title: The orphan nuclear receptor NR4A1 specifies a distinct subpopulation of quiescent myeloid-biased long-term HSCs.
abstract: Hematopoiesis is maintained throughout life by self-renewing hematopoietic stem cells (HSCs) that differentiate to produce both myeloid and lymphoid cells. The NR4A family of orphan nuclear receptors, which regulates cell fate in many tissues, appears to play a key role in HSC proliferation and differentiation. Using a NR4A1(GFP) BAC transgenic reporter mouse we have investigated NR4A1 expression and its regulation in early hematopoiesis. We show that NR4A1 is most highly expressed in a subset of Lin(-) Sca-1(+) c-Kit(+) CD48(-) CD150(+) long-term (LT) HSCs, and its expression is tightly associated with HSC quiescence. We also show that NR4A1 expression in HSCs is induced by PGE2, a known enhancer of stem cell engraftment potential. Finally, we find that both NR4A1(GFP+) and NR4A1(GFP-) HSCs successfully engraft primary and secondary irradiated hosts; however, NR4A1(GFP+) HSCs are distinctly myeloid-biased. These results show that NR4A1 expression identifies a highly quiescent and distinct population of myeloid-biased LT-HSCs.
authors.affiliation: Department of Microbiology and Immunology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA.
authors.forename: Ruben H
authors.initials: RH
authors.lastname: Land
authors.forename: Anna K
authors.initials: AK
authors.lastname: Rayne
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Vanderbeck
authors.forename: Trevor S
authors.initials: TS
authors.lastname: Barlowe
authors.forename: Shwetha
authors.initials: S
authors.lastname: Manjunath
authors.forename: Matthew
authors.initials: M
authors.lastname: Gross
authors.forename: Sophie
authors.initials: S
authors.lastname: Eiger
authors.forename: Peter S
authors.initials: PS
authors.lastname: Klein
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Cunningham
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Emerson
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Punt
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism*
chemical_list: C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1
keywords: Hematopoiesis; Hematopoietic stem cell; Myeloid bias; NR4A1 (Nur77); PGE2; Quiescence