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PubMed1999

Long- and medium-chain triacylglycerols in nutritional support of liver regeneration of partially hepatectomized rats.

An appropriate choice for a suitable diet during liver regeneration still remains an enigma. To investigate the effect of isocaloric enteral feeding with medium-chain triacylglycerols (MCT) and long-chain triacylglycerols (LCT) supplement (MCT+LCT, 40%:60% w:w) (178 kJ/kg b.w./24 h), rat liver regeneration was studied 24 and 72 h after partial hepatectomy. The liver DNA synthesis 24 h after partial hepatectomy was significantly higher in the MCT+LCT-supplemented rats (30.2+/-8.2 x 10(3) dpm/mg liver DNA) compared to MCT-treated animals (18.1+/-5.7 x 10(3) dpm/mg liver DNA). Liver protein synthesis was non-significantly elevated both 24 and 72 h after surgery in MCT+LCT-supplemented rats (13.7+/-1.1 and 10.9+/-3.1 x 10(3) dpm/mg liver protein). Seventy-two hours after partial hepatectomy, the hepatocyte mitotic activity was significantly increased in MCT+LCT- supplemented group vs. LCT- or MCT-fed rats (3.3+/-0.7 vs. 1.9+/-0.7 or 1.0+/-0.6 mitoses per 1000 hepatocytes), thus exhibiting an increased proliferative potential. The results showed a qualitative difference according to the proportion of MCT to LCT in the enteral supplements. Overfeeding with MCT decreased body weight, increased liver weight by its fatty infiltration, increased rat mortality rate and reduced spontaneous caloric intake. We conclude that the balanced supplement of MCT+LCT (40%:60% w:w) preserves liver regeneration, whereas overfeeding with MCT seems to be deleterious.

Animal Feed↗
PubMed1957

Xanthine oxidase activity in regenerating liver.

The xanthine oxidase activity of mouse regenerating liver has been shown to be elevated during the period of rapid liver growth and proliferation. This increase is evident when the enzyme activity is expressed per unit wet tissue weight, per unit nitrogen, or per cell. The adrenal cortex probably plays only a minor role in implementing this phenomenon. Further augmentation of the xanthine oxidase level of regenerating liver is not induced by the administration of large quantities of the substrate, xanthine, to the animal.

Animals↗
PubMed2005

Expression of hypoxia inducible factor-1alpha during liver regeneration induced by partial hepatectomy in rats.

BACKGROUND/AIMS: It has been well established that hypoxia inducible factor-1alpha (HIF-1alpha) transcribes essential factors in cell preservation, including angiogenesis, during hypoxia. However, the transition of HIF-1alpha expression during liver regeneration remains unknown. In this study, a role of HIF-1alpha was experimentally elucidated in relation to sinusoidal endothelial reconstruction during liver regeneration. METHODS: Expression of HIF-1alpha was evaluated in the regenerating liver following 70% hepatectomy in rats. Expressions of nuclear HIF-1alpha, vascular endothelial growth factor (VEGF) and fms-like tyrosine kinase-1 (flt-1) were measured by Western blot and liver blood flow by a laser Doppler. Sinusoidal endothelial cell area (SECA) and HIF-1alpha were localized by immunohistochemistry. HIF-1alpha mRNA was measured by reverse transcription-polymerase chain reaction. RESULT: Liver blood flow and SECA were lowest 36 and 72 h following hepatectomy, respectively. Nuclear HIF-1alpha peaked at 24 h and continuously increased 72-120 h following hepatectomy. This transition was fully supported by histological HIF-1alpha expression and HIF-1alpha mRNA up-regulation. VEGF and flt-1 peaked at 120 and 12 h, respectively. CONCLUSIONS: A significant evaluation in HIF-1alpha expression was revealed in regenerating rat livers. HIF-1alpha expression was preceded by VEGF and flt-1 expression and thus may be related to sinusoidal endothelial reconstruction.

Animals↗
PubMed2000

Liver regeneration and function in donor and recipient after right lobe adult to adult living donor liver transplantation.

BACKGROUND: Regeneration of the liver to a predetermined size after resection or transplantation is a well described phenomenon, but the time course over which these events occur has not been well defined. It is not clear how initial liver mass, reperfusion, immunosuppression, or steatosis influence this process. METHODS: Liver regeneration was assessed prospectively by volumetric magnetic resonance imaging (MRI) in living right lobe liver donors and the recipients of these grafts. Imaging was performed at regular intervals through 60 days after resection/transplantation, and liver mass was determined. Liver function tests and synthetic function were monitored throughout the study period in donors and recipients of these grafts as well as recipients of cadaveric grafts. RESULTS: MRI consistently overestimated liver mass by a mean of 45 g (+/-65) (range 10-123). Donor liver mass increased by 101%, 110%, 115%, and 144% at 7, 14, 30, and 60 days after resection, respectively. Recipient liver mass increased by 87,101, 119, and 99% at 7, 14, 30, and 60 days after transplantation, respectively. Steatosis did not influence the degree of regeneration or graft function, nor was there a functional difference between grafts of >1% graft to recipient body weight ratio or <1%. CONCLUSIONS: MRI accurately determines right lobe mass. Most liver regeneration occurs in the 1st week after resection or transplantation, and the time course does not differ significantly in donors or recipients. The mass of the graft or remnant segment affects the duration of the regeneration process, with a smaller initial liver mass prolonging the course. Steatosis of <30% had no bearing on liver function or regeneration and, therefore, should not be an absolute criterion for exclusion of donors. A calculated graft to recipient body weight ratio of 0.8% is adequate for right lobe living donor liver transplantation.

Adult↗
PubMed1998

Impaired liver regeneration in inducible nitric oxide synthasedeficient mice.

The mechanisms that permit adult tissues to regenerate when injured are not well understood. Initiation of liver regeneration requires the injury-related cytokines, tumor necrosis factor (TNF) alpha and interleukin (IL) 6, and involves the activation of cytokine-regulated transcription factors such as NF-kappabeta and STAT3. During regeneration, TNFalpha and IL-6 promote hepatocyte viability, as well as proliferation, because interventions that inhibit either cytokine not only block hepatocyte DNA synthesis, but also increase liver cell death. These observations suggest that the cytokines induce hepatoprotective factors in the regenerating liver. Given evidence that nitric oxide can prevent TNF-mediated activation of the pro-apoptotic protease caspase 3 and protect hepatocytes from cytokine-mediated death, cytokine-inducible nitric oxide synthase (iNOS) may be an important hepatoprotective factor in the regenerating liver. In support of this hypothesis we report that the hepatocyte proliferative response to partial liver resection is severely inhibited in transgenic mice with targeted disruption of the iNOS gene. Instead, partial hepatectomy is followed by increased caspase 3 activity, hepatocyte death, and liver failure, despite preserved induction of TNFalpha, IL-6, NF-kappabeta, and STAT3. These results suggest that during successful tissue regeneration, injury-related cytokines induce factors, such as iNOS and its product, NO, that protect surviving cells from cytokine-mediated death.

Animals↗
PubMed1990

Depressed liver regeneration after partial hepatectomy of germ-free, athymic and lipopolysaccharide-resistant mice.

A hypothesis has been proposed by this laboratory that endogenous gut-derived lipopolysaccharide is responsible for systemic endotoxemia in animals with acute liver injury particularly after partial (67%) hepatectomy. Systemic lipopolysaccharide and possibly fibrin aggregates or tissue debris then elicit release of cytokines from phagocytizing macrophages and/or monocytes that may be essential for normal liver regeneration. To test this hypothesis liver regeneration was assessed in germ-free euthymic mice that lack the gram-negative bacterial source of lipopolysaccharide, as well as being deficient in lymphoid tissue and relatively resistant to endotoxin. To complement the germ-free animals, conventional athymic nude BALB/c mice and conventional lipopolysaccharide-resistant C3H/HeJ mice were also examined. Liver regeneration, quantified by [3H] thymidine incorporation into hepatic DNA after partial hepatectomy was performed on mice anesthetized with ether, was significantly depressed in germ-free euthymic and conventional athymic BALB/c mice and delayed in conventional lipopolysaccharide-resistant C3H/HeJ mice, as compared with conventional control BALB/c and C3H/HeN animals. Pretreatment of conventional euthymic control mice with lipopolysaccharide 24 hr before surgery significantly stimulated hepatic DNA synthesis after 67% liver resection. Germ-free euthymic, conventional athymic, and conventional lipopolysaccharide-resistant mice pretreated with endotoxin did not manifest significant stimulation of liver regeneration. Evidence is reviewed that cytokine release in response to endotoxin was depressed in germ-free euthymic, conventional athymic, and conventional lipopolysaccharide-resistant mice as compared with conventional euthymic controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Up-regulated transcriptional repressors SnoN and Ski bind Smad proteins to antagonize transforming growth factor-beta signals during liver regeneration.

Transforming growth factor-beta (TGF-beta) functions as an antiproliferative factor for hepatocytes. However, for unexplained reasons, hepatocytes become resistant to TGF-beta signals and can proliferate despite the presence of TGF-beta during liver regeneration. TGF-beta is up-regulated during liver regeneration, although it is not known whether it is active or latent. TGF-beta activity may be examined by assessing Smad activation, a downstream signaling pathway. Smad pathway activation during liver regeneration induced by partial hepatectomy or CC4 injury was examined by assessing the levels of phospho-Smad2 and Smad2-Smad4 complexes. We found that Smad proteins were slightly activated in quiescent liver, but that their activation was further enhanced in regenerating liver. Interestingly, TGF-beta/Smad pathway inhibitors (SnoN and Ski) were up-regulated during regeneration, and notably, SnoN was induced mainly in hepatocytes. SnoN and Ski are transcriptional repressors that may render some cells resistant to TGF-beta via binding Smad proteins. Complexes between SnoN, Ski, and the activated Smad proteins were detected from 2 to 120 h during the major proliferative phase in regenerating liver. Inhibitory complexes decreased after liver mass restitution (5-15 days), suggesting that persistently activated Smad proteins might participate in returning the liver to a quiescent state. Our data show that active TGF-beta/Smad signals are present during regeneration and suggest that SnoN/Ski induction might explain hepatocyte resistance to TGF-beta during the proliferative phase.

Animals↗
PubMed2006

Id2 leaves the chromatin of the E2F4-p130-controlled c-myc promoter during hepatocyte priming for liver regeneration.

The Id (inhibitor of DNA binding or inhibitor of differentiation) helix-loop-helix proteins are involved in the regulation of cell growth, differentiation and cancer. The fact that the molecular mechanisms of liver regeneration are not completely understood prompted us to study the fate of Id2 in proliferating liver. Id2 increases in liver regeneration after partial hepatectomy, following the early induction of its gene. Co-immunoprecipitation shows that Id2 forms a complex with E2F4, p130 and mSin3A in quiescent liver and all these components are present at the c-myc promoter as shown using ChIP (chromatin immunoprecipitation). Activation of c-myc during hepatocyte priming (G0-G1 transition) correlates with the dissociation of Id2 and HDAC (histone deacetylase), albeit p130 remains bound at least until 6 h. Moreover, as the G0-G1 transition progresses, Id2 and HDAC again bind the c-myc promoter concomitantly with the repression of this gene. The time course of c-myc binding to the Id2 promoter, as determined by ChIP assays is compatible with a role of the oncoprotein as a transcriptional inducer of Id2 in liver regeneration. Immunohistochemical analysis shows that Id2 also increases in proliferating hepatocytes after bile duct ligation. In this case, the pattern of Id2 presence in the c-myc promoter parallels that found in regenerating liver. Our results may suggest a control role for Id2 in hepatocyte priming, through a p130 dissociation-independent regulation of c-myc.

Animals↗
PubMed2004

Effects of Zuogui Wan on neurocyte apoptosis and down-regulation of TGF-beta1 expression in nuclei of arcuate hypothalamus of monosodium glutamate -liver regeneration rats.

AIM: To inquire into the effects and mechanism of Zuogui Wan (Pills for Kidney Yin) on neurocyte apoptosis in nuclei of arcuate hypothalamus (ARN) of monosodium glutamate (MSG)-liver regeneration rats, and the mechanism of liver regeneration by using optic microscope, electron microscope and in situ end labeling technology to adjust nerve-endocrine-immunity network. METHODS: Neurocyte apoptosis in ARN of the experiment rats was observed by using optic microscope, electron microscope and in situ end labeling technology. Expression of TGF-beta1 in ARN was observed by using immunohistochemistry method. RESULTS: The expression of TGF-beta1 in rats of model group was increased with the increase of ARN neurocyte apoptosis index (AI) (t = 8.3097, 12.9884, P<0.01). As compared with the rats of model group, the expression of TGF-beta1 in rats of Zuogui Wan treatment group was decreased with the significant decrease of ARN neurocyte apoptosis (t = 4.5624, 11.1420, P<0.01). CONCLUSION: Brain neurocyte calcium ion overexertion and TGF-beta1 protein participate in the adjustment and control of ARN neurocyte apoptosis in MSG-liver regeneration-rats. Zuogui Wan can prevent ARN neurocyte apoptosis of MSG-liver regeneration in rats by down-regulating the expression of TGF-beta1, and influence liver regeneration through adjusting nerve-endocrine-immune network.

Animals↗
PubMed1983

Alterations in the activities of hepatic plasma-membrane and microsomal enzymes during liver regeneration.

A marked increase in the activities of rat liver plasma-membrane (Na+ + K+)-stimulated ATPase and microsomal Ca2+-stimulated ATPase was observed 18h after partial hepatectomy. Lipid analyses for both membrane preparations reveal that in partially hepatectomized rats the cholesterol and sphingomyelin content are decreased with a subsequent decrease in the cholesterol/phospholipid molar ratio compared with those of sham-operated animals. Changes in the allosteric properties of plasma-membrane (Na+ + K+)-stimulated ATPase by F- (as reflected by changes in the Hill coefficient) indicated a fluidization of the lipid bilayer of both membrane preparations in 18 h-regenerating liver. The amphipathic dodecyl glucoside incorporated into the hepatic plasma membranes evoked a marked increase in the (Na+ + K+)-stimulated ATPase and 5'-nucleotidase activities. The lack of effect of the glucoside on the Lubrol-PX-solubilized 5'-nucleotidase indicates that changes in the activities of the membrane-bound enzymes caused by the glucoside are due to modulation of the membrane fluidity. Dodecyl glucoside appears to increase the membrane fluidity, evaluated through changes in the Hill coefficient for plasma-membrane (Na+ + K+)-stimulated ATPase. The biological significance of these data is discussed in terms of the differences and changes in the interaction of membrane-bound enzymes with membrane lipids during liver regeneration.

Animals↗
PubMed1995

In vivo amino acid fluxes in regenerating liver after two-thirds hepatectomy in the rat.

BACKGROUND/AIMS: Recent reports in the literature suggest that liver cell swelling following amino acid influx exerts anabolic and anti-catabolic effects. We have tested the possibility that rapid liver growth after partial hepatectomy is promoted by an increased amino acid-influx and that this is associated with an increased hepatic water content and a decreased rate of proteolysis. METHODS: Two-thirds hepatectomy was performed in rats. Plasma liver flow and amino acid fluxes were measured after 24 or 48 h. RESULTS: Plasma liver flow was increased 24 and 48 h after partial hepatectomy or sham-operation in pair-fed animals. At these time points, in both groups there was a specific two- to threefold increased net hepatic uptake of the amino acids alanine and glycine, both being transported by the sodium-coupled amino acid transport system A/ASC. No changes in uptake of system N transported amino acids were observed. Both in partially hepatectomized and sham-operated pair-fed animals, the hepatic uptake of alanine and glycine was accompanied by a minor increase in tissue water (from 68 to 70%). Proteolysis, measured by leucine efflux, was only reduced in regenerating livers. CONCLUSIONS: We conclude that cell swelling is not an important factor in the stimulation of net protein synthesis during liver regeneration.

Amino Acids↗
PubMed1983

Late phase of liver restoration following partial hepatectomy in phenobarbital-treated rats. I. Effect of preoperative and postoperative phenobarbital treatment on organ weight, protein and DNA content of the normal and the regenerating liver.

Rats were treated with phenobarbital (50 mg/kg) for 7 days prior to or after partial hepatectomy. Liver weight, protein, DNA, and RNA content were determined in liver tissue removed at operation as well as in regenerating liver 7 days later at the time of death. When rats were treated with phenobarbital in the preoperative period an increase in liver weight secondary to cell hyperplasia was observed as compared to livers of rats treated with sodium chloride. The weight of regenerating liver of preoperatively treated rats did not differ from the controls, but protein concentration was significantly higher (P less than or equal to 0.001). When phenobarbital was applied only in the postoperative period, a highly significant (P less than or equal to 0.001) enlargement of the regenerating liver tissue was found secondary to cell hypertrophy without hyperplasia, whereas protein concentration was unchanged. An increased RNA/DNA ratio, however, suggests that further protein synthesis is enhanced. The results show that both preoperative and postoperative phenobarbital treatment aids in hepatic tissue enlargement, though by a different mechanism.

Animals↗
PubMed1990

Effect of ethanol on polyamine synthesis during liver regeneration in rats.

Ethanol consumption retards the hepatic regenerative response to injury. This may contribute to the pathogenesis of liver injury in alcoholic individuals. The mechanisms responsible for ethanol-associated inhibition of liver regeneration are poorly understood. To determine if the antiregenerative effects of ethanol involve modulation of polyamine metabolism, parameters of polyamine synthesis were compared before and during surgically induced liver regeneration in ethanol-fed rats and isocalorically maintained controls. After partial hepatectomy, induction of the activity of ornithine decarboxylase (ODC), the rate limiting enzyme for polyamine synthesis, was delayed in rats that had been fed ethanol. This was correlated with reduced levels of putrescine, ODC's immediate product. Increases in hepatic spermidine and spermine were also inhibited. Differences in ODC activity between ethanol-fed and control rats could not be explained by differences in the expression of ODC mRNA or by differences in ODC apoenzyme concentrations, suggesting that chronic ethanol intake inactivates ODC posttranslationally. Supplemental putrescine, administered at partial hepatectomy and 4 and 8 h thereafter, increased hepatic putrescine concentrations and markedly improved DNA synthesis and liver regeneration in ethanol-fed rats. These data suggest that altered polyamine metabolism may contribute to the inhibition of liver regeneration that occurs after chronic exposure to ethanol.

Animals↗
PubMed2002

Delayed liver regeneration with negative regulation of hepatocyte growth factor and positive regulation of transforming growth factor-beta1 mRNA after portal branch ligation in biliary obstructed rats.

BACKGROUND: The influence of obstructive jaundice on liver regeneration is still controversial. The aim of this study was to investigate liver regeneration after portal branch ligation (PBL) in the jaundiced rat, focusing on hepatocyte growth factor (HGF) and transforming growth factor-beta1 (TGF-beta 1). METHODS: Male Wistar rats underwent PBL or a sham operation 7 days after a common bile duct ligation. Liver wet weight, proliferating cell nuclear antigen labeling, HGF and TGF-beta 1 mRNA expression, and immunohistochemical staining with alpha-smooth muscle actin antibody were studied. RESULTS: The rate of liver regeneration in jaundiced liver was decreased as compared to a non-jaundiced liver. DNA synthesis in the jaundiced non-ligated lobe was significantly lower than in the non-jaundiced liver as was the peak level of HGF mRNA expression after PBL. In contrast, the level of TGF-beta 1 mRNA expression was higher in the jaundiced liver, and alpha-smooth muscle actin staining showed that hepatic stellate cells were gradually activated into myofibroblast-like cells. CONCLUSIONS: Obstructive jaundice decreased the expression of HGF mRNA and increased the expression of TGF-beta 1 mRNA, resulting in delayed liver regeneration after PBL. We suggest that hepatic stellate cells activated in obstructive jaundice may affect the expression of these growth factors.

Actins↗
PubMed1997

Zinc and metallothioneins on cellular immune effectiveness during liver regeneration in young and old mice.

Partial hepatectomy in young mice (pHx) induces thymic atrophy, disregulation of thymocytes subsets and a strong accumulation of zinc in thymic tissue after 1-2 days of liver regeneration. Zinc is relevant for good immune functioning. Restoration of zinc into both the thymus and thymocytes subsets in the late period of liver regeneration is observed in young pHx mice. These findings have suggested a link between the thymus and the liver influencing T-cell functions and involving zinc. This kind of link could be relevant in aging because thymic involution, negative crude zinc balance and crippled immune functions are constant events. The preminence of a liver extrathymic T-cell pathway after pHx or during aging has been suggested. Thus the study of pHx in young and old mice may offer a good model to better understand the role played both by thymic involution and by liver extrathymic T-cell pathway and the role of zinc in these physiological processes during aging. Young pHx mice after 1-2 days of liver regeneration show: reduced thymic endocrine activity, increment of double negative (DN) thymocytes subsets, impairment of peripheral immune efficiency (PHA, NK activity and IL-2) and negative crude zinc balance, which are all restored in the late period of liver regeneration. By contrast the thymic and peripheral immune defects and the negative crude zinc balance, already present in old sham mice, are not modified during liver regeneration in old pHx mice. Circulating leukocytes and lymphocytes are not significantly modified both in young and old pHx mice as compared to respective sham controls. Zinc may also be crucial for extrathymic T-cells pathway, being preminent in aging, rather than in young age, due to its metallothioneins (MT) binding capacity. MT are significantly increased in young pHx and in aging inducing a low zinc-free quota for thymic and peripheral immune efficiency in young pHx mice, and for extrathymic T-cell pathway, in old age. Thus low zinc bioavailability, due to MT, may play a pivotal role, not only for thymocytes but also for liver extrathymic T-cell pathway.

Aging↗
PubMed1992

Changes in cell surface expression of fibronectin and fibronectin receptor during liver regeneration.

The surface expression of fibronectin and its major integrin receptor in liver, integrin alpha 5 beta 1, was studied during liver regeneration after partial hepatectomy. Using immunoblotting, plasma membranes isolated from livers at different regeneration stages were found to contain 6- to 8-fold elevated levels of fibronectin, alpha 5 and beta 1 at 12-24 h after the operation. Normal levels were gradually restored during the following 8-9 days. The membrane-associated fibronectin lacked the ED-A domain, suggesting that it consisted of plasma fibronectin. A prominent fibronectin fragment (180 kDa) was present at 12-24 h after surgery, possibly reflecting turnover of the pericellular matrix during cell division. Indirect immunohistochemical staining of liver sections revealed beta 1 and fibronectin mainly in the sinusoidal region of the hepatocyte plasma membrane. The distribution was not markedly altered during liver regeneration. The results suggest that the fibronectin-mediated contacts between the cells and the extracellular matrix increase during the pre-replicative and proliferative phases of liver regeneration. The significance of these results for the growth and for the structure of the liver during regeneration and development is discussed.

Animals↗
PubMed1983

Changes in chromatin structure during rat liver regeneration as demonstrated by thermal melting analyses.

Chromatin was isolated from regenerating rat livers at different times after 2/3 hepatectomy and enriched with respect to active sequences. Thermal melting analyses of the material resulted in profiles reflecting the specific structural organization of the chromatin during different phases of the regeneration process: The high transcriptional activity of the chromatin 1, 16, and 36 hours after hepatectomy is demonstrated by a high proportion of DNA-protein complexes melting between 80 degrees C and 85 degrees C, while the period of active DNA synthesis 24 hours after hepatectomy is reflected by high amounts of components with Tm around 90 degrees C.

Animals↗
PubMed2003

Gene expression profiling reveals the mechanism and pathophysiology of mouse liver regeneration.

Comprehensive analysis of the changes in gene expression during liver regeneration was carried out by using an in-house microarray composed of 2,304 distinct mouse liver cDNA clones. Mice were subjected to partial two-thirds hepatectomy, and changes in mRNA levels were monitored up to 48 h. Of the 2,304 genes analyzed, 496 genes showed expression levels measurable at all time points after the partial hepatectomy. 317 genes were up- or down-regulated 2-fold or more at least at one time point during liver regeneration and were classified into eight clusters based on their expression patterns. With a more stringent cut-off value of +/-2 S.D., 68 genes were listed and were classified into five clusters. In these two analyses with different clustering criteria, functionally categorized genes showed similar cluster distributions. Genes involved in protein synthesis and posttranslational processing were significantly enriched in the cluster characterized by rapid gene activation and subsequent persistence. This suggests the importance of modulating the efficiency of protein supply and/or altering the composition of protein population from the early phase of hepatocyte proliferation. Genes for two major liver functions, i.e. plasma protein secretion and intermediate metabolism were enriched in distinct clusters exhibiting the features of gradual gene activation and sustained repression, respectively. Therefore, these genes are differentially regulated during the regeneration, possibly leading to changes in the flow of amino acids and energy from enzyme proteins to plasma proteins in their synthesis. Thus, clustering analysis of expression patterns of functionally classified genes gave insights into mechanism and pathophysiology of liver regeneration.

Animals↗