Developing a systems-based understanding of hematopoietic stem cell cycle control

To maintain hematologic homeostasis, hematopoietic stem cells (HSCs) undergo multiple rounds of cell division throughout their lives. Under steady-state conditions, adult HSCs are relatively quiescent and reside primarily in hypoxic bone marrow niches. In response to physiologic stimuli, normal HSCs either reenter the cell division cycle or remain in quiescence. A large body of work has focused on understanding the mechanistic underpinnings balancing differentiation against self-renewal programs in cycling HSCs. Numerous reports from genetically engineered mouse models harboring mutations in key pathways governing proliferation control, DNA damage responses, and metabolic regulation indicate the critical roles these processes play in determining HSC self-renewing versus blood-lineage-reconstituting divisions. In this chapter, we integrate these findings and highlight the cellular networks that control HSC function and fitness by regulating HSC cycling.