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PubMed1995

Substance P, bombesin, and leucine-enkephalin immunoreactivities are restored in the frog tectum after optic nerve regeneration.

Extensive regeneration of the optic nerve takes place in adult Amphibia. In this study, we have determined whether one aspect of retinotectal organisation, namely immunoreactive laminae in the retinorecipient layers of the optic tectum, is restored after optic nerve regeneration. To do so, the distributions of substance-P, bombesin, and leucine-enkephalin immunoreactivities were examined in the optic tectum of the frog Litoria (Hyla) moorei. Results of a normal series were compared with those at intervals up to 84 days and at 196 days after either unilateral deafferentation or optic nerve crush. In the normal series, distinct neuropeptide immunoreactive laminae were located within the retinorecipient tectal layers. There were two major laminae with substance-P, two with bombesin, and one with leucine-enkephalin immunoreactivities. Additional faint laminae of both substance-P and bombesin immunoreactivity were present in the tectal region that receives input from the visual streak. In addition, labelling of cell bodies and dendrites was seen elsewhere in the tectum. All except one immunoreactive lamina changed after deafferentation. The deeper of those with substance-P immunoreactivity, along with both bombesin laminae, were eventually lost; the lamina with leucine-enkephalin immunoreactivity was halved in intensity. We assume that these laminae are wholely or, in the case of the leucine-enkephalin lamina, partially associated with primary optic input. By contrast, the more superficial lamina with substance-P immunoreactivity remained unchanged and is presumably not directly related to visual input. During nerve regeneration, the intensity of all laminae associated with optic input initially fell as in the deafferentation series but, in the long term, recovered to approximately 80% of normal intensities. We conclude that ganglion cells associated with each of the immunoreactivities tested had successfully regenerated. The reduced intensity of immunoreactivities after regeneration is due presumably in part to the cell loss from the ganglion cell population. Furthermore, we discuss the findings of similar studies for Rana pipiens (Kuljis and Karten [1983] J. Comp. Neurol. 217:239-251 and [1985] 240:1-15) in light of the present findings. We argue that some of the previous observations can be reinterpreted to indicate that regeneration was not limited to ganglion cells associated with substance-P immunoreactivity as first thought.

Animals↗
PubMed1995

Molecular basis of interactions between regenerating adult rat thalamic axons and Schwann cells in peripheral nerve grafts I. Neural cell adhesion molecules.

To gain insight into the possible molecular mechanisms underlying axonal regeneration of neurons of the adult central nervous system (CNS), we have investigated, by in situ hybridization and by immunocytochemistry, the localization and sites of synthesis of the neurite outgrowth-promoting cell surface molecules L1, N-CAM and its highly sialylated form, N-CAM-PSA, in and around peripheral nerve grafts implanted into the thalamus of adult rats. Normal unoperated adult rat thalamus contains N-CAM and L1 but no N-CAM-PSA immunoreactive axons. Between 7 days and 13 weeks after graft implantation, L1, N-CAM and N-CAM-PSA were all present at the surface of axonal sprouts in the brain parenchyma close to grafts and in the central parts of Schwann cell columns within grafts. Schwann cell membranes were L1 and N-CAM positive at all postgraft survival times, more strongly at 2-4 weeks than other times, but were associated with N-CAM-PSA reaction product only where they abutted N-CAM-PSA positive axons. Schwann cell membranes apposed to basal laminae (which were avoided by regenerating CNS axons) were L1, N-CAM and N-CAM-PSA negative. Between 3 days and 8 weeks after grafting, N-CAM and L1 mRNA were generally weakly upregulated in neurons of the ipsilateral thalamus, but, most conspicuously, L1 mRNA was strongly upregulated in the neurons of the thalamic reticular nucleus; these neurons are known to regenerate axons very effectively into peripheral nerve grafts and are the probable source of most of the axons which enter thalamic grafts. N-CAM and L1 mRNA were also strongly upregulated in presumptive Schwann cells in the graft. These results show that regenerating CNS axons (re)express N-CAM-PSA and upregulate L1 and N-CAM, suggesting that all of these molecules may play a role in cellular interactions during the regeneration of CNS axons. Furthermore L1 synthesis appears to be particularly well correlated with the ability of CNS neurons to regenerate axons into peripheral nerve grafts.

Animals↗
PubMed2003

Recruitment of postmitotic neurons into the regenerating spinal cord of urodeles.

By using fluorescent tracers, we have investigated the origin of the cells that form the regenerating spinal cord after tail amputation in urodele amphibians. We show that spinal cord cells immediately adjacent to the amputation plane die and are removed by phagocytic cells. Spinal cells just anterior to these dying cells are destined to make the majority of the regenerating cord. The largest contribution is likely to come from the radial ependymal cells, but we also demonstrate that postmitotic neurons in this location can translocate into the regenerating cord. These neurons integrate into the regenerate structure and survive for at least 4 weeks. We find no evidence that these translocated neurons dedifferentiate and divide during this regeneration process. We discuss the possibility that these neurons survive long term in the regenerate cord and become part of the functional neuronal circuitry.

Ambystoma↗
PubMed2003

Intercalary regeneration in planarians.

How can a planarian regenerate its entire body from a small portion of its body? Neoblasts, the totipotent stem cells of planarian, are assumed to be able to produce all missing cell types. However, we do not know how the cell fate of these cells is controlled during regeneration. Our recent studies with molecular markers suggest that intercalary regeneration is the fundamental principle in planarian regeneration. Here, we introduce the intercalation induced by ectopic grafting along the anteroposterior (A-P), dorsoventral (D-V), and left-right (L-R) axes. Blastema formation is evoked by ectopic D-V interactions after wound closure. Intercalation between the blastema and stump induces rearrangement of the positional identities along the A-P axis. Consequently, totipotent stem cells change their differentiation patterns according to the newly rearranged positional identities along the A-P, D-V, and L-R axes. According to the classic view, the blastema is regarded as the place where undifferentiated cells accumulate and regenerative events occur. Here, we propose a new interpretation, i.e., that the blastema may work as a signaling center inducing intercalary regeneration. Also, the roles of molecules and genes involved in intercalary regeneration are discussed.

Animals↗
PubMed2003

Expression and neural control of follistatin versus myostatin genes during regeneration of mouse soleus.

Follistatin and myostatin are two secreted proteins involved in the control of muscle mass during development. These two proteins have opposite effects on muscle growth, as documented by genetic models. The aims of this work were to analyze in mouse, by using in situ hybridization, the spatial and temporal expression patterns of follistatin and myostatin mRNAs during soleus regeneration after cardiotoxin injury, and to investigate the influence of innervation on the accumulation of these two transcripts. Follistatin transcripts could be detected in activated satellite cells as early as the first stages of regeneration and were transiently expressed in forming myotubes. In contrast, myostatin mRNAs accumulated persistently throughout the regeneration process as well as in adult control soleus. Denervation significantly affected both follistatin and myostatin transcript accumulation, but in opposite ways. Muscle denervation persistently reduced the levels of myostatin transcripts as early as the young myotube stage, whereas the levels of follistatin mRNA were strongly increased in the small myotubes in the late stages of regeneration. These results are discussed with regard to the potential functions of both follistatin, as a positive regulator of muscle differentiation, and myostatin, as a negative regulator of skeletal muscle growth. We suggest that the belated up-regulation of the follistatin mRNA level in the small myotubes of the regenerating soleus as well as the down-regulation of the myostatin transcript level after denervation contribute to the differentiation process in denervated regenerating muscle.

Animals↗
PubMed2003

Intercalary and supernumerary regeneration in the limbs of the frog, Xenopus laevis.

Anuran amphibians, such as Xenopus laevis, can regenerate their limbs only when they are young tadpoles, whereas urodele amphibians have a regenerative ability throughout their lives. It is still unclear whether anuran and urodele use the same mechanism during regeneration. In the present study, we analyzed intercalary and supernumerary regeneration in Xenopus. In contrast to urodele blastema that induces intercalary regeneration along the proximodistal (PD) axis, intercalation did not occur in the Xenopus limb bud when the presumptive zeugopodium (fibula and tibia) was removed. However, when the limb bud tip (presumptive autopodium) was transplanted to the presumptive stylopodium (femur) with a 180-degree rotation at stage 52, the complete zeugopodium was regenerated. These results were similar to the results of urodele mature limbs, suggesting that Xenopus limb buds are equivalent to the urodele mature limbs but not to the urodele blastemas. We hypothesized that the ability for intercalation depends on the expression pattern of fibroblast growth factor (fgf)-8, because the expression of fgf-8 in the urodele spreads over the whole blastema and is close enough to activate the growth of the stump. To test this hypothesis, an FGF-8-soaked bead was implanted at the boundary between the stump and tip of a Xenopus limb bud. Intercalary regeneration was induced at stages 52 and 53. These results suggest that the Xenopus limb bud possesses the potential for intercalation, but endogenous FGF-8 in the apical ectodermal ridge (AER) does not induce intercalation to the stump because of the long distance between the AER and stump.

Animals↗
PubMed2004

cProx1 immunoreactivity distinguishes progenitor cells and predicts hair cell fate during avian hair cell regeneration.

In birds, mature sensory hair cells are regenerated continually in vestibular epithelia and after damage in the auditory basilar papilla. Molecular mechanisms governing the cellular processes associated with hair cell regeneration are poorly understood. Transcription factors are critical regulators of cell proliferation and differentiation in developing tissues. We examined immunoreactivity for cProx1 during both ongoing and damage-induced hair cell regeneration in chickens. Homologues of this divergent homeobox transcription factor are required for cell cycle withdrawal and differentiation in several vertebrate and invertebrate tissues. In the mitotically quiescent basilar papilla, a population of resting progenitor cells (supporting cells) shows faint nuclear immunoreactivity for cProx1. When auditory hair cell regeneration is triggered by experimental damage, nuclear cProx1 immunolabel is highly elevated in approximately 50% of dividing progenitor cells. Shortly after cytokinesis, all sibling pairs show symmetric patterns of nuclear cProx1 labeling, but pairs with asymmetric labeling emerge shortly thereafter. Strongly immunoreactive cells acquire the hair cell fate, whereas cells with low nuclear immunoreactivity differentiate as supporting cells. By contrast, cProx1 is not detected in any dividing progenitor cells during ongoing regeneration in the utricle. However, nuclear cProx1 immunoreactivity becomes asymmetric in postmitotic sibling cells, and as in the basilar papilla, cells with elevated cProx1 label differentiate as hair cells. In conclusion, cProx1 immunolabeling varies across sensory epithelial progenitors and distinguishes early differentiating hair cells from supporting cells. cProx1 may regulate the proliferative or differentiative capacities of progenitor cells and specify hair cell fate in postmitotic cells during avian hair cell regeneration.

Animals↗
PubMed2006

Newt orthologue of Growth arrest-specific 6 (NvGas6) is implicated in stress response during newt forelimb regeneration.

Red-spotted newts are capable of regenerating various structures and organs through the process of epimorphic regeneration. Receptor tyrosine kinases (RTKs) and their ligands are important for normal cellular development and physiology but most have not yet been characterised during regeneration. We have isolated a newt orthologue of Growth arrest-specific 6 (NvGas6), and examined its expression during forelimb regeneration and within a blastema cell line (B1H1). During limb regeneration, NvGas6 expression increases upon amputation, peaks during maximal blastema cell proliferation, and is subsequently downregulated during redifferentiation. Transcripts are localised to the wound epithelium and distal mesenchymal cells during dedifferentiation and proliferative phases, and scattered within redifferentiating tissues during later stages. In B1H1 cultures, NvGas6 is upregulated under reduced serum conditions and myogenesis. Treatment with mimosine and colchicine or exposure to heat shock or anoxia results in upregulation of NvGas6 expression. Taken together, our findings suggest that during regeneration, NvGas6 expression may be upregulated in response to cellular stress.

Amino Acid Sequence↗
PubMed2006

Analysis of scleraxis and dermo-1 genes in a regenerating limb of Xenopus laevis.

Xenopus laevis larvae can regenerate an exact replica of the missing part of a limb after amputation at an early limb bud stage. However, this regenerative capacity gradually decreases during metamorphosis, and a froglet is only able to regenerate hypomorphic cartilage, resulting in a spike-like structure (spike). It has been reported that the spike has tissue deformities, e.g., a muscleless structure. However, our previous study demonstrated that the muscleless feature of the spike can be improved. The existence of other kinds of tissue, such as tendon, has not been clarified. In this study, we focused on the tendon and dermis, and we isolated the scleraxis and dermo-1 genes, which are known to be marker genes for the tendon and dermis, respectively. The expressions of these genes were investigated in both the developmental and regenerating processes of a Xenopus limb. Although muscle was needed to maintain scleraxis expression, scleraxis transcription was detectable in the muscleless spike. Additionally, although grafting of matured skin, including dermal tissue, inhibited limb regeneration, the expression of dermo-1, a dermal marker gene, was detected from the early stage of the froglet blastema. These results indicate that tendon precursor cells and dermal cells exist in the regenerating froglet blastema. Our results support the idea that spike formation in postmetamorphic Xenopus limbs is epimorphic regeneration.

Amino Acid Sequence↗
PubMed2001

Retroviral labeling of Schwann cells: in vitro characterization and in vivo transplantation to improve peripheral nerve regeneration.

Transplantation of Schwann cells (SCs) is a promising treatment modality to improve neuronal regeneration. Identification of the transplanted cells is an important step when studying the development of this method. Genetic labeling is the most stable and reliable method of cell identification, but it is still unclear whether it has deleterious effect on SC characteristics. Our aim was to achieve a stable population of SCs transduced with the lacZ gene at a high frequency using a retroviral vector in vitro, and to follow the labeled SC in vitro to assess their viability and phenotypic marker expression. Furthermore, we transplanted lacZ-labeled SCs in a conduit to repair peripheral nerve to investigate their effect on nerve regeneration in vivo. Rat and human SCs were cultured and transduced with an MFG lacZ nls marker gene, achieving a transduction rate of 80% and 70%, respectively. Rat SCs were kept in culture for 27 weeks and examined every 4 weeks for expression of lacZ, viability, and phenotypic marker expression of GFAP, p75, MHC I and II. Throughout this period, transduced rat SCs remained viable and continued to proliferate. The proportion of cells expressing lacZ dropped only by 10% and the expression of phenotypic markers remained stable. Transduced human SCs were followed up for 4 weeks in culture. They proliferated and continued to express the lacZ gene and phenotypic marker expression of GFAP and p75 was preserved. Primary culture of transduced rat SCs were transplanted, syngeneically, in a conduit to bridge a 10 mm gap in sciatic nerve and the grafts were examined after 3 weeks for the presence and participation of labeled SCs and for axonal regeneration distance. Transplanted transduced rat SCs were clearly identified, taking part in the regeneration process and enhancing the axonal regeneration rate by 100% (at the optimal concentration) compared to conduits without SCs. Thus, retroviral introduction of lacZ gene has no deleterious effect on SCs in vitro and these SCs take part and enhance nerve regeneration in vivo.

Animals↗
PubMed2004

Olfactory ensheathing cell grafts have minimal influence on regeneration at the dorsal root entry zone following rhizotomy.

The effectiveness of grafts of olfactory ensheathing cells (OECs) as a means of promoting functional reconnection of regenerating primary afferent fibers was investigated following dorsal root injury. Adult rats were subjected to dorsal root section and reanastomosis and at the same operation a suspension of purified OECs was injected at the dorsal root entry zone and/or into the sectioned dorsal root. Regeneration of dorsal root fibers was then assessed after a survival period ranging from 1 to 6 months. In 11 animals, electrophysiology was used to look for evidence of functional reconnection of regenerating dorsal root fibers. However, electrical stimulation of lesioned dorsal roots failed to evoke detectable cord dorsum or field potentials within the spinal cord of any of the animals examined, indicating that reconnection of regenerating fibers with spinal cord neurones had not occurred. In a further 11 rats, immunocytochemical labeling and biotin dextran tracing of afferent fibers in the lesioned roots was used to determine whether regenerating fibers were able to grow into the spinal cord in the presence of an OEC graft. Although a few afferent fibers could be seen to extend for a limited distance into the spinal cord, similar minimal in-growth was seen in control animals that had not been injected with OECs. We therefore conclude that OEC grafts are of little or no advantage in promoting the in-growth of regenerating afferent fibers at the dorsal root entry zone following rhizotomy.

Action Potentials↗
PubMed2007

Skin-derived stem cells transplanted into resorbable guides provide functional nerve regeneration after sciatic nerve resection.

The regeneration in the peripheral nervous system is often incomplete and the treatment of severe lesions with nerve tissue loss is primarily aimed at recreating nerve continuity. Guide tubes of various types, filled with Schwann cells, stem cells, or nerve growth factors are attractive as an alternative therapy to nerve grafts. In this study, we evaluated whether skin-derived stem cells (SDSCs) can improve peripheral nerve regeneration after transplantation into nerve guides. We compared peripheral nerve regeneration in adult rats with sciatic nerve gaps of 16 mm after autologous transplantation of GFP-labeled SDSCs into two different types of guides: a synthetic guide, obtained by dip coating with a L-lactide and trimethylene carbonate (PLA-TMC) copolymer and a collagen-based guide. The sciatic function index and the recovery rates of the compound muscle action potential were significantly higher in the animals that received SDSCs transplantation, in particular, into the collagen guide, compared to the control guides filled only with PBS. For these guides the morphological and immunohistochemical analysis demonstrated an increased number of myelinated axons expressing S100 and Neurofilament 70, suggesting the presence of regenerating nerve fibers along the gap. GFP positive cells were found around regenerating nerve fibers and few of them were positive for the expression of glial markers as S-100 and glial fibrillary acidic protein. RT-PCR analysis confirmed the expression of S100 and myelin basic protein in the animals treated with the collagen guide filled with SDSCs. These data support the hypothesis that SDSCs could represent a tool for future cell therapy applications in peripheral nerve regeneration.

Action Potentials↗
PubMedDate not supplied

Hepatocyte and Kupffer cell functions during liver regeneration in streptozotocin-diabetic rats.

The insulinoprivic influence of acute severe streptozotocin diabetes on liver regeneration in rats was evaluated by determining liver weights as well as hepatocyte and Kupffer cell functional capacities. Functional capacities were assessed by bromosulfophthalein uptake for hepatocytes and carbon phagocytosis for Kupffer cells. Evaluation immediately after partial hepatectomy revealed a 66% reduction of liver mass, a 63% decrease in hepatocyte bromosulfophthalein removal, and a 65% decline in Kupffer cell carbon phagocytosis. Per cent recovery at 48-hr posthepatectomy was considerably greater for carbon phagocytosis than for bromosulfophthalein removal by regenerating livers. This apparent difference in functional recovery was likely due in part to enhanced non-Kupffer cell carbon phagocytosis. No significant differences of the three regeneration indices were noted for untreated streptozotocin-diabetic rats compared to nondiabetic animals. However, insulin administration to fasted streptozotocin diabetics significantly stimulated liver regeneration above that of untreated fasted rats and almost equivalent to that of pair-fed animals. Fasted rats had in general slower liver regeneration than pair-fed animals as expected. Furthermore, insulin administration to fasted nondiabetic rats after partial hepatectomy caused severe hypoglycemia and resulted in a further depression of liver regeneration.

Animals↗
PubMedDate not supplied

The effect of chronic ethanol feeding on ornithine decarboxylase activity and liver regeneration.

The effects of ethanol on liver regeneration are poorly understood. Acute and chronic exposure to ethanol have been found to exert opposite effects on the induction of ornithine decarboxylase, the rate-limiting enzyme for polyamine biosynthesis. Polyamines are necessary for DNA synthesis and liver regeneration after chemical or surgical liver injury. Short-term exposure to ethanol, which inhibits ornithine decarboxylase has been shown to inhibit DNA synthesis and liver regeneration, whereas more chronic exposure to ethanol increases ornithine decarboxylase activity and therefore could conceivably stimulate DNA synthesis and regeneration. To explore this later possibility, the effects of chronic ethanol consumption on ornithine decarboxylase activity, DNA synthesis and liver regeneration were studied in rats after sham laparotomy and partial hepatectomy. Chronic ethanol feeding failed to inhibit the induction of ornithine decarboxylase that occurred after partial hepatectomy and yet significantly inhibited posthepatectomy DNA synthesis and restitution of liver mass. These data suggest that the induction of hepatic polyamine biosynthesis is dissociated from DNA synthesis and liver regeneration after chronic consumption of ethanol.

Alcohol Drinking↗
PubMed1994

Rapid induction of mRNAs for liver regeneration factor and insulin-like growth factor binding protein-1 in primary cultures of rat hepatocytes by hepatocyte growth factor and epidermal growth factor.

Liver regeneration factor belongs to the leucine-zipper family of transcription factors. It was originally cloned and characterized through differential screening of a regenerating rat liver cDNA library. The mRNA for liver regeneration factor-1 is barely detectable in normal rat liver but is dramatically induced after two-thirds hepatectomy, with a peak 1 to 3 hr after surgery. The nature of the signaling molecule(s) for this rapid induction is not known. It has been suggested that the liver regeneration factor-1 protein product, through complex interactions with other transcription factors such as c-Jun and Jun-B, controls expression of genes that are required during the G1 phase of hepatic growth. Hepatocyte growth factor has been shown to be the most potent mitogen for hepatocytes in vitro and in vivo. Plasma levels of hepatocyte growth factor rapidly (within 30 min) increase after loss of hepatic parenchyma induced by partial hepatectomy or carbon tetrachloride treatment. It has been postulated that hepatocyte growth factor plays a crucial role in stimulating the hepatocyte to enter the cell cycle. In this communication, we report that addition of pure hepatocyte growth factor to primary cultures of rat hepatocytes in the absence of serum and insulin results in rapid and transient induction of liver regeneration factor-1 mRNA (more than 20-fold) with a peak of expression 1 hr after treatment. The levels of jun-B and c-fos mRNAs, which are also known to be induced during the early hours of liver regeneration, were also increased after treatment of isolated hepatocytes with hepatocyte growth factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Activating Transcription Factor 3↗
PubMed2005

Differential lymphotoxin-beta and interferon gamma signaling during mouse liver regeneration induced by chronic and acute injury.

The liver regenerates after acute injury via hepatocyte cell division; during chronic injury, when hepatocyte replication is impaired or blocked, liver progenitor oval cells mediate liver regeneration. If both regeneration options are blocked in animal models, then liver failure and death ensues. The mechanisms underlying oval cell induction, proliferation, and subsequent liver regeneration remain poorly characterized. In particular, cell-signaling pathways that distinguish the alternative pathways are unknown. This study shows that in a mouse model, hepatic expression of lymphotoxin-beta (LTbeta) and interferon gamma (IFNgamma) transcripts is increased in response to the choline-deficient, ethionine-supplemented (CDE) diet, which induces oval cell-mediated liver regeneration. Oval cells express LTbeta and IFNgamma transcripts, contributing to the increased expression in the liver of mice fed the CDE diet. An attenuated oval cell response to such a diet was observed in LTbeta receptor-, LTbeta-, and IFNgamma-gene targeted mice. Loss of LTbeta and LTbeta receptor signaling reduced the number of oval cells expressing A6 and muscle pyruvate kinase. The lack of IFNgamma signaling reduced muscle pyruvate kinase(+), but not A6(+), oval cells. In contrast, partial hepatectomy suppressed LTbeta and IFNgamma transcripts. We also show that IFNgamma induces STAT-3 phosphorylation in an oval cell line. In conclusion, LTbeta, LTbeta receptor, and IFNgamma are involved in oval cell-mediated, but not hepatocyte-mediated, liver regeneration, and the absence of these pathways impairs the oval cell-dependent regenerative response.

Acute Disease↗
PubMed2006

Liver regeneration.

During liver regeneration after partial hepatectomy, normally quiescent hepatocytes undergo one or two rounds of replication to restore the liver mass by a process of compensatory hyperplasia. A large number of genes are involved in liver regeneration, but the essential circuitry required for the process may be categorized into three networks: cytokine, growth factor and metabolic. There is much redundancy within each network, and intricate interactions exist between them. Thus, loss of function from a single gene rarely leads to complete blockage of liver regeneration. The innate immune system plays an important role in the initiation of liver regeneration after partial hepatectomy, and new cytokines and receptors that participate in initiation mechanisms have been identified. Hepatocytes primed by these agents readily respond to growth factors and enter the cell cycle. Presumably, the increased metabolic demands placed on hepatocytes of the regenerating liver are linked to the machinery needed for hepatocyte replication, and may function as a sensor that calibrates the regenerative response according to body demands. In contrast to the regenerative process after partial hepatectomy, which is driven by the replication of existing hepatocytes, liver repopulation after acute liver failure depends on the differentiation of progenitor cells. Such cells are also present in chronic liver diseases, but their contribution to the production of hepatocytes in those conditions is unknown. Most of the new knowledge about the molecular and cellular mechanisms of liver regeneration is both conceptually important and directly relevant to clinical problems.

Animals↗
PubMed2006

STAT1 contributes to dsRNA inhibition of liver regeneration after partial hepatectomy in mice.

Increasing evidence suggests that liver regeneration is suppressed in patients with chronic HCV infection; however, the underlying mechanisms remain unclear. Previously, we demonstrated that injection of the synthetic double-stranded RNA (dsRNA) poly I:C to mimic viral infection suppresses liver regeneration in the partial hepatectomy (PHx) model, whereby IFN-gamma contributes to the inhibition. In this study, we examined the role of the IFN-gamma-activated downstream signal (STAT1) and genes (IRF-1, p21(cip1), and SOCS1) in liver regeneration and hepatocyte proliferation. Results show that disruption of the STAT1 gene abolished poly I:C suppression of liver regeneration and the inhibitory effect of poly I:C on liver regeneration was diminished in IRF-1(-/-) and p21(cip1-/-)mice. Treatment with IFN-gamma in vitro inhibited cell proliferation of wild-type mouse hepatocytes, but not STAT1(-/-) hepatocytes. The inhibitory effect of IFN-gamma on cell proliferation was also diminished in IRF-1(-/-) and p21(cip1-/-) hepatocytes, but enhanced in SOCS1(-/-) hepatocytes. Hepatocyte proliferation was unaffected by treatment with poly I:C alone, but when hepatocytes were co-cultured with liver lymphocytes, proliferation was inhibited by IFN-gamma/STAT1-dependent mechanisms. Moreover, in HCV-infected livers with cirrhosis, activation of STAT1 was detected and correlated positively with liver injury (elevated serum levels of AST) but negatively with hepatocyte proliferation (hepatocyte PCNA and Ki-67 positive immunostaining). In conclusion, STAT1 is involved in dsRNA suppression of liver regeneration; not only does STAT1 activation contribute to liver injury, it may also block liver repair through inhibition of hepatocyte proliferation in HCV-infected patients, playing an important role in the pathogenesis of disease.

Animals↗