Abstract
During inflammation and infection, hematopoietic stem and progenitor cells are stimulated to proliferate and differentiate into mature immune cells, especially of the myeloid lineage. MicroRNA-146a (miR-146a) is a critical negative regulator of inflammation. Deletion of miR-146a produces effects that appear as dysregulated inflammatory hematopoiesis, leading to a decline in the number and quality of hematopoietic stem cells (HSCs), excessive myeloproliferation, and, ultimately, to HSC exhaustion and hematopoietic neoplasms. At the cellular level, the defects are attributable to both an intrinsic problem in the miR-146a-deficient HSCs and extrinsic effects of lymphocytes and nonhematopoietic cells. At the molecular level, this involves a molecular axis consisting of miR-146a, signaling protein TRAF6, transcriptional factor NF-κB, and cytokine IL-6. This study has identified miR-146a to be a critical regulator of HSC homeostasis during chronic inflammation in mice and provided a molecular connection between chronic inflammation and the development of bone marrow failure and myeloproliferative neoplasms. DOI:http://dx.doi.org/10.7554/eLife.00537.001.
Highlights
Hematopoietic stem cells (HSCs) have the ability to self-renew and replenish the entire hematopoietic repertoire during the lifetime of an organism
We purified by FACS various types of hematopoietic stem and progenitor cell (HSPC) populations from young wild-type (WT) mice
This expression pattern suggests that miR-146a and miR-146b could be functional in cells as primitive as the long-term HSCs and throughout hematopoietic development
Summary
Hematopoietic stem cells (HSCs) have the ability to self-renew and replenish the entire hematopoietic repertoire during the lifetime of an organism. Balanced self-renewal vs differentiation of HSCs is intricately regulated to ensure the long-term maintenance of HSCs and the hematopoietic system (Seita and Weissman, 2010). Under stressed conditions, such as inflammation and infection, the balance is shifted in favor of hematopoietic stem and progenitor cell (HSPC) proliferation and differentiation to produce more mature immune cells (King and Goodell, 2011). Numerous recent studies have shown that TLR activation or interferon stimulation leads to proliferation, skewed myeloid differentiation and impaired engraftment, and self-renewal of HSCs (Essers et al, 2009; Baldridge et al, 2010; Esplin et al, 2011). Mice engrafted with p50 or c-Rel knockout HSCs or RelA knockout fetal HSCs develop
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