Preoperative albumin-bilirubin score and liver resection percentage determine postoperative liver regeneration after partial hepatectomy

BACKGROUND The success of liver resection relies on the ability of the remnant liver to regenerate.Most of the knowledge regarding the pathophysiological basis of liver regeneration comes from rodent studies,and data on humans are scarce.Additionally,there is limited knowledge about the preoperative factors that influence postoperative regeneration.AIM To quantify postoperative remnant liver volume by the latest volumetric software and investigate perioperative factors that affect posthepatectomy liver regenera-tion.METHODS A total of 268 patients who received partial hepatectomy were enrolled.Patients were grouped into right hepatectomy/trisegmentectomy(RH/Tri),left hepa-tectomy(LH),segmentectomy(Seg),and subsegmentectomy/nonanatomical hepatectomy(Sub/Non)groups.The regeneration index(RI)and late rege-neration rate were defined as(postoperative liver volume)/[total functional liver volume(TFLV)]×100 and(RI at 6-months-RI at 3-months)/RI at 6-months,respectively.The lower 25th percentile of RI and the higher 25th percentile of late regeneration rate in each group were defined as“low regeneration”and“delayed regeneration”.“Restoration to the original size”was defined as regeneration of the liver volume by more than 90%of the TFLV at 12 months postsurgery.RESULTS The numbers of patients in the RH/Tri,LH,Seg,and Sub/Non groups were 41,53,99 and 75,respectively.The RI plateaued at 3 months in the LH,Seg,and Sub/Non groups,whereas the RI increased until 12 months in the RH/Tri group.According to our multivariate analysis,the preoperative albumin-bilirubin(ALBI)score was an independent factor for low regeneration at 3 months[odds ratio(OR)95%CI=2.80(1.17-6.69),P=0.02;per 1.0 up]and 12 months[OR=2.27(1.01-5.09),P=0.04;per 1.0 up].Multivariate analysis revealed that only liver resection percentage[OR=1.03(1.00-1.05),P=0.04]was associated with delayed regeneration.Furthermore,multivariate analysis demonstrated that the preoperative ALBI score[OR=2.63(1.00-1.05),P=0.02;per 1.0 up]and liver resection percentage[OR=1.02(1.00-1.05),P=0.04;per 1.0 up]were found to be independent risk factors associated with volume restoration failure.CONCLUSION Liver regeneration posthepatectomy was determined by the resection percentage and preoperative ALBI score.This knowledge helps surgeons decide the timing and type of rehepatectomy for recurrent cases.

ZBTB20 is involved in liver regeneration after partial hepatectomy in mouse

BACKGROUND: A better understanding of the molecular mechanisms in liver regeneration holds promise for exploring the new potential therapy for liver failure. The present study was to investigate the role of zinc finger and BTB domain-containing protein 20(ZBTB20), a potential factor associated with liver regeneration, in a model of 70% hepatectomy in mice. METHODS: Parameters for liver proliferation such as liver/body ratio and BrdU positivity were obtained via direct measurement and immunohistochemistry. The levels of zinc fingers and homeoboxes 2(ZHX2), ZBTB20, alpha-fetoprotein(AFP) and glypican 3(GPC3) transcripts in the regenerating liver tissue of a 70% hepatectomy rodent model were monitored by real-time PCR analysis at different time points. Knockdown of ZBTB20 was performed to characterize its regulatory function. RESULTS: A negatively regulating relationship between ZHX2, ZBTB20 and AFP, GPC3 was revealed from 24 to 72 hours after 70% hepatectomy. ZBTB20 appears to negatively regulate AFP and GPC3 transcription since the knockdown of ZBTB20 promoted the proliferation of hepatocytes and the expression of AFP and GPC3. CONCLUSION: In addition to AFP, GPC3 and ZHX2, ZBTB20 is a new regulator in liver regeneration and the decrease of ZBTB20 expression following 70% hepatectomy promotes AFP and GPC3 expression.

Effects of pHGF on Hepatocyte DNA Synthesis after Partial Hepatectomy in Rats

The effects of pHGF on the changes of hepatocyte proliferative cycle and liver regenerative capacity after partial hepatectomized rats were observed by flow cytometry (FCM). The results were as follows:1)S phase fraction (SPF) in group of normal rats (group A) accounted for 9. 89% and increased gradually within 6 h, following a peak at 12th h or 36th h after operation, but in the group of pHGF-treated rats (group B) the peak appeared at 24th h after operation; 2 )Proliferatioll index (PI) of group A was 19. 6 % before partial hepatectomy, increased to 34. 91% within 6 h and reached a peaks at 12th or 36th h after operation, and in group B the peak appeared at 48th h after operation. There were significant differences between two groups in SPF and PI (P<0. 01). The weight of liver began to increase 12 h after operation, and almost reached the preoperative weight 5 days after operation. These findings suggest that PHGF can promote the DNA synthesis and segmentation of hepatocyte.

Effects of terlipressin versus splenectomy on liver regeneration after partial hepatectomy in rats: What we know so far?

To the editor:We read with great interest the article entitled "Comparative study of the effects of terlipressin versus splenectomy on liver regeneration after partial hepatectomy in rats" by Ulmer et al.[1].The aim of this study was to analyse the impact of terlipressin ver-

Value of partial hepatectomy for the treatment of hilar cholangiocarcinoma: a Meta-analysis study

Objective To discuss the value of partial hepatectomy in patients with hilar cholangiocarcinoma.Methods English articles related to hilar cholangiocarcinoma were screened from January 1,1990 to May 12,2019 in the Pub Med,MEDLINE,EMBASE,and Cochrane Library databases.Information on postoperative radical cure,survival,morbidity,and mortality after surgery were extracted from articles that met the inclusion criteria for the meta-analysis.Results Twenty-two articles that met the inclusion criteria were classified into 4 study groups: the hepatectomy radical cure group(19 articles),the hepatectomy survival group(16 articles),the hepatectomy morbidity group(9 articles),and the hepatectomy mortality group(17 articles).We found that the rate of radical cure after partial hepatectomy(odds ratio [OR] 0.32,95% confidence interval [CI] 0.20-0.51) and the survival rate(hazard ratio [HR] 0.67,95% CI 0.58-0.79) were significantly higher than after simple bile duct resection,but that morbidity(OR 1.99,95% CI 1.37-2.90) and mortality(OR 2.71,95% CI 1.47-4.98) in patients within the partial hepatectomy group were also higher than in the simple bile duct resection group,taking into account the significant heterogeneity in the articles pertaining to the hepatectomy radical cure group(I^2=68.3%,P=0.000),a sub-group analysis was subsequently conducted.Its results showed that when the branches of the secondary bile ducts were not involved during hilar cholangiocarcinoma,then a bile duct resection had a similar radical cure outcome as combined partial hepatectomy(OR 0.94,95% CI 0.54-1.65).Conclusion Partial hepatectomy can increase the proportion of radical cure in patients with hilar cholangiocarcinoma and extend the survival time after surgery.However,the morbidity and mortality after surgery are higher than those in simple bile duct resections.Therefore,simple bile duct resection is still a relevant and efficient tool in the treatment of Bismuth-Corlette Type Ⅰ and Ⅱ hilar cholangiocarcinomas.

Liver structural transformation after partial hepatectomy and repeated partial hepatectomy in rats: A renewed view on liver regeneration

BACKGROUND The phenomenon of liver regeneration after partial hepatectomy(PH)is still a subject of considerable interest due to the increasing frequency of half liver transplantation on the one hand,and on the other hand,new surgical approaches which allow removal of massive space-occupying hepatic tumors,which earlier was considered as inoperable.Interestingly,the mechanisms of liver regeneration are extensively studied after PH but less attention is paid to the architectonics of the regenerated organ.Because of this,the question“How does the structure of regenerated liver differ from normal,regular liver?”has not been fully answered yet.Furthermore,almost without any attention is left the liver's structural transformation after repeated hepatectomy(of the re-regenereted liver).ATM To compare the architectonics of the lobules and circulatory bed of normal,regenerated and re-regenerated livers.METHODS The livers of 40 adult,male,albino Wistar rats were studied.14 rats were subjected to PH-the 1st study group(SG1);10 rats underwent repeated PH–the 2nd study group(SG2);16 rats were subjected to sham operation-control group(CG);The livers were studied after 9 months from PH,and after 6 months from repeated PH.Cytological(Schiff reaction for the determination of DNA concentration),histological(H&E,Masson trichrome,CK8 Immunohistochemical marker,transparent slides after Indian Ink injection,),morphometrical(hepatocytes areas,perimeters and ploidy)and Electron Microscopical(Scanning Electron Microscopy of corrosion casts)methods were used.RESULTS In the SG1 and SG2,the area of hepatocytes and their perimeter are increased compared to the CG(P<0.05).However,the areas and perimeters of the hepatocytes of the SG1 and SG2 groups reveal a lesser difference.In regenerated(SG1)and re-regenerated(SG2)livers,the hepatocytes form the remodeled lobules,which size(300-1200μm)exceeds the sizes of the lobules from CG(300-600μm).The remodeled lobules(especially the“mega-lobules”with the sizes 1000-1200μm)contain the transformed meshworks of the sinusoids,the part of which is dilated asymmetrically.This meshwork might have originated from the several portal venules(interlobular and/or inlet).The boundaries between the adjacent lobules(including mega-lobules)are widened and filled by connective tissue fibers,which gives the liver parenchyma a nodular look.In SG2 the unevenness of sinusoid diameters,as well as the boundaries between the lobules(including the mega-lobules)are more vividly expressed in comparison with SG1.The liver tissue of both SG1 and SG2 is featured by the slightly expressed ductular reaction.CONCLUSION Regenerated and re-regenerated livers in comparison with normal liver contain hypertrophied hepatocytes with increased ploidy which together with transformed sinusoidal and biliary meshworks form the remodeled lobulli.

Effects of pHGF on Renal Cellular DNA Synthesis after Partial Hepatectomy in Rats

Summary: The effects of pro-hepatocyte growth factor (pHGF) on the changes of renal cellular proliferative cycle of partial hepatectomized rats were observed by flow cytometry (FCM). S phase fraction (SPF) of control rats (group A) accounted for 7.58 % and increased gradually within 6 h, following a peak at 12th or 36th h after operation, but in pHGF-treated rats (group B) the peak appeared at 24th h after operation. Proliferation index (PI) of group A was 13. 2 % before partial hepatectomy, increased within 6 h and reached a peak at 12th or 36th h after operation, and in group B the peak appeared at 48th h after operation. There were significant differences in SPF and PI between two groups (P<0. 01 ). These findings suggest that PHGF may nonspecifically promote the DNA synthesis of renal cells.

The Use of Erythropoietin in Liver Regeneration in Pigs after Partial Hepatectomy

A partial hepatectomy is a surgical procedure performed during the living-donor liver transplantation and sometimes the only option for patients with hepatocarcinoma. However the remnant liver after the hepatectomy is still a major concern. Therefore, the process of liver regeneration has been a constant theme of study in order to optimize this process. Erythropoietin, a hormone produced by the kidney and involved in protecting organs like heart, liver and kidney itself against injuries can be one of these factors that could accelerate the liver regeneration. This study aims to observe if erythropoietin can accelerate the process of liver regeneration after partial hepatectomy in pigs. Methods: 8 pigs were classified into 2 groups of 4 pigs each: the control group and the test group. The animals in the first group underwent an application of saline solution subcutaneous on the day before the hepatectomy. Instead of saline solution, the test groups received a subcutaneous injection of 200 UI/lg of recombinant erythropoietin also on the day before the surgical procedure. After 7 days since the hepatectomy, in each animal the liver was biopsied in two regions, one next to the hepatectomy section and other far from it. The liver regeneration was analyzed using Ki-67. Results: Pigs from control group presented the following results: Control pig I: 30% of regeneration in the hepatectomy section and 10% in the region far from it;control pig II 24% and 4%;control pig III 27% and 7%. The test group presented no significant liver regeneration since Ki-67 could not identify cell proliferation in neither the biopsied areas. Conclusion: Since the number of pigs was not statistically significant, we could not conclude any further hypothesis. We strong believe that enhancing the number of pigs and testing different doses, we will be able to reach further conclusions.

Capn3 depletion causes Chk1 and Wee1 accumulation and disrupts synchronization of cell cycle reentry during liver regeneration after partial hepatectomy

Recovery of liver mass to a healthy liver donor by compensatory regeneration after partial hepatectomy(PH)is a prerequisite for liver transplantation.Synchronized cell cycle reentry of the existing hepatocytes after PH is seemingly a hallmark of liver compensatory regeneration.Although the molecular control of the PH-triggered cell cycle reentry has been extensively studied,little is known about how the synchronization is achieved after PH.The nucleolus-localized protein cleavage complex formed by the nucleolar protein Digestive-organ expansion factor(Def)and cysteine proteinase Calpain 3(Capn3)has been implicated to control wounding healing during liver regeneration through selectively cleaving the tumor suppressor p53 in the nucleolus.However,whether the Def-Capn3 complex participates in regulating the synchronization of cell cycle reentry after PH is unknown.In this report,we generated a zebrafish capn3b null mutant(capn3b^(Δ19Δ14)).The homozygous mutant was viable and fertile,but suffered from a delayed liver regeneration after PH.Delayed liver regeneration in capn3b^(Δ19Δ14)was due to disruption of synchronized cell proliferation after PH.Mass spectrometry(MS)analysis of nuclear proteins revealed that a number of negative regulators of cell cycle are accumulated in the capn3b^(Δ19Δ14)liver after PH.Moreover,we demonstrated that Check-point kinase 1(Chk1)and Wee1,two key negative regulators of G2 to M transition,are substrates of Capn3.We also demonstrated that Chk1 and Wee1 were abnormally accumulated in the nucleoli of amputated capn3bΔ19Δ14 liver.In conclusion,our findings suggest that the nucleolar-localized Def-Capn3 complex acts as a novel regulatory pathway for the synchronization of cell cycle reentry,at least partially,through inactivating Chk1 and Wee1 during liver regeneration after PH.

Hepatic vagotomy blunts liver regeneration after hepatectomy by downregulating the expression of interleukin-22

BACKGROUND Rapid regeneration of the residual liver is one of the key determinants of successful partial hepatectomy(PHx).At present,there is a lack of recognized safe,effective,and stable drugs to promote liver regeneration.It has been reported that vagus nerve signaling is beneficial to liver regeneration,but the potential mechanism at play here is not fully understood.AIM To explore the effect and mechanism of hepatic vagus nerve in liver regeneration after PHx.METHODS A PHx plus hepatic vagotomy(Hv)mouse model was established.The effect of Hv on liver regeneration after PHx was determined by comparing the liver regeneration levels of the PHx-Hv group and the PHx-sham group mice.In order to further investigate the role of interleukin(IL)-22 in liver regeneration inhibition mediated by Hv,the levels of IL-22 in the PHx-Hv group and the PHx-sham group was measured.The degree of liver injury in the PHx-Hv group and the PHx-sham group mice was detected to determine the role of the hepatic vagus nerve in liver injury after PHx.RESULTS Compared to control-group mice,Hv mice showed severe liver injury and weakened liver regeneration after PHx.Further research found that Hv downregulates the production of IL-22 induced by PHx and blocks activation of the signal transducer and activator of transcription 3(STAT3)pathway then reduces the expression of various mitogenic and anti-apoptotic proteins after PHx.Exogenous IL-22 reverses the inhibition of liver regeneration induced by Hv and alleviates liver injury,while treatment with IL-22 binding protein(an inhibitor of IL-22 signaling)reduce the concentration of IL-22 induced by PHx,inhibits the activation of the STAT3 signaling pathway in the liver after PHx,thereby hindering liver regeneration and aggravating liver injury in PHx-sham mice.CONCLUSION Hv attenuates liver regeneration after hepatectomy,and the mechanism may be related to the fact that Hv downregulates the production of IL-22,then blocks activation of the STAT3 pathway.

Patterns of cancer recurrence in localized resected hepatocellular carcinoma

BACKGROUND： Tumor resection in non-metastatic hepato- cellular carcinoma （HCC） patients with adequate liver reserve offers a potential cure, but has a high 5-year recurrence rate. We analyzed the patterns of cancer relapse after partial hepa- tectomy to guide post-operative management.

Toll-like receptor 5-mediated signaling enhances liver regeneration in mice

Background:Toll-like receptor 5(TLR5)-mediated pathways play critical roles in regulating the hepatic immune response and show hepatoprotective effects in mouse models of hepatic diseases.However,the role of TLR5 in experimental models of liver regeneration has not been reported.This study aimed to investigate the role of TLR5 in partial hepatectomy(PHx)-induced liver regeneration.Methods:We performed 2/3 PHx in wild-type(WT)mice,TLR5 knockout mice,or TLR5 agonist CBLB502 treated mice,as a model of liver regeneration.Bacterial flagellin content was measured with ELISA,and hepatic TLR5 expression was determined with quantitative PCR analyses and flow cytometry.To study the effects of TLR5 on hepatocyte proliferation,we analyzed bromodeoxyuridine(BrdU)incorporation and proliferating cell nuclear antigen(PCNA)expression with immunohistochemistry(IHC)staining.The effects of TLR5 during the priming phase of liver regeneration were examined with quantitative PCR analyses of immediate early gene mRNA levels,and with Western blotting analysis of hepatic NF-κB and STAT3 activation.Cytokine and growth factor production after PHx were detected with real-time PCR and cytometric bead array(CBA)assays.Oil Red O staining and hepatic lipid concentrations were analyzed to examine the effect of TLR5 on hepatic lipid accumulation after PHx.Results:The bacterial flagellin content in the serum and liver increased,and the hepatic TLR5 expression was significantly up-regulated in WT mice after PHx.TLR5-deficient mice exhibited diminished numbers of BrdU-and PCNA-positive cells,suppressed immediate early gene expression,and decreased cytokine and growth factor production.Moreover,PHx-induced hepatic NF-κB and STAT3 activation was inhibited in Tlr5–/–mice,as compared with WT mice.Consistently,the administration of CBLB502 significantly promoted PHx-mediated hepatocyte proliferation,which was correlated with enhanced production of proinflammatory cytokines and the recruitment of macrophages and neutrophils in the liver.Furthermore,Tlr5–/–mice displayed significantly lower hepatic lipid concentrations and smaller Oil Red O positive areas than those in control mice after PHx.Conclusions:We reveal that TLR5 activation contributes to the initial events of liver regeneration after PHx.Our findings demonstrate that TLR5 signaling positively regulates liver regeneration and suggest the potential of TLR5 agonist to promote liver regeneration.

Diwu Yanggan Modulates the Wnt/β-catenin Pathway and Inhibits Liver Carcinogenesis Signaling in 2-AAF/PH Model Rats

The activation of the Wnt/β-catenin signaling pathway in oval cells after liver injury is implicated in hepatocarcinogenesis.Diwu Yanggan capsule is a Chinese herbal medicine that has been used for treating liver disorder.The present study aimed to examine the mechanism by which Diwu Yanggan inhibits liver carcinogenesis,and the involvement of the Wnt/β-catenin signaling pathway.Diwu Yanggan capsule was administered to 2-acetaminofluorene/partial hepatectomy(2-AAF/PH)rats,a murine model of liver injury.The biomarkers of oval cells and key proteins in the Wnt/p-catenin signaling pathway were assessed on postoperative day 8,10,14,17,19 and 22.The results showed that treatment with Diwu Yanggan was associated with reduced expression of oval cell and stem cell biomarkers in the 2-AAF/PH animals.The expression pattern of key proteins in the Wnt/β-catenin pathway was altered in Diwu Yanggan-treated animals,indicating that the Diwu Yanggan treatment accelerated the activation of the Wnt/β-catenin pathway in the initial stage and contributed to its deactivation in the later stage.Histological findings indicated that hepatocyte proliferation was suppressed in Diwu Yanggan-treated animals,compared with untreated 2-AAF/PH animals.Taken together,Diwu Yanggan capsule may reduce the risk of hepatocarcinogenesis by modulating the Wnt/β-catenin signaling pathway.

Molecular pathways of liver regeneration:A comprehensive review

The liver is a unique parenchymal organ with a regenerative capacity allowing it to restore up to 70%of its volume.Although knowledge of this phenomenon dates back to Greek mythology(the story of Prometheus),many aspects of liver regeneration are still not understood.A variety of different factors,including inflammatory cytokines,growth factors,and bile acids,promote liver regeneration and control the final size of the organ during typical regeneration,which is performed by mature hepatocytes,and during alternative regeneration,which is performed by recently identified resident stem cells called“hepatic progenitor cells”.Hepatic progenitor cells drive liver regeneration when hepatocytes are unable to restore the liver mass,such as in cases of chronic injury or excessive acute injury.In liver maintenance,the body mass ratio is essential for homeostasis because the liver has numerous functions;therefore,a greater understanding of this process will lead to better control of liver injuries,improved transplantation of small grafts and the discovery of new methods for the treatment of liver diseases.The current review sheds light on the key molecular pathways and cells involved in typical and progenitor-dependent liver mass regeneration after various acute or chronic injuries.Subsequent studies and a better understanding of liver regeneration will lead to the development of new therapeutic methods for liver diseases.

MKK4 inhibitor:the hope for liver failure prevention and potential small liver graft transplantation

Liver regeneration represents a fascinating concept that spans from ancient mythology to modern medical science.In Greek mythology,Prometheus,a hero who defied Zeus by stealing fire and giving it to humanity,was subjected to a severe punishment.He was bound to a rock where,each day,an eagle would feast on his liver,which would then miracu-lously regenerate overnight.This myth underscores the liver’s unique regenerative abilities,a feature that is not just le-gendary but also scientifically recognized.

Constitutive androstane receptor induced-hepatomegaly and liver regeneration is partially via yes-associated protein activation

The constitutive androstane receptor(CAR, NR3 I1) belongs to nuclear receptor superfamily.It was reported that CAR agonist TCPOBOP induces hepatomegaly but the underlying mechanism remains largely unknown. Yes-associated protein(YAP) is a potent regulator of organ size. The aim of this study is to explore the role of YAP in CAR activation-induced hepatomegaly and liver regeneration.TCPOBOP-induced CAR activation on hepatomegaly and liver regeneration was evaluated in wildtype(WT) mice, liver-specific YAP-deficient mice, and partial hepatectomy(PHx) mice. The results demonstrate that TCPOBOP can increase the liver-to-body weight ratio in wild-type mice and PHx mice.Hepatocytes enlargement around central vein(CV) area was observed, meanwhile hepatocytesproliferation was promoted as evidenced by the increased number of KI67+cells around portal vein(PV)area. The protein levels of YAP and its downstream targets were upregulated in TCPOBOP-treated mice and YAP translocation can be induced by CAR activation. Co-immunoprecipitation results suggested a potential proteineprotein interaction of CAR and YAP. However, CAR activation-induced hepatomegaly can still be observed in liver-specific YAP-deficient(Yape/e) mice. In summary, CAR activation promotes hepatomegaly and liver regeneration partially by inducing YAP translocation and interaction with YAP signaling pathway, which provides new insights to further understand the physiological functions of CAR.

Adipose tissue induces a better liver regeneration after living liver donation in normal weight donors

Background:Extrahepatic body fat could be a relevant factor affecting liver regeneration after partial hepatectomy.The aim of this study was to evaluate the potential role of body fatty tissue in liver regeneration capacity after liver resection in a cohort of living donors.Methods:We observed liver regeneration in 120 patients:70 living donors who underwent right hepatectomy and 50 recipients who got a right graft transplantation.Liver volumetry and body fat analysis were performed based on the computed tomography images with volumetry software.The gain of liver volume was calculated between three points in time considering the absolute and percentage values:before surgery and early(median 10 days,range 4-21 days)and late(median 27 weeks,range 18-40 weeks)after surgery.Pearson’s correlation was used to examine the potential correlation between adipose tissue and liver regeneration.Results:Pearson’s correlation showed a significant correlation between the subcutaneous fat mass index(sFMI)and early(r=0.173,P=0.030),as well late(r=0.395,P=0.0004)percental liver volume gain in the whole collective.Under stratification in donor’s and recipient’s collectives,the effect of extrahepatic adipose tissue appears in multiple regression only in the donor’s collective:early(β=0.219,T=2.137,P=0.036)and late(β=0.390,T=2.552,P=0.015)percental volume gain.Conclusions:Subcutaneous adipose tissue is a positive predictive factor to estimate the goodness of liver regeneration after partial hepatectomy in normosthenic donors.

Fenofibrate-promoted hepatomegaly and liver regeneration are PPARα-dependent and partially related to the YAP pathway

Fenofibrate,a peroxisome proliferator-activated receptor α(PPARα)agonist,is widely prescribed for hyperlipidemia management.Recent studies also showed that it has therapeutic potential in various liver diseases.However,its effects on hepatomegaly and liver regeneration and the involved mechanisms remain unclear.Here,the study showed that fenofibrate significantly promoted liver enlargement and regeneration post-partial hepatectomy in mice,which was dependent on hepatocyteexpressed PPARα.Yes-associated protein(YAP)is pivotal in manipulating liver growth and regeneration.We further identified that fenofibrate activated YAP signaling by suppressing its K48-linked ubiquitination,promoting its K63-linked ubiquitination,and enhancing the interaction and transcriptional activity of the YAP-TEAD complex.Pharmacological inhibition of YAP-TEAD interaction using verteporfin or suppression of YAP using AAV Yap shRNA in mice significantly attenuated fenofibrate-induced hepatomegaly.Other factors,such as MYC,KRT23,RAS,and RHOA,might also participate in fenofibrate-promoted hepatomegaly and liver regeneration.These studies demonstrate that fenofibratepromoted liver enlargement and regeneration are PPARα-dependent and partially through activating the YAP signaling,with clinical implications of fenofibrate as a novel therapeutic agent for promoting liver regeneration.

Menstrual blood-derived mesenchymal stem cells differentiate into functional hepatocyte-like cells

Orthotopic liver transplantation(OLT)is the only proven effective treatment for both end-stage and metabolic liver diseases.Hepatocyte transplantation is a promising alternative for OLT,but the lack of available donor livers has hampered its clinical application.Hepatocyte-like cells(HLCs)differentiated from many multi-potential stem cells can help repair damaged liver tissue.Yet almost suitable cells currently identified for human use are difficult to harvest and involve invasive procedures.Recently,a novel mesenchymal stem cell derived from human menstrual blood(MenSC)has been discovered and obtained easily and repeatedly.In this study,we examined whether the MenSCs are able to differentiate into functional HLCs in vitro.After three weeks of incubation in hepatogenic differentiation medium containing hepatocyte growth factor(HGF),fibroblast growth factor-4(FGF-4),and oncostain M(OSM),cuboidal HLCs were observed,and cells also expressed hepatocyte-specific marker genes including albumin(ALB),α-fetoprotein(AFP),cytokeratin 18/19(CK18/19),and cytochrome P450 1A1/3A4(CYP1A1/3A4).Differentiated cells further demonstrated in vitro mature hepatocyte functions such as urea synthesis,glycogen storage,and indocyanine green(ICG)uptake.After intrasplenic transplantation into mice with 2/3 partial hepatectomy,the MenSC-derived HLCs were detected in recipient livers and expressed human ALB protein.We also showed that MenSC-derived HLC transplantation could restore the serum ALB level and significantly suppressed transaminase activity of liver injury animals.In conclusion,MenSCs may serve as an ideal,easily accessible source of material for tissue engineering and cell therapy of liver tissues.

The Involvement of Heat Shock Proteins in Murine Liver Regeneration

Partial hepatectomy （PHx） in mammals is a very common experimental model to investigate the process of liver regeneration. The surgery itself could give birth to a series of stresses, such as the temporary raise of body temperature and the ischaemia-reperfusion injury. Heat shock proteins （HSPs） were a family of stress-inducible proteins involved in maintaining cell homeostasis and regulating the immune system. In our study, we intended to investigate the expression and role of HSPs in liver regeneration. Using RT-PCR and Western blotting, we determined the expression in regenerating liver of HSP27, HSP60, HSP70 and HSP90 in mRNA level and protein level, respectively, with mice treated with sham operation as controls. We also used quercertin as an inhibitior of HSPs to explore their effects on liver regeneration. We found that hepatic expression of HSPs increased at the early phase of liver regeneration and declined to the constitutively low level later. Moreover, quercetin pretreatment delayed the progress of liver regeneration in mice via inhibition of HSPs. The results indicated that HSPs played an important role in liver regeneration. Cellular ＆ Molecular Immunology. 2007;4（1）：53-57.