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miR-146a regulates hematopoietic stem cell maintenance and cell cycle entry

Woltosz, Joanna Wegrzyn and Knapp, David and Copley, Michael and Ibrahim, Rawa and Umlandt, Patricia and Fuller, Megan and Baltimore, David and Boldin, Mark and Eaves, Connie and Karsan, Aly (2013) miR-146a regulates hematopoietic stem cell maintenance and cell cycle entry. Experimental Hematology, 41 (8). S17. ISSN 0301-472X. https://resolver.caltech.edu/CaltechAUTHORS:20130906-140108923

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Abstract

Maintenance of blood homeostasis depends on the balance between self-renewal of hematopoietic stem cells (HSCs) and their differentiation into blood cell progenitors. A variety of different intrinsic or extrinsic regulators, including multiple microRNA (miRNA) species, have been described to play a role in the regulation of these processes. Disruption of any of these regulators could lead to stem cell exhaustion or increased risk of leukemogenesis. Given recent reports of the role of miR-146a in malignant hematopoiesis, we evaluated its role in hematopoietic stem progenitor cell (HSPC) function. We show that miR-146a is highly expressed in HSCs and its expression decreases in committed progenitors. miR-146a- deficient HSCs had dramatically reduced self-renewal capacity as measured by serial competitive bone marrow transplantation assays. The lower self-renewal capacity was accompanied by decreased quiescence in miR-146a-deficient cells, as revealed by decreased proportion of miR-146a-/- HSPCs (Lin- Sca-1+ c-kit-, LSK) in G0 of the cell cycle (Ki-67- negative), and their increased proliferation, measured by BrdU incorporation. We further showed that increased proliferation of HSPCs is cell intrinsic. By sorting EPCR+ CD48- CD150+ (ESLAM) HSCs and examining cell division kinetics at the single cell level, we found that miR-146a-/- HSC undergo cell division earlier and differentiate more rapidly than wild-type HSCs, thereby producing larger colonies containing more differentiated (Lin+) cells. Our data provide evidence that miR-146a loss attenuates HSC quiescence and impairs their self-renewal ability, leading to hyperproliferation of progenitor cells. The phenotype seen is cell autonomous and the findings suggest that miR-146a plays a critical role in maintaining long term HSC function.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://www.sciencedirect.com/science/article/pii/S0301472X13002841PublisherArticle
ORCID:
AuthorORCID
Baltimore, David0000-0001-8723-8190
Boldin, Mark0000-0003-4593-0669
Additional Information:© 2013 Elsevier
Issue or Number:8
Record Number:CaltechAUTHORS:20130906-140108923
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20130906-140108923
Official Citation:Joanna Wegrzyn Woltosz, David Knapp, Michael Copley, Rawa Ibrahim, Patricia Umlandt, Megan Fuller, David Baltimore, Mark Boldin, Connie Eaves, Aly Karsan, miR-146a regulates hematopoietic stem cell maintenance and cell cycle entry, Experimental Hematology, Volume 41, Issue 8, Supplement, August 2013, Page S17, ISSN 0301-472X, http://dx.doi.org/10.1016/j.exphem.2013.05.064. (http://www.sciencedirect.com/science/article/pii/S0301472X13002841)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:41147
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:06 Sep 2013 21:45
Last Modified:03 Oct 2019 05:46

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