title: Identification of multipotent progenitors that emerge prior to hematopoietic stem cells in embryonic development.
abstract: Hematopoiesis in the embryo proceeds in a series of waves, with primitive erythroid-biased waves succeeded by definitive waves, within which the properties of hematopoietic stem cells (multilineage potential, self-renewal, and engraftability) gradually arise. Whereas self-renewal and engraftability have previously been examined in the embryo, multipotency has not been thoroughly addressed, especially at the single-cell level or within well-defined populations. To identify when and where clonal multilineage potential arises during embryogenesis, we developed a single-cell multipotency assay. We find that, during the initiation of definitive hematopoiesis in the embryo, a defined population of multipotent, engraftable progenitors emerges that is much more abundant within the yolk sac (YS) than the aorta-gonad-mesonephros (AGM) or fetal liver. These experiments indicate that multipotent cells appear in concert within both the YS and AGM and strongly implicate YS-derived progenitors as contributors to definitive hematopoiesis.
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine (ISCBRM), Stanford University, Stanford, CA 94305, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Inlay
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Serwold
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine (ISCBRM), Stanford University, Stanford, CA 94305, USA.
authors.forename: Adriane
authors.initials: A
authors.lastname: Mosley
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine (ISCBRM), Stanford University, Stanford, CA 94305, USA ; Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Fathman
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine (ISCBRM), Stanford University, Stanford, CA 94305, USA.
authors.forename: Ivan K
authors.initials: IK
authors.lastname: Dimov
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine (ISCBRM), Stanford University, Stanford, CA 94305, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Seita
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine (ISCBRM), Stanford University, Stanford, CA 94305, USA ; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D040881:CD11a Antigen / Q000235:genetics; D002454:Cell Differentiation; D019070:Cell Lineage; D003114:Colony-Forming Units Assay; D047108:Embryonic Development / Q000235:genetics; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D016130:Immunophenotyping; D051917:Leukosialin / Q000235:genetics / Q000378:metabolism; D051379:Mice; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D010641:Phenotype; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D015017:Yolk Sac / Q000196:embryology
chemical_list: D000954:Antigens, Surface; D040881:CD11a Antigen; D051917:Leukosialin; D019009:Proto-Oncogene Proteins c-kit
references.citation: Blood. 2008 Jun 15;111(12):5562-70
references.pmid: 18424665
references.citation: Nature. 1993 Jul 1;364(6432):67-70
references.pmid: 8316299
references.citation: Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):773-7
references.pmid: 7846049
references.citation: Dev Cell. 2005 Mar;8(3):365-75
references.pmid: 15737932
references.citation: Annu Rev Immunol. 2007;25:745-85
references.pmid: 17201678
references.citation: EMBO J. 2000 Jun 1;19(11):2465-74
references.pmid: 10835345
references.citation: Immunity. 2002 Dec;17(6):749-56
references.pmid: 12479821
references.citation: Curr Protoc Cell Biol. 2007 Sep;Chapter 23:Unit 23.6
references.pmid: 18228507
references.citation: Br J Haematol. 1970 Mar;18(3):279-96
references.pmid: 5491581
references.citation: Genes Dev. 2009 Oct 15;23(20):2376-81
references.pmid: 19833765
references.citation: Cell Stem Cell. 2008 Mar 6;2(3):252-63
references.pmid: 18371450
references.citation: Curr Opin Cell Biol. 2010 Oct;22(5):651-8
references.pmid: 20708398
references.citation: Nat Rev Immunol. 2011 Jun;11(6):416-26
references.pmid: 21597477
references.citation: Immunity. 1997 Sep;7(3):335-44
references.pmid: 9324354
references.citation: Trends Genet. 1995 Sep;11(9):359-66
references.pmid: 7482788
references.citation: Nature. 2007 Apr 26;446(7139):1056-61
references.pmid: 17377529
references.citation: Cell Stem Cell. 2008 Dec 4;3(6):625-36
references.pmid: 19041779
references.citation: Nature. 2000 Mar 9;404(6774):193-7
references.pmid: 10724173
references.citation: Dev Biol. 2001 Feb 15;230(2):230-42
references.pmid: 11161575
references.citation: Immunity. 1994 Jul;1(4):291-301
references.pmid: 7889417
references.citation: Development. 2003 Nov;130(22):5437-44
references.pmid: 14507780
references.citation: Blood. 2008 Apr 1;111(7):3435-8
references.pmid: 17932251
references.citation: Blood. 2013 Oct 3;122(14):2338-45
references.pmid: 23863896
references.citation: Genesis. 2007 Sep;45(9):593-605
references.pmid: 17868096
references.citation: Science. 1991 Mar 29;251(5001):1611-3
references.pmid: 1672776
references.citation: Cell. 1996 Sep 20;86(6):907-16
references.pmid: 8808626
references.citation: Development. 1999 Nov;126(22):5073-84
references.pmid: 10529424
references.citation: Blood. 1997 Mar 15;89(6):2176-83
references.pmid: 9058742
references.citation: Blood. 2006 Mar 15;107(6):2317-21
references.pmid: 16304059
references.citation: Nature. 2010 Mar 4;464(7285):116-20
references.pmid: 20154729
references.citation: Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6776-80
references.pmid: 9192641
references.citation: J Exp Med. 2011 Jun 6;208(6):1305-15
references.pmid: 21624936
references.citation: Dev Dyn. 2006 Dec;235(12):3413-22
references.pmid: 17072878
references.citation: Immunity. 2001 Sep;15(3):477-85
references.pmid: 11567637
references.citation: Cold Spring Harb Symp Quant Biol. 1977;41 Pt 1:9-21
references.pmid: 302194
references.citation: Blood. 2010 Jul 29;116(4):544-53
references.pmid: 20442369
references.citation: Proc Natl Acad Sci U S A. 1995 Oct 24;92(22):10302-6
references.pmid: 7479772
references.citation: Development. 2002 Nov;129(21):4891-9
references.pmid: 12397098
references.citation: Cell. 1996 Sep 20;86(6):897-906
references.pmid: 8808625
references.citation: Dev Cell. 2005 Mar;8(3):377-87
references.pmid: 15737933
references.citation: Nature. 1993 Jul 1;364(6432):64-7
references.pmid: 8316298
references.citation: Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10110-4
references.pmid: 8234265
references.citation: Proc Natl Acad Sci U S A. 2012 Mar 20;109(12):4515-20
references.pmid: 22392989
references.citation: Exp Hematol. 1994 Sep;22(10):979-84
references.pmid: 7522185
references.citation: Cell Stem Cell. 2008 Jul 3;3(1):99-108
references.pmid: 18593562
references.citation: Immunity. 1998 Jun;8(6):761-9
references.pmid: 9655490