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 language | English |
|---|---|
| Pages (from-to) | 799-811 |
| Number of pages | 13 |
| Journal | Cell Stem Cell |
| Volume | 11 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Dec 7 2012 |
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ASJC Scopus subject areas
- Cell Biology
- Molecular Medicine
- Genetics
Cite this
Attenuation of miR-126 activity expands HSC in vivo without exhaustion. / Lechman, Eric R.; Gentner, Bernhard; Van Galen, Peter; Giustacchini, Alice; Saini, Massimo; Boccalatte, Francesco E.; Hiramatsu, Hidefumi; Restuccia, Umberto; Bachi, Angela; Voisin, Veronique; Bader, Gary D.; Dick, John E.; Naldini, Luigi.
In: Cell Stem Cell, Vol. 11, No. 6, 07.12.2012, p. 799-811.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Attenuation of miR-126 activity expands HSC in vivo without exhaustion
AU - Lechman, Eric R.
AU - Gentner, Bernhard
AU - Van Galen, Peter
AU - Giustacchini, Alice
AU - Saini, Massimo
AU - Boccalatte, Francesco E.
AU - Hiramatsu, Hidefumi
AU - Restuccia, Umberto
AU - Bachi, Angela
AU - Voisin, Veronique
AU - Bader, Gary D.
AU - Dick, John E.
AU - Naldini, Luigi
PY - 2012/12/7
Y1 - 2012/12/7
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84870894496&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2012.09.001
DO - 10.1016/j.stem.2012.09.001
M3 - Article
C2 - 23142521
AN - SCOPUS:84870894496
VL - 11
SP - 799
EP - 811
JO - Cell Stem Cell
JF - Cell Stem Cell
SN - 1934-5909
IS - 6
ER -