title: Attenuation of miR-126 activity expands HSC in vivo without exhaustion.
abstract: Lifelong blood cell production is governed through the poorly understood integration of cell-intrinsic and -extrinsic control of hematopoietic stem cell (HSC) quiescence and activation. MicroRNAs (miRNAs) coordinately regulate multiple targets within signaling networks, making them attractive candidate HSC regulators. We report that miR-126, a miRNA expressed in HSC and early progenitors, plays a pivotal role in restraining cell-cycle progression of HSC in vitro and in vivo. miR-126 knockdown by using lentiviral sponges increased HSC proliferation without inducing exhaustion, resulting in expansion of mouse and human long-term repopulating HSC. Conversely, enforced miR-126 expression impaired cell-cycle entry, leading to progressively reduced hematopoietic contribution. In HSC/early progenitors, miR-126 regulates multiple targets within the PI3K/AKT/GSK3β pathway, attenuating signal transduction in response to extrinsic signals. These data establish that miR-126 sets a threshold for HSC activation and thus governs HSC pool size, demonstrating the importance of miRNA in the control of HSC function.
authors.affiliation: Campbell Family Institute, Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Lechman
authors.forename: Bernhard
authors.initials: B
authors.lastname: Gentner
authors.forename: Peter
authors.initials: P
authors.lastname: van Galen
authors.forename: Alice
authors.initials: A
authors.lastname: Giustacchini
authors.forename: Massimo
authors.initials: M
authors.lastname: Saini
authors.forename: Francesco E
authors.initials: FE
authors.lastname: Boccalatte
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Hiramatsu
authors.forename: Umberto
authors.initials: U
authors.lastname: Restuccia
authors.forename: Angela
authors.initials: A
authors.lastname: Bachi
authors.forename: Veronique
authors.initials: V
authors.lastname: Voisin
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bader
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014183:Transplantation, Heterologous
chemical_list: C527111:MIRN126 microRNA, human; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3