Attenuation of miR-126 activity expands HSC in vivo without exhaustion

Eric R. Lechman, Bernhard Gentner, Peter Van Galen, Alice Giustacchini, Massimo Saini, Francesco E. Boccalatte, Hidefumi Hiramatsu, Umberto Restuccia, Angela Bachi, Veronique Voisin, Gary D. Bader, John E. Dick, Luigi Naldini

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)799-811
Number of pages13
JournalCell Stem Cell
Volume11
Issue number6
DOIs
Publication statusPublished - Dec 7 2012

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ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine
  • Genetics

Cite this

Lechman, E. R., Gentner, B., Van Galen, P., Giustacchini, A., Saini, M., Boccalatte, F. E., Hiramatsu, H., Restuccia, U., Bachi, A., Voisin, V., Bader, G. D., Dick, J. E., & Naldini, L. (2012). Attenuation of miR-126 activity expands HSC in vivo without exhaustion. Cell Stem Cell, 11(6), 799-811. https://doi.org/10.1016/j.stem.2012.09.001