Platelets are anucleate fragments mainly involved in hemostasis and thrombosis,and there is emerging evidence that platelets have other nonhemostatic potentials in inflammation,angiogenesis,regeneration and ischemia/r...Platelets are anucleate fragments mainly involved in hemostasis and thrombosis,and there is emerging evidence that platelets have other nonhemostatic potentials in inflammation,angiogenesis,regeneration and ischemia/reperfusion injury(I/R injury),which are involved in the physiological and pathological processes during living donor liver transplantation(LDLT).LDLT is sometimes associated with impaired regeneration and severe I/R injury,leading to postoperative complications and decreased patient survival.Recent studies have suggested that perioperative thrombocytopenia is associated with poor graft regeneration and postoperative morbidity in the short and long term after LDLT.Although it is not fully understood whether thrombocytopenia is the cause or result,increasing platelet counts are frequently suggested to improve posttransplant outcomes in clinical studies.Based on rodent experiments,previous studies have identified that platelets stimulate liver regeneration after partial hepatectomy.However,the role of platelets in LDLT is controversial,as platelets are supposed to aggravate I/R injury in the liver.Recently,a rat model of partial liver transplantation(LT)was used to demonstrate that thrombopoietin-induced thrombocytosis prior to surgery accelerated graft regeneration and improved the survival rate after transplantation.It was clarified that platelet-derived liver regeneration outweighed the associated risk of I/R injury after partial LT.Clinical strategies to increase perioperative platelet counts,such as thrombopoietin,thrombopoietin receptor agonist and platelet transfusion,may improve graft regeneration and survival after LDLT.展开更多
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 ...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.展开更多
BACKGROUND To solve the problem of liver transplantation donor insufficiency,an alternative cell transplantation therapy was investigated.We focused on amniotic epithelial cells(AECs)as a cell source because,unlike in...BACKGROUND To solve the problem of liver transplantation donor insufficiency,an alternative cell transplantation therapy was investigated.We focused on amniotic epithelial cells(AECs)as a cell source because,unlike induced pluripotent stem cells,they are cost-effective and non-tumorigenic.The utilization of AECs in regenerative medicine,however,is in its infancy.A general profile for AECs has not been comprehensively analyzed.Moreover,no hepatic differentiation protocol for AECs has yet been established.To this end,we independently compiled human AEC libraries,purified amniotic stem cells(ASCs),and co-cultured them with mesenchymal stem cells(MSCs)and human umbilical vein endothelial cell(HUVECs)in a 3D system which induces functional hepatic organoids.AIM To characterize AECs and generate functional hepatic organoids from ASCs and other somatic stem cells METHODS AECs,MSCs,and HUVECs were isolated from the placentae and umbilical cords of cesarean section patients.Amnion and primary AEC stemness characteristics and heterogeneity were analyzed by immunocytochemistry,Alkaline phosphatase(AP)staining,and flow cytometry.An adherent AEC subpopulation was selected and evaluated for ASC purification quality by a colony formation assay.AEC transcriptomes were compared with those for other hepatocytes cell sources by bioinformatics.The 2D and 3D culture were compared by relative gene expression using several differentiation protocols.ASCs,MSCs,and HUVECs were combined in a 3D co-culture system to generate hepatic organoids whose structure was compared with a 3D AEC sphere and whose function was elucidated by immunofluorescence imaging,periodic acid Schiff,and an indocyanine green(ICG)test.RESULTS AECs have certain stemness markers such as EPCAM,SSEA4,and E-cadherin.One AEC subpopulation was also either positive for AP staining or expressed the TRA-1-60 and TRA-1-81 stemness markers.Moreover,it could form colonies and its frequency was enhanced ten-fold in the adherent subpopulation after selective primary passage.Bioinformatics analysis of ribose nucleic acid sequencing revealed that the total AEC gene expression was distant from those of pluripotent stem cells and hepatocytes but some gene expression overlapped among these cells.TJP1,associated with epidermal growth factor receptor,and MET,associated with hepatocyte growth factor receptor,were upregulated and may be important for hepatic differentiation.In conventional flat culture,the cells turned unviable and did not readily differentiate into hepatocytes.In 3D culture,however,hepatic gene expression of the AEC sphere was elevated even under a two-step differentiation protocol.Furthermore,the organoids derived from the MSC and HUVEC co-culture showed 3D structure with polarity,hepatic-like glycogen storage,and ICG absorption/elimination.CONCLUSION Human amniotic epithelial cells are heterogeneous and certain subpopulations have high stemness.Under a 3D co-culture system,functional hepatic organoids were generated in a multicellular microenvironment.展开更多
BACKGROUND Orthotopic liver transplantation(OLT)is the only treatment for end-stage liver failure;however,graft shortage impedes its applicability.Therefore,studies investigating alternative therapies are plenty.Never...BACKGROUND Orthotopic liver transplantation(OLT)is the only treatment for end-stage liver failure;however,graft shortage impedes its applicability.Therefore,studies investigating alternative therapies are plenty.Nevertheless,no study has comprehensively analyzed these therapies from different perspectives.AIM To summarize the current status of alternative transplantation therapies for OLT and to support future research.METHODS A systematic literature search was performed using PubMed,Cochrane Library and EMBASE for articles published between January 2010 and 2018,using the following MeSH terms:[(liver transplantation)AND cell]OR[(liver transplantation)AND differentiation]OR[(liver transplantation)AND organoid]OR[(liver transplantation)AND xenotransplantation].Various types of studies describing therapies to replace OLT were retrieved for full-text evaluation.Among them,we selected articles including in vivo transplantation.RESULTS A total of 89 studies were selected.There are three principle forms of treatment for liver failure:Xeno-organ transplantation,scaffold-based transplantation,and cell transplantation.Xeno-organ transplantation was covered in 14 articles,scaffold-based transplantation was discussed in 22 articles,and cell transplantation was discussed in 53 articles.Various types of alternative therapies were discussed:Organ liver,25 articles;adult hepatocytes,31 articles;fetal hepatocytes,three articles;mesenchymal stem cells(MSCs),25 articles;embryonic stem cells,one article;and induced pluripotent stem cells,three articles and other sources.Clinical applications were discussed in 12 studies:Cell transplantation using hepatocytes in four studies,five studies using umbilical cord-derived MSCs,three studies using bone marrow-derived MSCs,and two studies using hematopoietic stem cells.CONCLUSION The clinical applications are present only for cell transplantation.Scaffold-based transplantation is a comprehensive treatment combining organ and cell transplantations,which warrants future research to find relevant clinical applications.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)accompanied by portal vein tumour thrombus(PVTT)presents an aggressive disease course,worsening liver function reserve,and a high recurrence rate.Clinical practice guidelines re...BACKGROUND Hepatocellular carcinoma(HCC)accompanied by portal vein tumour thrombus(PVTT)presents an aggressive disease course,worsening liver function reserve,and a high recurrence rate.Clinical practice guidelines recommend systemic therapy as the first-line option for HCC with portal invasion.However,to achieve longer survival in these patients,the treatment strategy should be concluded with removal of the tumour by locoregional therapy.We experienced a case of initially unresectable HCC with main PVTT converted to radical hepatectomy after lenvatinib treatment.CASE SUMMARY A 59-year-old male with chronic hepatitis C infection visited our clinic as a regular post-surgery follow-up.Contrast-enhanced abdominal computed tomography revealed a liver mass diffusely located at the lateral segment with a massive PVTT extending from the umbilical portion to the main and contralateral third-order portal branches.With the diagnosis of unresectable HCC with Vp4(main trunk/contralateral branch)PVTT,lenvatinib was started at 12 mg/d.The computed tomography taken 3 mo after starting lenvatinib showed regression of the PVTT,which had retreated to the contralateral first-order portal branch.He tolerated the full dose without major adverse effects.With cessation of lenvatinib for 7 d,radical left lobectomy and PVTT thrombectomy were conducted.The patient’s postoperative course was uneventful.Microscopically,the primary lesion showed fibrotic changes,with moderately to poorly differentiated tumour cells surrounded by granulation tissues in some areas.The majority of the PVTT showed necrosis.He was alive without recurrence for 8 mo.CONCLUSION This is the first case of HCC with Vp4 PVTT in which radical conversion hepatectomy was succeeded after lenvatinib treatment.展开更多
文摘Platelets are anucleate fragments mainly involved in hemostasis and thrombosis,and there is emerging evidence that platelets have other nonhemostatic potentials in inflammation,angiogenesis,regeneration and ischemia/reperfusion injury(I/R injury),which are involved in the physiological and pathological processes during living donor liver transplantation(LDLT).LDLT is sometimes associated with impaired regeneration and severe I/R injury,leading to postoperative complications and decreased patient survival.Recent studies have suggested that perioperative thrombocytopenia is associated with poor graft regeneration and postoperative morbidity in the short and long term after LDLT.Although it is not fully understood whether thrombocytopenia is the cause or result,increasing platelet counts are frequently suggested to improve posttransplant outcomes in clinical studies.Based on rodent experiments,previous studies have identified that platelets stimulate liver regeneration after partial hepatectomy.However,the role of platelets in LDLT is controversial,as platelets are supposed to aggravate I/R injury in the liver.Recently,a rat model of partial liver transplantation(LT)was used to demonstrate that thrombopoietin-induced thrombocytosis prior to surgery accelerated graft regeneration and improved the survival rate after transplantation.It was clarified that platelet-derived liver regeneration outweighed the associated risk of I/R injury after partial LT.Clinical strategies to increase perioperative platelet counts,such as thrombopoietin,thrombopoietin receptor agonist and platelet transfusion,may improve graft regeneration and survival after LDLT.
文摘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.
基金Supported by National Natural Science Foundation of China,No.81770621Ministry of Education,Culture,Sports,Science,and Technology of Japan,KAKENHI,No.16K15604,No.18H02866Japan Science and Technology Agency-Japan International Cooperation Agency’s(JST-JICA)Science and Technology Research Partnership for Sustainable Development(SATREPS)Project
文摘BACKGROUND To solve the problem of liver transplantation donor insufficiency,an alternative cell transplantation therapy was investigated.We focused on amniotic epithelial cells(AECs)as a cell source because,unlike induced pluripotent stem cells,they are cost-effective and non-tumorigenic.The utilization of AECs in regenerative medicine,however,is in its infancy.A general profile for AECs has not been comprehensively analyzed.Moreover,no hepatic differentiation protocol for AECs has yet been established.To this end,we independently compiled human AEC libraries,purified amniotic stem cells(ASCs),and co-cultured them with mesenchymal stem cells(MSCs)and human umbilical vein endothelial cell(HUVECs)in a 3D system which induces functional hepatic organoids.AIM To characterize AECs and generate functional hepatic organoids from ASCs and other somatic stem cells METHODS AECs,MSCs,and HUVECs were isolated from the placentae and umbilical cords of cesarean section patients.Amnion and primary AEC stemness characteristics and heterogeneity were analyzed by immunocytochemistry,Alkaline phosphatase(AP)staining,and flow cytometry.An adherent AEC subpopulation was selected and evaluated for ASC purification quality by a colony formation assay.AEC transcriptomes were compared with those for other hepatocytes cell sources by bioinformatics.The 2D and 3D culture were compared by relative gene expression using several differentiation protocols.ASCs,MSCs,and HUVECs were combined in a 3D co-culture system to generate hepatic organoids whose structure was compared with a 3D AEC sphere and whose function was elucidated by immunofluorescence imaging,periodic acid Schiff,and an indocyanine green(ICG)test.RESULTS AECs have certain stemness markers such as EPCAM,SSEA4,and E-cadherin.One AEC subpopulation was also either positive for AP staining or expressed the TRA-1-60 and TRA-1-81 stemness markers.Moreover,it could form colonies and its frequency was enhanced ten-fold in the adherent subpopulation after selective primary passage.Bioinformatics analysis of ribose nucleic acid sequencing revealed that the total AEC gene expression was distant from those of pluripotent stem cells and hepatocytes but some gene expression overlapped among these cells.TJP1,associated with epidermal growth factor receptor,and MET,associated with hepatocyte growth factor receptor,were upregulated and may be important for hepatic differentiation.In conventional flat culture,the cells turned unviable and did not readily differentiate into hepatocytes.In 3D culture,however,hepatic gene expression of the AEC sphere was elevated even under a two-step differentiation protocol.Furthermore,the organoids derived from the MSC and HUVEC co-culture showed 3D structure with polarity,hepatic-like glycogen storage,and ICG absorption/elimination.CONCLUSION Human amniotic epithelial cells are heterogeneous and certain subpopulations have high stemness.Under a 3D co-culture system,functional hepatic organoids were generated in a multicellular microenvironment.
基金National Natural Science Foundation of China,No.81770621Ministry of Education,Culture,Sports,Science,and Technology of Japan,KAKENHI,No.18H02866and Japan Science and Technology Agency-Japan International Cooperation Agency's(JST-JICA)Science and Technology Research Partnership for Sustainable Development(SATREPS)Project,No.JPMJSA1506.
文摘BACKGROUND Orthotopic liver transplantation(OLT)is the only treatment for end-stage liver failure;however,graft shortage impedes its applicability.Therefore,studies investigating alternative therapies are plenty.Nevertheless,no study has comprehensively analyzed these therapies from different perspectives.AIM To summarize the current status of alternative transplantation therapies for OLT and to support future research.METHODS A systematic literature search was performed using PubMed,Cochrane Library and EMBASE for articles published between January 2010 and 2018,using the following MeSH terms:[(liver transplantation)AND cell]OR[(liver transplantation)AND differentiation]OR[(liver transplantation)AND organoid]OR[(liver transplantation)AND xenotransplantation].Various types of studies describing therapies to replace OLT were retrieved for full-text evaluation.Among them,we selected articles including in vivo transplantation.RESULTS A total of 89 studies were selected.There are three principle forms of treatment for liver failure:Xeno-organ transplantation,scaffold-based transplantation,and cell transplantation.Xeno-organ transplantation was covered in 14 articles,scaffold-based transplantation was discussed in 22 articles,and cell transplantation was discussed in 53 articles.Various types of alternative therapies were discussed:Organ liver,25 articles;adult hepatocytes,31 articles;fetal hepatocytes,three articles;mesenchymal stem cells(MSCs),25 articles;embryonic stem cells,one article;and induced pluripotent stem cells,three articles and other sources.Clinical applications were discussed in 12 studies:Cell transplantation using hepatocytes in four studies,five studies using umbilical cord-derived MSCs,three studies using bone marrow-derived MSCs,and two studies using hematopoietic stem cells.CONCLUSION The clinical applications are present only for cell transplantation.Scaffold-based transplantation is a comprehensive treatment combining organ and cell transplantations,which warrants future research to find relevant clinical applications.
文摘BACKGROUND Hepatocellular carcinoma(HCC)accompanied by portal vein tumour thrombus(PVTT)presents an aggressive disease course,worsening liver function reserve,and a high recurrence rate.Clinical practice guidelines recommend systemic therapy as the first-line option for HCC with portal invasion.However,to achieve longer survival in these patients,the treatment strategy should be concluded with removal of the tumour by locoregional therapy.We experienced a case of initially unresectable HCC with main PVTT converted to radical hepatectomy after lenvatinib treatment.CASE SUMMARY A 59-year-old male with chronic hepatitis C infection visited our clinic as a regular post-surgery follow-up.Contrast-enhanced abdominal computed tomography revealed a liver mass diffusely located at the lateral segment with a massive PVTT extending from the umbilical portion to the main and contralateral third-order portal branches.With the diagnosis of unresectable HCC with Vp4(main trunk/contralateral branch)PVTT,lenvatinib was started at 12 mg/d.The computed tomography taken 3 mo after starting lenvatinib showed regression of the PVTT,which had retreated to the contralateral first-order portal branch.He tolerated the full dose without major adverse effects.With cessation of lenvatinib for 7 d,radical left lobectomy and PVTT thrombectomy were conducted.The patient’s postoperative course was uneventful.Microscopically,the primary lesion showed fibrotic changes,with moderately to poorly differentiated tumour cells surrounded by granulation tissues in some areas.The majority of the PVTT showed necrosis.He was alive without recurrence for 8 mo.CONCLUSION This is the first case of HCC with Vp4 PVTT in which radical conversion hepatectomy was succeeded after lenvatinib treatment.
