Stem Cell Therapies for Treatment of Liver Disease

Clara Nicolas, Yujia Wang, Jennifer Luebke-Wheeler, Scott L Nyberg, Clara Nicolas, Yujia Wang, Jennifer Luebke-Wheeler, Scott L Nyberg

Abstract

Cell therapy is an emerging form of treatment for several liver diseases, but is limited by the availability of donor livers. Stem cells hold promise as an alternative to the use of primary hepatocytes. We performed an exhaustive review of the literature, with a focus on the latest studies involving the use of stem cells for the treatment of liver disease. Stem cells can be harvested from a number of sources, or can be generated from somatic cells to create induced pluripotent stem cells (iPSCs). Different cell lines have been used experimentally to support liver function and treat inherited metabolic disorders, acute liver failure, cirrhosis, liver cancer, and small-for-size liver transplantations. Cell-based therapeutics may involve gene therapy, cell transplantation, bioartificial liver devices, or bioengineered organs. Research in this field is still very active. Stem cell therapy may, in the future, be used as a bridge to either liver transplantation or endogenous liver regeneration, but efficient differentiation and production protocols must be developed and safety must be demonstrated before it can be applied to clinical practice.

Keywords: bioartificial liver; cell therapy; cell transplant; gene correction; induced pluripotent stem cells; liver disease; regenerative medicine; stem cell.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Production of embryonic stem cells and induced pluripotent stem cells.
Figure 2
Figure 2
Repopulation of FAH-deficient pig livers with human hepatocytes. Nitisinone (NTBC) is used to treat FAH-deficient animals while hepatocyte engraftment and proliferation takes place.
Figure 3
Figure 3
Gene correction of iPSC for the production of patient-specific disease-free hepatocytes.

References

    1. Taub R. Liver regeneration: From myth to mechanism. Nat. Rev. Mol. Cell Biol. 2004;5:836–847. doi: 10.1038/nrm1489.
    1. Cantz T., Manns M.P., Ott M. Stem cells in liver regeneration and therapy. Cell Tissue Res. 2008;331:271–282. doi: 10.1007/s00441-007-0483-6.
    1. Riehle K.J., Dan Y.Y., Campbell J.S., Fausto N. New concepts in liver regeneration. J. Gastroenterol. Hepatol. 2011;26(Suppl. 1):S203–S212. doi: 10.1111/j.1440-1746.2010.06539.x.
    1. Rush G.F., Gorski J.R., Ripple M.G., Sowinski J., Bugelski P., Hewitt W.R. Organic hydroperoxide-induced lipid peroxidation and cell death in isolated hepatocytes. Toxicol. Appl. Pharmacol. 1985;78:473–483. doi: 10.1016/0041-008X(85)90255-8.
    1. Mitaka T. The current status of primary hepatocyte culture. Int. J. Exp. Pathol. 1998;79:393–409. doi: 10.1046/j.1365-2613.1998.00083.x.
    1. Boess F., Kamber M., Romer S., Gasser R., Muller D., Albertini S., Suter L. Gene expression in two hepatic cell lines, cultured primary hepatocytes and liver slices compared to the in vivo liver gene expression in rats: Possible implications for toxicogenomics use of in vitro systems. Toxicol. Sci. 2003;73:386–402. doi: 10.1093/toxsci/kfg064.
    1. Lloyd T.D., Orr S., Skett P., Berry D.P., Dennison A.R. Cryopreservation of hepatocytes: A review of current methods for banking. Cell Tissue Bank. 2003;4:3–15. doi: 10.1023/A:1026392216017.
    1. Evarts R.P., Nagy P., Marsden E., Thorgeirsson S.S. A precursor—Product relationship exists between oval cells and hepatocytes in rat liver. Carcinogenesis. 1987;8:1737–1740. doi: 10.1093/carcin/8.11.1737.
    1. Lázaro C.A., Rhim J.A., Yamada Y., Fausto N. Generation of hepatocytes from oval cell precursors in culture. Cancer Res. 1998;58:5514–5522.
    1. Kubota H., Reid L.M. Clonogenic hepatoblasts, common precursors for hepatocytic and biliary lineages, are lacking classical major histocompatibility complex class I antigen. Proc. Natl. Acad. Sci. USA. 2000;97:12132–12137. doi: 10.1073/pnas.97.22.12132.
    1. Fausto N., Campbell J.S. The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech. Dev. 2003;120:117–130. doi: 10.1016/S0925-4773(02)00338-6.
    1. Oertel M., Rosencrantz R., Chen Y.Q., Thota P.N., Sandhu J.S., Dabeva M.D., Pacchia A.L., Adelson M.E., Dougherty J.P., Shafritz D.A. Repopulation of rat liver by fetal hepatoblasts and adult hepatocytes transduced ex vivo with lentiviral vectors. Hepatology. 2003;37:994–1005. doi: 10.1053/jhep.2003.50183.
    1. Haridass D., Yuan Q., Becker P.D., Cantz T., Iken M., Rothe M., Narain N., Bock M., Nörder M., Legrand N., et al. Repopulation efficiencies of adult hepatocytes, fetal liver progenitor cells, and embryonic stem cell-derived hepatic cells in albumin-promoter-enhancer urokinase-type plasminogen activator mice. Am. J. Pathol. 2009;175:1483–1492. doi: 10.2353/ajpath.2009.090117.
    1. Mahieu-Caputo D., Allain J.E., Branger J., Coulomb A., Delgado J.P., Andreoletti M., Mainot S., Frydman R., Leboulch P., Di Santo J.P., et al. Repopulation of athymic mouse liver by cryopreserved early human fetal hepatoblasts. Hum. Gene Ther. 2004;15:1219–1228. doi: 10.1089/hum.2004.15.1219.
    1. Hayner N.T., Braun L., Yaswen P., Brooks M., Fausto N. Isozyme profiles of oval cells, parenchymal cells, and biliary cells isolated by centrifugal elutriation from normal and preneoplastic livers. Cancer Res. 1984;44:332–338.
    1. Schmelzer E., Wauthier E., Reid L.M. The phenotypes of pluripotent human hepatic progenitors. Stem Cells. 2006;24:1852–1858. doi: 10.1634/stemcells.2006-0036.
    1. Xu Y.Q., Liu Z.C. Therapeutic potential of adult bone marrow stem cells in liver disease and delivery approaches. Stem Cell Rev. 2008;4:101–112. doi: 10.1007/s12015-008-9019-z.
    1. Bianco P., Robey P.G., Simmons P.J. Mesenchymal stem cells: Revisiting history, concepts, and assays. Cell Stem Cell. 2008;2:313–319. doi: 10.1016/j.stem.2008.03.002.
    1. Ding D.C., Shyu W.C., Lin S.Z. Mesenchymal stem cells. Cell Transplant. 2011;20:5–14. doi: 10.3727/096368910X.
    1. Cho K.A., Ju S.Y., Cho S.J., Jung Y.J., Woo S.Y., Seoh J.Y., Han H.S., Ryu K.H. Mesenchymal stem cells showed the highest potential for the regeneration of injured liver tissue compared with other subpopulations of the bone marrow. Cell Biol. Int. 2009;33:772–777. doi: 10.1016/j.cellbi.2009.04.023.
    1. Shi M., Liu Z.W., Wang F.S. Immunomodulatory properties and therapeutic application of mesenchymal stem cells. Clin. Exp. Immunol. 2011;164:1–8. doi: 10.1111/j.1365-2249.2011.04327.x.
    1. Lee O.K., Kuo T.K., Chen W.M., Lee K.D., Hsieh S.L., Chen T.H. Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood. 2004;103:1669–1675. doi: 10.1182/blood-2003-05-1670.
    1. Kestendjieva S., Kyurkchiev D., Tsvetkova G., Mehandjiev T., Dimitrov A., Nikolov A., Kyurchiev S. Characterization of mesenchymal stem cells isolated from the human umbilical cord. Cell Biol. Int. 2008;32:724–732. doi: 10.1016/j.cellbi.2008.02.002.
    1. Yen B.L., Huang H.I., Chien C.C., Jui H.Y., Ko B.S., Yao M., Shun C.T., Yen M.L., Lee M.C., Chen Y.C. Isolation of multipotent cells from human term placenta. Stem Cells. 2005;23:3–9. doi: 10.1634/stemcells.2004-0098.
    1. Di Campli C., Piscaglia A.C., Pierelli L., Rutella S., Bonanno G., Alison M.R., Mariotti A., Vecchio F.M., Nestola M., Monego G., et al. A human umbilical cord stem cell rescue therapy in a murine model of toxic liver injury. Dig Liver Dis. 2004;36:603–613. doi: 10.1016/j.dld.2004.03.017.
    1. Zaret K.S., Grompe M. Generation and regeneration of cells of the liver and pancreas. Science. 2008;322:1490–1494. doi: 10.1126/science.1161431.
    1. McLaren A. Ethical and social considerations of stem cell research. Nature. 2001;414:129–131. doi: 10.1038/35102194.
    1. Swijnenburg R.J., Schrepfer S., Govaert J.A., Cao F., Ransohoff K., Sheikh A.Y., Haddad M., Connolly A.J., Davis M.M., Robbins R.C., et al. Immunosuppressive therapy mitigates immunological rejection of human embryonic stem cell xenografts. Proc. Natl. Acad. Sci. USA. 2008;105:12991–12996. doi: 10.1073/pnas.0805802105.
    1. Tolosa L., Caron J., Hannoun Z., Antoni M., Lopez S., Burks D., Castell J.V., Weber A., Gomez-Lechon M.J., Dubart-Kupperschmitt A. Transplantation of hESC-derived hepatocytes protects mice from liver injury. Stem Cell Res. Ther. 2015;6:246. doi: 10.1186/s13287-015-0227-6.
    1. Zacharias D.G., Nelson T.J., Mueller P.S., Hook C.C. The science and ethics of induced pluripotency: What will become of embryonic stem cells? Mayo Clin. Proc. 2011;86:634–640. doi: 10.4065/mcp.2011.0054.
    1. Takahashi K., Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–676. doi: 10.1016/j.cell.2006.07.024.
    1. Vallier L. Putting induced pluripotent stem cells to the test. Nat. Biotechnol. 2015;33:1145–1146. doi: 10.1038/nbt.3401.
    1. Marchetto M.C., Yeo G.W., Kainohana O., Marsala M., Gage F.H., Muotri A.R. Transcriptional signature and memory retention of human-induced pluripotent stem cells. PLoS ONE. 2009;4:e7076. doi: 10.1371/journal.pone.0007076.
    1. Kim K., Doi A., Wen B., Ng K., Zhao R., Cahan P., Kim J., Aryee M.J., Ehrlich L.I., Yabuuchi A., et al. Epigenetic memory in induced pluripotent stem cells. Nature. 2010;467:285–290. doi: 10.1038/nature09342.
    1. Liu H., Ye Z., Kim Y., Sharkis S., Jang Y.Y. Generation of endoderm-derived human induced pluripotent stem cells from primary hepatocytes. Hepatology. 2010;51:1810–1819. doi: 10.1002/hep.23626.
    1. Miura K., Okada Y., Aoi T., Okada A., Takahashi K., Okita K., Nakagawa M., Koyanagi M., Tanabe K., Ohnuki M., et al. Variation in the safety of induced pluripotent stem cell lines. Nat. Biotechnol. 2009;27:743–745. doi: 10.1038/nbt.1554.
    1. Choi S.M., Kim Y., Liu H., Chaudhari P., Ye Z., Jang Y.Y. Liver engraftment potential of hepatic cells derived from patient-specific induced pluripotent stem cells. Cell Cycle. 2011;10:2423–2427. doi: 10.4161/cc.10.15.16869.
    1. Nishino K., Toyoda M., Yamazaki-Inoue M., Fukawatase Y., Chikazawa E., Sakaguchi H., Akutsu H., Umezawa A. DNA methylation dynamics in human induced pluripotent stem cells over time. PLoS Genet. 2011;7:e1002085. doi: 10.1371/journal.pgen.1002085.
    1. Hartjes K.A., Li X., Martinez-Fernandez A., Roemmich A.J., Larsen B.T., Terzic A., Nelson T.J. Selection via pluripotency-related transcriptional screen minimizes the influence of somatic origin on iPSC differentiation propensity. Stem Cells. 2014;32:2350–2359. doi: 10.1002/stem.1734.
    1. Bar-Nur O., Russ H.A., Efrat S., Benvenisty N. Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells. Cell Stem Cell. 2011;9:17–23. doi: 10.1016/j.stem.2011.06.007.
    1. Stadtfeld M., Nagaya M., Utikal J., Weir G., Hochedlinger K. Induced pluripotent stem cells generated without viral integration. Science. 2008;322:945–949. doi: 10.1126/science.1162494.
    1. Fusaki N., Ban H., Nishiyama A., Saeki K., Hasegawa M. Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc. Jpn. Acad. Ser. B. 2009;85:348–362. doi: 10.2183/pjab.85.348.
    1. Warren L., Manos P.D., Ahfeldt T., Loh Y.H., Li H., Lau F., Ebina W., Mandal P.K., Smith Z.D., Meissner A., et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell. 2010;7:618–630. doi: 10.1016/j.stem.2010.08.012.
    1. Kim D., Kim C.H., Moon J.I., Chung Y.G., Chang M.Y., Han B.S., Ko S., Yang E., Cha K.Y., Lanza R., et al. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell. 2009;4:472–476. doi: 10.1016/j.stem.2009.05.005.
    1. Hou P., Li Y., Zhang X., Liu C., Guan J., Li H., Zhao T., Ye J., Yang W., Liu K., et al. Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science. 2013;341:651–654. doi: 10.1126/science.1239278.
    1. Yu Y., Hongling L., Ikeda Y., Amiot B., Rinaldo P., Duncan S., Nyberg S.L. Hepatocyte-like cells differentiated from human induced pluripotent stem cells: Relevance to cellular therapies. Stem Cell Res. 2012;9:196–207. doi: 10.1016/j.scr.2012.06.004.
    1. Asgari S., Pournasr B., Salekdeh G.H., Ghodsizadeh A., Ott M., Baharvand H. Induced pluripotent stem cells: A new era for hepatology. J. Hepatol. 2010;53:738–751. doi: 10.1016/j.jhep.2010.05.009.
    1. Si-Tayeb K., Noto F.K., Nagaoka M., Li J., Battle M.A., Duris C., et al. Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells. Hepatology. 2010;51:297–305. doi: 10.1002/hep.23354.
    1. Ma X., Duan Y., Tschudy-Seney B., Roll G., Behbahan I.S., Ahuja T.P., et al. Highly efficient differentiation of functional hepatocytes from human induced pluripotent stem cells. Stem Cells Transl. Med. 2013;2:409–419. doi: 10.5966/sctm.2012-0160.
    1. Chen Y.F., Tseng C.Y., Wang H.W., Kuo H.C., Yang V.W., Lee O.K. Rapid generation of mature hepatocyte-like cells from human induced pluripotent stem cells by an efficient three-step protocol. Hepatology. 2012;55:1193–1203. doi: 10.1002/hep.24790.
    1. Rashid S.T., Corbineau S., Hannan N., Marciniak S.J., Miranda E., Alexander G., Huang-Doran I., Griffin J., Ahrlung-Richter L., Skepper J., et al. Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J. Clin. Investig. 2010;120:3127–3136. doi: 10.1172/JCI43122.
    1. Asgari S., Moslem M., Bagheri-Lankarani K., Pournasr B., Miryounesi M., Baharvand H. Differentiation and Transplantation of Human Induced Pluripotent Stem Cell-derived Hepatocyte-like Cells. Stem Cell Rev. 2013;9:493–504. doi: 10.1007/s12015-011-9330-y.
    1. Huang P., Zhang L., Gao Y., He Z., Yao D., Wu Z., Cen J., Chen X., Liu C., Hu Y., et al. Direct reprogramming of human fibroblasts to functional and expandable hepatocytes. Cell Stem Cell. 2014;14:370–384. doi: 10.1016/j.stem.2014.01.003.
    1. Du Y., Wang J., Jia J., Song N., Xiang C., Xu J., Hou Z., Su X., Liu B., Jiang T., et al. Human hepatocytes with drug metabolic function induced from fibroblasts by lineage reprogramming. Cell Stem Cell. 2014;14:394–403. doi: 10.1016/j.stem.2014.01.008.
    1. Liu Z., Tang Y., Lu S., Zhou J., Du Z., Duan C., Li Z., Wang C. The tumourigenicity of iPS cells and their differentiated derivates. J. Cell. Mol. Med. 2013;17:782–791. doi: 10.1111/jcmm.12062.
    1. Dhodapkar K.M., Feldman D., Matthews P., Radfar S., Pickering R., Turkula S., Zebroski H., Dhodapkar M.V. Natural immunity to pluripotency antigen OCT4 in humans. Proc. Natl. Acad. Sci. USA. 2010;107:8718–8723. doi: 10.1073/pnas.0915086107.
    1. De Almeida P.E., Ransohoff J.D., Nahid A., Wu J.C. Immunogenicity of pluripotent stem cells and their derivatives. Circ. Res. 2013;112:549–561. doi: 10.1161/CIRCRESAHA.111.249243.
    1. Tan Y., Ooi S., Wang L. Immunogenicity and tumorigenicity of pluripotent stem cells and their derivatives: Genetic and epigenetic perspectives. Curr. Stem Cell Res. Ther. 2014;9:63–72. doi: 10.2174/1574888X113086660068.
    1. Takayama K., Kawabata K., Nagamoto Y., Kishimoto K., Tashiro K., Sakurai F., Tachibana M., Kanda K., Hayakawa T., Furue M.K., et al. 3D spheroid culture of hESC/hiPSC-derived hepatocyte-like cells for drug toxicity testing. Biomaterials. 2013;34:1781–1789. doi: 10.1016/j.biomaterials.2012.11.029.
    1. Lei Y., Jeong D., Xiao J., Schaffer D.V. Developing defined and scalable 3D culture systems for culturing human pluripotent stem cells at high densities. Cell. Mol. Bioeng. 2014;7:172–183. doi: 10.1007/s12195-014-0333-z.
    1. Gieseck R.L., 3rd, Hannan N.R., Bort R., Hanley N.A., Drake R.A., Cameron G.W., Wynn T.A., Valier L. Maturation of induced pluripotent stem cell derived hepatocytes by 3D-culture. PLoS ONE. 2014;9:e86372. doi: 10.1371/journal.pone.0086372.
    1. Zhu S., Rezvani M., Harbell J., Mattis A.N., Wolfe A.R., Benet L.Z., Willenbring H., Ding S. Mouse liver repopulation with hepatocytes generated from human fibroblasts. Nature. 2014;508:93–97. doi: 10.1038/nature13020.
    1. Zhao T., Zhang Z.N., Rong Z., Xu Y. Immunogenicity of induced pluripotent stem cells. Nature. 2011;474:212–215. doi: 10.1038/nature10135.
    1. Wernig M., Meissner A., Cassady J.P., Jaenisch R. c-Myc is dispensable for direct reprogramming of mouse fibroblasts. Cell Stem Cell. 2008;2:10–12. doi: 10.1016/j.stem.2007.12.001.
    1. Hong S.G., Winkler T., Wu C., Guo V., Pittaluga S., Nicolae A., Donahue R.E., Metzger M.E., Price S.D., Uchida N., et al. Path to the clinic: Assessment of iPSC-based cell therapies in vivo in a nonhuman primate model. Cell Rep. 2014;7:1298–1309. doi: 10.1016/j.celrep.2014.04.019.
    1. Wilson A.A., Ying L., Liesa M., Segeritz C.P., Mills J.A., Shen S.S., Jean J., Lonza G.C., Liberti D.C., Lang A.H., et al. Emergence of a stage-dependent human liver disease signature with directed differentiation of alpha-1 antitrypsin-deficient iPS cells. Stem Cell Rep. 2015;4:873–885. doi: 10.1016/j.stemcr.2015.02.021.
    1. Sampaziotis F., Segeritz C.P., Vallier L. Potential of human induced pluripotent stem cells in studies of liver disease. Hepatology. 2015;62:303–311. doi: 10.1002/hep.27651.
    1. Lagasse E., Connors H., Al-Dhalimy M., Rettsma M., Dohse M., Osborne L., Wang X., Finegold M., Weissman I.L., Grompe M. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat. Med. 2000;6:1229–1234. doi: 10.1038/81326.
    1. Grompe M., Strom S. Mice with human livers. Gastroenterology. 2013;145:1209–1214. doi: 10.1053/j.gastro.2013.09.009.
    1. Hickey R., Mao S., Glorioso J., Lillegard J., Fisher J., Amiot B., Rinaldo P., Harding C.O., Marler R., Finegold M.J., et al. Fumarylacetoacetate hydrolase deficient pigs are a novel large animal model of metabolic liver disease. Stem Cell Res. 2014;13:144–153. doi: 10.1016/j.scr.2014.05.003.
    1. Choi D., Oh H.J., Chang U.J., Koo S.K., Jiang J.X., Hwang S.Y., Lee J.D., Yeoh G.C., Shin H.S., Lee J.S., et al. In vivo differentiation of mouse embryonic stem cells into hepatocytes. Cell Transplant. 2002;11:359–368.
    1. Hu C., Li L. In vitro and in vivo hepatic differentiation of adult somatic stem cells and extraembryonic stem cells for treating end stage liver diseases. Stem Cells Int. 2015;2015:871972. doi: 10.1155/2015/871972.
    1. Cantz T., Sharma A.D., Ott M. Concise review: Cell therapies for hereditary metabolic liver diseases-concepts, clinical results, and future developments. Stem Cells. 2015;33:1055–1062. doi: 10.1002/stem.1920.
    1. Fox I.J., Chowdhury J.R., Kaufman S.S., Goertzen T.C., Chowdhury N.R., Warkentin P.I., Dorko K., Sauter B.V., Strom S.C. Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N. Engl. J. Med. 1998;338:1422–146.
    1. Dhawan A., Mitry R.R., Hughes R.D. Hepatocyte transplantation for liver-based metabolic disorders. J. Inherit. Metab. Dis. 2006;29:431–435. doi: 10.1007/s10545-006-0245-8.
    1. Najimi M., Khuu D.N., Lysy P.A., Jazouli N., Abarca J., Sempoux C., Sokal E.M. Adult-derived human liver mesenchymal-like cells as a potential progenitor reservoir of hepatocytes? Cell Transplant. 2007;16:717–728. doi: 10.3727/000000007783465154.
    1. Garate Z., Davis B.R., Quintana-Bustamante O., Segovia J.C. New frontier in regenerative medicine: Site-specific gene correction in patient-specific induced pluripotent stem cells. Hum. Gene Ther. 2013;24:571–583. doi: 10.1089/hum.2012.251.
    1. Choi S.M., Kim Y., Shim J.S., Park J.T., Wang R.H., Leach S.D., Liu J.O., Deng C., Ye Z., Jang Y.Y. Efficient drug screening and gene correction for treating liver disease using patient-specific stem cells. Hepatology. 2013;57:2458–2468. doi: 10.1002/hep.26237.
    1. Eggenschwiler R., Loya K., Wu G., Sharma A.D., Sgodda M., Zychlinski D., Herr C., Steinemann D., Teckman J., Bals R., et al. Sustained knockdown of a disease-causing gene in patient-specific induced pluripotent stem cells using lentiviral vector-based gene therapy. Stem Cells Transl. Med. 2013;2:641–654. doi: 10.5966/sctm.2013-0017.
    1. Chun Y.S., Chaudhari P., Jang Y.Y. Applications of patient-specific induced pluripotent stem cells; focused on disease modeling, drug screening and therapeutic potentials for liver disease. Int. J. Biol. Sci. 2010;6:796–805. doi: 10.7150/ijbs.6.796.
    1. Yusa K., Rashid S.T., Strick-Marchand H., Varela I., Liu P.Q., Paschon D.E., Miranda E., Ordóñez A., Hannan N.R., Rouhani F.J., et al. Targeted gene correction of a1-antitrypsin deficiency in induced pluripotent stem cells. Nature. 2011;478:391–396. doi: 10.1038/nature10424.
    1. Fattahi F., Asgari S., Pournasr B., Seifinejad A., Totonchi M., Taei A., Aghdami N., Salekdeh G.H., Baharvand H. Disease-corrected hepatocyte-like cells from familial hypercholesterolemia-induced pluripotent stem cells. Mol. Biotechnol. 2013;54:863–873. doi: 10.1007/s12033-012-9635-3.
    1. Raya A., Rodriguez-Piza I., Navarro S., Richard-Patin Y., Guenechea G., Sanchez-Sanes A., Consiglio A., Bueren J., Izpisua Belmonte J.C. A protocol describing the genetic correction of somatic human cells and subsequent generation of iPS cells. Nat. Protoc. 2010;5:647–660. doi: 10.1038/nprot.2010.9.
    1. Duncan A.W., Dorrell C., Grompe M. Stem cells and liver regeneration. Gastroenterology. 2009;137:466–481. doi: 10.1053/j.gastro.2009.05.044.
    1. Rutherford A., Chung R.T. Acute liver failure: Mechanisms of hepatocyte injury and regeneration. Semin. Liver Dis. 2008;28:167–174. doi: 10.1055/s-2008-1073116.
    1. Millis J.M., Losanoff J.E. Technology insight: Liver support systems. Nat. Clin. Pract. Gastroenterol. Hepatol. 2005;2:398–405. doi: 10.1038/ncpgasthep0254.
    1. Pareja E., Cortes M., Bonora A., Fuset P., Orbis F., Lopez R., Mir J. New alternatives to the treatment of acute liver failure. Transplant. Proc. 2010;42:2959–2961. doi: 10.1016/j.transproceed.2010.07.056.
    1. Chen Y., Li J., Liu X., Zhao W., Wang Y., Wang X. Transplantation of immortalized human fetal hepatocytes prevents acute liver failure in 90% hepatectomized mice. Transplant. Proc. 2010;42:1907–1914. doi: 10.1016/j.transproceed.2010.01.061.
    1. Joshi M., P B.P., He Z., Holgersson J., Olausson M., Sumitran-Holgersson S. Fetal liver-derived mesenchymal stromal cells augment engraftment of transplanted hepatocytes. Cytotherapy. 2012;14:657–669. doi: 10.3109/14653249.2012.663526.
    1. Shi X.L., Zhang Y., Gu J.Y., Ding Y.T. Coencapsulation of hepatocytes with bone marrow mesenchymal stem cells improves hepatocyte-specific functions. Transplantation. 2009;88:1178–1185. doi: 10.1097/TP.0b013e3181bc288b.
    1. Zhu X., He B., Zhou X., Ren J. Effects of transplanted bone-marrow-derived mesenchymal stem cells in animal models of acute hepatitis. Cell Tissue Res. 2013;351:477–486. doi: 10.1007/s00441-012-1524-3.
    1. Qu M., Cui J., Zhu J., Ma Y., Yuan X., Shi J., Guo D., Li C. Bone marrow-derived mesenchymal stem cells suppress NK cell recruitment and activation in PolyI:C-induced liver injury. Biochem. Biophys. Res. Commun. 2015;466:173–179. doi: 10.1016/j.bbrc.2015.08.125.
    1. Parekkadan B., van Poll D., Suganuma K., Carter E.A., Berthiaume F., Tilles A.W., Yarmush M.L. Mesenchymal stem cell-derived molecules reverse fulminant hepatic failure. PLoS ONE. 2007;2:e941. doi: 10.1371/journal.pone.0000941.
    1. Tan C.Y., Lai R.C., Wong W., Dan Y.Y., Lim S.K., Ho H.K. Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models. Stem Cell Res. Ther. 2014;5:76. doi: 10.1186/scrt465.
    1. Nyberg S. Bridging the gap: Advances in artificial liver support. Liver Transpl. 2012;18:S10–S14. doi: 10.1002/lt.23506.
    1. McKenzie T.J., Lillegard J.B., Nyberg S.L. Artificial and bioartificial liver support. Semin. Liver Dis. 2008;28:210–217. doi: 10.1055/s-2008-1073120.
    1. Demetriou A.A., Brown R.S., Jr., Busuttil R.W., Fair J., McGuire B.M., Rosenthal P., Am Esch J.S., 2nd, Lerut J., Nyberg S.L., Salizzoni M., et al. Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure. Ann. Surg. 2004;239:660–667. doi: 10.1097/01.sla.0000124298.74199.e5.
    1. Carpentier B., Gautier A., Legallais C. Artificial and bioartificial liver devices: Present and future. Gut. 2009;58:1690–1702. doi: 10.1136/gut.2008.175380.
    1. Ellis A.J., Hughes R.D., Wendon J.A., Dunne J., Langley P.G., Kelly J.H., Gislason G.T., Sussman N.L., Williams R. Pilot-controlled trial of the extracorporeal liver assist device in acute liver failure. Hepatology. 1996;24:1446–1451. doi: 10.1002/hep.510240625.
    1. Kjaergard L., Liu J., Als-Nielsen B., Gluud C. Artificial and bioartificial support systems for acute and acute-on-chronic liver failure: A systematic review. JAMA. 2003;289:217–222. doi: 10.1001/jama.289.2.217.
    1. Zheng Z., Li X., Li Z., Ma X. Artificial and bioartificial liver support systems for acute and acute-on-chronic hepatic failure: A meta-analysis and meta-regression. Exp Ther Med. 2013;6:929–936.
    1. Parent R., Marion M.J., Furio L., Trepo C., Petit M.A. Origin and characterization of a human bipotent liver progenitor cell line. Gastroenterology. 2004;126:1147–1156. doi: 10.1053/j.gastro.2004.01.002.
    1. Hoekstra R., Nibourg G.A., van der Hoeven T.V., Ackermans M.T., Hakvoort T.B., van Gulik T.M., Lamers W.H., Elferink L.P., Chamuleau R.A. The HepaRG cell line is suitable for bioartificial liver application. Int. J. Biochem. Cell Biol. 2011;43:1483–1489. doi: 10.1016/j.biocel.2011.06.011.
    1. Nibourg G.A., Hoekstra R., van der Hoeven T.V., Ackermans M.T., Hakvoort T.B., van Gulik T.M., Chamuleau R.A. Increased hepatic functionality of the human hepatoma cell line HepaRG cultured in the AMC bioreactor. Int. J. Biochem. Cell Biol. 2013;45:1860–1868. doi: 10.1016/j.biocel.2013.05.038.
    1. Nibourg G.A., Hoekstra R., van der Hoeven T.V., Ackermans M.T., Hakvoort T.B., van Gulik T.M., Chamuleau R.A. Effects of acute-liver-failure-plasma exposure on hepatic functionality of HepaRG-AMC-bioartificial liver. Liver Int. 2013;33:516–524. doi: 10.1111/liv.12090.
    1. Nibourg G.A., Chamuleau R.A., van der Hoeven T.V., Maas M.A., Ruiter A.F., Lamers W.H., Oude Elferink R.P., van Gulik T.M., Hoekstra R. Liver progenitor cell line HepaRG differentiated in a bioartificial liver effectively supplies liver support to rats with acute liver failure. PLoS ONE. 2012;7:e38778. doi: 10.1371/journal.pone.0038778.
    1. Glorioso J., Mao S., Rodysill B., Mounajjed T., Kremers W., Elgilani F., Hickey R.D., Haugaa H., Rose C.F., Amiot B., et al. Pivotal preclinical trial of the spheroid reservoir bioartificial liver. J. Hepatol. 2015;63:388–398. doi: 10.1016/j.jhep.2015.03.021.
    1. Yu Y., Wang X., Nyberg S.L. Potential and Challenges of Induced Pluripotent Stem Cells in Liver Diseases Treatment. J Clin Med. 2014;3:997–1017. doi: 10.3390/jcm3030997.
    1. Soto-Gutierrez A., Kobayashi N., Rivas-Carrillo J.D., Navarro-Alvarez N., Zhao D., Okitsu T., Noguchi H., Basma H., Tabata Y., Chen Y., et al. Reversal of mouse hepatic failure using an implanted liver-assist device containing ES cell-derived hepatocytes. Nat. Biotechnol. 2006;24:1412–1419. doi: 10.1038/nbt1257.
    1. Iwamuro M., Shiraha H., Nakaji S., Furutani M., Kobayashi N., Takaki A., Yamamoto K. A preliminary study for constructing a bioartificial liver device with induced pluripotent stem cell-derived hepatocytes. Biomed. Eng. Online. 2012;11:93. doi: 10.1186/1475-925X-11-93.
    1. Terai S., Ishikawa T., Omori K., Aoyama K., Marumoto Y., Urata Y., Yokoyama Y., Uchida K., Yamasaki T., Fujii Y., et al. Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. Stem Cells. 2006;24:2292–2298. doi: 10.1634/stemcells.2005-0542.
    1. Yannaki E., Anagnostopoulos A., Kapetanos D., Xagorari A., Iordanidis F., Batsis I., Kaloyannidis P., Athanasiou E., Dourvas G., Kitis G., et al. Lasting amelioration in the clinical course of decompensated alcoholic cirrhosis with boost infusions of mobilized peripheral blood stem cells. Exp Hematol. 2006;34:1583–1587. doi: 10.1016/j.exphem.2006.06.012.
    1. Han Y., Yan L., Han G., Zhou X., Hong L., Yin Z., Zhang X., Wang S., Wang J., Sun A., et al. Controlled trials in hepatitis B virus-related decompensate liver cirrhosis: Peripheral blood monocyte transplant versus granulocyte-colony-stimulating factor mobilization therapy. Cytotherapy. 2008;10:390–396. doi: 10.1080/14653240802129901.
    1. Lukashyk S.P., Tsyrkunov V.M., Isaykina Y.I., Romanova O.N., Shymanskiy A.T., Aleynikova O.V., Kravchuk R.I. Mesenchymal Bone Marrow-derived Stem Cells Transplantation in Patients with HCV Related Liver Cirrhosis. J. Clin. Transl. Hepatol. 2014;2:217–221. doi: 10.14218/JCTH.2014.00027.
    1. Kantarcioglu M., Demirci H., Avcu F., Karslioglu Y., Babayigit M.A., Karaman B., Ozturk K., Gurel H., Akdogan Kayhan M., Kaçar S., et al. Efficacy of autologous mesenchymal stem cell transplantation in patients with liver cirrhosis. Turk. J. Gastroenterol. 2015;26:244–250. doi: 10.5152/tjg.2015.0074.
    1. Tang W.P., Akahoshi T., Piao J.S., Narahara S., Murata M., Kawano T., Hamano N., Ikeda T., Hashizume M. Basic fibroblast growth factor-treated adipose tissue-derived mesenchymal stem cell infusion to ameliorate liver cirrhosis via paracrine hepatocyte growth factor. J. Gastroenterol. Hepatol. 2015;30:1065–1074. doi: 10.1111/jgh.12893.
    1. Lin P.C., Chiou T.W., Lin Z.S., Huang K.C., Lin Y.C., Huang P.C., Syu W.S., Harn H.J., Lin S.Z. A proposed novel stem cell therapy protocol for liver cirrhosis. Cell Transplant. 2015;24:533–540. doi: 10.3727/096368915X687228.
    1. Jung K.H., Uhm Y.K., Lim Y.J., Yim S.V. Human umbilical cord blood-derived mesenchymal stem cells improve glucose homeostasis in rats with liver cirrhosis. Int. J. Oncol. 2011;39:137–143.
    1. Yovchev M.I., Xue Y., Shafritz D.A., Locker J., Oertel M. Repopulation of the fibrotic/cirrhotic rat liver by transplanted hepatic stem/progenitor cells and mature hepatocytes. Hepatology. 2014;59:284–295. doi: 10.1002/hep.26615.
    1. Cardinale V., Carpino G., Gentile R., Napoletano C., Rahimi H., Franchitto A., Semeraro R., Nuti M., Onori P., Berloco P.B., et al. Transplantation of human fetal biliary tree stem/progenitor cells into two patients with advanced liver cirrhosis. BMC Gastroenterol. 2014;14:204. doi: 10.1186/s12876-014-0204-z.
    1. Zhang Z., Wang F.S. Stem cell therapies for liver failure and cirrhosis. J Hepatol. 2013;59:183–185. doi: 10.1016/j.jhep.2013.01.018.
    1. Liu T., Wang Y., Tai G., Zhang S. Could co-transplantation of iPS cells derived hepatocytes and MSCs cure end-stage liver disease? Cell Biol. Int. 2009;33:1180–1183. doi: 10.1016/j.cellbi.2009.08.007.
    1. Espejel S., Roll G.R., McLaughlin K.J., Lee A.Y., Zhang J.Y., Laird D.J., Okita K., Yamanaka S., Willenbring H. Induced pluripotent stem cell-derived hepatocytes have the functional and proliferative capabilities needed for liver regeneration in mice. J. Clin. Investig. 2010;120:3120–3126. doi: 10.1172/JCI43267.
    1. Ferrero A., Viganò L., Polastri R., Muratore A., Eminefendic H., Regge D., Capussotti L. Postoperative liver dysfunction and future remnant liver: Where is the limit? World J. Surg. 2007;31:1643–1651. doi: 10.1007/s00268-007-9123-2.
    1. Am Esch J.S., 2nd, Knoefel W.T., Klein M., Ghodsizad A., Fuerst G., Poll L.W., Piechaczek C., Burchardt E.R., Feifel N., Stoldt V., et al. Portal application of autologous CD133+ bone marrow cells to the liver: A novel concept to support hepatic regeneration. Stem Cells. 2005;23:463–470. doi: 10.1634/stemcells.2004-0283.
    1. Furst G., Schulte am Esch J., Poll L.W., Hosch S.B., Fritz L.B., Klein M., Godehardt E., Krieg A., Wecker B., Stoldt V., et al. Portal vein embolization and autologous CD133+ bone marrow stem cells for liver regeneration: Initial experience. Radiology. 2007;243:171–179. doi: 10.1148/radiol.2431060625.
    1. Ismail A., Fouad O., Abdelnasser A., Chowdhury A., Selim A. Stem cell therapy improves the outcome of liver resection in cirrhotics. J. Gastrointest. Cancer. 2010;41:17–23. doi: 10.1007/s12029-009-9092-9.
    1. Conrad R., Remberger M., Cederlund K., Ringden O., Barkholt L. A comparison between low intensity and reduced intensity conditioning in allogeneic hematopoietic stem cell transplantation for solid tumors. Haematologica. 2008;93:265–272. doi: 10.3324/haematol.11672.
    1. Restifo N.P., Dudley M.E., Rosenberg S.A. Adoptive immunotherapy for cancer: Harnessing the T cell response. Nat. Rev. 2012;12:269–281. doi: 10.1038/nri3191.
    1. Takayama T., Sekine T., Makuuchi M., Yamasaki S., Kosuge T., Yamamoto J., Shimada K., Sakamoto M., Hirohashi S., Ohashi Y., et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: A randomised trial. Lancet. 2000;356:802–807. doi: 10.1016/S0140-6736(00)02654-4.
    1. Lei F., Zhao B., Haque R., Xiong X., Budgeon L., Christensen N.D., Wu Y., Song J. In vivo programming of tumor antigen-specific T lymphocytes from pluripotent stem cells to promote cancer immunosurveillance. Cancer Res. 2011;71:4742–4747. doi: 10.1158/0008-5472.CAN-11-0359.
    1. Deng Q., Zhang Z., Feng X., Li T., Liu N., Lai J., Shuai L., Xiong Q., Fu C., Zou H., et al. TRAIL-secreting mesenchymal stem cells promote apoptosis in heat-shock-treated liver cancer cells and inhibit tumor growth in nude mice. Gene Ther. 2014;21:317–327. doi: 10.1038/gt.2013.88.
    1. Sharkis S.J., Jones R.J., Civin C., Jang Y.Y. Pluripotent stem cell-based cancer therapy: Promise and challenges. Sci. Transl. Med. 2012;4:127ps9. doi: 10.1126/scitranslmed.3003920.
    1. Takayama K., Morisaki Y., Kuno S., Nagamoto Y., Harada K., Furukawa N., Ohtaka M., Nishimura K., Imagawa K., Sakurai F., et al. Prediction of interindividual differences in hepatic functions and drug sensitivity by using human iPS-derived hepatocytes. Proc. Natl. Acad. Sci. USA. 2014;111:16772–16777. doi: 10.1073/pnas.1413481111.
    1. Yersiz H., Cameron A., Carmody I., Zimmerman M., Kelly B., Ghobrial R., Farmer D.G., Busuttil R.W. Split liver transplantation. Transplant. Proc. 2006;38:602–603. doi: 10.1016/j.transproceed.2005.12.064.
    1. Dahm F., Georgiev P., Clavien P.A. Small-for-Size Syndrome After Partial Liver Transplantation: Definition, Mechanisms of Disease and Clinical Implications. Am. J. Transplant. 2005;5:2605–2610. doi: 10.1111/j.1600-6143.2005.01081.x.
    1. Gonzalez H.D., Liu Z.W., Cashman S., Fusai G.K. Small for size syndrome following living donor and split liver transplantation. World J. Gastrointest. Surg. 2010;2:389–394. doi: 10.4240/wjgs.v2.i12.389.
    1. Zhong Z., Schwabe R.F., Kai Y., He L., Yang L., Bunzendahl H., Brenner D.A., Lemasters J.J. Liver regeneration is suppressed in small-for-size liver grafts after transplantation: Involvement of c-Jun N-terminal kinase, cyclin D1, and defective energy supply. Transplantation. 2006;82:241–250. doi: 10.1097/01.tp.0000228867.98158.d2.
    1. Pan N., Lv X., Liang R., Wang L., Liu Q. Suppression of graft regeneration, not ischemia/reperfusion injury, is the primary cause of small-for-size syndrome after partial liver transplantation in mice. PLoS ONE. 2014;9:e93636. doi: 10.1371/journal.pone.0093636.
    1. Yu Y., Yao A.-.H., Chen N., Pu L.-.Y., Fan Y., Lv L., Sun B.C., Li G.Q., Wang X.H. Mesenchymal Stem Cells Over-expressing Hepatocyte Growth Factor Improve Small-for-size Liver Grafts Regeneration. Mol. Ther. 2007;15:1382–1389.
    1. Yu Y., Lu L., Qian X., Chen N., Yao A., Pu L., Zhang F., Li X., Kong L., Sun B., et al. Antifibrotic effect of hepatocyte growth factor-expressing mesenchymal stem cells in small-for-size liver transplant rats. Stem Cells Dev. 2010;19:903–914. doi: 10.1089/scd.2009.0254.
    1. Wang W., Du Z., Yan J., Ma D., Shi M., Zhang M., Peng C., Li H. Mesenchymal stem cells promote liver regeneration and prolong survival in small-for-size liver grafts: Involvement of C-Jun N-terminal kinase, cyclin D1, and NF-kappaB. PLoS ONE. 2014;9:e112532. doi: 10.1371/journal.pone.0112532.
    1. Du Z., Wei C., Cheng K., Han B., Yan J., Zhang M., Peng C., Liu Y. Mesenchymal stem cell-conditioned medium reduces liver injury and enhances regeneration in reduced-size rat liver transplantation. J. Surg. Res. 2013;183:907–915. doi: 10.1016/j.jss.2013.02.009.
    1. Owen A., Newsome P.N. Mesenchymal stromal cell therapy in liver disease: Opportunities and lessons to be learnt? Am. J. Physiol. Gastrointest. Liver Physiol. 2015;309:G791–G800. doi: 10.1152/ajpgi.00036.2015.
    1. Uygun B.E., Soto-Gutierrez A., Yagi H., Izamis M.L., Guzzardi M.A., Shulman C., Milwid J., Kobayashi N., Tilles A., Berthiaume F., et al. Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat. Med. 2010;16:814–820. doi: 10.1038/nm.2170.
    1. Uygun B.E., Yarmush M.L., Uygun K. Application of whole-organ tissue engineering in hepatology. Nat. Rev. Gastroenterol. Hepatol. 2012;9:738–744. doi: 10.1038/nrgastro.2012.140.
    1. Ishii T., Fukumitsu K., Yasuchika K., Adachi K., Kawase E., Suemori H., Nakatsuji N., Ikai I., Uemoto S. Effects of extracellular matrixes and growth factors on the hepatic differentiation of human embryonic stem cells. Am. J. Physiol. Gastrointest. Liver Physiol. 2008;295:G313–G321. doi: 10.1152/ajpgi.00072.2008.
    1. Palakkan A.A., Hay D.C., Anil Kumar P.R., Kumary T.V., Ross J.A. Liver tissue engineering and cell sources: Issues and challenges. Liver Int. 2013;33:666–676. doi: 10.1111/liv.12134.
    1. Takebe T., Sekine K., Enomura M., Koike H., Kimura M., Ogaeri T., Zhang R.R., Ueno Y., Zheng Y.W., Koike N., et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature. 2013;499:481–484. doi: 10.1038/nature12271.
    1. Fox I.J., Duncan S.A. Engineering liver tissue from induced pluripotent stem cells: A first step in generating new organs for transplantation? Hepatology. 2013;58:2198–2201. doi: 10.1002/hep.26737.
    1. Wertheim J.A., Baptista P.M., Soto-Gutierrez A. Cellular therapy and bioartificial approaches to liver replacement. Curr. Opin. Organ. Transplant. 2012;17:235–240. doi: 10.1097/MOT.0b013e3283534ec9.
    1. Kumar A., Pati N.T., Sarin S.K. Use of stem cells for liver diseases-current scenario. J. Clin. Exp. Hepatol. 2011;1:17–26. doi: 10.1016/S0973-6883(11)60114-X.
    1. Hiura H., Toyoda M., Okae H., Sakurai M., Miyauchi N., Sato A., Kiyokawa N., Okita H., Miyagawa Y., Akutsu H., et al. Stability of genomic imprinting in human induced pluripotent stem cells. BMC Genet. 2013;14:32. doi: 10.1186/1471-2156-14-32.
    1. Harding J., Roberts R.M., Mirochnitchenko O. Large animal models for stem cell therapy. Stem Cell Res. Ther. 2013;4:23. doi: 10.1186/scrt171.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa