MIR148A family regulates cardiomyocyte differentiation of human embryonic stem cells by inhibiting the DLL1-mediated NOTCH signaling pathway
MIR148A family regulates cardiomyocyte differentiation of human embryonic stem cells by inhibiting the DLL1-mediated NOTCH signaling pathway
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MIR148A家族通过抑制DLL1介导的NOTCH信号通路调节人胚胎干细胞的心肌细胞分化
DOI：
10.1016/j.yjmcc.2019.06.014
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发表时间：
2019-09-01
影响因子：
5
通讯作者：
Lei, Wei
中科院分区：
文献类型：
--
作者：
Fang, Xing;Miao, Shumei;Lei, Wei
MicroRNA（miRNA）作为一类天然存在的RNA，在心脏生理学和病理学中发挥着重要作用。有许多 miRNA 在心肌细胞发生过程中表现出多种多样的表达模式。在这里，我们重点关注 MIR148A 家族，该家族由 MIR148A、MIR148B 和 MIR152 组成，并共享相同的种子序列。所有 MIR148A 家族成员的表达水平在人胚胎干细胞 (hESC) 分化为心肌细胞的过程中逐渐增加。 MIR148A家族（MIR148A-TKO）的缺失导致心脏诱导后心肌细胞比例下降，但通过MIR148A家族成员的异位表达得以恢复。转录组分析表明，MIR148A 家族可以部分抑制原条细胞的轴旁中胚层分化。反过来，这些 miRNA 促进了外侧中胚层和心肌细胞的分化。此外，NOTCH配体Delta-like 1（DLL1）被验证为MIR148A家族的靶基因，敲低DLL1可以促进MIR148A-TKO hESCs的心肌细胞分化。因此，我们的结果表明 MIR148A 家族可以通过抑制不需要的轴旁中胚层谱系定向来促进心肌细胞分化，这提高了我们对 hESC 心肌细胞分化的理解。
MicroRNAs (miRNAs), as a class of naturally occurring RNAs, play important roles in cardiac physiology and pathology. There are many miRNAs that show multifarious expression patterns during cardiomyocyte genesis. Here, we focused on the MIR148A family, which is composed of MIR148A, MIR148B and MIR152, and shares the same seed sequences. The expression levels of all MIR148A family members progressively increased during the differentiation of human embryonic stem cells (hESCs) into cardiomyocytes. The deletion of MIR148A family (MIR148A-TKO) resulted in a decreased proportion of cardiomyocytes after cardiac induction, which was restored by the ectopic expression of MIR148A family members. Transcriptome analyses indicated that the MIR148A family could partially repress paraxial mesodermal differentiation from primitive streak cells. In turn, these miRNAs promoted lateral mesoderm and cardiomyocyte differentiation. Furthermore, the NOTCH ligand Delta-like 1 (DLL1) was validated as the target gene of MIR148A family, and knockdown of DLL1 could promote the cardiomyocyte differentiation of MIR148A-TKO hESCs. Thus, our results demonstrate MIR148A family could promote cardiomyocyte differentiation by inhibiting undesired paraxial mesoderm lineage commitment, which improves our understanding on cardiomyocyte differentiation from hESCs.