School of Medicine, Hunan Normal University, Changsha, Hunan, People's Republic of China.
Stem Cell Program and Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA, USA.
Stem Cells. 2023 Apr 25;41(4):341-353. doi: 10.1093/stmcls/sxad005.
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 induced MEF2C expression in endothelial lineage cells. The specific upregulation of MEF2C during the commitment of endothelial lineage was dependent on the extracellular signal regulated kinase (ERK). Moreover, knockdown of MEF2C with 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.
人诱导多能干细胞（hiPSCs）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，而且还构成了理解调节血管细胞分化和功能的机制的优秀模型。在这里，我们报道肌细胞增强因子 2C（MEF2C）转录因子，但不是 MEF2 家族的任何其他成员，在血管祖细胞和 hiPSC 内皮细胞（EC）的分化过程中被强烈上调。血管内皮生长因子（VEGF）在血管谱系细胞中强烈诱导 MEF2C 表达。MEF2C 在血管谱系细胞的定向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，用 shRNA 在 hiPSCs 中敲低 MEF2C 不会影响这些 hiPSCs 中 EC 的分化，但大大降低了 hiPSC 衍生的 EC 的迁移和管状形成能力。通过染色质免疫沉淀测序、全基因组 RNA 测序、定量 RT-PCR 和 MEF2C 抑制或敲低的 hiPSC 衍生内皮谱系细胞的免疫染色分析与对照 hiPSC 衍生 ECs 相比，我们鉴定出 TNF 相关凋亡诱导配体（TRAIL）和跨膜蛋白 100（TMEM100）作为 MEF2C 的新靶标。这项研究证明了 MEF2C 在调节人 EC 功能中的重要作用，并强调了 MEF2C 及其下游效应物作为治疗与血管功能障碍相关疾病的潜在靶点。
