P19^INK4d Controls hematopoietic stem cells in a cell-autonomous manner during genotoxic stress and through the microenvironment during aging

Hematopoietic stem cells (HSCs) are characterized by the capacity for self-renewal and the ability to reconstitute the entire hematopoietic compartment. Thrombopoietin maintains adult HSCs in a quiescent state through the induction of cell cycle inhibitors p57^Kip2 and p19^INK4d. Using the p19^INK4d-/- mouse model, we investigated the role of p19^INK4d in basal and stress-induced hematopoiesis. We demonstrate that p19^INK4d is involved in the regulation of HSC quiescence by inhibition of the G0/G1 cell cycle transition. Under genotoxic stress conditions, the absence of p19^INK4d in HSCs leads to accelerated cell cycle exit, accumulation of DNA double-strand breaks, and apoptosis when cells progress to the S/G2-M stages of the cell cycle. Moreover, p19^INK4d controls the HSC microenvironment through negative regulation of megakaryopoiesis. Deletion of p19^INK4d results in megakaryocyte hyperproliferation and increased transforming growth factor β1 secretion. This leads to fibrosis in the bone marrow and spleen, followed by loss of HSCs during aging.