CHOP Deficiency Enhances Hematopoietic Stem Cell Function via Reducing ATF3/ROS Induced Cell Apoptosis

Hematopoietic stem cells (HSCs) reside in a quiescent niche to reserve their capacity of self-renewal. Upon hematopoietic injuries, HSCs enter the cell cycle and encounter protein homeostasis problems caused by accumulation of mis-folded proteins. However, the mechanism by which protein homeostasis influences HSC function and maintenance remains poorly understood. Here, we show that C/EBP homologous protein (CHOP), which is demonstrated previously, induces cell death upon tunicamycin induced unfolded protein response (UPR), plays an important role in HSCs regeneration. CHOP-/- mice showed normal hematopoietic stem and progenitor cell frequencies in steady state. However, when treated with 5-FU, CHOP deficiency resulted in higher survival rates, associated with an increased number of HSCs and reduced level of apoptosis. In serial competitive transplantation experiments, CHOP-/- HSCs showed a dramatic enhancement of repopulation ability and a reduction of protein aggresomes. Mechanistically, CHOP deletion causes reduced ATF3 expression and further leads to decreased protein aggregation and ROS. In addition, CHOP-/- HSCs exhibited an increased resistance to IR-induced DNA damage and improved HSCs homeostasis and function in telomere-dysfunctional (G3Terc-/-) mice. In summary, these findings disclose a new role of CHOP in the regulation of the HSCs function and homeostasis through reducing ATF3 and ROS signaling.