Biphasic Regulation of Mesenchymal Genes Controls Fate Switches During Hematopoietic Differentiation of Human Pluripotent Stem Cells.
Biphasic Regulation of Mesenchymal Genes Controls Fate Switches During Hematopoietic Differentiation of Human Pluripotent Stem Cells.
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间充质基因的双相调控控制人类多能干细胞造血分化过程中的命运转换
DOI：
10.1002/advs.202001019
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发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Zhou J
中科院分区：
文献类型：
--
作者：
Wang H;Wang M;Wen Y;Xu C;Chen X;Wu D;Su P;Zhou W;Cheng T;Shi L;Zhou J
上皮-间质转化（EMT）或其逆过程间质-上皮转化（MET）发生在多种生理和病理过程中。然而，完整的 EMT-MET 过程是否存在以及人类造血过程中的潜在功能仍然很大程度上难以捉摸。利用基于人类多能干细胞 (hPSC) 的系统，发现虽然 EMT 发生在人类造血分化开始时，但随后在分化过程中并未检测到 MET。相反，在 hPSC 的造血分化过程中观察到间充质基因的双相激活。间充质基因的表达在从多能性到中胚层的命运转换期间上调，在造血内皮细胞（HE）阶段持续，并在造血内皮细胞（HEP）分化为造血祖细胞（HPC）期间减弱。在人类和小鼠体内造血发育过程中也观察到间充质基因的类似表达模式。 Wnt 信号及其下游基因 SNAI1 介导间充质基因的上调和中胚层诱导多能性的启动。抑制转化生长因子-β (TGF-β) 信号传导和下调 HAND1（TGF-β 的下游基因）是间充质基因下调和 HEP 产生 HPC 能力所必需的。这些结果表明间充质基因的双相调节是人类造血过程中的重要机制。在此，在转录组水平的造血发育过程中发现了间充质基因的双相调节。 SNAI1和HAND1介导的间充质基因的动态表达对于人类造血过程中的命运转换至关重要。这些发现提供了对控制人类早期造血发育的分子机制的见解。
Epithelial‐mesenchymal transition (EMT) or its reverse process mesenchymal‐epithelial transition (MET) occurs in multiple physiological and pathological processes. However, whether an entire EMT–MET process exists and the potential function during human hematopoiesis remain largely elusive. Utilizing human pluripotent stem cell (hPSC)‐based systems, it is discovered that while EMT occurs at the onset of human hematopoietic differentiation, MET is not detected subsequently during differentiation. Instead, a biphasic activation of mesenchymal genes during hematopoietic differentiation of hPSCs is observed. The expression of mesenchymal genes is upregulated during the fate switch from pluripotency to the mesoderm, sustained at the hemogenic endothelium (HE) stage, and attenuated during hemogenic endothelial cell (HEP) differentiation to hematopoietic progenitor cells (HPCs). A similar expression pattern of mesenchymal genes is also observed during human and murine hematopoietic development in vivo. Wnt signaling and its downstream gene SNAI1 mediate the up‐regulation of mesenchymal genes and initiation of mesoderm induction from pluripotency. Inhibition of transforming growth factor‐β (TGF‐β) signaling and downregulation of HAND1, a downstream gene of TGF‐β, are required for the downregulation of mesenchymal genes and the capacity of HEPs to generate HPCs. These results suggest that the biphasic regulation of mesenchymal genes is an essential mechanism during human hematopoiesis. Herein, biphasic regulation of mesenchymal genes is found during hematopoietic development at the transcriptomic level. The dynamic expression of mesenchymal genes mediated by SNAI1 and HAND1 is essential for the fate switches during human hematopoiesis. These findings provide insights into the molecular mechanisms governing early human hematopoietic development.
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连续的 EMT-MET 机制驱动人胚胎干细胞向肝细胞分化。
影响因子：
16.6
作者：
Li Q;Hutchins AP;Chen Y;Li S;Shan Y;Liao B;Zheng D;Shi X;Li Y;Chan WY;Pan G;Wei S;Shu X;Pei D
通讯作者：
Pei D
影响因子：
21.3
作者：
Boroviak T;Loos R;Bertone P;Smith A;Nichols J
通讯作者：
Nichols J
影响因子：
16.6
作者：
Lin, Yongshun;Li, Xiao-Yan;Willis, Amanda L.;Liu, Chengyu;Chen, Guokai;Weiss, Stephen J.
通讯作者：
Weiss, Stephen J.
影响因子：
5.3
作者：
Carver, EA;Jiang, RL;Gridley, T
通讯作者：
Gridley, T
间充质到上皮的转变启动并且是小鼠成纤维细胞核重编程所必需的
影响因子：
23.9
作者：
Li, Ronghui;Liang, Jialiang;Pei, Duanqing
通讯作者：
Pei, Duanqing