Role of MEF2C in the Endothelial Cells Derived from Human Induced Pluripotent Stem Cells
Role of MEF2C in the Endothelial Cells Derived from Human Induced Pluripotent Stem Cells
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MEF2C 在人诱导多能干细胞衍生的内皮细胞中的作用
DOI：
10.1093/stmcls/sxad005
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发表时间：
2023-01-14
期刊：
影响因子：
5.2
通讯作者：
Zhou，Ping
中科院分区：
文献类型：
--
作者：
Li，Tao;Conroy，Kelsey L.;Zhou，Ping
人诱导多能干细胞（hiPSC）不仅为血管疾病的潜在治疗应用提供了丰富的血管细胞来源，而且构成了理解调节血管细胞分化和功能的机制的极好模型。在这里，我们报道了肌细胞增强因子2C（MEF 2C）转录因子，而不是MEF 2家族的任何其他成员，在hiPSC的血管祖细胞和内皮细胞（EC）分化过程中强烈上调。血管内皮生长因子（VEGF）可强烈诱导内皮细胞表达MEF 2C。MEF 2C在内皮细胞分化过程中的特异性上调依赖于细胞外信号调节激酶（ERK）。此外，在hiPSC中用shRNA敲低MEF 2C并不影响这些hiPSC的EC的分化，但大大降低了hiPSC衍生的EC的迁移和管形成能力。通过染色质免疫沉淀测序、全基因组RNA测序、定量RT-PCR和免疫染色分析，对MEF 2C抑制或敲低的hiPSC衍生的内皮细胞谱系细胞与对照hiPSC衍生的EC进行比较，我们鉴定了肿瘤坏死因子相关的细胞凋亡诱导配体（TRAIL）和跨膜蛋白100（TMEM 100）作为MEF 2C的新靶点。这项研究证明了MEF 2C在调节人类EC功能中的重要作用，并强调了MEF 2C及其下游效应物作为治疗血管功能障碍相关疾病的潜在靶点。
Human induced pluripotent stem cells (hiPSCs) not only provide an abundant source of vascular cells for potential therapeutic applications in vascular disease but also constitute an excellent model for understanding the mechanisms that regulate the differentiation and the functionality of vascular cells. Here, we reported that myocyte enhancer factor 2C (MEF2C) transcription factor, but not any other members of the MEF2 family, was robustly upregulated during the differentiation of vascular progenitors and endothelial cells (ECs) from hiPSCs. Vascular endothelial growth factors (VEGF) strongly inducedMEF2Cexpression in endothelial lineage cells. The specific upregulation ofMEF2Cduring the commitment of endothelial lineage was dependent on the extracellular signal regulated kinase (ERK). Moreover, knockdown ofMEF2Cwith shRNA in hiPSCs did not affect the differentiation of ECs from these hiPSCs, but greatly reduced the migration and tube formation capacity of the hiPSC-derived ECs. Through a chromatin immunoprecipitation-sequencing, genome-wide RNA-sequencing, quantitative RT-PCR, and immunostaining analyses of the hiPSC-derived endothelial lineage cells with MEF2C inhibition or knockdown compared to control hiPSC-derived ECs, we identified TNF-related apoptosis inducing ligand (TRAIL) and transmembrane protein 100 (TMEM100) as novel targets of MEF2C. This study demonstrates an important role for MEF2C in regulating human EC functions and highlights MEF2C and its downstream effectors as potential targets to treat vascular malfunction-associated diseases.