The MicroRNA-132 and MicroRNA-212 Cluster Regulates Hematopoietic Stem Cell Maintenance and Survival with Age by Buffering FOXO3 Expression

MicroRNAs are critical post-transcriptional regulators of hematopoietic cell-fate decisions, though little remains known about their role in aging hematopoietic stem cells (HSCs). We found that the microRNA-212/132 cluster (Mirc19) is enriched in HSCs and is upregulated during aging. Both overexpression and deletion of microRNAs in this cluster leads to inappropriate hematopoiesis with age. Enforced expression of miR-132 in the bone marrow of mice led to rapid HSC cycling and depletion. A genetic deletion of Mirc19 in mice resulted in HSCs that had altered cycling, function, and survival in response to growth factor starvation. We found that miR-132 exerted its effect on aging HSCs by targeting the transcription factor FOXO3, a known aging associated gene. Our data demonstrate that Mirc19 plays a role in maintaining balanced hematopoietic output by buffering FOXO3 expression. We have thus identified it as a potential target that might play a role in age-related hematopoietic defects. •The miR-212/132 cluster (Mirc19) is enriched in HSCs and upregulated with age•Mirc19 regulates HSC cycling, function, and survival through autophagy•Enforced expression or deletion of Mirc19 leads to inappropriate hematopoiesis•miR-132 directly targets FOXO3 and buffers its expression in aging HSCs Aging hematopoietic stem cells (HSCs) must maintain normal hematopoietic output despite years of replication stress. Baltimore and colleagues show that microRNA-132 helps maintain the balance of HSC survival and normal immune cell production by buffering the transcription factor FOXO3, a known regulator of HSC cycling, function, and survival.