A Bcl11a-driven mechanism maintaining hematopoietic stem cell functionality gives rise to dysfunction during aging [Cut & Tag]

However, the mechanisms underlying HSC dysfunction and disruption of hematopoiesis during aging remain unclear. Utilizing an inducible mosaic mouse model, we discovered that Bcl11a levels increase in HSCs with age, mitigating functional decline while also promoting myeloid cell and IL-1β production in the bone marrow, thus accelerating HSC attrition non-cell autonomously.

Notably, aging-related inflammation augments the expressions of both Bcl11a and Fc receptors (FcRs) in HSCs. FcR signaling activation induces HSC differentiation, which is counteracted by Bcl11a through repressing FcRγ expression to maintain HSC function. Deletion of FcRγ in Bcl11a-mosaic mice abolishes the non-cell autonomous effect on deteriorating HSCs.