Lethal and sublethal effects of programmed cell death pathways on hematopoietic stem cells.

Programmed cell death is an evolutionally conserved cellular process in multicellular organisms that eliminates unnecessary or rogue cells during development, infection, and carcinogenesis. Hematopoietic stem cells (HSCs) are a rare, self-renewing and multipotent cell population necessary for establishment and regeneration of the hematopoietic system. Counterintuitively, key components necessary for programmed cell death induction are abundantly expressed in long-lived HSCs, which often survive myeloablative stress by engaging pro-survival response that counteracts cell death-inducing stimuli. While HSCs are well-known for their apoptosis resistance, recent studies have revealed their unique vulnerability to certain types of programmed necrosis, such as necroptosis and ferroptosis. Moreover, emerging evidence has shown that programmed cell death pathways can be sublethally activated to cause non-lethal consequences such as innate immune response, organelle dysfunction, and mutagenesis. In this review, we summarize recent findings on how the divergent cell death programs are molecularly regulated in HSCs. We then discuss potential side effects caused by sublethal activation of programmed cell death pathways on functionality of surviving HSCs.