MicroRNA miR-125a controls hematopoietic stem cell number.
MicroRNAs influence hematopoietic differentiation, but little is known about their effects on the stem cell state. Here, we report that the microRNA processing enzyme Dicer is essential for stem cell persistence in vivo and a specific microRNA, miR-125a, controls the size of the stem cell population by regulating hematopoietic stem/progenitor cell (HSPC) apoptosis. Conditional deletion of Dicer revealed an absolute dependence for the multipotent HSPC population in a cell-autonomous manner, with increased HSPC apoptosis in mutant animals. An evolutionarily conserved microRNA cluster containing miR-99b, let-7e, and miR-125a was preferentially expressed in long-term hematopoietic stem cells. MicroRNA miR-125a alone was capable of increasing the number of hematopoietic stem cells in vivo by more than 8-fold. This result was accomplished through a differentiation stage-specific reduction of apoptosis in immature hematopoietic progenitors, possibly through targeting multiple proapoptotic genes. Bak1 was directly down-regulated by miR-125a and expression of a 3'UTR-less Bak1 blocked miR-125a-induced hematopoietic expansion in vivo. These data demonstrate cell-state-specific regulation by microRNA and identify a unique microRNA functioning to regulate the stem cell pool size.
Guo
Shangqin
S
Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Lu
Jun
J
Schlanger
Rita
R
Zhang
Hao
H
Wang
Judy Y
JY
Fox
Michelle C
MC
Purton
Louise E
LE
Fleming
Heather H
HH
Cobb
Bradley
B
Merkenschlager
Matthias
M
Golub
Todd R
TR
Scadden
David T
DT
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002452:Cell Count; D002454:Cell Differentiation; D053487:DEAD-box RNA Helicases / Q000502:physiology*; D015536:Down-Regulation; D004722:Endoribonucleases / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006706:Homeostasis; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D008969:Molecular Sequence Data; D043244:Ribonuclease III; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics
C494773:Bak1 protein, mouse; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; D050998:bcl-2 Homologous Antagonist-Killer Protein; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases