Cotransplantation With Adipose Tissue-derived Stem Cells Improves Engraftment of Transplanted Hepatocytes.
Journal
Transplantation
ISSN: 1534-6080
Titre abrégé: Transplantation
Pays: United States
ID NLM: 0132144
Informations de publication
Date de publication:
01 10 2022
01 10 2022
Historique:
pubmed:
12
4
2022
medline:
4
10
2022
entrez:
11
4
2022
Statut:
ppublish
Résumé
Hepatocyte transplantation is expected to be an alternative therapy to liver transplantation; however, poor engraftment is a severe obstacle to be overcome. The adipose tissue-derived stem cells (ADSCs) are known to improve engraftment of transplanted pancreatic islets, which have many similarities to the hepatocytes. Therefore, we examined the effects and underlying mechanisms of ADSC cotransplantation on hepatocyte engraftment. Hepatocytes and ADSCs were cotransplanted into the renal subcapsular space and livers of syngeneic analbuminemic rats, and the serum albumin level was quantified to evaluate engraftment. Immunohistochemical staining and fluorescent staining to trace transplanted cells in the liver were also performed. To investigate the mechanisms, cocultured supernatants were analyzed by a multiplex assay and inhibition test using neutralizing antibodies for target factors. Hepatocyte engraftment at both transplant sites was significantly improved by ADSC cotransplantation ( P < 0.001, P < 0.001). In the renal subcapsular model, close proximity between hepatocytes and ADSCs was necessary to exert this effect. Unexpectedly, ≈50% of transplanted hepatocytes were attached by ADSCs in the liver. In an in vitro study, the hepatocyte function was significantly improved by ADSC coculture supernatant ( P < 0.001). The multiplex assay and inhibition test demonstrated that hepatocyte growth factor, vascular endothelial growth factor, and interleukin-6 may be key factors for the abovementioned effects of ADSCs. The present study revealed that ADSC cotransplantation can improve the engraftment of transplanted hepatocytes. This effect may be based on crucial factors, such as hepatocyte growth factor, vascular endothelial growth factor, and interleukin-6, which are secreted by ADSCs.
Sections du résumé
BACKGROUND
Hepatocyte transplantation is expected to be an alternative therapy to liver transplantation; however, poor engraftment is a severe obstacle to be overcome. The adipose tissue-derived stem cells (ADSCs) are known to improve engraftment of transplanted pancreatic islets, which have many similarities to the hepatocytes. Therefore, we examined the effects and underlying mechanisms of ADSC cotransplantation on hepatocyte engraftment.
METHODS
Hepatocytes and ADSCs were cotransplanted into the renal subcapsular space and livers of syngeneic analbuminemic rats, and the serum albumin level was quantified to evaluate engraftment. Immunohistochemical staining and fluorescent staining to trace transplanted cells in the liver were also performed. To investigate the mechanisms, cocultured supernatants were analyzed by a multiplex assay and inhibition test using neutralizing antibodies for target factors.
RESULTS
Hepatocyte engraftment at both transplant sites was significantly improved by ADSC cotransplantation ( P < 0.001, P < 0.001). In the renal subcapsular model, close proximity between hepatocytes and ADSCs was necessary to exert this effect. Unexpectedly, ≈50% of transplanted hepatocytes were attached by ADSCs in the liver. In an in vitro study, the hepatocyte function was significantly improved by ADSC coculture supernatant ( P < 0.001). The multiplex assay and inhibition test demonstrated that hepatocyte growth factor, vascular endothelial growth factor, and interleukin-6 may be key factors for the abovementioned effects of ADSCs.
CONCLUSIONS
The present study revealed that ADSC cotransplantation can improve the engraftment of transplanted hepatocytes. This effect may be based on crucial factors, such as hepatocyte growth factor, vascular endothelial growth factor, and interleukin-6, which are secreted by ADSCs.
Identifiants
pubmed: 35404871
doi: 10.1097/TP.0000000000004130
pii: 00007890-202210000-00015
pmc: PMC9521584
doi:
Substances chimiques
Antibodies, Neutralizing
0
Interleukin-6
0
Serum Albumin
0
Vascular Endothelial Growth Factor A
0
Hepatocyte Growth Factor
67256-21-7
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1963-1973Informations de copyright
Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.
Déclaration de conflit d'intérêts
The authors declare no conflicts of interest.
Références
Kasahara M, Umeshita K, Inomata Y, et al.; Japanese Liver Transplantation Society. Long-term outcomes of pediatric living donor liver transplantation in Japan: an analysis of more than 2200 cases listed in the registry of the Japanese Liver Transplantation Society. Am J Transplant. 2013;13:1830–1839.
Lee SG, Hwang S, Kim KH, et al. Toward 300 liver transplants a year. Surg Today. 2009;39:367–373.
Schramm C, Bubenheim M, Adam R, et al.; European Liver Intestine Transplant Association. Primary liver transplantation for autoimmune hepatitis: a comparative analysis of the European Liver Transplant Registry. Liver Transpl. 2010;16:461–469.
Umeshita K, Eguchi S, Egawa H, et al. Liver transplantation in Japan: registry by the Japanese Liver Transplantation Society. Hepatol Res. 2019;49:964–980.
Bilir BM, Guinette D, Karrer F, et al. Hepatocyte transplantation in acute liver failure. Liver Transpl. 2000;6:32–40.
Strom SC, Bruzzone P, Cai H, et al. Hepatocyte transplantation: clinical experience and potential for future use. Cell Transplant. 2006;15 Suppl 1:S105–S110.
Ibars EP, Cortes M, Tolosa L, et al. Hepatocyte transplantation program: lessons learned and future strategies. World J Gastroenterol. 2016;22:874–886.
Jorns C, Ellis EC, Nowak G, et al. Hepatocyte transplantation for inherited metabolic diseases of the liver. J Intern Med. 2012;272:201–223.
Yoshida S, Yamagata Y, Murayama K, et al. The influence of collagen III expression on the efficiency of cell isolation with the use of collagenase H. Transplant Proc. 2014;46:1942–1944.
Fukuoka K, Inagaki A, Nakamura Y, et al. The optimization of short-term hepatocyte preservation before transplantation. Transplant Direct. 2017;3:e176.
Matsumura M, Imura T, Inagaki A, et al. A simple and useful predictive assay for evaluating the quality of isolated hepatocytes for hepatocyte transplantation. Sci Rep. 2019;9:6166.
Ogasawara H, Inagaki A, Fathi I, et al. Preferable transplant site for hepatocyte transplantation in a rat model. Cell Transplant. 2021;30:9636897211040012.
Saitoh Y, Inagaki A, Fathi I, et al. Improvement of hepatocyte engraftment by co-transplantation with pancreatic islets in hepatocyte transplantation. J Tissue Eng Regen Med. 2021;15:361–374.
Hamman KJ, Winn SR, Harding CO. Hepatocytes from wild-type or heterozygous donors are equally effective in achieving successful therapeutic liver repopulation in murine phenylketonuria (PKU). Mol Genet Metab. 2011;104:235–240.
Smets FN, Chen Y, Wang LJ, et al. Loss of cell anchorage triggers apoptosis (anoikis) in primary mouse hepatocytes. Mol Genet Metab. 2002;75:344–352.
Sufiandi S, Obara H, Enosawa S, et al. Improvement of infusion process in cell transplantation: effect of shear stress on hepatocyte viability under horizontal and vertical syringe orientation. Cell Med. 2015;7:59–66.
Massip-Salcedo M, Roselló-Catafau J, Prieto J, et al. The response of the hepatocyte to ischemia. Liver Int. 2007;27:6–16.
Gustafson EK, Elgue G, Hughes RD, et al. The instant blood-mediated inflammatory reaction characterized in hepatocyte transplantation. Transplantation. 2011;91:632–638.
Goto M, Groth CG, Nilsson B, et al. Intraportal pig islet xenotransplantation into athymic mice as an in vivo model for the study of the instant blood-mediated inflammatory reaction. Xenotransplantation. 2004;11:195–202.
Bennet W, Sundberg B, Lundgren T, et al. Damage to porcine islets of Langerhans after exposure to human blood in vitro, or after intraportal transplantation to cynomologus monkeys: protective effects of sCR1 and heparin. Transplantation. 2000;69:711–719.
Lee CA, Dhawan A, Smith RA, et al. Instant blood-mediated inflammatory reaction in hepatocyte transplantation: current status and future perspectives. Cell Transplant. 2016;25:1227–1236.
Goto M, Tjernberg J, Dufrane D, et al. Dissecting the instant blood-mediated inflammatory reaction in islet xenotransplantation. Xenotransplantation. 2008;15:225–234.
Goto M, Johansson H, Maeda A, et al. Low molecular weight dextran sulfate prevents the instant blood-mediated inflammatory reaction induced by adult porcine islets. Transplantation. 2004;77:741–747.
Tokodai K, Goto M, Inagaki A, et al. Attenuation of cross-talk between the complement and coagulation cascades by C5a blockade improves early outcomes after intraportal islet transplantation. Transplantation. 2010;90:1358–1365.
Tokodai K, Goto M, Inagaki A, et al. Effect of synthetic protease inhibitor gabexate mesilate on attenuation of coagulant activity and cytokine release in a rat model of islet transplantation. Transplant Proc. 2011;43:3176–3178.
Johansson H, Goto M, Dufrane D, et al. Low molecular weight dextran sulfate: a strong candidate drug to block IBMIR in clinical islet transplantation. Am J Transplant. 2006;6:305–312.
Zhang J, Liu Y, Chen Y, et al. Adipose-derived stem cells: current applications and future directions in the regeneration of multiple tissues. Stem Cells Int. 2020;2020:8810813.
Rodriguez AM, Pisani D, Dechesne CA, et al. Transplantation of a multipotent cell population from human adipose tissue induces dystrophin expression in the immunocompetent mdx mouse. J Exp Med. 2005;201:1397–1405.
Jang S, Cho HH, Cho YB, et al. Functional neural differentiation of human adipose tissue-derived stem cells using bFGF and forskolin. BMC Cell Biol 2010;11:25.
Najimi M, Khuu DN, Lysy PA, et al. Adult-derived human liver mesenchymal-like cells as a potential progenitor reservoir of hepatocytes? Cell Transplant. 2007;16:717–728.
Wankhade UD, Shen M, Kolhe R, et al. Advances in adipose-derived stem cells isolation, characterization, and application in regenerative tissue engineering. Stem Cells Int. 2016;2016:3206807.
Nie C, Yang D, Xu J, et al. Locally administered adipose-derived stem cells accelerate wound healing through differentiation and vasculogenesis. Cell Transplant. 2011;20:205–216.
Yang Y, Lin H, Shen H, et al. Mesenchymal stem cell-derived extracellular matrix enhances chondrogenic phenotype of and cartilage formation by encapsulated chondrocytes in vitro and in vivo. Acta Biomater. 2018;69:71–82.
Xiao B, Rao F, Guo ZY, et al. Extracellular matrix from human umbilical cord-derived mesenchymal stem cells as a scaffold for peripheral nerve regeneration. Neural Regen Res. 2016;11:1172–1179.
Chen Y, Li C, Li C, et al. Tailorable hydrogel improves retention and cardioprotection of intramyocardial transplanted mesenchymal stem cells for the treatment of acute myocardial infarction in mice. J Am Heart Assoc. 2020;9:e013784.
van Poll D, Parekkadan B, Cho CH, et al. Mesenchymal stem cell-derived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo. Hepatology. 2008;47:1634–1643.
Ge Y, Zhang Q, Li H, et al. Adipose-derived stem cells alleviate liver apoptosis induced by ischemia-reperfusion and laparoscopic hepatectomy in swine. Sci Rep. 2018;8:16878.
Fitzpatrick E, Wu Y, Dhadda P, et al. Coculture with mesenchymal stem cells results in improved viability and function of human hepatocytes. Cell Transplant. 2015;24:73–83.
Yamada S, Shimada M, Utsunomiya T, et al. Trophic effect of adipose tissue-derived stem cells on porcine islet cells. J Surg Res. 2014;187:667–672.
Yeung TY, Seeberger KL, Kin T, et al. Human mesenchymal stem cells protect human islets from pro-inflammatory cytokines. PLoS One. 2012;7:e38189.
Ohmura Y, Tanemura M, Kawaguchi N, et al. Combined transplantation of pancreatic islets and adipose tissue-derived stem cells enhances the survival and insulin function of islet grafts in diabetic mice. Transplantation. 2010;90:1366–1373.
Sakata N, Goto M, Yoshimatsu G, et al. Utility of co-transplanting mesenchymal stem cells in islet transplantation. World J Gastroenterol. 2011;17:5150–5155.
Bunnell BA, Flaat M, Gagliardi C, et al. Adipose-derived stem cells: isolation, expansion and differentiation. Methods. 2008;45:115–120.
Yan W, Lin C, Guo Y, et al. N-cadherin overexpression mobilizes the protective effects of mesenchymal stromal cells against ischemic heart injury through a β-catenin-dependent manner. Circ Res. 2020;126:857–874.
Bhargava R, Senior PA, Ackerman TE, et al. Prevalence of hepatic steatosis after islet transplantation and its relation to graft function. Diabetes. 2004;53:1311–1317.
Maffi P, Angeli E, Bertuzzi F, et al. Minimal focal steatosis of liver after islet transplantation in humans: a long-term study. Cell Transplant. 2005;14:727–733.
Negi S, Jetha A, Aikin R, et al. Analysis of beta-cell gene expression reveals inflammatory signaling and evidence of dedifferentiation following human islet isolation and culture. PLoS One. 2012;7:e30415.
Tsung A, Klune JR, Zhang X, et al. HMGB1 release induced by liver ischemia involves Toll-like receptor 4 dependent reactive oxygen species production and calcium-mediated signaling. J Exp Med. 2007;204:2913–2923.
Saito Y, Goto M, Maya K, et al. Brain death in combination with warm ischemic stress during isolation procedures induces the expression of crucial inflammatory mediators in the isolated islets. Cell Transplant. 2010;19:775–782.
Goto M, Imura T, Inagaki A, et al. The impact of ischemic stress on the quality of isolated pancreatic islets. Transplant Proc. 2010;42:2040–2042.
Moll G, Ankrum JA, Kamhieh-Milz J, et al. Intravascular mesenchymal stromal/stem cell therapy product diversification: time for new clinical guidelines. Trends Mol Med. 2019;25:149–163.
Uematsu SS, Inagaki A, Nakamura Y, et al. The optimization of the prevascularization procedures for improving subcutaneous islet engraftment. Transplantation. 2018;102:387–395.
Yasunami Y, Nakafusa Y, Nitta N, et al. A novel subcutaneous site of islet transplantation superior to the liver. Transplantation. 2018;102:945–952.
Sakata N, Aoki T, Yoshimatsu G, et al. Strategy for clinical setting in intramuscular and subcutaneous islet transplantation. Diabetes Metab Res Rev. 2014;30:1–10.
Rafael E, Tibell A, Rydén M, et al. Intramuscular autotransplantation of pancreatic islets in a 7-year-old child: a 2-year follow-up. Am J Transplant. 2008;8:458–462.
Bissig KD, Le TT, Woods NB, et al. Repopulation of adult and neonatal mice with human hepatocytes: a chimeric animal model. Proc Natl Acad Sci USA. 2007;104:20507–20511.
Garcia GE, Xia Y, Chen S, et al. NF-kappaB-dependent fractalkine induction in rat aortic endothelial cells stimulated by IL-1beta, TNF-alpha, and LPS. J Leukoc Biol. 2000;67:577–584.
Furie MB, Randolph GJ. Chemokines and tissue injury. Am J Pathol. 1995;146:1287–1301.
Wilson GC, Kuboki S, Freeman CM, et al. CXC chemokines function as a rheostat for hepatocyte proliferation and liver regeneration. PLoS One. 2015;10:e0120092.
Chandrasekar B, Smith JB, Freeman GL. Ischemia-reperfusion of rat myocardium activates nuclear factor-KappaB and induces neutrophil infiltration via lipopolysaccharide-induced CXC chemokine. Circulation. 2001;103:2296–2302.
Kyurkchiev D, Bochev I, Ivanova-Todorova E, et al. Secretion of immunoregulatory cytokines by mesenchymal stem cells. World J Stem Cells. 2014;6:552–570.
Cressman DE, Greenbaum LE, DeAngelis RA, et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science. 1996;274:1379–1383.
Schirmacher P, Peters M, Ciliberto G, et al. Hepatocellular hyperplasia, plasmacytoma formation, and extramedullary hematopoiesis in interleukin (IL)-6/soluble IL-6 receptor double-transgenic mice. Am J Pathol. 1998;153:639–648.
Yeoh GC, Ernst M, Rose-John S, et al. Opposing roles of gp130-mediated STAT-3 and ERK-1/ 2 signaling in liver progenitor cell migration and proliferation. Hepatology. 2007;45:486–494.
Fujii M, Yamanouchi K, Sakai Y, et al. In vivo construction of liver tissue by implantation of a hepatic non-parenchymal/adipose-derived stem cell sheet. J Tissue Eng Regen Med. 2018;12:e287–e295.
Jiao Z, Ma Y, Liu X, et al. Adipose-derived stem cell transplantation attenuates inflammation and promotes liver regeneration after ischemia-reperfusion and hemihepatectomy in swine. Stem Cells Int. 2019;2019:2489584.
Inagaki M, Furukawa H, Satake Y, et al. Replacement of liver parenchyma in analbuminemic rats with allogenic hepatocytes is facilitated by intrabone marrow-bone marrow transplantation. Cell Transplant. 2011;20:1479–1489.