Cartilage oligomeric matrix protein is a novel notch ligand driving embryonic stem cell differentiation towards the smooth muscle lineage
Cartilage oligomeric matrix protein is a novel notch ligand driving embryonic stem cell differentiation towards the smooth muscle lineage
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软骨寡聚基质蛋白是一种新型缺口配体，可驱动胚胎干细胞向平滑肌谱系分化
DOI：
10.1016/j.yjmcc.2018.07.002
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发表时间：
2018-08-01
影响因子：
5
通讯作者：
Fu, Yi
中科院分区：
文献类型：
--
作者：
Ma, Baihui;Yao, Fang;Fu, Yi
软骨寡聚基质蛋白（COMP）是血管细胞外基质（ECM）的保护性成分，维持成熟血管平滑肌细胞（VSMCs）的稳态。然而，COMP是否调节干细胞向平滑肌谱系的分化仍然是难以捉摸的。首先，纯化小鼠COMP在体外和体内均可直接诱导小鼠胚胎干细胞（ESC）向vsmc分化，而内源性COMP的沉默可显著抑制ESC- vsmc的分化。rna测序结果显示，在ESC-VSMC分化过程中，Notch信号被COMP显著激活，而Notch信号的抑制则减弱了COMP导向的ESC-VSMC分化。此外，COMP缺乏抑制Notch激活和小鼠VSMC分化。通过沉默不同的Notch受体，我们发现Notch1主要介导comp启动的ESC-VSMC分化。在机制上，COMP n端直接与Notch1的EGF11-12结构域相互作用并激活Notch1信号，这被共免疫沉淀和哺乳动物双杂交实验证明。综上所述，COMP作为Notch1的潜在配体，从而驱动ESC-VSMC分化。
Cartilage oligomeric matrix protein (COMP), a protective component of vascular extracellular matrix (ECM), maintains the homeostasis of mature vascular smooth muscle cells (VSMCs). However, whether COMP modulates the differentiation of stem cells towards the smooth muscle lineage is still elusive. Firstly, purified mouse COMP directly induced mouse embryonic stem cell (ESC) differentiation into VSMCs both in vitro and in vivo, while the silencing of endogenous COMP markedly inhibited ESC-VSMC differentiation. RNA-Sequencing revealed that Notch signaling was significantly activated by COMP during ESC-VSMC differentiation, whereas the inhibition of Notch signaling attenuated COMP-directed ESC-VSMC differentiation. Furthermore, COMP deficiency inhibited Notch activation and VSMC differentiation in mice. Through silencing distinct Notch receptors, we identified that Notch1 mainly mediated COMP-initiated ESC-VSMC differentiation. Mechanistically, COMP N-terminus directly interacted with the EGF11-12 domain of Notch1 and activated Notch1 signaling, as evidenced by co-immunoprecipitation and mammalian two-hybrid assay. In conclusion, COMP served as a potential ligand of Notch1, thereby driving ESC-VSMC differentiation.