title: Human umbilical cord mesenchymal stem cells and derived hepatocyte-like cells exhibit similar therapeutic effects on an acute liver failure mouse model.
abstract: Mesenchymal stem cells (MSCs) have exhibited therapeutic effects in multiple animal models so that are promising liver substitute for transplantation treatment of end-stage liver diseases. However, it has been shown that over-manipulation of these cells increased their tumorigenic potential, and that reducing the in vitro culture time could minimize the risk. In this study, we used a D-galactosamine plus lipopolysaccharide (Gal/LPS)-induced acute liver failure mouse model, which caused death of about 50% of the mice with necrosis of more than 50% hepatocytes, to compare the therapeutic effects of human umbilical cord MSCs (hUCMSCs) before and after induction of differentiation into hepatocyte (i-Heps). Induction of hUCMSCs to become i-Heps was achieved by treatment of the cells with a group of growth factors within 4 weeks. The resulted i-Heps exhibited a panel of human hepatocyte biomarkers including cytokeratin (hCK-18), α-fetoprotein (hAFP), albumin (hALB), and hepatocyte-specific functions glycogen storage and urea metabolism. We demonstrated that transplantation of both cell types through tail vein injection rescued almost all of the Gal/LPS-intoxicated mice. Although both cell types exhibited similar ability in homing at the mouse livers, the populations of the hUCMSCs-derived cells, as judged by expressing hAFP, hCK-18 and human hepatocyte growth factor (hHGF), were small. These observations let us to conclude that the hUCMSCs was as effective as the i-Heps in treatment of the mouse acute liver failure, and that the therapeutic effects of hUCMSCs were mediated largely via stimulation of host hepatocyte regeneration, and that delivery of the cells through intravenous injection was effective.
authors.affiliation: Laboratory for Gene and Cell Therapy, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China; Department of Stomatology, Shenzhen Seventh (Yantian District) People's Hospital, Shenzhen, China.
authors.forename: Ruiping
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Laboratory for Gene and Cell Therapy, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
authors.forename: Zhuokun
authors.initials: Z
authors.lastname: Li
authors.affiliation: Laboratory for Gene and Cell Therapy, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
authors.forename: Chengyi
authors.initials: C
authors.lastname: He
authors.affiliation: Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China.
authors.forename: Ronglin
authors.initials: R
authors.lastname: Li
authors.affiliation: Laboratory for Gene and Cell Therapy, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Xia
authors.affiliation: Department of Stomatology, The 5th Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.
authors.forename: Chunyang
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China; Department of Anatomy, The University of Hong Kong, Hong Kong, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Laboratory for Gene and Cell Therapy, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China.
authors.forename: Zhi-Ying
authors.initials: ZY
authors.lastname: Chen
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004195:Disease Models, Animal; D005312:Fetal Blood; D022781:Hepatocytes / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D017114:Liver Failure, Acute / Q000378:metabolism* / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID
references.citation: PLoS One. 2007 Sep 26;2(9):e941
references.pmid: 17895982
references.citation: Leukemia. 2009 May;23(5):925-33
references.pmid: 19148141
references.citation: Cancer Res. 2009 Jul 1;69(13):5331-9
references.pmid: 19509230
references.citation: J Pathol. 2009 Nov;219(3):294-305
references.pmid: 19718709
references.citation: Science. 2004 Nov 26;306(5701):1568-71
references.pmid: 15567866
references.citation: Hepatology. 2008 May;47(5):1634-43
references.pmid: 18395843
references.citation: Cell. 2008 May 16;133(4):704-15
references.pmid: 18485877
references.citation: Gastroenterology. 2008 Mar;134(3):833-48
references.pmid: 18243183
references.citation: Rev Physiol Biochem Pharmacol. 1974;(71):77-106
references.pmid: 4375846
references.citation: Eur J Med Res. 2013 Sep 30;18:34
references.pmid: 24079479
references.citation: Arch Plast Surg. 2012 Nov;39(6):593-9
references.pmid: 23233883
references.citation: Cell Biol Int. 2010 Apr 27;34(6):601-5
references.pmid: 20178458
references.citation: Gastroenterology. 2008 Jun;134(7):2111-21, 2121.e1-3
references.pmid: 18455168
references.citation: BMC Gastroenterol. 2012 Jul 12;12:88
references.pmid: 22788801
references.citation: Cell Transplant. 2013;22(10):1785-99
references.pmid: 23394436
references.citation: Cell Mol Immunol. 2012 May;9(3):208-14
references.pmid: 22327211
references.citation: Cancer Lett. 2009 Aug 18;281(1):32-41
references.pmid: 19342158
references.citation: Hepatology. 2005 Dec;42(6):1364-72
references.pmid: 16317692
references.citation: J Gastroenterol Hepatol. 2009 Jan;24(1):70-7
references.pmid: 18624899
references.citation: Sci China Life Sci. 2010 Sep;53(9):1073-84
references.pmid: 21104367
references.citation: Nature. 2007 Oct 4;449(7162):557-63
references.pmid: 17914389
references.citation: Cell Res. 2008 Apr;18(4):500-7
references.pmid: 18364678
references.citation: Stem Cell Rev Rep. 2012 Dec;8(4):1155-62
references.pmid: 22983818
references.citation: Mol Ther. 2009 Sep;17(9):1504-8
references.pmid: 19584815
references.citation: Lancet. 2010 Jul 17;376(9736):190-201
references.pmid: 20638564
references.citation: Tissue Eng Part A. 2009 Nov;15(11):3377-88
references.pmid: 19397469
references.citation: Liver Transpl. 2008 Oct;14 Suppl 2:S97-101
references.pmid: 18825687