title: Brief report: Parthenogenetic embryonic stem cells are an effective cell source for therapeutic liver repopulation.
abstract: Parthenogenesis is the development of an oocyte without fertilization. Mammalian parthenogenetic (PG) embryos are not viable, but can develop into blastocysts from which embryonic stem cells (ESCs) have been derived in mouse and human. PG ESCs are frequently homozygous for alleles encoding major histocompatibility complex (MHC) molecules. MHC homozygosity permits much more efficient immune matching than MHC heterozygosity found in conventional ESCs, making PG ESCs a promising cell source for cell therapies requiring no or little immune suppression. However, findings of restricted differentiation and proliferation of PG cells in developmental chimeras have cast doubt on the potential of PG ESC derivatives for organ regeneration. To address this uncertainty, we determined whether PG ESC derivatives are effective in rescuing mice with lethal liver failure due to deficiency of fumarylacetoacetate hydrolase (Fah). In developmental chimeras generated by injecting wild-type PG ESCs into Fah-deficient blastocysts, PG ESCs differentiated into hepatocytes that could repopulate the liver, provide normal liver function, and facilitate long-term survival of adult mice. Moreover, after transplantation into adult Fah-deficient mice, PG ESC-derived hepatocytes efficiently engrafted and proliferated, leading to high-level liver repopulation. Our results show that--despite the absence of a paternal genome--PG ESCs can form therapeutically effective hepatocytes.
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, California, USA; Department of Surgery, Division of Transplantation, University of California San Francisco, San Francisco, California, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Espejel
authors.forename: Sigrid
authors.initials: S
authors.lastname: Eckardt
authors.forename: Jack
authors.initials: J
authors.lastname: Harbell
authors.forename: Garrett R
authors.initials: GR
authors.lastname: Roll
authors.forename: K John
authors.initials: KJ
authors.lastname: McLaughlin
authors.forename: Holger
authors.initials: H
authors.lastname: Willenbring
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000502:physiology / Q000637:transplantation*; D022781:Hepatocytes / Q000502:physiology; D006801:Humans; D008099:Liver / Q000473:pathology / Q000503:physiopathology; D017093:Liver Failure / Q000628:therapy*; D008115:Liver Regeneration; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010312:Parthenogenesis; D020176:Tyrosinemias / Q000628:therapy*
keywords: Embryonic stem cells; Liver cell therapy; Liver regeneration; Liver repopulation; Parthenogenesis; Pluripotent stem cells
references.citation: Hum Mol Genet. 2009 Jun 15;18(12):2177-87
references.pmid: 19324901
references.citation: Genes Dev. 1993 Dec;7(12A):2298-307
references.pmid: 8253378
references.citation: J Clin Invest. 2011 Dec;121(12):4850-60
references.pmid: 22105172
references.citation: Science. 1983 Dec 2;222(4627):1034-6
references.pmid: 6648518
references.citation: Nat Biotechnol. 2007 Sep;25(9):1045-50
references.pmid: 17704765
references.citation: Gastroenterology. 2008 Mar;134(3):878-81
references.pmid: 18325397
references.citation: Cloning Stem Cells. 2008 Mar;10(1):11-24
references.pmid: 18092905
references.citation: Development. 1994 Jun;120(6):1473-82
references.pmid: 8050357
references.citation: Proc Natl Acad Sci U S A. 1981 Sep;78(9):5425-9
references.pmid: 6946481
references.citation: J Clin Invest. 2010 Sep;120(9):3120-6
references.pmid: 20739754
references.citation: Development. 1989 May;106(1):29-35
references.pmid: 2627886
references.citation: Histochem Cell Biol. 2006 Mar;125(3):247-57
references.pmid: 16195892
references.citation: Trends Genet. 2011 Mar;27(3):81-8
references.pmid: 21334090
references.citation: Stem Cells. 2005 Aug;23(7):914-22
references.pmid: 15941857
references.citation: J Biol Chem. 1991 Nov 25;266(33):22444-50
references.pmid: 1718994
references.citation: Nature. 1984 Apr 5-11;308(5959):548-50
references.pmid: 6709062
references.citation: Nat Med. 2004 Jul;10(7):744-8
references.pmid: 15195088
references.citation: Science. 2007 Jan 26;315(5811):482-6
references.pmid: 17170255
references.citation: Nat Biotechnol. 2007 Aug;25(8):903-10
references.pmid: 17664939
references.citation: Genes Dev. 2007 Feb 15;21(4):409-19
references.pmid: 17322401
references.citation: Nat Genet. 1996 Mar;12(3):266-73
references.pmid: 8589717
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13344-9
references.pmid: 14581617
references.citation: PLoS Genet. 2010 Jan;6(1):e1000803
references.pmid: 20062522
references.citation: Nat Genet. 1995 Aug;10(4):453-60
references.pmid: 7545495
references.citation: Cell. 1984 May;37(1):179-83
references.pmid: 6722870
references.citation: Dev Genes Evol. 1997 Jan;206(6):377-388
references.pmid: 27747399
references.citation: Biol Lett. 2012 Dec 23;8(6):983-5
references.pmid: 22977071
references.citation: J Clin Invest. 2013 Mar;123(3):1285-98
references.pmid: 23434590
references.citation: J Hepatol. 2003 Feb;38(2):156-63
references.pmid: 12547403
references.citation: Rouxs Arch Dev Biol. 1995 Aug;204(7-8):436-443
references.pmid: 28305863
references.citation: Cloning Stem Cells. 2007 Fall;9(3):432-49
references.pmid: 17594198
references.citation: Development. 1990 Jan;108(1):203-11
references.pmid: 2351065