Tbx6 Induces Nascent Mesoderm from Pluripotent Stem Cells and Temporally Controls Cardiac versus Somite Lineage Diversification.
Tbx6 Induces Nascent Mesoderm from Pluripotent Stem Cells and Temporally Controls Cardiac versus Somite Lineage Diversification.
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DOI：
10.1016/j.stem.2018.07.001
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发表时间：
2018-09-06
期刊：
影响因子：
23.9
通讯作者：
Ieda M
中科院分区：
文献类型：
--
作者：
Sadahiro T;Isomi M;Muraoka N;Kojima H;Haginiwa S;Kurotsu S;Tamura F;Tani H;Tohyama S;Fujita J;Miyoshi H;Kawamura Y;Goshima N;Iwasaki YW;Murano K;Saito K;Oda M;Andersen P;Kwon C;Uosaki H;Nishizono H;Fukuda K;Ieda M
中胚层起源于多能性上胚层并分化成多个谱系;然而，其潜在的分子机制尚不清楚。Tbx 6在近轴中胚层中富集，并参与体节的形成，但其在其他中胚层中的功能仍然难以捉摸。在这里，使用基于直接重编程的筛选、小鼠胚胎中的单细胞RNA-seq和多能干细胞（PSC）中的定向心脏分化，我们证明了Tbx 6从PSC诱导新生中胚层，并通过其时间表达确定心血管和体节谱系特化。使用CRISPR/Cas9技术敲除小鼠PSC中的Tbx 6抑制中胚层和心血管分化，而瞬时Tbx 6表达通过直接上调Mesp 1、抑制Sox 2和激活BMP/Nodal/Wnt信号传导诱导小鼠和人PSC的中胚层和心血管特化。值得注意的是，延长Tbx 6表达抑制心脏分化和诱导体节谱系，包括骨骼肌和软骨细胞。因此，Tbx 6对于中胚层诱导和随后的谱系多样化至关重要。Sadahiro等人表明，Tbx 6对于中胚层诱导和随后来自多能干细胞（PSC）的谱系多样化至关重要。瞬时Tbx 6表达诱导小鼠和人PSC的新生中胚层和心血管谱系，而长期Tbx 6表达抑制心脏分化并诱导体节谱系，包括骨骼肌和软骨细胞。
The mesoderm arises from pluripotent epiblasts and differentiates into multiple lineages; however, the underlying molecular mechanisms are unclear. Tbx6 is enriched in the paraxial mesoderm and is implicated in somite formation, but its function in other mesoderms remains elusive. Here, using direct reprogramming-based screening, single-cell RNA-seq in mouse embryos, and directed cardiac differentiation in pluripotent stem cells (PSCs), we demonstrated that Tbx6 induces nascent mesoderm from PSCs and determines cardiovascular and somite lineage specification via its temporal expression. Tbx6 knockout in mouse PSCs using CRISPR/Cas9 technology inhibited mesoderm and cardiovascular differentiation, whereas transient Tbx6 expression induced mesoderm and cardiovascular specification from mouse and human PSCs via direct upregulation of Mesp1, repression of Sox2, and activation of BMP/Nodal/Wnt signaling. Notably, prolonged Tbx6 expression suppressed cardiac differentiation and induced somite lineages, including skeletal muscle and chondrocytes. Thus, Tbx6 is critical for mesoderm induction and subsequent lineage diversification. Sadahiro et al. show that Tbx6 is critical for mesoderm induction and subsequent lineage diversification from pluripotent stem cells (PSCs). Transient Tbx6 expression induced nascent mesoderm and cardiovascular lineages from mouse and human PSCs, whereas prolonged Tbx6 expression suppressed cardiac differentiation and induced somite lineages, including skeletal muscle and chondrocytes.
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