Open AccessBiphasic Regulation of Mesenchymal Genes Controls Fate Switches During Hematopoietic Differentiation of Human Pluripotent Stem Cells
Author(s) -
Wang Hongtao,
Wang Mengge,
Wen Yuqi,
Xu Changlu,
Chen Xiaoyuan,
Wu Dan,
Su Pei,
Zhou Wen,
Cheng Tao,
Shi Lihong,
Zhou Jiaxi
Publication year - 2020
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202001019
Subject(s) - mesenchymal stem cell , microbiology and biotechnology , biology , mesoderm , induced pluripotent stem cell , cellular differentiation , snai1 , haematopoiesis , stem cell , epithelial–mesenchymal transition , downregulation and upregulation , embryonic stem cell , genetics , gene
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.