpholinos basepair with a complementary RNA sequence to either block pre-mRNA splicing or m
Evans, Richard H.
Microwave links are widely used at live outside broadcast events for carrying video signals from mobile cameras such as those carried on the shoulder or fitted to vehicles. A digital frame store synchronizer is required when using a remote radio-camera and this has caused additional problems with variable quality signals. During moments of weak signal strength when threshold noise appears in the picture, a video synchronizer may lose synchronization and produce an unnatural freeze-frame effect. A new device called RINSE (Regeneration and Insertion of New Sync Equipment) is described which replaces the old variable quality syncs with 'flywheel' regenerated syncs. When connected between the microwave receiver and the synchronizer, it cleans up the syncs and allows the synchronizer to pass the video without the freeze frame artifacts which would further degrade the picture. By operating the synchronizer with an external sync input from RINSE it will carry any video signal transparently for a short time irrespective of the noise level.
Yannas, I. V.; Lee, E.; Orgill, D. P.; Skrabut, E. M.; Murphy, G. F.
Regeneration of the dermis does not occur spontaneously in the adult mammal. The epidermis is regenerated spontaneously provided there is a dermal substrate over which it can migrate. Certain highly porous, crosslinked collagen--glycosaminoglycan copolymers have induced partial morphogenesis of skin when seeded with dermal and epidermal cells and then grafted on standard, full-thickness skin wounds in the adult guinea pig. A mature epidermis and a nearly physiological dermis, which lacked hair follicles but was demonstrably different from scar, were regenerated over areas as large as 16 cm2. These chemical analogs of extracellular matrices were morphogenetically active provided that the average pore diameter ranged between 20 and 125 μ m, the resistance to degradation by collagenase exceeded a critical limit, and the density of autologous dermal and epidermal cells inoculated therein was >5 × 104 cells per cm2 of wound area. Unseeded copolymers with physical structures that were within these limits delayed the onset of wound contraction by about 10 days but did not eventually prevent it. Seeded copolymers not only delayed contraction but eventually arrested and reversed it while new skin was being regenerated. The data identify a model extracellular matrix that acts as if it were an insoluble growth factor with narrowly specified physicochemical structure, functioning as a transient basal lamina during morphogenesis of skin.
Yannas, I V; Lee, E; Orgill, D P; Skrabut, E M; Murphy, G F
Regeneration of the dermis does not occur spontaneously in the adult mammal. The epidermis is regenerated spontaneously provided there is a dermal substrate over which it can migrate. Certain highly porous, crosslinked collagen-glycosaminoglycan copolymers have induced partial morphogenesis of skin when seeded with dermal and epidermal cells and then grafted on standard, full-thickness skin wounds in the adult guinea pig. A mature epidermis and a nearly physiological dermis, which lacked hair follicles but was demonstrably different from scar, were regenerated over areas as large as 16 cm2. These chemical analogs of extracellular matrices were morphogenetically active provided that the average pore diameter ranged between 20 and 125 microns, the resistance to degradation by collagenase exceeded a critical limit, and the density of autologous dermal and epidermal cells inoculated therein was greater than 5 x 10(4) cells per cm2 of wound area. Unseeded copolymers with physical structures that were within these limits delayed the onset of wound contraction by about 10 days but did not eventually prevent it. Seeded copolymers not only delayed contraction but eventually arrested and reversed it while new skin was being regenerated. The data identify a model extracellular matrix that acts as if it were an insoluble growth factor with narrowly specified physiochemical structure, functioning as a transient basal lamina during morphogenesis of skin. Images PMID:2915988
Moss, Larry G.; Caplan, Tanner V.
Abstract Blood vessel networks provide nutrients and gaseous exchange that are essential for functions. Pancreatic islet capillaries deliver oxygen to endocrine cells while transporting hormones to organs and peripheral locations throughout the body. We have developed a zebrafish diabetes model in which adult islets can be followed in vivo during beta cell regeneration while calibrating changes in beta cell mass and fasting blood glucose levels. After genetic ablation, beta cells are initially dysfunctional or dying, and blood glucose levels increase fourfold. During a 2-week period, hyperglycemia eventually normalizes as beta cell mass regenerates. We show that mCherry-fluorescent, insulin-positive beta cells re-emerge in close contact with the vascular endothelium. Alterations in the dense vascular network of zebrafish islets were visualized by the expression of green fluorescent protein (GFP) in endothelial cells derived from the Fli transcription factor promoter. The rapid destruction and regeneration of beta cell mass was evaluated in the same animal over time, providing a functional model for investigating the interactions of islet cell types with vascular cells as well as the consequences of hyperglycemia on other tissues. Regenerating adult zebrafish can be utilized as vertebrate, metabolically active models for generating new insights into treatments for type 2 diabetes. PMID:23682836
Wasser, Hannah; Biller, Alexandra; Antonopoulos, Georgios; Meyer, Heiko; Bicker, Gerd; Stern, Michael
The olfactory pathway of the locust Locusta migratoria is characterized by a multiglomerular innervation of the antennal lobe (AL) by olfactory receptor neurons (ORNs). After crushing the antenna and thereby severing ORN axons, changes in the AL were monitored. First, volume changes were measured at different times post-crush with scanning laser optical tomography in 5th instar nymphs. AL volume decreased significantly to a minimum volume at 4 days post-crush, followed by an increase. Second, anterograde labeling was used to visualize details in the AL and antennal nerve (AN) during de- and regeneration. Within 24 h post-crush (hpc) the ORN fragments distal to the lesion degenerated. After 48 hpc, regenerating fibers grew through the crush site. In the AL, labeled ORN projections disappeared completely and reappeared after a few days. A weak topographic match between ORN origin on the antenna and the position of innervated glomeruli that was present in untreated controls did not reappear after regeneration. Third, the cell surface marker fasciclin I that is expressed in ORNs was used for quantifying purposes. Immunofluorescence was measured in the AL during de- and regeneration in adults and 5th instar nymphs: after a rapid but transient, decrease, it reappeared. Both processes happen faster in 5th instar nymphs than in adults.
Circulation 103, 882–888 (2001). 52. Biernaskie, J. et al. SKPs derive from hair follicle precursors and exhibit properties of adult dermal stem cells...3). * indicates significant difference between indicated groups using Holm’s t- test . (P < 0.01). (l–s) Immunostaining of isolated sm-mHC − cells...and the tissue from which the cells were derived using student’s t- test (P < 0.05). † indicates significant difference between inferior vena cava and
Xin, Mei; Olson, Eric N; Bassel-Duby, Rhonda
As the adult mammalian heart has limited potential for regeneration and repair, the loss of cardiomyocytes during injury and disease can result in heart failure and death. The cellular processes and regulatory mechanisms involved in heart growth and development can be exploited to repair the injured adult heart through 'reawakening' pathways that are active during embryogenesis. Heart function has been restored in rodents by reprogramming non-myocytes into cardiomyocytes, by expressing transcription factors (GATA4, HAND2, myocyte-specific enhancer factor 2C (MEF2C) and T-box 5 (TBX5)) and microRNAs (miR-1, miR-133, miR-208 and miR-499) that control cardiomyocyte identity. Stimulating cardiomyocyte dedifferentiation and proliferation by activating mitotic signalling pathways involved in embryonic heart growth represents a complementary approach for heart regeneration and repair. Recent advances in understanding the mechanistic basis of heart development offer exciting opportunities for effective therapies for heart failure.
Liao, Song-Yan; Tse, Hung-Fat
Heart failure after myocardial infarction is the leading cause of mortality and morbidity worldwide. Existing medical and interventional therapies can only reduce the loss of cardiomyocytes during myocardial infarction but are unable to replenish the permanent loss of cardiomyocytes after the insult, which contributes to progressive pathological left ventricular remodeling and progressive heart failure. As a result, cell-based therapies using multipotent (adult) stem cells and pluripotent stem cells (embryonic stem cells or induced pluripotent stem cells) have been explored as potential therapeutic approaches to restore cardiac function in heart failure. Nevertheless, the optimal cell type with the best therapeutic efficacy and safety for heart regeneration is still unknown. In this review, the potential pros and cons of different types of multipotent (adult) stem cells and pluripotent stem cells that have been investigated in preclinical and clinical studies are reviewed, and the future perspective of stem cell-based therapy for heart regeneration is discussed.
Tufts, Debra Roben
The digital native has been the darling of market research and a major focus of education consternation throughout the first decade of the 2000s. These are the children and young adults the literature describes as those born after 1980 and who exhibit high technical savvy, particularly as it pertains to information and communication technology…
Myung, Peggy S; Takeo, Makoto; Ito, Mayumi; Atit, Radhika P
β-Catenin, a key transducer molecule of Wnt signaling, is required for adult hair follicle growth and regeneration. However, the cellular source of Wnt ligands required for Wnt/β-catenin activation during anagen induction is unknown. In this study, we genetically deleted Wntless (Wls), a gene required for Wnt ligand secretion by Wnt-producing cells, specifically in the hair follicle epithelium during telogen phase. We show that epithelial Wnt ligands are required for anagen, as loss of Wls in the follicular epithelium resulted in a profound hair cycle arrest. Both the follicular epithelium and dermal papilla showed markedly decreased Wnt/β-catenin signaling during anagen induction compared with control hair follicles. Surprisingly, hair follicle stem cells that are responsible for hair regeneration maintained expression of stem cell markers but exhibited significantly reduced proliferation. Finally, we demonstrate that epidermal Wnt ligands are critical for adult wound-induced de novo hair formation. Collectively, these data show that Wnt ligands secreted by the hair follicle epithelium are required for adult hair follicle regeneration and provide new insight into potential cellular targets for the treatment of hair disorders such as alopecia.
Liu, Shan; Zhou, Jingli; Zhang, Xuan; Liu, Yang; Chen, Jin; Hu, Bo; Song, Jinlin; Zhang, Yuanyuan
Stem cell therapy aims to replace damaged or aged cells with healthy functioning cells in congenital defects, tissue injuries, autoimmune disorders, and neurogenic degenerative diseases. Among various types of stem cells, adult stem cells (i.e., tissue-specific stem cells) commit to becoming the functional cells from their tissue of origin. These cells are the most commonly used in cell-based therapy since they do not confer risk of teratomas, do not require fetal stem cell maneuvers and thus are free of ethical concerns, and they confer low immunogenicity (even if allogenous). The goal of this review is to summarize the current state of the art and advances in using stem cell therapy for tissue repair in solid organs. Here we address key factors in cell preparation, such as the source of adult stem cells, optimal cell types for implantation (universal mesenchymal stem cells vs. tissue-specific stem cells, or induced vs. non-induced stem cells), early or late passages of stem cells, stem cells with endogenous or exogenous growth factors, preconditioning of stem cells (hypoxia, growth factors, or conditioned medium), using various controlled release systems to deliver growth factors with hydrogels or microspheres to provide apposite interactions of stem cells and their niche. We also review several approaches of cell delivery that affect the outcomes of cell therapy, including the appropriate routes of cell administration (systemic, intravenous, or intraperitoneal vs. local administration), timing for cell therapy (immediate vs. a few days after injury), single injection of a large number of cells vs. multiple smaller injections, a single site for injection vs. multiple sites and use of rodents vs. larger animal models. Future directions of stem cell-based therapies are also discussed to guide potential clinical applications.
Liu, Shan; Zhou, Jingli; Zhang, Xuan; Liu, Yang; Chen, Jin; Hu, Bo; Song, Jinlin; Zhang, Yuanyuan
Stem cell therapy aims to replace damaged or aged cells with healthy functioning cells in congenital defects, tissue injuries, autoimmune disorders, and neurogenic degenerative diseases. Among various types of stem cells, adult stem cells (i.e., tissue-specific stem cells) commit to becoming the functional cells from their tissue of origin. These cells are the most commonly used in cell-based therapy since they do not confer risk of teratomas, do not require fetal stem cell maneuvers and thus are free of ethical concerns, and they confer low immunogenicity (even if allogenous). The goal of this review is to summarize the current state of the art and advances in using stem cell therapy for tissue repair in solid organs. Here we address key factors in cell preparation, such as the source of adult stem cells, optimal cell types for implantation (universal mesenchymal stem cells vs. tissue-specific stem cells, or induced vs. non-induced stem cells), early or late passages of stem cells, stem cells with endogenous or exogenous growth factors, preconditioning of stem cells (hypoxia, growth factors, or conditioned medium), using various controlled release systems to deliver growth factors with hydrogels or microspheres to provide apposite interactions of stem cells and their niche. We also review several approaches of cell delivery that affect the outcomes of cell therapy, including the appropriate routes of cell administration (systemic, intravenous, or intraperitoneal vs. local administration), timing for cell therapy (immediate vs. a few days after injury), single injection of a large number of cells vs. multiple smaller injections, a single site for injection vs. multiple sites and use of rodents vs. larger animal models. Future directions of stem cell-based therapies are also discussed to guide potential clinical applications. PMID:27338364
Saponara, Enrica; Grabliauskaite, Kamile; Bombardo, Marta; Buzzi, Raphael; Silva, Alberto B; Malagola, Ermanno; Tian, Yinghua; Hehl, Adrian B; Schraner, Elisabeth M; Seleznik, Gitta M; Zabel, Anja; Reding, Theresia; Sonda, Sabrina; Graf, Rolf
The exocrine pancreas exhibits a distinctive capacity for tissue regeneration and renewal following injury. This regenerative ability has important implications for a variety of disorders, including pancreatitis and pancreatic cancer, diseases associated with high morbidity and mortality. Thus, understanding its underlying mechanisms may help in developing therapeutic interventions. Serotonin has been recognized as a potent mitogen for a variety of cells and tissues. Here we investigated whether serotonin exerts a mitogenic effect in pancreatic acinar cells in three regenerative models, inflammatory tissue injury following pancreatitis, tissue loss following partial pancreatectomy, and thyroid hormone-stimulated acinar proliferation. Genetic and pharmacological techniques were used to modulate serotonin levels in vivo. Acinar dedifferentiation and cell cycle progression during the regenerative phase were investigated over the course of 2 weeks. By comparing acinar proliferation in the different murine models of regeneration, we found that serotonin did not affect the clonal regeneration of mature acinar cells. Serotonin was, however, required for acinar dedifferentiation following inflammation-mediated tissue injury. Specifically, lack of serotonin resulted in delayed up-regulation of progenitor genes and delayed the formation of acinar-to-ductal metaplasia and defective acinar cell proliferation. We identified serotonin-dependent acinar secretion as a key step in progenitor-based regeneration, as it promoted acinar cell dedifferentiation and the recruitment of type 2 macrophages. Finally, we identified a regulatory Hes1-Ptfa axis in the uninjured adult pancreas, activated by zymogen secretion. Our findings indicated that serotonin plays a critical role in the regeneration of the adult pancreas following pancreatitis by promoting the dedifferentiation of acinar cells.
Golding, Anne; Levin, Michael; Kaplan, David L.
In certain amphibian models limb regeneration can be promoted or inhibited by the local wound bed environment. This research introduces a device that can be utilized as an experimental tool to characterize the conditions that promotes limb regeneration in the adult frog (Xenopus laevis) model. In particular, this device was designed to manipulate the local wound environment via a hydrogel insert. Initial characterization of the hydrogel insert revealed that this interaction had a significant influence on mechanical forces to the animal, due to the contraction of the hydrogel. The material and mechanical properties of the hydrogel insert were a factor in the device design in relation to the comfort of the animal and the ability to effectively manipulate the amputation site. The tunable features of the hydrogel were important in determining the pro-regenerative effects in limb regeneration, which was measured by cartilage spike formation and quantified by micro-computed tomography. The hydrogel insert was a factor in the observed morphological outcomes following amputation. Future work will focus on characterizing and optimizing the device’s observed capability to manipulate biological pathways that are essential for limb regeneration. However, the present work provides a framework for the role of a hydrogel in the device and a path forward for more systematic studies. PMID:27257960
CRISCIMANNA, ANGELA; SPEICHER, JULIE A.; HOUSHMAND, GOLBAHAR; SHIOTA, CHIYO; PRASADAN, KRISHNA; Ji, BAOAN; LOGSDON, CRAIG D.; GITTES, GEORGE K.; ESNI, FARZAD
BACKGROUND & AIMS There have been conflicting results on a cell of origin in pancreatic regeneration. These discrepancies predominantly stem from lack of specific markers for the pancreatic precursors/stem cells, as well as differences in the targeted cells and severity of tissue injury in the experimental models so far proposed. We attempted to create a model that used diphtheria toxin receptor (DTR) to ablate specific cell populations, control the extent of injury, and avoid induction of the inflammatory response. METHODS To target specific types of pancreatic cells, we crossed R26DTR or R26dtR/lacZ mice with transgenic mice that express the Cre recombinase in the pancreas, under control of the Pdx1 (global pancreatic) or elastase (acinar-specific) promoters. RESULTS Exposure of PdxCre;R26DTR mice to diphtheria toxin resulted in extensive ablation of acinar and endocrine tissues but not ductal cells. Surviving cells within the ductal compartment contributed to regeneration of endocrine and acinar cells via recapitulation of the embryonic pancreatic developmental program. However, following selective ablation of acinar tissue in ElaCre-ERT2;R26DTR mice, regeneration likely occurred by reprogramming of ductal cells to acinar lineage. CONCLUSIONS In the pancreas of adult mice, epithelial cells within the ductal compartment contribute to regeneration of endocrine and acinar cells. The severity of injury determines the regenerative mechanisms and cell types that contribute to this process. PMID:21763240
Broughton, Kathleen M; Sussman, Mark A
Much has changed since our survey of the landscape for myocardial regeneration powered by adult stem cells 4 years ago.(1) The intervening years since that first review has witnessed an explosive expansion of studies that advance both understanding and implementation of adult stem cells in promoting myocardial repair. Painstaking research from innumerable laboratories throughout the world is prying open doors that may lead to restoration of myocardial structure and function in the wake of pathological injury. This global effort has produced deeper mechanistic comprehension coupled with an evolving appreciation for the complexity of myocardial regeneration in the adult context. Undaunted by both known and (as yet) unknown challenges, pursuit of myocardial regenerative medicine mediated by adult stem cell therapy has gathered momentum fueled by tantalizing clues and visionary goals. This concise review takes a somewhat different perspective than our initial treatise, taking stock of the business sector that has become an integral part of the field while concurrently updating state of affairs in cutting edge research. Looking retrospectively at advancement over the years as all reviews eventually must, the fundamental lesson to be learned is best explained by Jonatan Mårtensson: "Success will never be a big step in the future. Success is a small step taken just now."
Porrello, Enzo R.; Mahmoud, Ahmed I.; Simpson, Emma; Johnson, Brett A.; Grinsfelder, David; Canseco, Diana; Mammen, Pradeep P.; Rothermel, Beverly A.; Olson, Eric N.; Sadek, Hesham A.
We recently identified a brief time period during postnatal development when the mammalian heart retains significant regenerative potential after amputation of the ventricular apex. However, one major unresolved question is whether the neonatal mouse heart can also regenerate in response to myocardial ischemia, the most common antecedent of heart failure in humans. Here, we induced ischemic myocardial infarction (MI) in 1-d-old mice and found that this results in extensive myocardial necrosis and systolic dysfunction. Remarkably, the neonatal heart mounted a robust regenerative response, through proliferation of preexisting cardiomyocytes, resulting in full functional recovery within 21 d. Moreover, we show that the miR-15 family of microRNAs modulates neonatal heart regeneration through inhibition of postnatal cardiomyocyte proliferation. Finally, we demonstrate that inhibition of the miR-15 family from an early postnatal age until adulthood increases myocyte proliferation in the adult heart and improves left ventricular systolic function after adult MI. We conclude that the neonatal mammalian heart can regenerate after myocardial infarction through proliferation of preexisting cardiomyocytes and that the miR-15 family contributes to postnatal loss of cardiac regenerative capacity. PMID:23248315
Hill, Caitlin E.; Harrison, Benjamin J.; Rau, Kris K.; Hougland, M. Tyler; Bunge, Mary Bartlett; Mendell, Lorne M.; Petruska, Jeffrey C.
Skin incision and nerve injury both induce painful conditions. Incisional and post-surgical pain is believed to arise primarily from inflammation of tissue and the subsequent sensitization of peripheral and central neurons. The role of axonal regeneration-related processes in development of pain has only been considered when there has been injury to the peripheral nerve itself, even though tissue damage likely induces injury of resident axons. We sought to determine if skin incision would affect expression of regeneration-related genes such as activating transcription factor 3 (ATF3) in dorsal root ganglion (DRG) neurons. ATF3 is absent from DRG neurons of the normal adult rodent, but is induced by injury of peripheral nerves and modulates the regenerative capacity of axons. Image analysis of immunolabeled DRG sections revealed that skin incision led to an increase in the number of DRG neurons expressing ATF3. RT-PCR indicated that other regeneration-associated genes (galanin, GAP-43, Gadd45a) were also increased, further suggesting an injury-like response in DRG neurons. Our finding that injury of skin can induce expression of neuronal injury/regeneration-associated genes may impact how clinical post-surgical pain is investigated and treated. Perspective Tissue injury, even without direct nerve injury, may induce a state of enhanced growth capacity in sensory neurons. Axonal regeneration-associated processes should be considered alongside nerve signal conduction and inflammatory/sensitization processes as possible mechanisms contributing to pain, particularly the transition from acute to chronic pain. PMID:20627820
Zhang, Lei; Wang, Huaxi; Yang, Yan; Liu, Hui; Zhang, Qihao; Xiang, Qi; Ge, Renshan; Su, Zhijian; Huang, Yadong
Highlights: •Nerve growth factor has shown significant changes on mRNA levels during Adult Leydig cells regeneration. •We established the organ culture model of rat seminiferous tubules with ethane dimethyl sulphonate (EDS) treatment. •Nerve growth factor has shown proliferation and differentiation-promoting effects on Adult stem Leydig cells. •Nerve growth factor induces progenitor Leydig cells to proliferate and differentiate and immature Leydig cells to proliferate. -- Abstract: Nerve growth factor (NGF) has been reported to be involved in male reproductive physiology. However, few reports have described the activity of NGF during Leydig cell development. The objective of the present study was to examine the role of NGF during stem-Leydig-cell (SLC) regeneration. We investigated the effects of NGF on Leydig-cell (LC) regeneration by measuring mRNA levels in the adult rat testis after ethane dimethanesulfonate (EDS) treatment. Furthermore, we used the established organ culture model of rat seminiferous tubules to examine the regulation of NGF during SLC proliferation and differentiation using EdU staining, real-time PCR and western blotting. Progenitor Leydig cells (PLCs) and immature Leydig cells (ILCs) were also used to investigate the effects of NGF on LCs at different developmental stages. NGF mRNA levels changed significantly during Leydig-cell regeneration in vivo. In vitro, NGF significantly promoted the proliferation of stem Leydig cells and also induced steroidogenic enzyme gene expression and 3β-HSD protein expression. The data from PLCs and ILCs showed that NGF could increase Cyclin D1 and Hsd 17b3 mRNA levels in PLCs and Cyclin D1 mRNA levels in ILCs. These results indicate that NGF may play an important role during LC regeneration by regulating the proliferation and differentiation of LCs at different developmental stages, from SLCs to PLCs and from PLCs to ILCs. The discovery of this effect of NGF on Leydig cells will provide useful
de Preux Charles, Anne-Sophie; Bise, Thomas; Baier, Felix; Marro, Jan; Jaźwińska, Anna
The adult heart is able to activate cardioprotective programmes and modifies its architecture in response to physiological or pathological changes. While mammalian cardiac remodelling often involves hypertrophic expansion, the adult zebrafish heart exploits hyperplastic growth. This capacity depends on the responsiveness of zebrafish cardiomyocytes to mitogenic signals throughout their entire life. Here, we have examined the role of inflammation on the stimulation of cell cycle activity in the context of heart preconditioning and regeneration. We used thoracotomy as a cardiac preconditioning model and cryoinjury as a model of cardiac infarction in the adult zebrafish. First, we performed a spatio-temporal characterization of leucocytes and cycling cardiac cells after thoracotomy. This analysis revealed a concomitance between the infiltration of inflammatory cells and the stimulation of the mitotic activity. However, decreasing the immune response using clodronate liposome injection, PLX3397 treatment or anti-inflammatory drugs surprisingly had no effect on the re-entry of cardiac cells into the cell cycle. In contrast, reducing inflammation using the same strategies after cryoinjury strongly impaired cardiac cell mitotic activity and the regenerative process. Taken together, our results show that, while the immune response is not necessary to induce cell-cycle activity in intact preconditioned hearts, inflammation is required for the regeneration of injured hearts in zebrafish. PMID:27440424
Fernandez Vallone, Valeria; Leprovots, Morgane; Strollo, Sandra; Vasile, Gabriela; Lefort, Anne; Libert, Frederick; Vassart, Gilbert; Garcia, Marie-Isabelle
Mouse fetal intestinal progenitors lining the epithelium prior to villogenesis grow as spheroids when cultured ex vivo and express the transmembrane glycoprotein Trop2 as a marker. Here, we report the characterization of Trop2-expressing cells from fetal pre-glandular stomach, growing as immortal undifferentiated spheroids, and their relationship with gastric development and regeneration. Trop2(+) cells generating gastric spheroids differed from adult glandular Lgr5(+) stem cells, but appeared highly related to fetal intestinal spheroids. Although they shared a common spheroid signature, intestinal and gastric fetal spheroid-generating cells expressed organ-specific transcription factors and were committed to intestinal and glandular gastric differentiation, respectively. Trop2 expression was transient during glandular stomach development, being lost at the onset of gland formation, whereas it persisted in the squamous forestomach. Undetectable under homeostasis, Trop2 was strongly re-expressed in glands after acute Lgr5(+) stem cell ablation or following indomethacin-induced injury. These highly proliferative reactive adult Trop2(+) cells exhibited a transcriptome displaying similarity with that of gastric embryonic Trop2(+) cells, suggesting that epithelium regeneration in adult stomach glands involves the partial re-expression of a fetal genetic program.
Cervera, Magdalena; Navarro, Antonio; Navarro, Luis; Peña, Leandro
Genetic transformation of mature trees is difficult because adult tissues are recalcitrant to Agrobacterium tumefaciens infection and transformation and because transgenic mature events are less competent for regeneration. We have shown that reinvigoration allows manipulation of the vegetative phase to increase the potential for transformation and regeneration without loss of competence for flowering and fruiting. To produce transgenic plants from clementine mandarin (Citrus clementina hort. ex Tanaka), we optimized the conditions of the source material both ex vitro and in vitro. Grafting of mature buds on juvenile rootstocks in the spring and preventing multiple bud sprouting by removing all but one bud permitted selection of vigorous first flushes for in vitro culture. Use of additional virulence genes from A. tumefaciens to increase transformation frequency and optimization of culture media and conditions to enhance explant cell competence for T-DNA integration and organogenesis resulted in efficient and reliable transgenic plant production. Transformed regenerants from explants, cultured in media without antibiotics, were identified by a screenable marker (either beta-glucuronidase or green fluorescent protein (GFP)), creating the possibility of generating transgenic clementine plants without antibiotic resistance marker genes. Stable integration of foreign genes was demonstrated by Southern blot analysis, and expression of these foreign genes was confirmed by detection of GFP fluorescence in leaves, floral organs and fruits of the transgenic plants.
Berry, M; Hunter, A S; Duncan, A; Lordan, J; Kirvell, S; Tsang, W L; Butt, A M
The anterior medullary velum (AMV) of adult Wistar rats was lesioned in the midsagittal plane, transecting all decussating axons including those of the central projection of the IVth nerve. At selected times up to 200 days after transection, the degenerative and regenerative responses of axons and glia were analyzed using transmission and scanning electron microscopy and immunohistochemistry. In particular, both the capacity of oligodendrocytes to remyelinate regenerated fibers and the stability of the CNS/PNS junctional zone of the IVth nerve rootlet were documented. Transected central AMV axons exhibited four patterns of fiber regeneration in which fibers grew: rostrocaudally in the reactive paralesion neuropil (Group 1); randomly within the AMV (Group 2); into the ipsilateral IVth nerve rootlet, after turning at the lesion edge and growing recurrently through the old degenerated contralateral central trochlear nerve trajectory (Group 3); and ectopically through paralesion tears in the ependyma onto the surface of the IVth ventricle (Group 4). Group 1-3 axons regenerated unperturbed through degenerating central myelin, reactive astrocytes, oligodendrocytes, microglia, and large accumulations of hematogenous macrophages. Only Group 3 axons survived long term in significant numbers, and all became myelinated by oligodendrocytes, ultimately establishing thin sheaths with relatively normal nodal gaps and intersegmental myelin sheath lengths. Schwann cells at the CNS/PNS junction of the IVth nerve rootlet did not invade the CNS, but astrocyte processes grew across the junction into the PNS portion of the IVth nerve. The basal lamina of the junctional glia limitans remained stable throughout the experimental period.
Hill, D L; Phillips, L M
Unilateral chorda tympani nerve sectioning was combined with institution of a sodium-restricted diet in adult rats to determine the role that environment has on the functional properties of regenerating taste receptor cells. Rats receiving chorda tympani sectioning but no dietary manipulation (cut controls) and rats receiving only the dietary manipulation (diet controls) had normal responses to a concentration series of NaCl, sodium acetate (NaAc), and NH4Cl. However, responses from the regenerated nerve in NaCl-restricted rats (40-120 d postsectioning) to NaCl and NaAc were reduced by as much as 30% compared to controls, indicating that regenerating taste receptors are influenced by environmental (dietary) factors. Responses to NH4Cl were normal; therefore, the effect appears specific to sodium salts. Surprisingly, in the same rats, NaCl responses from the contralateral, intact chorda tympani were up to 40% greater than controls. Thus, in the same rat, there was over a twofold difference in sodium responses between the right and left chorda tympani nerves. A study of the time course of the functional alterations in the intact nerve revealed that responses to NaCl were extremely low immediately following sectioning (about 20% of the normal response), and then increased monotonically during the following 50 d until relative response magnitudes became supersensitive. This function occurred even when the cut chorda tympani was prevented from reinnervating lingual epithelia, demonstrating that events related to regeneration do not play a role in the functional properties of the contralateral side of the tongue.(ABSTRACT TRUNCATED AT 250 WORDS)
Davies, Erin L; Lei, Kai; Seidel, Christopher W; Kroesen, Amanda E; McKinney, Sean A; Guo, Longhua; Robb, Sofia Mc; Ross, Eric J; Gotting, Kirsten; Alvarado, Alejandro Sánchez
Planarian neoblasts are pluripotent, adult somatic stem cells and lineage-primed progenitors that are required for the production and maintenance of all differentiated cell types, including the germline. Neoblasts, originally defined as undifferentiated cells residing in the adult parenchyma, are frequently compared to embryonic stem cells yet their developmental origin remains obscure. We investigated the provenance of neoblasts during Schmidtea mediterranea embryogenesis, and report that neoblasts arise from an anarchic, cycling piwi-1+ population wholly responsible for production of all temporary and definitive organs during embryogenesis. Early embryonic piwi-1+ cells are molecularly and functionally distinct from neoblasts: they express unique cohorts of early embryo enriched transcripts and behave differently than neoblasts in cell transplantation assays. Neoblast lineages arise as organogenesis begins and are required for construction of all major organ systems during embryogenesis. These subpopulations are continuously generated during adulthood, where they act as agents of tissue homeostasis and regeneration.
Rijntjes, Eddy; van Kesteren-Buiting, Anita; Keijer, Jaap; Teerds, Katja J
Chronic prenatally induced dietary hypothyroidism delays adult-type Leydig cell development, but does not block this process. Using a chemical model to induce hypothyroidism, it was suggested that development of a new population of Leydig cells was completely inhibited following the addition of the cytotoxic compound ethane-1,2-dimethyl sulphonate (EDS). In this study, we used a dietary approach to induce hypothyroidism and reinvestigated the regeneration of the Leydig cell population following EDS administration. Eighty-four day old euthyroid and chronically hypothyroid rats received an injection of EDS and were killed directly before or at regular intervals up to 77 days after EDS. In some control and hypothyroid animals, the first progenitor-type Leydig cells were observed at day 12 after EDS. At day 16, Leydig cell progenitors were present in all rats. The percentage of proliferating Leydig cells peaked in the euthyroid animals at day 21 after EDS. In the hypothyroid testis such a peak was not observed, although the percentage of proliferating regenerating Leydig cells was significantly higher from days 35 to 56 compared with the controls. This suggested that the wave of Leydig cell proliferation was delayed in the hypothyroid animals as compared with the euthyroid controls. On the day of EDS injection, the Leydig/Sertoli cell ratio was 37% lower in the hypothyroid rats compared with the controls. The Leydig/Sertoli cell ratio remained lower in the EDS-treated hypothyroid animals compared with the controls at all time points investigated. At day 77 after EDS, the Leydig cell population had returned to its pre-treatment size in both groups. Plasma testosterone production was reduced to below detectable levels immediately after EDS injection, and started to increase again on day 16, reaching pre-treatment values on day 21 in both groups. Taken together, severely reduced thyroid hormone levels did not block the regeneration of the adult-type Leydig cell population
Valarmathi, Mani T; Goodwin, Richard L; Fuseler, John W; Davis, Jeffrey M; Yost, Michael J; Potts, Jay D
Adult bone marrow stromal cells (BMSCs) are capable of differentiating into cardiomyocyte-like cells in vitro and contribute to myocardial regeneration in vivo. Consequently, BMSCs may potentially play a vital role in cardiac repair and regeneration. However, this concept has been limited by inadequate and inconsistent differentiation of BMSCs into cardiomyocytes along with poor survival and integration of neo-cardiomyocytes after implantation into ischemic myocardium. In order to overcome these barriers and to explore adult stem cell based myocardial regeneration, we have developed an in vitro model of three-dimensional (3-D) cardiac muscle using rat ventricular embryonic cardiomyocytes (ECMs) and BMSCs. When ECMs and BMSCs were seeded sequentially onto a 3-D tubular scaffold engineered from topographically aligned type I collagen-fibers and cultured in basal medium for 7, 14, 21, or 28 days, the maturation and co-differentiation into a cardiomyocyte lineage was observed. Phenotypic induction was characterized at morphological, immunological, biochemical and molecular levels. The observed expression of transcripts coding for cardiomyocyte phenotypic markers and the immunolocalization of cardiomyogenic lineage-associated proteins revealed typical expression patterns of neo-cardiomyogenesis. At the biochemical level differentiating cells exhibited appropriate metabolic activity and at the ultrastructural level myofibrillar and sarcomeric organization were indicative of an immature phenotype. Our 3-D co-culture system sustains the ECMs in vitro continuum of differentiation process and simultaneously induces the maturation and differentiation of BMSCs into cardiomyocyte-like cells. Thus, this novel 3-D co-culture system provides a useful in vitro model to investigate the functional role and interplay of developing ECMs and BMSCs during cardiomyogenic differentiation.
Chen, Bingbing; Chen, Dongxin; Jiang, Zheli; Li, Jingyang; Liu, Shiwen; Dong, Yaoyao; Yao, Wenwen; Akingbemi, Benson; Ge, Renshan; Li, Xiaokun
The objective of the present study is to determine whether methoxychlor (MXC) exposure in adulthood affects rat Leydig cell regeneration and to compare its effects with estradiol (E2). Adult 90-day-old male Sprague-Dawley rats received ethane dimethane sulfonate (EDS) to eliminate the adult Leydig cell population. Subsequently, rats were randomly assigned to four groups and gavaged with corn oil (control), 0.25 mg/kg E2 and 10 or 100 mg/kg MXC daily from days 5 to 30 post-EDS treatment. The results showed that MXC and E2 reduced serum testosterone levels on day 58 post-EDS treatment. qPCR showed Hsd17b3 mRNA levels were downregulated 7–15 fold by E2 and MXC, indicating that development of the new population of Leydig cells was arrested at the earlier stage. This observation was supported by the results of histochemical staining, which demonstrated that Leydig cells in MXC-treated testis on day 58 post-EDS treatment were mostly progenitor Leydig cells. However, Pdgfb mRNA levels were downregulated, while Lif transcript levels were increased by MXC. In contrast, E2 did not affect gene expression for these growth factors. In conclusion, our findings indicated that both MXC and E2 delayed rat Leydig cell regeneration in the EDS-treated model, presumably acting by different mechanisms. PMID:24806340
Xin, Mei; Olson, Eric N.; Bassel-Duby, Rhonda
As the adult mammalian heart has limited potential for regeneration and repair, the loss of cardiomyocytes during injury and disease can result in heart failure and death. The cellular processes and regulatory mechanisms involved in heart growth and development can be exploited to repair the injured adult heart through ‘reawakening’ pathways that are active during embryogenesis. Heart function has been restored in rodents by reprogramming non-myocytes into cardiomyocytes, by expressing transcription factors (GATA4, HAND2, myocyte-specific enhancer factor 2C (MEF2C) and T-box 5 (TBX5)) and microRNAs (miR-1, miR-133, miR-208 and miR-499) that control cardiomyocyte identity. Stimulating cardiomyocyte dedifferentiation and proliferation by activating mitotic signalling pathways involved in embryonic heart growth represents a complementary approach for heart regeneration and repair. Recent advances in understanding the mechanistic basis of heart development offer exciting opportunities for effective therapies for heart failure. PMID:23839576
Sambasivan, Ramkumar; Yao, Roseline; Kissenpfennig, Adrien; Van Wittenberghe, Laetitia; Paldi, Andràs; Gayraud-Morel, Barbara; Guenou, Hind; Malissen, Bernard; Tajbakhsh, Shahragim; Galy, Anne
Distinct cell populations with regenerative capacity have been reported to contribute to myofibres after skeletal muscle injury, including non-satellite cells as well as myogenic satellite cells. However, the relative contribution of these distinct cell types to skeletal muscle repair and homeostasis and the identity of adult muscle stem cells remain unknown. We generated a model for the conditional depletion of satellite cells by expressing a human diphtheria toxin receptor under control of the murine Pax7 locus. Intramuscular injection of diphtheria toxin during muscle homeostasis, or combined with muscle injury caused by myotoxins or exercise, led to a marked loss of muscle tissue and failure to regenerate skeletal muscle. Moreover, the muscle tissue became infiltrated by inflammatory cells and adipocytes. This localised loss of satellite cells was not compensated for endogenously by other cell types, but muscle regeneration was rescued after transplantation of adult Pax7(+) satellite cells alone. These findings indicate that other cell types with regenerative potential depend on the presence of the satellite cell population, and these observations have important implications for myopathic conditions and stem cell-based therapeutic approaches.
Fassmann, Wesley N.; McDonald, Samuel J.; Thomson, Scott L.; Fish, Frank E.
During feeding, humpback whales turn with a turn radius of up to 1 /6th of their length towards schools of fish enclosed by bubble nets. This high maneuverability requirement is facilitated by high aspect ratio flippers with leading edge tubercles that delay stall. Previous experimental and computational studies have used idealized models, such as airfoils with scalloped leading edges, to explore the influence of leading edge tubercles on boundary layer separation, vortex generation, and airfoil lift and drag characteristics. Owing to the substantial size of the flipper, no studies have been performed on a digitized adult humpback flipper with real geometry. In this study the hydrodynamics of a realistic humpback flipper model were explored. The model was developed by digitizing a sequence of 18 images circumscribing the suspended flipper of a beached humpback whale. A physical prototype was constructed based on the resulting 3D model, along with a complementary model with the tubercles removed. Experimentally-obtained measurements of lift and drag were used to study the influence of the tubercles. In the presentation, digitization and flow measurement methods are described, and the flow data and results are presented and discussed.
Uygur, Aysu; Lee, Richard T.
Adult humans fail to regenerate their hearts following injury, and this failure to regenerate myocardium is a leading cause of heart failure and death worldwide. Although all adult mammals appear to lack significant cardiac regeneration potential, some vertebrates can regenerate myocardium throughout life. In addition, new studies indicate that mammals have cardiac regeneration potential during development and very soon after birth. The mechanisms of heart regeneration among model organisms, including neonatal mice, appear remarkably similar. Orchestrated waves of inflammation, matrix deposition and remodeling, and cardiomyocyte proliferation are commonly seen in heart regeneration models. Understanding why adult mammals develop extensive scarring instead of regeneration is a crucial goal for regenerative biology. PMID:26906733
Liuzzi, F J; Lasek, R J
Lumbar dorsal roots of adult frogs were crushed or cut and reanastomosed. Following survival times of up to 75 days, the regenerating dorsal roots were recut and anterogradely injury-filled with horseradish peroxidase. This revealed that in the adult frog, regenerating axons re-enter the spinal cord. Comparison of the distribution of these axons with that of normal dorsal root axons showed that there is a partial restoration of the segmental distribution in the gray matter. However, the long ascending sensory tract of the dorsal funiculus was not restored. The dorsal funiculus was markedly gliotic and had relatively few labelled, regenerated axons. The labelled axons that were seen in the dorsal funiculus either extended longitudinally for a distance just beneath the pia, apparently in association with the glia limitans, or traversed the region to enter the dorsal gray matter. Most of the large and small diameter axons that entered the gray matter did so by passing through the region of the dorsolateral fasciculus. Within the gray matter, small diameter, regenerated axons arborized in the region of the dorsal terminal field, a region that has been shown in the normal frog to receive cutaneous afferents only. Many large diameter axons, presumably muscle afferents, arborized in the ventral terminal field, a region shown in the normal frog to receive muscle afferents exclusively. However, many of these large diameter axons had arborizations that extended to both terminal fields, thus suggesting that some abberant connections are made during dorsal root regeneration in the adult frog.
Jacobs, Gloria E.; Castek, Jill; Pizzolato, Andrew; Reder, Stephen; Pendell, Kimberly
In this column, the authors discuss emerging research in the field of adult digital literacy acquisition. The authors argue that the field of adult digital literacy acquisition has been under-researched, especially in relation to multiliteracies and multimodal literacy practices. Data emerging from a large scale mixed methods study of adults…
Kidd, Terry T., Ed.; Keengwe, Jared, Ed.
As instructors move further into the incorporation of 21st century technologies in adult education, a new paradigm of digitally-enriched mediated learning has emerged. This book provides a comprehensive framework of trends and issues related to adult learning for the facilitation of authentic learning in the age of digital technology. This…
Adult learning today takes place primarily within walled classrooms or in other indoor settings, and often in front of various types of digital screens. As adults have adopted the digital technologies and indoor lifestyle attributed to the so-called "Net Generation," we have become detached from contact with the natural world outdoors.…
Boldrin, Luisa; Zammit, Peter Steven; Muntoni, Francesco; Morgan, Jennifer Elizabeth
Changes that occur in the skeletal muscle environment with the progress of muscular dystrophies may affect stem cell function and result in impaired muscle regeneration. It has previously been suggested that the success of stem cell transplantation could therefore be dependent both on the properties of the cell itself and on the host muscle environment. Here we engrafted young and mature adult mdx-nude mice, which are the genetic homolog of Duchenne muscular dystrophy, with a small number of satellite cells freshly isolated from young, normal donor mice. We found that the donor satellite cells contributed to muscle regeneration and self-renewal as efficiently within mature adult, as in young, dystrophic host muscle. Donor-derived satellite cells also contributed to robust regeneration after further injury, showing that they were functional despite the more advanced dystrophic muscle environment. These findings provide evidence that muscle tissue in a later stage of dystrophy may be effectively treated by stem cells.
Frank, T. C.; Dye, B. J.; Newlands, S. D.; Dickman, J. D.
OBJECTIVE: The purpose of this study was to develop a technique to investigate the regeneration of utricular hair cells in the adult pigeon (Columba livia) following complete hair cell loss through administration of streptomycin. STUDY DESIGN: Experimental animal study. METHODS: Animals were divided into four groups. Group 1 received 10 to 15 days of systemic streptomycin injections. Animals in Groups 2 and 3 received a single direct placement of a 1-, 2-, 4-, or 8-mg streptomycin dose into the perilymphatic space. Animals in Groups 1 and 2 were analyzed within 1 week from injection to investigate hair cell destruction, whereas Group 3 was investigated at later dates to study hair cell recovery. Group 4 animals received a control injection of saline into the perilymphatic space. Damage and recovery were quantified by counting hair cells in isolated utricles using scanning electron microscopy. RESULTS: Although systemic injections failed to reliably achieve complete utricular hair cell destruction, a single direct placement of a 2-, 4-, or 8-mg streptomycin dose caused complete destruction within the first week. Incomplete hair cell loss was observed with the 1-mg dose. Over the long term, regeneration of the hair cells was seen with the 2-mg dose but not the 8-mg dose. Control injections of saline into the perilymphatic space caused no measurable hair cell loss. CONCLUSIONS: Direct placement of streptomycin into the perilymph is an effective, reliable method for complete destruction of utricular hair cells while preserving the regenerative potential of the neuroepithelium.
Thomas, Jennifer L.; Thummel, Ryan
Light-induced retinal degeneration (LIRD) is commonly used in both rodents and zebrafish to damage rod and cone photoreceptors. In adult zebrafish, photoreceptor degeneration triggers Müller glial cells to re-enter the cell cycle and produce transient-amplifying progenitors. These progenitors continue to proliferate as they migrate to the damaged area, where they ultimately give rise to new photoreceptors. Currently, there are two widely-used LIRD paradigms, each of which results in varying degrees of photoreceptor loss and corresponding differences in the regeneration response. As more genetic and pharmacological tools are available to test the role of individual genes of interest during regeneration, there is a need to develop a robust LIRD paradigm. Here we describe a LIRD protocol that results in widespread and consistent loss of both rod and cone photoreceptors in which we have combined the use of two previously established LIRD techniques. Furthermore, this protocol can be extended for use in pigmented animals, which eliminates the need to maintain transgenic lines of interest on the albino background for LIRD studies. PMID:24192580
Bernier-Latmani, Jeremiah; Cisarovsky, Christophe; Demir, Cansaran Saygili; Bruand, Marine; Jaquet, Muriel; Davanture, Suzel; Ragusa, Simone; Siegert, Stefanie; Dormond, Olivier; Benedito, Rui; Radtke, Freddy; Luther, Sanjiv A.; Petrova, Tatiana V.
The small intestine is a dynamic and complex organ that is characterized by constant epithelium turnover and crosstalk among various cell types and the microbiota. Lymphatic capillaries of the small intestine, called lacteals, play key roles in dietary fat absorption and the gut immune response; however, little is known about the molecular regulation of lacteal function. Here, we performed a high-resolution analysis of the small intestinal stroma and determined that lacteals reside in a permanent regenerative, proliferative state that is distinct from embryonic lymphangiogenesis or quiescent lymphatic vessels observed in other tissues. We further demonstrated that this continuous regeneration process is mediated by Notch signaling and that the expression of the Notch ligand delta-like 4 (DLL4) in lacteals requires activation of VEGFR3 and VEGFR2. Moreover, genetic inactivation of Dll4 in lymphatic endothelial cells led to lacteal regression and impaired dietary fat uptake. We propose that such a slow lymphatic regeneration mode is necessary to match a unique need of intestinal lymphatic vessels for both continuous maintenance, due to the constant exposure to dietary fat and mechanical strain, and efficient uptake of fat and immune cells. Our work reveals how lymphatic vessel responses are shaped by tissue specialization and uncover a role for continuous DLL4 signaling in the function of adult lymphatic vasculature. PMID:26529256
Rizzoti, Karine; Akiyama, Haruhiko; Lovell-Badge, Robin
Pituitary hormone deficiencies, with Growth Hormone deficiency being most frequent (1 in 3,500-10,000 births), cause significant morbidity. Regeneration of missing endocrine cells would be a significant improvement over hormone replacement therapies, which incur side effects and do not mimic physiological secretion patterns. Recent in vitro studies have identified a population of adult pituitary progenitors that express the HMG box transcription factors SOX2 and SOX9. Here, we apply cell-lineage tracing analysis to demonstrate that SOX2- and SOX9-expressing progenitors can self-renew and give rise to endocrine cells in vivo, suggesting that they are tissue stem cells. Moreover, we show that they can become mobilized and differentiate into the appropriate endocrine cell types in response to physiological stress. Our results highlight the pituitary as a model for exploring how physiological changes influence stem cell behavior and suggest that manipulation of endogenous pituitary stem cells is a potential therapeutic strategy for pituitary deficiencies.
Cui, Qi; Yip, Henry K; Zhao, Robert C H; So, Kwok-Fai; Harvey, Alan R
In vitro, cyclic AMP (cAMP) elevation alters neuronal responsiveness to diffusible growth factors and myelin-associated inhibitory molecules. Here we used an established in vivo model of adult central nervous system injury to investigate the effects of elevated cAMP on neuronal survival and axonal regeneration. We studied the effects of intraocular injections of neurotrophic factors and/or a cAMP analogue (CPT-cAMP) on the regeneration of axotomized rat retinal ganglion cell (RGC) axons into peripheral nerve autografts. Elevation of cAMP alone did not significantly increase RGC survival or the number of regenerating RGCs. Ciliary neurotrophic factor increased RGC viability and axonal regrowth, the latter effect substantially enhanced by coapplication with CPT-cAMP. Under these conditions over 60% of surviving RGCs regenerated their axons. Neurotrophin-4/5 injections also increased RGC viability, but there was reduced long-distance axonal regrowth into grafts, an effect partially ameliorated by cAMP elevation. Thus, cAMP can act cooperatively with appropriate neurotrophic factors to promote axonal regeneration in the injured adult mammalian central nervous system.
Kikuta, Shu; Sakamoto, Takashi; Nagayama, Shin; Kanaya, Kaori; Kinoshita, Makoto; Kondo, Kenji; Tsunoda, Koichi; Mori, Kensaku; Yamasoba, Tatsuya
Although it is well known that injury induces the generation of a substantial number of new olfactory sensory neurons (OSNs) in the adult olfactory epithelium (OE), it is not well understood whether olfactory sensory input influences the survival and maturation of these injury-induced OSNs in adults. Here, we investigated whether olfactory sensory deprivation affected the dynamic incorporation of newly generated OSNs 3, 7, 14, and 28 d after injury in adult mice. Mice were unilaterally deprived of olfactory sensory input by inserting a silicone tube into their nostrils. Methimazole, an olfactotoxic drug, was also injected intraperitoneally to bilaterally ablate OSNs. The OE was restored to its preinjury condition with new OSNs by day 28. No significant differences in the numbers of olfactory marker protein-positive mature OSNs or apoptotic OSNs were observed between the deprived and nondeprived sides 0-7 d after injury. However, between days 7 and 28, the sensory-deprived side showed markedly fewer OSNs and mature OSNs, but more apoptotic OSNs, than the nondeprived side. Intrinsic functional imaging of the dorsal surface of the olfactory bulb at day 28 revealed that responses to odor stimulation were weaker in the deprived side compared with those in the nondeprived side. Furthermore, prevention of cell death in new neurons 7-14 d after injury promoted the recovery of the OE. These results indicate that, in the adult OE, sensory deprivation disrupts compensatory OSN regeneration after injury and that newly generated OSNs have a critical time window for sensory-input-dependent survival 7-14 d after injury.
Kwiecien, Jacek M; Avram, Ronen
Studies of regeneration of transected adult central nervous system (CNS) axons are difficult due to lack of appropriate in vivo models. In adult rats, we described filum terminale (FT), a caudal slender extension of the sacral spinal cord and an integral part of the central nervous system (CNS), to use it as a model of spinal cord injury. FT is more than 3 cm long, encompasses a central canal lined with ependymal cells surrounded by a narrow band of axons interspersed with oligodendrocytes and astrocytes but not neurons. Two weeks after the crush of FT, histological, ultrastructural, and axonal tracing studies revealed long distance descending axonal regeneration uniquely in close proximity of the ependymal cells of the central canal. Ependymal cells extended basal processes to form channels encompassing axons apparently regenerating at a rate of more than 2 mm a day. Remarkable increase of axonal sprouting was observed in the sacral spinal cord of Long Evans Shaker (LES) rats with crushed FT. FT offers an excellent model to study mechanisms of axonal regeneration regulated by ependymal cells in the adult CNS.
Wegener, Marie; Bader, Augustinus; Giri, Shibashish
The recently developed ability to differentiate primary adult stem cells and induced pluripotent stem cells (iPSCs) into cardiomyocytes is providing unprecedented opportunities to produce an unlimited supply of cardiomyocytes for use in patients with heart disease. Here, we examine the evidence for the preclinical use of such cells for successful heart regeneration. We also describe advances in the identification of new cardiac molecular and cellular targets to induce proliferation of cardiomyocytes for heart regeneration. Such new advances are paving the way for a new innovative drug development process for the treatment of heart disease.
Davies, Erin L; Lei, Kai; Seidel, Christopher W; Kroesen, Amanda E; McKinney, Sean A; Guo, Longhua; Robb, Sofia MC; Ross, Eric J; Gotting, Kirsten; Alvarado, Alejandro Sánchez
Planarian neoblasts are pluripotent, adult somatic stem cells and lineage-primed progenitors that are required for the production and maintenance of all differentiated cell types, including the germline. Neoblasts, originally defined as undifferentiated cells residing in the adult parenchyma, are frequently compared to embryonic stem cells yet their developmental origin remains obscure. We investigated the provenance of neoblasts during Schmidtea mediterranea embryogenesis, and report that neoblasts arise from an anarchic, cycling piwi-1+ population wholly responsible for production of all temporary and definitive organs during embryogenesis. Early embryonic piwi-1+ cells are molecularly and functionally distinct from neoblasts: they express unique cohorts of early embryo enriched transcripts and behave differently than neoblasts in cell transplantation assays. Neoblast lineages arise as organogenesis begins and are required for construction of all major organ systems during embryogenesis. These subpopulations are continuously generated during adulthood, where they act as agents of tissue homeostasis and regeneration. DOI: http://dx.doi.org/10.7554/eLife.21052.001 PMID:28072387
Fiegel, H C; Lange, Claudia; Kneser, U; Lambrecht, W; Zander, A R; Rogiers, X; Kluth, D
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.
Hewson, Jennifer; Danbrook, Claire; Sieppert, Jackie
A five day Digital Storytelling course was offered to Social Work students, integrating a three day workshop with older adult storytellers who shared stories related to the theme stories of home. A course evaluation was conducted exploring the Digital Storytelling experience and learning in an intergenerational setting. Findings from surveys…
Jelfs, Anne; Richardson, John T. E.
In June 2010, a survey was carried out to explore access to digital technology, attitudes to digital technology and approaches to studying across the adult life span in students taking courses with the UK Open University. In total, 7000 people were surveyed, of whom more than 4000 responded. Nearly all these students had access to a computer and…
Some studies of technology use by immigrants have explored the role of digital media in their maintenance of affiliations with their nations of origin. However, the potential for transnational social networks to serve as "resources" that facilitate digital literacy socialization for adult immigrant learners remains unexplored. In this…
Dupraz, Sebastián; Grassi, Diego; Karnas, Diana; Nieto Guil, Alvaro F; Hicks, David; Quiroga, Santiago
Axonal regeneration is an essential condition to re-establish functional neuronal connections in the injured adult central nervous system (CNS), but efficient regrowth of severed axons has proven to be very difficult to achieve. Although significant progress has been made in identifying the intrinsic and extrinsic mechanisms involved, many aspects remain unresolved. Axonal development in embryonic CNS (hippocampus) requires the obligate activation of the insulin-like growth factor 1 receptor (IGF-1R). Based on known similarities between axonal growth in fetal compared to mature CNS, we decided to examine the expression of the IGF-1R, using an antibody to the βgc subunit or a polyclonal anti-peptide antibody directed to the IGF-R (C20), in an in vitro model of adult CNS axonal regeneration, namely retinal ganglion cells (RGC) derived from adult rat retinas. Expression of both βgc and the β subunit recognized by C20 antibody were low in freshly isolated adult RGC, but increased significantly after 4 days in vitro. As in embryonic axons, βgc was localised to distal regions and leading growth cones in RGC. IGF-1R-βgc co-localised with activated p85 involved in the phosphatidylinositol-3 kinase (PI3K) signaling pathway, upon stimulation with IGF-1. Blocking experiments using either an antibody which neutralises IGF-1R activation, shRNA designed against the IGF-1R sequence, or the PI3K pathway inhibitor LY294002, all significantly reduced axon regeneration from adult RGC in vitro (∼40% RGC possessed axons in controls vs 2-8% in the different blocking studies). Finally, co-transfection of RGC with shRNA to silence IGF-1R together with a vector containing a constitutively active form of downstream PI3K (p110), fully restored axonal outgrowth in vitro. Hence these data demonstrate that axonal regeneration in adult CNS neurons requires re-expression and activation of IGF-1R, and targeting this system may offer new therapeutic approaches to enhancing axonal
Williams, Ryan R; Venkatesh, Ishwariya; Pearse, Damien D; Udvadia, Ava J; Bunge, Mary Bartlett
Unlike CNS neurons in adult mammals, neurons in fish and embryonic mammals can regenerate their axons after injury. These divergent regenerative responses are in part mediated by the growth-associated expression of select transcription factors. The basic helix-loop-helix (bHLH) transcription factor, MASH1/Ascl1a, is transiently expressed during the development of many neuronal subtypes and regulates the expression of genes that mediate cell fate determination and differentiation. In the adult zebrafish (Danio rerio), Ascl1a is also transiently expressed in retinal ganglion cells (RGCs) that regenerate axons after optic nerve crush. Utilizing transgenic zebrafish with a 3.6 kb GAP43 promoter that drives expression of an enhanced green fluorescent protein (EGFP), we observed that knock-down of Ascl1a expression reduces both regenerative gap43 gene expression and axonal growth after injury compared to controls. In mammals, the development of noradrenergic brainstem neurons requires MASH1 expression. In contrast to zebrafish RGCs, however, MASH1 is not expressed in the mammalian brainstem after spinal cord injury (SCI). Therefore, we utilized adeno-associated viral (AAV) vectors to overexpress MASH1 in four month old rat (Rattus norvegicus) brainstem neurons in an attempt to promote axon regeneration after SCI. We discovered that after complete transection of the thoracic spinal cord and implantation of a Schwann cell bridge, animals that express MASH1 exhibit increased noradrenergic axon regeneration and improvement in hindlimb joint movements compared to controls. Together these data demonstrate that MASH1/Ascl1a is a fundamental regulator of axonal growth across vertebrates and can induce modifications to the intrinsic state of neurons to promote functional regeneration in response to CNS injury.
Pearse, Damien D.; Udvadia, Ava J.; Bunge, Mary Bartlett
Unlike CNS neurons in adult mammals, neurons in fish and embryonic mammals can regenerate their axons after injury. These divergent regenerative responses are in part mediated by the growth-associated expression of select transcription factors. The basic helix-loop-helix (bHLH) transcription factor, MASH1/Ascl1a, is transiently expressed during the development of many neuronal subtypes and regulates the expression of genes that mediate cell fate determination and differentiation. In the adult zebrafish (Danio rerio), Ascl1a is also transiently expressed in retinal ganglion cells (RGCs) that regenerate axons after optic nerve crush. Utilizing transgenic zebrafish with a 3.6 kb GAP43 promoter that drives expression of an enhanced green fluorescent protein (EGFP), we observed that knock-down of Ascl1a expression reduces both regenerative gap43 gene expression and axonal growth after injury compared to controls. In mammals, the development of noradrenergic brainstem neurons requires MASH1 expression. In contrast to zebrafish RGCs, however, MASH1 is not expressed in the mammalian brainstem after spinal cord injury (SCI). Therefore, we utilized adeno-associated viral (AAV) vectors to overexpress MASH1 in four month old rat (Rattus norvegicus) brainstem neurons in an attempt to promote axon regeneration after SCI. We discovered that after complete transection of the thoracic spinal cord and implantation of a Schwann cell bridge, animals that express MASH1 exhibit increased noradrenergic axon regeneration and improvement in hindlimb joint movements compared to controls. Together these data demonstrate that MASH1/Ascl1a is a fundamental regulator of axonal growth across vertebrates and can induce modifications to the intrinsic state of neurons to promote functional regeneration in response to CNS injury. PMID:25751153
Suzuki, Takahiro; Izutsu, Koji; Kako, Shinichi; Ohta, Satoshi; Hangaishi, Akira; Kanda, Yoshinobu; Motokura, Toru; Chiba, Shigeru; Kurokawa, Mineo
Langerhans cell histiocytosis (LCH) is a proliferative disorder of Langerhans cells and extremely rare in adults. Adult LCH is often associated with osteolytic bone lesions, but large bone-defective lesions have been rarely reported. We report an adult case of LCH accompanied by large osteolytic lesions in the skull that successfully responded to chemotherapy. A 47-year-old woman with LCH who had multiple, large osteolytic areas of more than 3 cm in diameter in the skull was admitted to our hospital. She was treated with systemic chemotherapy consisting of prednisolone, vinblastine, and 6-mercaptopurine. Twelve months later, when she completed the treatment, osteolytic areas were covered with hard osseous tissue, and X-ray examination confirmed regeneration of the bone. This case indicates that chemotherapy can be effective even for the treatment of large osteolytic lesions in adult LCH patients.
Li, Chunyi; Yang, Fuhe; Sheppard, Allan
Mammalian organ regeneration is the "Holy Grail" of modern regenerative biology and medicine. The most dramatic organ replacement is known as epimorphic regeneration. To date our knowledge of epimorphic regeneration has come from studies of amphibians. Notably, these animals have the ability to reprogram phenotypically committed cells at the amputation plane toward an embryonic-like cell phenotype (dedifferentiation). The capability of mammals to initiate analogous regeneration, and whether similar mechanisms would be involved if it were to occur, remain unclear. Deer antlers are the only mammalian appendages capable of full renewal, and therefore offer a unique opportunity to explore how nature has solved the problem of mammalian epimorphic regeneration. Following casting of old hard antlers, new antlers regenerate from permanent bony protuberances, known as pedicles. Studies through morphological and histological examinations, tissue deletion and transplantation, and cellular and molecular techniques have demonstrated that antler renewal is markedly different from that of amphibian limb regeneration (dedifferentiation-based), being a stem cell-based epimorphic process. Antler stem cells reside in the pedicle periosteum. We envisage that epimorphic regeneration of mammalian appendages, other than antler, could be made possible by recreating comparable milieu to that which supports the elaboration of that structure from the pedicle periosteum.
Münch, Juliane; González-Rajal, Alvaro; de la Pompa, José Luis
Zebrafish have the capacity to regenerate several organs, including the heart and fins. Fin regeneration is epimorphic, involving the formation at the amputation plane of a mass of undifferentiated, proliferating mesenchymal progenitor-like cells, called blastema. This tissue provides all the cell types that form the fin, so that after damage or amputation the fin pattern and structure are fully restored. How blastema cells remain in this progenitor-like state is poorly understood. Here, we show that the Notch pathway plays an essential role during fin regeneration. Notch signalling is activated during blastema formation and remains active throughout the regeneration process. Chemical inhibition or morpholino-mediated knockdown of Notch signalling impairs fin regeneration via decreased proliferation accompanied by reduced expression of Notch target genes in the blastema. Conversely, overexpression of a constitutively active form of the Notch1 receptor (N1ICD) in the regenerating fin leads to increased proliferation and to the expansion of the blastema cell markers msxe and msxb, as well as increased expression of the proliferation regulator aldh1a2. This blastema expansion prevents regenerative fin outgrowth, as indicated by the reduction in differentiating osteoblasts and the inhibition of bone regeneration. We conclude that Notch signalling maintains blastema cells in a plastic, undifferentiated and proliferative state, an essential requirement for fin regeneration.
Hall, Amanda K.; Bernhardt, Jay M.; Dodd, Virginia; Vollrath, Morgan W.
Objective: Innovations in health information technology (HIT) provide opportunities to reduce health care spending, improve quality of care, and improve health outcomes for older adults. However, concerns relating to older adults' limited access and use of HIT, including use of the Internet for health information, fuel the digital health divide…
Patel, Rita; Dubrovskiy, Denis; Döllinger, Michael
Purpose: The aim of this study is to quantify and identify characteristic vibratory motion in typically developing prepubertal children and young adults using high-speed digital imaging. Method: The vibrations of the vocal folds were recorded from 27 children (ages 5-9 years) and 35 adults (ages 21-45 years), with high speed at 4,000 frames per…
Kretz, Alexandra; Happold, Caroline J; Marticke, Julia K; Isenmann, Stefan
The cytokine hormone erythropoietin (EPO) has proved neuroprotective in CNS injury, and clinical trials for ischemic stroke are ongoing. The capability of EPO to restore postmitotic CNS architecture and function by fibre regeneration has not been examined. Here, we compared in vitro outgrowth capacity of adult retinal ganglion cells (RGCs) following optic nerve (ON) lesion in the presence and absence of EPO. Immediate EPO conditioning in vivo, or delayed EPO treatment of cultures with 10--10,000 IU rhEPO significantly increased numbers (2.66-fold) and length (8.31-fold) of newly generated neurites, without evoking rheological complications. EPO induced Stat3 phosphorylation in RGCs, and inhibition of Jak2/Stat3 abolished EPO-induced growth. EPO-facilitated neuritogenesis was paralleled by upregulation of Bcl-X(L), a Bcl-2 homologue capable of promoting RGC regeneration. The PI3K/Akt pathway was also involved in antiapoptotic and regeneration-enhancing EPO actions. In conclusion, EPO treatment may offer a unique dual-function strategy for neuroprotection and regeneration.
Hirata, Akira; Masaki, Toshihiro; Motoyoshi, Kazuo; Kamakura, Keiko
Whether nerve growth factor (NGF) promotes peripheral nerve regeneration in vivo, in particular in adults, is controversial. We therefore examined the effect of exogenous NGF on nerve regeneration and the expression of GAP 43 (growth-associated protein 43) in adult rats. NGF was infused intrathecally via an osmotic mini-pump, while control rats received artificial cerebrospinal fluid. Two days after the infusion was initiated, the right sciatic nerves were transected or crushed, and the animals allowed to survive for 3 to 11 days. The right DRG, the right proximal stump of the transected sciatic nerve, and the posterior horn of the spinal cord were examined by Western blotting, immunohistochemistry, and electron microscopy. GAP 43 immunoreactivity in the NGF-treated animals was significantly lower than in the aCSF-treated controls. Electron microscopy showed that the number of myelinated and unmyelinated axons decreased significantly in the NGF-treated rats as compared with the controls. These findings are indicative that exogenous NGF delayed GAP 43 induction and the early phase of peripheral nerve regeneration and supports the hypothesis that the loss of NGF supply from peripheral targets via retrograde transport caused by axotomy serves as a signal for DRG neurons to invoke regenerative responses. NGF administered intrathecally may delay the neurons' perception of the reduction of the endogenous NGF, causing a delay in conversion of DRG neurons from the normal physiological condition to regrowth state.
Li, Songshan; Yang, Chao; Zhang, Li; Gao, Xin; Wang, Xuejie; Liu, Wen; Wang, Yuqi; Jiang, Songshan; Wong, Yung Hou; Zhang, Yifeng; Liu, Kai
Cell-type–specific G protein-coupled receptor (GPCR) signaling regulates distinct neuronal responses to various stimuli and is essential for axon guidance and targeting during development. However, its function in axonal regeneration in the mature CNS remains elusive. We found that subtypes of intrinsically photosensitive retinal ganglion cells (ipRGCs) in mice maintained high mammalian target of rapamycin (mTOR) levels after axotomy and that the light-sensitive GPCR melanopsin mediated this sustained expression. Melanopsin overexpression in the RGCs stimulated axonal regeneration after optic nerve crush by up-regulating mTOR complex 1 (mTORC1). The extent of the regeneration was comparable to that observed after phosphatase and tensin homolog (Pten) knockdown. Both the axon regeneration and mTOR activity that were enhanced by melanopsin required light stimulation and Gq/11 signaling. Specifically, activating Gq in RGCs elevated mTOR activation and promoted axonal regeneration. Melanopsin overexpression in RGCs enhanced the amplitude and duration of their light response, and silencing them with Kir2.1 significantly suppressed the increased mTOR signaling and axon regeneration that were induced by melanopsin. Thus, our results provide a strategy to promote axon regeneration after CNS injury by modulating neuronal activity through GPCR signaling. PMID:26831088
Blum, Nicola; Begemann, Gerrit
Adult teleosts rebuild amputated fins through a proliferation-dependent process called epimorphic regeneration, in which a blastema of cycling progenitor cells replaces the lost fin tissue. The genetic networks that control formation of blastema cells from formerly quiescent stump tissue and subsequent blastema function are still poorly understood. Here, we investigated the cellular and molecular consequences of genetically interfering with retinoic acid (RA) signaling for the formation of the zebrafish blastema. We show that RA signaling is upregulated within the first few hours after fin amputation in the stump mesenchyme, where it controls Fgf, Wnt/β-catenin and Igf signaling. Genetic inhibition of the RA pathway at this stage blocks blastema formation by inhibiting cell cycle entry of stump cells and impairs the formation of the basal epidermal layer, a signaling center in the wound epidermis. In the established blastema, RA signaling remains active to ensure the survival of the highly proliferative blastemal population by controlling expression of the anti-apoptotic factor bcl2. In addition, RA signaling maintains blastema proliferation through the activation of growth-stimulatory signals mediated by Fgf and Wnt/β-catenin signaling, as well as by reducing signaling through the growth-inhibitory non-canonical Wnt pathway. The endogenous roles of RA in adult vertebrate appendage regeneration are uncovered here for the first time. They provide a mechanistic framework to understand previous observations in salamanders that link endogenous sources of RA to the regeneration process itself and support the hypothesis that the RA signaling pathway is an essential component of vertebrate tissue regeneration.
Weber, Anke; Hochmann, Sarah; Cimalla, Peter; Gärtner, Maria; Kuscha, Veronika; Hans, Stefan; Geffarth, Michaela; Kaslin, Jan; Koch, Edmund; Brand, Michael
Light-induced lesions are a powerful tool to study the amazing ability of photoreceptors to regenerate in the adult zebrafish retina. However, the specificity of the lesion towards photoreceptors or regional differences within the retina are still incompletely understood. We therefore characterized the process of degeneration and regeneration in an established paradigm, using intense white light from a fluorescence lamp on swimming fish (diffuse light lesion). We also designed a new light lesion paradigm where light is focused through a microscope onto the retina of an immobilized fish (focused light lesion). Focused light lesion has the advantage of creating a locally restricted area of damage, with the additional benefit of an untreated control eye in the same animal. In both paradigms, cell death is observed as an immediate early response, and proliferation is initiated around 2 days post lesion (dpl), peaking at 3 dpl. We furthermore find that two photoreceptor subtypes (UV and blue sensitive cones) are more susceptible towards intense white light than red/green double cones and rods. We also observed specific differences within light lesioned areas with respect to the process of photoreceptor degeneration: UV cone debris is removed later than any other type of photoreceptor in light lesions. Unspecific damage to retinal neurons occurs at the center of a focused light lesion territory, but not in the diffuse light lesion areas. We simulated the fish eye optical properties using software simulation, and show that the optical properties may explain the light lesion patterns that we observe. Furthermore, as a new tool to study retinal degeneration and regeneration in individual fish in vivo, we use spectral domain optical coherence tomography. Collectively, the light lesion and imaging assays described here represent powerful tools for studying degeneration and regeneration processes in the adult zebrafish retina. PMID:24303018
Lorber, Barbara; Berry, Martin; Logan, Ann
In the present study the effects of lens injury on retinal ganglion cell axon/neurite re-growth were investigated in adult mice. In vivo, lens injury promoted successful regeneration of retinal ganglion cell axons past the optic nerve lesion site, concomitant with the invasion of macrophages into the eye and the presence of activated retinal astrocytes/Muller cells. In vitro, retinal ganglion cells from lens-lesioned mice grew significantly longer neurites than those from intact mice, which correlated with the presence of enhanced numbers of activated retinal astrocytes/Muller cells. Co-culture of retinal ganglion cells from intact mice with macrophage-rich lesioned lens/vitreous body led to increased neurite lengths compared with co-culture with macrophage-free intact lens/vitreous body, pointing to a neurotrophic effect of macrophages. Furthermore, retinal ganglion cells from mice that had no lens injury but had received intravitreal Zymosan injections to stimulate macrophage invasion into the eye grew significantly longer neurites compared with controls, as did retinal ganglion cells from intact mice co-cultured with macrophage-rich vitreous body from Zymosan-treated mice. The intact lens, but not the intact vitreous body, exerted a neurotrophic effect on retinal ganglion cell neurite outgrowth, suggesting that lens-derived neurotrophic factor(s) conspire with those derived from macrophages in lens injury-stimulated axon regeneration. Together, these results show that lens injury promotes retinal ganglion cell axon regeneration/neurite outgrowth in adult mice, an observation with important implications for axon regeneration studies in transgenic mouse models.
Gao, Yudan; Yang, Zhaoyang; Li, Xiaoguang
The central nervous system (CNS) has very restricted intrinsic regeneration ability under the injury or disease condition. Innovative repair strategies, therefore, are urgently needed to facilitate tissue regeneration and functional recovery. The published tissue repair/regeneration strategies, such as cell and/or drug delivery, has been demonstrated to have some therapeutic effects on experimental animal models, but can hardly find clinical applications due to such methods as the extremely low survival rate of transplanted cells, difficulty in integrating with the host or restriction of blood–brain barriers to administration patterns. Using biomaterials can not only increase the survival rate of grafts and their integration with the host in the injured CNS area, but also sustainably deliver bioproducts to the local injured area, thus improving the microenvironment in that area. This review mainly introduces the advances of various strategies concerning facilitating CNS regeneration. PMID:27047678
Berg, Daniel A; Kirkham, Matthew; Wang, Heng; Frisén, Jonas; Simon, András
Appropriate termination of regenerative processes is critical for producing the correct number of cells in tissues. Here we provide evidence for an end-product inhibition of dopamine neuron regeneration that is mediated by dopamine. Ablation of midbrain dopamine neurons leads to complete regeneration in salamanders. Regeneration involves extensive neurogenesis and requires activation of quiescent ependymoglia cells, which express dopamine receptors. Pharmacological compensation for dopamine loss by L-dopa inhibits ependymoglia proliferation and regeneration in a dopamine receptor-signaling-dependent manner, specifically after ablation of dopamine neurons. Systemic administration of the dopamine receptor antagonist haloperidol alone causes ependymoglia proliferation and the appearance of excessive number of neurons. Our data show that stem cell quiescence is under dopamine control and provide a model for termination once normal homeostasis is restored. The findings establish a role for dopamine in the reversible suppression of neurogenesis in the midbrain and have implications for regenerative strategies in Parkinson's disease.
Wong, Yvonne J; Whishaw, Ian Q
The evolutionary origins and variations of the precision grip, in which an object is held between the thumb and other digits, are poorly understood. This is surprising because the neural basis of this grasp pattern, including the motor cortex and pyramidal tract have received extensive study. Most previous work has shown that features of an object to be grasped (external factors) determine grasp patterns. The objective of the present study was to investigate individual differences (central factors) in use of the pincer and other precision grips. The grasping patterns of male and female young adults, older adults and children were examined as they reached (with both left and right hand) for five small beads (3-16 mm diameter). Frame-by-frame analysis of grasping indicated a high degree of variability in digit contact strategies, purchase patterns and digit posture both within and between subjects. (1) The contact strategies consisted of five variations, depending on whether the thumb or the index finger dragged or stabilized the bead for grasping. (2) Purchase patterns consisted of seven different types of precision grips, involving the thumb and various combinations of other digits. (3) There were four variations stemming from the posture of the non-grasping digits. Grip patterns of the left and right hands were correlated in individual subjects, as were strategies used for different bead sizes. Females displayed slightly more variability in grasp patterns than did males, and digit width (obtained from photocopies of the subjects' hands) was weakly correlated with the grasp patterns used. Although it was expected that the pincer would be used for all objects, it was preferentially used for only the smallest object except for older adults who used the pincer grasp on most objects. The variability in digit contact strategies, purchase patterns, and posture of the non-grasping digits indicates that central factors (innate or learning-induced architecture of the left
MacNeil, R. Gavin; Clough, Launa G.; Dirain, Marvin; Sandesara, Bhanuprasad; Pahor, Marco; Manini, Todd M.; Leeuwenburgh, Christiaan
Repair of skeletal muscle after injury is a key aspect of maintaining proper musculoskeletal function. Studies have suggested that regenerative processes, including myogenesis and angiogenesis, are impaired during advanced age, but evidence from humans is limited. This study aimed to compare active muscle regeneration between healthy young and older adults. We evaluated changes in clinical, biochemical, and immunohistochemical indices of muscle regeneration at precisely 2 (T2) and 7 (T3) days following acute muscle injury. Men and women, aged 18-30 and ≥70 years, matched for gender and body mass index, performed 150 unilateral, eccentric contractions of the plantar flexors at 110% of one repetition maximum. Data were analyzed using analysis of covariance, adjusted for gender, habitual physical activity, and baseline level of the outcome. A total of 30 young (n = 15; 22.5 ± 3.7 yr) and older (n = 15; 75.8 ± 5.0 yr) adults completed the study. Following muscle injury, force production declined 16% and 14% in young and older adults, respectively, by T2 and in each group, returned to 93% of baseline strength by T3. Despite modest differences in the pattern of response, postinjury changes in intramuscular concentrations of myogenic growth factors and number of myonuclear (4′,6-diamidino-2-phenylindole+ and paired box 7+) cells were largely similar between groups. Likewise, postinjury changes in serum and intramuscular indices of inflammation (e.g., TNF-α and monocyte chemoattractant protein-1) and angiogenesis (e.g., VEGF and kinase insert domain receptor) did not differ significantly between groups. These findings suggest that declines in physical activity and increased co-morbidity may contribute to age-related impairments in active muscle regeneration rather than aging per se. PMID:23493365
Buford, Thomas W; MacNeil, R Gavin; Clough, Launa G; Dirain, Marvin; Sandesara, Bhanuprasad; Pahor, Marco; Manini, Todd M; Leeuwenburgh, Christiaan
Repair of skeletal muscle after injury is a key aspect of maintaining proper musculoskeletal function. Studies have suggested that regenerative processes, including myogenesis and angiogenesis, are impaired during advanced age, but evidence from humans is limited. This study aimed to compare active muscle regeneration between healthy young and older adults. We evaluated changes in clinical, biochemical, and immunohistochemical indices of muscle regeneration at precisely 2 (T2) and 7 (T3) days following acute muscle injury. Men and women, aged 18-30 and ≥70 years, matched for gender and body mass index, performed 150 unilateral, eccentric contractions of the plantar flexors at 110% of one repetition maximum. Data were analyzed using analysis of covariance, adjusted for gender, habitual physical activity, and baseline level of the outcome. A total of 30 young (n = 15; 22.5 ± 3.7 yr) and older (n = 15; 75.8 ± 5.0 yr) adults completed the study. Following muscle injury, force production declined 16% and 14% in young and older adults, respectively, by T2 and in each group, returned to 93% of baseline strength by T3. Despite modest differences in the pattern of response, postinjury changes in intramuscular concentrations of myogenic growth factors and number of myonuclear (4',6-diamidino-2-phenylindole+ and paired box 7+) cells were largely similar between groups. Likewise, postinjury changes in serum and intramuscular indices of inflammation (e.g., TNF-α and monocyte chemoattractant protein-1) and angiogenesis (e.g., VEGF and kinase insert domain receptor) did not differ significantly between groups. These findings suggest that declines in physical activity and increased co-morbidity may contribute to age-related impairments in active muscle regeneration rather than aging per se.
Demiris, George; Thompson, Hilaire J.; Lazar, Amanda; Lin, Shih-Yin
Study Objective: The purpose of this study was to examine the feasibility of a digital companion system used by older adults with mild cognitive impairment (MCI). We utilized a commercially available system that is comprehensive in its functionalities (including conversation ability, use of pictures and other media, and reminders) to explore the system’s impact on older adults ‘ social interactions, anxiety, depressive symptoms, and acceptance of the system. Study Design: We conducted a three-month mixed methods evaluation study of the digital companion. Results: Ten female community-dwelling older adults (average age 78.3 years) participated in the study. Overall, participants utilized the tool regularly and appreciated its presence and their interactions. Participants scored higher at the end of the study in cognition and social support scales, and lower in presence of depressive symptoms. Conclusion: Findings indicate the feasibility of a digital companion for people with MCI and inform the need for additional research. PMID:28269845
Chen, Shuyuan; Shimoda, Masayuki; Chen, Jiaxi; Matsumoto, Shinichi; Grayburn, Paul A
The molecular mechanism of β-cell regeneration remains poorly understood. Cyclin D2/CDK4 expresses in normal β cells and maintains adult β-cell growth. We hypothesized that gene therapy with cyclin D2/CDK4/GLP-1 plasmids targeted to the pancreas of STZ-treated rats by ultrasound-targeted microbubble destruction (UTMD) would force cell cycle re-entry of residual G(0)-phase islet cells into G(1)/S phase to regenerate β cells. A single UTMD treatment induced β-cell regeneration with reversal of diabetes for 6 mo without evidence of toxicity. We observed that this β-cell regeneration was not mediated by self-replication of pre-existing β cells. Instead, cyclin D2/CDK4/GLP-1 initiated robust proliferation of adult pancreatic progenitor cells that exist within islets and terminally differentiate to mature islets with β cells and α cells.
Huang, ZhengRu; Hu, ZiZhong; Xie, Ping; Liu, QingHuai
Activating PI3K/AKT/mTOR signaling pathway via deleting phosphatase and tensin homolog (PTEN) has been confirmed to enhance intrinsic growth capacity of neurons to facilitate the axons regeneration of central nervous system after injury. Considering conditional gene deletion is currently not available in clinical practice, we exploited capsid residue tyrosine 444 to phenylalanine mutated single-stranded adeno-associated virus serotype 2 (AAV2) as a vector delivering short hairpin RNA to silence PTEN to promote retinal ganglion cells (RGCs) survival and axons regeneration in adult rat optic nerve axotomy paradigm. We found that mutant AAV2 displayed higher infection efficiency to RGCs and Müller cells by intravitreal injection, mediated PTEN suppression, resulted in much more RGCs survival and more robust axons regeneration compared with wild type AAV2, due to the different extent of the mTOR complex-1 activation and glutamate aspartate transporter (GLAST) regulation. These results suggest that high efficiency AAV2-mediated PTEN knockdown represents a practicable therapeutic strategy for optic neuropathy. PMID:28323869
Li, Hongjie; Qi, Yanyan; Jasper, Heinrich
The gastrointestinal (GI) tract of metazoans is lined by a series of regionally distinct epithelia. To maintain structure and function of the GI tract, regionally diversified differentiation of somatic stem cell (SC) lineages is critical. The adult Drosophila midgut provides an accessible model to study SC regulation and specification in a regionally defined manner. SCs of the posterior midgut (PM) have been studied extensively, but the control of SCs in the middle midgut (MM) is less well understood. The MM contains a stomach-like copper cell region (CCR) that is regenerated by gastric stem cells (GSSCs) and contains acid-secreting copper cells (CCs). Bmp-like Decapentaplegic (Dpp) signaling determines the identity of GSSCs, and is required for CC regeneration, yet the precise control of Dpp signaling activity in this lineage remains to be fully established. Here, we show that Dad, a negative feedback regulator of Dpp signaling, is dynamically regulated in the GSSC lineage to allow CC differentiation. Dad is highly expressed in GSSCs and their first daughter cells, the gastroblasts (GBs), but has to be repressed in differentiating CCs to allow Dpp-mediated differentiation into CCs. We find that the Hox gene ultrabithorax (Ubx) is required for this regulation. Loss of Ubx prevents Dad repression in the CCR, resulting in defective CC regeneration. Our study highlights the need for dynamic control of Dpp signaling activity in the differentiation of the GSSC lineage and identifies Ubx as a critical regulator of this process.
Lahne, Manuela; Li, Jingling; Marton, Rebecca M.
Loss of retinal neurons in adult zebrafish (Danio rerio) induces a robust regenerative response mediated by the reentry of the resident Müller glia into the cell cycle. Upon initiating Müller glia proliferation, their nuclei migrate along the apicobasal axis of the retina in phase with the cell cycle in a process termed interkinetic nuclear migration (INM). We examined the mechanisms governing this cellular process and explored its function in regenerating the adult zebrafish retina. Live-cell imaging revealed that the majority of Müller glia nuclei migrated to the outer nuclear layer (ONL) to divide. These Müller glia formed prominent actin filaments at the rear of nuclei that had migrated to the ONL. Inhibiting actin filament formation or Rho-associated coiled-coil kinase (Rock) activity, which is necessary for phosphorylation of myosin light chain and actin myosin-mediated contraction, disrupted INM with increased numbers of mitotic nuclei remaining in the basal inner nuclear layer, the region where Müller glia typically reside. Double knockdown of Rho-associated coiled-coil kinase 2a (Rock2a) and Rho-associated coiled-coil kinase 2b (Rock2b) similarly disrupted INM and reduced Müller glial cell cycle reentry. In contrast, Rock inhibition immediately before the onset of INM did not affect Müller glia proliferation, but subsequently reduced neuronal progenitor cell proliferation due to early cell cycle exit. Long-term, Rock inhibition increased the generation of mislocalized ganglion/amacrine cells at the expense of rod and cone photoreceptors. In summary, INM is driven by an actin-myosin-mediated process controlled by Rock2a and Rock2b activity, which is required for sufficient proliferation and regeneration of photoreceptors after light damage. SIGNIFICANCE STATEMENT The human retina does not replace lost or damaged neurons, ultimately causing vision impairment. In contrast, zebrafish are capable of regenerating lost neurons. Understanding the mechanisms
Nadal-Ginard, Bernardo; Ellison, Georgina M; Torella, Daniele
Resident cardiac stem cells in embryonic, neonatal and adult mammalian heart have been identified by different membrane markers and transcription factors. However, despite a flurry of publications no consensus has been reached on the identity and actual regenerative effects of the adult cardiac stem cells. Intensive research on the adult mammalian heart's capacity for self-renewal of its muscle cell mass has led to a consensus that new cardiomyocytes (CMs) are indeed formed throughout adult mammalian life albeit at a disputed frequency. The physiological significance of this renewal, the origin of the new CMs, and the rate of adult CM turnover are still highly debated. Myocyte replacement, particularly after injury, was originally attributed to differentiation of a stem cell compartment. More recently, it has been reported that CMs are mainly replaced by the division of pre-existing post-mitotic CMs. These latter results, if confirmed, would shift the target of regenerative therapy toward boosting mature CM cell-cycle re-entry. Despite this controversy, it is documented that the adult endogenous c-kit(pos) cardiac stem cells (c-kit(pos) eCSCs) participate in adaptations to myocardial stress, and, when transplanted into the myocardium, regenerate most cardiomyocytes and microvasculature lost in an infarct. Nevertheless, the in situ myogenic potential of adult c-kit(pos) cardiac cells has been questioned. To revisit the regenerative potential of c-kit(pos) eCSCs, we have recently employed experimental protocols of severe diffuse myocardial damage in combination with several genetic murine models and cell transplantation approaches showing that eCSCs are necessary and sufficient for CM regeneration, leading to complete cellular, anatomical, and functional myocardial recovery. Here we will review the available data on adult eCSC biology and their regenerative potential placing it in the context of the different claimed mechanisms of CM replacement. These data are in
Ross, D. T.; Das, G. D.
Retinal afferent ingrowth to embryonic neural transplants in the adult rat superior colliculus may represent either sprouting of intact axons or the regeneration of transected axons. If ingrowth represents regeneration of damaged retinofugai axons, then lesions that axotomize more retinofugal axons at the transplantation site should induce greater retinal afferent ingrowth. Alternately, if ingrowth represents terminal or collateral sprouting of intact retinofugal axons at or near the transplant/host optic layer interface, then the magnitude of retinal afferent ingrowth should be directly related to the total area of this interface. To test between these two hypotheses surgical knife wounds were made either parallel (in the sagittal plane) or perpendicular (in the transverse plane) to the course of axons in the stratum opticum, embryonic neocortical tissue was transplanted at the coordinates of these tectal slits, and retinal afferent ingrowth visualized 1-90 days after surgery using anterogradely transported HRP. A zone of traumatic reaction (ztr) in the optic layers was seen in every case, characterized by hypertrophied axons and swollen terminal clubs at 1 day. Between 30 and 90 days the damaged retinofugal axons in the zone formed dense fascicles and neuroma-like tangles. Retinal afferent ingrowth occurred only across transplant interface regions with the ztr. The magnitude of ingrowth was directly related to the area of the ztr interface and not the total optic layer interface area. Retinal afferent ingrowth appears to reflect the intrinsic regenerative capacity of adult mammalian retinal ganglion cells and not sprouting of undamaged axons. PMID:7703292
Park, Sora; Burford, Sally
This study examined whether gaining access to a new digital device enhanced the digital media literacy of young adults and what factors determine such change. Thirty-five young adults were given a mobile tablet device and observed for one year. Participants engaged in an online community, responding regularly to online surveys and discussion…
Neumann, Simona; Skinner, Kate; Basbaum, Allan I.
The peripheral axonal branch of primary sensory neurons readily regenerates after peripheral nerve injury, but the central branch, which courses in the dorsal columns of the spinal cord, does not. However, if a peripheral nerve is transected before a spinal cord injury, sensory neurons that course in the dorsal columns will regenerate, presumably because their intrinsic growth capacity is enhanced by the priming peripheral nerve lesion. As the effective priming lesion is made before the spinal cord injury it would clearly have no clinical utility, and unfortunately, a priming lesion made after a spinal cord injury results in an abortive regenerative response. Here, we show that two priming lesions, one made at the time of a spinal cord injury and a second 1 week after a spinal cord injury, in fact, promote dramatic regeneration, within and beyond the lesion. The first lesion, we hypothesize, enhances intrinsic growth capacity, and the second one sustains it, providing a paradigm for promoting CNS regeneration after injury. primary afferents | dorsal columns | neurite outgrowth | sprouting | priming
Marston, Hannah R.
There were two objectives to this study: (a) to establish flow and (2) to establish whether computer game interaction or content was important to the older adult, using the Nintendo Wii and the Sony PlayStation 2 consoles. An earlier study had identified the sports genre as a preference, and three games (golf, tennis, and boxing) were selected…
Sharma, Sue Ann; Deschaine, Mark E.
Digital curation provides a way to transcend traditional academic fields of study and create instructional materials available to support adolescent and adult literacy initiatives. The instructional capabilities that Web 2.0 tools offer provide curators with the ability to reach audiences in a way that has not been possible in the past. The…
Fu, Qiuli; Gremeaux, Lies; Luque, Raul M; Liekens, Daisy; Chen, Jianghai; Buch, Thorsten; Waisman, Ari; Kineman, Rhonda; Vankelecom, Hugo
The pituitary gland constitutes, together with the hypothalamus, the regulatory core of the endocrine system. Whether the gland is capable of cell regeneration after injury, in particular when suffered at adult age, is unknown. To investigate the adult pituitary's regenerative capacity and the response of its stem/progenitor cell compartment to damage, we constructed a transgenic mouse model to conditionally destroy pituitary cells. GHCre/iDTR mice express diphtheria toxin (DT) receptor after transcriptional activation by Cre recombinase, which is driven by the GH promoter. Treatment with DT for 3 d leads to gradual GH(+) (somatotrope) cell obliteration with a final ablation grade of 80-90% 1 wk later. The stem/progenitor cell-clustering side population promptly expands after injury, concordant with the immediate increase in Sox2(+) stem/progenitor cells. In addition, folliculo-stellate cells, previously designated as pituitary stem/progenitor cells and significantly overlapping with Sox2(+) cells, also increase in abundance. In situ examination reveals expansion of the Sox2(+) marginal-zone niche and appearance of remarkable Sox2(+) cells that contain GH. When mice are left after the DT-provoked lesion, GH(+) cells considerably regenerate during the following months. Double Sox2(+)/GH(+) cells are observed throughout the regenerative period, suggesting recovery of somatotropes from stem/progenitor cells, as further supported by 5-ethynyl-2'-deoxyuridine (EdU) pulse-chase lineage tracing. In conclusion, our study demonstrates that the adult pituitary gland holds regenerative competence and that tissue repair follows prompt activation and plausible involvement of the stem/progenitor cells.
Kalman, Yoram M; Kavé, Gitit; Umanski, Daniil
This study examined how younger and older adults approach simple and complex computerized writing tasks. Nineteen younger adults (age range 21-31, mean age 26.1) and 19 older adults (age range 65-83, mean age 72.1) participated in the study. Typing speed, quantitative measures of outcome and process, and self-corrections were recorded. Younger adults spent a lower share of their time on actual typing, and demonstrated more prevalent use of delete keys than did older adults. Within the older group, there was no correlation between the total time spent on the entire task and the number of corrections, but increased typing speed was related to more errors. The results suggest that the approach to the task was different across age groups, either because of age or because of cohort effects. We discuss the interplay of speed and accuracy with regard to digital writing, and its implications for the design of human-computer interactions.
Background A complex life cycle, such as complete metamorphosis, is a key innovation that can promote diversification of species. The evolution of a morphologically distinct larval stage is thought to have enabled insects to occupy broader ecological niches and become the most diverse metazoan taxon, yet the extent to which larval and adult morphologies can evolve independently remains unknown. Perturbation of larval limb regeneration allows us to generate larval legs and antennae with altered limb morphologies, which may be used to explore the developmental continuity that might exist between larval and adult appendages. In this study, we determined the roles of several appendage patterning transcription factors, abrupt (ab), dachshund (dac), Distal-less (Dll), and spineless (ss), in the red flour beetle, Tribolium castaneum, during larval appendage regeneration. The functions of these genes in regenerating and non-regenerating limbs were compared using RNA interference. Results During limb regeneration, dac and ss were necessary to re-pattern the same larval structures as those patterned during embryogenesis. Removal of these two genes led to larval appendage patterning defects that were carried over to the adult legs. Surprisingly, even though maternal knockdown of ab had minimal effects on limb allocation and patterning in the embryo, it was necessary for blastema growth, an earlier phase of regeneration. Finally, knockdown of Dll prevented the blastema-like bumps from re-differentiating into appendages. Conclusions Our results suggest that, similar to vertebrates, the re-patterning phase of Tribolium larval limb regeneration relies on the same genes that are used during embryonic limb patterning. Thus, the re-patterning phase of regeneration is likely to be regulated by taxon-specific patterning mechanisms. Furthermore, Ab and Dll appear to play important roles during blastema proliferation and re-differentiation, respectively. Finally, our results show that
Favero, Morgana; Cangiano, Alberto; Busetto, Giuseppe
Gap junctions (GJs) between neurons are present in both the newborn and the adult nervous system, and although important roles have been suggested or demonstrated in a number of instances, in many other cases a full understanding of their physiological role is still missing. GJs are expressed in the rodent lumbar cord at birth and mediate both dye and electrical coupling between motor neurons. This expression has been proposed to mediate: (i) fast synchronization of motoneuronal spike activity, in turn linked to the process of refinement of neuromuscular connections, and (ii) slow synchronization of locomotor-like oscillatory activity. Soon after birth this coupling disappears. Since in the adult rat regeneration of motor fibers after peripheral nerve injury leads to a recapitulation of synaptic refinement at the target muscles, we tested whether GJs between motor neurons are transiently re-expressed. We found that in conditions of maximal responsiveness of lumbar motor neurons (such as no depression by anesthetics, decerebrate release of activity of subsets of motor neurons, use of temporal and spatial summation by antidromic and orthodromic stimulations, testing of large ensembles of motor neurons) no firing is observed in ventral root axons in response to antidromic spike invasion of nearby counterparts. We conclude that junctional coupling between motor neurons is not required for the refinement of neuromuscular innervation in the adult.
Rapchak, Marcia; Behary, Robert
As information literacy programs become more robust, finding methods of reaching students beyond the traditional undergraduate has become a priority for many institutions. At Duquesne University, efforts have been made to reach adult learners in an accelerated program targeted to nontraditional students, much of which is provided online. This…
Plikus, Maksim V.; Van Spyk, Elyse Noelani; Pham, Kim; Geyfman, Mikhail; Kumar, Vivek; Takahashi, Joseph S.; Andersen, Bogi
Historically work on peripheral circadian clocks has been focused on organs and tissues that have prominent metabolic functions, such as liver, fat and muscle. In recent years, skin is emerging as a model for studying circadian clock regulation of cell proliferation, stem cell functions, tissue regeneration, aging and carcinogenesis. Morphologically skin is complex, containing multiple cell types and structures, and there is evidence for a functional circadian clock in most, if not all, of its cell types. Despite the complexity, skin stem cell populations are well defined, experimentally tractable and exhibit prominent daily cell proliferation cycles. Hair follicle stem cells also participate in recurrent, long-lasting cycles of regeneration -- the hair growth cycles. Among other advantages of skin is a broad repertoire of available genetic tools enabling the creation of cell-type specific circadian mutants. Also, due to the accessibility of the skin, in vivo imaging techniques can be readily applied to study the circadian clock and its outputs in real time, even at the single-cell level. Skin provides the first line of defense against many environmental and stress factors that exhibit dramatic diurnal variations such as solar UV radiation and temperature. Studies have already linked the circadian clock to the control of UVB-induced DNA damage and skin cancers. Due to the important role that skin plays in the defense against microorganisms, it represents a promising model system to further explore the role of the clock in the regulation of the body's immune functions. To that end, recent studies have already linked the circadian clock to psoriasis, one of the most common immune-mediated skin disorders. The skin also provides opportunities to interrogate clock regulation of tissue metabolism in the context of stem cells and regeneration. Furthermore, many animal species feature prominent seasonal hair molt cycles, offering an attractive model for investigating the
Plikus, Maksim V; Van Spyk, Elyse N; Pham, Kim; Geyfman, Mikhail; Kumar, Vivek; Takahashi, Joseph S; Andersen, Bogi
Historically, work on peripheral circadian clocks has been focused on organs and tissues that have prominent metabolic functions, such as the liver, fat, and muscle. In recent years, skin has emerged as a model for studying circadian clock regulation of cell proliferation, stem cell functions, tissue regeneration, aging, and carcinogenesis. Morphologically, skin is complex, containing multiple cell types and structures, and there is evidence for a functional circadian clock in most, if not all, of its cell types. Despite the complexity, skin stem cell populations are well defined, experimentally tractable, and exhibit prominent daily cell proliferation cycles. Hair follicle stem cells also participate in recurrent, long-lasting cycles of regeneration: the hair growth cycles. Among other advantages of skin is a broad repertoire of available genetic tools enabling the creation of cell type-specific circadian mutants. Also, due to the accessibility of skin, in vivo imaging techniques can be readily applied to study the circadian clock and its outputs in real time, even at the single-cell level. Skin provides the first line of defense against many environmental and stress factors that exhibit dramatic diurnal variations such as solar ultraviolet (UV) radiation and temperature. Studies have already linked the circadian clock to the control of UVB-induced DNA damage and skin cancers. Due to the important role that skin plays in the defense against microorganisms, it also represents a promising model system to further explore the role of the clock in the regulation of the body's immune functions. To that end, recent studies have already linked the circadian clock to psoriasis, one of the most common immune-mediated skin disorders. Skin also provides opportunities to interrogate the clock regulation of tissue metabolism in the context of stem cells and regeneration. Furthermore, many animal species feature prominent seasonal hair molt cycles, offering an attractive model
Wu, Ya-Huei; Damnée, Souad; Kerhervé, Hélène; Ware, Caitlin; Rigaud, Anne-Sophie
Purpose In a society where technology progresses at an exponential rate, older adults are often unaware of the existence of different kinds of information and communication technologies (ICTs). To bridge the gap, we launched a 2-year project, during which we conducted focus groups (FGs) with demonstrations of ICTs, allowing older adults to try them out and to share their opinions. This study aimed at investigating how participants perceived this kind of initiative and how they reacted to different kinds of ICTs. Patients and methods In total, 14 FGs were conducted with community-dwelling older adults, with a frequency of two FGs on the same topic once per trimester. Twenty-three older adults (four men and 19 women) attended at least one FG but only nearly half of them were regular attendants (ten participating in at least five sessions). Age of participants ranged from 63 years to 88 years, with a mean of 77.1 years. All of them had completed secondary education. The analyses of the data were performed according to inductive thematic analysis. Results Four overarching themes emerged from the analysis. The first concerned participants’ motivation for and assessment of the project. The second theme identified the underlying factors of the “digital divide” between the younger and the older generations. The third theme concerned the factors of technology adoption among older adults. The fourth one identified participants’ attitudes toward assistive ICTs, designed specifically for older adults (“gerontechnologies”). Discussions and conclusion This project encouraging older adults to be informed about different kinds of ICTs was positively rated. With regard to ICTs, participants perceived a digital divide. The underlying factors are generation/cohort effects, cognitive and physical decline related to aging, and negative attitudes toward technologies. However, more and more older adults adopt different kinds of ICTs in order to fit in with the society
Iskovich, Svetlana; Kaminitz, Ayelet; Yafe, Michal Pearl; Mizrahi, Keren; Stein, Jerry; Yaniv, Isaac; Askenasy, Nadir
Regenerative medicine opens new avenues and promises towards more effective therapies for autoimmune disorders. Current therapeutic strategies for type I diabetes focus on three major directions, with distinct advantages and disadvantages: arrest of autoimmunity, islet transplantation and generation of neoislets. There is mounting evidence that candidate stem cells residing in the hematopoietic compartments participate in regeneration of pancreatic islets following chemical and autoimmune injury in vivo. The apparent major mechanisms include immunomodulation, revascularization, support of endogenous beta-cell regeneration and differentiation into insulin-producing cells. Review of the current evidence suggests that some divergent observations depend primarily on the experimental design, which both limits and accentuates developmental events. The flood of publications reporting negative results appears to reflect primarily suboptimal experimental conditions for differentiation of putative stem cells, rather than limited developmental plasticity. Stem cells modulate the course of autoimmune diabetes through multiple mechanisms, including de novo generation of units capable to sense, produce and secrete insulin. Therefore, the charged debate over controversies surrounding developmental plasticity should not impede attempts to design curative therapies for this disease.
Hsu, Wen-Chuin; Chu, Yi-Chuan; Fung, Hon-Chung; Wai, Yau-Yau; Wang, Jiun-Jie; Lee, Jiann-Der; Chen, Yi-Chun
Abstract Mounting evidence shows that hyperhomocysteinemia is a risk factor for cognitive decline. This study enrolled subjects with normal serum levels of B12 and folate and performed thorough neuropsychological assessments to illuminate the independent role of homocysteine on cognitive functions. Participants between ages 50 and 85 were enrolled with Modified Hachinski ischemic score of <4, adequate visual and auditory acuity to allow neuropsychological testing, and good general health. Subjects with cognitive impairment resulting from secondary causes were excluded. Each of the participants completed evaluations of general intellectual function, including the Mini-Mental State Examination, Cognitive Abilities Screening Instrument, Clinical Dementia Rating, and a battery of neuropsychological assessments. This study enrolled 225 subjects (90 subjects younger than 65 years and 135 subjects aged 65 years or older). The sex proportion was similar between the 2 age groups. Years of education were significantly fewer in the elderly (7.49 ± 5.40 years) than in the young (9.76 ± 4.39 years, P = 0.001). There was no significant difference in body mass index or levels of vitamin B12 and folate between the 2 age groups. Homocysteine levels were significantly higher in the elderly group compared to the younger group (10.8 ± 2.7 vs. 9.5 ± 2.5 μmol/L, respectively, P = 0.0006). After adjusting for age, sex, and education, only the Digit Symbol Substitution (DSS) score was significantly lower in subjects with hyperhomocysteinemia (homocysteine >12 μmol/L) than those with homocysteine ≤12 μmol/L in the elderly group (DSS score: 7.1 ± 2.7 and 9.0 ± 3.0, respectively, beta = −1.6, 95% confidence interval [CI] = −2.8∼−0.5, P = 0.001) and borderline significance was noted in the combined age group (beta = −1.1, 95% CI = −2.1∼−0.1, P = 0.04). We did not find an association between
Buchanan, Limin; Kelly, Bridget; Yeatman, Heather
Young adults experience faster weight gain and consume more unhealthy food than any other age groups. The impact of online food marketing on "digital native" young adults is unclear. This study examined the effects of online marketing on young adults' consumption behaviours, using energy drinks as a case example. The elaboration likelihood model of persuasion was used as the theoretical basis. A pre-test post-test experimental research design was adopted using mixed-methods. Participants (aged 18-24) were randomly assigned to control or experimental groups (N = 30 each). Experimental group participants' attitudes towards and intended purchase and consumption of energy drinks were examined via surveys and semi-structured interviews after their exposure to two popular energy drink brands' websites and social media sites (exposure time 8 minutes). Exposure to digital marketing contents of energy drinks improved the experimental group participants' attitudes towards and purchase and consumption intention of energy drinks. This study indicates the influential power of unhealthy online marketing on cognitively mature young adults. This study draws public health attentions to young adults, who to date have been less of a focus of researchers but are influenced by online food advertising.
Mizbani, Amir; Luca, Edlira; Rushing, Elisabeth J.
MicroRNAs (miRNAs) are important regulators of skeletal muscle regeneration, but the underlying mechanisms are still incompletely understood. Here, comparative miRNA sequencing analysis of myogenic progenitor cells (MPs) and non-myogenic fibroblast-adipocyte progenitors (FAPs) during cardiotoxin (CTX)-induced muscle injury uncovered miR-501 as a novel muscle-specific miRNA. miR-501 is an intronic miRNA and its expression levels in MPs correlated with its host gene, chloride channel, voltage-sensitive 5 (Clcn5). Pharmacological inhibition of miR-501 dramatically blunted the induction of embryonic myosin heavy chain (MYH3) and, to a lesser extent, adult myosin isoforms during muscle regeneration, and promoted small-diameter neofibers. An unbiased target identification approach in primary myoblasts validated gigaxonin as a target of miR-501 that mimicked the effect of miR-501 inhibition on MYH3 expression. In the mdx mouse model, which models a pathological disease state, not only was miR-501 induced in regenerating skeletal muscle, but also its serum levels were increased, which correlated with the disease state of the animals. Our results suggest that miR-501 plays a key role in adult muscle regeneration and might serve as a novel serum biomarker for the activation of adult muscle stem cells. PMID:27707793
New cartilaginous tissues in lizards is formed during the regeneration of the tail or after vertebral damage. In order to understand the origin of new cartilaginous cells in the embryo and after injury of adult vertebrae we have studied the distribution of proliferating cartilaginous cells in the vertebral column of embryos and adults of the lizard Anolis lineatopus using autoradiography for H3-thymidine and light and ultrastructural immunocytochemistry for 5BrdU. Proliferating sclerotomal cells initially surround the notochord in a segmental pattern and give rise to the chondrocytes of the vertebral centrum that replace the original chordal cells. Qualitative observations show that proliferating sclerotomal cells dilute the labeling up to 13 days post-injection but a few maintain the labeling as long labeling retention cells and remain in the inter-centra and perichondrium after birth. These cells supply new chondroblasts for post-natal growth of vertebrae but can also proliferate in case of vertebral damage or tail amputation in lizards, a process that sustains tail regeneration. The lack of somitic organization in the regenerating tail impedes the re-formation of a segmental vertebral column that is instead replaced by a continuous cartilaginous tube. It is hypothesized that long labeling retaining cells might represent stem/primordial cells, and that their permanence in the inter-vertebral cartilages and the nearby perichondrium in adult lizards pre-adapt these reptiles to elicit a broad cartilage regeneration in case of injury of the vertebrae.
Yu, Ke; Fischbach, Shane; Xiao, Xiangwei
Islet transplantation is an effective therapy for severe diabetes. Nevertheless, the short supply of donor pancreases constitutes a formidable obstacle to its extensive clinical application. This shortage heightens the need for alternative sources of insulin-producing beta cells. Since mature beta cells have a very slow proliferation rate, which further declines with age, great efforts have been made to identify beta cell progenitors in the adult pancreas. However, the question whether facultative beta cell progenitors indeed exist in the adult pancreas remains largely unresolved. In the current review, we discuss the problems in past studies and review the milestone studies and recent publications.
Yu, Ke; Fischbach, Shane; Xiao, Xiangwei
Islet transplantation is an effective therapy for severe diabetes. Nevertheless, the short supply of donor pancreases constitutes a formidable obstacle to its extensive clinical application. This shortage heightens the need for alternative sources of insulin-producing beta cells. Since mature beta cells have a very slow proliferation rate, which further declines with age, great efforts have been made to identify beta cell progenitors in the adult pancreas. However, the question whether facultative beta cell progenitors indeed exist in the adult pancreas remains largely unresolved. In the current review, we discuss the problems in past studies and review the milestone studies and recent publications. PMID:25429702
Goldstein, Bradley J; Goss, Garrett M; Hatzistergos, Konstantinos E; Rangel, Erika B; Seidler, Barbara; Saur, Dieter; Hare, Joshua M
The olfactory epithelium houses chemosensory neurons, which transmit odor information from the nose to the brain. In adult mammals, the olfactory epithelium is a uniquely robust neuroproliferative zone, with the ability to replenish its neuronal and non-neuronal populations due to the presence of germinal basal cells. The stem and progenitor cells of these germinal layers, and their regulatory mechanisms, remain incompletely defined. Here we show that progenitor cells expressing c-Kit, a receptor tyrosine kinase marking stem cells in a variety of embryonic tissues, are required for maintenance of the adult neuroepithelium. Mouse genetic fate-mapping analyses show that embryonically, a c-Kit(+) population contributes to olfactory neurogenesis. In adults under conditions of normal turnover, there is relatively sparse c-Kit(+) progenitor cell (ckPC) activity. However, after experimentally induced neuroepithelial injury, ckPCs are activated such that they reconstitute the neuronal population. There are also occasional non-neuronal cells found to arise from ckPCs. Moreover, the selective depletion of the ckPC population, utilizing temporally controlled targeted diphtheria toxin A expression, results in failure of neurogenesis after experimental injury. Analysis of this model indicates that most ckPCs reside among the globose basal cell populations and act downstream of horizontal basal cells, which can serve as stem cells. Identification of the requirement for olfactory c-Kit-expressing progenitors in olfactory maintenance provides new insight into the mechanisms involved in adult olfactory neurogenesis. Additionally, we define an important and previously unrecognized site of adult c-Kit activity.
Tsai, Hsin-Yi Sandy; Shillair, Ruth; Cotten, Shelia R
This study examines how older adults learn to use tablet computers. Learning to use new technologies can help older adults to be included in today's digital society. However, learning to use new technologies is not always easy, especially for older adults. This study focuses on how older adults learn to use a specific technology, tablet computers, and the role that social support plays in this process. Data for this project are from 21 in-depth interviews with individuals who own tablet computers. We examine how older adults engage with tablet devices and increase their digital literacy. The findings suggest that, for older adults to start to use tablets, social support plays an important role. In addition, a key way that many participants report gaining expertise with the technology is through "playing around" with the tablets. Suggestions for how to help older adults learn to use new technologies are detailed.
Zhao, Y; Zuo, Y; Wang, X L; Huo, H J; Jiang, J M; Yan, H B; Xiao, Y L
We investigated the effect of neural stem cells (NSC) and erythropoietin (EPO) on axon regeneration in adult rats with transected spinal cord injury, and provided an experimental basis for clinical treatment. Forty Wistar rats with T10-transected spinal cord injury were randomly divided into four groups of ten rats: a control group (group A), an NSC-transplant group (group B), an NSC-transplant and EPO group (group C), and an EPO group (group D). Biotinylated dextran amines (BDA) anterograde corticospinal cord neuronal tracing and Fluoro-Gold (FG) retrograde tracing were carried out at the 8th week after operation to observe the regeneration of nerve fibers. The Basso, Beattie, and Bresnahan (BBB) locomotor score was used to evaluate restoration. 1) BDA and FG immunofluorescence staining: in group C, a large number of regenerated axons were observed and some penetrated the injured area. In group B, only a small number of regenerated axons were observed and none penetrated the injured area. In group D, only sporadic regenerated nerve fibers were observed occasionally, while in group A, no axonal regeneration was observed. In group C, a small number of cones and axons emitted yellow fluorescence, and no FG-labeled cells were observed in the other groups. 2) The BBB scores for group C were higher than those for the other groups, and the differences were statistically significance (P < 0.05). NSC transplantation combined with EPO intraperitoneal injection may benefit axon regeneration in rats with transected spinal cord injury, and accelerate the functional recovery of the hindlimb locomotor.
Cowles, Martis W; Brown, David D R; Nisperos, Sean V; Stanley, Brianna N; Pearson, Bret J; Zayas, Ricardo M
In contrast to most well-studied model organisms, planarians have a remarkable ability to completely regenerate a functional nervous system from a pluripotent stem cell population. Thus, planarians provide a powerful model to identify genes required for adult neurogenesis in vivo. We analyzed the basic helix-loop-helix (bHLH) family of transcription factors, many of which are crucial for nervous system development and have been implicated in human diseases. However, their potential roles in adult neurogenesis or central nervous system (CNS) function are not well understood. We identified 44 planarian bHLH homologs, determined their patterns of expression in the animal and assessed their functions using RNAi. We found nine bHLHs expressed in stem cells and neurons that are required for CNS regeneration. Our analyses revealed that homologs of coe, hes (hesl-3) and sim label progenitors in intact planarians, and following amputation we observed an enrichment of coe(+) and sim(+) progenitors near the wound site. RNAi knockdown of coe, hesl-3 or sim led to defects in CNS regeneration, including failure of the cephalic ganglia to properly pattern and a loss of expression of distinct neuronal subtype markers. Together, these data indicate that coe, hesl-3 and sim label neural progenitor cells, which serve to generate new neurons in uninjured or regenerating animals. Our study demonstrates that this model will be useful to investigate how stem cells interpret and respond to genetic and environmental cues in the CNS and to examine the role of bHLH transcription factors in adult tissue regeneration.
Houle, John D; Tom, Veronica J; Mayes, Debra; Wagoner, Gail; Phillips, Napoleon; Silver, Jerry
Chondroitinase-ABC (ChABC) was applied to a cervical level 5 (C5) dorsal quadrant aspiration cavity of the adult rat spinal cord to degrade the local accumulation of inhibitory chondroitin sulfate proteoglycans. The intent was to enhance the extension of regenerated axons from the distal end of a peripheral nerve (PN) graft back into the C5 spinal cord, having bypassed a hemisection lesion at C3. ChABC-treated rats showed (1) gradual improvement in the range of forelimb swing during locomotion, with some animals progressing to the point of raising their forelimb above the nose, (2) an enhanced ability to use the forelimb in a cylinder test, and (3) improvements in balance and weight bearing on a horizontal rope. Transection of the PN graft, which cuts through regenerated axons, greatly diminished these functional improvements. Axonal regrowth from the PN graft correlated well with the behavioral assessments. Thus, many more axons extended for much longer distances into the cord after ChABC treatment and bridge insertion compared with the control groups, in which axons regenerated into the PN graft but growth back into the spinal cord was extremely limited. These results demonstrate, for the first time, that modulation of extracellular matrix components after spinal cord injury promotes significant axonal regeneration beyond the distal end of a PN bridge back into the spinal cord and that regenerating axons can mediate the return of useful function of the affected limb.
Wang, Xiaofei; Hu, Jianguo; She, Yun; Smith, George M; Xu, Xiao-Ming
Our previous study shows that conventional protein kinases C (cPKCs) are key signaling mediators that are activated by extracellular inhibitory molecules. Inhibition of cPKC by intrathecal infusion of a cPKC inhibitor, GÖ6976, into the site of dorsal hemisection (DH) induces regeneration of lesioned dorsal column sensory, but not corticospinal tract (CST), axons. Here, we investigated whether a direct cortical delivery of GÖ6976 into the soma of corticospinal neurons promotes regeneration of CST and the recovery of forelimb function in rats with cervical spinal cord injuries. We report that cortical delivery of GÖ6976 reduced injury-induced activation of conventional PKCα and PKCβ1 in CST neurons, promoted regeneration of CST axons through and beyond a cervical DH at C4, formed new synapses on target neurons caudal to the injury, and enhanced forelimb functional recovery in adult rats. When combined with lenti-Chondroitinase ABC treatment, cortical administration of GÖ6976 promoted even greater CST axonal regeneration and recovery of forelimb function. Thus, this study has demonstrated a novel strategy that can promote anatomical regeneration of damaged CST axons and partial recovery of forelimb function. Importantly, such an effect is critically dependent on the efficient blockage of injury-induced PKC activation in the soma of layer V CST neurons.
Xu, Jia-jun; Chen, Er-yu; Lu, Chang-lin; He, Cheng
Sciatic nerves in adult male rats were transected and reunited via a silicone chamber. This was followed by a focal injection of recombinant ciliary neurotrophic factor (CNTF). To evaluate the effect of this therapeutic approach and to explore its possible mechanisms, nerve regeneration was traced by horseradish peroxidase retrograde labeling. Functional recovery was evaluated by functional assessment of the hind feet and the expression of a number of proteins was detected using immunohistochemistry. The results showed that a single administration of CNTF could promote regeneration of motor axons, with improved functional recovery in adult rats. Growth associated protein (GAP)-43, S100, CD68 and major histocompatibility complex class II immunoreactivity in the regenerative and distal nerves suggested that CNTF could promote axon regeneration, Schwann cell migration, monocyte infiltration and activation. CNTF might also indirectly promote axonal regeneration by further activating the JAK-STAT3 pathway and subsequently upregulating phosphotyrosine, GAP-43 and S100 expression to enhance proliferation, growth and migration of Schwann cells. CNTF has suggested important targets for pharmacological intervention in peripheral nerve disease and injury.
Ritchey, Katherine C; Meyer, Deborah; Ice, Gillian H
Evaluation and removal of home hazards is an invaluable method for preventing in-home falls and preserving independent living. Current processes for conducting home hazard assessments are impractical from a whole population standpoint given the substantial resources required for implementation. Digital photography offers an opportunity to remotely evaluate an environment for falling hazards. However, reliability of this method has only been tested under the direction of skilled therapists. Ten community dwelling adults over the age of 65 were recruited from local primary care practices between July, 2009 and February, 2010. In-home (IH) assessments were completed immediately after a photographer, blinded to the assessment form, took digital photographs (DP) of the participant home. A different non-therapist assessor then reviewed the photographs and completed a second assessment of the home. Kappa statistic was used to analyze the reliability between the two independent assessments. Home assessments completed by a non-therapist using digital photographs had a substantial agreement (Kappa = 0.61, p < 0.001) with in-home assessments completed by another non-therapist. Additionally, the DP assessments agreed with the IH assessments on the presence or absence of items 96.8% of the time. This study showed that non-therapists can reliably conduct home hazard evaluations using digital photographs.
Kalman, Yoram M.; Kavé, Gitit; Umanski, Daniil
This study examined how younger and older adults approach simple and complex computerized writing tasks. Nineteen younger adults (age range 21–31, mean age 26.1) and 19 older adults (age range 65–83, mean age 72.1) participated in the study. Typing speed, quantitative measures of outcome and process, and self-corrections were recorded. Younger adults spent a lower share of their time on actual typing, and demonstrated more prevalent use of delete keys than did older adults. Within the older group, there was no correlation between the total time spent on the entire task and the number of corrections, but increased typing speed was related to more errors. The results suggest that the approach to the task was different across age groups, either because of age or because of cohort effects. We discuss the interplay of speed and accuracy with regard to digital writing, and its implications for the design of human-computer interactions. PMID:26473904
Tögel, Florian; Westenfelder, Christof
Stem cells have been recognized as a potential tool for the development of innovative therapeutic strategies. There are in general two types of stem cells, embryonic and adult stem cells. While embryonic stem cell therapy has been riddled with problems of allogeneic rejection and ethical concerns, adult stem cells have long been used in the treatment of hematological malignancies. With the recognition of additional, potentially therapeutic characteristics, bone marrow-derived stem cells have become a tool in regenerative medicine. The bone marrow is an ideal source of stem cells because it is easily accessible and harbors two types of stem cells. Hematopoietic stem cells give rise to all blood cell types and have been shown to exhibit plasticity, while multipotent marrow stromal cells are the source of osteocytes, chondrocytes, and fat cells and have been shown to support and generate a large number of different cell types. This review describes the general characteristics of these stem cell populations and their current and potential future applications in regenerative medicine.
Wang, Hong-Ju; Hu, Jian-Guo; Shen, Lin; Wang, Rui; Wang, Qi-Yi; Zhang, Chen; Xi, Jin; Zhou, Jian-Sheng; Lü, He-Zuo
The previous studies suggested that some subpopulations of T lymphocytes against central nervous system (CNS) antigens, such as myelin basic protein (MBP), are neuroprotective. But there were few reports about the effect of these T cells on axon regeneration. In this study, the neonatally thymectomied (Tx) adult rats which contain few T lymphocytes were subjected to spinal cord hemisection and then passively immunized with MBP-activated T cells (MBP-T). The regeneration and dieback of transected axons of cortico-spinal tract (CST) were detected by biotin dextran amine (BDA) tracing. The behavioral assessments were performed using the Basso, Beattie, and Bresnahan locomotor rating scale. We found that passive transferring of MBP-T could attenuate axonal dieback. However, no significant axon regeneration and behavioral differences were observed among the normal, Tx and sham-Tx (sTx) rats with or without MBP-T passive immunization. These results indicate that passive transferring of MBP-T cells can attenuate axonal dieback and promote neuroprotection following spinal cord injury (SCI), but may not promote axon regeneration.
Vergara, M Natalia; Smiley, Laura K; Del Rio-Tsonis, Katia; Tsonis, Panagiotis A
Adult newts are able to regenerate their retina and lens after injury or complete removal through transdifferentiation of the pigmented epithelial tissues of the eye. This process needs to be tightly controlled, and several different mechanisms are likely to be recruited for this function. The Na(+)/K(+) ATPase is a transmembrane protein that establishes electrochemical gradients through the transport of Na(+) and K(+) and has been implicated in the modulation of key cellular processes such as cell division, migration and adhesion. Even though it is expressed in all cells, its isoform composition varies with cell type and is tightly controlled during development and regeneration. In the present study we characterize the expression pattern of Na(+)/K(+) ATPase alpha1 in the adult newt eye and during the process of lens and retina regeneration. We show that this isoform is up-regulated in undifferentiated cells during transdifferentiation. Such change in composition could be one of the mechanisms that newt cells utilize to modulate this process.
Tsai, Hsin-Yi Sandy; Shillair, Ruth; Cotten, Shelia R; Winstead, Vicki; Yost, Elizabeth
Using information and communication technologies (ICTs) can improve older adults' quality of life. ICT use is associated with decreased feelings of loneliness and depression, along with increased feelings of independence and personal growth. However, limited access and low technological self-efficacy are key reasons why some groups, especially older adults, are excluded from being fully engaged in the digital world. In this study, we focus on older adults' technological self-efficacy, which is related to their actual use of technology and the second level digital divide. Specifically, we examine: 1) how older adults decide to use a new technology, tablet computers; 2) how they conquer the barrier of technological self-efficacy through using tablets; and 3) the impacts of using this new technology in their lives. Twenty-one in-depth interviews were conducted with older adults residing in independent living communities in a medium-sized city in the Deep South region of the United States. Observational and enactive learning played important roles for older adults in using tablets. Seeing others use tablets, getting recommendations from family members, or having tablets given to them were the primary reasons they started to use tablet computers. The ease of use feature of tablets helped solve the problem of lacking technological self-efficacy. Using tablets helped increase a sense of connectedness. Tablet computers may be one way to increase digital inclusion among older adults.
Kumar, Ranjan; Sinha, Sarthak; Hagner, Andrew; Stykel, Morgan; Raharjo, Eko; Singh, Karun K; Midha, Rajiv; Biernaskie, Jeff
Functional outcomes following delayed peripheral nerve repair are poor. Schwann cells (SCs) play key roles in supporting axonal regeneration and remyelination following nerve injury, thus understanding the impact of chronic denervation on SC function is critical toward developing therapies to enhance regeneration. To improve our understanding of SC function following acute versus chronic-denervation, we performed functional assays of SCs from adult rodent sciatic nerve with acute- (Day 5 post) or chronic-denervation (Day 56 post), versus embryonic nerves. We also compared Schwann cells derived from adult skin-derived precursors (aSKP-SCs) as an accessible, autologous alternative to supplement the distal (denervated) nerve. We found that acutely-injured SCs and aSKP-SCs exhibited superior proliferative capacity, promotion of neurite outgrowth and myelination of axons, both in vitro and following transplant into a sciatic nerve crush injury model, while chronically-denervated SCs were severely impaired. Acute injury caused re-activation of transcription factors associated with an immature and pro-myelinating SC state (Oct-6, cJun, Sox2, AP2α, cadherin-19), but was diminished with prolonged denervation in vivo and could not be rescued following expansion in vitro suggesting that this is a permanent deficiency. Interestingly, aSKP-SCs closely resembled acutely injured and embryonic SCs, exhibiting elevated expression of these same transcription factors. In summary, prolonged denervation resulted in SC deficiency in several functional parameters that may contribute to impaired regeneration. In contrast, aSKP-SCs closely resemble the regenerative attributes ascribed to acutely-denervated or embryonic SCs emphasizing their potential as an accessible and autologous source of glia cells to enhance nerve regeneration, particularly following delays to surgical repair.
Wang, Xingxing; Byrne, Alexandra B.
Abstract After traumatic damage of the brain or spinal cord, many surviving neurons are disconnected, and recovery of function is limited by poor axon regeneration. Recent data have suggested that poly ADP-ribosylation plays a role in limiting axonal regrowth such that inhibition of poly (ADP-ribose) polymerase (PARP) may have therapeutic efficacy for neurological recovery after trauma. Here, we tested systemic administration of the PARP inhibitor, veliparib, and showed effective suppression of PARylation in the mouse CNS. After optic nerve crush injury or dorsal hemisection of the thoracic spinal cord in mice, treatment with veliparib at doses with pharmacodynamic action had no benefit for axonal regeneration or functional recovery. We considered whether PARP gene family specificity might play a role. In vitro mouse cerebral cortex axon regeneration experiments revealed that short hairpin RNA (shRNA)-mediated suppression of PARP1 promoted axonal regeneration, whereas suppression of other PARP isoforms either had no effect or decreased regeneration. Therefore, we examined recovery from neurological trauma in mice lacking PARP1. No increase of axonal regeneration was observed in Parp1–/– mice after optic nerve crush injury or dorsal hemisection of the thoracic spinal cord, and there was no improvement in motor function recovery. Thus, comprehensive in vivo analysis reveals no indication that clinical PARP inhibitors will on their own provide benefit for recovery from CNS trauma. PMID:28032120
Thompson, Sierra; Muzinic, Laura; Muzinic, Christopher; Niemiller, Matthew L; Voss, S Randal
Multiple factors are thought to cause limb abnormalities in amphibian populations by altering processes of limb development and regeneration. We examined adult and juvenile axolotls (Ambystoma mexicanum) in the Ambystoma Genetic Stock Center (AGSC) for limb and digit abnormalities to investigate the probability of normal regeneration after bite injury. We observed that 80% of larval salamanders show evidence of bite injury at the time of transition from group housing to solitary housing. Among 717 adult axolotls that were surveyed, which included solitary-housed males and group-housed females, approximately half presented abnormalities, including examples of extra or missing digits and limbs, fused digits, and digits growing from atypical anatomical positions. Bite injury likely explains these limb defects, and not abnormal development, because limbs with normal anatomy regenerated after performing rostral amputations. We infer that only 43% of AGSC larvae will present four anatomically normal looking adult limbs after incurring a bite injury. Our results show regeneration of normal limb anatomy to be less than perfect after bite injury.
Thompson, Sierra; Muzinic, Laura; Muzinic, Christopher; Niemiller, Matthew L.
Abstract Multiple factors are thought to cause limb abnormalities in amphibian populations by altering processes of limb development and regeneration. We examined adult and juvenile axolotls (Ambystoma mexicanum) in the Ambystoma Genetic Stock Center (AGSC) for limb and digit abnormalities to investigate the probability of normal regeneration after bite injury. We observed that 80% of larval salamanders show evidence of bite injury at the time of transition from group housing to solitary housing. Among 717 adult axolotls that were surveyed, which included solitary‐housed males and group‐housed females, approximately half presented abnormalities, including examples of extra or missing digits and limbs, fused digits, and digits growing from atypical anatomical positions. Bite injury probably explains these limb defects, and not abnormal development, because limbs with normal anatomy regenerated after performing rostral amputations. We infer that only 43% of AGSC larvae will present four anatomically normal looking adult limbs after incurring a bite injury. Our results show regeneration of normal limb anatomy to be less than perfect after bite injury. PMID:25745564
Cohen, Jamie; Penney, Dana L; Davis, Randall; Libon, David J; Swenson, Rodney A; Ajilore, Olusola; Kumar, Anand; Lamar, Melissa
Psychomotor slowing has been documented in depression. The digital Clock Drawing Test (dCDT) provides: (i) a novel technique to assess both cognitive and motor aspects of psychomotor speed within the same task and (ii) the potential to uncover subtleties of behavior not previously detected with non-digitized modes of data collection. Using digitized pen technology in 106 participants grouped by Age (younger/older) and Affect (euthymic/unmedicated depressed), we recorded cognitive and motor output by capturing how the clock is drawn rather than focusing on the final product. We divided time to completion (TTC) for Command and Copy conditions of the dCDT into metrics of percent of drawing (%Ink) versus non-drawing (%Think) time. We also obtained composite Z-scores of cognition, including attention/information processing (AIP), to explore associations of %Ink and %Think times to cognitive and motor performance. Despite equivalent TTC, %Ink and %Think Command times (Copy n.s.) were significant (AgeXAffect interaction: p=.03)-younger depressed spent a smaller proportion of time drawing relative to thinking compared to the older depressed group. Command %Think time negatively correlated with AIP in the older depressed group (r=-.46; p=.02). Copy %Think time negatively correlated with AIP in the younger depressed (r=-.47; p=.03) and older euthymic groups (r=-.51; p=.01). The dCDT differentiated aspects of psychomotor slowing in depression regardless of age, while dCDT/cognitive associates for younger adults with depression mimicked patterns of older euthymics.
A comprehensive transcriptome survey, or “Gene Atlas,” provides information essential for a complete understanding of the genomic biology of an organism. Using a digital gene expression approach, we developed a Gene Atlas of RNA abundance in 92 adult, juvenile and fetal cattle tissues. The samples...
Jimoyiannis, Athanassios; Gravani, Maria
The research reported in this paper aspires to shed light into adult digital literacy using learners' and educators' experiences and perceptions at Second Chance Schools, a project in Greece aiming at combating social exclusion through education. In exploring the above, this investigation uses a case-study approach within a qualitative paradigm…
Gamliel, Tova; Hazan, Haim
In Israel's Multigenerational Connection Program (MCP), children instruct adults in computer and Internet use. Taking children's advantage in digital literacy as a given, the study examines their generational status in computerized encounters that MCP creates in two schools, one Jewish and one Arab. The data were gathered by means of qualitative…
Patel, Rita; Dubrovskiy, Denis; Döllinger, Michael
PURPOSE The aim of this study is to quantify and identify characteristic vibratory motion in typically developing prepubertal children and young adults using high-speed digital imaging. METHOD The vibrations of the vocal folds were recorded from 27 children (ages 5-9 years) and 35 adults (ages 21-45 years), with high speed at 4,000 frames per second for sustained phonation. Kinematic features of amplitude periodicity, time periodicity, phase asymmetry, spatial symmetry, and glottal gap index were analyzed from the glottal area waveform across mean and standard deviation (i.e., intercycle variability) for each measure. RESULTS Children exhibited lower mean amplitude periodicity compared to men and women and lower time periodicity compared to men. Children and women exhibited greater variability in amplitude periodicity, time periodicity, phase asymmetry, and glottal gap index compared to men. Women had lower mean values of amplitude periodicity and time periodicity compared to men. CONCLUSION Children differed both spatially but more temporally in vocal fold motion, suggesting the need for the development of children-specific kinematic norms. Results suggest more uncontrolled vibratory motion in children, reflecting changes in the vocal fold layered structure and aero-acoustic source mechanisms.
Tsai, Hsin-yi Sandy; Shillair, Ruth; Cotten, Shelia R.; Winstead, Vicki; Yost, Elizabeth
Using information and communication technologies (ICTs) can improve older adults’ quality of life. ICT use is associated with decreased feelings of loneliness and depression, along with increased feelings of independence and personal growth. However, limited access and low technological self-efficacy are key reasons why some groups, especially older adults, are excluded from being fully engaged in the digital world. In this study, we focus on older adults’ technological self-efficacy, which is related to their actual use of technology and the second level digital divide. Specifically, we examine: 1) how older adults decide to use a new technology, tablet computers; 2) how they conquer the barrier of technological self-efficacy through using tablets; and 3) the impacts of using this new technology in their lives. Twenty-one in-depth interviews were conducted with older adults residing in independent living communities in a medium-sized city in the Deep South region of the United States. Observational and enactive learning played important roles for older adults in using tablets. Seeing others use tablets, getting recommendations from family members, or having tablets given to them were the primary reasons they started to use tablet computers. The ease of use feature of tablets helped solve the problem of lacking technological self-efficacy. Using tablets helped increase a sense of connectedness. Tablet computers may be one way to increase digital inclusion among older adults. PMID:26877583
Cheng, Lei; Liu, Yi; Zhao, Hua; Zhang, Wen; Guo, Ying-Jun; Nie, Lin
Highlights: •CDNF was successfully transfected by a lentiviral vector into the distal sciatic nerve. •CDNF improved S-100, NF200 expression and nerve regeneration after sciatic injury. •CDNF improved the remyelination and thickness of the regenerated sciatic nerve. •CDNF improved gastrocnemius muscle weight and sciatic functional recovery. -- Abstract: Peripheral nerve injury is often followed by incomplete and unsatisfactory functional recovery and may be associated with sensory and motor impairment of the affected limb. Therefore, a novel method is needed to improve the speed of recovery and the final functional outcome after peripheral nerve injuries. This report investigates the effect of lentiviral-mediated transfer of conserved dopamine neurotrophic factor (CDNF) on regeneration of the rat peripheral nerve in a transection model in vivo. We observed notable overexpression of CDNF protein in the distal sciatic nerve after recombinant CDNF lentiviral vector application. We evaluated sciatic nerve regeneration after surgery using light and electron microscopy and the functional recovery using the sciatic functional index and target muscle weight. HE staining revealed better ordered structured in the CDNF-treated group at 8 weeks post-surgery. Quantitative analysis of immunohistochemistry of NF200 and S-100 in the CDNF group revealed significant improvement of axonal and Schwann cell regeneration compared with the control groups at 4 weeks and 8 weeks after injury. The thickness of the myelination around the axons in the CDNF group was significantly higher than in the control groups at 8 weeks post-surgery. The CDNF group displayed higher muscle weights and significantly increased sciatic nerve index values. Our findings suggest that CDNF gene therapy could provide durable and stable CDNF protein concentration and has the potential to enhance peripheral nerve regeneration, morphological and functional recovery following nerve injury, which suggests a
Nacu, Eugen; Tanaka, Elly M
Salamander limb regeneration is a classical model of tissue morphogenesis and patterning. Through recent advances in cell labeling and molecular analysis, a more precise, mechanistic understanding of this process has started to emerge. Long-standing questions include to what extent limb regeneration recapitulates the events observed in mammalian limb development and to what extent are adult- or salamander- specific aspects deployed. Historically, researchers studying limb development and limb regeneration have proposed different models of pattern formation. Here we discuss recent data on limb regeneration and limb development to argue that although patterning mechanisms are likely to be similar, cell plasticity and signaling from nerves play regeneration-specific roles.
Li, Cai; Hu, Rong; Yang, Qi; Luo, Ming; Li, Wei; Yu, Shaohua
The coherent reception of intensity modulated signal has been recently widely investigated, in which the signal is recovered by the envelop detection. High linewidth tolerance is achieved with such scheme. However, strong optical carrier exists during the transmission, which degrades the optical power efficiency. In this paper, an efficient modulation scheme for discrete multi-tone (DMT) signal is proposed based on the Mach-Zehnder modulator (MZM). Different from the traditional intensity modulation, the proposed method employs both intensity and phase domain. Thus, the optical carrier power can be greatly reduced by adjusting the bias of MZM around the null point. By employing coherent detection and digital carrier regeneration (DCR), the carrier suppressed DMT signal can be recovered using envelop detection. No carrier frequency or phase estimation is required. Numerical investigations are made to demonstrate the feasibility, in which significant improvements are found for the proposed DCR method, showing great tolerance against laser linewidth and carrier power reduction. Finally, a 124-Gb/s transmission of polarization-division multiplexed DMT (PDM-DMT) signal is demonstrated over 100-km SSMF, with only -8 dB optical carrier to signal power ratio (CSPR).
Over the past decade, Prensky's distinctions between "digital immigrants" and "digital natives" have been oft-referenced. Much has been written about digital native students as a part of the Net generation or as Millennials. However, little work fully considers the impact of digital immigrant discourse within the fields of…
Rinkevich, Baruch; Rinkevich, Yuval
A number of challenges have hindered the development of a unified theory for metazoan regeneration. To describe the full range of complex regeneration phenomena in Animalia, we suggest that metazoans that regenerate missing body parts exhibit biological attributes that are tailored along a morpho-spatial regeneration continuum, illustrated in its polar scenarios by the USA “stars and stripes” flag. Type 1 organisms (“T1, ‘stars’”) are typical colonial organisms (but contain unitary taxa) that are able to regenerate “whole new stars”, namely, whole bodies and colonial modules, through systemic induction and sometimes multiple regeneration foci (hollow regeneration spheres, resembling the blastula) that compete for dominance. They regenerate soma and germ constituents with pluripotent adult stem cells and exhibit somatic-embryogenesis mode of ontogeny. Type 2 organisms (“T2, ‘stripes’”) are capable of limited regeneration of somatic constituents via fate-restricted stem cells, and regenerate through centralized inductions that lead to a single regeneration front. T2 organisms are unitary and use preformistic mode of ontogeny. T1 and T2 organisms also differ in interpretation of what constitutes positional information. T2 organisms also execute alternative, less effective, regeneration designs (i.e., scar formation). We assigned 15 characteristics that distinguish between T1/T2 strategies: those involving specific regeneration features and those operating on biological features at the whole-organism level. Two model organisms are discussed, representing the two strategies of T1/T2 along the regeneration continuum, the Botrylloides whole body regeneration (T1) and the mouse digit-tip regeneration (T2) phenomena. The above working hypothesis also postulates that regeneration is a primeval attribute of metazoans. As specified, the “stars and stripes” paradigm allows various combinations of the biological features assigned to T1 and T2
Quarta, Serena; Baeumer, Bastian E; Scherbakov, Nadja; Andratsch, Manfred; Rose-John, Stefan; Dechant, Georg; Bandtlow, Christine E; Kress, Michaela
After nerve injury, adult sensory neurons can regenerate peripheral axons and reconnect with their target tissue. Initiation of outgrowth, as well as elongation of neurites over long distances, depends on the signaling of receptors for neurotrophic growth factors. Here, we investigated the importance of gp130, the signaling subunit of neuropoietic cytokine receptors in peripheral nerve regeneration. After sciatic nerve crush, functional recovery in vivo was retarded in SNS-gp130(-/-) mice, which specifically lack gp130 in sensory neurons. Correspondingly, a significantly reduced number of free nerve endings was detected in glabrous skin from SNS-gp130(-/-) compared with control mice after nerve crush. Neurite outgrowth and STAT3 activation in vitro were severely reduced in cultures in gp130-deficient cultured neurons. Surprisingly, in neurons obtained from SNS-gp130(-/-) mice the increase in neurite length was reduced not only in response to neuropoietic cytokine ligands of gp130 but also to nerve growth factor (NGF), which does not bind to gp130-containing receptors. Neurite outgrowth in the absence of neurotrophic factors was partially rescued in gp130-deficient neurons by leptin, which activates STAT3 downstream of leptic receptor and independent of gp130. The neurite outgrowth response of gp130-deficient neurons to NGF was fully restored in the presence of leptin. Based on these findings, gp130 signaling via STAT3 activation is suggested not only to be an important regulator of peripheral nerve regeneration in vitro and in vivo, but as determining factor for the growth promoting action of NGF in adult sensory neurons.
Mescher, A.L.; Munaim, S.I.
The extracellular matrix (ECM) of the distal tissues in a newt limb stump is completely reorganized in the 2-3-week period following amputation. In view of numerous in vitro studies showing that extracellular material influences cellular migration and proliferation, it is likely that the changes in the limb's ECM are important activities in the process leading to regeneration of such limbs. Using biochemical, autoradiographic, and histochemical techniques we studied temporal and spatial differences in the synthesis of glycosaminoglycans (GAGs) during the early, nerve-dependent phase of limb regeneration. Hyaluronic acid synthesis began with the onset of tissue dedifferentiation, became maximal within 1 weeks, and continued throughout the period of active cell proliferation. Chondroitin sulfate synthesis began somewhat later, increased steadily, and reached very high levels during chondrogenesis. During the first 10 days after amputation, distributions of sulfated and nonsulfated GAGs were both uniform throughout dedifferentiating tissues, except for a heavier localization near the bone. Since nerves are necessary to promote the regenerative process, we examined the neural influence on synthesis and accumulation of extracellular GAGs. Denervation decreased GAG production in all parts of the limb stump by approximately 50%. Newt dorsal root ganglia and brain-derived fibroblast growth factor each produced twofold stimulation of GAG synthesis in cultured 7-day regenerates. The latter effect was primarily on synthesis of hyaluronic acid. The results indicate that the trophic action of nerves on amphibian limb regeneration includes a positive influence on synthesis and extracellular accumulation of GAGs.
Ptomey, Lauren T.; Willis, Erik A.; Honas, Jeffery J.; Mayo, Matthew S.; Washburn, Richard A.; Herrmann, Stephen D.; Sullivan, Debra K.; Donnelly, Joseph E.
Background Recent reports have questioned the adequacy of self-report measures of dietary intake as the basis for scientific conclusions regarding the associations of dietary intake and health, and reports have recommended the development and evaluation of better methods for the assessment of dietary intake in free-living individuals. We developed a procedure that utilized pre- and post-meal digital photographs in combination with dietary recalls (DP+R) to assess energy intake during ad libitum eating in a cafeteria setting. Objective To compare mean daily energy intake of overweight and obese young adults assessed by a DP+R method with mean total daily energy expenditure assessed by doubly labelled water (TDEEDLW). Methods Energy intake was assessed using the DP+R method in 91 overweight and obese young adults (age = 22.9±3.2 yrs., BMI=31.2 ± 5.6 kg·m2, female = 49%) over 7-days of ad libitum eating in a University cafeteria. Foods consumed outside the cafeteria (i.e., snacks, non-cafeteria meals) were assessed using multiple-pass recall procedures using food models and standardized, neutral probing questions. TDEEDLW was assessed in all participants over the 14-day period. Results The mean energy intakes estimated by DP+R and TDEEDLW were not significantly different (DP+R = 2912 ± 661 kcal/d; TDEEDLW = 2849 ± 748 kcal/d, p = 0.42). The DP+R method overestimated TDEEDLW by 63 ± 750 kcal/d (6.8 ± 28%). Conclusion Results suggest that the DP+R method provides estimates of energy intake comparable to those obtained by TDEEDLW. PMID:26122282
Galimov, Artur; Merry, Troy L; Luca, Edlira; Rushing, Elisabeth J; Mizbani, Amir; Turcekova, Katarina; Hartung, Angelika; Croce, Carlo M; Ristow, Michael; Krützfeldt, Jan
The expansion of myogenic progenitors (MPs) in the adult muscle stem cell niche is critical for the regeneration of skeletal muscle. Activation of quiescent MPs depends on the dismantling of the basement membrane and increased access to growth factors such as fibroblast growth factor-2 (FGF2). Here, we demonstrate using microRNA (miRNA) profiling in mouse and human myoblasts that the capacity of FGF2 to stimulate myoblast proliferation is mediated by miR-29a. FGF2 induces miR-29a expression and inhibition of miR-29a using pharmacological or genetic deletion decreases myoblast proliferation. Next generation RNA sequencing from miR-29a knockout myoblasts (Pax7(CE/+) ; miR-29a(flox/flox) ) identified members of the basement membrane as the most abundant miR-29a targets. Using gain- and loss-of-function experiments, we confirm that miR-29a coordinately regulates Fbn1, Lamc1, Nid2, Col4a1, Hspg2 and Sparc in myoblasts in vitro and in MPs in vivo. Induction of FGF2 and miR-29a and downregulation of its target genes precedes muscle regeneration during cardiotoxin (CTX)-induced muscle injury. Importantly, MP-specific tamoxifen-induced deletion of miR-29a in adult skeletal muscle decreased the proliferation and formation of newly formed myofibers during both CTX-induced muscle injury and after a single bout of eccentric exercise. Our results identify a novel miRNA-based checkpoint of the basement membrane in the adult muscle stem cell niche. Strategies targeting miR-29a might provide useful clinical approaches to maintain muscle mass in disease states such as ageing that involve aberrant FGF2 signaling.
Regenerative medicine promises to greatly impact on human health by improving repair outcomes in a range of tissues and injury contexts. Successful therapies will rely on identifying both intrinsic and extrinsic biological circuits that control wound healing, proliferation, cell survival, and developmental cell fate. Animals such as the zebrafish and the salamander display powerful examples of near-perfect regeneration and scar-free healing in a range of injury contexts not attained in mammals. By studying regeneration in a range of highly regenerative species that maintain regenerative potential throughout life, many instructive and permissive factors have been identified that could assist in the development of regenerative therapies. This review highlights some of the recent observations in immune regulation, epigenetic regulation, stem cell mobilization, and regenerative signatures that have improved our understanding of the regenerative process. Potential opportunities in harnessing this knowledge for future translation into the clinic are discussed.
Muse cells are a novel population of nontumorigenic pluripotent stem cells, highly resistant to cellular stress. These cells are present in every connective tissue and intrinsically express pluripotent stem markers such as Nanog, Oct3/4, Sox2, and TRA1-60. Muse cells are able to differentiate into cells from all three embryonic germ layers both spontaneously and under media-specific induction. Unlike ESCs and iPSCs, Muse cells exhibit low telomerase activity and asymmetric division and do not undergo tumorigenesis or teratoma formation when transplanted into a host organism. Muse cells have a high capacity for homing into damaged tissue and spontaneous differentiation into cells of compatible tissue, leading to tissue repair and functional restoration. The ability of Muse cells to restore tissue function may demonstrate the role of Muse cells in a highly conserved cellular mechanism related to cell survival and regeneration, in response to cellular stress and acute injury. From an evolutionary standpoint, genes pertaining to the regenerative capacity of an organism have been lost in higher mammals from more primitive species. Therefore, Muse cells may offer insight into the molecular and evolutionary bases of autonomous tissue regeneration and elucidate the molecular and cellular mechanisms that prevent mammals from regenerating limbs and organs, as planarians, newts, zebrafish, and salamanders do. PMID:28070194
Siren, Anu; Knudsen, Sine Grønborg
Based on data from a survey (n = 3291) and 14 qualitative interviews among Danish older adults, this study investigated the use of, and attitudes toward, information communications technology (ICT) and the digital delivery of public services. While age, gender, and socioeconomic status were associated with use of ICT, these determinants lost their explanatory power when we controlled for attitudes and experiences. We identified three segments that differed in their use of ICT and attitudes toward digital service delivery. As nonuse of ICT often results from the lack of willingness to use it rather than from material or cognitive deficiencies, policy measures for bridging the digital divide should focus on skills and confidence rather than on access or ability.
Kumar, Anoop; Gates, Phillip B; Czarkwiani, Anna; Brockes, Jeremy P
Limb development in salamanders differs from other tetrapods in that the first digits to form are the two most anterior (preaxial dominance). This has been proposed as a salamander novelty and its mechanistic basis is unknown. Salamanders are the only adult tetrapods able to regenerate the limb, and the contribution of preaxial dominance to limb regeneration is unclear. Here we show that during early outgrowth of the limb bud, a small cohort of cells express the orphan gene Prod1 together with Bmp2, a critical player in digit condensation in amniotes. Disruption of Prod1 with a gene-editing nuclease abrogates these cells, and blocks formation of the radius and ulna, and outgrowth of the anterior digits. Preaxial dominance is a notable feature of limb regeneration in the larval newt, but this changes abruptly after metamorphosis so that the formation of anterior and posterior digits occurs together within the autopodium resembling an amniote-like pattern.
Kumar, Anoop; Gates, Phillip B.; Czarkwiani, Anna; Brockes, Jeremy P.
Limb development in salamanders differs from other tetrapods in that the first digits to form are the two most anterior (preaxial dominance). This has been proposed as a salamander novelty and its mechanistic basis is unknown. Salamanders are the only adult tetrapods able to regenerate the limb, and the contribution of preaxial dominance to limb regeneration is unclear. Here we show that during early outgrowth of the limb bud, a small cohort of cells express the orphan gene Prod1 together with Bmp2, a critical player in digit condensation in amniotes. Disruption of Prod1 with a gene-editing nuclease abrogates these cells, and blocks formation of the radius and ulna, and outgrowth of the anterior digits. Preaxial dominance is a notable feature of limb regeneration in the larval newt, but this changes abruptly after metamorphosis so that the formation of anterior and posterior digits occurs together within the autopodium resembling an amniote-like pattern. PMID:26498026
Herrero, Astrid; Prigent, Julie; Lombard, Catherine; Rosseels, Valérie; Daujat-Chavanieu, Martine; Breckpot, Karine; Najimi, Mustapha; Deblandre, Gisèle; Sokal, Etienne M
There is growing evidence that cell therapy constitutes a promising strategy for liver regenerative medicine. In the setting of hepatic cancer treatments, cell therapy could prove a useful therapeutic approach for managing the acute liver failure that occurs following extended hepatectomy. In this study, we examined the influence of delivering adult-derived human liver stem/progenitor cells (ADHLSCs) at two different early time points in an immunodeficient mouse model (Rag2-/-IL2Rγ-/-) that had undergone a 70% hepatectomy procedure. The hepatic mesenchymal cells were intrasplenically infused either immediately after surgery (n = 26) or following a critical 3-day period (n = 26). We evaluated the cells' capacity to engraft at day 1 and day 7 following transplantation by means of human Alu qPCR quantification, along with histological assessment of human albumin and α-smooth muscle actin. In addition, cell proliferation (anti-mouse and human Ki-67 staining) and murine liver weight were measured in order to evaluate liver regeneration. At day 1 posttransplantation, the ratio of human to mouse cells was similar in both groups, whereas 1 week posttransplantation this ratio was significantly improved (p < 0.016) in mice receiving ADHLSC injection at day 3 posthepatectomy (1.7%), compared to those injected at the time of surgery (1%). On the basis of liver weight, mouse liver regeneration was more extensive 1 week posttransplantation in mice transplanted with ADHLSCs (+65.3%) compared to that of mice from the sham vehicle group (+42.7%). In conclusion, infusing ADHLSCs 3 days after extensive hepatectomy improves the cell engraftment and murine hepatic tissue regeneration, thereby confirming that ADHLSCs could be a promising cell source for liver cell therapy and hepatic tissue repair.
Endo, Tetsuya; Yoshino, Jun; Kado, Koji; Tochinai, Shin
Urodele amphibians are highly regenerative animals. After partial removal of the brain in urodeles, ependymal cells around the wound surface proliferate, differentiate into neurons and glias and finally regenerate the lost tissue. In contrast to urodeles, this type of brain regeneration is restricted only to the larval stages in anuran amphibians (frogs). In adult frogs, whereas ependymal cells proliferate in response to brain injury, they cannot migrate and close the wound surface, resulting in the failure of regeneration. Therefore frogs, in particular Xenopus, provide us with at least two modes to study brain regeneration. One is to study normal regeneration by using regenerative larvae. In this type of study, the requirement of reconnection between a regenerating brain and sensory neurons was demonstrated. Functional restoration of a regenerated telencephalon was also easily evaluated because Xenopus shows simple responses to the stimulus of a food odor. The other mode is to compare regenerative larvae and non-regenerative adults. By using this mode, it is suggested that there are regeneration-competent cells even in the non-regenerative adult brain, and that immobility of those cells might cause the failure of regeneration. Here we review studies that have led to these conclusions.
Liu, Ming; Zhu, Jin-Gai; Yu, Zhang-Bin; Song, Gui-Xian; Shen, Ya-Hui; Liu, Yao-Qiu; Zhu, Chun; Qian, Ling-Mei
Accumulating evidence has revealed that the mammalian heart possesses a measurable capacity for renewal. Neonatal mice retain a regenerative capacity over a short time-frame (≤6 days), but this capacity is lost by 7 days of age. In the present study, differential gene expression profiling of mouse cardiac tissue was performed to further elucidate the mechanisms underlying this process. The global gene expression patterns of the neonatal C57BL/6J mouse heart were examined at three key time-points (1, 6 and 7 days old) using digital gene expression analysis. In the distribution of total clean tags, high-expression tags (>100 copies) were found to be predominant, whereas low expression tags (<5 copies) occupied the majority of distinct tag distributions. In total, 306 differentially expressed genes (DEGs) were detected in cardiac tissue, with the expression levels of 115 genes upregulated and those of 191 genes downregulated in 7-day-old mice compared with expression levels in 1- and 6-day-old mice, respectively. The expression levels of five DEGs were confirmed using quantitative polymerase chain reaction. Gene ontology analysis revealed a large proportion of DEGs distributed throughout the cell, and these DEGs were associated with binding as well as catalytic, hydrolase, transferase and molecular transducer activities. Furthermore, these genes were involved in cellular, metabolic and developmental processes, as well as biological regulation and signaling pathways. Pathway analysis identified the oxidative phosphorylation pathway to be the process most significantly putatively affected by the differential expression of these genes. These data provide the basis for future analysis of the gene expression patterns that regulate the molecular mechanism of cardiac regeneration.
Millay, Douglas P; Sutherland, Lillian B; Bassel-Duby, Rhonda; Olson, Eric N
Regeneration of injured adult skeletal muscle involves fusion of activated satellite cells to form new myofibers. Myomaker is a muscle-specific membrane protein required for fusion of embryonic myoblasts, but its potential involvement in adult muscle regeneration has not been explored. We show that myogenic basic helix-loop-helix (bHLH) transcription factors induce myomaker expression in satellite cells during acute and chronic muscle regeneration. Moreover, genetic deletion of myomaker in adult satellite cells completely abolishes muscle regeneration, resulting in severe muscle destruction after injury. Myomaker is the only muscle-specific protein known to be absolutely essential for fusion of embryonic and adult myoblasts.
Millay, Douglas P.; Sutherland, Lillian B.; Bassel-Duby, Rhonda
Regeneration of injured adult skeletal muscle involves fusion of activated satellite cells to form new myofibers. Myomaker is a muscle-specific membrane protein required for fusion of embryonic myoblasts, but its potential involvement in adult muscle regeneration has not been explored. We show that myogenic basic helix–loop–helix (bHLH) transcription factors induce myomaker expression in satellite cells during acute and chronic muscle regeneration. Moreover, genetic deletion of myomaker in adult satellite cells completely abolishes muscle regeneration, resulting in severe muscle destruction after injury. Myomaker is the only muscle-specific protein known to be absolutely essential for fusion of embryonic and adult myoblasts. PMID:25085416
Oviedo, Néstor J; Nicolas, Cindy L; Adams, Dany S; Levin, Michael
INTRODUCTIONIn recent years, planarians have been increasingly recognized as an emerging model organism amenable to molecular genetic techniques aimed at understanding complex biological tasks commonly observed among metazoans. Growing evidence suggests that this model organism is uniquely poised to inform us about the mechanisms of tissue regeneration, stem cell regulation, tissue turnover, pharmacological action of diverse drugs, cancer, and aging. This article provides an overview of the planarian model system with special attention to the species Schmidtea mediterranea. Additionally, information is provided about the most popular use of this organism, together with modern genomic resources and technical approaches.
Satoh, Akira; Mitogawa, Kazumasa; Makanae, Aki
Limb regeneration ability, which can be observed in amphibians, has been investigated as a representative phenomenon of organ regeneration. Recently, an alternative experimental system called the accessory limb model was developed to investigate early regulation of amphibian limb regeneration. The accessory limb model contributed to identification of limb regeneration inducers in urodele amphibians. Furthermore, the accessory limb model may be applied to other species to explore universality of regeneration mechanisms. This review aims to connect the insights recently gained to emboss universality of regeneration mechanisms among species. The defined molecules (BMP7 (or2) + FGF2 + FGF8) can transform skin wound healing to organ (limb) regeneration responses. The same molecules can initiate regeneration responses in some species.
Lim, Fei Tieng; Ogawa, Satoshi; Smith, A Ian; Parhar, Ishwar S
The central nervous system (CNS) of the non-mammalian vertebrates has better neuroregenerative capability as compared with the mammalian CNS. Regeneration of habenula was observed 40 days after damage in zebrafish. During the early stage of regeneration, we found a significant increase of apoptotic cells on day-1 post-damage and of proliferative cells on day-3 post-damage. To identify the molecular factor(s) involved in the early stages of neuroregeneration, differentially expressed proteins during sham, 20- and 40-h post-habenula damage were investigated by proteomic approach by using two-dimensional differential gel electrophoresis (2D-DIGE) coupled with Matrix-Assisted Laser Desorption/Ionization-Time-of-Flight (MALDI-ToF) and tandem mass spectrometry. Protein profiles revealed 17 differentially (>1.5-fold) expressed proteins: 10 upregulated, 4 downregulated, 2 proteins were found to be downregulated at the early stage but upregulated at a later stage, and 1 protein was found to be upregulated at 2 different time points. All proteins identified can be summarized under few molecular processes involved in the early stages of neuroregeneration in zebrafish CNS: apoptosis regulation (Wnt inhibitory factor 1 [WIF1]), neuroprotection (metallothionein), cell proliferation (Spred2, ependymin, Lhx1, and Wnts), differentiation (Spred2, Lhx9, and Wnts), and morphogenesis (cytoplasmic actins and draculin). These protein profiling results suggest that drastic molecular changes occur in the neuroregenerative process during this period, which includes cell proliferation, differentiation, and protection.
Taylor, Andrew L; Rodger, Jennifer; Stirling, R Victoria; Beazley, Lyn D; Dunlop, Sarah A
Retinotectal topography is established during development and relies on the sequential recruitment of glutamate receptors within postsynaptic tectal cells. NMDA receptors underpin plastic changes at early stages when retinal ganglion cell (RGC) terminal arbors are widespread and topography is coarse; AMPA/kainate receptors mediate fast secure neurotransmission characteristic of mature circuits once topography is refined. Here, we have examined the relative contributions of these receptors to visually evoked activity in normal adult goldfish, in which retinotectal topography is constantly adjusted to compensate for the continual neurogenesis and the addition of new RGC arbors. Furthermore, we examined animals at two stages of optic nerve regeneration. In the first, RGC arbors are widespread and receptive fields large resulting in coarse topography; in the second, RGC arbors are pruned to reduce receptive fields leading to refined topography. Antagonists were applied to the tectum during multiunit recording of postsynaptic responses. Normal goldfish have low levels of NMDA receptor-mediated activity and high levels of AMPA/kainate. When coarse topography has been restored, NMDA receptor-mediated activity is increased and that of AMPA/kainate decreased. Once topography has been refined, the balance of NMDA and AMPA/kainate receptor-mediated activity returns to normal. The data suggest that glutamatergic neurotransmission in normal adult goldfish is dual with NMDA receptors fine-tuning topography and AMPA receptors allowing stable synaptic function. Furthermore, the normal operation of both receptors allows a response to injury in which the balance can be transiently reversed to restore topography and vision.
Li, Rui; Wu, Jiang; Lin, Zhenkun; Nangle, Matthew R; Li, Yi; Cai, Pingtao; Liu, Dan; Ye, Libin; Xiao, Zecong; He, Chaochao; Ye, Jingjing; Zhang, Hongyu; Zhao, Yingzheng; Wang, Jian; Li, Xiaokun; He, Yan; Ye, Qingsong; Xiao, Jian
The prototypical neurotrophin, nerve growth factor (NGF), plays an important role in the development and maintenance of many neurons in both the central and peripheral nervous systems, and can promote functional recovery after peripheral nerve injury in adulthood. However, repair of peripheral nerve defects is hampered by the short half-life of NGF in vivo, and treatment with either NGF alone or NGF contained in synthetic nerve conduits is inferior to the use of nerve autografts, the current gold standard. We tested the reparative ability of a single local injection of a polyvalent coacervate containing polycation-poly(ethylene argininylaspartate diglyceride; PEAD), heparin, and NGF, in adult rats following sciatic nerve crush injury, using molecular, histological and behavioral approaches. In vitro assays demonstrated that NGF was loaded into the coacervate at nearly 100% efficiency, and was protected from proteolytic degradation. In vivo, the coacervate enhanced NGF bioavailability, leading to a notable improvement in motor function (track walking analysis) after 30days. The NGF coacervate treatment was also associated with better weight gain and reduction in atrophy of the gastrocnemius muscle. Furthermore, light and electron microscopy showed that the number of myelinated axons and axon-to-fiber ratio (G-ratio) were significantly higher in NGF coacervate-treated rats compared with control groups. Expression of markers of neural tissue regeneration (MAP-2, S-100β, MBP and GAP-43), as well as proliferating Schwann cells and myelin-axon relationships (GFAP and NF200), were also increased. These observations suggest that even a single administration of NGF coacervate could have therapeutic value for peripheral nerve regeneration and functional recovery.
Atkinson, Patrick J; Wise, Andrew K; Flynn, Brianna O; Nayagam, Bryony A; Richardson, Rachael T
The degeneration of hair cells in the mammalian cochlea results in permanent sensorineural hearing loss. This study aimed to promote the regeneration of sensory hair cells in the mature cochlea and their reconnection with auditory neurons through the introduction of ATOH1, a transcription factor known to be necessary for hair cell development, and the introduction of neurotrophic factors. Adenoviral vectors containing ATOH1 alone, or with neurotrophin-3 and brain derived neurotrophic factor were injected into the lower basal scala media of guinea pig cochleae four days post ototoxic deafening. Guinea pigs treated with ATOH1 gene therapy, alone, had a significantly greater number of cells expressing hair cell markers compared to the contralateral non-treated cochlea when examined 3 weeks post-treatment. This increase, however, did not result in a commensurate improvement in hearing thresholds, nor was there an increase in synaptic ribbons, as measured by CtBP2 puncta after ATOH1 treatment alone, or when combined with neurotrophins. However, hair cell formation and synaptogenesis after co-treatment with ATOH1 and neurotrophic factors remain inconclusive as viral transduction was reduced due to the halving of viral titres when the samples were combined. Collectively, these data suggest that, whilst ATOH1 alone can drive non-sensory cells towards an immature sensory hair cell phenotype in the mature cochlea, this does not result in functional improvements after aminoglycoside-induced deafness.
Laing, Catherine M; Moules, Nancy J; Estefan, Andrew; Lang, Mike
The purpose of this philosophical hermeneutic study was to understand the effects on health care providers (HCPs) of watching digital stories made by (past and present) pediatric and adolescent/young adult (AYA) oncology patients. Twelve HCPs participated in a focus group where they watched digital stories made by pediatric/AYA oncology patients and participated in a discussion related to the impact the stories had on them personally and professionally. Findings from this research revealed that HCPs found digital stories to be powerful, therapeutic, and educational tools. Health care providers described uses for digital stories ranging from education of newly diagnosed families to training of new staff. Digital stories, we conclude, can be an efficient and effective way through which to understand the patient experience, implications from which can range from more efficient patient care delivery to decision making. Recommendations for incorporating digital storytelling into healthcare delivery are offered.
Expressing Constitutively Active Rheb in Adult Dorsal Root Ganglion Neurons Enhances the Integration of Sensory Axons that Regenerate Across a Chondroitinase-Treated Dorsal Root Entry Zone Following Dorsal Root Crush
Wu, Di; Klaw, Michelle C.; Kholodilov, Nikolai; Burke, Robert E.; Detloff, Megan R.; Côté, Marie-Pascale; Tom, Veronica J.
While the peripheral branch of dorsal root ganglion neurons (DRG) can successfully regenerate after injury, lesioned central branch axons fail to regrow across the dorsal root entry zone (DREZ), the interface between the dorsal root and the spinal cord. This lack of regeneration is due to the limited regenerative capacity of adult sensory axons and the growth-inhibitory environment at the DREZ, which is similar to that found in the glial scar after a central nervous system (CNS) injury. We hypothesized that transduction of adult DRG neurons using adeno-associated virus (AAV) to express a constitutively-active form of the GTPase Rheb (caRheb) will increase their intrinsic growth potential after a dorsal root crush. Additionally, we posited that if we combined that approach with digestion of upregulated chondroitin sulfate proteoglycans (CSPG) at the DREZ with chondroitinase ABC (ChABC), we would promote regeneration of sensory axons across the DREZ into the spinal cord. We first assessed if this strategy promotes neuritic growth in an in vitro model of the glial scar containing CSPG. ChABC allowed for some regeneration across the once potently inhibitory substrate. Combining ChABC treatment with expression of caRheb in DRG significantly improved this growth. We then determined if this combination strategy also enhanced regeneration through the DREZ after dorsal root crush in adult rats in vivo. After unilaterally crushing C4-T1 dorsal roots, we injected AAV5-caRheb or AAV5-GFP into the ipsilateral C5-C8 DRGs. ChABC or PBS was injected into the ipsilateral dorsal horn at C5-C8 to digest CSPG, for a total of four animal groups (caRheb + ChABC, caRheb + PBS, GFP + ChABC, GFP + PBS). Regeneration was rarely observed in PBS-treated animals, whereas short-distance regrowth across the DREZ was observed in ChABC-treated animals. No difference in axon number or length between the ChABC groups was observed, which may be related to intraganglionic inflammation induced by the
Mahmoud, Ahmed I; O'Meara, Caitlin C; Gemberling, Matthew; Zhao, Long; Bryant, Donald M; Zheng, Ruimao; Gannon, Joseph B; Cai, Lei; Choi, Wen-Yee; Egnaczyk, Gregory F; Burns, Caroline E; Burns, C Geoffrey; MacRae, Calum A; Poss, Kenneth D; Lee, Richard T
Some organisms, such as adult zebrafish and newborn mice, have the capacity to regenerate heart tissue following injury. Unraveling the mechanisms of heart regeneration is fundamental to understanding why regeneration fails in adult humans. Numerous studies have revealed that nerves are crucial for organ regeneration, thus we aimed to determine whether nerves guide heart regeneration. Here, we show using transgenic zebrafish that inhibition of cardiac innervation leads to reduction of myocyte proliferation following injury. Specifically, pharmacological inhibition of cholinergic nerve function reduces cardiomyocyte proliferation in the injured hearts of both zebrafish and neonatal mice. Direct mechanical denervation impairs heart regeneration in neonatal mice, which was rescued by the administration of neuregulin 1 (NRG1) and nerve growth factor (NGF) recombinant proteins. Transcriptional analysis of mechanically denervated hearts revealed a blunted inflammatory and immune response following injury. These findings demonstrate that nerve function is required for both zebrafish and mouse heart regeneration.
Yalçın Irmak, Aylin; Erdoğan, Semra
The games that adolescents and young people used to play in the play grounds and on the streets have been replaced in recent years with cyber games played in front of the computer on the internet or in game arcades. This changing culture has particularly brought up the concept of "digital game addiction", a condition that stems from the steadily growing passion for digital games and their excessived and uncontrolled usage among adolescents and young people. Game addiction in the psychiatry literature has been described as an impulse control disorder characterized by the symptoms such as "the inability to control the time spent on game-playing", "a loss of interest in other activities", "continuing to play despite the adverse effects" and "feeling psychologically deprived when not being able to play"."Although digital game addiction has not been accepted by psychiatric authorities as a psychiatric disorder yet, the increasing psychiatry referrals due to the problems accompanying this disorder, the efforts of families to seek support and solutions, the evidence that similarities with other types of addiction have been revealed by researchers, as well as the current prevalence rates are all factors that suggest the existence of important of the examination of issue. Despite the discussions about the digital game addiction, the literature on the subject is increasing. This article offers an overview of digital game-playing behavior in the light of current literature, seeking to share its findings with health care professionals.
Hariharan, Iswar K; Serras, Florenci
Drosophila imaginal discs, the larval precursors of adult structures such as the wing and leg, are capable of regenerating after damage. During the course of regeneration, discs can sometimes generate structures that are appropriate for a different type of disc, a phenomenon termed transdetermination. Until recently, these phenomena were studied by physically fragmenting discs and then transplanting them into the abdomens of adult female flies. This field has experienced a renaissance following the development of genetic ablation systems that can damage precisely defined regions of the disc without the need for surgery. Together with more traditional approaches, these newer methods have generated many novel insights into wound healing, the mechanisms that drive regenerative growth, plasticity during regeneration and systemic effects of tissue damage and regeneration.
Londt, Susan Cole
The Digital Family Oral History Pilot (DFOHP) data were collected and catalogued on a private website blog for family members to learn about their grandfather (ALP) who died without telling his own story. This study examined the outcomes and perceptions of the family members who were engaged with the pilot. A self-selected sample of 17 family…
Pike, Anne; Adams, Anne
Previous research has highlighted the value of technology to enhance learning. However, digital inclusion research has argued that many issues such as skills, access, usability and choice impact on the effectiveness of technology to enhance learning. The findings in this paper add to the debate by highlighting the importance of value and context.…
Mein, Erika; Fuentes, Brenda; Soto Más, Francisco; Muro, Andrés
The increasing digitization of information and communication has undoubtedly impacted the ways in which people in the United States access and interpret health information. Although the traditional emphasis of health literacy research has been the comprehension of health-related texts such as patient information forms, prescriptions, and medicine labels, the increased use of electronic means to locate health information requires more critical engagement with texts beyond basic comprehension. In accessing electronic health information, patients need to be able to navigate the vast amount of online health information and to interpret and synthesize health information across multiple sources (i.e. websites) while also evaluating the credibility of these sources. Recent health literacy research has examined the increased role of the media literacy in influencing health behaviors (Bergsma & Carney, 2008) and the role of increased access to computers (Salovey et al., 2009), but little (if any) research to date has provided recommendations for best practices related to meeting the health literacy demands required by digitization. This article attempts to fill this gap by exploring the use of the internet as a key source of health information and by looking at best practices in teaching digital health literacy. It describes the development of a digital literacy component within a community-based health literacy/ESL curriculum funded by the National Institutes of Health and implemented on the US-Mexico border. PMID:23730533
Neogeography provides a link between the science of geography and digital art. The carriers of this link are geospatial technologies (global navigational satellite systems such as the global positioning system, Geographical Information System [GIS] and satellite imagery) along with ubiquitous information and communication technologies (such as…
Mein, Erika; Fuentes, Brenda; Soto Más, Francisco; Muro, Andrés
The increasing digitization of information and communication has undoubtedly impacted the ways in which people in the United States access and interpret health information. Although the traditional emphasis of health literacy research has been the comprehension of health-related texts such as patient information forms, prescriptions, and medicine labels, the increased use of electronic means to locate health information requires more critical engagement with texts beyond basic comprehension. In accessing electronic health information, patients need to be able to navigate the vast amount of online health information and to interpret and synthesize health information across multiple sources (i.e. websites) while also evaluating the credibility of these sources. Recent health literacy research has examined the increased role of the media literacy in influencing health behaviors (Bergsma & Carney, 2008) and the role of increased access to computers (Salovey et al., 2009), but little (if any) research to date has provided recommendations for best practices related to meeting the health literacy demands required by digitization. This article attempts to fill this gap by exploring the use of the internet as a key source of health information and by looking at best practices in teaching digital health literacy. It describes the development of a digital literacy component within a community-based health literacy/ESL curriculum funded by the National Institutes of Health and implemented on the US-Mexico border.
Li, Lingsheng; Vikani, Ami R.; Harris, Gregory C.; Lin, Frank R.
Objective To investigate the feasibility of using a digital language processor (DLP) to objectively quantify the auditory and social environment of older adults. Design Thirty-seven participants aged 64–91 residing in a retirement community were asked to wear a DLP to record their auditory and language environment during one waking day. Recordings were analyzed with specialized software to derive quantitative estimates such as the number of spoken words heard and percent of time spent around meaningful speech versus television/radio. Results Adequate DLP recordings that began before 10 A.M. and lasted for ≥ 10 hours were collected from 24 participants. The mean duration of recording was 13 hours and 13 minutes, and individuals spent a mean of 26.7% (range=4% – 58%) of their waking day near a television or other electronic sounds. The projected mean word count over a maximum of 16 hours was 33,141 with nearly a 14-fold range between the lowest and highest observed values (range=5120 – 77,882). Conclusions High-quality objective data on the auditory environment of older adults can be feasibly measured with the DLP. Findings from this study may guide future studies investigating auditory and language outcomes in older adults. PMID:25122146
Zhang, Yiqiang; Mignone, John; MacLellan, W. Robb
After decades of believing the heart loses the ability to regenerate soon after birth, numerous studies are now reporting that the adult heart may indeed be capable of regeneration, although the magnitude of new cardiac myocyte formation varies greatly. While this debate has energized the field of cardiac regeneration and led to a dramatic increase in our understanding of cardiac growth and repair, it has left much confusion in the field as to the prospects of regenerating the heart. Studies applying modern techniques of genetic lineage tracing and carbon-14 dating have begun to establish limits on the amount of endogenous regeneration after cardiac injury, but the underlying cellular mechanisms of this regeneration remained unclear. These same studies have also revealed an astonishing capacity for cardiac repair early in life that is largely lost with adult differentiation and maturation. Regardless, this renewed focus on cardiac regeneration as a therapeutic goal holds great promise as a novel strategy to address the leading cause of death in the developed world. PMID:26269526
Schall, K A; Holoyda, K A; Grant, C N; Levin, D E; Torres, E R; Maxwell, A; Pollack, H A; Moats, R A; Frey, M R; Darehzereshki, A; Al Alam, D; Lien, C; Grikscheit, T C
Loss of significant intestinal length from congenital anomaly or disease may lead to short bowel syndrome (SBS); intestinal failure may be partially offset by a gain in epithelial surface area, termed adaptation. Current in vivo models of SBS are costly and technically challenging. Operative times and survival rates have slowed extension to transgenic models. We created a new reproducible in vivo model of SBS in zebrafish, a tractable vertebrate model, to facilitate investigation of the mechanisms of intestinal adaptation. Proximal intestinal diversion at segment 1 (S1, equivalent to jejunum) was performed in adult male zebrafish. SBS fish emptied distal intestinal contents via stoma as in the human disease. After 2 wk, S1 was dilated compared with controls and villus ridges had increased complexity, contributing to greater villus epithelial perimeter. The number of intervillus pockets, the intestinal stem cell zone of the zebrafish increased and contained a higher number of bromodeoxyuridine (BrdU)-labeled cells after 2 wk of SBS. Egf receptor and a subset of its ligands, also drivers of adaptation, were upregulated in SBS fish. Igf has been reported as a driver of intestinal adaptation in other animal models, and SBS fish exposed to a pharmacological inhibitor of the Igf receptor failed to demonstrate signs of intestinal adaptation, such as increased inner epithelial perimeter and BrdU incorporation. We describe a technically feasible model of human SBS in the zebrafish, a faster and less expensive tool to investigate intestinal stem cell plasticity as well as the mechanisms that drive intestinal adaptation.
Band, Rebecca; Saunderson, Kathryn; Hanlon, Peter; Little, Paul; McManus, Richard J; Yardley, Lucy; Mair, Frances S
Background Digital interventions, defined as any intervention accessed and taking input from patients in the form of a computer/Web-based program or mobile phoned-based app, can potentially help empower patients to self-manage long-term conditions such as hypertension. Importantly, digital interventions have the potential to provide patients with personalized information and support for active involvement in treatment as well as cost saving. Objective The purpose of this systematic review is to synthesize the evidence for using digital interventions to support patient self-management of hypertension, and determine their impact on control and reduction of blood pressure, other clinical outcomes, quality of life, medication adherence, health service utilization, and economic benefits. Methods A systematic search of bibliographic databases including Medline, Embase, CINAHL, and PsycINFO will be undertaken. Abstracts and citations will be independently screened by 2 researchers against predetermined inclusion criteria. Any disagreements will be resolved by discussion and further consideration of the inclusion criteria. Only randomized controlled trials which have been published in peer peer-reviewed journals with a diagnosis of hypertension will be considered. Inclusion criteria will be (1) adults (age ≥ 18 years) with hypertension (as defined by the primary authors); (2) an interactive digital intervention compared with usual care; and (3) outcomes of objectively measured change in blood pressure. Data extraction from identified articles will be undertaken by 2 independent reviewers using a uniform template. The main outcomes are systolic blood pressure (SBP) and diastolic blood pressure (DBP), and quality of life indicators. Secondary outcomes include cost- effectiveness, medication adherence, emotional well-being, and physical activity. Risk of bias of included studies will be assessed using the Cochrane tool. Results Our research is currently ongoing. Data will
Schall, K. A.; Holoyda, K. A.; Grant, C. N.; Levin, D. E.; Torres, E. R.; Maxwell, A.; Pollack, H. A.; Moats, R. A.; Frey, M. R.; Darehzereshki, A.; Al Alam, D.; Lien, C.
Loss of significant intestinal length from congenital anomaly or disease may lead to short bowel syndrome (SBS); intestinal failure may be partially offset by a gain in epithelial surface area, termed adaptation. Current in vivo models of SBS are costly and technically challenging. Operative times and survival rates have slowed extension to transgenic models. We created a new reproducible in vivo model of SBS in zebrafish, a tractable vertebrate model, to facilitate investigation of the mechanisms of intestinal adaptation. Proximal intestinal diversion at segment 1 (S1, equivalent to jejunum) was performed in adult male zebrafish. SBS fish emptied distal intestinal contents via stoma as in the human disease. After 2 wk, S1 was dilated compared with controls and villus ridges had increased complexity, contributing to greater villus epithelial perimeter. The number of intervillus pockets, the intestinal stem cell zone of the zebrafish increased and contained a higher number of bromodeoxyuridine (BrdU)-labeled cells after 2 wk of SBS. Egf receptor and a subset of its ligands, also drivers of adaptation, were upregulated in SBS fish. Igf has been reported as a driver of intestinal adaptation in other animal models, and SBS fish exposed to a pharmacological inhibitor of the Igf receptor failed to demonstrate signs of intestinal adaptation, such as increased inner epithelial perimeter and BrdU incorporation. We describe a technically feasible model of human SBS in the zebrafish, a faster and less expensive tool to investigate intestinal stem cell plasticity as well as the mechanisms that drive intestinal adaptation. PMID:26089336
Delello, Julie A; McWhorter, Rochell R
America's older adult population is increasing at a dramatic rate due to better health care, technology, and improved living conditions. However, as individuals 65 years and older begin to live longer and experience multiple life changes, there is a larger incidence of social isolation leading to loneliness, depression, and a general decline in health. This mixed-method study aimed to explore whether information and communication technologies, specifically iPads, improved the lives of older adults. Our findings suggest that the use of technology increased knowledge, elicited closer family ties, and led to a greater overall connection to society.
Perng, Cherng-Kang; Kao, Chung-Lan; Yang, Yi-Ping; Lin, Han-Tso; Lin, Wen-Bin; Chu, Yue-Ru; Wang, Hsiao-Jung; Ma, Hsu; Ku, Hung-Hai; Chiou, Shih-Hwa
Skin tissue engineering is a possible solution for the treatment of extensive skin defect. The ultimate goal of skin tissue engineering is to restore the complete functions of native skin, but until now the structures and functions of skins are only partially restored. By negative immunoselection (CD45 and glycophorin A), we isolated and cultivated adult human bone marrow stem cells (hBMSCs) that are of multilineage differentiation potential. In this study, we first demonstrated that by using gelatin/thermo-sensitive poly N-isopropylacrylamide (pNIPAAm) and the immunocompromised mice model, the hBMSCs possess the differentiation potential of epidermis and the capability of healing skin wounds. The in vitro observations and the results of the scanning electron microscope showed that the hBMSCs can attach and proliferate in the gelatin/thermo-sensitive pNIPAAm. To further monitor the in vivo growth effect of the hBMSCs in the skin-defected nude mice, the green fluorescence protein (GFP) gene was transduced into the hBMSCs by the murine stem cell viral vector. The results showed that the rates of cell growth and wound recovery in the hBMSC-treated group were significantly higher than those in the control group, which was only treated with the gelatin/pNIPAAm (p < 0.01). More importantly, the re-epithelialization markers of human pan-cytokeratin and E-cadherin were significantly increased on day 7, day 14, and day 21 after the hBMSC-scaffold with the pNIPAAM in the mice with skin defects (p < 0.05). Moreover, the stem cell markers of human CD13 and CD105 were gradually decreased during the period of wound healing. In sum, this novel method provides a transferring system for cell therapies and maintains its temperature-sensitive property of easy-peeling by lower-temperature treatment. In addition, the in vitro and in vivo GFP imaging systems provide a new imaging modality for understanding the differentiation process and the effective expression of stem cells in wound
Cohen, Jamie; Penney, Dana L.; Davis, Randall; Libon, David J.; Swenson, Rodney A.; Ajilore, Olusola; Kumar, Anand; Lamar, Melissa
Objective Psychomotor slowing has been documented in depression. The digital Clock Drawing Test (dCDT) provides: i) a novel technique to assess both cognitive and motor aspects of psychomotor speed within the same task and ii) the potential to uncover subtleties of behavior not previously detected with non-digitized modes of data collection. Method Using digitized pen technology in 106 participants grouped by Age (younger/older) and Affect (euthymic/unmedicated depressed), we recorded cognitive and motor output by capturing how the clock is drawn rather than focusing on the final product. We divided time to completion (TTC) for Command and Copy conditions of the dCDT into metrics of percent of drawing (%Ink) versus non-drawing (%Think) time. We also obtained composite z-scores of cognition, including attention/ information processing (AIP), to explore associations of %Ink and %Think times to cognitive and motor performance. Results Despite equivalent TTC, %Ink and %Think Command times (Copy n.s.) were significant (AgeXAffect interaction:p=.03)—younger depressed spent a smaller proportion of time drawing relative to thinking compared to the older depressed group. Command %Think time negatively correlated with AIP in the older depressed group (r=−.46;p=.02). Copy %Think time negatively correlated with AIP in the younger depressed (r=−.47;p=.03) and older euthymic groups (r=−.51;p=.01). Conclusion The dCDT differentiated aspects of psychomotor slowing in depression regardless of age, while dCDT/cognitive associates for younger adults with depression mimicked patterns of older euthymics. PMID:25222513
Peters-Strickland, Timothy; Pestreich, Linda; Hatch, Ainslie; Rohatagi, Shashank; Baker, Ross A; Docherty, John P; Markovtsova, Lada; Raja, Praveen; Weiden, Peter J; Walling, David P
Objective Digital medicine system (DMS) is a novel drug–device combination that objectively measures and reports medication ingestion. The DMS consists of medication embedded with an ingestible sensor (digital medicine), a wearable sensor, and software applications. This study evaluated usability of the DMS in adults with schizophrenia rated by both patients and their health care providers (HCPs) during 8-week treatment with prescribed doses of digital aripiprazole. Methods Six US sites enrolled outpatients into this Phase IIa, open-label study (NCT02219009). The study comprised a screening phase, a training phase (three weekly site visits), and a 5-week independent phase. Patients and HCPs independently rated usability of and satisfaction with the DMS. Results Sixty-seven patients were enrolled, and 49 (73.1%) patients completed the study. The mean age (SD) of the patients was 46.6 years (9.7 years); the majority of them were male (74.6%), black (76.1%), and rated mildly ill on the Clinical Global Impression – Severity scale (70.1%). By the end of week 8 or early termination, 82.1% (55/67) of patients had replaced the wearable sensor independently or with minimal assistance, based on HCP rating. The patients used the wearable sensor for a mean (SD) of 70.7% (24.7%) and a median of 77.8% of their time in the trial. The patients contacted a call center most frequently at week 1. At the last visit, 78% (47/60) of patients were somewhat satisfied/satisfied/extremely satisfied with the DMS. Conclusion A high proportion of patients with schizophrenia were able to use the DMS and reported satisfaction with the DMS. These data support the potential utility of the DMS in clinical practice. PMID:27785036
Spector, M S; Auer, K L; Jarvis, W D; Ishac, E J; Gao, B; Kunos, G; Dent, P
To study the mechanisms by which catecholamines regulate hepatocyte proliferation after partial hepatectomy (PHX), hepatocytes were isolated from adult male rats 24 h after sham operation or two-thirds PHX and treated with catecholamines and other agonists. In freshly isolated sham cells, p42 mitogen-activated protein (MAP) kinase activity was stimulated by the alpha1-adrenergic agonist phenylephrine (PHE). Activation of p42 MAP kinase by growth factors was blunted by pretreatment of sham hepatocytes with glucagon but not by that with the beta2-adrenergic agonist isoproterenol (ISO). In PHX cells, the ability of PHE to activate p42 MAP kinase was dramatically reduced, whereas ISO became competent to inhibit p42 MAP kinase activation. PHE treatment of sham but not PHX and ISO treatment of PHX but not sham hepatocytes also activated the stress-activated protein (SAP) kinases p46/54 SAP kinase and p38 SAP kinase. These data demonstrate that an alpha1- to beta2-adrenergic receptor switch occurs upon PHX and results in an increase in SAP kinase versus MAP kinase signaling by catecholamines. In primary cultures of hepatocytes, ISO treatment of PHX but not sham cells inhibited [3H]thymidine incorporation. In contrast, PHE treatment of sham but not PHX cells stimulated [3H]thymidine incorporation, which was reduced by approximately 25 and approximately 95% with specific inhibitors of p42 MAP kinase and p38 SAP kinase function, respectively. Inhibition of the p38 SAP kinase also dramatically reduced basal [3H]thymidine incorporation. These data suggest that p38 SAP kinase plays a permissive role in liver regeneration. Alterations in the abilities of catecholamines to modulate the activities of protein kinase A and the MAP and SAP kinase pathways may represent one physiological mechanism by which these agonists can regulate hepatocyte proliferation after PHX. PMID:9199291
OECD Publishing, 2015
Having the highest levels of skills in problem solving using ICT (information and communication technologies) increases chances of participating in the labour force by six percentage points compared with adults who have the lowest levels of these skills, even after accounting for various other factors, such as age, gender, level of education,…
Weidert, John William
Rapid advancements in technology and the proliferation of mobile communication devices available in the marketplace require that community college administrators and teachers better understand levels of digital communication technology adoption and how adult learners currently use them. Such an understanding is necessary to developing the…
Banerjee, Meenal; Kanitkar, Meghana; Bhonde, Ramesh R
The phenomenon of pancreatic regeneration in mammals has been well documented. It has been shown that pancreatic tissue is able to regenerate in several species of mammal after surgical insult. This tissue is also known to have the potential to maintain or increase its beta-cell mass in response to metabolic demands during pregnancy and obesity. Since deficiency in beta-cell mass is the hallmark of most forms of diabetes, it is worthwhile understanding pancreatic regeneration in the context of this disease. With this view in mind, this article aims to discuss the potential use in clinical strategies of knowledge that we obtained from studies carried out in animal models of diabetes. Approaches to achieve this goal involve the use of biomolecules, adult stem cells and gene therapy. Various molecules, such as glucagon-like peptide-1, beta-cellulin, nicotinamide, gastrin, epidermal growth factor-1 and thyroid hormone, play major roles in the initiation of endogenous islet regeneration in diabetes. The most accepted hypothesis is that these molecules stimulate islet precursor cells to undergo neogenesis or to induce replication of existing beta-cells, emphasizing the importance of pancreas-resident stem/progenitor cells in islet regeneration. Moreover, the potential of adult stem cell population from bone marrow, umbilical cord blood, liver, spleen, or amniotic membrane, is also discussed with regard to their potential to induce pancreatic regeneration.
Wright, Michelle F; Li, Yan
Using the general strain theory as a theoretical framework, the present longitudinal study investigated both face-to-face and cyber victimization in relation to cyber-displaced aggression. Longitudinal data were collected from 130 (70 women) young adults who completed measures assessing their victimization (face-to-face and cyber), cyber aggression, and both face-to-face and cyber-displaced aggression. Findings indicated that victimization in both social contexts (face-to-face and cyber) contributed to cyber-displaced aggression 6 months later (Time 2), after controlling for gender, cyber aggression, face-to-face displaced aggression, and cyber-displaced aggression at Time 1. A significant two-way interaction revealed that Time 1 cyber victimization was more strongly related to Time 2 cyber-displaced aggression when young adults had higher levels of face-to-face victimization at Time 1. Implications of these findings are discussed as well as a call for more research investigating displaced aggression in the cyber context.
Hsieh, Sung-Tsang; Chu, Nai-Shin
Cutaneous nerve regeneration following toe-to-finger transplantation was studied by immunohistochemical technique using antibody to protein gene product 9.5 (PGP 9.5) which is a specific neuronal marker. By this technique, epidermal and dermal nerves were semi-quantified and the Meissner's corpuscles were quantified. There were also quantitative sensory tests (QST) including pinprick, pressure and temperature, as well as electrophysiological studies including digital nerve sensory conduction, digital nerve somatosensory evoked potentials and sympathetic skin response at the pulp of the transplanted toes. The opposite corresponding normal finger and normal toe served as controls. Study subjects were 20 adult patients with toe-to-finger transplantation for at least one year. A score system was used to quantify the results of histochemical, psychophysiological and electrophysiological studies. Clinically 7 patients had good recovery and 13 patients had poor recovery. Cutaneous nerve regeneration in the transplanted toes was incomplete with epidermal nerve, dermal nerve and the Meissner's corpuscle significantly reduced. The nerve regeneration was correlated with clinical recovery, QST and electrophysiological data. These findings indicate that immunohischemical technique is useful to evaluate skin nerve regeneration following toe-to-finger transplantation, and that although nerve regeneration did occur, it was incomplete and correlated with the severity of hand injury.
Seok, Soonhwa; DaCosta, Boaventura
This study investigated relationships between digital propensity and support needs as well as predictors of digital propensity in the context of support intensity, age, gender, and social maturity. A total of 118 special education teachers rated the support intensity, digital propensity, and social maturity of 352 students with intellectual disability. Leveraging the Digital Propensity Index, Supports Intensity Scale, and the Social Maturity Scale, descriptive statistics, correlations, multiple regressions, and regression analyses were employed. The findings revealed significant relationships between digital propensity and support needs. In addition, significant predictors of digital propensity were found with regard to support intensity, age, gender, and social maturity.
Wang, Hom-Lay; Greenwell, Henry; Fiorellini, Joseph; Giannobile, William; Offenbacher, Steven; Salkin, Leslie; Townsend, Cheryl; Sheridan, Phillip; Genco, Robert J
Untreated periodontal disease leads to tooth loss through destruction of the attachment apparatus and tooth-supporting structures. The goals of periodontal therapy include not only the arrest of periodontal disease progression,but also the regeneration of structures lost to disease where appropriate. Conventional surgical approaches (e.g., flap debridement) continue to offer time-tested and reliable methods to access root surfaces,reduce periodontal pockets, and attain improved periodontal form/architecture. However, these techniques offer only limited potential towards recovering tissues destroyed during earlier disease phases. Recently, surgical procedures aimed at greater and more predictable regeneration of periodontal tissues and functional attachment close to their original level have been developed, analyzed, and employed in clinical practice. This paper provides a review of the current understanding of the mechanisms, cells, and factors required for regeneration of the periodontium and of procedures used to restore periodontal tissues around natural teeth. Targeted audiences for this paper are periodontists and/or researchers with an interest in improving the predictability of regenerative procedures. This paper replaces the version published in 1993.
The ultimate goal of periodontal therapy is the regeneration of the tissues destroyed as a result of periodontal disease. Currently, two clinical techniques, based on the principles of "guided tissue regeneration" (GTR) or utilization of the biologically active agent "enamel matrix derivative" (EMD), can be used for the regeneration of intrabony and Class II mandibular furcation periodontal defects. In cases where additional support and space-making requirements are necessary, both of these procedures can be combined with a bone replacement graft. There is no evidence that the combined use of GTR and EMD results in superior clinical results compared to the use of each material in isolation. Great variability in clinical outcomes has been reported in relation to the use of both EMD and GTR, and these procedures can be generally considered to be unpredictable. Careful case selection and treatment planning, including consideration of patient, tooth, site and surgical factors, is required in order to optimize the outcomes of treatment. There are limited data available for the clinical effectiveness of other biologically active molecules, such as growth factors and platelet concentrates, and although promising results have been reported, further clinical trials are required in order to confirm their effectiveness. Current active areas of research are centred on tissue engineering and gene therapy strategies which may result in more predictable regenerative outcomes in the future.
Knoll, Fabien; Bordy, Emese M.; de Kock, Michiel O.; Redelstorff, Ragna
Fragmentary caudal ends of the left and right mandible assigned to Lesothosaurus diagnosticus, an early ornithischian, was recently discovered in the continental red bed succession of the upper Elliot Formation (Lower Jurassic) at Likhoele Mountain (Mafeteng District) in Lesotho. Using micro-CT scanning, this mandible could be digitally reconstructed in 3D. The replacement teeth within the better preserved (left) dentary were visualised. The computed tomography dataset suggests asynchronous tooth replacement in an individual identified as an adult on the basis of bone histology. Clear evidence for systematic wear facets created by attrition is lacking. The two most heavily worn teeth are only apically truncated. Our observations of this specimen as well as others do not support the high level of dental wear expected from the semi-arid palaeoenvironment in which Lesothosaurus diagnosticus lived. Accordingly, a facultative omnivorous lifestyle, where seasonality determined the availability, quality, and abundance of food is suggested. This would have allowed for adaptability to episodes of increased environmental stress. PMID:28265518
Months 1-18) Introduction: The zebrafish spinal cord model system is unique because of the co-existence of brainstem neurons that do ( regenerators ) and...3: To identify genes involved in axon regeneration from brainstem neurons in the injured adult zebrafish spinal cord. Experiments will be...performed to label brainstem neurons with fast blue that do or do not, regenerate an axon across an injury in the adult zebrafish spinal cord. Non
1-12) Introduction: The zebrafish spinal cord model system is unique because of the co-existence of brainstem neurons that do ( regenerators ) and...11 SOW: Specifc Aim 3: To identify genes involved in axon regeneration from brainstem neurons in the injured adult zebrafish spinal cord...Experiments will be performed to label brainstem neurons with fast blue that do or do not, regenerate an axon across an injury in the adult zebrafish
will determine the relationship between L1.1 and neurocan and its role in axon regeneration from adult zebrafish brainstem neurons in vitro. The...determine the relationship between L1.1 and neurocan and its role in axon regeneration from adult zebrafish brainstem neurons in vitro. Increased...concerning the potential interactions between neurocan and L1 and the role they play in axonal regeneration seen in the zebrafish . 18 Figure
McLean, Gary; Band, Rebecca; Saunderson, Kathryn; Hanlon, Peter; Murray, Elizabeth; Little, Paul; McManus, Richard J.; Yardley, Lucy; Mair, Frances S.
Objective: To synthesize the evidence for using interactive digital interventions (IDIs) to support patient self-management of hypertension, and to determine their impact on control and reduction of blood pressure. Method: Systematic review with meta-analysis was undertaken with a search performed in MEDLINE, EMBASE, CINAHL, PsycINFO, ERIC, Cochrane Library, DoPHER, TROPHI, Social Science Citation Index and Science Citation Index. The population was adults (>18 years) with hypertension, intervention was an IDI and the comparator was usual care. Primary outcomes were change in SBP and DBP. Only randomized controlled trials and studies published in journals and in English were eligible. Eligible IDIs included interventions accessed through a computer, smartphone or other hand-held device. Results: Four out of seven studies showed a significantly greater reduction for intervention compared to usual care for SBP, with no difference found for three. Overall, IDIs significantly reduced SBP, with the weighted mean difference being −3.74 mmHg [95% confidence interval (CI) −2.19 to −2.58] with no heterogeneity observed (I-squared = 0.0%, P = 0.990). For DBP, four out of six studies indicated a greater reduction for intervention compared to controls, with no difference found for two. For DBP, a significant reduction of −2.37 mmHg (95% CI −0.40 to −4.35) was found, but considerable heterogeneity was noted (I-squared = 80.1%, P = <0.001). Conclusion: IDIs lower both SBP and DBP compared to usual care. Results suggest these findings can be applied to a wide range of healthcare systems and populations. However, sustainability and long-term clinical effectiveness of these interventions remain uncertain. PMID:26845284
Davis, Leonard C.; Pacala, Theodore; Sippel, George R.
A method for manufacturing a hot side regenerator cross arm seal assembly having a thermally stablilized wear coating with a substantially flat wear surface thereon to seal between low pressure and high pressure passages to and from the hot inboard side of a rotary regenerator matrix includes the steps of forming a flat cross arm substrate member of high nickel alloy steel; fixedly securing the side edges of the substrate member to a holding fixture with a concave surface thereacross to maintain the substrate member to a slightly bent configuration on the fixture surface between the opposite ends of the substrate member to produce prestress therein; applying coating layers on the substrate member including a wear coating of plasma sprayed nickel oxide/calcium flouride material to define a wear surface of slightly concave form across the restrained substrate member between the free ends thereon; and thereafter subjecting the substrate member and the coating thereon to a heat treatment of 1600.degree. F. for sixteen hours to produce heat stabilizing growth in the coating layers on the substrate member and to produce a thermally induced growth stress in the wear surface that substantially equalizes the prestress in the substrate whereby when the cross arm is removed from the fixture surface following the heat treatment step a wear face is formed on the cross arm assembly that will be substantially flat between the ends.
Lehoczky, Jessica A
Some mammalian digit tips, including those of mice and human children, can regenerate following amputation, whereas mammalian limb regeneration does not occur. One major difference between the digit tip and the rest of the limb is the presence of the nail, which is necessary for this type of regeneration. This couples well with the finding that canonical Wnt signalling and Lgr6, an agonist of Wnt signalling that marks nail stem cells, are necessary for digit tip regeneration. This viewpoint essay discusses the role of the nail in digit tip regeneration and explores whether nail stem cells and their presumptive niche can be solely accountable for why regeneration is possible in the digit tip, but not the rest of the limb.
Somorjai, Ildikó M. L.; Garcia-Fernàndez, Jordi; Escrivà, Hector
An important question in biology is why some animals are able to regenerate, whereas others are not. The basal chordate amphioxus is uniquely positioned to address the evolution of regeneration. We report here the high regeneration potential of the European amphioxus Branchiostoma lanceolatum. Adults regenerate both anterior and posterior structures, including neural tube, notochord, fin, and muscle. Development of a classifier based on tail regeneration profiles predicts the assignment of young and old adults to their own class with >94% accuracy. The process involves loss of differentiated characteristics, formation of an msx-expressing blastema, and neurogenesis. Moreover, regeneration is linked to the activation of satellite-like Pax3/7 progenitor cells, the extent of which declines with size and age. Our results provide a framework for understanding the evolution and diversity of regeneration mechanisms in vertebrates. PMID:22203957
Vladimirova, I G
Changes in the weight and oxygen consumption were studied during regeneration of the tail in adult axolotls and larvae. The curve of the increase in weight of the regenerating tail in both age groups is S-shaped. The intensity of respiration of the regenerating tail increases in adult axolotls and in larvae at the blastema stage; in adult axolotls there is also a second increase in the intensity of respiration of the regenerating tail during differentiation of the muscles. The relationship between weight and the rate of respiration was compared during regeneration of the tail in axolotl and the normal growth of the animals. Whereas growth of the animals was characterized by the relationship QO2 equals aPk with a constant value of k, during regeneration the various stages of this process have their own corresponding values of k.
Breckwoldt, Kaja; Weinberger, Florian; Eschenhagen, Thomas
Regenerating an injured heart holds great promise for millions of patients suffering from heart diseases. Since the human heart has very limited regenerative capacity, this is a challenging task. Numerous strategies aiming to improve heart function have been developed. In this review we focus on approaches intending to replace damaged heart muscle by new cardiomyocytes. Different strategies for the production of cardiomyocytes from human embryonic stem cells or human induced pluripotent stem cells, by direct reprogramming and induction of cardiomyocyte proliferation are discussed regarding their therapeutic potential and respective advantages and disadvantages. Furthermore, different methods for the transplantation of pluripotent stem cell-derived cardiomyocytes are described and their clinical perspectives are discussed. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.
Joy, Stephen; Kaplan, Edith; Fein, Deborah
The primary role of speed in determining Digit Symbol scores is well established. Among the important questions that remain to be resolved are: (1) whether speed accounts for all of the age-related decline in Digit Symbol scores, and (2) whether memory ability makes any significant contribution to Digit Symbol performance, especially after controlling for speed. We analyzed data from the WAIS-III/WMS-III standardization sample to resolve these issues. As expected, speed (Digit Symbol-Copy) correlated very strongly with Digit Symbol--Coding. Memory (Digit Symbol--Incidental Learning or WMS-III index scores) correlated more moderately with Digit Symbol-Coding. Even after controlling for variance in Coding explained by Copying, a statistically significant proportion of the residual variance was explicable in terms of memory functions. The contribution of memory to Digit Symbol--Coding, while relatively small, is real. In addition, a small portion of the age-associated decline in Coding scores cannot be accounted for by Copying scores.
Liu, Hsiu Tan; Squires, Bonita; Liu, Chun Jung
We can gain a better understanding of short-term memory processes by studying different language codes and modalities. Three experiments were conducted to investigate: (a) Taiwanese Sign Language (TSL) digit spans in Chinese/TSL hearing bilinguals (n = 32); (b) American Sign Language (ASL) digit spans in English/ASL hearing bilinguals (n = 15);…
Le, Thi Yen Loan; Thavapalachandran, Sujitha; Kizana, Eddy; Chong, James Jh
Numerous pharmacological and device therapies have improved adverse cardiac remodelling and mortality in heart failure. However, none are able to regenerate damaged cardiac tissue. Stem cell based therapies using multipotent (adult) stem cells and pluripotent stem cells are new approaches that could potentially achieve the elusive goal of true cardiac regeneration. Over the past two decades, various stem cell based approaches have been shown to improve left ventricular function in pre-clinical animal models. Promising results rapidly led to clinical trials, initially using bone marrow-derived mononuclear cells, then mesenchymal stromal cell populations and, more recently, progenitor cells from the adult heart itself. These have been shown to be safe and have advanced our understanding of potential suitable recipients, cell delivery routes, and possible mechanisms of action. However, efficacy in these trials has been inconsistent. Human pluripotent stem cells (hPSCs) are another potential source of stem cells for cardiac regeneration. They could theoretically provide an unlimited source of cardiomyocytes or cardiac progenitors. Pre-clinical studies in both small and large animal models have shown robust engraftment and improvements in cardiac function. The first clinical trial using hPSC-derived cardiac derivatives has now commenced and others are imminent. In this brief review article, we summarise recent developments in stem cell therapies aimed at cardiac regeneration, including discussion of types of cell and non-cell-based strategies being explored.
Oviedo, Néstor J; Beane, Wendy S
A better understanding of the forces controlling cell growth will be essential for developing effective therapies in regenerative medicine and cancer. Historically, the literature has linked cancer and tissue regeneration-proposing regeneration as both the source of cancer and a method to inhibit tumorigenesis. This review discusses two powerful regeneration models, the vertebrate urodele amphibians and invertebrate planarians, in light of cancer regulation. Urodele limb and eye lens regeneration is described, as well as the planarian's emergence as a molecular and genetic model system in which recent insights begin to molecularly dissect cancer and regeneration in adult tissues.
Sereysky, Jedd B; Flatow, Evan L; Andarawis-Puri, Nelly
Tendinopathies are common muskoloskeletal injuries that lead to pain and disability. Development and pathogenesis of tendinopathy is attributed to progressive pathological changes to the structure, function, and biology of tendon. The nature of this disease state, whether acquired by acute or chronic injury, is being actively investigated. Scarring, disorganized tissue, and loss of function characterize adult tendon healing. Recent work from animal models has begun to reveal the potential for adult mammalian tendon regeneration, the replacement of diseased with innate tissue. This review discusses what is known about musculoskeletal regeneration from a molecular perspective and how these findings can be applied to tendinopathy. Non-mammalian and mammalian models are discussed with emphasis on the potential of Murphy Roths Large mice to serve as a model of adult tendon regeneration. Comparison of regeneration in non-mammals, foetal mammals and adult mammals emphasizes distinctly different contributing factors to effective regeneration.
Sereysky, Jedd B; Flatow, Evan L; Andarawis-Puri, Nelly
Tendinopathies are common muskoloskeletal injuries that lead to pain and disability. Development and pathogenesis of tendinopathy is attributed to progressive pathological changes to the structure, function, and biology of tendon. The nature of this disease state, whether acquired by acute or chronic injury, is being actively investigated. Scarring, disorganized tissue, and loss of function characterize adult tendon healing. Recent work from animal models has begun to reveal the potential for adult mammalian tendon regeneration, the replacement of diseased with innate tissue. This review discusses what is known about musculoskeletal regeneration from a molecular perspective and how these findings can be applied to tendinopathy. Non-mammalian and mammalian models are discussed with emphasis on the potential of Murphy Roths Large mice to serve as a model of adult tendon regeneration. Comparison of regeneration in non-mammals, foetal mammals and adult mammals emphasizes distinctly different contributing factors to effective regeneration. PMID:23772908
Radhakrishnan, Kavita; Toprac, Paul; O'Hair, Matt; Bias, Randolph; Mackert, Mike; Xie, Bo; Kim, Miyong; Bradley, Paul
Effective self-management can decrease up to 50% of heart failure (HF) hospitalizations. However, self-management by patients with HF remains poor. We describe the development and usability testing of an interactive digital e-health game (IDEG) for older patients with HF in Central Texas, USA. Majority of the participants (5 out of 6) who participated in the usability testing found the game interesting, enjoyable and helpful to play. Developing an IDEG that is satisfying and acceptable to older adults with HF is feasible.
Derry, David M
Control of regeneration and wound healing are scientific and clinical objectives. In 1997, topical Lugol's iodine solution applied daily for 3 days to a 50 year old facial scar lead to hyperemic scar tissue. As a working hypothesis, the author proposed topical iodine could initiate, control and complete human scar regeneration. In 2005, after collecting three more surgical scars, topical iodine applications began. Within 3 days all four scars started regenerating. Stopping topical iodine halted the process. Within a week an appropriate adult scar formed. Digital cameras recorded events. Regeneration is complex and slow. Its appearance depends on whether scar is covered with plastic or open. Iodine's chemical properties are discussed along with their reaction with epithelial cells. As there are no visible signs detectable changes from oral iodine on regeneration, details of iodine staining are more thoroughly described. Not all, but most important results are presented. Topical iodine induces hair growth in and around scars. Hair is regeneration's workhorse, moving purposefully in all directions under arrector pili muscle power delivering regenate material accurately to scar tissues and coordinating centers. In addition, hair repeatedly self amputates possibly strengthening regenerating tissues. Two types of regenate material show under plastic wrap: white and globular. The white regenate appears and behaves somewhat like snow, but can be yellow, green or brown depending iodine content. The globular form of regenate material maybe derived from white regenate material with hair's help. Globular regenate material is larger, nondescript, variable in size and color (depends on iodine content) and seemed usually associated with hair. There are two centrally placed coordinating centers 5 mm apart on major scars. Wrist centers have a palpable, but not visible ridge, between them whereas abdominal centers do not. Wrist centers lasted through all regeneration of the wrist
Hind, M; Gilthorpe, A; Stinchcombe, S; Maden, M
The use of retinoids to induce human lung regeneration is under investigation in a number of studies in patients with chronic obstructive pulmonary disease (COPD). Retinoic acid (RA) has complex pleiotropic functions during vertebrate patterning and development and can induce regeneration in a number of different organ systems. Studies of retinoid signalling during lung development might provide a molecular basis to explain pharmacological induction of alveolar regeneration in adult models of lung disease. In this review the role of endogenous RA signalling during alveologenesis is explored and data suggesting that a number of exogenous retinoids can induce regeneration in the adult lung are discussed. Current controversies in this area are highlighted and a hypothesis of lung regeneration is put forward. Understanding the cellular and molecular mechanisms of induction of regeneration will be central for effective translation into patients with lung disease and may reveal novel insights into the pathogenesis of alveolar disease and senescence.
Kwon, Min Jung; Yoon, Hyuk Jun; Kim, Byung Gon
Axons in central nervous system (CNS) do not regenerate spontaneously after injuries such as stroke and traumatic spinal cord injury. Both intrinsic and extrinsic factors are responsible for the regeneration failure. Although intensive research efforts have been invested on extrinsic regeneration inhibitors, the extent to which glial inhibitors contribute to the regeneration failure in vivo still remains elusive. Recent experimental evidence has rekindled interests in intrinsic factors for the regulation of regeneration capacity in adult mammals. In this review, we propose that activating macrophages with pro-regenerative molecular signatures could be a novel approach for boosting intrinsic regenerative capacity of CNS neurons. Using a conditioning injury model in which regeneration of central branches of dorsal root ganglia sensory neurons is enhanced by a preceding injury to the peripheral branches, we have demonstrated that perineuronal macrophages surrounding dorsal root ganglia neurons are critically involved in the maintenance of enhanced regeneration capacity. Neuron-derived chemokine (C-C motif) ligand 2 (CCL2) seems to mediate neuron-macrophage interactions conveying injury signals to perineuronal macrophages taking on a soley pro-regenerative phenotype, which we designate as regeneration-associated macrophages (RAMs). Manipulation of the CCL2 signaling could boost regeneration potential mimicking the conditioning injury, suggesting that the chemokine-mediated RAM activation could be utilized as a regenerative therapeutic strategy for CNS injuries.
Kwon, Min Jung; Yoon, Hyuk Jun; Kim, Byung Gon
Axons in central nervous system (CNS) do not regenerate spontaneously after injuries such as stroke and traumatic spinal cord injury. Both intrinsic and extrinsic factors are responsible for the regeneration failure. Although intensive research efforts have been invested on extrinsic regeneration inhibitors, the extent to which glial inhibitors contribute to the regeneration failure in vivo still remains elusive. Recent experimental evidence has rekindled interests in intrinsic factors for the regulation of regeneration capacity in adult mammals. In this review, we propose that activating macrophages with pro-regenerative molecular signatures could be a novel approach for boosting intrinsic regenerative capacity of CNS neurons. Using a conditioning injury model in which regeneration of central branches of dorsal root ganglia sensory neurons is enhanced by a preceding injury to the peripheral branches, we have demonstrated that perineuronal macrophages surrounding dorsal root ganglia neurons are critically involved in the maintenance of enhanced regeneration capacity. Neuron-derived chemokine (C-C motif) ligand 2 (CCL2) seems to mediate neuron-macrophage interactions conveying injury signals to perineuronal macrophages taking on a soley pro-regenerative phenotype, which we designate as regeneration-associated macrophages (RAMs). Manipulation of the CCL2 signaling could boost regeneration potential mimicking the conditioning injury, suggesting that the chemokine-mediated RAM activation could be utilized as a regenerative therapeutic strategy for CNS injuries. PMID:27857723
Stoick-Cooper, Cristi L; Weidinger, Gilbert; Riehle, Kimberly J; Hubbert, Charlotte; Major, Michael B; Fausto, Nelson; Moon, Randall T
In contrast to mammals, lower vertebrates have a remarkable capacity to regenerate complex structures damaged by injury or disease. This process, termed epimorphic regeneration, involves progenitor cells created through the reprogramming of differentiated cells or through the activation of resident stem cells. Wnt/beta-catenin signaling regulates progenitor cell fate and proliferation during embryonic development and stem cell function in adults, but its functional involvement in epimorphic regeneration has not been addressed. Using transgenic fish lines, we show that Wnt/beta-catenin signaling is activated in the regenerating zebrafish tail fin and is required for formation and subsequent proliferation of the progenitor cells of the blastema. Wnt/beta-catenin signaling appears to act upstream of FGF signaling, which has recently been found to be essential for fin regeneration. Intriguingly, increased Wnt/beta-catenin signaling is sufficient to augment regeneration, as tail fins regenerate faster in fish heterozygous for a loss-of-function mutation in axin1, a negative regulator of the pathway. Likewise, activation of Wnt/beta-catenin signaling by overexpression of wnt8 increases proliferation of progenitor cells in the regenerating fin. By contrast, overexpression of wnt5b (pipetail) reduces expression of Wnt/beta-catenin target genes, impairs proliferation of progenitors and inhibits fin regeneration. Importantly, fin regeneration is accelerated in wnt5b mutant fish. These data suggest that Wnt/beta-catenin signaling promotes regeneration, whereas a distinct pathway activated by wnt5b acts in a negative-feedback loop to limit regeneration.
Massey, Philip M
With more people turning to the Internet for health information, a few questions remain: Which populations represent the remaining few who have never used the Internet, and where do they go for health information? The purpose of this study is to describe population characteristics and sources of health information among U.S. adults who do not use the Internet. Data from 3 iterations of the Health Information National Trends Survey (n = 1,722) are used to examine trends in health information sources. Weighted predicted probabilities demonstrate changes in information source over time. Older adults, minority populations, and individuals with low educational attainment represent a growing percentage of respondents who have looked for health information but have never used the Internet, highlighting trends in digital information disparities. However, 1 in 10 respondents who have never used the Internet also indicate that the Internet was their first source of health information, presumably through surrogates. Findings highlight digital disparities in information seeking and the complex nature of online information seeking. Future research should examine how individuals conceptualize information sources, measure skills related to evaluating information and sources, and investigate the social nature of information seeking. Health care organizations and public health agencies can leverage the multifaceted nature of information seeking to better develop information resources to increase information access by vulnerable populations.
adult zebrafish (Specific Aim 1). We also will examine in vivo the role of PTP σ in inhibition of axon regeneration (Specific Aim 2). In addition, we...AWARD NUMBER: W81XWH-11-1-0645 TITLE: Molecular Determinants Fundamental to Axon Regeneration ... Regeneration after SCI 5b. GRANT NUMBER W81XWH-11-1-0645 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Jeffrey Alan Plunkett, Ph.D
Campbell, Leah J; Suárez-Castillo, Edna C; Ortiz-Zuazaga, Humberto; Knapp, Dunja; Tanaka, Elly M; Crews, Craig M
Urodele amphibians are unique among adult vertebrates in their ability to regenerate missing limbs. The process of limb regeneration requires several key tissues including a regeneration-competent wound epidermis called the regeneration epithelium (RE). We used microarray analysis to profile gene expression of the RE in the axolotl, a Mexican salamander. A list of 125 genes and expressed sequence tags (ESTs) showed a ≥1.5-fold expression in the RE than in a wound epidermis covering a lateral cuff wound. A subset of the RE ESTs and genes were further characterized for expression level changes over the time-course of regeneration. This study provides the first large scale identification of specific gene expression in the RE.
Diabetes mellitus results from inadequate mass of insulin-producing pancreatic beta cells. Type 1 diabetes is characterized by absolute loss of beta cells due to autoimmune-mediated destruction. Type 2 diabetes is characterized by relative deficiency of beta cells due to lack of compensation for insulin resistance. Restoration of deficient beta cell mass by transplantation from exogenous sources or by endogenous regeneration of insulin-producing cells would be therapeutic options. Mature beta cells have an ability to proliferate; however, it has been shown to be difficult to expand adult beta cells in vitro. Alternatively, regeneration of beta cells from embryonic and adult stem cells and pancreatic progenitor cells is an attractive method to restore islet cell mass. With information obtained from the biology of pancreatic development, direct differentiation of stem and progenitor cells toward a pancreatic beta cell phenotype has been tried using various strategies, including forced expression of beta cell-specific transcription factors. Further research is required to understand how endogenous beta cells differentiate and to develop methods to regenerate beta cells for clinically applicable therapies for diabetes.
Barclay, John A.; Steyert, William A.
The disclosure is directed to an active magnetic regenerator apparatus and method. Brayton, Stirling, Ericsson, and Carnot cycles and the like may be utilized in an active magnetic regenerator to provide efficient refrigeration over relatively large temperature ranges.
Han, Peidong; Zhou, Xiao-Hai; Chang, Nannan; Xiao, Cheng-Lu; Yan, Shouyu; Ren, He; Yang, Xin-Zhuang; Zhang, Mei-Ling; Wu, Qing; Tang, Boyang; Diao, Ju-Peng; Zhu, Xiaojun; Zhang, Chuanmao; Li, Chuan-Yun; Cheng, Heping; Xiong, Jing-Wei
While the adult human heart has very limited regenerative potential, the adult zebrafish heart can fully regenerate after 20% ventricular resection. Although previous reports suggest that developmental signaling pathways such as FGF and PDGF are reused in adult heart regeneration, the underlying intracellular mechanisms remain largely unknown. Here we show that H2O2 acts as a novel epicardial and myocardial signal to prime the heart for regeneration in adult zebrafish. Live imaging of intact hearts revealed highly localized H2O2 (∼30 μM) production in the epicardium and adjacent compact myocardium at the resection site. Decreasing H2O2 formation with the Duox inhibitors diphenyleneiodonium (DPI) or apocynin, or scavenging H2O2 by catalase overexpression markedly impaired cardiac regeneration while exogenous H2O2 rescued the inhibitory effects of DPI on cardiac regeneration, indicating that H2O2 is an essential and sufficient signal in this process. Mechanistically, elevated H2O2 destabilized the redox-sensitive phosphatase Dusp6 and hence increased the phosphorylation of Erk1/2. The Dusp6 inhibitor BCI achieved similar pro-regenerative effects while transgenic overexpression of dusp6 impaired cardiac regeneration. H2O2 plays a dual role in recruiting immune cells and promoting heart regeneration through two relatively independent pathways. We conclude that H2O2 potentially generated from Duox/Nox2 promotes heart regeneration in zebrafish by unleashing MAP kinase signaling through a derepression mechanism involving Dusp6. PMID:25124925
Reines, Brandon; Cheng, Lily I; Matzinger, Polly
Complete regeneration of damaged extremities, including both the epithelium and the underlying tissues, is thought to occur mainly in embryos, fetuses, and juvenile mammals, but only very rarely in adult mammals. Surprisingly, we found that common strains of mice are able to regenerate all of the tissues necessary to completely fill experimentally punched ear holes, but only if punched at middle age. Although young postweaning mice regrew the epithelium without typical pre-scar granulation tissue, they showed only minimal regeneration of connective tissues. In contrast, mice punched at 5-11 months of age showed true amphibian-like blastema formation and regrowth of cartilage, fat, and dermis, with blood vessels, sebaceous glands, hair follicles, and, in black mice, melanocytes. These data suggest that at least partial appendage regeneration may be more common in adult mammals than previously thought and call into question the common view that regenerative ability is lost with age. The data suggest that the age at which various inbred mouse strains become capable of epimorphic regeneration may be correlated with adult body weight.
Cheng, Lily I.; Matzinger, Polly
Abstract Complete regeneration of damaged extremities, including both the epithelium and the underlying tissues, is thought to occur mainly in embryos, fetuses, and juvenile mammals, but only very rarely in adult mammals. Surprisingly, we found that common strains of mice are able to regenerate all of the tissues necessary to completely fill experimentally punched ear holes, but only if punched at middle age. Although young postweaning mice regrew the epithelium without typical pre-scar granulation tissue, they showed only minimal regeneration of connective tissues. In contrast, mice punched at 5–11 months of age showed true amphibian-like blastema formation and regrowth of cartilage, fat, and dermis, with blood vessels, sebaceous glands, hair follicles, and, in black mice, melanocytes. These data suggest that at least partial appendage regeneration may be more common in adult mammals than previously thought and call into question the common view that regenerative ability is lost with age. The data suggest that the age at which various inbred mouse strains become capable of epimorphic regeneration may be correlated with adult body weight. PMID:19226206
Papadatou-Pastou, Marietta; Martin, Maryanne
The adequacy of three competing theories of hormonal effects on cerebral laterality are compared using functional transcranial Doppler sonography (fTCD). Thirty-three adult males participated in the study (21 left-handers). Cerebral lateralization was measured by fTCD using an extensively validated word generation task. Adult salivary testosterone (T) and cortisol (C) concentrations were measured by luminescence immunoassay and prenatal T exposure was indirectly estimated by the somatic marker of 2nd to 4th digit length ratio (2D:4D). A significant quadratic relationship between degree of cerebral laterality for language and adult T concentrations was observed, with enhanced T levels for strong left hemisphere dominance and strong right hemisphere dominance. No systematic effects on laterality were found for cortisol or 2D:4D. Findings suggest that higher levels of T are associated with a relatively attenuated degree of interhemispheric sharing of linguistic information, providing support for the callosal and the sexual differentiation hypotheses rather than the Geschwind, Behan and Galaburda (GBG) hypothesis.
Simkin, Jennifer; Sammarco, Mimi C.; Dawson, Lindsay A.; Schanes, Paula P.; Yu, Ling
Abstract In the mouse, digit tip regeneration progresses through a series of discrete stages that include inflammation, histolysis, epidermal closure, blastema formation, and redifferentiation. Recent studies reveal how each regenerative stage influences subsequent stages to establish a blastema that directs the successful regeneration of a complex mammalian structure. The focus of this review is on early events of healing and how an amputation wound transitions into a functional blastema. The stepwise formation of a mammalian blastema is proposed to provide a model for how specific targeted treatments can enhance regenerative performance in humans. PMID:27499871
Rahman, Qazi; Wilson, Glenn D; Abrahams, Sharon
Previous evidence suggests that sexual orientation influences performance on a number of cognitive functions known to be sexually dimorphic. This investigation examined the performance of 240 right-handed subjects (60 heterosexual men, 60 homosexual men, 60 heterosexual women and 60 homosexual women) on one of the most commonly used neuropsychological tests to show normative sex differences, the Digit-Symbol Substitution test of the WAIS-R. Analysis of scaled Digit-Symbol scores revealed that heterosexual women and homosexual men outperformed heterosexual men. The magnitude of these differences were modest by standard criteria. No differences were found between heterosexual and homosexual women. The findings implicate within-sex variation in one test that relies on intact executive function.
Boffeli, Troy J; Collier, Rachel C
Intrinsic plus foot deformity has primarily been associated with cerebral palsy and involves spastic contracture of the intrinsic musculature with resultant toe deformities. Digital deformity is caused by a dynamic imbalance between the intrinsic muscles in the foot and extrinsic muscles in the lower leg. Spastic contracture of the toes frequently involves curling under of the lesser digits or contracture of the hallux into valgus or plantarflexion deformity. Patients often present with associated pressure ulcers, deformed toenails, shoe or brace fitting challenges, and pain with ambulation or transfers. Four different patterns of intrinsic plus foot deformity have been observed by the authors that likely relate to the different patterns of muscle involvement. Case examples are provided of the 4 patterns of intrinsic plus foot deformity observed, including global intrinsic plus lesser toe deformity, isolated intrinsic plus lesser toe deformity, intrinsic plus hallux valgus deformity, and intrinsic plus hallux flexus deformity. These case examples are presented to demonstrate each type of deformity and our approach for surgical management according to the contracture pattern. The surgical approach has typically involved tenotomy, capsulotomy, or isolated joint fusion. The main goals of surgical treatment are to relieve pain and reduce pressure points through digital realignment in an effort to decrease the risk of pressure sores and allow more effective bracing to ultimately improve the patient's mobility.
Villar, Cristina C; Cochran, David L
The concept that only fibroblasts from the periodontal ligament or undifferentiated mesenchymal cells have the potential to re-create the original periodontal attachment has been long recognized. Based on this concept, guided tissue regeneration has been applied with variable success to regenerate periodontal defects. Quantitative analysis of clinical outcomes after guided tissue regeneration suggests that this therapy is a successful and predictable procedure to treat narrow intrabony defects and class II mandibular furcations, but offers limited benefits in the treatment of other types of periodontal defects.
Coronal Pulpotomy Technique Analysis as an Alternative to Pulpectomy for Preserving the Tooth Vitality, in the Context of Tissue Regeneration: A Correlated Clinical Study across 4 Adult Permanent Molars
Solomon, Raji Viola; Faizuddin, Umrana; Karunakar, Parupalli; Deepthi Sarvani, Grandhala; Sree Soumya, Sevvana
Aim. (1) The aim of the clinical study revolves around the accurate diagnosis, proper case selection, and the management of acute irreversible pulpitis in permanent molars with closed apices using conservative and economical treatment modalities like vital pulpotomies with regenerative approaches over conventional root canal procedures. (2) To evaluate the use of autologous substances such as platelet concentrates and calcium silicate based materials in promoting the healing and regeneration of the inflamed pulp. Summary. Vital pulpotomy was performed on 5 carious involved, permanent molars diagnosed with acute irreversible pulpitis in 17- to 22-year-old patients. Taking into consideration the patient's age and the condition of the underlying pulp tissue, PRF pulpotomy was planned in view of preserving the vitality of the intact radicular pulps. Regenerative procedures with second generation blood matrices were chosen to encourage the recovery of the inflamed pulps. The systematic follow-up examinations performed at 3, 6, 9, 12, 18, 22, and 24 months revealed a successful clinical and radiological outcome. Within the limits of the present clinical study and correlating the success across the treated clinical cases, we safely conclude the potential scope of regenerative pulpotomy approaches in acute irreversible pulpitis in adult permanent teeth. PMID:26097752
Kelly, Mary T; Oliffe, John L; Bottorff, Joan L
Background Young adults have high rates of tobacco use compared to other subpopulations, yet there are relatively few tobacco interventions specifically targeted to this group. Picture Me Smokefree is an online tobacco reduction and cessation intervention for young adults that uses digital photography and social networking. Objective The main goal of the project was to determine the feasibility of engaging young adults in participating in user-driven, online forums intended to provide peer support and motivate critical reflection about tobacco use and cessation among this high-use, hard-to-reach population. A related aim was to explore the influence of gender-related factors on participation, in order to determine the need for online interventions to be tailored to the specific gender preferences reflecting young men and women’s participation styles. Methods A total of 60 young adults ages 19-24 years who self-identified as current cigarette smokers or who had quit within the last year were recruited from across British Columbia, Canada, and participated in an online photo group on Facebook over a period of 12 consecutive weeks. A variety of data collection methods were used including tracking online activity, a brief online follow-up survey, and qualitative interviews with study participants. Data analysis involved descriptive statistics on recruitment, retention, and participation and qualitative (eg, narrative analysis, synthesis of feedback) feedback about participant engagement. Results Findings from this study suggest good potential for Facebook as an accessible, low-cost platform for engaging young adults to reflect on the reasons for their tobacco use, the benefits of quitting or reducing, and the best strategies for tobacco reduction. Young adults’ frequent use of mobile phones and other mobile devices to access social networking permitted ease of access and facilitated real-time peer-to-peer support across a diverse group of participants. However, our
Tsai, Hsin-yi Sandy; Shillair, Ruth; Cotten, Shelia R.; Winstead, Vicki; Yost, Elizabeth
Using information and communication technologies (ICTs) can improve older adults' quality of life. ICT use is associated with decreased feelings of loneliness and depression, along with increased feelings of independence and personal growth. However, limited access and low technological self-efficacy are key reasons why some groups, especially…
Rajnay, Z W; Butler, J R; Lindsay, R R; Vernino, A R
Recent advances in digital imaging technology have opened up new horizons for dental researchers. This study demonstrates the efficacy of a new technique for measuring regeneration in surgically created molar furcal defects. The investigators evaluated histologic material from a recently completed animal study using five adult baboons. In the animal study, surgically created molar furcation defects were treated using the principles of guided tissue regeneration. From the histologic data of one animal a computer calculated the volume of new bone, connective tissue, epithelium, and cementum as a percentage of the original defect size. The results of this study indicated that digital imaging technology is a useful research tool for determining the volume of defect fill in surgically treated Grade II molar furcation defects in the baboon animal model.
Learning To Bridge the Digital Divide: Schooling for Tomorrow. Education and Skills. [National Center on Adult Literacy (NCAL)/Organization for Economic Cooperation and Development (OECD) Roundtable (5th, Philadelphia, Pennsylvania, December 8-10, 1999)].
Jame, Edwyn; Istance, David
This publication builds on the papers and discussions of the Fifth National Center on Adult Literacy (NCAL)/Organization for Economic Cooperation and Development (OECD) Roundtable. The volume presents an analysis of the "learning digital divide" in different countries--developed and developing--and the policies and innovations designed…
Jiang, Michael Qize; Zhao, Ying-Ying; Cao, Wenyuan; Wei, Zheng Zachory; Gu, Xiaohuan; Wei, Ling; Yu, Shan Ping
Focal cerebral ischemia results in an ischemic core surrounded by the peri-infarct region (penumbra). Most research attention has been focused on penumbra while the pattern of cell fates inside the ischemic core is poorly defined. In the present investigation, we tested the hypothesis that, inside the ischemic core, some neuronal and vascular cells could survive the initial ischemic insult while regenerative niches might exist many days after stroke in the adult brain. Adult mice were subjected to focal cerebral ischemia induced by permanent occlusion of distal branches of the middle cerebral artery (MCA) plus transient ligations of bilateral common carotid artery (CCA). The ischemic insult uniformly reduced the local cerebral blood flow (LCBF) by 90%. Massive cell death occurred due to multiple mechanisms and a significant infarction was cultivated in the ischemic cortex 24 h later. Nevertheless, normal or even higher levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) persistently remained in the core tissue, some NeuN-positive and Glut-1/College IV-positive cells with intact ultrastructural features resided in the core 7-14 days post stroke. BrdU-positive but TUNEL-negative neuronal and endothelial cells were detected in the core where extensive extracellular matrix infrastructure developed. Meanwhile, GFAP-positive astrocytes accumulated in the penumbra and Iba-1-positive microglial/macrophages invaded the core several days after stroke. The long term survival of neuronal and vascular cells inside the ischemic core was also seen after a severe ischemic stroke induced by permanent embolic occlusion of the MCA. We demonstrate that a therapeutic intervention of pharmacological hypothermia could save neurons/endothelial cells inside the core. These data suggest that the ischemic core is an actively regulated brain region with residual and newly formed viable neuronal and vascular cells acutely and chronically after at
Mitashov, V. I.; Brushlinskaya, N. V.; Grigoryan, E. N.; Tuchkova, S. Ya.; Anton, H. J.
In this paper most important data obtained in studies on the effect of space flight conditions on regeneration in the adult newt are summarized. We demonstrate a phenomenon of synchronization of limb and lens regeneration and increase in its rate during and after space flight. We also describe a peculiarities of cell proliferation in lens, limb and tail regenerates and of the process of minced muscle regeneration.
Jalan, V.M.; Frost, D.G.
A spent solid sorbent resulting from the removal of hydrogen sulfide from a fuel gas flow is regenerated with a steam-air mixture. The mixture of steam and air may also include additional nitrogen or carbon dioxide. The gas mixture contacts the spent sorbent containing metal sulfide at a temperature above 500/sup 0/C to regenerate the sulfide to metal oxide or carbonate. Various metal species including the period four transition metals and the lanthanides are suitable sorbents that may be regenerated by this method. In addition, the introduction of carbon dioxide gas permits carbonates such as those of strontium, barium and calcium to be regenerated. The steam permits regeneration of spent sorbent without formation of metal sulfate. Moreover, the regeneration will proceed with low oxygen concentrations and will occur without the increase in temperature to minimize the risk of sintering and densification of the sorbent. This method may be used for high-temperature fuel cells.
Schwarz, Lauren R; Gfeller, Jeffrey D; Oliveri, Michael V
The WAIS-III Digit Span and Vocabulary subtests were investigated as indicators of feigned cognitive impairment. Participants included 64 undergraduates randomly assigned to control, symptom-coached, or test-coached groups. Six previously researched validity indicators were examined. We hypothesized that symptom-coached participants would perform worse relative to test-coached simulators. Analyses determined both simulator groups performed lower than controls on all indicators except Vocabulary. Symptom-coached participants, however, did not differ from test-coached participants on any indicator. Classification accuracies for these six indicators ranged from 42 to 78%. While the WAIS-III validity indicators hold some promise, they should not be employed as independent measures.
Sheĭman, I M; Sedel'nikov, Z V; Kreshchenko, N D
We studied the intensity of blastema growth in operated planarians at an early stage of regeneration as a function of the following factors: area of regenerate and its function and number of regeneration foci (volume of regeneration). There was no direct dependence between the intensity of regeneration and the size of regenerating fragment, as well as the volume of regeneration. Some specific features of the early stage of regeneration have been described, which suggest its determinate character. The behavior of neoblasts during formation of blastemas with different localization is discussed.
Reddien, Peter W
Planarians are flatworms capable of regenerating all body parts. Planarian regeneration requires neoblasts, a population of dividing cells that has been studied for over a century. Neoblast progeny generate new cells of blastemas, which are the regenerative outgrowths at wounds. If the neoblasts comprise a uniform population of cells during regeneration (e.g. they are all uncommitted and pluripotent), then specialization of new cell types should occur in multipotent, non-dividing neoblast progeny cells. By contrast, recent data indicate that some neoblasts express lineage-specific transcription factors during regeneration and in uninjured animals. These observations raise the possibility that an important early step in planarian regeneration is the specialization of neoblasts to produce specified rather than naïve blastema cells.
Kreshchenko, N D
The obtained and published data on pharynx regeneration in planarians have been reviewed. Planarians can regenerate from a small body fragment and restore all missing organs including the pharynx. The pharynx is a relatively autonomous organ with a differentiated structure and specialized function. Pharynx regeneration has specific features, and its studies are of considerable theoretical interest. Pharynx regeneration can also be a convenient model to study the molecular mechanisms of regeneration that remain undisclosed. In addition, this model can be used to test biologically active compounds in order to elucidate their effect on morphogenesis. This subject of investigation benefits by a simpler and more adequate analysis as well as a possibility to use large numbers of animals and small quantities of analyzed substances.
Franklin, Jerrold E.
The feasibility of fabricating an Air Turbo Ramjet (ATR) regenerator containing intricate hydraulic passages from a ceramic material in order to allow operation with high temperature combustion gas and to reduce weight as compared with metallic materials was demonstrated. Platelet technology, ceramic tape casting, and multilayer ceramic packaging techniques were used in this fabrication of subscale silicon nitride components. Proof-of-concept demonstrations were performed to simulate a methane cooled regenerator for an ATR engine. The regenerator vane was designed to operate at realistic service conditions, i.e., 600 psi in a 3500 R (3040 F), 500 fps combustion gas environment. A total of six regenerators were fabricated and tested. The regenerators were shown to be able to withstand internal pressurization to 1575 psi. They were subjected to testing in 500 fps, 3560 R (3100 F) air/propane combustion products and were operated satisfactorily for an excess of 100 hr and 40 thermal cycles which exceeded 2460 R (2000 F).
Abstract We performed a chemical screen to look for novel inhibitors of zebrafish caudal fin regeneration. In a pilot screen, 520 compounds were tested. Two compounds, budesonide and AGN192403, abrogated fin regeneration. One compound in particular, AGN192403, targets the imidazoline receptor, a pathway not previously linked to fin regeneration. In addition to inhibiting regeneration of the adult fin, AGN192403 also blocked regeneration of the larval fin fold. Finally, the inhibitory effect of AGN192403 on fin regeneration persisted after removal of the drug. These studies demonstrate that chemical screening is feasible in adult zebrafish and that it is a reasonable strategy to use for exploring the biology of regeneration. PMID:20384483
Yannas, Ioannis V
We review the available evidence for regeneration of adult organs of very diverse nature and examine the applicability of simple rules that can be used to summarize these treatments. In the field of regenerative medicine no widely accepted paradigm is currently available that can guide formulation of new theories on the mechanism of regeneration in adults and open new directions for improved regeneration outcomes. The four rules have emerged from multiyear quantitative studies with skin and peripheral nerve regeneration using scaffold libraries based on a simple, well-defined collagen scaffold. These largely quantitative rules distinguish sharply between spontaneously regenerative and nonregenerative tissues, select the two reactants that are required for regeneration, recognize the essential modification of the wound healing process that must be realized prior to regeneration, and identify three structural features of scaffolds that are required for regenerative activity. The combined evidence points at certain requirements for the structure of a collagen scaffold with regenerative activity. An active scaffold emerges as a temporarily insoluble collagen surface, equipped with sufficient ligands for integrins of contractile cells, that inhibits wound contraction while also serving as a topographic template for new stroma synthesis. The four rules, based on studies with just two organs (skin and peripheral nerves), are now viewed in the context of ongoing studies using scaffolds based on decellularized matrices, which are mostly based on collagen. Decellularized matrices have been used during the past few years to regenerate, in whole or in part, the urethra, the abdominal wall, the Achilles tendon, the bladder, the trachea and other organs in several animal models and occasionally in humans. Although these acellular matrices are distinctly different from simple collagen scaffolds, and the methods used by the investigators are still evolving, the results obtained
Yan, Irene K.; Wang, Xue; Asmann, Yan W.; Haga, Hiroaki; Patel, Tushar
Background and Aims Although a key determinant of hepatic recovery after injury is active liver regeneration, the ability to detect ongoing regeneration is lacking. The restoration of liver mass after hepatectomy involves systemic changes with coordinated changes in gene expression guiding regenerative responses, activation of progenitor cells, and proliferation of quiescent hepatocytes. We postulated that these responses involve intercellular communication involving extracellular RNA and that these could represent biomarkers of active regenerative responses. Methods RNA sequencing was performed to identify temporal changes in serum extracellular non-coding RNA after partial hepatectomy in C57BL/6 male mice. Tissue expression of selected RNA was performed by microarray analysis and validated using qRT-PCR. Digital PCR was used to detect and quantify serum expression of selected RNA. Results A peak increase in extracellular RNA content occurred six hours after hepatectomy. RNA sequencing identified alterations in several small non-coding RNA including known and novel microRNAs, snoRNAs, tRNA, antisense and repeat elements after partial hepatectomy. Combinatorial effects and network analyses identified signal regulation, protein complex assembly, and signal transduction as the most common biological processes targeted by miRNA that altered. miR-1A and miR-181 were most significantly altered microRNA in both serum and in hepatic tissues, and their presence in serum was quantitated using digital PCR. Conclusions Extracellular RNA selectively enriched during acute regeneration can be detected within serum and represent biomarkers of ongoing liver regeneration in mice. The ability to detect ongoing active regeneration would improve the assessment of hepatic recovery from liver injury. PMID:27415797
Bejjani, Rachid El; Hammarlund, Marc
Summary Many neurons have limited capacity to regenerate their axons after injury. Neurons in the mammalian CNS do not regenerate, and even neurons in the PNS often fail to regenerate to their former targets. This failure is likely due in part to pathways that actively restrict regeneration; however, only a few factors that limit regeneration are known. Here, using single-neuron analysis of regeneration in vivo, we show that Notch/lin-12 signaling inhibits the regeneration of mature C. elegans neurons. Notch signaling suppresses regeneration by acting autonomously in the injured cell to prevent growth cone formation. The metalloprotease and gamma-secretase cleavage events that lead to Notch activation during development are also required for its activity in regeneration. Furthermore, blocking Notch activation immediately after injury improves regeneration. Our results define a novel, post-developmental role for the Notch pathway as a repressor of axon regeneration in vivo. PMID:22284182
Bergmann, Andreas; Steller, Hermann
Most metazoans have at least some ability to regenerate damaged cells and tissues, although the regenerative capacity varies depending on the species, organ, or developmental stage. Cell replacement and regeneration occur in two contexts: renewal of spent cells during tissue homeostasis (homeostatic growth), and in response to external injury, wounding, or amputation (epimorphic regeneration). Model organisms that display remarkable regenerative capacity include amphibians, planarians, Hydra, and the vertebrate liver. In addition, several mammalian organs--including the skin, gut, kidney, muscle, and even the human nervous system--have some ability to replace spent or damaged cells. Although the regenerative response is complex, it typically involves the induction of new cell proliferation through formation of a blastema, followed by cell specification, differentiation, and patterning. Stem cells and undifferentiated progenitor cells play an important role in both tissue homeostasis and tissue regeneration. Stem cells are typically quiescent or passing slowly through the cell cycle in adult tissues, but they can be activated in response to cell loss and wounding. A series of studies, mostly performed in Drosophila as well as in Hydra, Xenopus, and mouse, has revealed an unexpected role of apoptotic caspases in the production of mitogenic signals that stimulate the proliferation of stem and progenitor cells to aid in tissue regeneration. This Review summarizes some of the key findings and discusses links to stem cell biology and cancer.
Bellas, Evangelia; Rollins, Amanda; Moreau, Jodie E; Lo, Tim; Quinn, Kyle P; Fourligas, Nicholas; Georgakoudi, Irene; Leisk, Gary G; Mazan, Melissa; Thane, Kristen E; Taeymans, Olivier; Hoffman, A M; Kaplan, D L; Kirker-Head, C A
Soft-tissue regeneration methods currently yield suboptimal clinical outcomes due to loss of tissue volume and a lack of functional tissue regeneration. Grafted tissues and natural biomaterials often degrade or resorb too quickly, while most synthetic materials do not degrade. In previous research we demonstrated that soft-tissue regeneration can be supported using silk porous biomaterials for at least 18 months in vivo in a rodent model. In the present study, we scaled the system to a survival study using a large animal model and demonstrated the feasibility of these biomaterials for soft-tissue regeneration in adult horses. Both slow and rapidly degrading silk matrices were evaluated in subcutaneous pocket and intramuscular defect depots. We showed that we can effectively employ an equine model over 6 months to simultaneously evaluate many different implants, reducing the number of animals needed. Furthermore, we were able to tailor matrix degradation by varying the initial format of the implanted silk. Finally, we demonstrate ultrasound imaging of implants to be an effective means for tracking tissue regeneration and implant degradation.
Le Moal, Emmeran; Pialoux, Vincent; Juban, Gaëtan; Groussard, Carole; Zouhal, Hassane; Chazaud, Bénédicte; Mounier, Rémi
Skeletal muscle shows high plasticity in response to external demand. Moreover, adult skeletal muscle is capable of complete regeneration after injury, due to the properties of muscle stem cells (MuSCs), the satellite cells, which follow a tightly regulated myogenic program to generate both new myofibers and new MuSCs for further needs. Although reactive oxygen species (ROS) and reactive nitrogen species (RNS) have long been associated with skeletal muscle physiology, their implication in the cell and molecular processes at work during muscle regeneration is more recent. This review focuses on redox regulation during skeletal muscle regeneration. An overview of the basics of ROS/RNS and antioxidant chemistry and biology occurring in skeletal muscle is first provided. Then, the comprehensive knowledge on redox regulation of MuSCs and their surrounding cell partners (macrophages, endothelial cells) during skeletal muscle regeneration is presented in normal muscle and in specific physiological (exercise-induced muscle damage, aging) and pathological (muscular dystrophies) contexts. Recent advances in the comprehension of these processes has led to the development of therapeutic assays using antioxidant supplementation, which result in inconsistent efficiency, underlying the need for new tools that are aimed at precisely deciphering and targeting ROS networks. This review should provide an overall insight of the redox regulation of skeletal muscle regeneration while highlighting the limits of the use of nonspecific antioxidants to improve muscle function. Antioxid. Redox Signal. 00, 000-000.
Männikkö, Niko; Billieux, Joël; Kääriäinen, Maria
Background and Aims The aim of this study was to identify problematic gaming behavior among Finnish adolescents and young adults, and evaluate its connection to a variety of psychological, social, and physical health symptoms. Methods This cross-sectional study was conducted with a random sample of 293 respondents aged from 13 to 24 years. Participants completed an online survey. Problematic gaming behavior was measured with the Game Addiction Scale (GAS). Self-reports covered health measures such as psychological health (psychopathological symptoms, satisfaction with life), social health (preferences for social interaction), and physical health (general health, Body Mass Index [BMI], body discomfort, physical activity). Results Problematic gaming behavior was found to relate to psychological and health problems, namely fatigue, sleep interference, depression and anxiety symptoms. Multiple linear regression indicated that the amount of weekly gaming, depression and a preference for online social interaction predicted increased problematic gaming symptoms. Conclusions This research emphasized that problematic gaming behavior had a strong negative correlation to a variety of subjective health outcomes. PMID:26690623
Bay-Cheng, Laina Y
The Digital Sexual Life History Calendar (d/SLHC) is a Web-based platform for collecting young adults' sexual histories. In addition to collecting diverse data, the d/SLHC was designed to benefit participants by enabling reflection on their sexual and relationship experiences in the context of other life events and circumstances. In a pilot study of the d/SLHC, survey data were collected to test whether creating a d/SLHC timeline had any impact on sexual well-being. A sample of 18- to 25-year-old participants recruited through Amazon Mechanical Turk (MTurk) completed an online survey about sexuality and relationships. Of those, 113 also completed d/SLHC timelines and 262 served as a comparison group. Six months later, participants from both groups were invited to complete a follow-up survey (total N = 249). Repeated-measures analysis of variance (ANOVA) results indicated that participants who completed d/SLHC timelines exhibited higher sexual esteem immediately following d/SLHC completion and at follow-up. No changes in sexual esteem were observed in the comparison group, and there were no differences between the groups with regard to sexual health behaviors and outcomes. These findings suggest that sexuality studies may have the potential to yield not only rich data for researchers but also rich experiences for participants.
Stock, Stuart R.; Ignatiev, Konstantin I.; Simon, Hans-Georg; De Carlo, Francesco
Newts are the most developed vertebrates which retain the ability as adults to regenerate missing limbs; they are, therefore, of great interest in terms understanding how such regeneration could be triggered in mammals. In this study, synchrotron microCT was used to study bone microstructure in control forelimbs and in forelimbs regenerated for periods from 37 to 85 days. The bone microstructure in newts has been largely neglected, and interesting patterns within the original bone and in the regenerating arm and hand are described. Periosteal bone formation in the regenerating arm and finger bones, delayed ossification of carpal (but not metacarpal) bones and the complex microstructure of the original carpal bones are areas where microCT reveals detail of particular interest.
Piran, Ron; Lee, Seung-Hee; Kuss, Pia; Hao, Ergeng; Newlin, Robbin; Millán, José Luis; Levine, Fred
Understanding the mechanisms by which cells sense and respond to injury is central to developing therapies to enhance tissue regeneration. Previously, we showed that pancreatic injury consisting of acinar cell damage+β-cell ablation led to islet cell transdifferentiation. Here, we report that the molecular mechanism for this requires activating protease-activated receptor-2 (PAR2), a G-protein-coupled receptor. PAR2 modulation was sufficient to induce islet cell transdifferentiation in the absence of β-cells. Its expression was modulated in an islet cell type-specific manner in murine and human type 1 diabetes (T1D). In addition to transdifferentiation, PAR2 regulated β-cell apoptosis in pancreatitis. PAR2's role in regeneration is broad, as mice lacking PAR2 had marked phenotypes in response to injury in the liver and in digit regeneration following amputation. These studies provide a pharmacologically relevant target to induce tissue regeneration in a number of diseases, including T1D. PMID:27809303
Yun, Maximina H; Gates, Phillip B; Brockes, Jeremy P
Extensive regeneration of the vertebrate body plan is found in salamander and fish species. In these organisms, regeneration takes place through reprogramming of differentiated cells, proliferation, and subsequent redifferentiation of adult tissues. Such plasticity is rarely found in adult mammalian tissues, and this has been proposed as the basis of their inability to regenerate complex structures. Despite their importance, the mechanisms underlying the regulation of the differentiated state during regeneration remain unclear. Here, we analyzed the role of the tumor-suppressor p53 during salamander limb regeneration. The activity of p53 initially decreases and then returns to baseline. Its down-regulation is required for formation of the blastema, and its up-regulation is necessary for the redifferentiation phase. Importantly, we show that a decrease in the level of p53 activity is critical for cell cycle reentry of postmitotic, differentiated cells, whereas an increase is required for muscle differentiation. In addition, we have uncovered a potential mechanism for the regulation of p53 during limb regeneration, based on its competitive inhibition by ΔNp73. Our results suggest that the regulation of p53 activity is a pivotal mechanism that controls the plasticity of the differentiated state during regeneration.
Gong, Tao; Xie, Jing; Liao, Jinfeng; Zhang, Tao; Lin, Shiyu; Lin, Yunfeng
The worldwide incidence of bone disorders and conditions has been increasing. Bone is a nanomaterials composed of organic (mainly collagen) and inorganic (mainly nano-hydroxyapatite) components, with a hierarchical structure ranging from nanoscale to macroscale. In consideration of the serious limitation in traditional therapies, nanomaterials provide some new strategy in bone regeneration. Nanostructured scaffolds provide a closer structural support approximation to native bone architecture for the cells and regulate cell proliferation, differentiation, and migration, which results in the formation of functional tissues. In this article, we focused on reviewing the classification and design of nanostructured materials and nanocarrier materials for bone regeneration, their cell interaction properties, and their application in bone tissue engineering and regeneration. Furthermore, some new challenges about the future research on the application of nanomaterials for bone regeneration are described in the conclusion and perspectives part. PMID:26558141
Calve, S.; Simon, H.-G.
Adult newts possess the ability to completely regenerate organs and appendages. Immediately after limb loss, the extracellular matrix (ECM) undergoes dramatic changes that may provide mechanical and biochemical cues to guide the formation of the blastema, which is comprised of uncommitted stem-like cells that proliferate to replace the lost structure. Skeletal muscle is a known reservoir for blastema cells but the mechanism by which it contributes progenitor cells is still unclear. To create physiologically relevant culture conditions for the testing of primary newt muscle cells in vitro, the spatio-temporal distribution of ECM components and the mechanical properties of newt muscle were analyzed. Tenascin-C and hyaluronic acid (HA) were found to be dramatically upregulated in the amputated limb and were co-expressed around regenerating skeletal muscle. The transverse stiffness of muscle measured in situ was used as a guide to generate silicone-based substrates of physiological stiffness. Culturing newt muscle cells under different conditions revealed that the cells are sensitive to both matrix coating and substrate stiffness: Myoblasts on HA-coated soft substrates display a rounded morphology and become more elongated as the stiffness of the substrate increases. Coating of soft substrates with matrigel or fibronectin enhanced cell spreading and eventual cell fusion.
Grishayenkov, B. G.
Various physicochemical methods of regenerating and conditioning air for spacecraft are described with emphasis on conditions which affect efficiency of the system. Life support systems used in closed, hermetically sealed environments are discussed with references to actual application in the Soviet Soyuz and Voskhod manned spacecraft. Temperature and humidity control, removal of carbon dioxide, oxygen regeneration, and removal of bacteria and viruses are among the factors considered.
Conceição, Simone C. O.; Martin, Larry G.
This chapter focuses on the role adult educators can play in assisting Black men to overcome the challenges faced in accessing and using digital technology and acquiring appropriate skills in a digital society.
Gaub, Perrine; Joshi, Yashashree; Wuttke, Anja; Naumann, Ulrike; Schnichels, Sven; Heiduschka, Peter; Di Giovanni, Simone
Axonal regeneration and related functional recovery following axonal injury in the adult central nervous system are extremely limited, due to a lack of neuronal intrinsic competence and the presence of extrinsic inhibitory signals. As opposed to what occurs during nervous system development, a weak proregenerative gene expression programme contributes to the limited intrinsic capacity of adult injured central nervous system axons to regenerate. Here we show, in an optic nerve crush model of axonal injury, that adenoviral (cytomegalovirus promoter) overexpression of the acetyltransferase p300, which is regulated during retinal ganglion cell maturation and repressed in the adult, can promote axonal regeneration of the optic nerve beyond 0.5 mm. p300 acetylates histone H3 and the proregenerative transcription factors p53 and CCAAT-enhancer binding proteins in retinal ganglia cells. In addition, it directly occupies and acetylates the promoters of the growth-associated protein-43, coronin 1 b and Sprr1a and drives the gene expression programme of several regeneration-associated genes. On the contrary, overall increase in cellular acetylation using the histone deacetylase inhibitor trichostatin A, enhances retinal ganglion cell survival but not axonal regeneration after optic nerve crush. Therefore, p300 targets both the epigenome and transcription to unlock a post-injury silent gene expression programme that would support axonal regeneration.
Jing, Xiaotang; Wang, Ting; Huang, Shaohua; Glorioso, Joseph C; Albers, Kathryn M
Factors that enhance the intrinsic growth potential of adult neurons are key players in the successful repair and regeneration of neurons following injury. Injury-induced activation of transcription factors has a central role in this process because they regulate expression of regeneration-associated genes. Sox11 is a developmentally expressed transcription factor that is significantly induced in adult neurons in response to injury. Its function in injured neurons is however undefined. Here, we report studies that use herpes simplex virus (HSV)-vector-mediated expression of Sox11 in adult sensory neurons to assess the effect of Sox11 overexpression on neuron regeneration. Cultured mouse dorsal root ganglia (DRG) neurons transfected with HSV-Sox11 exhibited increased neurite elongation and branching relative to naïve and HSV-vector control treated neurons. Neurons from mice injected in foot skin with HSV-Sox11 exhibited accelerated regeneration of crushed saphenous nerves as indicated by faster regrowth of axons and nerve fibers to the skin, increased myelin thickness and faster return of nerve and skin sensitivity. Downstream targets of HSV-Sox11 were examined by analyzing changes in gene expression of known regeneration-associated genes. This analysis in combination with mutational and chromatin immunoprecipitation assays indicates that the ability of Sox11 to accelerate in vivo nerve regeneration is dependent on its transcriptional activation of the regeneration-associated gene, small proline rich protein 1a (Sprr1a). This finding reveals a new functional linkage between Sox11 and Sprr1a in adult peripheral neuron regeneration.
Bouzaffour, Mohamed; Dufourcq, Pascale; Lecaudey, Virginie; Haas, Petra; Vriz, Sophie
The chemokine stromal cell-derived factor-1 (SDF1) was originally identified as a pre-B cell stimulatory factor but has been recently implicated in several other key steps in differentiation and morphogenesis. In addition, SDF1 as well as FGF signalling pathways have recently been shown to be involved in the control of epimorphic regeneration. In this report, we address the question of a possible interaction between the two signalling pathways during adult fin regeneration in zebrafish. Using a combination of pharmaceutical and genetic tools, we show that during epimorphic regeneration, expression of sdf1, as well as of its cognate receptors, cxcr4a, cxcr4b and cxcr7 are controlled by FGF signalling. We further show that, Sdf1a negatively regulates the expression of fgf20a. Together, these results lead us to propose that: 1) the function of Fgf in blastema formation is, at least in part, relayed by the chemokine Sdf1a, and that 2) Sdf1 exerts negative feedback on the Fgf pathway, which contributes to a transient expression of Fgf20a downstream genes at the beginning of regeneration. However this feedback control can be bypassed since the Sdf1 null mutants regenerate their fin, though slower. Very few mutants for the regeneration process were isolated so far, illustrating the difficulty in identifying genes that are indispensable for regeneration. This observation supports the idea that the regeneration process involves a delicate balance between multiple pathways.
Bone regeneration is a complex, well-orchestrated physiological process of bone formation, which can be seen during normal fracture healing, and is involved in continuous remodelling throughout adult life. However, there are complex clinical conditions in which bone regeneration is required in large quantity, such as for skeletal reconstruction of large bone defects created by trauma, infection, tumour resection and skeletal abnormalities, or cases in which the regenerative process is compromised, including avascular necrosis, atrophic non-unions and osteoporosis. Currently, there is a plethora of different strategies to augment the impaired or 'insufficient' bone-regeneration process, including the 'gold standard' autologous bone graft, free fibula vascularised graft, allograft implantation, and use of growth factors, osteoconductive scaffolds, osteoprogenitor cells and distraction osteogenesis. Improved 'local' strategies in terms of tissue engineering and gene therapy, or even 'systemic' enhancement of bone repair, are under intense investigation, in an effort to overcome the limitations of the current methods, to produce bone-graft substitutes with biomechanical properties that are as identical to normal bone as possible, to accelerate the overall regeneration process, or even to address systemic conditions, such as skeletal disorders and osteoporosis. PMID:21627784
Stewart, Scott; Rojas-Muñoz, Agustin; Izpisúa Belmonte, Juan Carlos
All cells have electric potentials across their membranes, but is there really compelling evidence to think that such potentials are used as instructional cues in developmental biology? Numerous reports indicate that, in fact, steady, weak bioelectric fields are observed throughout biology and function during diverse biological processes, including development. Bioelectric fields, generated upon amputation, are also likely to play a key role during vertebrate regeneration by providing the instructive cues needed to direct migrating cells to form a wound epithelium, a structure unique to regenerating animals. However, mechanistic insight is still sorely lacking in the field. What are the genes required for bioelectric-dependent cell migration during regeneration? The power of genetics combined with the use of zebrafish offers the best opportunity for unbiased identification of the molecular players in bioelectricity.
Wei, Guobao; Ma, Peter X.
Biomaterials play a pivotal role in regenerative medicine, which aims to regenerate and replace lost/dysfunctional tissues or organs. Biomaterials (scaffolds) serve as temporary 3D substrates to guide neo tissue formation and organization. It is often beneficial for a scaffolding material to mimic the characteristics of extracellular matrix (ECM) at the nanometer scale and to induce certain natural developmental or/and wound healing processes for tissue regeneration applications. This article reviews the fabrication and modification technologies for nanofibrous, nanocomposite, and nanostructured drug-delivering scaffolds. ECM-mimicking nanostructured biomaterials have been shown to actively regulate cellular responses including attachment, proliferation, differentiation and matrix deposition. Nano-scaled drug delivery systems can be successfully incorporated into a porous 3D scaffold to enhance the tissue regeneration capacity. In conclusion, nano-structured biomateials are a very exciting and rapidly expanding research area, and are providing new enabling technologies for regenerative medicine. PMID:19946357
Woods, R. R.; Marshall, R. D.; Schubert, F. H.; Heppner, D. B.
Preliminary designs were generated for two electrochemically regenerable carbon dioxide absorber concepts. Initially, an electrochemically regenerable absorption bed concept was designed. This concept incorporated the required electrochemical regeneration components in the absorber design, permitting the absorbent to be regenerated within the absorption bed. This hardware was identified as the electrochemical absorber hardware. The second hardware concept separated the functional components of the regeneration and absorption process. This design approach minimized the extravehicular activity component volume by eliminating regeneration hardware components within the absorber. The electrochemical absorber hardware was extensively characterized for major operating parameters such as inlet carbon dioxide partial pressure, process air flow rate, operational pressure, inlet relative humidity, regeneration current density and absorption/regeneration cycle endurance testing.
Fox, Edward A.; Urs, Shalini R.
Provides an overview of digital libraries research, practice, and literature. Highlights include new technologies; redefining roles; historical background; trends; creating digital content, including conversion; metadata; organizing digital resources; services; access; information retrieval; searching; natural language processing; visualization;…
Kotton, Darrell N; Morrisey, Edward E
Recent studies have shown that the respiratory system has an extensive ability to respond to injury and regenerate lost or damaged cells. The unperturbed adult lung is remarkably quiescent, but after insult or injury progenitor populations can be activated or remaining cells can re-enter the cell cycle. Techniques including cell-lineage tracing and transcriptome analysis have provided novel and exciting insights into how the lungs and trachea regenerate in response to injury and have allowed the identification of pathways important in lung development and regeneration. These studies are now informing approaches for modulating the pathways that may promote endogenous regeneration as well as the generation of exogenous lung cell lineages from pluripotent stem cells. The emerging advances, highlighted in this Review, are providing new techniques and assays for basic mechanistic studies as well as generating new model systems for human disease and strategies for cell replacement. PMID:25100528
Vigneswara, Vasanthy; Kundi, Sarina; Ahmed, Zubair
The poor or lack of injured adult central nervous system (CNS) axon regeneration results in devastating consequences and poor functional recovery. The interplay between the intrinsic and extrinsic factors contributes to robust inhibition of axon regeneration of injured CNS neurons. The insufficient or lack of trophic support for injured neurons is considered as one of the major obstacles contributing to their failure to survive and regrow their axons after injury. In the CNS, many of the signalling pathways associated with neuronal survival and axon regeneration are regulated by several classes of receptor tyrosine kinases (RTK) that respond to a variety of ligands. This paper highlights and summarises the most relevant recent findings pertinent to different classes of the RTK family of molecules, with a particular focus on elucidating their role in CNS axon regeneration. PMID:22848811
Kumar, Anoop; Brockes, Jeremy P
Many regeneration contexts require the presence of regenerating nerves as a transient component of the progenitor cell niche. Here we review nerve involvement in regeneration of various structures in vertebrates and invertebrates. Nerves are also implicated as persistent determinants in the niche of certain stem cells in mammals, as well as in Drosophila. We consider our present understanding of the cellular and molecular mechanisms underlying nerve dependence, including evidence of critical interactions with glia and non-neural cell types. The example of the salamander aneurogenic limb illustrates that developmental interactions between the limb bud and its innervation can be determinative for adult regeneration. These phenomena provide a different perspective on nerve cells to that based on chemical and electrical excitability.
A digital, all-optical temperature sensor design concept based on optical sampling and digital encoding is presented. The proposed sensor generates 2M binary digital codewords of length M bits. The codewords are generated serially and, therefore, only a single output fiber line is required. A multiplexing scheme, which minimizes the power requirement per sensor array and facilitates a cost-effective digit regeneration for remote monitoring over long distance, is presented. The sensor arrays are used as building blocks to configure large scale sensor networks based on LAN topologies.
Eckart, Francis H.
A rotary regenerator disc matrix has a face seal with a cross arm and arcuate rim segments joined by prestress clamps to prestrain the arcuate rim seals so as to compensate seal rim twisting or coning and resultant disc face seal leakage as produced by operating thermal gradients across the seal.
Nuester, J.; Twining, B. S.
Bioavailability of nutrients is an essential factor controlling primary productivity in the ocean. In addition to macronutrients such as nitrogen and phosphorous, availability of the trace element iron unequivocally affects growth rates and community structure of phytoplankton and thereby primary productivity in many ocean regions. External sources of iron such as Aeolian dust, upwelling of Fe-rich waters, and hydrothermal are reduced in high-nutrient low-chlorophyll regions, and most Fe used by phytoplankton has been regenerated by zooplankton. While zooplankton regeneration of Fe was first shown two decades ago, major factors controlling this process such as chemical composition of prey and grazer taxonomy are not well constrained. As pH varies significantly in digestive systems between protozoa and mesozooplankton, we hypothesize that the extent and the bioavailability of regenerated Fe is a function of the digestive physiology. Furthermore, major element components such as silica for diatoms and calcium carbonate for cocolithophores may be able to buffer the pH of digestive systems of different grazer taxa. Such effects may further influence the magnitude and bioavailability of regenerated Fe. In order to constrain the effect of grazer taxonomy and chemical composition of prey on Fe bioavailability, 55Fe-labeled phytoplankton were fed to different grazers and unlabeled phytoplankton were subsequently inoculated to the filtrate of the grazing experiment in the regrowth phase of the experiment, and the uptake of 55Fe into the phytoplankton biomass was monitored over time. A parallel uptake experiment using inorganic 55Fe was used to compare the bioavailability of regenerated and inorganic Fe to the same phytoplankton species. Furthermore, some samples of the inorganic and the regenerated uptake experiments were treated with an oxalate rinse to remove any adsorbed Fe. This allowed us to estimate the adsorption of 55Fe from either source to the cell walls of
Johnson, S. L.; Weston, J. A.
When amputated, the fins of adult zebrafish rapidly regenerate the missing tissue. Fin regeneration proceeds through several stages, including wound healing, establishment of the wound epithelium, recruitment of the blastema from mesenchymal cells underlying the wound epithelium, and differentiation and outgrowth of the regenerate. We screened for temperature-sensitive mutations that affect the regeneration of the fin. Seven mutations were identified, including five that fail to regenerate their fins, one that causes slow growth during regeneration, and one that causes dysmorphic bumps or tumors to develop in the regenerating fin. reg5 mutants fail to regenerate their caudal fins, whereas reg6 mutants develop dysmorphic bumps in their regenerates at the restrictive temperature. Temperature-shift experiments indicate that reg5 and reg6 affect different stages of regeneration. The critical period for reg5 occurs during the early stages of regeneration before or during establishment of the blastema, resulting in defects in subsequent growth of the blastema and failure to differentiate bone-forming cells. The critical period for reg6 occurs after the onset of bone differentiation and during early stages of regenerative outgrowth. Both reg5 and reg6 also show temperature-sensitive defects in embryonic development or in ontogenetic outgrowth of the juvenile fin. PMID:8601496
O'Donovan, Kevin J.
Following damage to the adult nervous system in conditions like stroke, spinal cord injury, or traumatic brain injury, many neurons die and most of the remaining spared neurons fail to regenerate. Injured neurons fail to regrow both because of the inhibitory milieu in which they reside as well as a loss of the intrinsic growth capacity of the neurons. If we are to develop effective therapeutic interventions that promote functional recovery for the devastating injuries described above, we must not only better understand the molecular mechanisms of developmental axonal growth in hopes of re-activating these pathways in the adult, but at the same time be aware that re-activation of adult axonal growth may proceed via distinct mechanisms. With this knowledge in hand, promoting adult regeneration of central nervous system neurons can become a more tractable and realistic therapeutic endeavor. PMID:27833527
Nachtrab, Gregory; Kikuchi, Kazu; Tornini, Valerie A; Poss, Kenneth D
Many fish and salamander species regenerate amputated fins or limbs, restoring the size and shape of the original appendage. Regeneration requires that spared cells retain or recall information encoding pattern, a phenomenon termed positional memory. Few factors have been implicated in positional memory during vertebrate appendage regeneration. Here, we investigated potential regulators of anteroposterior (AP) pattern during fin regeneration in adult zebrafish. Sequence-based profiling from tissues along the AP axis of uninjured pectoral fins identified many genes with region-specific expression, several of which encoded transcription factors with known AP-specific expression or function in developing embryonic pectoral appendages. Transgenic reporter strains revealed that regulatory sequences of the transcription factor gene alx4a activated expression in fibroblasts and osteoblasts within anterior fin rays, whereas hand2 regulatory sequences activated expression in these same cell types within posterior rays. Transgenic overexpression of hand2 in all pectoral fin rays did not affect formation of the proliferative regeneration blastema, yet modified the lengths and widths of regenerating bones. Hand2 influenced the character of regenerated rays in part by elevation of the vitamin D-inactivating enzyme encoded by cyp24a1, contributing to region-specific regulation of bone metabolism. Systemic administration of vitamin D during regeneration partially rescued bone defects resulting from hand2 overexpression. Thus, bone-forming cells in a regenerating appendage maintain expression throughout life of transcription factor genes that can influence AP pattern, and differ across the AP axis in their expression signatures of these and other genes. These findings have implications for mechanisms of positional memory in vertebrate tissues.
Khan, P A; Tsilfidis, C; Liversage, R A
A central theme concerning the epimorphic regenerative potential of urodele amphibian appendages is that limb regeneration in the adult parallels larval limb development. Results of previous research have led to the suggestion that homeobox containing genes are "re-expressed" during the epimorphic regeneration of forelimbs of adult Notophthalmus viridescens in patterns which retrace larval limb development. However, to date no literature exists concerning expression patterns of any homeobox containing genes during larval development of this species. The lack of such information has been a hindrance in exploring the similarities as well as differences which exist between limb regeneration in adults and limb development in larvae. Here we report the first such results of the localization of Hox C6 (formerly, NvHBox-1) in developing and regenerating forelimbs of N. viridescens larvae as demonstrated by whole-mount in situ hybridization. Inasmuch as the pattern of Hox C6 expression is similar in developing forelimb buds of larvae and epimorphically regenerating forelimb blastemata of both adults and larvae, our results support the paradigm that epimorphic regeneration in adult newts parallels larval forelimb development. However, in contrast with observations which document the presence of Hox C6 in both intact, as well as regenerating hindlimbs and tails of adult newts, our results reveal no such Hox C6 expression during larval development of hindlimbs or the tail. As such, our findings indicate that critical differences in larval hindlimb and tail development versus adult expression patterns of this gene in these two appendages may be due primarily to differences in gene regulation as opposed to gene function. Thus, the apparent ability of urodeles to regulate genes in such a highly co-ordinated fashion so as to replace lost, differentiated, appendicular structures in adult animals may assist, at least in part, in better elucidating the phenomenon of epimorphic
Dawson, Amy J; Miotke, Jill A; Meyer, Ronald L
A great deal of effort has been invested in using trophic factors and other bioactive molecules to promote cell survival and axonal regeneration in the adult central nervous system. Far less attention has been paid to investigating potential effects that trophic factors may have that might interfere with recovery. In the visual system, BDNF has been previously reported to prevent regeneration. To test if BDNF is inherently incompatible with regeneration, BDNF was given intraocularly during optic nerve regeneration in the adult goldfish. In vivo imaging and anatomical analysis of selectively labeled axons were used as a sensitive assay for effects on regeneration within the tectum. BDNF had no detectable inhibitory effect on the ability of axons to regenerate. Normal numbers of axons regenerated into the tectum, exhibited dynamic growth and retractions similar to controls, and were able to navigate to their correct target zone in the tectum. However, BDNF was found to have additional effects that adversely affected the quality of regeneration. It promoted premature branching at ectopic locations, diminished the growth rate of axons through the tectum, and resulted in the formation of ectopic collaterals. Thus, although BDNF has robust effects on axonal behavior, it is, nevertheless, compatible with axonal regeneration, axon navigation and the formation of terminal arbors.
Tang, Elieza G.; Arany, Praveen R.
Low level light therapy (LLLT) has been widely reported to reduce pain and inflammation and enhance wound healing and tissue regeneration in various settings. LLLT has been noted to have both stimulatory and inhibitory biological effects and these effects have been termed Photobiomodulation (PBM). Several elegant studies have shown the key role of Cytochrome C oxidase and ROS in initiating this process. The downstream biological responses remain to be clearly elucidated. Our work has demonstrated activation of an endogenous latent growth factor complex, TGF-β1, as one of the major biological events in PBM. TGF-β1 has critical roles in various biological processes especially in inflammation, immune responses, wound healing and stem cell biology. This paper overviews some of the studies demonstrating the efficacy of PBM in promoting tissue regeneration.
Anversa, Piero; Kajstura, Jan; Rota, Marcello; Leri, Annarosa
This article discusses current understanding of myocardial biology, emphasizing the regeneration potential of the adult human heart and the mechanisms involved. In the last decade, a novel conceptual view has emerged. The heart is no longer considered a postmitotic organ, but is viewed as a self-renewing organ characterized by a resident stem cell compartment responsible for tissue homeostasis and cardiac repair following injury. Additionally, HSCs possess the ability to transdifferentiate and acquire the cardiomyocyte, vascular endothelial, and smooth muscle cell lineages. Both cardiac and hematopoietic stem cells may be used therapeutically in an attempt to reverse the devastating consequences of chronic heart failure of ischemic and nonischemic origin. PMID:23281411
Ramer, Matt S; Bishop, Thomas; Dockery, Peter; Mobarak, Makarim S; O'Leary, Donald; Fraher, John P; Priestley, John V; McMahon, Stephen B
Injured dorsal root axons fail to regenerate into the adult spinal cord, leading to permanent sensory loss. We investigated the ability of intrathecal neurotrophin-3 (NT3) to promote axonal regeneration across the dorsal root entry zone (DREZ) and functional recovery in adult rats. Quantitative electron microscopy showed robust penetration of CNS tissue by regenerating sensory axons treated with NT3 at 1 and 2 weeks postrhizotomy. Light and electron microscopical anterograde tracing experiments showed that these axons reentered appropriate and ectopic laminae of the dorsal horn, where they formed vesicle-filled synaptic buttons. Cord dorsum potential recordings confirmed that these were functional. In behavioral studies, NT3-treated (but not untreated or vehicle-treated) rats regained proprioception. Recovery depended on NT3-mediated sensory regeneration: preventing regeneration by root excision prevented recovery. NT3 treatment allows sensory axons to overcome inhibition present at the DREZ and may thus serve to promote functional recovery following dorsal root avulsions in humans.
Roychoudhury, Subir (Inventor); Perry, Jay (Inventor); Walsh, Dennis (Inventor)
A method for regenerable adsorption includes providing a substrate that defines at least one layer of ultra short channel length mesh capable of conducting an electrical current therethrough, coating at least a portion of the substrate with a desired sorbent for trace contaminant control or CO.sub.2 sorption, resistively heating the substrate, and passing a flowstream through the substrate and in contact with the sorbent.
Chronic periodontitis is a destructive disease that affects the supporting structures of the teeth including periodontal ligament, cementum, and alveolar bone. If left untreated, patients may lose multiple teeth and extensive prosthetic treatment will be required. In order to re-engineer lost tooth-supporting tissues, various therapeutic modalities have been used clinically. Periodontal regeneration procedures including guided tissue regeneration have achieved substantial effects. However, there are several issues to be solved. They are highly technique-sensitive, applicable to limited cases which are susceptible to treatment, and supposed to have relatively low predictability. Therefore, it is necessary to develop new approaches to improve the predictability and effectiveness of regenerative therapies for periodontal tissues. Recently, the concept of tissue engineering has been introduced to restore lost tissues more effectively where the biological process of healing is mimicked. To achieve this, integration of three key elements is required: progenitor/stem cells, growth factors and the extracellular matrix scaffold. Although it has been shown that implantation of bone marrow-derived mesenchymal stem cells into periodontal osseous defects induced regeneration of cementum, periodontal ligament and alveolar bone in dogs, further extensive preclinical studies are required. On the other hand, application of growth factors, particularly basic fibroblast growth factor in the treatment of human periodontitis, is promising and is now in clinical trial. Furthermore, the rate of release of growth factor from the scaffold also can profoundly affect the results of tissue engineering strategies and the development of new materials is expected. In addition, as tissue regenerative potential is negatively regulated by aging, the effects of aging have to be clarified to gain complete regeneration.
Gawriluk, Thomas R; Simkin, Jennifer; Thompson, Katherine L; Biswas, Shishir K; Clare-Salzler, Zak; Kimani, John M; Kiama, Stephen G; Smith, Jeramiah J; Ezenwa, Vanessa O; Seifert, Ashley W
Why mammals have poor regenerative ability has remained a long-standing question in biology. In regenerating vertebrates, injury can induce a process known as epimorphic regeneration to replace damaged structures. Using a 4-mm ear punch assay across multiple mammalian species, here we show that several Acomys spp. (spiny mice) and Oryctolagus cuniculus completely regenerate tissue, whereas other rodents including MRL/MpJ 'healer' mice heal similar injuries by scarring. We demonstrate ear-hole closure is independent of ear size, and closure rate can be modelled with a cubic function. Cellular and genetic analyses reveal that injury induces blastema formation in Acomys cahirinus. Despite cell cycle re-entry in Mus musculus and A. cahirinus, efficient cell cycle progression and proliferation only occurs in spiny mice. Together, our data unite blastema-mediated regeneration in spiny mice with regeneration in other vertebrates such as salamanders, newts and zebrafish, where all healthy adults regenerate in response to injury.
Eguchi, Goro; Eguchi, Yukiko; Nakamura, Kenta; Yadav, Manisha C; Millán, José Luis; Tsonis, Panagiotis A
The extent to which adult newts retain regenerative capability remains one of the greatest unanswered questions in the regeneration field. Here we report a long-term lens regeneration project spanning 16 years that was undertaken to address this question. Over that time, the lens was removed 18 times from the same animals, and by the time of the last tissue collection, specimens were at least 30 years old. Regenerated lens tissues number 18 and number 17, from the last and the second to the last extraction, respectively, were analysed structurally and in terms of gene expression. Both exhibited structural properties identical to lenses from younger animals that had never experienced lens regeneration. Expression of mRNAs encoding key lens structural proteins or transcription factors was very similar to that of controls. Thus, contrary to the belief that regeneration becomes less efficient with time or repetition, repeated regeneration, even at old age, does not alter newt regenerative capacity.
Alwes, Frederike; Enjolras, Camille; Averof, Michalis
Regeneration is a complex and dynamic process, mobilizing diverse cell types and remodelling tissues over long time periods. Tracking cell fate and behaviour during regeneration in active adult animals is especially challenging. Here, we establish continuous live imaging of leg regeneration at single-cell resolution in the crustacean Parhyale hawaiensis. By live recordings encompassing the first 4-5 days after amputation, we capture the cellular events that contribute to wound closure and morphogenesis of regenerating legs with unprecedented resolution and temporal detail. Using these recordings we are able to track cell lineages, to generate fate maps of the blastema and to identify the progenitors of regenerated epidermis. We find that there are no specialized stem cells for the epidermis. Most epidermal cells in the distal part of the leg stump proliferate, acquire new positional values and contribute to new segments in the regenerating leg. DOI: http://dx.doi.org/10.7554/eLife.19766.001 PMID:27776632
Tu, Michelle Kim; Borodinsky, Laura Noemi
Tissue regeneration entails replenishing of damaged cells, appropriate cell differentiation and inclusion of regenerated cells into functioning tissues. In adult humans, the capacity of the injured spinal cord and muscle to self-repair is limited. In contrast, the amphibian larva can regenerate its tail after amputation with complete recovery of muscle, notochord and spinal cord. The cellular and molecular mechanisms underlying this phenomenon are still unclear. Here we show that upon injury muscle cell precursors exhibit Ca(2+) transients that depend on Ca(2+) release from ryanodine receptor-operated stores. Blockade of these transients impairs muscle regeneration. Furthermore, inhibiting Ca(2+) transients in the regenerating tail prevents the activation and proliferation of muscle satellite cells, which results in deficient muscle replenishment. These findings suggest that Ca(2+)-mediated activity is critical for the early stages of muscle regeneration, which may lead to developing effective therapies for tissue repair.
Chen, William C. W.; Wang, Zhouguang; Missinato, Maria Azzurra; Park, Dae Woo; Long, Daniel Ward; Liu, Heng-Jui; Zeng, Xuemei; Yates, Nathan A.; Kim, Kang; Wang, Yadong
Heart attack is a global health problem that leads to significant morbidity, mortality, and health care burden. Adult human hearts have very limited regenerative capability after injury. However, evolutionarily primitive species generally have higher regenerative capacity than mammals. The extracellular matrix (ECM) may contribute to this difference. Mammalian cardiac ECM may not be optimally inductive for cardiac regeneration because of the fibrotic, instead of regenerative, responses in injured adult mammalian hearts. Given the high regenerative capacity of adult zebrafish hearts, we hypothesize that decellularized zebrafish cardiac ECM (zECM) made from normal or healing hearts can induce mammalian heart regeneration. Using zebrafish and mice as representative species of lower vertebrates and mammals, we show that a single administration of zECM, particularly the healing variety, enables cardiac functional recovery and regeneration of adult mouse heart tissues after acute myocardial infarction. zECM-treated groups exhibit proliferation of the remaining cardiomyocytes and multiple cardiac precursor cell populations and reactivation of ErbB2 expression in cardiomyocytes. Furthermore, zECM exhibits pro-proliferative and chemotactic effects on human cardiac precursor cell populations in vitro. These contribute to the structural preservation and correlate with significantly higher cardiac contractile function, notably less left ventricular dilatation, and substantially more elastic myocardium in zECM-treated hearts than control animals treated with saline or decellularized adult mouse cardiac ECM. Inhibition of ErbB2 activity abrogates beneficial effects of zECM administration, indicating the possible involvement of ErbB2 signaling in zECM-mediated regeneration. This study departs from conventional focuses on mammalian ECM and introduces a new approach for cardiac tissue regeneration. PMID:28138518
Qin, Zhao; Barthel, Linda K; Raymond, Pamela A
In a microarray-based gene profiling analysis of Müller glia-derived retinal stem cells in light-damaged retinas from adult zebrafish, we found that 2 genes required for regeneration of fin and heart tissues in zebrafish, hspd1 (heat shock 60-kDa protein 1) and mps1 (monopolar spindle 1), were up-regulated. Expression of both genes in the neurogenic Müller glia and progenitors was independently verified by quantitative reverse transcriptase PCR and in situ hybridization. Functional analysis of temperature-sensitive mutants of hspd1 and mps1 revealed that both are necessary for Müller glia-based cone photoreceptor regeneration in adult zebrafish retina. In the amputated fin, hspd1 is required for the induction of mesenchymal stem cells and blastema formation, whereas mps1 is required at a later step for rapid cell proliferation and outgrowth. This temporal sequence of hspd1 and mps1 function is conserved in the regenerating retina. Comparison of gene expression profiles from regenerating zebrafish retina, caudal fin, and heart muscle revealed additional candidate genes potentially implicated in injury-induced epimorphic regeneration in diverse zebrafish tissues.
Brockes, Jeremy P; Gates, Phillip B
Limb regeneration in adult salamanders proceeds by formation of a mound of progenitor cells called the limb blastema. It provides several pointers for regenerative medicine. These include the role of differentiated cells in the origin of the blastema, the role of regenerating axons of peripheral nerves and the importance of cell specification in conferring morphogenetic autonomy on the blastema. One aspect of regeneration that has received less attention is the ability to undergo multiple episodes without detectable change in the outcome, and with minimal effect of aging. We suggest that, although such pointers are valuable, it is important to understand why salamanders are the only adult tetrapod vertebrates able to regenerate their limbs. Although this remains a controversial issue, the existence of salamander-specific genes that play a significant role in the mechanism of regeneration provides evidence for the importance of local evolution, rather than a purely ancestral mechanism. The three-finger protein called Prod1 is discussed in the present article as an exemplar of this approach.
Gnecchi, Massimiliano; Pisano, Federica; Bariani, Riccardo
Heart diseases are a very common health problem in developed as well as developing countries. In particular, ischemic heart disease and heart failure represent a plague for the patients and for the society. Loss of cardiac tissue after myocardial infarction or dysfunctioning tissue in nonischemic cardiomyopathies may result in cardiac failure. Despite great advancements in the treatment of these diseases, there is a substantial unmet need for novel therapies, ideally addressing repair and regeneration of the damaged or lost myocardium. Along this line, cardiac cell based therapies have gained substantial attention. Three main approaches are currently under investigation: stem cell therapy with either embryonic or adult stem cells; generation of patient-specific induced pluripotent stem cells; stimulation of endogenous regeneration trough direct reprogramming of fibroblasts into cardiomyocytes, activation of resident cardiac stem cells or induction of native resident cardiomyocytes to reenter the cell cycle. All these strategies need to be optimized since their efficiency is low.It has recently become clear that cardiac signaling and transcriptional pathways are intimately intertwined with microRNA molecules which act as modulators of cardiac development, function, and disease. Moreover, miRNA also regulates stem cell differentiation. Here we describe how miRNA may circumvent hurdles that hamper the field of cardiac regeneration and stem cell therapy, and how miRNA may result as the most suitable solution for the damaged heart.
Vadalà, Gianluca; Russo, Fabrizio; Ambrosio, Luca; Loppini, Mattia; Denaro, Vincenzo
Intervertebral disc regeneration field is rapidly growing since disc disorders represent a major health problem in industrialized countries with very few possible treatments. Indeed, current available therapies are symptomatic, and surgical procedures consist in disc removal and spinal fusion, which is not immune to regardable concerns about possible comorbidities, cost-effectiveness, secondary risks and long-lasting outcomes. This review paper aims to share recent advances in stem cell therapy for the treatment of intervertebral disc degeneration. In literature the potential use of different adult stem cells for intervertebral disc regeneration has already been reported. Bone marrow mesenchymal stromal/stem cells, adipose tissue derived stem cells, synovial stem cells, muscle-derived stem cells, olfactory neural stem cells, induced pluripotent stem cells, hematopoietic stem cells, disc stem cells, and embryonic stem cells have been studied for this purpose either in vitro or in vivo. Moreover, several engineered carriers (e.g., hydrogels), characterized by full biocompatibility and prompt biodegradation, have been designed and combined with different stem cell types in order to optimize the local and controlled delivery of cellular substrates in situ. The paper overviews the literature discussing the current status of our knowledge of the different stem cells types used as a cell-based therapy for disc regeneration. PMID:27247704
Periodontitis is a major chronic inflammatory disorder that can lead to the destruction of the periodontal tissues and, ultimately, tooth loss. It is a major cause of tooth loss in adults and a substantial public-health burden worldwide. There is thus a significant need for periodontal ligament (PDL) regeneration to enable functional mechanical support of tooth prostheses and prevent occlusal overloading. The goal of stem cell-based dental tissue engineering, is to create tooth-like structures using scaffold materials to guide the dental stem cells. Current resorbable membranes act as an epithelial tissue down-growth into the defect, favoring the regeneration of periodontal tissues. In order to develop synthetic grafts for these applications, different biocompatible materials have been used to fabricate fibers with different structures and morphologies. This study demonstrated the feasibility of using a composite material that combines the advantage of multiple materials to synthesize polyvinyl alcohol/ chitosan blend fiber scaffolds to promote PDL regeneration and to achieve a synthetic composite that match the native PDL modulus. Morphology, dispersibility, and mechanical properties of blend nanofibrous mats were characterized by scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy and tensile test.
Vanden Berg-Foels, Wendy S
Tissue engineering uses cells, signaling molecules, and/or biomaterials to regenerate injured or diseased tissues. Ex vivo expanded mesenchymal stem cells (MSC) have long been a cornerstone of regeneration therapies; however, drawbacks that include altered signaling responses and reduced homing capacity have prompted investigation of regeneration based on endogenous MSC recruitment. Recent successful proof-of-concept studies have further motivated endogenous MSC recruitment-based approaches. Stem cell migration is required for morphogenesis and organogenesis during development and for tissue maintenance and injury repair in adults. A biomimetic approach to in situ tissue regeneration by endogenous MSC requires the orchestration of three main stages: MSC recruitment, MSC differentiation, and neotissue maturation. The first stage must result in recruitment of a sufficient number of MSC, capable of effecting regeneration, to the injured or diseased tissue. One of the challenges for engineering endogenous MSC recruitment is the selection of effective chemoattractant(s). The objective of this review is to synthesize and evaluate evidence of recruitment efficacy by reported chemoattractants, including growth factors, chemokines, and other more recently appreciated MSC chemoattractants. The influence of MSC tissue sources, cell culture methods, and the in vitro and in vivo environments is discussed. This growing body of knowledge will serve as a basis for the rational design of regenerative therapies based on endogenous MSC recruitment. Successful endogenous MSC recruitment is the first step of successful tissue regeneration.
Hughes, F J; Ghuman, M; Talal, A
Periodontitis affects around 15 per cent of human adult populations. While periodontal treatment aimed at removing the bacterial cause of the disease is generally very successful, the ability predictably to regenerate the damaged tissues remains a major unmet objective for new treatment strategies. Existing treatments include the use of space-maintaining barrier membranes (guided tissue regeneration), use of graft materials, and application of bioactive molecules to induce regeneration, but their overall effects are relatively modest and restricted in application. The periodontal ligament is rich in mesenchymal stem cells, and the understanding of the signalling molecules that may regulate their differentation has increased enormously in recent years. Applying these principles for the development of new tissue engineering strategies for periodontal regeneration will require further work to determine the efficacy of current experimental preclinical treatments, including pharmacological application of growth factors such as bone morphogenetic proteins (BMPs) or Wnts, use of autologous stem cell reimplantation strategies, and development of improved biomaterial scaffolds. This article describes the background to this problem, addresses the current status of periodontal regeneration, including the background biology, and discusses the potential for some of these experimental therapies to achieve the goal of clinically predictable periodontal regeneration.
Parisi, Ludovica; Manfredi, Edoardo
Within the nervous system, regeneration is limited, and this is due to the small amount of neural stem cells, the inhibitory origin of the stem cell niche and often to the development of a scar which constitutes a mechanical barrier for the regeneration. Regarding these aspects, many efforts have been done in the research of a cell component that combined with scaffolds and growth factors could be suitable for nervous regeneration in regenerative medicine approaches. Autologous mesenchymal stem cells represent nowadays the ideal candidate for this aim, thank to their multipotency and to their amount inside adult tissues. However, issues in their harvesting, through the use of invasive techniques, and problems involved in their ageing, require the research of new autologous sources. To this purpose, the recent discovery of a stem cells component in teeth, and which derive from neural crest cells, has came to the light the possibility of using dental stem cells in nervous system regeneration. In this work, in order to give guidelines on the use of dental stem cells for neural regeneration, we briefly introduce the concepts of regeneration and regenerative medicine, we then focus the attention on odontogenesis, which involves the formation and the presence of a stem component in different parts of teeth, and finally we describe some experimental approaches which are exploiting dental stem cells for neural studies. PMID:28123398
Guardiola, Ombretta; Andolfi, Gennaro; Tirone, Mario; Iavarone, Francescopaolo; Brunelli, Silvia; Minchiotti, Gabriella
Skeletal muscle regeneration is a physiological process that occurs in adult skeletal muscles in response to injury or disease. Acute injury-induced skeletal muscle regeneration is a widely used, powerful model system to study the events involved in muscle regeneration as well as the mechanisms and different players. Indeed, a detailed knowledge of this process is essential for a better understanding of the pathological conditions that lead to skeletal muscle degeneration, and it aids in identifying new targeted therapeutic strategies. The present work describes a detailed and reproducible protocol to induce acute skeletal muscle regeneration in mice through a single intramuscular injection of cardiotoxin (CTX). CTX belongs to the family of snake venom toxins and causes myolysis of myofibers, which eventually triggers the regeneration events. The dynamics of skeletal muscle regeneration is evaluated by histological analysis of muscle sections. The protocol also illustrates the experimental procedures for dissecting, freezing, and cutting the Tibialis Anterior muscle, as well as the routine Hematoxylin & Eosin staining that is widely used for subsequent morphological and morphometric analysis.
Yildirim, Sibel; Fu, Susan Y; Kim, Keith; Zhou, Hong; Lee, Chang Hun; Li, Ang; Kim, Sahng Gyoon; Wang, Shuang; Mao, Jeremy J
A tooth is a complex biological organ and consists of multiple tissues including the enamel, dentin, cementum and pulp. Tooth loss is the most common organ failure. Can a tooth be regenerated? Can adult stem cells be orchestrated to regenerate tooth structures such as the enamel, dentin, cementum and dental pulp, or even an entire tooth? If not, what are the therapeutically viable sources of stem cells for tooth regeneration? Do stem cells necessarily need to be taken out of the body, and manipulated ex vivo before they are transplanted for tooth regeneration? How can regenerated teeth be economically competitive with dental implants? Would it be possible to make regenerated teeth affordable by a large segment of the population worldwide? This review article explores existing and visionary approaches that address some of the above-mentioned questions. Tooth regeneration represents a revolution in stomatology as a shift in the paradigm from repair to regeneration: repair is by metal or artificial materials whereas regeneration is by biological restoration. Tooth regeneration is an extension of the concepts in the broad field of regenerative medicine to restore a tissue defect to its original form and function by biological substitutes. PMID:21789959
Introduction Regeneration is a widespread phenomenon in the animal kingdom, but the capacity to restore damaged or missing tissue varies greatly between different phyla and even within the same phylum. However, the distantly related Acoelomorpha and Platyhelminthes share a strikingly similar stem-cell system and regenerative capacity. Therefore, comparing the underlying mechanisms in these two phyla paves the way for an increased understanding of the evolution of this developmental process. To date, Isodiametra pulchra is the most promising candidate as a model for the Acoelomorpha, as it reproduces steadily under laboratory conditions and is amenable to various techniques, including the silencing of gene expression by RNAi. In order to provide an essential framework for future studies, we report the succession of regeneration events via the use of cytochemical, histological and microscopy techniques, and specify the total number of cells in adult individuals. Results Isodiametra pulchra is not capable of regenerating a new head, but completely restores all posterior structures within 10 days. Following amputation, the wound closes via the contraction of local muscle fibres and an extension of the dorsal epidermis. Subsequently, stem cells and differentiating cells invade the wound area and form a loosely delimited blastema. After two days, the posterior end is re-patterned with the male (and occasionally the female) genital primordium being apparent. Successively, these primordia differentiate into complete copulatory organs. The size of the body and also of the male and female copulatory organs, as well as the distance between the copulatory organs, progressively increase and by nine days copulation is possible. Adult individuals with an average length of 670 μm consist of approximately 8100 cells. Conclusion Isodiametra pulchra regenerates through a combination of morphallactic and epimorphic processes. Existing structures are “re-modelled” and provide a
Harel, Noam Y.; Strittmatter, Stephen M.
The precise wiring of the adult mammalian CNS originates during a period of stunning growth, guidance and plasticity that occurs during and shortly after development. When injured in adults, this intricate system fails to regenerate. Even when the obstacles to regeneration are cleared, growing adult CNS fibres usually remain misdirected and fail to reform functional connections. Here, we attempt to fill an important niche related to the topics of nervous system development and regeneration. We specifically contrast the difficulties faced by growing fibres within the adult context to the precise circuit-forming capabilities of developing fibres. In addition to focusing on methods to stimulate growth in the adult, we also expand on approaches to recapitulate development itself. PMID:16858389
Colombo, G. V.; Putnam, D. F.
Iodine-dispensing resin can be regenerated after iodine content has been depleted, without being removed from water system. Resin is used to make water potable by killing bacteria, fungi, and viruses. Regeneration technique may be come basis of water purifier for very long space missions. Enough crystalline iodine for multiple regenerations during mission can be stored in one small cartridge. Cartridge could be inserted in waterline as necessary on signal from iodine monitor or timer.
Mechling, Linda C.; Seid, Nicole H.
The purpose of this study was to evaluate use of a personal digital assistant (PDA) with picture, auditory, and video prompts as a portable self-prompting device to facilitate independent pedestrian travel by three high school age students with moderate intellectual disabilities. Using a multiple probe design across three destinations and their…
Maderson, Paul F A; Hillenius, Willem J; Hiller, Uwe; Dove, Carla C
Understanding of the regeneration of feathers, despite a 140 year tradition of study, has remained substantially incomplete. Moreover, accumulated errors and mis-statements in the literature have confounded the intrinsic difficulties in describing feather regeneration. Lack of allusion to Rudall's (Rudall  Biochem Biophys Acta 1:549-562) seminal X-ray diffraction study that revealed two distinct keratins, beta- and alpha-, in a mature feather, is one of the several examples where lack of citation long inhibited progress in understanding. This article reviews and reevaluates the available literature and provides a synthetic, comprehensive, morphological model for the regeneration of a generalized, adult contour feather. Particular attention is paid to several features that have previously been largely ignored. Some of these, such as the beta-keratogenic sheath and the alpha-keratogenic, supra-umbilical, pulp caps, are missing from mature, functional feathers sensu stricto because they are lost through preening, but these structures nevertheless play a critical role in development. A new developmental role for a tissue unique to feathers, the medullary pith of the rachis and barb rami, and especially its importance in the genesis of the superior umbilical region (SUR) that forms the transition from the spathe (rachis and vanes) to the calamus, is described. It is postulated that feathers form through an intricate interplay between cyto- and histodifferentiative processes, determined by patterning signals that emanate from the dermal core, and a suite of interacting biomechanical forces. Precisely regulated patterns of loss of intercellular adhesivity appear to be the most fundamental aspect of feather morphogenesis and regeneration: rather than a hierarchically branched structure, it appears more appropriate to conceive of feathers as a sheet of mature keratinocytes that is "full of holes.
Neff, Anton W; King, Michael W; Harty, Mark W; Nguyen, Trent; Calley, John; Smith, Rosamund C; Mescher, Anthony L
The multi-C2H2 zinc-finger domain containing transcriptional regulators of the spalt (SAL) family plays important developmental regulatory roles. In a competitive subtractive hybridization screen of genes expressed in Xenopus laevis hindlimb regeneration blastemas, we identified a SAL family member that, by phylogenetic analysis, falls in the same clade as human SALL4 and have designated it as XlSALL4. Mutations of human SALL4 have been linked to Okihiro syndrome, which includes preaxial (anterior) limb defects. The expression pattern of XlSALL4 transcripts during normal forelimb and hindlimb development and during hindlimb regeneration at the regeneration-competent and regeneration-incompetent stages is temporally and regionally dynamic. We show for the first time that a SAL family member (XlSALL4) is expressed at the right place and time to play a role regulating both digit identity along the anterior/posterior axis and epimorphic limb regeneration.
Pellettieri, Jason; Fitzgerald, Patrick; Watanabe, Shigeki; Mancuso, Joel; Green, Douglas R; Sánchez Alvarado, Alejandro
Many long-lived organisms, including humans, can regenerate some adult tissues lost to physical injury or disease. Much of the previous research on mechanisms of regeneration has focused on adult stem cells, which give rise to new tissue necessary for the replacement of missing body parts. Here we report that apoptosis of differentiated cells complements stem cell division during regeneration in the planarian Schmidtea mediterranea. Specifically, we developed a whole-mount TUNEL assay that allowed us to document two dramatic increases in the rate of apoptosis following amputation-an initial localized response near the wound site and a subsequent systemic response that varies in magnitude depending on the type of fragment examined. The latter cell death response can be induced in uninjured organs, occurs in the absence of planarian stem cells, and can also be triggered by prolonged starvation. Taken together, our results implicate apoptosis in the restoration of proper anatomical scale and proportion through remodeling of existing tissues. We also report results from initial mechanistic studies of apoptosis in planarians, which revealed that a S. mediterranea homolog of the antiapoptotic gene BCL2 is required for cell survival in adult animals. We propose that apoptosis is a central mechanism working in concert with stem cell division to restore anatomical form and function during metazoan regeneration.
Regeneration therapy can be classified into three categories. The first category, in vitro regeneration therapy, makes use of transplanted cultured cells, including embryonic stem (ES) cells, pancreatic precursor cells and beta-cell lines, in conjunction with immunosuppressive therapy or immunoisolation for the treatment of patients with Type 1 diabetes. In the second type of regeneration therapy, ex vivo regeneration therapy, a patient's own cells, such as bone marrow stem cells, are transiently removed and induced to differentiate into beta-cells in vitro. However, at the present time, insulin-producing cells cannot be generated from bone marrow stem cells. In vivo regeneration therapy, the third type of regeneration therapy, enables impaired tissue to regenerate from a patient's own cells in vivo. beta-Cell neogenesis from non-beta-cells, and beta-cell proliferation in vivo have been considered in particular as regeneration therapies for patients with Type 2 diabetes. Regeneration therapy for pancreatic beta-cells can be combined with various other therapeutic strategies, including islet transplantation, cell-based therapy, gene therapy and drug therapy, to promote beta-cell proliferation and neogenesis; it is hoped that these strategies will, in the future, provide a cure for diabetes.
Candas, E.; Flacke, J.; Yomralioglu, T.
In Turkey, rapid population growth, informal settlements, and buildings and infrastructures vulnerable to natural hazards are seen as the most important problems of cities. Particularly disaster risk cannot be disregarded, as large parts of various cities are facing risks from earthquakes, floods and landslides and have experienced loss of lives in the recent past. Urban regeneration is an important planning tool implemented by local and central governments in order to reduce to disaster risk and to design livable environments for the citizens. The Law on the Regeneration of Areas under Disaster Risk, commonly known as the Urban Regeneration Law, was enacted in 2012 (Law No.6306, May 2012). The regulation on Implementation of Law No. 6306 explains the fundamental steps of the urban regeneration process. The relevant institutions furnished with various authorities such as expropriation, confiscation and changing the type and place of your property which makes urban regeneration projects very important in terms of property rights. Therefore, urban regeneration projects have to be transparent, comprehensible and acceptable for all actors in the projects. In order to understand the urban regeneration process, the legislation and projects of different municipalities in Istanbul have been analyzed. While some steps of it are spatial data demanding, others relate to land values. In this paper an overview of the urban regeneration history and activities in Turkey is given. Fundamental steps of the urban regeneration process are defined, and particularly spatial-data demanding steps are identified.
Naaz, Afshan; Shahzad, Anwar; Anis, Mohammad
An efficient method for cloning Syzygium cumini (above 40 years old) through mature nodal segments has been successfully developed and that could be exploited for large-scale production of this valuable multipurpose tree. Nodal segments from mature tree were taken as explants and cultured on MS basal medium with different cytokinins (BA, Kin, AdS). The application of BA proved to be the best responsive cytokinin for the induction of shoot buds and shoots, but the proliferated shoots exhibited slower and stunted growth accompanied with abscission of leaves and shoot tip necrosis (STN). The problem of leaf abscission and STN was considerably reduced by the application of an adjuvant, adenine sulphate (AdS) in the optimal medium which led to the production of a maximum of 14 shoots. Further improvement in shoot bud regeneration and improved growth pattern of the regenerating tissue was obtained on the media comprised of MS + BA (10 μM) + GA3 (2.5 μM). A total number of 15 shoots with mean shoot length of 5.9 cm was obtained. The healthy elongated shoots were then rooted on MS basal augmented with NAA (5 μM). The plantlets obtained were healthy and were successfully acclimatized and transferred under field condition with 70 % survival rate.
Daniel, Gregory B
Medical imaging is rapidly moving toward a digital-based image system. An understanding of the principles of digital imaging is necessary to evaluate features of imaging systems and can play an important role in purchasing decisions.
Vasil'ev, A Iu; Bulanova, I M; Mal'ginov, N N; Tarasenko, I V; Tarasenko, S V; Kiseleva, E V; Drobyshev, A Iu; Volozhin, A I
In experiment on 16 grown-up chinchilla rabbits the dynamic of reparative regeneration was evaluated by digital microfocal rontgenography in the terms of 1, 2 and 4 months. Bone defect of the 8capital CHE, Cyrillic8 mm size in the region of mandible angle was caused by surgical laser Smart 2940 D+ on the right side and by physiodespenser Surgec XT on the left side. Surgical laser use let to reduce intact mother bone traumatisation and to improve remote results of bone tissue regeneration. After bone defect creation bone tissue regeneration was put into effect by all 3 callus types - endosteal, periosteal and intermediary.
Carter, D R; Beaupré, G S; Giori, N J; Helms, J A
Skeletal regeneration is accomplished by a cascade of biologic processes that may include differentiation of pluripotential tissue, endochondral ossification, and bone remodeling. It has been shown that all these processes are influenced strongly by the local tissue mechanical loading history. This article reviews some of the mechanobiologic principles that are thought to guide the differentiation of mesenchymal tissue into bone, cartilage, or fibrous tissue during the initial phase of regeneration. Cyclic motion and the associated shear stresses cause cell proliferation and the production of a large callus in the early phases of fracture healing. For intermittently imposed loading in the regenerating tissue: (1) direct intramembranous bone formation is permitted in areas of low stress and strain; (2) low to moderate magnitudes of tensile strain and hydrostatic tensile stress may stimulate intramembranous ossification; (3) poor vascularity can promote chondrogenesis in an otherwise osteogenic environment; (4) hydrostatic compressive stress is a stimulus for chondrogenesis; (5) high tensile strain is a stimulus for the net production of fibrous tissue; and (6) tensile strain with a superimposed hydrostatic compressive stress will stimulate the development of fibrocartilage. Finite element models are used to show that the patterns of tissue differentiation observed in fracture healing and distraction osteogenesis can be predicted from these fundamental mechanobiologic concepts. In areas of cartilage formation, subsequent endochondral ossification normally will proceed, but it can be inhibited by intermittent hydrostatic compressive stress and accelerated by octahedral shear stress (or strain). Later, bone remodeling at these sites can be expected to follow the same mechanobiologic adaptation rules as normal bone.
Andone, Diana; Dron, Jon; Pemberton, Lyn; Boyne, Chris
While most existing online learning environments cater for needs identified during the 1990s, a new generation of digital students has emerged in the developed world. Digital students are young adults who have grown up with digital technologies integrated as an everyday feature of their lives. Digital students use technology differently, fluidly…
Gray, McMahan; Champagne, Kenneth J.; Fauth, Daniel; Beckman, Eric
Two new classes of amine-based sorbents are disclosed. The first class comprises new polymer-immobilized tertiary amine sorbents; the second class new polymer-bound amine sorbents. Both classes are tailored to facilitate removal of acid anhydrides, especially carbon dioxide (CO.sub.2), from effluent gases. The amines adsorb acid anhydrides in a 1:1 molar ratio. Both classes of amine sorbents adsorb in the temperature range from about 20.degree. C. upwards to 90.degree. C. and can be regenerated by heating upwards to 100.degree. C.
Yang, Arthur Jing-Min; Zhang, Yuehua
A nanoporous reactive adsorbent incorporates a relatively small number of relatively larger reactant, e.g. metal, enzyme, etc. particles (10) forming a discontinuous or continuous phase interspersed among and surrounded by a continuous phase of smaller adsorbent particles (12) and connected interstitial pores (14) therebetween. The reactive adsorbent can effectively remove inorganic or organic impurities in a liquid by causing the liquid to flow through the adsorbent. For example, silver ions may be adsorbed by the adsorbent particles (12) and reduced to metallic silver by reducing metal, such as irons, as the reactant particles (10). The column can be regenerated by backwashing with the liquid effluent containing, for example, acetic acid.
Defines a digital photograph as a numerical record of light electronically measured and recorded by a computer's scanner. States that most personal computers cannot do digital photography successfully and that digital pictures can be hard to manage and present a storage problem. Finds that, once the school has the hardware/software, picture…
Isman, Aytekin; Canan Gungoren, Ozlem
Era in which we live is known and referred as digital age.In this age technology is rapidly changed and developed. In light of these technological advances in 21st century, schools have the responsibility of training "digital citizen" as well as a good citizen. Digital citizens must have extensive skills, knowledge, Internet and …
Kim, Tae Beom; Kim, Khae Hawn
Second to fourth digit ratio is the ratio of second to fourth digit length. It has been known that digit ratio is sexually dimorphic in humans, such that males tend to have lower digit ratio (longer fourth digits relative to second digits) than females. Digit ratio is thought to be a biomarker of the balance between fetal testosterone (FT) and fetal estrogen (FE) in a relatively narrow developmental window at the end of the first trimester of pregnancy. On the contrary, the relationships between digit ratio and levels of sex steroids in adults are not clear. Most correlational studies between digit ratio and adult sex steroids have revealed that this association is statistically not significant. However, for many years, a lot of researches showed negative relationships between digit ratio and sports performance such as rugby, surfing, rowing, sprinting, endurance, and hand grip strength. Here, we discuss possible mechanisms about the relationships between digit ratio and sports performance. PMID:28119871
Kim, Tae Beom; Kim, Khae Hawn
Second to fourth digit ratio is the ratio of second to fourth digit length. It has been known that digit ratio is sexually dimorphic in humans, such that males tend to have lower digit ratio (longer fourth digits relative to second digits) than females. Digit ratio is thought to be a biomarker of the balance between fetal testosterone (FT) and fetal estrogen (FE) in a relatively narrow developmental window at the end of the first trimester of pregnancy. On the contrary, the relationships between digit ratio and levels of sex steroids in adults are not clear. Most correlational studies between digit ratio and adult sex steroids have revealed that this association is statistically not significant. However, for many years, a lot of researches showed negative relationships between digit ratio and sports performance such as rugby, surfing, rowing, sprinting, endurance, and hand grip strength. Here, we discuss possible mechanisms about the relationships between digit ratio and sports performance.
Chen, Nuan; Tian, Lingling; He, Liumin; Ramakrishna, Seeram
Diseases and disorders associated with nervous system such as injuries by trauma and neurodegeneration are shown to be one of the most serious problems in medicine, requiring innovative strategies to trigger and enhance the nerve regeneration. Tissue engineering aims to provide a highly biomimetic environment by using a combination of cells, materials and suitable biological cues, by which the lost body part may be regenerated or even fully rebuilt. Electrospinning, being able to produce extracellular matrix (ECM)-like nanostructures with great flexibility in design and choice of materials, have demonstrated their great potential for fabrication of nerve tissue engineered scaffolds. The review here begins with a brief description of the anatomy of native nervous system, which provides basic knowledge and ideas for the design of nerve tissue scaffolds, followed by five main parts in the design of electrospun nerve tissue engineered scaffolds including materials selection, structural design, in vitro bioreactor, functionalization and cellular support. Performances of biomimetic electrospun nanofibrous nerve implant devices are also reviewed. Finally, future directions for advanced electrospun nerve tissue engineered scaffolds are discussed.
Chen, Nuan; Tian, Lingling; He, Liumin; Ramakrishna, Seeram
Diseases and disorders associated with nervous system such as injuries by trauma and neurodegeneration are shown to be one of the most serious problems in medicine, requiring innovative strategies to trigger and enhance the nerve regeneration. Tissue engineering aims to provide a highly biomimetic environment by using a combination of cells, materials and suitable biological cues, by which the lost body part may be regenerated or even fully rebuilt. Electrospinning, being able to produce extracellular matrix (ECM)-like nanostructures with great flexibility in design and choice of materials, have demonstrated their great potential for fabrication of nerve tissue engineered scaffolds. The review here begins with a brief description of the anatomy of native nervous system, which provides basic knowledge and ideas for the design of nerve tissue scaffolds, followed by five main parts in the design of electrospun nerve tissue engineered scaffolds including materials selection, structural design, in vitro bioreactor, functionalization and cellular support. Performances of biomimetic electrospun nanofibrous nerve implant devices are also reviewed. Finally, future directions for advanced electrospun nerve tissue engineered scaffolds are discussed. PMID:27857724
Jeffery, William R
Regeneration studies in the tunicate Ciona intestinalis have recently been focused on the potential of adult stem cells to replace injured tissues and organs during the adult life cycle using the oral siphon (OS) as a model. The OS has oral siphon pigment organs (OPOs) along its rim and an underlying network of muscle fibers in its tube. Different regeneration processes are triggered by OS amputation at the tip, along the tube, or at the base. One process involves the replacement of OPOs without new cell division by direct differentiation of locally deployed stem cells or stem cells that migrate from the branchial sac. Another process involves blastema formation by the migration of progenitor cells produced from branchial sac stem cells. The capacity for complete and accurate OS regeneration declines continuously during the adult life cycle. Finally, after an age threshold is reached, OS regeneration ceases in old animals. The loss of regeneration capacity in old animals involves the depletion of stem cells in the branchial sac, the inability of branchial sac progenitor cells to migrate to the sites of regeneration, and defective oral pigment organ replacement. The significance of the OS model for studying regeneration, stem cells, and aging will be enhanced by the application of molecular methods.
Sauer, Richard L.; Colombo, Gerald V.; Jolly, Clifford D.
Iodinated resin bed for disinfecting water regenerated to extend useful life. Water flows through regeneration bed of crystalline iodine during regeneration. At other times, flow diverted around regeneration bed. Although regeneration cycle manually controlled readily automated to start and stop according to signals from concentration sensors. Further benefit of regeneration is bed provides highly concentrated biocide source when needed. Concentrated biocide used to superiodinate system after contamination from routine maintenance or unexpected introduction of large concentration of microbes.
Thorndyke, M C; Chen, W C; Beesley, P W; Patruno, M
Until very recently echinoderm regeneration research and indeed echinoderm research in general has suffered because of the lack of critical mass. In terms of molecular studies of regeneration, echinoderms in particular have lagged behind other groups in this respect. This is in sharp contrast to the major advances achieved with molecular and genetic techniques in the study of embryonic development in echinoderms. The aim of our studies has been to identify genes involved in the process of regeneration and in particular neural regeneration in different echinoderm species. Our survey included the asteroid Asterias rubens and provided evidence for the expression of Hox gene homologues in regenerating radial nerve cords. Present evidence suggests: 1) ArHox1 expression is maintained in intact radial nerve cord and may be upregulated during regeneration. 2) ArHox1 expression may contribute to the dedifferentiation and/or cell proliferation process during epimorphic regeneration. From the crinoid Antedon bifida, we have been successful in cloning a fragment of a BMP2/4 homologue (AnBMP2/4) and analysing its expression during arm regeneration. Here, we discuss the importance of this family of growth factors in several regulatory spheres, including maintaining the identity of pluripotent blastemal cells or as a classic skeletal morphogenic regulator. There is clearly substantial scope for future echinoderm research in the area of molecular biology and certain aspects are discussed in this review.
Watson, Ian Robert
This research builds upon the discourse surrounding digital natives. A literature review into the digital native phenomena was undertaken and found that researchers are beginning to identify the digital native as not one cohesive group but of individuals influenced by other factors. Primary research by means of questionnaire survey of technologies…
Burns, Joseph C; Stone, Jennifer S
Vestibular sensation is essential for gaze stabilization, balance, and perception of gravity. The vestibular receptors in mammals, Type I and Type II hair cells, are located in five small organs in the inner ear. Damage to hair cells and their innervating neurons can cause crippling symptoms such as vertigo, visual field oscillation, and imbalance. In adult rodents, some Type II hair cells are regenerated and become re-innervated after damage, presenting opportunities for restoring vestibular function after hair cell damage. This article reviews features of vestibular sensory cells in mammals, including their basic properties, how they develop, and how they are replaced after damage. We discuss molecules that control vestibular hair cell regeneration and highlight areas in which our understanding of development and regeneration needs to be deepened.
Radhakrishnan, Janani; Krishnan, Uma Maheswari; Sethuraman, Swaminathan
Tissue engineering promises to be an effective strategy that can overcome the lacuna existing in the current pharmacological and interventional therapies and heart transplantation. Heart failure continues to be a major contributor to the morbidity and mortality across the globe. This may be attributed to the limited regeneration capacity after the adult cardiomyocytes are terminally differentiated or injured. Various strategies involving acellular scaffolds, stem cells, and combinations of stem cells, scaffolds and growth factors have been investigated for effective cardiac tissue regeneration. Recently, injectable hydrogels have emerged as a potential candidate among various categories of biomaterials for cardiac tissue regeneration due to improved patient compliance and facile administration via minimal invasive mode that treats complex infarction. This review discusses in detail on the advances made in the field of injectable materials for cardiac tissue engineering highlighting their merits over their preformed counterparts.
Pessina, Patrizia; Kharraz, Yacine; Jardí, Mercè; Fukada, So-ichiro; Serrano, Antonio L; Perdiguero, Eusebio; Muñoz-Cánoves, Pura
Preservation of cell identity is necessary for homeostasis of most adult tissues. This process is challenged every time a tissue undergoes regeneration after stress or injury. In the lethal Duchenne muscular dystrophy (DMD), skeletal muscle regenerative capacity declines gradually as fibrosis increases. Using genetically engineered tracing mice, we demonstrate that, in dystrophic muscle, specialized cells of muscular, endothelial, and hematopoietic origins gain plasticity toward a fibrogenic fate via a TGFβ-mediated pathway. This results in loss of cellular identity and normal function, with deleterious consequences for regeneration. Furthermore, this fibrogenic process involves acquisition of a mesenchymal progenitor multipotent status, illustrating a link between fibrogenesis and gain of progenitor cell functions. As this plasticity also was observed in DMD patients, we propose that mesenchymal transitions impair regeneration and worsen diseases with a fibrotic component.
Bei, Fengfeng; Lee, Henry Hing Cheong; Liu, Xuefeng; Gunner, Georgia; Jin, Hai; Ma, Long; Wang, Chen; Hou, lijun; Hensch, Takao K.; Frank, Eric; Sanes, Joshua R.; Chen, Chinfei; Fagiolini, Michela; He, Zhigang
Although a number of repair strategies have been shown to promote axon outgrowth following neuronal injury in the mammalian central nervous system, it remains unclear whether regenerated axons establish functional synapses and support behavior. Here, in both juvenile and adult mice, we show that either PTEN and SOCS3 co-deletion, or co-overexpression of osteopontin (OPN)/insulin-like growth factor 1 (IGF1)/ciliary neurotrophic factor (CNTF), induces regrowth of retinal axons and formation of functional synapses in the superior colliculus (SC), but not significant recovery of visual function. Further analyses suggest that regenerated axons fail to conduct action potentials from the eye to the SC due to lack of myelination. Consistent with this idea, administration of voltage-gated potassium channel blockers restores conduction and results in increased visual acuity. Thus, enhancing both regeneration and conduction effectively improves function after optic nerve injury. PMID:26771493
Fernandez, E; Pallini, R; Lauretti, L; La Marca, F; Scogna, A; Rossi, G F
Little is known about the mechanisms at play in nerve regeneration after nerve injury. Personal studies are reported regarding motonuclear changes after regeneration of injured cranial nerves, in particular of the facial and oculomotor nerves, as well as the influence that the natural molecule acetyl-L-carnitine (ALC) has on post-axotomy cranial nerve motoneuron degeneration after facial and vagus nerve lesions. Adult and newborn animal models were used. Massive motoneuron response after nerve section and reconstruction was observed in the motonuclei of all nerves studied. ALC showed to have significant neuroprotective effects on the degeneration of axotomized motoneurons. Complex quantitative, morphological and somatotopic nuclear changes occurred that sustain new hypotheses regarding the capacities of motoneurons to regenerate and the possibilities of new neuron proliferation. The particularities of such observations are described and discussed.
Agata, Kiyokazu; Tasaki, Junichi; Nakajima, Elizabeth; Umesono, Yoshihiko
Planarians have strong regenerative abilities derived from their adult pluripotent stem cell (neoblast) system. However, the molecular mechanisms involved in planarian regeneration have long remained a mystery. In particular, no anterior-specifying factor(s) could be found, although Wnt family proteins had been successfully identified as posterior-specifying factors during planarian regeneration (Gurley et al., 2008; Petersen and Reddien, 2008). A recent textbook of developmental biology therefore proposes a Wnt antagonist as a putative anterior factor (Gilbert, 2013). That is, planarian regeneration was supposed to be explained by a single decreasing gradient of the β-catenin signal from tail to head. However, recently we succeeded in demonstrating that in fact the extracellular-signal regulated kinases (ERK) form a decreasing gradient from head to tail to direct the reorganization of planarian body regionality after amputation (Umesono et al., 2013).
Hu, J. Y.; Wang, W.; Luo, E. C.; Chen, Y. Y.
The regenerator is a key component that transfers energy between heat and work. The conversion efficiency is significantly influenced by the acoustic field in the regenerator. Much effort has been spent to quantitatively determine this influence, but few comprehensive experimental verifications have been performed because of difficulties in modulating and measuring the acoustic field. In this paper, a method requiring two compressors is introduced and theoretically investigated that achieves acoustic field modulation in the regenerator. One compressor outputs the acoustic power for the regenerator; the other acts as a phase shifter. A RC load dissipates the acoustic power out of both the regenerator and the latter compressor. The acoustic field can be modulated by adjusting the current in the two compressors and opening the RC load. The acoustic field is measured with pressure sensors instead of flow-field imaging equipment, thereby greatly simplifying the experiment.
Chen, Zhiguo; Pradhan, Sanjay; Liu, Chiachi; Le, Lu Q
Peripheral nerves have the potential to regenerate axons and reinnervate end organs. Chronic denervation and disturbed nerve regeneration are thought to contribute to peripheral neuropathy, pain, and pruritus in the skin. The capacity of denervated distal nerves to support axonal regeneration requires proliferation by Schwann cells, which guide regenerating axons to their denervated targets. However, adult peripheral nerve Schwann cells do not retain a growth-permissive phenotype, as is required to produce new glia. Therefore, it is believed that following injury, mature Schwann cells dedifferentiate to a progenitor/stem cell phenotype to promote axonal regrowth. In this study, we show that skin-derived precursors (SKPs), a recently identified neural crest-related stem cell population in the dermis of skin, are an alternative source of progenitors for cutaneous nerve regeneration. Using in vivo and in vitro three-dimensional cutaneous nerve regeneration models, we show that the SKPs are neurotropic toward injured nerves and that they have a full capacity to differentiate into Schwann cells and promote axon regeneration. The identification of SKPs as a physiologic source of progenitors for cutaneous nerve regeneration in the skin, where SKPs physiologically reside, has important implications for understanding early cellular events in peripheral nerve regeneration. It also provides fertile ground for the elucidation of intrinsic and extrinsic factors within the nerve microenvironment that likely play essential roles in cutaneous nerve homeostasis.
Chen, Zhiguo; Pradhan, Sanjay; Liu, Chiachi; Le, Lu Q.
Peripheral nerves have the potential to regenerate axons and reinnervate end organs. Chronic denervation and disturbed nerve regeneration are thought to contribute to peripheral neuropathy, pain and pruritus in the skin. The capacity of denervated distal nerves to support axonal regeneration requires proliferation by Schwann cells, which guide regenerating axons to their denervated targets. However, adult peripheral nerve Schwann cells do not retain a growth-permissive phenotype, as is required to produce new glia. Therefore, it is believed that following injury, mature Schwann cells de-differentiate to a progenitor/stem cell phenotype to promote axonal re-growth. In this study, we show that Skin-derived precursors (SKPs), a recently identified neural-crest related stem cell population in the dermis of skin, are an alternative source of progenitors for cutaneous nerve regeneration. Using in vivo and in vitro 3-D cutaneous nerve regeneration models, we show that the SKPs are neurotropic toward injured nerves and that they have a full capacity to differentiate into Schwann cells and promote axon regeneration. The identification of SKPs as a physiologic source of progenitors for cutaneous nerve regeneration in the skin, where SKPs physiologically reside, has important implications for understanding early cellular events in peripheral nerve regeneration. It also provides fertile ground for the elucidation of intrinsic and extrinsic factors within the nerve microenvironment that likely play essential roles in cutaneous nerve homeostasis. PMID:22851518
Delaspre, Fabien; Beer, Rebecca L.; Rovira, Meritxell; Huang, Wei; Wang, Guangliang; Gee, Stephen; Vitery, Maria del Carmen; Wheelan, Sarah J.
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
Staecker, Hinrich; Schlecker, Christina; Kraft, Shannon; Praetorius, Mark; Hsu, Chi; Brough, Douglas E.
Objectives/Hypothesis Determine the optimal design characteristics of an adenoviral vector to deliver atoh1 and induce regeneration of vestibular hair cells. Study Design Evaluation of a mouse model of intra-labyrinthine gene delivery. Tissue culture of mouse and human macular organs. Methods Macular organs from adult C57Bl/6 mice were treated with binding modified and alternate adenovectors expressing green fluorescent protein (gfp) or luciferase (L). Expression of marker genes was determined over time to determine vector transfection efficiency. The inner ear of adult mice was then injected with modified vectors. Expression of gfp and distribution of vector DNA was followed. Hearing and balance function was evaluated in normal animals to ensure safety of the novel vector designs. An optimized vector was identified and tested for its ability to induce hair cell regeneration in a mouse vestibulopathy model. Finally this vector was tested for its ability to induce hair cell regeneration in human tissue. Results Ad5 serotype based vectors were identified as having a variety of different binding capacities for inner ear tissue. This makes it difficult to limit the dose of vector due to entry into non-targeted cells. Screening of rare adenovector serotypes demonstrated that Ad28 based vectors were ideally suited for delivery to supporting cells and therefore useful for hair cell regeneration studies. Utilization of an Ad28 based vector to deliver atoh1 to a mouse model of vestibular loss resulted significant functional recovery of balance. This vector was also capable of transfecting human macular organs and inducing regeneration of human vestibular hair cells in vitro. Conclusions Improvement in vector design can lead to more specific cell based delivery and reduction of non specific delivery of the trans gene leading to the development of optimized molecular therapeutics to induce hair cell regeneration. Level of Evidence N/A Controlled basic science study. PMID
Makanae, Aki; Mitogawa, Kazumasa
Abstract Limb regeneration is a representative phenomenon of organ regeneration in urodele amphibians, such as an axolotl. An amputated limb starts regenerating from a remaining stump (proximal) to lost finger tips (distal). In the present case, proximal−distal (PD) reorganization takes place in a regenerating tissue, called a blastema. It has been a mystery how an induced blastema recognizes its position and restores an exact replica of missing parts. Recently, a new experimental system called the accessory limb model (ALM) has been established. The gained ALM phenotypes are demanding to reconsider the reorganization PD positional values. Based on the ALM phenotype, it is reasonable to hypothesize that reorganization of positional values has a certain discontinuity and that two different regeneration systems cooperatively reorganize the PD axis to restore an original structure. In this review, PD axis reestablishments are focused on limb regeneration. Knowledge from ALM studies in axolotls and Xenopus is providing a novel concept of PD axis reorganization in limb regeneration. PMID:27499860
Athanasiou, Kyriacos A; Responte, Donald J; Brown, Wendy E; Hu, Jerry C
As this review was prepared specifically for the American Society of Mechanical Engineers H.R. Lissner Medal, it primarily discusses work toward cartilage regeneration performed in Dr. Kyriacos A. Athanasiou's laboratory over the past 25 years. The prevalence and severity of degeneration of articular cartilage, a tissue whose main function is largely biomechanical, have motivated the development of cartilage tissue engineering approaches informed by biomechanics. This article provides a review of important steps toward regeneration of articular cartilage with suitable biomechanical properties. As a first step, biomechanical and biochemical characterization studies at the tissue level were used to provide design criteria for engineering neotissues. Extending this work to the single cell and subcellular levels has helped to develop biochemical and mechanical stimuli for tissue engineering studies. This strong mechanobiological foundation guided studies on regenerating hyaline articular cartilage, the knee meniscus, and temporomandibular joint (TMJ) fibrocartilage. Initial tissue engineering efforts centered on developing biodegradable scaffolds for cartilage regeneration. After many years of studying scaffold-based cartilage engineering, scaffoldless approaches were developed to address deficiencies of scaffold-based systems, resulting in the self-assembling process. This process was further improved by employing exogenous stimuli, such as hydrostatic pressure, growth factors, and matrix-modifying and catabolic agents, both singly and in synergistic combination to enhance neocartilage functional properties. Due to the high cell needs for tissue engineering and the limited supply of native articular chondrocytes, costochondral cells are emerging as a suitable cell source. Looking forward, additional cell sources are investigated to render these technologies more translatable. For example, dermis isolated adult stem (DIAS) cells show potential as a source of
This article explores the ways in which adult immigrants engaged in discussion about immigration news at a web design course during the passing of Senate Bill 1070 in Arizona. Drawing on the method and theory of mediated discourse analysis, two focal interactions reveal the diverse positions that students took up in relation to anti-immigrant…
Mahdy, Mohamed A A; Lei, Hsiao Yin; Wakamatsu, Jun-Ichi; Hosaka, Yoshinao Z; Nishimura, Takanori
In the present study, we examined muscle regeneration following two types of chemical injuries, cardiotoxin (CTX) and glycerol, in order to compare their effect on the morphological characteristics during muscle regeneration, in addition we studied the structural changes of the intramuscular connective tissue (IMCT) during the regeneration process, by scanning electron microscopy (SEM) after digestion of the cellular elements of the muscle with sodium hydroxide. Tibialis anterior (TA) muscles of adult male mice were injected either with CTX or glycerol. Muscle degeneration was greater in the CTX-injured model than in the glycerol-injured model at day 4 post injection. Muscle regeneration started at day 7 in both the CTX and glycerol models. However, the CTX-injured model showed a higher myotube density and larger myotube diameter than the glycerol-injured model at days 10 and 14 post injection. On other hand, adipocyte infiltration was detected in the glycerol-injured model. In contrast, no adipocytes could be detected in the CTX-injured model. Furthermore, ultrastructural analysis showed a significant difference in myofiber damage and regeneration between the two models. SEM of the IMCT showed a transient increase in endomysial collagen deposition at early stages of regeneration in the CTX-injured model. In contrast, glycerol-injured model showed slight endomysial collagen deposition. Our results suggest that changes in IMCT affect the efficiency of muscle regeneration. Studying the three dimensional structure of IMCT may help clinical therapies to reduce skeletal muscle fibrosis. To our knowledge this is the first time the changes in IMCT following CTX and glycerol injury using SEM-cell maceration technique have been compared.
Tonelli, Paolo; Duvina, Marco; Barbato, Luigi; Biondi, Eleonora; Nuti, Niccolò; Brancato, Leila; Rose, Giovanna Delle
Summary The edentulism of the jaws and the periodontal disease represent conditions that frequently leads to disruption of the alveolar bone. The loss of the tooth and of its bone of support lead to the creation of crestal defects or situation of maxillary atrophy. The restoration of a functional condition involves the use of endosseous implants who require adequate bone volume, to deal with the masticatory load. In such situations the bone need to be regenerated, taking advantage of the biological principles of osteogenesis, osteoinduction and osteoconduction. Several techniques combine these principles with different results, due to the condition of the bone base on which we operate changes, the surgical technique that we use, and finally for the bone metabolic conditions of the patient who can be in a state of systemic osteopenia or osteoporosis; these can also affect the result of jaw bone reconstruction. PMID:22461825
Colombo, Gerald V.; Jolly, Clifford D.; Sauer, Richard L.
The Microbial Check Valve (MCV) is used on the Space Shuttle to impart an iodine residual to the drinking water to maintain microbial control. Approximately twenty MCV locations have been identified in the Space Station Freedom design, each with a 90-day life. This translates to 2400 replacement units in 30 years of operation. An in situ regeneration concept has been demonstrated that will reduce this replacement requirement to less than 300 units based on data to date. A totally automated system will result in significant savings in crew time, resupply requirements, and replacement costs. An additional feature of the device is the ability to provide a concentrated biocide source (200 mg/liter of I2) that can be used to superiodinate systems routinely or after a microbial upset.
The ability of injured peripheral nerves to regenerate and reinnervate their original targets is a characteristic feature of the peripheral nervous system (PNS). On the other hand, neurons of the central nervous system (CNS), including retinal ganglion cell (RGC) axons, are incapable of spontaneous regeneration. In the adult PNS, axonal regeneration after injury depends on well-orchestrated cellular and molecular processes that comprise a highly reproducible series of degenerative reactions distal to the site of injury. During this fine-tuned process, named Wallerian degeneration, a remodeling of the distal nerve fragment prepares a permissive microenvironment that permits successful axonal regrowth originating from the proximal nerve fragment. Therefore, a multitude of adjusted intrinsic and extrinsic factors are important for surviving neurons, Schwann cells, macrophages and fibroblasts as well as endothelial cells in order to achieve successful regeneration. The aim of this review is to summarize relevant extrinsic cellular and molecular determinants of successful axonal regeneration in rodents that contribute to the regenerative microenvironment of the PNS.
Akram, Khondoker M; Patel, Neil; Spiteri, Monica A; Forsyth, Nicholas R
The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction. Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development. Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors. Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC) show evidences of their regenerative capacity in the repair of injured and diseased lungs. With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality. In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases.
Scimone, M Lucila; Srivastava, Mansi; Bell, George W; Reddien, Peter W
Planarians can regenerate any missing body part, requiring mechanisms for the production of organ systems in the adult, including their prominent tubule-based filtration excretory system called protonephridia. Here, we identify a set of genes, Six1/2-2, POU2/3, hunchback, Eya and Sall, that encode transcription regulatory proteins that are required for planarian protonephridia regeneration. During regeneration, planarian stem cells are induced to form a cell population in regeneration blastemas expressing Six1/2-2, POU2/3, Eya, Sall and Osr that is required for excretory system formation. POU2/3 and Six1/2-2 are essential for these precursor cells to form. Eya, Six1/2-2, Sall, Osr and POU2/3-related genes are required for vertebrate kidney development. We determined that planarian and vertebrate excretory cells express homologous proteins involved in reabsorption and waste modification. Furthermore, we identified novel nephridia genes. Our results identify a transcriptional program and cellular mechanisms for the regeneration of an excretory organ and suggest that metazoan excretory systems are regulated by genetic programs that share a common evolutionary origin.
Scimone, M. Lucila; Srivastava, Mansi; Bell, George W.; Reddien, Peter W.
Planarians can regenerate any missing body part, requiring mechanisms for the production of organ systems in the adult, including their prominent tubule-based filtration excretory system called protonephridia. Here, we identify a set of genes, Six1/2-2, POU2/3, hunchback, Eya and Sall, that encode transcription regulatory proteins that are required for planarian protonephridia regeneration. During regeneration, planarian stem cells are induced to form a cell population in regeneration blastemas expressing Six1/2-2, POU2/3, Eya, Sall and Osr that is required for excretory system formation. POU2/3 and Six1/2-2 are essential for these precursor cells to form. Eya, Six1/2-2, Sall, Osr and POU2/3-related genes are required for vertebrate kidney development. We determined that planarian and vertebrate excretory cells express homologous proteins involved in reabsorption and waste modification. Furthermore, we identified novel nephridia genes. Our results identify a transcriptional program and cellular mechanisms for the regeneration of an excretory organ and suggest that metazoan excretory systems are regulated by genetic programs that share a common evolutionary origin. PMID:21937596
Akram, Khondoker M.; Patel, Neil; Spiteri, Monica A.; Forsyth, Nicholas R.
The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction. Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development. Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors. Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC) show evidences of their regenerative capacity in the repair of injured and diseased lungs. With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality. In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases. PMID:26797607
Lush, Mark E.; Piotrowski, Tatjana
Damage or destruction of sensory hair cells in the inner ear leads to hearing or balance deficits that can be debilitating, especially in older adults. Unfortunately, the damage is permanent, as regeneration of the inner ear sensory epithelia does not occur in mammals. Zebrafish and other non-mammalian vertebrates have the remarkable ability to regenerate sensory hair cells and understanding the molecular and cellular basis for this regenerative ability will hopefully aid us in designing therapies to induce regeneration in mammals. Zebrafish not only possess hair cells in the ear but also in the sensory lateral line system. Hair cells in both organs are functionally analogous to hair cells in the inner ear of mammals. The lateral line is a mechanosensory system found in most aquatic vertebrates that detects water motion and aids in predator avoidance, prey capture, schooling and mating. Although hair cell regeneration occurs in both the ear and lateral line, most research to date has focused on the lateral line due to its relatively simple structure and accessibility. Here we review the recent discoveries made during the characterization of hair cell regeneration in zebrafish. PMID:25045019
Gandhi, Chandrashekhar R
'Augmenter of liver regeneration' (ALR) (also known as hepatic stimulatory substance or hepatopoietin) was originally found to promote growth of hepatocytes in the regenerating or injured liver. ALR is expressed ubiquitously in all organs, and exclusively in hepatocytes in the liver. ALR, a survival factor for hepatocytes, exhibits significant homology with ERV1 (essential for respiration and viability) protein that is essential for the survival of the yeast, Saccharomyces cerevisiae. ALR comprises 198 to 205 amino acids (approximately 22 kDa), but is post-translationally modified to three high molecular weight species (approximately 38 to 42 kDa) found in hepatocytes. ALR is present in mitochondria, cytosol, endoplasmic reticulum, and nucleus. Mitochondrial ALR may be involved in oxidative phosphorylation, but also functions as sulfhydryl oxidase and cytochrome c reductase, and causes Fe/S maturation of proteins. ALR, secreted by hepatocytes, stimulates synthesis of TNF-α, IL-6, and nitric oxide in Kupffer cells via a G-protein coupled receptor. While the 22 kDa rat recombinant ALR does not stimulate DNA synthesis in hepatocytes, the short form (15 kDa) of human recombinant ALR was reported to be equipotent as or even stronger than TGF-α or HGF as a mitogen for hepatocytes. Altered serum ALR levels in certain pathological conditions suggest that it may be a diagnostic marker for liver injury/disease. Although ALR appears to have multiple functions, the knowledge of its role in various organs, including the liver, is extremely inadequate, and it is not known whether different ALR species have distinct functions. Future research should provide better understanding of the expression and functions of this enigmatic molecule.
James, Roshan; Deng, Meng; Laurencin, Cato T.; Kumbar, Sangamesh G.
This manuscript focuses on bone repair/regeneration using tissue engineering strategies, and highlights nanobiotechnology developments leading to novel nanocomposite systems. About 6.5 million fractures occur annually in USA, and about 550,000 of these individual cases required the application of a bone graft. Autogenous and allogenous bone have been most widely used for bone graft based therapies; however, there are significant problems such as donor shortage and risk of infection. Alternatives using synthetic and natural biomaterials have been developed, and some are commercially available for clinical applications requiring bone grafts. However, it remains a great challenge to design an ideal synthetic graft that very closely mimics the bone tissue structurally, and can modulate the desired function in osteoblast and progenitor cell populations. Nanobiomaterials, specifically nanocomposites composed of hydroxyapatite (HA) and/or collagen are extremely promising graft substitutes. The biocomposites can be fabricated to mimic the material composition of native bone tissue, and additionally, when using nano-HA (reduced grain size), one mimics the structural arrangement of native bone. A good understanding of bone biology and structure is critical to development of bone mimicking graft substitutes. HA and collagen exhibit excellent osteoconductive properties which can further modulate the regenerative/healing process following fracture injury. Combining with other polymeric biomaterials will reinforce the mechanical properties thus making the novel nano-HA based composites comparable to human bone. We report on recent studies using nanocomposites that have been fabricated as particles and nanofibers for regeneration of segmental bone defects. The research in nanocomposites, highlight a pivotal role in the future development of an ideal orthopaedic implant device, however further significant advancements are necessary to achieve clinical use.
Erler, Piril; Sweeney, Alexandra; Monaghan, James R
Some animals have the ability to generate large numbers of oocytes throughout life. This raises the question whether persistent adult germline stem cell populations drive continuous oogenesis and whether they are capable of mounting a regenerative response after injury. Here we demonstrate the presence of adult oogonial stem cells (OSCs) in the adult axolotl salamander ovary and show that ovarian injury induces OSC activation and functional regeneration of the ovaries to reproductive capability. Cells that have morphological similarities to germ cells were identified in the developing and adult ovaries via histological analysis. Genes involved in germ cell maintenance including Vasa, Oct4, Sox2, Nanog, Bmp15, Piwil1, Piwil2, Dazl, and Lhx8 were expressed in the presumptive OSCs. Colocalization of Vasa protein with H3 mitotic marker showed that both oogonial and spermatogonial adult stem cells were mitotically active. Providing evidence of stemness and viability of adult OSCs, enhanced green fluorescent protein (EGFP) adult OSCs grafted into white juvenile host gonads gave rise to EGFP OSCs, and oocytes. Last, the axolotl ovaries completely regenerated after partial ovariectomy injury. During regeneration, OSC activation resulted in rapid differentiation into new oocytes, which was demonstrated by Vasa(+) /BrdU(+) coexpression. Furthermore, follicle cell proliferation promoted follicle maturation during ovarian regeneration. Overall, these results show that adult oogenesis occurs via proliferation of endogenous OSCs in a tetrapod and mediates ovarian regeneration. This study lays the foundations to elucidate mechanisms of ovarian regeneration that will assist regenerative medicine in treating premature ovarian failure and reduced fertility. Stem Cells 2017;35:236-247.
Walters, Bradley J; Zuo, Jian
The organ of Corti in the mammalian inner ear is comprised of mechanosensory hair cells (HCs) and nonsensory supporting cells (SCs), both of which are believed to be terminally post-mitotic beyond late embryonic ages. Consequently, regeneration of HCs and SCs does not occur naturally in the adult mammalian cochlea, though recent evidence suggests that these cells may not be completely or irreversibly quiescent at earlier postnatal ages. Furthermore, regenerative processes can be induced by genetic and pharmacological manipulations, but, more and more reports suggest that regenerative potential declines as the organ of Corti continues to age. In numerous mammalian systems, such effects of aging on regenerative potential are well established. However, in the cochlea, the problem of regeneration has not been traditionally viewed as one of aging. This is an important consideration as current models are unable to elicit widespread regeneration or full recovery of function at adult ages yet regenerative therapies will need to be developed specifically for adult populations. Still, the advent of gene targeting and other genetic manipulations has established mice as critically important models for the study of cochlear development and HC regeneration and suggests that auditory HC regeneration in adult mammals may indeed be possible. Thus, this review will focus on the pursuit of regeneration in the postnatal and adult mouse cochlea and highlight processes that occur during postnatal development, maturation, and aging that could contribute to an age-related decline in regenerative potential. Second, we will draw upon the wealth of knowledge pertaining to age related senescence in tissues outside of the ear to synthesize new insights and potentially guide future research aimed at promoting HC regeneration in the adult cochlea.
Takeoka, Aya; Jindrich, Devin L.; Muñoz-Quiles, Cintia; Zhong, Hui; van den Brand, Rubia; Pham, Daniel L.; Ziegler, Matthias D.; Ramón-Cueto, Almudena; Roy, Roland R.; Edgerton, V. Reggie
Reports based primarily on anatomical evidence suggest that olfactory ensheathing glia (OEG) transplantation promotes axon regeneration across a complete spinal cord transection in adult rats. Based on functional, electrophysiological, and anatomical assessments, we found that OEG promoted axon regeneration across a complete spinal cord transection and that this regeneration altered motor responses over time. At 7 months after transection, 70% of OEG-treated rats showed motor-evoked potentials in hindlimb muscles after transcranial electric stimulation. Furthermore, a complete spinal cord retransection performed 8 months after injury demonstrated that this axon regeneration suppressed locomotor performance and decreased the hypersensitive hindlimb withdrawal response to mechanical stimulation. OEG transplantation alone promoted reorganization of lumbosacral locomotor networks and, when combined with long-term training, enhanced some stepping measures. These novel findings demonstrate that OEG promote regeneration of mature axons across a complete transection and reorganization of spinal circuitry, both of which contribute to sensorimotor function. PMID:21411671
McCusker, Catherine D; Diaz-Castillo, Carlos; Sosnik, Julian; Q Phan, Anne; Gardiner, David M
The Mexican Axolotl is one of the few tetrapod species that is capable of regenerating complete skeletal elements in injured adult limbs. Whether the skeleton (bone and cartilage) plays a role in the patterning and contribution to the skeletal regenerate is currently unresolved. We tested the induction of pattern formation, the effect on cell proliferation, and contributions of skeletal tissues (cartilage, bone, and periosteum) to the regenerating axolotl limb. We found that bone tissue grafts from transgenic donors expressing GFP fail to induce pattern formation and do not contribute to the newly regenerated skeleton. Periosteum tissue grafts, on the other hand, have both of these activities. These observations reveal that skeletal tissue does not contribute to the regeneration of skeletal elements; rather, these structures are patterned by and derived from cells of non-skeletal connective tissue origin.
Rajaram, Kamya; Summerbell, Emily R.
Zebrafish are capable of robust and spontaneous regeneration of injured retina. Constant intense light exposure to adult albino zebrafish specifically causes apoptosis of rod and cone photoreceptor cells and is an excellent model to study the molecular mechanisms underlying photoreceptor regeneration. However, this paradigm has only been applied to lesion zebrafish of the nonpigmented albino genetic background, which precludes the use of numerous transgenic reporter lines that are widely used to study regeneration. Here, we explored the effectiveness of constant intense light exposure in causing photoreceptor apoptosis and stimulating regeneration in normally pigmented zebrafish retinas. We show that constant intense light exposure causes widespread photoreceptor damage in the dorsal-central retinas of pigmented zebrafish. Photoreceptor loss triggers dedifferentiation and proliferation of Müller glia as well as progenitor cell proliferation. We also demonstrate that the timeline of regeneration response is comparable between the albino and the pigmented retinas. PMID:25324680
Tanaka, Hibiki Vincent; Ng, Nathaniel Chuen Yin; Yang Yu, Zhan; Casco-Robles, Martin Miguel; Maruo, Fumiaki; Tsonis, Panagiotis A; Chiba, Chikafumi
The newt, a urodele amphibian, is able to repeatedly regenerate its limbs throughout its lifespan, whereas other amphibians deteriorate or lose their ability to regenerate limbs after metamorphosis. It remains to be determined whether such an exceptional ability of the newt is either attributed to a strategy, which controls regeneration in larvae, or on a novel one invented by the newt after metamorphosis. Here we report that the newt switches the cellular mechanism for limb regeneration from a stem/progenitor-based mechanism (larval mode) to a dedifferentiation-based one (adult mode) as it transits beyond metamorphosis. We demonstrate that larval newts use stem/progenitor cells such as satellite cells for new muscle in a regenerated limb, whereas metamorphosed newts recruit muscle fibre cells in the stump for the same purpose. We conclude that the newt has evolved novel strategies to secure its regenerative ability of the limbs after metamorphosis.
Seno, Hiromi; Shigemoto, Mikiko
An enormously developed giant cheliped with the other small one characterizes the adult male fiddler crab. Some experiments with artificial severances of cheliped indicate that such a handedness in the cheliped size is maintained even after the regeneration of severed cheliped. Other experimental researches give some results about an unknown physiological system which controls the emergence and the regeneration of the handedness in the cheliped size. In this paper, with two hypothesized factors relevant to the regeneration of a severed cheliped, we propose a simple mathematical model to describe the experimental result about the cheliped regeneration with a handedness after the cheliped severance for the fiddler crab. Our model gives a suggestion about an underlying system for the cheliped regeneration in the fiddler crab or some other crustacean species.
Tanaka, Hibiki Vincent; Ng, Nathaniel Chuen Yin; Yang Yu, Zhan; Casco-Robles, Martin Miguel; Maruo, Fumiaki; Tsonis, Panagiotis A.; Chiba, Chikafumi
The newt, a urodele amphibian, is able to repeatedly regenerate its limbs throughout its lifespan, whereas other amphibians deteriorate or lose their ability to regenerate limbs after metamorphosis. It remains to be determined whether such an exceptional ability of the newt is either attributed to a strategy, which controls regeneration in larvae, or on a novel one invented by the newt after metamorphosis. Here we report that the newt switches the cellular mechanism for limb regeneration from a stem/progenitor-based mechanism (larval mode) to a dedifferentiation-based one (adult mode) as it transits beyond metamorphosis. We demonstrate that larval newts use stem/progenitor cells such as satellite cells for new muscle in a regenerated limb, whereas metamorphosed newts recruit muscle fibre cells in the stump for the same purpose. We conclude that the newt has evolved novel strategies to secure its regenerative ability of the limbs after metamorphosis. PMID:27026263
Guardiola, Ombretta; Lafuste, Peggy; Brunelli, Silvia; Iaconis, Salvatore; Touvier, Thierry; Mourikis, Philippos; De Bock, Katrien; Lonardo, Enza; Andolfi, Gennaro; Bouché, Ann; Liguori, Giovanna L; Shen, Michael M; Tajbakhsh, Shahragim; Cossu, Giulio; Carmeliet, Peter; Minchiotti, Gabriella
Skeletal muscle regeneration mainly depends on satellite cells, a population of resident muscle stem cells. However, our understanding of the molecular mechanisms underlying satellite cell activation is still largely undefined. Here, we show that Cripto, a regulator of early embryogenesis, is a novel regulator of muscle regeneration and satellite cell progression toward the myogenic lineage. Conditional inactivation of cripto in adult satellite cells compromises skeletal muscle regeneration, whereas gain of function of Cripto accelerates regeneration, leading to muscle hypertrophy. Moreover, we provide evidence that Cripto modulates myogenic cell determination and promotes proliferation by antagonizing the TGF-β ligand myostatin. Our data provide unique insights into the molecular and cellular basis of Cripto activity in skeletal muscle regeneration and raise previously undescribed implications for stem cell biology and regenerative medicine.
Digital Imaging is the computer processed numerical representation of physical images. Enhancement of images results in easier interpretation. Quantitative digital image analysis by Perceptive Scientific Instruments, locates objects within an image and measures them to extract quantitative information. Applications are CAT scanners, radiography, microscopy in medicine as well as various industrial and manufacturing uses. The PSICOM 327 performs all digital image analysis functions. It is based on Jet Propulsion Laboratory technology, is accurate and cost efficient.
Gey, Manuel; Wanner, Renate; Schilling, Corinna; Pedro, Maria T.; Sinske, Daniela
Axon injury in the peripheral nervous system (PNS) induces a regeneration-associated gene (RAG) response. Atf3 (activating transcription factor 3) is such a RAG and ATF3's transcriptional activity might induce ‘effector’ RAGs (e.g. small proline rich protein 1a (Sprr1a), Galanin (Gal), growth-associated protein 43 (Gap43)) facilitating peripheral axon regeneration. We provide a first analysis of Atf3 mouse mutants in peripheral nerve regeneration. In Atf3 mutant mice, facial nerve regeneration and neurite outgrowth of adult ATF3-deficient primary dorsal root ganglia neurons was decreased. Using genome-wide transcriptomics, we identified a neuropeptide-encoding RAG cluster (vasoactive intestinal peptide (Vip), Ngf, Grp, Gal, Pacap) regulated by ATF3. Exogenous administration of neuropeptides enhanced neurite growth of Atf3 mutant mice suggesting that these molecules might be effector RAGs of ATF3's pro-regenerative function. In addition to the induction of growth-promoting molecules, we present data that ATF3 suppresses growth-inhibiting molecules such as chemokine (C-C motif) ligand 2. In summary, we show a pro-regenerative ATF3 function during PNS nerve regeneration involving transcriptional activation of a neuropeptide-encoding RAG cluster. ATF3 is a general injury-inducible factor, therefore ATF3-mediated mechanisms identified herein might apply to other cell and injury types. PMID:27581653
Most tissues in the body are made up of more than one cell type. For successful tissue regeneration, it is essential to simulate the natural conditions of the cellular environment as much as possible. In a coculture system, two or more cell types are brought together, interact, and communicate in the same culture environment. The coculture system provides a powerful in vitro tool in research on cell-to-cell communications, repair, and regeneration. This review provides an overview on recent studies on general platforms and applications of coculture systems to enhance musculoskeletal regeneration, with a particular focus on osteogenesis, chondrogensis, and angiogenesis.
Della Giovampaola, Cristian; Engheta, Nader
Balancing complexity and simplicity has played an important role in the development of many fields in science and engineering. One of the well-known and powerful examples of such balance can be found in Boolean algebra and its impact on the birth of digital electronics and the digital information age. The simplicity of using only two numbers, '0' and '1', in a binary system for describing an arbitrary quantity made the fields of digital electronics and digital signal processing powerful and ubiquitous. Here, inspired by the binary concept, we propose to develop the notion of digital metamaterials. Specifically, we investigate how one can synthesize an electromagnetic metamaterial with a desired permittivity, using as building blocks only two elemental materials, which we call 'metamaterial bits', with two distinct permittivity functions. We demonstrate, analytically and numerically, how proper spatial mixtures of such metamaterial bits lead to elemental 'metamaterial bytes' with effective material parameters that are different from the parameters of the metamaterial bits. We then apply this methodology to several design examples of optical elements, such as digital convex lenses, flat graded-index digital lenses, digital constructs for epsilon-near-zero (ENZ) supercoupling and digital hyperlenses, thus highlighting the power and simplicity of the methodology.
Sobotka, Werner K.
Digital printing is described as a tool to replace conventional printing machines completely. Still this goal was not reached until now with any of the digital printing technologies to be described in the paper. Productivity and costs are still the main parameters and are not really solved until now. Quality in digital printing is no problem anymore. Definition of digital printing is to transfer digital datas directly on the paper surface. This step can be carried out directly or with the use of an intermediate image carrier. Keywords in digital printing are: computer- to-press; erasable image carrier; image carrier with memory. Digital printing is also the logical development of the new digital area as it is pointed out in Nicholas Negropotes book 'Being Digital' and also the answer to networking and Internet technologies. Creating images text and color in one country and publishing the datas in another country or continent is the main advantage. Printing on demand another big advantage and last but not least personalization the last big advantage. Costs and being able to coop with this new world of prepress technology is the biggest disadvantage. Therefore the very optimistic growth rates for the next few years are really nonexistent. The development of complete new markets is too slow and the replacing of old markets is too small.
Moraleda, Jose M; Blanquer, Miguel; Bleda, Patricia; Iniesta, Paqui; Ruiz, Francisco; Bonilla, Sonia; Cabanes, Carmen; Tabares, Lucía; Martinez, Salvador
Adult stem cells may be an invaluable source of plastic cells for tissue regeneration. The bone marrow contains different subpopulations of adult stem cells easily accessible for transplantation. However the therapeutic value of adult stem cell is a question of debate in the scientific community. We have investigated the potential benefits of adult hematopoietic stem cell transplantation in animal models of demyelinating and motor neuron diseases. Our results suggest that transplantation of HSC have direct and indirect neuroregenerative and neuroprotective effects.
Kochegarov, Andrei; Lemanski, Larry F
In this review, we focus on new approaches that could lead to the regeneration of heart muscle and the restoration of cardiac muscle function derived from newly-formed cardiomyocytes. Various strategies for the production of cardiomyocytes from embryonic stem cells, induced pluripotent stem cells, adult bone marrow stem cells and cardiac spheres from human heart biopsies are described. Pathological conditions which lead to atherosclerosis and coronary artery disease often are followed by myocardial infarction causing myocardial cell death. After cell death, there is very little self-regeneration of the cardiac muscle tissue, which is replaced by non-contractile connective tissue, thus weakening the ability of the heart muscle to contract fully and leading to heart failure. A number of experimental research approaches to stimulate heart muscle regeneration with the hope of regaining normal or near normal heart function in the damaged heart muscle have been attempted. Some of these very interesting studies have used a variety of stem cell types in combination with potential cardiogenic differentiation factors in an attempt to promote differentiation of new cardiac muscle for possible future use in the clinical treatment of patients who have suffered heart muscle damage from acute myocardial infarctions or related cardiovascular diseases. Although progress has been made in recent years relative to promoting the differentiation of cardiac muscle tissue from non-muscle cells, much work remains to be done for this technology to be used routinely in translational clinical medicine to treat patients with damaged heart muscle tissue and return such individuals to pre-heart-attack activity levels.
Kochegarov, Andrei; Lemanski, Larry F
In this review, we focus on new approaches that could lead to the regeneration of heart muscle and the restoration of cardiac muscle function derived from newly-formed cardiomyocytes. Various strategies for the production of cardiomyocytes from embryonic stem cells, induced pluripotent stem cells, adult bone marrow stem cells and cardiac spheres from human heart biopsies are described. Pathological conditions which lead to atherosclerosis and coronary artery disease often are followed by myocardial infarction causing myocardial cell death. After cell death, there is very little self-regeneration of the cardiac muscle tissue, which is replaced by non-contractile connective tissue, thus weakening the ability of the heart muscle to contract fully and leading to heart failure. A number of experimental research approaches to stimulate heart muscle regeneration with the hope of regaining normal or near normal heart function in the damaged heart muscle have been attempted. Some of these very interesting studies have used a variety of stem cell types in combination with potential cardiogenic differentiation factors in an attempt to promote differentiation of new cardiac muscle for possible future use in the clinical treatment of patients who have suffered heart muscle damage from acute myocardial infarctions or related cardiovascular diseases. Although progress has been made in recent years relative to promoting the differentiation of cardiac muscle tissue from non-muscle cells, much work remains to be done for this technology to be used routinely in translational clinical medicine to treat patients with damaged heart muscle tissue and return such individuals to pre-heart-attack activity levels. PMID:28096630
Sauer, Richard L.; Colombo, Gerald V.; Jolly, Clifford D.
Iodinated resin bed for disinfecting water regenerated to extend its useful life. Water flows through regeneration bed of crystalline iodine during regeneration. At other times, flow diverted around regeneration bed. Although regeneration cycle was manually controlled in demonstration, readily automated to start and stop according to signals and stop according to signals from concentration sensors. Further benefit of regeneration is that regeneration bed provides highly concentrated biocide source (200 mg/L) when needed. Concentrated biocide used to superiodinate system after contamination from routine maintenance or unexpected introduction of large concentration of microbes.
Figure 10. Zebrafish Spinal cord transection. Isolated spinal column of transected zebrafish spinal cord (rostral to left), panel A. Arrows...mammalian spinal cord, axon regeneration is frustrated by inhibitors such as chondroitin sulfate proteoglycans (CSPGs) expressed by reactive astrocytes...present at the injury site. In adult zebrafish, Danio rerio, some brainstem neuronsare able to grow their axon beyond a spinal cord injury, even
Zhu, Shaowei; Matsubara, Yoichi
A numerical method for regenerators is introduced in this paper. It is not only suitable for the regenerators in cryocoolers and Stirling engines, but also suitable for the stacks in acoustic engines and the pulse tubes in pulse tube refrigerators. The numerical model is one dimensional periodic unsteady flow model. The numerical method is based on the control volume concept with the implicitly solve method. The iteration acceleration method, which considers the one-dimensional periodic unsteady problem as the steady two-dimensional problem, is used for decreasing the calculation time. By this method, the regenerator in an inertance tube pulse tube refrigerator was simulated. The result is useful for understanding how the inefficiency of the regenerator changes with the inertance effect.
Yang, Qingpo; Li, Zhen; Li, Hui; Li, Yanrong; Yang, Yuhui; Zhang, Qingwen; Liu, Xiaoxia
After injury many insects could regenerate lost limb. In this study, Helicoverpa armigera Hubner and Locusta migratoria manilensis (Meyen, 1835) were chosen to compare the regeneration potency of holometabolous and hemimetabolous insects. We employed the classical approach of surgical excision to verify the regeneration ability and to investigate the factors that affect the extent of regeneration. The results found that H. armigera could regenerate intact legs when the larval legs were excised at the first and second instar and that legs of adult H. armigera had a close relationship with their larval counterparts. However, the adult legs became malformed or disappeared when excised at other older instars. For the L. migratoria, we found the legs have weak partial regeneration ability when amputation was conducted at the joint of two segments. The regeneration potency might be stronger the more proximal the operation. Regeneration process had a negative impact on the larval development. This is the first report of complete leg regeneration capacity having a strong correlation with the instar but not with the position where amputation occurred for H. armigera, while for the L. migratoria, partial regenerative ability had a close relationship with the position where amputation occurred but not with instars.
Yang, Qingpo; Li, Zhen; Li, Hui; Li, Yanrong; Yang, Yuhui; Zhang, Qingwen; Liu, Xiaoxia
After injury many insects could regenerate lost limb. In this study, Helicoverpa armigera Hubner and Locusta migratoria manilensis (Meyen, 1835) were chosen to compare the regeneration potency of holometabolous and hemimetabolous insects. We employed the classical approach of surgical excision to verify the regeneration ability and to investigate the factors that affect the extent of regeneration. The results found that H. armigera could regenerate intact legs when the larval legs were excised at the first and second instar and that legs of adult H. armigera had a close relationship with their larval counterparts. However, the adult legs became malformed or disappeared when excised at other older instars. For the L. migratoria, we found the legs have weak partial regeneration ability when amputation was conducted at the joint of two segments. The regeneration potency might be stronger the more proximal the operation. Regeneration process had a negative impact on the larval development. This is the first report of complete leg regeneration capacity having a strong correlation with the instar but not with the position where amputation occurred for H. armigera, while for the L. migratoria, partial regenerative ability had a close relationship with the position where amputation occurred but not with instars.
Weil, Brian R.; Canty, John M.
Cell-based therapy has emerged as a promising approach to combat the myocyte loss and cardiac remodeling that characterize the progression of left ventricular dysfunction to heart failure. Several clinical trials conducted during the past decade have shown that a variety of autologous bone marrow- and peripheral blood-derived stem and progenitor cell populations can be safely administered to patients with ischemic heart disease and yield modest improvements in cardiac function. Concurrently, rapid progress has been made at the preclinical level to identify novel therapeutic cell populations, delineate the mechanisms underlying cell-mediated cardiac repair, and optimize cell-based approaches for clinical use. The following review summarizes the progress that has been made in this rapidly evolving field over the past decade and examines how our current understanding of the mechanisms involved in successful cardiac regeneration should direct future investigation in this area. Particular emphasis is placed on discussion of the general hypothesis that the benefits of cell therapy primarily result from stimulation of endogenous cardiac repair processes that have only recently been identified in the adult mammalian heart, rather than direct differentiation of exogenous cells. Continued scientific investigation in this area will guide the optimization of cell-based approaches for myocardial regeneration, with the ultimate goal of clinical implementation and substantial improvement in our ability to restore cardiac function in ischemic heart disease patients. PMID:23577634
Weil, Brian R; Canty, John M
Cell-based therapy has emerged as a promising approach to combat the myocyte loss and cardiac remodelling that characterize the progression of left ventricular dysfunction to heart failure. Several clinical trials conducted over the past decade have shown that a variety of autologous bone-marrow- and peripheral-blood-derived stem and progenitor cell populations can be safely administered to patients with ischaemic heart disease and yield modest improvements in cardiac function. Concurrently, rapid progress has been made at the pre-clinical level to identify novel therapeutic cell populations, delineate the mechanisms underlying cell-mediated cardiac repair and optimize cell-based approaches for clinical use. The following review summarizes the progress that has been made in this rapidly evolving field over the past decade and examines how our current understanding of the mechanisms involved in successful cardiac regeneration should direct future investigation in this area. Particular emphasis is placed on discussion of the general hypothesis that the benefits of cell therapy primarily result from stimulation of endogenous cardiac repair processes that have only recently been identified in the adult mammalian heart, rather than direct differentiation of exogenous cells. Continued scientific investigation in this area will guide the optimization of cell-based approaches for myocardial regeneration, with the ultimate goal of clinical implementation and substantial improvement in our ability to restore cardiac function in ischaemic heart disease patients.
Kao, Richard T; Conte, Greg; Nishimine, Dee; Dault, Scott
As a result of periodontal regeneration research, a series of clinical techniques have emerged that permit tissue engineering to be performed for more efficient regeneration and repair of periodontal defects and improved implant site development. Historically, periodontal regeneration research has focused on a quest for "magic filler" material. This search has led to the development of techniques utilizing autologous bone and bone marrow, allografts, xenografts, and various man-made bone substitutes. Though these techniques have had limited success, the desire for a more effective regenerative approach has resulted in the development of tissue engineering techniques. Tissue engineering is a relatively new field of reconstructive biology which utilizes mechanical, cellular, or biologic mediators to facilitate reconstruction/regeneration of a particular tissue. In periodontology, the concept of tissue engineering had its beginnings with guided tissue regeneration, a mechanical approach utilizing nonresorbable membranes to obtain regeneration in defects. In dental implantology, guided bone regeneration membranes +/- mechanical support are used for bone augmentation of proposed implant placement sites. With the availability of partially purified protein mixture from developing teeth and growth factors from recombinant technology, a new era of tissue engineering whereby biologic mediators can be used for periodontal regeneration. The advantage of recombinant growth factors is this tissue engineering device is consistent in its regenerative capacity, and variations in regenerative response are due to individual healing response and/or poor surgical techniques. In this article, the authors review how tissue engineering has advanced and discuss its impact on the clinical management of both periodontal and osseous defects in preparation for implant placement. An understanding of these new tissue engineering techniques is essential for comprehending today's ever
Discussion of digital imaging technology focuses on its potential use for preservation of library materials. Topics addressed include converting microfilm to digital; the high cost of conversion from paper or microfilm; quality; indexing; database management issues; incompatibility among imaging systems; longevity; cooperative pilot projects; and…
In recent years, the Internet has become a digital commons of commerce and education. However, accessibility standards have often been overlooked online, and the digital equivalents to curb-cuts and other physical accommodations have only rarely been implemented to serve those with print disabilities. (A print disability can be a learning…
Presenting the current status of the Digital TMI project to visiting members of the FAA Command Center. Digital TMI is an effort to store national-level traffic management initiatives in a standards-compliant manner. Work is funded by the FAA.
Rai, Mamta; Nongthomba, Upendra; Grounds, Miranda D
Many aspects of skeletal muscle biology are remarkably similar between mammals and tiny insects, and experimental models of mice and flies (Drosophila) provide powerful tools to understand factors controlling the growth, maintenance, degeneration (atrophy and necrosis), and regeneration of normal and diseased muscles, with potential applications to the human condition. This review compares the limb muscles of mice and the indirect flight muscles of flies, with respect to the mechanisms of adult myofiber formation, homeostasis, atrophy, hypertrophy, and the response to muscle degeneration, with some comment on myogenic precursor cells and common gene regulatory pathways. There is a striking similarity between the species for events related to muscle atrophy and hypertrophy, without contribution of any myoblast fusion. Since the flight muscles of adult flies lack a population of reserve myogenic cells (equivalent to satellite cells), this indicates that such cells are not required for maintenance of normal muscle function. However, since satellite cells are essential in postnatal mammals for myogenesis and regeneration in response to myofiber necrosis, the extent to which such regeneration might be possible in flight muscles of adult flies remains unclear. Common cellular and molecular pathways for both species are outlined related to neuromuscular disorders and to age-related loss of skeletal muscle mass and function (sarcopenia). The commonality of events related to skeletal muscles in these disparate species (with vast differences in size, growth duration, longevity, and muscle activities) emphasizes the combined value and power of these experimental animal models.
Mathew, Lijoy K; Sengupta, Sumitra; Franzosa, Jill A; Perry, Jessica; La Du, Jane; Andreasen, Eric A; Tanguay, Robert L
Zebrafish have the remarkable ability to regenerate body parts including the heart and fins by a process referred to as epimorphic regeneration. Recent studies have illustrated that similar to adult zebrafish, early life stage larvae also possess the ability to regenerate the caudal fin. A comparative microarray analysis was used to determine the degree of conservation in gene expression among the regenerating adult caudal fin, adult heart, and larval fin. Results indicate that these tissues respond to amputation/injury with strikingly similar genomic responses. Comparative analysis revealed raldh2, a rate-limiting enzyme for the synthesis of retinoic acid, as one of the most highly induced genes across the three regeneration platforms. In situ localization and functional studies indicate that raldh2 expression is critical for the formation of wound epithelium and blastema. Patterning during regenerative outgrowth was considered to be the primary function of retinoic acid signaling; however, our results suggest that it is also required for early stages of tissue regeneration. Expression of raldh2 is regulated by Wnt and fibroblast growth factor/ERK signaling.
Shue, Li; Yufeng, Zhang; Mony, Ullas
Periodontal disease is characterized by the destruction of periodontal tissues. Various methods of regenerative periodontal therapy, including the use of barrier membranes, bone replacement grafts, growth factors and the combination of these procedures have been investigated. The development of biomaterials for tissue engineering has considerably improved the available treatment options above. They fall into two broad classes: ceramics and polymers. The available ceramic-based materials include calcium phosphate (eg, tricalcium phosphate and hydroxyapatite), calcium sulfate and bioactive glass. The bioactive glass bonds to the bone with the formation of a layer of carbonated hydroxyapatite in situ. The natural polymers include modified polysaccharides (eg, chitosan,) and polypeptides (collagen and gelatin). Synthetic polymers [eg, poly(glycolic acid), poly(L-lactic acid)] provide a platform for exhibiting the biomechanical properties of scaffolds in tissue engineering. The materials usually work as osteogenic, osteoconductive and osteoinductive scaffolds. Polymers are more widely used as a barrier material in guided tissue regeneration (GTR). They are shown to exclude epithelial downgrowth and allow periodontal ligament and alveolar bone cells to repopulate the defect. An attempt to overcome the problems related to a collapse of the barrier membrane in GTR or epithelial downgrowth is the use of a combination of barrier membranes and grafting materials. This article reviews various biomaterials including scaffolds and membranes used for periodontal treatment and their impacts on the experimental or clinical management of periodontal defect. PMID:23507891
Sauer, Richard L. (Inventor); Colombo, Gerald V. (Inventor); Jolly, Clifford D. (Inventor)
A method and apparatus are disclosed for maintaining continuous, long-term microbial control in the water supply for potable, hygiene, and experimental water for space activities, as well as treatment of water supplies on Earth. The water purification is accomplished by introduction of molecular iodine into the water supply to impart a desired iodine residual. The water is passed through an iodinated anion exchange resin bed. The iodine is bound as I-(sub n) at the anion exchange sites and releases I(sub 2) into the water stream flowing through the bed. The concentration of I(sub 2) in the flowing water gradually decreases and, in the prior art, the ion-exchange bed has had to be replaced. In a preferred embodiment, a bed of iodine crystals is provided with connections for flowing water therethrough to produce a concentrated (substantially saturated) aqueous iodine solution which is passed through the iodinated resin bed to recharge the bed with bound iodine. The bed of iodine crystals is connected in parallel with the iodinated resin bed and is activated periodically (e.g., by timer, by measured flow of water, or by iodine residual level) to recharge the bed. Novelty resides in the capability of inexpensively and repeatedly regenerating the ion-exchange bed in situ.
Bayascas, J R; Castillo, E; Muñoz-Mármol, A M; Saló, E
Platyhelminthes are widely considered to be the sister group of coelomates (Philippe, H., Chenuil, A. and Adoutte, A. (1994)Development 1994 Supplement, 15-24) and the first organisms to show bilateral symmetry and cephalization. Within this phylum, the freshwater planarians (Turbellaria, Tricladida) have been used as model systems for studying bidirectional regeneration (Slack, J. M. W. (1980) J. Theor. Biol 82, 105-140). We have been attempting to identify potential pattern-control genes involved in the regeneration of planarian heads and tails after amputation. Since Hox cluster genes determine positional identity along the anteroposterior axis in a wide range of animals (Slack, J. M. W., Holland, P. W. H. and Graham, C. F. (1993) Nature 361,490-492), we performed an extensive search for Hox-related genes in the planarian Dugesia(G)tigrina. Sequence analyses of seven planarian Dthox genes (Dthox-A to Dthox-G) reveal high similarities with the homeodomain region of the Hox cluster genes, allowing us to assign planarian Dthox genes to anterior and medial Hox cluster paralogous groups. Whole-mount in situ hybridization studies in regenerating adults showed very early, synchronous and colocalized activation of Dthox-D, Dthox-A, Dthox-C, Dthox-E, Dthox-G and Dthox-F. After one hour of regeneration a clear expression was observed in all Dthox genes studied. In addition, all seemed to be expressed in the same regenerative tissue, although in the last stages of regeneration (9 to 15 days) a differential timing of deactivation was observed. The same Dthox genes were also expressed synchronously and were colocalized during intercalary regeneration, although their expression was delayed. Terminal regeneration showed identical Dthox gene expression in anterior and posterior blastemas, which may prevent these genes from directing the distinction between head and tail. Finally, continuous expression along the whole lateral blastema in sagittal regenerates reflected a
Nakatani, Yuki; Kawakami, Atsushi; Kudo, Akira
The phenomenon of 'epimorphic regeneration', a complete reformation of lost tissues and organs from adult differentiated cells, has been fascinating many biologists for many years. While most vertebrate species including humans do not have a remarkable ability for regeneration, the lower vertebrates such as urodeles and fish have exceptionally high regeneration abilities. In particular, the teleost fish has a high ability to regenerate a variety of tissues and organs including scales, muscles, spinal cord and heart among vertebrate species. Hence, an understanding of the regeneration mechanism in teleosts will provide an essential knowledge base for rational approaches to tissue and organ regeneration in mammals. In the last decade, small teleost fish such as the zebrafish and medaka have emerged as powerful animal models in which a variety of developmental, genetic and molecular approaches are applicable. In addition, rapid progress in the development of genome resources such as expressed sequence tags and genome sequences has accelerated the speed of the molecular analysis of regeneration. This review summarizes the current status of our understanding of the cellular and molecular basis of regeneration, particularly that regarding fish fins.
Satoh, Akira; Cummings, Gillian M C; Bryant, Susan V; Gardiner, David M
The ability of animals to repair tissue damage is widespread and impressive. Among tissues, the repair and remodeling of bone occurs during growth and in response to injury; however, loss of bone above a threshold amount is not regenerated, resulting in a "critical-size defect" (CSD). The development of therapies to replace or regenerate a CSD is a major focus of research in regenerative medicine and tissue engineering. Adult urodeles (salamanders) are unique in their ability to regenerate complex tissues perfectly, yet like mammals do not regenerate a CSD. We report on an experimental model for the regeneration of a CSD in the axolotl (the Excisional Regeneration Model) that allows for the identification of signals to induce fibroblast dedifferentiation and skeletal regeneration. This regenerative response is mediated in part by BMP signaling, as is the case in mammals; however, a complete regenerative response requires the induction of a population of undifferentiated, regeneration-competent cells. These cells can be induced by signaling from limb amputation to generate blastema cells that can be grafted to the wound, as well as by signaling from a nerve and a wound epithelium to induce blastema cells from fibroblasts within the wound environment.
Wenemoser, Danielle; Reddien, Peter W
Regeneration requires signaling from a wound site for detection of the wound and a mechanism that determines the nature of the injury to specify the appropriate regenerative response. Wound signals and tissue responses to wounds that elicit regeneration remain poorly understood. Planarians are able to regenerate from essentially any type of injury and present a novel system for the study of wound responses in regeneration initiation. Newly developed molecular and cellular tools now enable study of regeneration initiation using the planarian Schmidtea mediterranea. Planarian regeneration requires adult stem cells called neoblasts and amputation triggers two peaks in neoblast mitoses early in regeneration. We demonstrate that the first mitotic peak is a body-wide response to any injury and that a second, local, neoblast response is induced only when injury results in missing tissue. This second response was characterized by recruitment of neoblasts to wounds, even in areas that lack neoblasts in the intact animal. Subsequently, these neoblasts were induced to divide and differentiate near the wound, leading to formation of new tissue. We conclude that there exist two functionally distinct signaling phases of the stem cell wound response that distinguish between simple injury and situations that require the regeneration of missing tissue.
Garza-Garcia, A Acely; Driscoll, Paul C; Brockes, Jeremy P
The most extensive regenerative ability in adult vertebrates is found in the salamanders. Although it is often suggested that regeneration is an ancestral property for vertebrates, our studies on the cell-surface three-finger-protein Prod 1 provide clear evidence for the importance of local evolution of limb regeneration in salamanders. Prod 1 is implicated in both patterning and growth in the regeneration of limbs. It interacts with well-conserved proteins such as the epidermal growth-factor receptor and the anterior gradient protein that are widely expressed in phylogeny. A detailed analysis of the structure and sequence of Prod 1 in relation to other vertebrate three-finger proteins in mammals and zebra fish supports the view that it is a salamander-specific protein. This is the first example of a taxon-specific protein that is clearly implicated in the mechanisms of regeneration. We propose the hypothesis that regeneration depends on the activity of taxon-specific components in orchestrating a cellular machinery that is extensively conserved between regenerating and non-regenerating taxa. This hypothesis has significant implications for our outlook on regeneration in vertebrates, as well as for the strategies employed in extending regenerative ability in mammals.
Godwin, James W; Rosenthal, Nadia
Salamanders and frogs are distinct orders of Amphibians with very different immune systems during adult life, exhibiting varying potential for scar free repair and regeneration. While salamanders can regenerate a range of body parts throughout all stages of life, regeneration is restricted to early stages of frog development. Comparison of these two closely related amphibian orders provides insights into the immunological influences on wound repair, and the different strategies that have evolved either to limit infection or to facilitate efficient regeneration. After injury, cells of the immune system are responsible for the removal of damaged cells and providing a cohort of important growth factors and signaling molecules. Immune cells not only regulate new vessel growth important for supplying essential nutrients to damaged tissue but, modulate the extracellular matrix environment by regulating fibroblasts and the scarring response. The profile of immune cell infiltration and their interaction with local tissue immune cells directly influences many aspects of the wound healing outcomes and can facilitate or prevent regeneration. Evidence is emerging that the transition from wound healing to regeneration is reliant on immune cell engagement and that the success of regeneration in amphibians may depend on complex interactions between stem cell progenitors and immune cell subsets. The potential immunological barriers to mammalian regeneration are discussed with implications for the successful delivery of stem cell therapeutic strategies in patients.
Wurster, Susann L., Ed.
Describes training and adult education resources available from ERIC: "Applications of an Adult Motivational Instructional Design Model"; "Visual and Digital Technologies for Adult Learning"; "Applications of Computer-Aided Instruction in Adult Education and Literacy"; and "The San Diego CWELL Project. Report of…
Hönekopp, Johannes; Bartholdt, Luise; Beier, Lothar; Liebert, Andreas
The relative length of the second (index) to the fourth (ring) finger (2D:4D) is a putative negative correlate of prenatal testosterone (T) exposure. Therefore, 2D:4D (and to a lesser extent D(r-l), the difference between 2D:4D in the right hand and in the left hand) has often been used to study effects of prenatal androgenization on human behavior and cognition. However, evidence suggests that 2D:4D may also be related to levels of circulating sex hormones in adults. This would question the validity of 2D:4D as a means of studying the effects of prenatal sex hormones. Here we present new data from two non-clinical samples (64 women and 102 men) regarding the relationships of 2D:4D and D(r-l) with circulating sex hormone levels. We then present a meta-analytic review of all the present evidence regarding this issue. The results suggest that, in the normal population, 2D:4D and D(r-l) are not associated with adult sex hormone levels. The findings from this current study add to the growing body of evidence demonstrating that 2D:4D is a suitable tool to study the effects of prenatal androgenization on human behavior and cognition.
Baird, Richard A.
The bullfrog saccule, a sensor of gravity and substrate-borne vibration, is a model system for hair cell transduction. Saccular hair cells also increase in number throughout adult life and rapidly recover after hair cell damage, making this organ an ideal system for studying hair cell development, repair, and regeneration. We have used of hair cell and supporting cell immunocytochemical markers to identify damaged hair cells and hair cell precursors in organotypic cultures of the bullfrog saccule. We then used an innovative combination of confocal, electron, and time-lapse microscopy to study the fate of damaged hair cells and the origin of new hair cells after gentamicin ototoxicity in normal and mitotically blocked saccular cultures. These studies have shown that gentamicin ototoxicity produces both lethal and sublethal hair cell damage. They have also shown that hair cell recovery in this organ takes place by both the repair of sublethally damaged hair cells and by the replacement of lost hair cells by mitotic regeneration. In parallel studies, we have used biophysical and molecular biological techniques to study the differentiation and innervation of developing, repairing, and regenerating hair cells. More specifically, we have used RT-PCR to obtain the bullfrog homologues of L-type voltage- gated calcium (L-VGCC) and large-conductance Ca(2+)-activated potassium (BK) channel genes. We have then obtained probes for these genes and, using in situ hybridization, begun to examine their expression in the bullfrog saccule and amphibian papilla. We have also used fluorescent-labeled channel toxins and channel toxin derivatives to determine the time of appearance of L-type voltage-gated calcium (L-VGCC) and Ca(2+)-activated potassium (BK) channels and to study dynamic changes in the number, distribution, and co-localization of these proteins in developing, repairing, and regenerating hair cells. Using time-lapse microscopy, we are also studying the dynamic relationship
Finds that the recent National Press Photographers Association code of ethics can serve as a model for any photography staff. Discusses how digital imaging is becoming commonplace in classrooms, due to decreasing costs and easier software. Explains digital terminology. Concludes that time saved in the darkroom and at the printer is now spent on…
Islam, Md. Rafiqul; Nakamura, Kenta; Casco-Robles, Martin Miguel; Kunahong, Ailidana; Inami, Wataru; Toyama, Fubito; Maruo, Fumiaki; Chiba, Chikafumi
The reprogramming of retinal pigment epithelium (RPE) cells in the adult newt immediately after retinal injury is an area of active research for the study of retinal disorders and regeneration. We demonstrate here that unlike embryonic/larval retinal regeneration, adult newt RPE cells are not directly reprogrammed into retinal stem/progenitor cells; instead, they are programmed into a unique state of multipotency that is similar to the early optic vesicle (embryo) but preserves certain adult characteristics. These cells then differentiate into two populations from which the prospective-neural retina and -RPE layers are formed with the correct polarity. Furthermore, our findings provide insight into the similarity between these unique multipotent cells in newts and those implicated in retinal disorders, such as proliferative vitreoretinopathy, in humans. These findings provide a foundation for biomedical approaches that aim to induce retinal self-regeneration for the treatment of RPE-mediated retinal disorders. PMID:25116407
Peiris, T Harshani; Hoyer, Katrina K; Oviedo, Néstor J
The immune system has been implicated as an important modulator of tissue regeneration. However, the mechanisms driving injury-induced immune response and tissue repair remain poorly understood. For over 200 years, planarians have been a classical model for studies on tissue regeneration, but the planarian immune system and its potential role in repair is largely unknown. We found through comparative genomic analysis and data mining that planarians contain many potential homologs of the innate immune system that are activated during injury and repair of adult tissues. These findings support the notion that the relationship between adult tissue repair and the immune system is an ancient feature of basal Bilateria. Further analysis of the planarian immune system during regeneration could potentially add to our understanding of how the innate immune system and inflammatory responses interplay with regenerative signals to induce scar-less tissue repair in the context of the adult organism.
Paveliev, Mikhail; Fenrich, Keith K.; Kislin, Mikhail; Kuja-Panula, Juha; Kulesskiy, Evgeny; Varjosalo, Markku; Kajander, Tommi; Mugantseva, Ekaterina; Ahonen-Bishopp, Anni; Khiroug, Leonard; Kulesskaya, Natalia; Rougon, Geneviève; Rauvala, Heikki
Chondroitin sulfate (CS) glycosaminoglycans inhibit regeneration in the adult central nervous system (CNS). We report here that HB-GAM (heparin-binding growth-associated molecule; also known as pleiotrophin), a CS-binding protein expressed at high levels in the developing CNS, reverses the role of the CS chains in neurite growth of CNS neurons in vitro from inhibition to activation. The CS-bound HB-GAM promotes neurite growth through binding to the cell surface proteoglycan glypican-2; furthermore, HB-GAM abrogates the CS ligand binding to the inhibitory receptor PTPσ (protein tyrosine phosphatase sigma). Our in vivo studies using two-photon imaging of CNS injuries support the in vitro studies and show that HB-GAM increases dendrite regeneration in the adult cerebral cortex and axonal regeneration in the adult spinal cord. Our findings may enable the development of novel therapies for CNS injuries. PMID:27671118
Peiris, T. Harshani; Hoyer, Katrina K.; Oviedo, Néstor J.
The immune system has been implicated as an important modulator of tissue regeneration. However, the mechanisms driving injury-induced immune response and tissue repair remain poorly understood. For over 200 years, planarians have been a classical model for studies on tissue regeneration, but the planarian immune system and its potential role in repair is largely unknown. We found through comparative genomic analysis and data mining that planarians contain many potential homologs of the innate immune system that are activated during injury and repair of adult tissues. These findings support the notion that the relationship between adult tissue repair and the immune system is an ancient feature of basal Bilateria. Further analysis of the planarian immune system during regeneration could potentially add to our understanding of how the innate immune system and inflammatory responses interplay with regenerative signals to induce scar-less tissue repair in the context of the adult organism. PMID:25082737
Qin, Song; Zou, Yuhua; Zhang, Chun-Li
Cytokine-induced activation of signal transducer and activator of transcription 3 (STAT3) promotes the regrowth of damaged axons in the adult central nervous system (CNS). Here we show that KLF4 physically interacts with STAT3 upon cytokine-induced phosphorylation of tyrosine 705 (Y705) on STAT3. This interaction suppresses STAT3-dependent gene expression by blocking its DNA-binding activity. The deletion of KLF4 in vivo induces axon regeneration of adult retinal ganglion cells (RGCs) via Janus kinase (JAK)-STAT3 signalling. This regeneration can be greatly enhanced by exogenous cytokine treatment, or removal of an endogenous JAK-STAT3 pathway inhibitor called suppressor of cytokine signalling 3 (SOCS3). These findings reveal an unexpected cross-talk between KLF4 and activated STAT3 in the regulation of axon regeneration that might have therapeutic implications in promoting repair of injured adult CNS.
Lim, Chay Ngee; Birnbaum, Angela K.; Brundage, Richard C.; Leppik, Ilo E.; Cloyd, James C.; Clark, Annie; Marino, Susan E.
A sequential pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was used to quantify the effects of a single dose of topiramate (100 or 200 mg) on working memory, attention, and psychomotor speed as measured by the Symbol-Digit Modalities Test (SDMT). Established on data pooled from 3 randomized, crossover studies in healthy subjects (19–55 years of age), using both oral and a novel stable-labeled intravenous (IV) formulation of topiramate, an inhibitory Emax model was found to characterize the topiramate concentration-SDMT score relationship well. At the EC50 of 2.85 μg/mL, this topiramate plasma concentration value was estimated to be associated with a 25.5% reduction of SDMT score relative to baseline. Age was an important determinant of the baseline SDMT score, with an estimated decrease of 1.13% in baseline SDMT score with every year of age. Moreover, this approach enabled the quantification of the practice effect observed with repeated administration of the neuropsychological test over shorter testing intervals than have previously been reported in the literature. The finding of a significant effect following a single dose of topiramate in the range widely used to treat migraine and epilepsy needs to be evaluated in a broader patient population undergoing chronic treatment, as the narrow range of resultant concentrations limits the generalizability of the findings. PMID:26395889
Menicanin, Danijela; Hynes, K; Han, J; Gronthos, S; Bartold, P M
The unique anatomy and composition of the periodontium make periodontal tissue healing and regeneration a complex process. Periodontal regeneration aims to recapitulate the crucial stages of wound healing associated with periodontal development in order to restore lost tissues to their original form and function and for regeneration to occur, healing events must progress in an ordered and programmed sequence both temporally and spatially, replicating key developmental events. A number of procedures have been employed to promote true and predictable regeneration of the periodontium. Principally, the approaches are based on the use of graft materials to compensate for the bone loss incurred as a result of periodontal disease, use of barrier membranes for guided tissue regeneration and use of bioactive molecules. More recently, the concept of tissue engineering has been integrated into research and applications of regenerative dentistry, including periodontics, to aim to manage damaged and lost oral tissues, through reconstruction and regeneration of the periodontium and alleviate the shortcomings of more conventional therapeutic options. The essential components for generating effective cellular based therapeutic strategies include a population of multi-potential progenitor cells, presence of signalling molecules/inductive morphogenic signals and a conductive extracellular matrix scaffold or appropriate delivery system. Mesenchymal stem cells are considered suitable candidates for cell-based tissue engineering strategies owing to their extensive expansion rate and potential to differentiate into cells of multiple organs and systems. Mesenchymal stem cells derived from multiple tissue sources have been investigated in pre-clinical animal studies and clinical settings for the treatment and regeneration of the periodontium.
Grigoryan, E.; Anton, H.; Mitashov, V.
For better understanding of micro-"g" effect on nervous tissue regeneration we have chosen the regeneration of the Urodele tail, because it utilizes many developmental processes and represents the most convenient model for experiments in Space. The special interesting aspect lies in the ability of regenerates to differentiate the spinal cord (SC) and this, in turn, has a potential of practical application. Meanwhile there are conclusive evidences suggesting the production by SC cells the neurotrophic factors promoting cell proliferation and differentiation in growing tail regenerate. Previously our studies on tail regeneration in the adult newt showed that the force of gravity clearly inf luences the events underlying the regeneration. We reported the significant increase of tail regeneration rate and tissue volume of tail regenerates in the newts exposed to real and simulated low "g". In Bion 11 mission animals that were exposed 14 days in microgravity and whose tails were operated two and four weeks before launch demonstrated the regenerates achieved 1.5 - 2 times the volume of those in 1"g" control. Results of this experiment indicated also that the regeneration of central and peripheral neurons and nerve fibers was carrying out faster under low "g" conditions than in 1 "g" control. Similar data were obtained in several experiments remodeling physiological weightlessness by mean of the clinostat. It led us to the hypothesis that the stimulation of tail regeneration is linked with an over activation of neurotrophic factors produced by quickly growing SC neurons. Now we've completed the experiment on tail regeneration in the newts Tr. alpestris subjected to 5 day long clinorotation after 6 days post tail amputation. The rate of primary- and secondary regeneration was evaluated at different time points after treatment. Cell proliferation, differentiation and expression of neurotrophic proteins in SC and other major tissue-type of regenerate were investigated by
Kashani, A.; Helvensteijn, B. P. M.; Feller, J. R.; Salerno, L. J.; Kittel, P.
Testing regenerators presents an interesting challenge. When incorporated into a cryocooler, a regenerator is intimately coupled to the other components: expander, heat exchangers, and compressor. It is difficult to isolate the performance of any single component. We have developed a low temperature test facility that will allow us to separate the performance of the regenerator from the rest of the cryocooler. The purpose of the facility is the characterization of test regenerators using novel materials and/or geometries in temperature ranges down to 15 K. It consists of the following elements: The test column has two regenerators stacked in series. The coldest stage regenerator is the device under test. The warmer stage regenerator contains a stack of stainless steel screen, a well-characterized material. A commercial cryocooler is used to fix the temperatures at both ends of the test regenerator, cooling both heat exchangers flanging the regenerator stack. Heaters allow varying the temperatures and allow measurement of the remaining cooling power, and thus, regenerator effectiveness. A linear compressor delivers an oscillating pressure to the regenerator assembly. An inertance tube and reservoir provide the proper phase difference between mass flow and pressure. This phase shift, along with the imposed temperature differential, simulates the conditions of the test regenerator when used in an actual pulse tube cryocooler. This paper presents development details of the regenerator test facility, and test results on a second stage, stainless steel screen test regenerator.
Rinkevich, Yuval; Paz, Guy; Rinkevich, Baruch; Reshef, Ram
Regeneration in adult chordates is confined to a few model cases and terminates in restoration of restricted tissues and organs. Here, we study the unique phenomenon of whole body regeneration (WBR) in the colonial urochordate Botrylloides leachi in which an entire adult zooid is restored from a miniscule blood vessel fragment. In contrast to all other documented cases, regeneration is induced systemically in blood vessels. Multiple buds appear simultaneously in newly established regeneration niches within vasculature fragments, stemming from composites of pluripotent blood cells and terminating in one functional zooid. We found that retinoic acid (RA) regulates diverse developmental aspects in WBR. The homologue of the RA receptor and a retinaldehyde dehydrogenase-related gene were expressed specifically in blood cells within regeneration niches and throughout bud development. The addition of RA inhibitors as well as RNA interference knockdown experiments resulted in WBR arrest and bud malformations. The administration of all-trans RA to blood vessel fragments resulted in doubly accelerated regeneration and multibud formation, leading to restored colonies with multiple zooids. The Botrylloides system differs from known regeneration model systems by several fundamental criteria, including epimorphosis without the formation of blastema and the induction of a “multifocal regeneration niche” system. This is also to our knowledge the first documented case of WBR from circulating blood cells that restores not only the soma, but also the germ line. This unique Botrylloides WBR process could serve as a new in vivo model system for regeneration, suggesting that RA signaling may have had ancestral roles in body restoration events. PMID:17341137
A great numbers of cardiovascular disease patients all over the world are suffering in the poor outcomes. Under this situation, cardiac regeneration therapy to reorganize the postnatal heart that is defined as a terminal differentiated-organ is a very important theme and mission for human beings. However, the temporary success of several clinical trials using usual cell types with uncertain cell numbers has provided the transient effect of cell therapy to these patients. We therefore should redevelop the evidence of cell-based cardiovascular regeneration therapy, focusing on targets (disease, patient’s status, cardiac function), materials (cells, cytokines, genes), and methodology (transplantation route, implantation technology, tissue engineering). Meanwhile, establishment of the induced pluripotent stem (iPS) cells is an extremely innovative technology which should be proposed as embryonic stem (ES) cellularization of post natal somatic cells, and this application have also showed the milestones of the direct conversion to reconstruct cardiomyocyte from the various somatic cells, which does not need the acquisition of the re-pluripotency. This review discusses the new advance in cardiovascular regeneration therapy from cardiac regeneration to cardiac re-organization, which is involved in recent progress of on-going clinical trials, basic research in cardiovascular regeneration, and the possibility of tissue engineering technology. PMID:23825492
Rao, Subramaniam M; Ugale, Gauri M; Warad, Shivaraj B
Periodontitis is an infectious inflammatory disease that results in attachment loss and bone loss. Regeneration of the periodontal tissues entails de novo formation of cementum, periodontal ligament, and alveolar bone. Several different approaches are currently being explored to achieve complete, reliable, and reproducible regeneration of periodontal tissues. The therapeutic management of new bone formation is one of the key issues in successful periodontal regeneration. Bone morphogenetic proteins form a unique group of proteins within the transforming growth factor superfamily of genes and have a vital role in the regulation in the bone induction and maintenance. The activity of bone morphogenetic proteins was first identified in the 1960s, but the proteins responsible for bone induction were unknown until the purification and cloning of human bone morphogenetic proteins in the 1980s, because of their osteoinductive potential. Bone morphogenetic proteins have gained a lot of interest as therapeutic agents for treating periodontal defects. A systematic search for data related to the use of bone morphogenetic proteins for the regeneration of periodontal defects was performed to recognize studies on animals and human (PUBMED, MEDLINE, COCHRANE, and Google search). All the studies included showed noticeable regeneration of periodontal tissues with the use of BMP. PMID:23626951
Mozdziak, P. E.; Truong, Q.; Macius, A.; Schultz, E.
Exposure of juvenile skeletal muscle to a weightless environment reduces growth and satellite cell mitotic activity. However, the effect of a weightless environment on the satellite cell population during muscle repair remains unknown. Muscle injury was induced in rat soleus muscles using the myotoxic snake venom, notexin. Rats were placed into hindlimb-suspended or weightbearing groups for 10 days following injury. Cellular proliferation during regeneration was evaluated using 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry and image analysis. Hindlimb suspension reduced (P < 0.05) regenerated muscle mass, regenerated myofiber diameter, uninjured muscle mass, and uninjured myofiber diameter compared to weightbearing rats. Hindlimb suspension reduced (P < 0.05) BrdU labeling in uninjured soleus muscles compared to weight-bearing muscles. However, hindlimb suspension did not abolish muscle regeneration because myofibers formed in the injured soleus muscles of hindlimb-suspended rats, and BrdU labeling was equivalent (P > 0.10) on myofiber segments isolated from the soleus muscles of hindlimb-suspended and weightbearing rats following injury. Thus, hindlimb suspension (weightlessness) does not suppress satellite cell mitotic activity in regenerating muscles before myofiber formation, but reduces growth of the newly formed myofibers.
Heber-Katz, Ellen; Zhang, Yong; Bedelbaeva, Khamila; Song, Fengyu; Chen, Xiaoping; Stocum, David L
Regeneration of ear punch holes in the MRL mouse and amputated limbs of the axolotl show a number of similarities. A large proportion of the fibroblasts of the uninjured MRL mouse ear are arrested in G2 of the cell cycle, and enter nerve-dependent mitosis after injury to form a ring-shaped blastema that regenerates the ear tissue. Multiple cell types contribute to the establishment of the regeneration blastema of the urodele limb by dedifferentiation, and there is substantial reason to believe that the cells of this early blastema are also arrested in G2, and enter mitosis under the influence of nerve-dependent factors supplied by the apical epidermal cap. Molecular analysis reveals other parallels, such as; (1) the upregulation of Evi5, a centrosomal protein that prevents mitosis by stabilizing Emi1, a protein that inhibits the degradation of cyclins by the anaphase promoting complex and (2) the expression of sodium channels by the epidermis. A central feature in the entry into the cell cycle by MRL ear fibroblasts is a natural downregulation of p21, and knockout of p21 in wild-type mice confers regenerative capacity on non-regenerating ear tissue. Whether the same is true for entry into the cell cycle in regenerating urodele limbs is presently unknown.
Salathé, Marcel; Bengtsson, Linus; Bodnar, Todd J.; Brewer, Devon D.; Brownstein, John S.; Buckee, Caroline; Campbell, Ellsworth M.; Cattuto, Ciro; Khandelwal, Shashank; Mabry, Patricia L.; Vespignani, Alessandro
Mobile, social, real-time: the ongoing revolution in the way people communicate has given rise to a new kind of epidemiology. Digital data sources, when harnessed appropriately, can provide local and timely information about disease and health dynamics in populations around the world. The rapid, unprecedented increase in the availability of relevant data from various digital sources creates considerable technical and computational challenges. PMID:22844241
Segers, Vincent F M; Lee, Richard T
Although most medicines have historically been small molecules, many newly approved drugs are derived from proteins. Protein therapies have been developed for treatment of diseases in almost every organ system, including the heart. Great excitement has now arisen in the field of regenerative medicine, particularly for cardiac regeneration after myocardial infarction. Every year, millions of people suffer from acute myocardial infarction, but the adult mammalian myocardium has limited regeneration potential. Regeneration of the heart after myocardium infarction is therefore an exciting target for protein therapeutics. In this review, we discuss different classes of proteins that have therapeutic potential to regenerate the heart after myocardial infarction. Protein candidates have been described that induce angiogenesis, including fibroblast growth factors and vascular endothelial growth factors, although thus far clinical development has been disappointing. Chemotactic factors that attract stem cells, e.g., hepatocyte growth factor and stromal cell-derived factor-1, may also be useful. Finally, neuregulins and periostin are proteins that induce cell-cycle reentry of cardiomyocytes, and growth factors like IGF-1 can induce growth and differentiation of stem cells. As our knowledge of the biology of regenerative processes and the role of specific proteins in these processes increases, the use of proteins as regenerative drugs could develop as a cardiac therapy.
Bai, Xue; Wang, Yingjie; Man, Lili; Zhang, Qing; Sun, Cheng; Hu, Wen; Liu, Yan; Liu, Mei; Gu, Xiaosong; Wang, Yongjun
The regeneration-competent adult animals have ability to regenerate their lost complex appendages with a near-perfect replica, owing to the positional identity acquired by the progenitor cells in the blastema, i.e. the blastemal cells. CD59, a CD59/Ly6 family member, has been identified as a regulator of positional identity in the tail blastemal cells of Gekko japonicus. To determine whether this function of CD59 is unique to the regenerative amniote(s) and how CD59 mediates PD axis patterning during tail regeneration, we examined its protective role on the complement-mediated cell lysis and intervened CD59 expression in the tail blastemal cells using an in vivo model of adenovirus transfection. Our data revealed that gecko CD59 was able to inhibit complement-mediated cell lysis. Meanwhile, CD59 functioned on positional identity through expression in cartilage precursor cells. Intervening positional identity by overexpression or siRNA knockdown of CD59 resulted in abnormal cartilaginous cone patterning due to the decreased differentiation of blastemal cells to cartilage precursor cells. The cartilage formation-related genes were found to be under the regulation of CD59. These results indicate that CD59, an evolutionarily transitional molecule linking immune and regenerative regulation, affects tail regeneration by mediating cartilage patterning. PMID:26238652
Itou, Junji; Oishi, Isao; Kawakami, Hiroko; Glass, Tiffany J; Richter, Jenna; Johnson, Austin; Lund, Troy C; Kawakami, Yasuhiko
Adult zebrafish possess a significant ability to regenerate injured heart tissue through proliferation of pre-existing cardiomyocytes, which contrasts with the inability of mammals to do so after the immediate postnatal period. Zebrafish therefore provide a model system in which to study how an injured heart can be repaired. However, it remains unknown what important processes cardiomyocytes are involved in other than partial de-differentiation and proliferation. Here we show that migration of cardiomyocytes to the injury site is essential for heart regeneration. Ventricular amputation induced expression of cxcl12a and cxcr4b, genes encoding a chemokine ligand and its receptor. We found that cxcl12a was expressed in the epicardial tissue and that Cxcr4 was expressed in cardiomyocytes. We show that pharmacological blocking of Cxcr4 function as well as genetic loss of cxcr4b function causes failure to regenerate the heart after ventricular resection. Cardiomyocyte proliferation was not affected but a large portion of proliferating cardiomyocytes remained localized outside the injury site. A photoconvertible fluorescent reporter-based cardiomyocyte-tracing assay demonstrates that cardiomyocytes migrated into the injury site in control hearts but that migration was inhibited in the Cxcr4-blocked hearts. By contrast, the epicardial cells and vascular endothelial cells were not affected by blocking Cxcr4 function. Our data show that the migration of cardiomyocytes into the injury site is regulated independently of proliferation, and that coordination of both processes is necessary for heart regeneration.
Druin, Allison; Bederson, Benjamin B.; Hourcade, Juan Pablo; Sherman, Lisa; Revelle, Glenda; Platner, Michele; Weng, Stacy
As more information resources become accessible using computers, the digital interfaces to those resources need to be appropriate for all people. However, when it comes to digital libraries, the interfaces have typically been designed for older children or adults. The researchers have begun to develop a digital library interface that is…
Discusses digital collections and digital libraries. Topics include broadband availability; digital rights protection; content, both non-profit and commercial; digitization of cultural content; sustainability; metadata harvesting protocol; infrastructure; authorship; linking multiple resources; data mining; digitization of reference works;…
This book approaches adult cardiac disease from the correlative imaging perspective. It includes chest X-rays and angiographs, 2-dimensional echocardiograms with explanatory diagrams for clarity, plus details on digital radiology, nuclear medicine techniques, CT and MRI. It also covers the normal heart, valvular heart disease, myocardial disease, pericardial disease, bacterial endocarditis, aortic aneurysm, cardiac tumors, and congenital heart disease of the adult. It points out those aspects where one imaging technique has significant superiority.
Jackman, Anthony V.
A seal assembly for disposition between a cross arm on a gas turbine engine block and a regenerator disc, the seal assembly including a platform coextensive with the cross arm, a seal and wear layer sealingly and slidingly engaging the regenerator disc, a porous and compliant support layer between the platform and the seal and wear layer porous enough to permit flow of cooling air therethrough and compliant to accommodate relative thermal growth and distortion, a dike between the seal and wear layer and the platform for preventing cross flow through the support layer between engine exhaust and pressurized air passages, and air diversion passages for directing unregenerated pressurized air through the support layer to cool the seal and wear layer and then back into the flow of regenerated pressurized air.
Fucinari, C. A.; Rahnke, C. J.; Rao, V. D. N.; Vallance, J. K.
The DOE/NASA Ceramic Regenerator Design and Reliability Program aims to develop ceramic regenerator cores that can be used in passenger car and industrial/truck gas turbine engines. The major cause of failure of early gas turbine regenerators was found to be chemical attack of the ceramic material. Improved materials and design concepts aimed at reducing or eliminating chemical attack were placed on durability test in Ford 707 industrial gas turbine engines late in 1974. Results of 53,065 hours of turbine engine durability testing are described. Two materials, aluminum silicate and magnesium aluminum silicate, show promise. Five aluminum silicate cores attained the durability objective of 10,000 hours at 800 C (1472 F). Another aluminum silicate core shows minimal evidence of chemical attack after 8071 hours at 982 C (1800 F). Results obtained in ceramic material screening tests, aerothermodynamic performance tests, stress analysis, cost studies, and material specifications are included.
Amir, Lisa R; Everts, Vincent; Bronckers, Antonius L J J
Bone has the capacity to regenerate in response to injury. During distraction osteogenesis, the renewal of bone is enhanced by gradual stretching of the soft connective tissues in the gap area between two separated bone segments. This procedure has received much clinical attention as a way to correct congenital growth retardation of bone tissue or to generate bone to fill skeletal defects. The process of bone regeneration involves a complex system of biological changes whereby mechanical stress is converted into a cascade of signals that activate cellular behavior resulting in (enhanced) formation of bone. Over the last decade, significant progress has been made in understanding the bone regeneration process during distraction osteogenesis. The mechanical and biological factors that are important for the success of the distraction treatment have been partially characterized and are discussed in this review.
Nasise, J.E.; Anderson, J.L.; Naruse, Y.
A Molecular Sieve Regeneration System (MSRS) was added to the existing Tritium Waste Treatment system (TWT) within the Tritium Systems Test Assembly (TSTA) at Los Alamos National Laboratory. The Department of Energy (DOE) no longer allows ``inventory by difference`` for radioactive wastes that are to be buried. The MSRS was designed and built to comply with this requirement. Within the TWT, water is generated by the catalytic conversion of hydrogen isotopes and removed by molecular sieve trapping prior to release to the environment. Molecular sieve regeneration is required to remove the trapped water and to rejuvenate the beds. The MSRS permits the collection and direct tritium assay of regenerated tritiated water from molecular sieve beds. This paper describes the MSRS in detail and how it is interfaced with the TWT.
Nasise, J.E.; Anderson, J.L. ); Naruse, Y. )
A Molecular Sieve Regeneration System (MSRS) was added to the existing Tritium Waste Treatment system (TWT) within the Tritium Systems Test Assembly (TSTA) at Los Alamos National Laboratory. The Department of Energy (DOE) no longer allows inventory by difference'' for radioactive wastes that are to be buried. The MSRS was designed and built to comply with this requirement. Within the TWT, water is generated by the catalytic conversion of hydrogen isotopes and removed by molecular sieve trapping prior to release to the environment. Molecular sieve regeneration is required to remove the trapped water and to rejuvenate the beds. The MSRS permits the collection and direct tritium assay of regenerated tritiated water from molecular sieve beds. This paper describes the MSRS in detail and how it is interfaced with the TWT.
The present invention provides a process for treating both cations and anions by using a self-regenerating, multi-ionic exchange resin column system which requires no separate regeneration steps. The process involves alternating ion-exchange chromatography for cations and anions in a multi-ionic exchange column packed with a mixture of cation and anion exchange resins. The multi-ionic mixed-charge resin column works as a multi-function column, capable of independently processing either cationic or anionic exchange, or simultaneously processing both cationic and anionic exchanges. The major advantage offered by the alternating multi-function ion exchange process is the self-regeneration of the resins.
Carlson, Bruce M
This article presents some general principles underlying regenerative phenomena in vertebrates, starting with the epimorphic regeneration of the amphibian limb and continuing with tissue and organ regeneration in mammals. Epimorphic regeneration following limb amputation involves wound healing, followed shortly by a phase of dedifferentiation that leads to the formation of a regeneration blastema. Up to the point of blastema formation, dedifferentiation is guided by unique regenerative pathways, but the overall developmental controls underlying limb formation from the blastema generally recapitulate those of embryonic limb development. Damaged mammalian tissues do not form a blastema. At the cellular level, differentiation follows a pattern close to that seen in the embryo, but at the level of the tissue and organ, regeneration is strongly influenced by conditions inherent in the local environment. In some mammalian systems, such as the liver, parenchymal cells contribute progeny to the regenerate. In others, e.g., skeletal muscle and bone, tissue-specific progenitor cells constitute the main source of regenerating cells. The substrate on which regeneration occurs plays a very important role in determining the course of regeneration. Epimorphic regeneration usually produces an exact replica of the structure that was lost, but in mammalian tissue regeneration the form of the regenerate is largely determined by the mechanical environment acting on the regenerating tissue, and it is normally an imperfect replica of the original. In organ hypertophy, such as that occurring after hepatic resection, the remaining liver mass enlarges, but there is no attempt to restore the original form.
Awal, Mehraj R.; Shay, James; McLoed, Melissa M.; Mazur, Eric; Gabel, Christopher V.
During development, a neuron transitions from a state of rapid growth to a stable morphology, and neurons within the adult mammalian CNS lose their ability to effectively regenerate in response to injury. Here, we identify a novel form of neuronal regeneration, which is remarkably independent of DLK-1/DLK, KGB-1/JNK, and other MAPK signaling factors known to mediate regeneration in Caenorhabditis elegans, Drosophila, and mammals. This DLK-independent regeneration in C. elegans has direct genetic and molecular links to a well-studied form of endogenous activity-dependent ectopic axon outgrowth in the same neuron type. Both neuron outgrowth types are triggered by physical lesion of the sensory dendrite or mutations disrupting sensory activity, calcium signaling, or genes that restrict outgrowth during neuronal maturation, such as SAX-1/NDR kinase or UNC-43/CaMKII. These connections suggest that ectopic outgrowth represents a powerful platform for gene discovery in neuronal regeneration. Moreover, we note numerous similarities between C. elegans DLK-independent regeneration and lesion conditioning, a phenomenon producing robust regeneration in the mammalian CNS. Both regeneration types are triggered by lesion of a sensory neurite via reduction of neuronal activity and enhanced by disrupting L-type calcium channels or elevating cAMP. Taken as a whole, our study unites disparate forms of neuronal outgrowth to uncover fresh molecular insights into activity-dependent control of the adult nervous system’s intrinsic regenerative capacity. PMID:27078101
Milner, Derek J; Cameron, Jo Ann
Skeletal muscle possesses a robust innate capability for repair of tissue damage. Natural repair of muscle damage is a stepwise process that requires the coordinated activity of a number of cell types, including infiltrating macrophages, resident myogenic and non-myogenic stem cells, and connective tissue fibroblasts. Despite the proficiency of this intrinsic repair capability, severe injuries that result in significant loss of muscle tissue overwhelm the innate repair process and require intervention if muscle function is to be restored. Recent advances in stem cell biology, regenerative medicine, and materials science have led to attempts at developing tissue engineering-based methods for repairing severe muscle defects. Muscle tissue also plays a role in the ability of tailed amphibians to regenerate amputated limbs through epimorphic regeneration. Muscle contributes adult stem cells to the amphibian regeneration blastema, but it can also contribute blastemal cells through the dedifferentiation of multinucleate myofibers into mononuclear precursors. This fascinating plasticity and its contributions to limb regeneration have prompted researchers to investigate the potential for mammalian muscle to undergo dedifferentiation. Several works have shown that mammalian myotubes can be fragmented into mononuclear cells and induced to re-enter the cell cycle, but mature myofibers are resistant to fragmentation. However, recent works suggest that there may be a path to inducing fragmentation of mature myofibers into proliferative multipotent cells with the potential for use in muscle tissue engineering and regenerative therapies.
Cook, J. A.; Fucinari, C. A.; Lingscheit, J. N.; Rahnke, C. J.; Rao, V. D.
Ceramic regenerator cores are considered that can be used in passenger car gas turbine engines, Stirling engines, and industrial/truck gas turbine engines. Improved materials and design concepts aimed at reducing or eliminating chemical attack were placed on durability tests/in industrial gas turbine engines. A regenerator core made from aluminum silicate shows minimal evidence of chemical attack damage after 7804 hours of engine test at 800 C and another showed little distress after 4983 hours at 982 C. The results obtained in ceramic material screening tests, aerothermodynamic performance tests, stress analysis, cost studies, and material specifications are also included.
Massaro, Donald; Massaro, Gloria Decarlo
Lung tissue elastic recoil and the dimension and number of pulmonary gas-exchange units (alveoli) are major determinants of gas-exchange function. Loss of gas-exchange function accelerates after menopause in the healthy aged and is progressively lost in individuals with chronic obstructive pulmonary disease (COPD). The latter, a disease of midlife and later, though more common in men than in women, is a disease to which women smokers and never smokers may be more susceptible than men; it is characterized by diminished lung tissue elastic recoil and presently irremediable alveolar loss. Ovariectomy in sexually immature rats diminishes the formation of alveoli, and estrogen prevents the diminution. In the present work, we found that estrogen receptor-alpha and estrogen receptor-beta, the only recognized mammalian estrogen receptors, are required for the formation of a full complement of alveoli in female mice. However, only the absence of estrogen receptor-beta diminishes lung elastic tissue recoil. Furthermore, ovariectomy in adult mice results, within 3 wk, in loss of alveoli and of alveolar surface area without a change of lung volume. Estrogen replacement, after alveolar loss, induces alveolar regeneration, reversing the architectural effects of ovariectomy. These studies 1) reveal estrogen receptors regulate alveolar size and number in a nonredundant manner, 2) show estrogen is required for maintenance of already formed alveoli and induces alveolar regeneration after their loss in adult ovariectomized mice, and 3) offer the possibility estrogen can slow alveolar loss and induce alveolar regeneration in women with COPD.
Arthur, Larry Matthew; Heber-Katz, Ellen
The MRL (Murphy Roths Large) mouse has provided a unique model of adult mammalian regeneration as multiple tissues show this important phenotype. Furthermore, the healing employs a blastema-like structure similar to that seen in amphibian regenerating tissue. Cells from the MRL mouse display DNA damage, cell cycle G2/M arrest, and a reduced level of p21CIP1/WAF. A functional role for p21 was confirmed when tissue injury in an adult p21-/- mouse showed a healing phenotype that matched the MRL mouse, with the replacement of tissues, including cartilage, and with hair follicle formation and a lack of scarring. Since the major canonical function of p21 is part of the p53/p21 axis, we explored the consequences of p53 deletion. A regenerative response was not seen in a p53-/- mouse and the elimination of p53 from the MRL background had no negative effect on the regeneration of the MRL.p53-/- mouse. An exploration of other knockout mice to identify p21-dependent, p53-independent regulatory pathways involved in the regenerative response revealed another significant finding showing that elimination of transforming growth factor-β1 displayed a healing response as well. These results are discussed in terms of their effect on senescence and differentiation.
The MRL (Murphy Roths Large) mouse has provided a unique model of adult mammalian regeneration as multiple tissues show this important phenotype. Furthermore, the healing employs a blastema-like structure similar to that seen in amphibian regenerating tissue. Cells from the MRL mouse display DNA damage, cell cycle G2/M arrest, and a reduced level of p21CIP1/WAF. A functional role for p21 was confirmed when tissue injury in an adult p21-/- mouse showed a healing phenotype that matched the MRL mouse, with the replacement of tissues, including cartilage, and with hair follicle formation and a lack of scarring. Since the major canonical function of p21 is part of the p53/p21 axis, we explored the consequences of p53 deletion. A regenerative response was not seen in a p53-/- mouse and the elimination of p53 from the MRL background had no negative effect on the regeneration of the MRL.p53-/- mouse. An exploration of other knockout mice to identify p21-dependent, p53-independent regulatory pathways involved in the regenerative response revealed another significant finding showing that elimination of transforming growth factor-β1 displayed a healing response as well. These results are discussed in terms of their effect on senescence and differentiation. PMID:21722344
Dun, Xin-Peng; Parkinson, David B.
Netrin-1 was the first axon guidance molecule to be discovered in vertebrates and has a strong chemotropic function for axonal guidance, cell migration, morphogenesis and angiogenesis. It is a secreted axon guidance cue that can trigger attraction by binding to its canonical receptors Deleted in Colorectal Cancer (DCC) and Neogenin or repulsion through binding the DCC/Uncoordinated (Unc5) A–D receptor complex. The crystal structures of Netrin-1/receptor complexes have recently been revealed. These studies have provided a structure based explanation of Netrin-1 bi-functionality. Netrin-1 and its receptor are continuously expressed in the adult nervous system and are differentially regulated after nerve injury. In the adult spinal cord and optic nerve, Netrin-1 has been considered as an inhibitor that contributes to axon regeneration failure after injury. In the peripheral nervous system, Netrin-1 receptors are expressed in Schwann cells, the cell bodies of sensory neurons and the axons of both motor and sensory neurons. Netrin-1 is expressed in Schwann cells and its expression is up-regulated after peripheral nerve transection injury. Recent studies indicated that Netrin-1 plays a positive role in promoting peripheral nerve regeneration, Schwann cell proliferation and migration. Targeting of the Netrin-1 signaling pathway could develop novel therapeutic strategies to promote peripheral nerve regeneration and functional recovery. PMID:28245592
Natural recovery from disease and damage in the adult mammalian central nervous system (CNS) is limited compared with that in lower vertebrate species, including fish and salamanders. Species-specific differences in the plasticity of the CNS reflect these differences in regenerative capacity. Despite numerous extensive studies in the field of CNS regeneration, our understanding of the molecular mechanisms determining the regenerative capacity of the CNS is still relatively poor. The discovery of adult neural stem cells (aNSCs) in mammals, including humans, in the early 1990s has opened up new possibilities for the treatment of CNS disorders via self-regeneration through the mobilization of these cells. However, we now know that aNSCs in mammals are not plastic enough to induce significant regeneration. In contrast, aNSCs in some regenerative species have been found to be as highly plastic as early embryonic neural stem cells (NSCs). We must expand our knowledge of NSCs and of regenerative processes in lower vertebrates in an effort to develop effective regenerative treatments for damaged CNS in humans.
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
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
Parish, Clare L; Beljajeva, Anna; Arenas, Ernest; Simon, András
Death and lack of functional regeneration of midbrain dopaminergic (DA) neurons, decreased DA input in the target striatum and movement anomalies characterise Parkinson's disease (PD). There is currently no cure for PD. One way to promote recovery would be to induce or enhance DA neurogenesis. Whether DA neurogenesis occurs in the adult midbrain is a matter of debate. Here, we describe the creation of a salamander 6-hydroxydopamine model of PD to examine midbrain DA regeneration. We demonstrate a robust and complete regeneration of the mesencephalic and diencephalic DA system after elimination of DA neurons. Regeneration is contributed by DA neurogenesis, leads to histological restoration, and to full recovery of motor behaviour. Molecular analyses of the temporal expression pattern of DA determinants indicate that the regenerating DA neurons mature along a similar developmental program as their mammalian counterparts during embryogenesis. We also find that the adult salamander midbrain can reactivate radial glia-like ependymoglia cells that proliferate. The salamander model provides insights into the mechanisms of DA regeneration/neurogenesis and may contribute to the development of novel regenerative strategies for the mammalian brain.
Leone, Marina; Magadum, Ajit; Engel, Felix B
The newt and the zebrafish have the ability to regenerate many of their tissues and organs including the heart. Thus, a major goal in experimental medicine is to elucidate the molecular mechanisms underlying the regenerative capacity of these species. A wide variety of experiments have demonstrated that naturally occurring heart regeneration relies on cardiomyocyte proliferation. Thus, major efforts have been invested to induce proliferation of mammalian cardiomyocytes in order to improve cardiac function after injury or to protect the heart from further functional deterioration. In this review, we describe and analyze methods currently used to evaluate cardiomyocyte proliferation. In addition, we summarize the literature on naturally occurring heart regeneration. Our analysis highlights that newt and zebrafish heart regeneration relies on factors that are also utilized in cardiomyocyte proliferation during mammalian fetal development. Most of these factors have, however, failed to induce adult mammalian cardiomyocyte proliferation. Finally, our analysis of mammalian neonatal heart regeneration indicates experiments that could resolve conflicting results in the literature, such as binucleation assays and clonal analysis. Collectively, cardiac regeneration based on cardiomyocyte proliferation is a promising approach for improving adult human cardiac function after injury, but it is important to elucidate the mechanisms arresting mammalian cardiomyocyte proliferation after birth and to utilize better assays to determine formation of new muscle mass.
Regeneration of cartilaginous tissues is limited in mammals but it occurs with variable extension in lizards (reptiles), including in their vertebrae. The ability of lizard vertebrae to regenerate cartilaginous tissue that is later replaced with bone has been analyzed using tritiated thymidine autoradiography and 5BrdU immunocytochemistry after single pulse or prolonged-pulse and chase experiments. The massive cartilage regeneration that can restore broad vertebral regions and gives rise to a long cartilaginous tube in the regenerating tail, depends from the permanence of some chondrogenic cells within adult vertebrae. Few cells that retain tritiated thymidine or 5-bromodeoxy-uridine for over 35 days are mainly localized in the inter-vertebral cartilage and in sparse chondrogenic regions of the neural arch of the vertebrae, suggesting that they are putative resident stem/progenitor cells. The study supports previous hypothesis indicating that the massive regeneration of the cartilaginous tissue in damaged vertebrae and in the regenerating tail of lizards derive from resident stem cells mainly present in the cartilaginous areas of the vertebrae including in the perichondrium that are retained in adult lizards as growing centers for most of their lifetime.
Grigoryan, Eleonora N.; Almeida, Eduardo; Poplinskaya, Valentina; Novikova, Julia; Domaratskaya, Elena; Aleinikova, Karina; Souza, Kenneth; Skidmore, Mike; Grigoryan, Eleonora N.
In September 2007 the joint, 12 day long experiment was carried out aboard Russian satellite Foton M3. The goal of the experiment was to study eye lens, tail and forelimb toe regeneration in adult 16 newts (Pl. waltl.) operated 10 days before taking-off. In spaceflight and synchronous ground control we used video recording, temperature and irradiation control, as well as constant availability of thymidine analog BrdU for its absorption via animals' skin. New techniques allowed us to analyze animals' behavior in hyperand microgravity periods of time, to take proper account of spaceflight factors, and measure accumulated pools of DNA-synthesizing cells in regenerating tissues. All tissue specimens obtained from animals were isolated in the day of landing and then prepared for morphological, immunochemical and molecular investigations. Synchronous control was shifted for two days and reproduced flight conditions except changes of gravity influence. As a result in flown animals as compared with synchronous ground control we found lens regeneration of 0.5-1 stage speeded up and an increased BrdU+ (S-phase) cell number in eye cornea, growth zone, limbus and newly forming lens. These features of regeneration were accompanied by an increase of FGF2 expression in eye growth zone and heat shock protein (HSP90) induction purely in retinal macroglial cells of regenerating eyes. Toe regeneration rate was equal and achieved the stage of accomplished healing of amputation area in both groups - "flown" and control animals. We found no essential differences in tail regeneration rate and tail regenerate sizes in the newts exposed to space and on ground. In both groups tail regeneration reached the stage IV-V when tail length and square were around 4.4 mm and 15.5 mm2, correspondingly. However we did observe remarkable changes of tail regenerate form and some of pigmentation. Computer morphometrical analysis showed that only in ground control animals the evident dorso
Hellström, Mats; Harvey, Alan R
In this paper we present a brief review of studies that have reported therapeutic benefits of elevated cAMP on plasticity and regeneration after injury to the central nervous system (CNS). We also provide new data on the cellular mechanisms by which elevation of cyclic adenosine monophosphate (cAMP) promotes cytokine driven regeneration of adult CNS axons, using the visual system as the experimental model. cAMP is a second messenger for many intracellular signalling pathways. Elevation of cAMP in the eye by intravitreal injection of the cell permeant analogue (8-(4-chlorophenylthio)-adenosine-3',5'-cyclic monophosphate; CPT-cAMP), when added to recombinant ciliary neurotrophic factor (rCNTF), significantly enhances rCNTF-induced regeneration of adult rat retinal ganglion cell (RGC) axons into peripheral nerve (PN) grafted onto transected optic nerve. This effect is mediated to some extent by protein kinase A (PKA) signalling, but CPT-cAMP also acts via PI3K/Akt signalling to reduce suppressor of cytokine signalling protein 3 (SOCS3) activity in RGCs. Another target for cAMP is the exchange protein activated by cAMP (Epac), which can also mediate cAMP-induced axonal growth. Here we describe some novel results and discuss to what extent the pro-regenerative effects of CPT-cAMP on adult RGCs are mediated via Epac as well as via PKA-dependent pathways. We used the established PN-optic nerve graft model and quantified the survival and regenerative growth of adult rat RGCs after intravitreal injection of rCNTF in combination with a selective activator of PKA and/or a specific activator of Epac. Viable RGCs were identified by βIII-tubulin immunohistochemistry and regenerating RGCs retrogradely labelled and quantified after an injection of fluorogold into the distal end of the PN grafts, 4 weeks post-transplantation. The specific agonists of either PKA or Epac were both effective in enhancing the effects of rCNTF on RGC axonal regeneration, but interestingly, injections
... embryonic development, as well as limb regeneration in amphibians. They found that the Wnt pathway was active ... nerve cells was crucial for limb regeneration in amphibians, so they wanted to examine their role in ...
Skinner, D.M.; Graham, D.E.; Holland, C.A.; Soumoff, C.; Mykles, D.L.
The regulation of molting and regeneration by two antagonistic hormones is discussed. The time course of ecdysteroid titers in crustacean tissues has been followed during molt and regeneration cycles. (ACR)
An essential feature of the engine patented by Robert Stirling in 1817 was the careful description of the idea of regeneration. In the standard thermodynamic cycle representation of the engine, regeneration is the storing and the reusing of the thermal energy released in the constant volume cooling part of the cycle. Due to the difficulty in treating regeneration quantitatively, introductory physics texts generally either ignore the concept or assume the regeneration to be perfect. As a result students obtain little or no understanding of regeneration. In addition there seem to be differing views in various texts about the efficiency of Stirling engines. In this work a simple finite element model regenerator is presented with which one can do simple calculations. The model does not accurately represent actual regeneration in a practical engine. But the model might help students gain better insight into Stirling engine efficiency and the idea of regeneration.
...) Digital signal regeneration (i.e., DTV signal demodulation, decoding, error processing, encoding... signals of DTV broadcast stations may be retransmitted to areas in which direct reception of such DTV... paragraph (f) of this section, a digital TV translator station may be used only to receive the signals of...
...) Digital signal regeneration (i.e., DTV signal demodulation, decoding, error processing, encoding... signals of DTV broadcast stations may be retransmitted to areas in which direct reception of such DTV... paragraph (f) of this section, a digital TV translator station may be used only to receive the signals of...
...) Digital signal regeneration (i.e., DTV signal demodulation, decoding, error processing, encoding... signals of DTV broadcast stations may be retransmitted to areas in which direct reception of such DTV... paragraph (f) of this section, a digital TV translator station may be used only to receive the signals of...
...) Digital signa