MicroRNA-146a acts as a guardian of the quality and longevity of hematopoietic stem cells in mice

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
eLife digest Hematopoietic stem cells are cells that both renew themselves and develop into any type of blood cell, including red blood cells and the several classes of immune cells. When an injury or infection occurs, it is vital that hematopoietic stem cells replenish themselves in addition to developing into the new blood cells that are needed to help the body recover. Injury and infection also lead to the inflammatory response: tissue becomes inflamed as cytokines and other molecules are released at the site of the damage to help maintain the body’s immunity. It is thought that inflammatory molecules directly affect the rate at which stem cells become immune cells, with the protein NF-κB having an important role, but the details of this process are not fully understood. To explore the connections between hematopoietic stem cells and the inflammatory response, Zhao et al. bred mice that do not produce a type of RNA called microRNA-146a. In wild-type mice, this RNA would inhibit the production of NF-κB, so the mutant mice have abnormally high levels of NF-κB. They found that the rate at which stem cells were being converted into immune cells in the mutant mice was so high that the stores of stems cells became exhausted, which was very detrimental to the health of the mice. They also went on to identify the signaling pathways that microRNA-146a influences in order to maintain supplies of stem cells and an adequate inflammatory response in healthy mice. Zhao et al. also studied individuals with human myelodysplastic syndrome, a severe blood disorder that is associated with faulty hematopoietic stem cells, and found that these individuals produce relatively little microRNA-146a. The establishment of a link between microRNA-146a and having an adequate level of hematopoietic stem cells could have implications for human health, given the importance of these cells in both the aging process and the immune response. DOI: http://dx.doi.org/10.7554/eLife.00537.002