Inflammatory exposure drives permanent impairment of hematopoietic stem cell self-renewal activity and accelerated aging.

Hematopoietic stem cells (HSCs) mediate regeneration of the hematopoietic system following injury, as exemplified by the transient activation of HSCs out of dormancy upon exposure to infection or inflammation. Such challenges have been documented to impair HSC function. However, whether this functional impairment extends beyond the duration of inflammatory exposure is unknown. To assess the effects of repeated inflammatory challenge, wild-type C57BL/6J mice were subjected to a dose escalation regimen of polyinosinic:polycytidylic acid (pI:pC) treatment mimicking viral infection. Unexpectedly, we observed an irreversible depletion of functional HSCs and hallmarks of accelerated aging in LT-HSCs. Single cell RNA sequencing of purified LT-HSCs [Lin(-) c-kit(+) sca-1(+) CD150(+) CD48(-) CD34(-)] isolated from the bone marrow of individual C57BL/6J mice treated with PBS or pI:pC (after 5 or 20 weeks recovery period). Single LT-HSC cells were subsequently captured on a small sized IFC using the Fluidigm C1 system.