Abstract
BACKGROUND:
Liver disease is one of the top causes of death globally. Although liver transplantation is a very effective treatment strategy, the shortage of available donor organs, waiting list mortality, and high costs of surgery remain huge problems. Stem cells are undifferentiated cells that can differentiate into a variety of cell types. Scientists are exploring the possibilities of generating hepatocytes from stem cells as an alternative for the treatment of liver diseases.
METHODS:
In this review, we summarized the updated researches in the field of stem cell-based therapies for liver diseases as well as the current challenges and future expectations for a successful cell-based liver therapy.
RESULTS:
Several cell types have been investigated for liver regeneration, such as embryonic stem cells, induced pluripotent stem cells, liver stem cells, mesenchymal stem cells, and hematopoietic stem cells. In vitro and in vivo studies have demonstrated that stem cells are promising cell sources for the liver regeneration.
CONCLUSION:
Stem cell-based therapy could be a promising therapeutic method for patients with end-stage liver disease, which may alleviate the need for liver transplantation in the future.
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References
Michalopoulos GK, DeFrances MC. Liver regeneration. Science. 1997;276:60–6.
Şentürk Ü, Yücedağ I, Polat K. Repetitive neural network (RNN) based blood pressure estimation using PPG and ECG signals. In 2018 2nd International Symposium on Multidisciplinary Studies and Innovative Technologies (ISMSIT) 2018 Oct 19. IEEE.
Song AT, Avelino-Silva VI, Pecora RA, Pugliese V, D’Albuquerque LA, Abdala E. Liver transplantation: fifty years of experience. World J Gastroenterol. 2014;20:5363–74.
Soltys KA, Setoyama K, Tafaleng EN, Soto Gutiérrez A, Fong J, Fukumitsu K, et al. Host conditioning and rejection monitoring in hepatocyte transplantation in humans. J Hepatol. 2017;66:987–1000.
Forbes SJ, Gupta S, Dhawan A. Cell therapy for liver disease: From liver transplantation to cell factory. J Hepatol. 2015;62:S157–69.
Volarevic V, Nurkovic J, Arsenijevic N, Stojkovic M. Concise review: therapeutic potential of mesenchymal stem cells for the treatment of acute liver failure and cirrhosis. Stem cells. 2014;32:2818–23.
Trounson A, McDonald C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell. 2015;17:11–22.
Lane SW, Williams DA, Watt FM. Modulating the stem cell niche for tissue regeneration. Nat Biotechnol. 2014;32:795–803.
Kopp JL, Grompe M, Sander M. Stem cells versus plasticity in liver and pancreas regeneration. Nat Cell Biol. 2016;18:238–45.
Katagiri H, Kushida Y, Nojima M, Kuroda Y, Wakao S, Ishida K, et al. A distinct subpopulation of bone marrow mesenchymal stem cells, muse cells, directly commit to the replacement of liver components. Am J Transplant. 2016;16:468–83.
Wagers AJ, Weissman IL. Plasticity of adult stem cells. Cell. 2004;116:639–48.
Itoh T, Miyajima A. Liver regeneration by stem/progenitor cells. Hepatology. 2014;59:1617–26.
Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282:1145–7.
Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292:154–6.
Ware CB, Nelson AM, Mecham B, Hesson J, Zhou W, Jonlin EC, et al. Derivation of naive human embryonic stem cells. Proc Natl Acad Sci U S A. 2014;111:4484–9.
Kuai XL, Shao N, Lu H, Xiao SD, Zheng Q. Differentiation of nonhuman primate embryonic stem cells into hepatocyte-like cells. J Dig Dis. 2014;15:27–34.
Brolén G, Sivertsson L, Björquist P, Eriksson G, Ek M, Semb H, et al. Hepatocyte-like cells derived from human embryonic stem cells specifically via definitive endoderm and a progenitor stage. J Biotechnol. 2010;145:284–94.
Woo DH, Kim SK, Lim HJ, Heo J, Park HS, Kang GY, et al. Direct and indirect contribution of human embryonic stem cell–derived hepatocyte-like cells to liver repair in mice. Gastroenterology. 2012;142:602–11.
Tolosa L, Caron J, Hannoun Z, Antoni M, López S, Burks D, et al. Transplantation of hESC-derived hepatocytes protects mice from liver injury. Stem Cell Res Ther. 2015;6:246.
Wang M, Yang X, Zhang P, Cai L, Yang X, Chen Y, et al. Sustained delivery growth factors with polyethyleneimine-modified nanoparticles promote embryonic stem cells differentiation and liver regeneration. Adv Sci (Weinh). 2016;3:1500393.
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.
Pettinato G, Wen X, Zhang N. Engineering strategies for the formation of embryoid bodies from human pluripotent stem cells. Stem Cells Dev. 2015;24:1595–609.
Ratajczak MZ, Bujko K, Wojakowski W. Stem cells and clinical practice: new advances and challenges at the time of emerging problems with induced pluripotent stem cell therapies. Pol Arch Med Wewn. 2016;126:879–90.
Cai J, Zhao Y, Liu Y, Ye F, Song Z, Qin H, et al. Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology. 2007;45:1229–39.
Noto FK, Duncan SA. Generation of hepatocyte-like cells from human pluripotent stem cells. In: Sell S, editor. Stem Cells Handbook. New York: Humana Press; 2013. p. 139–47.
Si-Tayeb K, Noto FK, Nagaoka M, Li J, Battle MA, Duris C, et al. Highly efficient generation of human hepatocyte–like cells from induced pluripotent stem cells. Hepatology. 2010;51:297–305.
Hannan NR, Segeritz CP, Touboul T, Vallier L. Production of hepatocyte-like cells from human pluripotent stem cells. Nat Protoc. 2013;8:430–7.
Takebe T, Sekine K, Enomura M, Koike H, Kimura M, Ogaeri T, et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature. 2013;499:481–4.
Liu H, Kim Y, Sharkis S, Marchionni L, Jang YY. In vivo liver regeneration potential of human induced pluripotent stem cells from diverse origins. Sci Transl Med. 2011; 3:82ra39.
Zhao T, Zhang ZN, Rong Z, Xu Y. Immunogenicity of induced pluripotent stem cells. Nature. 2011;474:212–5.
Guha P, Morgan JW, Mostoslavsky G, Rodrigues NP, Boyd AS. Lack of immune response to differentiated cells derived from syngeneic induced pluripotent stem cells. Cell Stem Cell. 2013;12:407–12.
Carraro A, Flaibani M, Cillo U, Michelotto L, Magrofuoco E, Buggio M, et al. A combining method to enhance the in vitro differentiation of hepatic precursor cells. Tissue Eng Part C Methods. 2010;16:1543–51.
Irudayaswamy A, Muthiah M, Zhou L, Hung H, Jumat NHB, Haque J, et al. Long-term fate of human fetal liver progenitor cells transplanted in injured mouse livers. Stem Cells. 2018;36:103–13.
Takase HM, Itoh T, Ino S, Wang T, Koji T, Akira S, et al. FGF7 is a functional niche signal required for stimulation of adult liver progenitor cells that support liver regeneration. Genes Dev. 2013;27:169–81.
Lu WY, Bird TG, Boulter L, Tsuchiya A, Cole AM, Hay T, et al. Hepatic progenitor cells of biliary origin with liver repopulation capacity. Nat Cell Biol. 2015;17:971–83.
Huch M, Dorrell C, Boj SF, van Es JH, Li VS, van de Wetering M, et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature. 2013;494:247–50.
Huch M, Gehart H, van Boxtel R, Hamer K, Blokzijl F, Verstegen MM, et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell. 2015;160:299–312.
Tuan RS, Boland G, Tuli R. Adult mesenchymal stem cells and cell-based tissue engineering. Arthritis Res Ther. 2003;5:32–45.
Liu ZJ, Zhuge Y, Velazquez OC. Trafficking and differentiation of mesenchymal stem cells. J Cell Biochem. 2009;106:984–91.
Kobolak J, Dinnyes A, Memic A, Khademhosseini A, Mobasheri A. Mesenchymal stem cells: Identification, phenotypic characterization, biological properties and potential for regenerative medicine through biomaterial micro-engineering of their niche. Methods. 2016;99:62–8.
Augello A, Kurth TB, De Bari C. Mesenchymal stem cells: a perspective from in vitro cultures to in vivo migration and niches. Eur Cell Mater. 2010;20:121–33.
Porada CD, Zanjani ED, Almeida-Porada G. Adult mesenchymal stem cells: a pluripotent population with multiple applications. Curr Stem Cell Res Ther. 2006;1:365–9.
Dowidar MF, El-Belbasi HI, Ayoub AG, Rashed LA, Elged DW. Biochemical and molecular studies on bone marrow derived stromal stem cells on liver injuries in rats. Zag Vet J. 2017;45:355–65.
Yin L, Zhu Y, Yang J, Ni Y, Zhou Z, Chen Y, et al. Adipose tissue-derived mesenchymal stem cells differentiated into hepatocyte-like cells in vivo and in vitro. Mol Med Rep. 2015;11:1722–32.
Lee SK, Lee SC, Kim SJ. A novel cell-free strategy for promoting mouse liver regeneration: utilization of a conditioned medium from adipose-derived stem cells. Hepatol Int. 2015;9:310–20.
Salama H, Zekri AR, Medhat E, Al Alim SA, Ahmed OS, Bahnassy AA, et al. Peripheral vein infusion of autologous mesenchymal stem cells in Egyptian HCV-positive patients with end-stage liver disease. Stem Cell Res Ther. 2014;5:70.
Wang L, Han Q, Chen H, Wang K, Shan GL, Kong F, et al. Allogeneic bone marrow mesenchymal stem cell transplantation in patients with UDCA-resistant primary biliary cirrhosis. Stem Cells Dev. 2014;23:2482–9.
Jang YO, Kim YJ, Baik SK, Kim MY, Eom YW, Cho MY, et al. Histological improvement following administration of autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: a pilot study. Liver Int. 2014;34:33–41.
Gómez-Aristizábal A, Keating A, Davies JE. Mesenchymal stromal cells as supportive cells for hepatocytes. Mol Ther. 2009;17:1504–8.
Rebelo SP, Costa R, Silva MM, Marcelino P, Brito C, Alves PM. Three-dimensional co-culture of human hepatocytes and mesenchymal stem cells: improved functionality in long-term bioreactor cultures. J Tissue Eng Regen Med. 2017;11:2034–45.
Wang J, Zhu Z, Huang Y, Wang P, Luo Y, Gao Y, et al. The subtype CD200-positive, chorionic mesenchymal stem cells from the placenta promote regeneration of human hepatocytes. Biotechnol Lett. 2014;36:1335–41.
Fitzpatrick E, Wu Y, Dhadda P, Hughes RD, Mitry RR, Qin H, et al. Coculture with mesenchymal stem cells results in improved viability and function of human hepatocytes. Cell Transplant. 2015;24:73–83.
Lagasse E, Connors H, Al-Dhalimy M, Reitsma M, Dohse M, Osborne L, et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med. 2000;6:1229–34.
Lehwald N, Duhme C, Wildner M, Kuhn S, Fürst G, Forbes SJ, et al. HGF and SDF-1-mediated mobilization of CD 133+ BMSC for hepatic regeneration following extensive liver resection. Liver Int. 2014;34:89–101.
Körbling M, Katz RL, Khanna A, Ruifrok AC, Rondon G, Albitar M, et al. Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells. N Engl J Med. 2002;346:738–46.
Wan Z, You S, Rong Y, Zhu B, Zhang A, Zang H, et al. CD34+ hematopoietic stem cells mobilization, paralleled with multiple cytokines elevated in patients with HBV-related acute-on-chronic liver failure. Dig Dis Sci. 2013;58:448–57.
Kollet O, Shivtiel S, Chen YQ, Suriawinata J, Thung SN, Dabeva MD, et al. HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver. J Clin Invest. 2003;112:160–9.
Yannaki E, Athanasiou E, Xagorari A, Constantinou V, Batsis I, Kaloyannidis P, et al. G-CSF–primed hematopoietic stem cells or G-CSF per se accelerate recovery and improve survival after liver injury, predominantly by promoting endogenous repair programs. Exp Hematol. 2005;33:108–19.
Zekri AR, Salama H, Medhat E, Musa S, Abdel-Haleem H, Ahmed OS, et al. The impact of repeated autologous infusion of haematopoietic stem cells in patients with liver insufficiency. Stem Cell Res Ther. 2015;6:118.
Jang YY, Collector MI, Baylin SB, Diehl AM, Sharkis SJ. Hematopoietic stem cells convert into liver cells within days without fusion. Nat Cell Biol. 2004;6:532–9.
Newsome PN, Johannessen I, Boyle S, Dalakas E, McAulay KA, Samuel K, et al. Human cord blood-derived cells can differentiate into hepatocytes in the mouse liver with no evidence of cellular fusion. Gastroenterology. 2003;124:1891–900.
Vassilopoulos G, Wang PR, Russell DW. Transplanted bone marrow regenerates liver by cell fusion. Nature. 2003;422:901–4.
Alison MR, Poulsom R, Jeffery R, Dhillon AP, Quaglia A, Jacob J, et al. Cell differentiation: hepatocytes from non-hepatic adult stem cells. Nature. 2000;406:257.
Martínez Sarrà E. Characterization of dental pulp pluripotent-like stem cells (DPPSC) and their mesodermal differentiation potential. Doctoral dissertation, Universitat Internacional de Catalunya, Barcelona; 2017.
Gil Recio C. Obtaining hepatocyte-like cells from dental pulppluripotent-like stem cells. Doctoral dissertation, Universitat Internacional de Catalunya, Barcelona; 2015.
Fairhall EA, Wallace K, White SA, Huang GC, Shaw JA, Wright SC, et al. Adult human exocrine pancreas differentiation to hepatocytes–potential source of a human hepatocyte progenitor for use in toxicology research. Toxicol Res (Camb). 2013;2:80–7.
Probert PM, Chung GW, Cockell SJ, Agius L, Mosesso P, White SA, et al. Utility of B-13 progenitor-derived hepatocytes in hepatotoxicity and genotoxicity studies. Toxicol Sci. 2014;137:350–70.
Wang RY, Shen CN, Lin MH, Tosh D, Shih C. Hepatocyte-like cells transdifferentiated from a pancreatic origin can support replication of hepatitis B virus. J Virol. 2005;79:13116–28.
Wallace K, Fairhall EA, Charlton KA, Wright MC. AR42J-B-13 cell: an expandable progenitor to generate an unlimited supply of functional hepatocytes. Toxicology. 2010;278:277–87.
Rong Z, Wang M, Hu Z, Stradner M, Zhu S, Kong H, et al. An effective approach to prevent immune rejection of human ESC-derived allografts. Cell Stem Cell. 2014;14:121–30.
Hynes RO. US policies on human embryonic stem cells. Nat Rev Mol Cell Biol. 2008;9:993–7.
Poulsom R, Alison MR, Forbes SJ, Wright NA. Adult stem cell plasticity. J Pathol. 2002;197:441–56.
Wang Y, Zhang Z, Chi Y, Zhang Q, Xu F, Yang Z, et al. Long-term cultured mesenchymal stem cells frequently develop genomic mutations but do not undergo malignant transformation. Cell Death Dis. 2013;4:e950.
Oishi K, Noguchi H, Yukawa H, Hayashi S. Differential ability of somatic stem cells. Cell Transplant. 2009;18:581–9.
Cawthorn WP, Scheller EL, MacDougald OA. Adipose tissue stem cells meet preadipocyte commitment: going back to the future. J Lipid Res. 2012;53:227–46.
Touboul T, Hannan NR, Corbineau S, Martinez A, Martinet C, Branchereau S, et al. Generation of functional hepatocytes from human embryonic stem cells under chemically defined conditions that recapitulate liver development. Hepatology. 2010;51:1754–65.
Siller R, Greenhough S, Naumovska E, Sullivan GJ. Small-molecule-driven hepatocyte differentiation of human pluripotent stem cells. Stem cell Reports. 2015;4:939–52.
Toivonen S, Lundin K, Balboa D, Ustinov J, Tamminen K, Palgi J, et al. Activin A and Wnt-dependent specification of human definitive endoderm cells. Exp Cell Res. 2013;319:2535–44.
Borowiak M, Maehr R, Chen S, Chen AE, Tang W, Fox JL, et al. Small molecules efficiently direct endodermal differentiation of mouse and human embryonic stem cells. Cell Stem Cell. 2009;4:348–58.
Takayama K, Inamura M, Kawabata K, Katayama K, Higuchi M, Tashiro K, et al. Efficient generation of functional hepatocytes from human embryonic stem cells and induced pluripotent stem cells by HNF4α transduction. Mol Ther. 2012;20:127–37.
Zhou M, Li P, Tan L, Qu S, Ying QL, Song H. Differentiation of mouse embryonic stem cells into hepatocytes induced by a combination of cytokines and sodium butyrate. J Cell Biochem. 2010;109:606–14.
Du C, Feng Y, Qiu D, Xu Y, Pang M, Cai N, et al. Highly efficient and expedited hepatic differentiation from human pluripotent stem cells by pure small-molecule cocktails. Stem Cell Res Ther. 2018;9:58.
Baxter M, Withey S, Harrison S, Segeritz CP, Zhang F, Atkinson-Dell R, et al. Phenotypic and functional analyses show stem cell-derived hepatocyte-like cells better mimic fetal rather than adult hepatocytes. J Hepatol. 2015;62:581–9.
Schwartz RE, Fleming HE, Khetani SR, Bhatia SN. Pluripotent stem cell-derived hepatocyte-like cells. Biotechnol Adv. 2014;32:504–13.
Meng Q. Three-dimensional culture of hepatocytes for prediction of drug-induced hepatotoxicity. Expert Opin Drug Metab Toxicol. 2010;6:733–46.
Nath S, Devi GR. Three-dimensional culture systems in cancer research: Focus on tumor spheroid model. Pharmacol Ther. 2016;163:94–108.
Shamir ER, Ewald AJ. Three-dimensional organotypic culture: experimental models of mammalian biology and disease. Nat Rev Mol Cell Biol. 2014;15:647–64.
Kim SE, An SY, Woo DH, Han J, Kim JH, Jang YJ, et al. Engraftment potential of spheroid-forming hepatic endoderm derived from human embryonic stem cells. Stem Cells Dev. 2013;22:1818–29.
Ravi M, Paramesh V, Kaviya SR, Anuradha E, Solomon FP. 3D cell culture systems: advantages and applications. J Cell Physiol. 2015;230:16–26.
Kim JH, Jang YJ, An SY, Son J, Lee J, Lee G, et al. Enhanced metabolizing activity of human ES cell-derived hepatocytes using a 3D culture system with repeated exposures to xenobiotics. Toxicol Sci. 2015;147:190–206.
Ramaiahgari SC, den Braver MW, Herpers B, Terpstra V, Commandeur JN, van de Water B, et al. A 3D in vitro model of differentiated HepG2 cell spheroids with improved liver-like properties for repeated dose high-throughput toxicity studies. Arch Toxicol. 2014;88:1083–95.
Cipriano M, Freyer N, Knöspel F, Oliveira NG, Barcia R, Cruz PE, et al. Self-assembled 3D spheroids and hollow-fibre bioreactors improve MSC-derived hepatocyte-like cell maturation in vitro. Arch Toxicol. 2017;91:1815–32.
Garnier D, Li R, Delbos F, Fourrier A, Collet C, Guguen-Guillouzo C, et al. Expansion of human primary hepatocytes in vitro through their amplification as liver progenitors in a 3D organoid system. Sci Rep. 2018;8:8222.
Vosough M, Omidinia E, Kadivar M, Shokrgozar MA, Pournasr B, Aghdami N, et al. Generation of functional hepatocyte-like cells from human pluripotent stem cells in a scalable suspension culture. Stem Cells Dev. 2013;22:2693–705.
Kang A, Park J, Ju J, Jeong GS, Lee SH. Cell encapsulation via microtechnologies. Biomaterials. 2014;35:2651–63.
Hashemi M, Kalalinia F. Application of encapsulation technology in stem cell therapy. Life Sci. 2015;143:139–46.
Meier RP, Montanari E, Morel P, Pimenta J, Schuurman HJ, Wandrey C, et al. Microencapsulation of hepatocytes and mesenchymal stem cells for therapeutic applications. Methods Mol Biol. 2017;1506:259–71.
Meier RP, Mahou R, Morel P, Meyer J, Montanari E, Muller YD, et al. Microencapsulated human mesenchymal stem cells decrease liver fibrosis in mice. J Hepatol. 2015;62:634–41.
Hu AB, Cai JY, Zheng QC, He XQ, Shan Y, Pan YL, et al. High-ratio differentiation of embryonic stem cells into hepatocytes in vitro. Liver Int. 2004;24:237–45.
Duan Y, Catana A, Meng Y, Yamamoto N, He S, Gupta S, et al. Differentiation and enrichment of hepatocyte-like cells from human embryonic stem cells in vitro and in vivo. Stem Cells. 2007;25:3058–68.
Kuai XL, Bian YH, Cong XQ, Li XL, Xiao SD. Differentiation of mouse embryonic stem cells into hepatocytes in vitro and in vivo. J Dig Dis. 2003;4:75–80.
Choi D, Oh HJ, Chang UJ, Koo SK, Jiang JX, Hwang SY, et al. In vivo differentiation of mouse embryonic stem cells into hepatocytes. Cell Transplant. 2002;11:359–68.
Kharaziha P, Hellström PM, Noorinayer B, Farzaneh F, Aghajani K, Jafari F, et al. Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection: a phase I-II clinical trial. Eur J Gastroenterol Hepatol. 2009;21:1199–205.
Sakai Y, Takamura M, Seki A, Sunagozaka H, Terashima T, Komura T, et al. Phase I clinical study of liver regenerative therapy for cirrhosis by intrahepatic arterial infusion of freshly isolated autologous adipose tissue-derived stromal/stem (regenerative) cell. Regen Ther. 2017;6:52–64.
Shi M, Liu Z, Wang Y, Xu R, Sun Y, Zhang M, et al. A pilot study of mesenchymal stem cell therapy for acute liver allograft rejection. Stem Cells Transl Med. 2017;6:2053–61.
El-Ansary M, Abdel-Aziz I, Mogawer S, Abdel-Hamid S, Hammam O, Teaema S, et al. Phase II trial: undifferentiated versus differentiated autologous mesenchymal stem cells transplantation in Egyptian patients with HCV induced liver cirrhosis. Stem Cell Rev. 2012;8:972–81.
Acknowledgements
This work was supported by the National Natural Science Fund of the People’s Republic of China (No. 81771304), the National Natural Science Youth Fund of the People’s Republic of China (No. 81601234 and No. 81601073), and the Health Special Fund of Jilin Province, China (SCZSY201616) and the Science and Technology Innovation Development Fund of Jilin (No. 201750246).
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Wang, J., Sun, M., Liu, W. et al. Stem Cell-Based Therapies for Liver Diseases: An Overview and Update. Tissue Eng Regen Med 16, 107–118 (2019). https://doi.org/10.1007/s13770-019-00178-y
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DOI: https://doi.org/10.1007/s13770-019-00178-y