PMID- 32871057 OWN - NLM STAT- MEDLINE DCOM- 20210902 LR - 20211204 IS - 1549-4918 (Electronic) IS - 1066-5099 (Print) IS - 1066-5099 (Linking) VI - 38 IP - 11 DP - 2020 Nov TI - The opposing roles of the mTOR signaling pathway in different phases of human umbilical cord blood-derived CD34(+) cell erythropoiesis. PG - 1492-1505 LID - 10.1002/stem.3268 [doi] AB - 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 beta-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. CI - (c) 2020 The Authors. Stem Cells published by Wiley Periodicals LLC on behalf of AlphaMed Press 2020. FAU - Liu, Qian AU - Liu Q AUID- ORCID: 0000-0002-7742-1175 AD - Laboratory of Molecular Cardiology, The First Affiliated Hospital of Shantou University Medical College, Shantou, People's Republic of China. AD - Shantou University Medical College, Shantou, People's Republic of China. FAU - Luo, Linhong AU - Luo L AD - Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shantou University Medical College, Shantou, People's Republic of China. FAU - Ren, Chunhong AU - Ren C AD - Department of International Medical Service, The First Affiliated Hospital of Shantou University Medical College, Shantou, People's Republic of China. FAU - Zou, Muping AU - Zou M AD - Laboratory of Molecular Cardiology, The First Affiliated Hospital of Shantou University Medical College, Shantou, People's Republic of China. FAU - Yang, Siqin AU - Yang S AD - Laboratory of Molecular Cardiology, The First Affiliated Hospital of Shantou University Medical College, Shantou, People's Republic of China. FAU - Cai, Bozhi AU - Cai B AD - Laboratory of Molecular Cardiology, The First Affiliated Hospital of Shantou University Medical College, Shantou, People's Republic of China. FAU - Wu, Libiao AU - Wu L AD - Laboratory of Molecular Cardiology, The First Affiliated Hospital of Shantou University Medical College, Shantou, People's Republic of China. FAU - Wang, Yunsheng AU - Wang Y AD - Laboratory of Molecular Cardiology, The First Affiliated Hospital of Shantou University Medical College, Shantou, People's Republic of China. FAU - Fu, Shan AU - Fu S AD - Shantou University Medical College, Shantou, People's Republic of China. FAU - Hua, Xu AU - Hua X AD - Shantou University Medical College, Shantou, People's Republic of China. FAU - Tang, Nianping AU - Tang N AD - Shantou University Medical College, Shantou, People's Republic of China. FAU - Huang, Shiping AU - Huang S AD - Shantou University Medical College, Shantou, People's Republic of China. FAU - Huang, Xianxi AU - Huang X AD - Intensive Care Unit, The First Affiliated Hospital of Shantou University Medical College, Shantou, People's Republic of China. FAU - Xin, Wen AU - Xin W AD - Beijing TransGen Biotech Co., Ltd., Beijing, People's Republic of China. FAU - Chen, Feiheng AU - Chen F AD - Department of Hematology, The First Affiliated Hospital of Shantou University Medical College, Shantou, People's Republic of China. FAU - Zhang, Xin AU - Zhang X AUID- ORCID: 0000-0001-5113-1420 AD - Laboratory of Molecular Cardiology, The First Affiliated Hospital of Shantou University Medical College, Shantou, People's Republic of China. AD - Shantou University Medical College, Shantou, People's Republic of China. AD - Department of Cardiology, The First Affiliated Hospital of Shantou University Medical College, Shantou, People's Republic of China. AD - Laboratory of Medical Molecular Imaging, The First Affiliated Hospital of Shantou University Medical College, Shantou, People's Republic of China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200901 PL - England TA - Stem Cells JT - Stem cells (Dayton, Ohio) JID - 9304532 RN - 0 (Antigens, CD34) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Antigens, CD34/*metabolism MH - Erythropoiesis/*genetics MH - Fetal Blood/*physiology MH - Humans MH - Mice MH - Signal Transduction MH - TOR Serine-Threonine Kinases/*genetics PMC - PMC7693065 OTO - NOTNLM OT - autophagy OT - erythropoiesis OT - hematopoietic stem cells OT - mTOR OT - rapamycin COIS- The authors declared no potential conflicts of interest. EDAT- 2020/09/02 06:00 MHDA- 2021/09/03 06:00 PMCR- 2020/11/27 CRDT- 2020/09/02 06:00 PHST- 2020/01/11 00:00 [received] PHST- 2020/06/25 00:00 [revised] PHST- 2020/07/10 00:00 [accepted] PHST- 2020/09/02 06:00 [pubmed] PHST- 2021/09/03 06:00 [medline] PHST- 2020/09/02 06:00 [entrez] PHST- 2020/11/27 00:00 [pmc-release] AID - STEM3268 [pii] AID - 10.1002/stem.3268 [doi] PST - ppublish SO - Stem Cells. 2020 Nov;38(11):1492-1505. doi: 10.1002/stem.3268. Epub 2020 Sep 1.