Attenuation of miR-126 Activity Expands HSC In Vivo without Exhaustion
Open accessAbstract
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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Post-transcriptional regulation by miRNAs is important in controlling stem cell quiescence, as shown in HSCs and MuSCs.
“This mode of post-transcriptional regulation has emerged as an important aspect in the control of stem cell quiescence, as recently demonstrated in HSCs88 and MuSCs51.”
From Molecular regulation of stem cell quiescence (2013) · cites this paper as [88]
Reducing miR-126 activity allows HSC proliferation without inducing exhaustion.
“reducing miR-126 activity allows HSC proliferation without inducing exhaustion88.”
From Molecular regulation of stem cell quiescence (2013) · cites this paper as [88]
In HSCs, miR-126 controls quiescence by attenuating multiple components of PI3K-AKT signalling.
“In HSCs, miR-126 controls stem cell quiescence by attenuating multiple components in the PI3K–AKT signalling pathway88.”
From Molecular regulation of stem cell quiescence (2013) · cites this paper as [88]
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Molecular regulation of stem cell quiescence
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“miRNA profiling of hematopoietic stem and progenitor cells (HSPCs) has identified several miRNAs as differentially expressed and functionally able to govern HSC properties (Gerrits et al., 2012; Lechman et al., 2012; O’Connell et al., 2008, 2010).”
- Authors
- 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.
- Affiliations
- University Health Network (CA)
- Vita-Salute San Raffaele University (IT)
- Kyoto University (JP)
- IRCCS Ospedale San Raffaele (IT)
- University of Toronto (CA)
- Corresponding author
- Dick, John E.
- Naldini, Luigi
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 11
- Issue
- 6
- Pages
- 799-811
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC3517970
- OpenAlex
- W2052209192
- Cited by
- 208
- References
- 34
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 8 · 2023: 12 · 2022: 13 · 2021: 16 · 2020: 12 · 2019: 18 · 2018: 11 · 2017: 22 · 2016: 29 · 2015: 24 · 2014: 20 · 2013: 11 · 2012: 1
- FWCI
- 11.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- National Cancer Institute (R01CA121941)
- National Institute of General Medical Sciences (P41GM103504)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- miR-126, hematopoietic stem cells, HSC quiescence, HSC expansion, HSC exhaustion, cell cycle progression, PI3K/Akt/GSK-3β signaling, microRNA regulation, long-term repopulating cells, hepatic stellate cell activation
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Cell Line, Hematopoiesis, Hematopoietic Stem Cells, Humans, Transplantation, Heterologous, Signal Transduction, Phosphatidylinositol 3-Kinases, MicroRNAs, Glycogen Synthase Kinase 3, Cell Proliferation, Proto-Oncogene Proteins c-akt, Mice, Gene Knockdown Techniques
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