title: Diverse and heritable lineage imprinting of early haematopoietic progenitors.
abstract: Haematopoietic stem cells (HSCs) and their subsequent progenitors produce blood cells, but the precise nature and kinetics of this production is a contentious issue. In one model, lymphoid and myeloid production branch after the lymphoid-primed multipotent progenitor (LMPP), with both branches subsequently producing dendritic cells. However, this model is based mainly on in vitro clonal assays and population-based tracking in vivo, which could miss in vivo single-cell complexity. Here we avoid these issues by using a new quantitative version of 'cellular barcoding' to trace the in vivo fate of hundreds of LMPPs and HSCs at the single-cell level. These data demonstrate that LMPPs are highly heterogeneous in the cell types that they produce, separating into combinations of lymphoid-, myeloid- and dendritic-cell-biased producers. Conversely, although we observe a known lineage bias of some HSCs, most cellular output is derived from a small number of HSCs that each generates all cell types. Crucially, in vivo analysis of the output of sibling cells derived from single LMPPs shows that they often share a similar fate, suggesting that the fate of these progenitors was imprinted. Furthermore, as this imprinting is also observed for dendritic-cell-biased LMPPs, dendritic cells may be considered a distinct lineage on the basis of separate ancestry. These data suggest a 'graded commitment' model of haematopoiesis, in which heritable and diverse lineage imprinting occurs earlier than previously thought.
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands. naik.s@wehi.edu.au
authors.forename: Shalin H
authors.initials: SH
authors.lastname: Naik
authors.forename: Leïla
authors.initials: L
authors.lastname: Perié
authors.forename: Erwin
authors.initials: E
authors.lastname: Swart
authors.forename: Carmen
authors.initials: C
authors.lastname: Gerlach
authors.forename: Nienke
authors.initials: N
authors.lastname: van Rooij
authors.forename: Rob J
authors.initials: RJ
authors.lastname: de Boer
authors.forename: Ton N
authors.initials: TN
authors.lastname: Schumacher
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage; D058893:DNA Barcoding, Taxonomic; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism; D018392:Genomic Imprinting; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D059010:Single-Cell Analysis
references.citation: Blood. 2010 Apr 1;115(13):2610-8
references.pmid: 20093403
references.citation: Cell. 2005 Apr 22;121(2):295-306
references.pmid: 15851035
references.citation: Genes Dev. 1997 Mar 15;11(6):774-85
references.pmid: 9087431
references.citation: Cell. 2005 Jul 1;121(7):1109-21
references.pmid: 15989959
references.citation: Nat Biotechnol. 2011 Oct 02;29(10):928-33
references.pmid: 21964413
references.citation: J Exp Med. 2008 Sep 29;205(10):2309-18
references.pmid: 18809713
references.citation: Immunity. 2002 Aug;17(2):117-30
references.pmid: 12196284
references.citation: Nat Rev Immunol. 2010 Sep;10(9):621-31
references.pmid: 20689559
references.citation: Cell Stem Cell. 2010 Mar 5;6(3):265-78
references.pmid: 20207229
references.citation: Genome Biol. 2008 Jan 24;9(1):R17
references.pmid: 18218067
references.citation: Mol Ther. 2008 Apr;16(4):741-8
references.pmid: 18334989
references.citation: Science. 2009 Sep 4;325(5945):1265-9
references.pmid: 19729659
references.citation: Curr Top Microbiol Immunol. 1992;177:59-71
references.pmid: 1353434
references.citation: Cell Stem Cell. 2007 Oct 11;1(4):416-27
references.pmid: 18371378
references.citation: Dev Cell. 2002 Jul;3(1):137-47
references.pmid: 12110174
references.citation: Cell Cycle. 2006 Feb;5(4):394-8
references.pmid: 16479167
references.citation: Cell Stem Cell. 2007 Aug 16;1(2):218-29
references.pmid: 18371352
references.citation: Science. 1996 Jul 12;273(5272):242-5
references.pmid: 8662508
references.citation: Ann N Y Acad Sci. 2005 Jun;1044:125-31
references.pmid: 15958705
references.citation: Immunol Cell Biol. 2008 Jul;86(5):439-52
references.pmid: 18414430
references.citation: Immunity. 2007 Apr;26(4):407-19
references.pmid: 17433729
references.citation: Nat Rev Immunol. 2008 Feb;8(2):95-106
references.pmid: 18204470
references.citation: Nat Immunol. 2007 Nov;8(11):1217-26
references.pmid: 17922015
references.citation: Methods Enzymol. 2006;411:134-93
references.pmid: 16939790
references.citation: Blood. 2006 Mar 15;107(6):2311-6
references.pmid: 16291588
references.citation: Nat Rev Immunol. 2007 Jan;7(1):19-30
references.pmid: 17170756
references.citation: Nat Rev Immunol. 2009 Apr;9(4):293-300
references.pmid: 19282853
references.citation: Cell. 2006 Jul 28;126(2):415-26
references.pmid: 16873070