C/EBP homologous protein deficiency enhances hematopoietic stem cell function via reducing ATF3/ROS-induced cell apoptosis,Aging Cell

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C/EBP homologous protein deficiency enhances hematopoietic stem cell function via reducing ATF3/ROS-induced cell apoptosis
Aging Cell ( IF 8.0 ) Pub Date : 2021-06-15 , DOI: 10.1111/acel.13382
Zhencan Shi ₁ , Daojun Diao ₁ , Yanan Zhao ₁ , Ying Luo ₁ , Yafei Li ₁ , Dingdong Liu ₁ , Kai Zhang ₁ , Yugang Qiu ₂ , Li Yu ₂ , Zhangfa Song ₃ , Zhenyu Ju ₁

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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 misfolded 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), demonstrated previously to induces cell death upon 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.

中文翻译：

C/EBP同源蛋白缺乏通过减少ATF3/ROS诱导的细胞凋亡增强造血干细胞功能

造血干细胞 (HSC) 存在于一个静止的生态位中，以保留其自我更新的能力。在造血损伤后，HSCs 进入细胞周期并遇到由错误折叠蛋白质积累引起的蛋白质稳态问题。然而，蛋白质稳态影响 HSC 功能和维持的机制仍然知之甚少。在这里，我们表明 C/EBP 同源蛋白 (CHOP) 在 HSC 再生中起重要作用，之前已证明它在未折叠蛋白反应 (UPR) 时诱导细胞死亡。CHOP ^-/-小鼠在稳定状态下表现出正常的造血干细胞和祖细胞频率。然而，当用 5-FU 治疗时，CHOP 缺乏导致更高的存活率，这与 HSC 数量增加和细胞凋亡水平降低有关。在一系列竞争性移植实验中，CHOP ^-/- HSC 显示出显着增强的再增殖能力和减少蛋白质聚集体。从机制上讲，CHOP 缺失导致 ATF3 表达减少，并进一步导致蛋白质聚集和 ROS 减少。此外，CHOP ^-/- HSCs 表现出对 IR 诱导的 DNA 损伤的抵抗力增强，并改善了 HSCs 稳态和端粒功能障碍（G3 Terc ^-/-）老鼠。总之，这些发现揭示了 CHOP 通过减少 ATF3 和 ROS 信号传导在调节 HSC 功能和稳态中的新作用。

更新日期：2021-07-16

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