The opposing roles of the mTOR signaling pathway in different phases of human umbilical cord blood-derived CD34(+) cell erythropoiesis.
The opposing roles of the mTOR signaling pathway in different phases of human umbilical cord blood-derived CD34(+) cell erythropoiesis.
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mTOR信号通路在人脐带血CD34细胞红细胞生成不同阶段的相反作用
DOI：
10.1002/stem.3268
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Liu Q;Luo L;Ren C;Zou M;Yang S;Cai B;Wu L;Wang Y;Fu S;Hua X;Tang N;Huang S;Huang X;Xin W;Chen F;Zhang X
作为一种不可或缺的、甚至是挽救生命的做法，红细胞（RBC）输注由于多种问题而具有挑战性，包括供应短缺、免疫不相容和血源性感染，因为捐献的血液是红细胞的唯一来源。尽管利用人类干细胞在体外大规模生产功能性红细胞是一种很有前景的替代方案，但由于对人类红细胞生成机制的了解不足，迄今为止还没有此类系统能够生产临床可输注红细胞的报道，而这对于优化体外红细胞生成系统至关重要。我们之前报道，抑制哺乳动物雷帕霉素靶点（mTOR）信号显着降低野生型小鼠骨髓中红系祖细胞的百分比。相比之下，雷帕霉素治疗显着改善了β地中海贫血小鼠模型中成红细胞的终末成熟和贫血。在本研究中，我们研究了不同时间点雷帕霉素抑制mTOR对体外人脐带血来源的CD34+细胞红细胞生成的影响及其潜在机制。我们的数据表明，雷帕霉素治疗通过抑制细胞周期进展和增殖，显着抑制红细胞生成的定型/增殖阶段的红细胞集落形成。相反，在红细胞生成的成熟阶段，mTOR 抑制通过增强自噬显着促进去核和线粒体清除。总的来说，我们的结果表明 mTOR 在调节人类红细胞生成的不同阶段中具有不同的作用。拟议的通过哺乳动物雷帕霉素靶点 (mTOR) 抑制剂雷帕霉素调节人红细胞分化的模型。在红细胞生成的增殖阶段，雷帕霉素通过抑制细胞周期进程和细胞增殖，显着抑制红细胞爆发形成单位（BFU-E）和红细胞集落形成单位（CFU-E）的形成。在终末期，雷帕霉素通过增强自噬促进去核和线粒体去除，从而加速红细胞成熟。
As an indispensable, even lifesaving practice, red blood cell (RBC) transfusion is challenging due to several issues, including supply shortage, immune incompatibility, and blood‐borne infections since donated blood is the only source of RBCs. Although large‐scale in vitro production of functional RBCs from human stem cells is a promising alternative, so far, no such system has been reported to produce clinically transfusable RBCs due to the poor understanding of mechanisms of human erythropoiesis, which is essential for the optimization of in vitro erythrocyte generation system. We previously reported that inhibition of mammalian target of rapamycin (mTOR) signaling significantly decreased the percentage of erythroid progenitor cells in the bone marrow of wild‐type mice. In contrast, rapamycin treatment remarkably improved terminal maturation of erythroblasts and anemia in a mouse model of β‐thalassemia. In the present study, we investigated the effect of mTOR inhibition with rapamycin from different time points on human umbilical cord blood‐derived CD34+ cell erythropoiesis in vitro and the underlying mechanisms. Our data showed that rapamycin treatment significantly suppressed erythroid colony formation in the commitment/proliferation phase of erythropoiesis through inhibition of cell‐cycle progression and proliferation. In contrast, during the maturation phase of erythropoiesis, mTOR inhibition dramatically promoted enucleation and mitochondrial clearance by enhancing autophagy. Collectively, our results suggest contrasting roles for mTOR in regulating different phases of human erythropoiesis. Proposed model for regulation of human erythroid differentiation by the mammalian target of rapamycin (mTOR) inhibitor rapamycin. In the proliferation phase of erythropoiesis, rapamycin significantly suppressed burst‐forming unit‐erythroid (BFU‐E) and colony‐forming unit‐erythroid (CFU‐E) formation through the inhibition of cell‐cycle progression and cell proliferation. In the terminal phase, rapamycin promoted enucleation and mitochondrial removal through enhancing autophagy, thereby accelerating erythroid cell maturation.
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通过 mTORC1 介导的蛋白质翻译调节红细胞生成过程中的线粒体生物发生。
影响因子：
21.3
作者：
Liu X;Zhang Y;Ni M;Cao H;Signer RAJ;Li D;Li M;Gu Z;Hu Z;Dickerson KE;Weinberg SE;Chandel NS;DeBerardinis RJ;Zhou F;Shao Z;Xu J
通讯作者：
Xu J
影响因子：
1.9
作者：
Cao, Yan;Cai, Jinyang;Zhang, Suping
通讯作者：
Zhang, Suping
DOI：
10.1016/j.bbamcr.2016.03.009
发表时间：
2016-06-01
影响因子：
5.1
作者：
Campos, Tania;Ziehe, Javiera;Castro, Ariel F.
通讯作者：
Castro, Ariel F.
影响因子：
1.9
作者：
Colligan, David;McGowan, Neil;Seghatchian, Jerard
通讯作者：
Seghatchian, Jerard
影响因子：
3.1
作者：
Fibach, Eitan;Bianchi, Nicoletta;Gambari, Roberto
通讯作者：
Gambari, Roberto