MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output.
The production of blood cells depends on a rare hematopoietic stem-cell (HSC) population, but the molecular mechanisms underlying HSC biology remain incompletely understood. Here, we identify a subset of microRNAs (miRNAs) that is enriched in HSCs compared with other bone-marrow cells. An in vivo gain-of-function screen found that three of these miRNAs conferred a competitive advantage to engrafting hematopoietic cells, whereas other HSC miRNAs attenuated production of blood cells. Overexpression of the most advantageous miRNA, miR-125b, caused a dose-dependent myeloproliferative disorder that progressed to a lethal myeloid leukemia in mice and also enhanced hematopoietic engraftment in human immune system mice. Our study identifies an evolutionarily conserved subset of miRNAs that is expressed in HSCs and functions to modulate hematopoietic output.
O'Connell
Ryan M
RM
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
Chaudhuri
Aadel A
AA
Rao
Dinesh S
DS
Gibson
William S J
WS
Balazs
Alejandro B
AB
Baltimore
David
D
D000818:Animals; D001854:Bone Marrow Cells; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006085:Graft Survival / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000737:chemistry* / Q000187:drug effects*; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000032:analysis* / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D009196:Myeloproliferative Disorders / Q000139:chemically induced / Q000473:pathology
D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse