IRF7 Suppresses Hematopoietic Regeneration under Stress via CXCR4.

Hematopoietic stem cells (HSCs) maintain quiescence under steady state, however, they are compelled to proliferate and expand to replenish the blood system under stress. The molecular basis underlying stress hematopoiesis remains to be fully understood. In this study, we reported that IRF7 represents an important regulator of stress hematopoiesis. Interferon regulatory factor 7 (IRF7) was dispensable for normal hematopoiesis, whereas its deficiency significantly enhanced hematopoietic stem and progenitor cells (HSPCs) regeneration and improved long-term repopulation of HSCs under stress. Mechanistic studies showed that CXCR4 was identified as a downstream target of IRF7. Overexpression of CXCR4 abrogated the enhanced proliferation and regeneration of IRF7-deficient HSPCs under stress. Similar results were obtained in HSCs from human umbilical cord blood. These observations demonstrated that IRF7 plays an important role in hematopoietic regeneration under stress. © AlphaMed Press 2020 SIGNIFICANCE STATEMENT: This study demonstrated that IRF7 is dispensable for steady-state hematopoiesis, whereas its deficiency enhances regeneration of hematopoietic stem and progenitor cells (HSPCs) under stress. Mechanistic studies show that the effects of IRF7 in HSPCs under stress are mediated through CXCR4. Similar results were obtained in human HSCs. These observations demonstrated an essential role of IRF7 in stress hematopoiesis. Silencing of IRF7 may have therapeutic value to improve hematopoietic recovery after hematopoietic injury or transplantation.