title: Differentiation and transplantation of human induced pluripotent stem cell-derived hepatocyte-like cells.
abstract: The generation of human induced pluripotent stem cells (hiPSCs) with a high differentiation potential provided a new source for hepatocyte generation not only for drug discovery and in vitro disease models, but also for cell replacement therapy. However, the reported hiPSC-derived hepatocyte-like cells (HLCs) were not well characterized and their transplantation, as the most promising clue of cell function was not reported. Here, we performed a growth factor-mediated differentiation of functional HLCs from hiPSCs and evaluated their potential for recovery of a carbon tetrachloride (CCl4)-injured mouse liver following transplantation. The hiPSC-derived hepatic lineage cells expressed hepatocyte-specific markers, showed glycogen and lipid storage activity, secretion of albumin (ALB), alpha-fetoprotein (AFP), urea, and CYP450 metabolic activity in addition to low-density lipoprotein (LDL) and indocyanin green (ICG) uptake. Similar results were observed with human embryonic stem cell (hESC)-derived HLCs. The transplantation of hiPSC-HLCs into a CCl4-injured liver showed incorporation of the hiPSC-HLCs into the mouse liver which resulted in a significant enhancement in total serum ALB after 1 week. A reduction of total serum LDH and bilirubin was seen when compared with the control and sham groups 1 and 5 weeks post-transplantation. Additionally, we detected human serum ALB and ALB-positive transplanted cells in both the host serum and livers, respectively, which showed functional integration of transplanted cells within the mouse livers. Therefore, our results have opened up a proof of concept that functional HLCs can be generated from hiPSCs, thus improving the general condition of a CCl4-injured mouse liver after their transplantation. These results may bring new insights in the clinical applications of hiPSCs once safety issues are overcome.
authors.affiliation: Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, PO Box 19395-4644, Tehran, Iran.
authors.forename: Samira
authors.initials: S
authors.lastname: Asgari
authors.forename: Mohsen
authors.initials: M
authors.lastname: Moslem
authors.forename: Kamran
authors.initials: K
authors.lastname: Bagheri-Lankarani
authors.forename: Behshad
authors.initials: B
authors.lastname: Pournasr
authors.forename: Maryam
authors.initials: M
authors.lastname: Miryounesi
authors.forename: Hossein
authors.initials: H
authors.lastname: Baharvand
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D002454:Cell Differentiation; D002460:Cell Line; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology* / Q000637:transplantation*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D008107:Liver Diseases / Q000097:blood / Q000473:pathology; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D002251:Carbon Tetrachloride
references.citation: Hepatology. 2010 May;51(5):1810-9
references.pmid: 20432258
references.citation: Hepatology. 2004 Dec;40(6):1304-11
references.pmid: 15565662
references.citation: Biochem Biophys Res Commun. 2008 Mar 14;367(3):546-52
references.pmid: 18182158
references.citation: J Hepatol. 2006;44(1 Suppl):S140-5
references.pmid: 16352366
references.citation: Stem Cell Rev Rep. 2010 Dec;6(4):622-32
references.pmid: 20821352
references.citation: Hepatology. 2010 May;51(5):1754-65
references.pmid: 20301097
references.citation: Stem Cell Rev Rep. 2011 Mar;7(1):103-18
references.pmid: 20182823
references.citation: Differentiation. 2008 Feb;76(2):107-17
references.pmid: 17573915
references.citation: Hepatology. 2010 Jan;51(1):329-35
references.pmid: 19877180
references.citation: Stem Cells. 2008 May;26(5):1117-27
references.pmid: 18292207
references.citation: Cell Transplant. 2001;10(3):329-42
references.pmid: 11437078
references.citation: Cell. 2007 Nov 30;131(5):861-72
references.pmid: 18035408
references.citation: Gastroenterology. 2009 Mar;136(3):990-9
references.pmid: 19026649
references.citation: Int J Dev Biol. 2010;54(5):877-86
references.pmid: 19876814
references.citation: Science. 2007 Dec 21;318(5858):1917-20
references.pmid: 18029452
references.citation: Hepatology. 2010 Jan;51(1):297-305
references.pmid: 19998274
references.citation: Dev Growth Differ. 2006 Feb;48(2):117-28
references.pmid: 16512855
references.citation: Stem Cell Rev Rep. 2010 Jun;6(2):270-81
references.pmid: 20376579
references.citation: Exp Clin Transplant. 2005 Jun;3(1):306-15
references.pmid: 15989675
references.citation: Cell Res. 2009 Nov;19(11):1233-42
references.pmid: 19736565
references.citation: J Clin Invest. 2010 Sep;120(9):3127-36
references.pmid: 20739751
references.citation: Stem Cell Rev Rep. 2010 Mar;6(1):96-107
references.pmid: 20012714
references.citation: J Biochem. 2003 Oct;134(4):551-8
references.pmid: 14607982
references.citation: J Hepatol. 2010 Oct;53(4):738-51
references.pmid: 20621379
references.citation: Aliment Pharmacol Ther. 2008 May;27(10):932-9
references.pmid: 18315586
references.citation: Nat Biotechnol. 2008 Mar;26(3):313-5
references.pmid: 18278034
references.citation: Ann Hepatol. 2004 Apr-Jun;3(2):48-53
references.pmid: 15257246
references.citation: J Clin Invest. 2010 Sep;120(9):3120-6
references.pmid: 20739754