Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons

EM Pietras, R Lakshminarasimhan… - Journal of Experimental …, 2014 - rupress.org
EM Pietras, R Lakshminarasimhan, JM Techner, S Fong, J Flach, M Binnewies, E Passegué
Journal of Experimental Medicine, 2014rupress.org
Type I interferons (IFN-1s) are antiviral cytokines that suppress blood production while
paradoxically inducing hematopoietic stem cell (HSC) proliferation. Here, we clarify the
relationship between the proliferative and suppressive effects of IFN-1s on HSC function
during acute and chronic IFN-1 exposure. We show that IFN-1–driven HSC proliferation is a
transient event resulting from a brief relaxation of quiescence-enforcing mechanisms in
response to acute IFN-1 exposure, which occurs exclusively in vivo. We find that this …
Type I interferons (IFN-1s) are antiviral cytokines that suppress blood production while paradoxically inducing hematopoietic stem cell (HSC) proliferation. Here, we clarify the relationship between the proliferative and suppressive effects of IFN-1s on HSC function during acute and chronic IFN-1 exposure. We show that IFN-1–driven HSC proliferation is a transient event resulting from a brief relaxation of quiescence-enforcing mechanisms in response to acute IFN-1 exposure, which occurs exclusively in vivo. We find that this proliferative burst fails to exhaust the HSC pool, which rapidly returns to quiescence in response to chronic IFN-1 exposure. Moreover, we demonstrate that IFN-1–exposed HSCs with reestablished quiescence are largely protected from the killing effects of IFNs unless forced back into the cell cycle due to culture, transplantation, or myeloablative treatment, at which point they activate a p53-dependent proapoptotic gene program. Collectively, our results demonstrate that quiescence acts as a safeguard mechanism to ensure survival of the HSC pool during chronic IFN-1 exposure. We show that IFN-1s can poise HSCs for apoptosis but induce direct cell killing only upon active proliferation, thereby establishing a mechanism for the suppressive effects of IFN-1s on HSC function.
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