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.

造血干细胞（HSCs）居于一种静止的微环境中，以此保留其自我更新的潜能。在遭受造血损伤后，HSCs进入细胞周期，并遭遇由错误折叠蛋白积累所引起的蛋白质稳态问题。然而，蛋白质稳态如何影响HSC的功能与维持的机制仍鲜为人知。在本研究中，我们揭示了C/EBP同源蛋白（CHOP），先前研究表明其在由氨基糖苷类抗生素诱导的未折叠蛋白反应（UPR）中引起细胞死亡，在HSC的再生过程中发挥着关键作用。CHOP-/-小鼠在稳态下表现出正常的造血干细胞和祖细胞频率。然而，当接受5-FU治疗后，CHOP的缺失导致更高的存活率，这与HSC数量的增加和细胞凋亡水平的降低相关。在连续的竞争性移植实验中，CHOP-/- HSCs表现出显著的重新填充能力提升和蛋白质聚集体减少。从机制上讲，CHOP的缺失导致ATF3表达减少，进而引起蛋白质聚集体和活性氧（ROS）的减少。此外，CHOP-/- HSCs表现出对IR诱导的DNA损伤的增强抵抗力，并在端粒功能障碍（G3Terc-/-）小鼠中改善了HSCs的稳态和功能。总之，这些发现揭示了CHOP在通过降低ATF3和ROS信号通路调节HSC功能与稳态中的新作用。