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Analyses of erythropoiesis from embryonic stem cell‐CD34+ and cord blood‐CD34+ cells reveal mechanisms for defective expansion and enucleation of embryomic stem cell‐erythroid cells
Authors:Shihui Wang  Huizhi Zhao  Huan Zhang  Chengjie Gao  Xinhua Guo  Lixiang Chen  Cheryl Lobo  Karina Yazdanbakhsh  Shijie Zhang  Xiuli An
Institution:1. School of Life Sciences, Zhengzhou University, Zhengzhou China ; 2. Laboratory of Membrane Biology, New York Blood Center, New York New York, USA ; 3. Laboratory of Blood Borne Parasites, New York Blood Center, New York New York, USA ; 4. Laboratory of Complement Biology, New York Blood Center, New York New York, USA
Abstract:Red blood cells (RBCs) generated ex vivo have the potential to be used for transfusion. Human embryonic stem cells (ES) and induced pluripotent stem cells (iPS) possess unlimited self‐renewal capacity and are the preferred cell sources to be used for ex vivo RBC generation. However, their applications are hindered by the facts that the expansion of ES/iPS‐derived erythroid cells is limited and the enucleation of ES/iPS‐derived erythroblasts is low compared to that derived from cord blood (CB) or peripheral blood (PB). To address this, we sought to investigate the underlying mechanisms by comparing the in vitro erythropoiesis profiles of CB CD34+ and ES CD34+ cells. We found that the limited expansion of ES CD34+ cell‐derived erythroid cells was associated with defective cell cycle of erythroid progenitors. In exploring the cellular and molecular mechanisms for the impaired enucleation of ES CD34+ cell‐derived orthochromatic erythroblasts (ES‐ortho), we found the chromatin of ES‐ortho was less condensed than that of CB CD34+ cell‐derived orthochromatic erythroblasts (CB‐ortho). At the molecular level, both RNA‐seq and ATAC‐seq analyses revealed that pathways involved in chromatin modification were down‐regulated in ES‐ortho. Additionally, the expression levels of molecules known to play important role in chromatin condensation or/and enucleation were significantly lower in ES‐ortho compared to that in CB‐ortho. Together, our findings have uncovered mechanisms for the limited expansion and impaired enucleation of ES CD34+ cell‐derived erythroid cells and may help to improve ex vivo RBC production from stem cells.
Keywords:ATAC‐  Seq  enucleation  erythropoiesis  RNA‐  Seq
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