Inserm U626, Université de la Méditerranée, Faculté de Médecine, Marseille, France.
Stem Cells Dev. 2011 Jul;20(7):1233-46. doi: 10.1089/scd.2010.0213. Epub 2010 Nov 24.
Embryonic stem (ES) cells differentiate in vitro into all cell lineages. We previously found that the p38 mitogen activated kinase (p38MAPK) pathway controls the commitment of ES cells toward either cardiomyogenesis (p38 on) or neurogenesis (p38 off ). In this study, we show that p38α knock-out ES cells do not differentiate into cardiac, endothelial, smooth muscle, and skeletal muscle lineages. Reexpression of p38MAPK in these cells partially rescues their mesodermal differentiation defects and corrects the high level of spontaneous neurogenesis of knock-out cells. Wild-type ES cells were treated with a p38MAPK-specific inhibitor during the differentiation process. These experiments allowed us to identify 2 early independent successive p38MAPK functions in the formation of mesodermal lineages. Further, the first one correlates with the regulation of the expression of Brachyury, an essential mesodermal-specific transcription factor, by p38MAPK. In conclusion, by genetic and biochemical approaches, we demonstrate that p38MAPK activity is essential for the commitment of ES cell into cardiac, endothelial, smooth muscle, and skeletal muscle mesodermal lineages.
胚胎干细胞（ES）在体外分化为所有细胞谱系。我们之前发现，p38 有丝分裂原激活的激酶（p38MAPK）通路控制 ES 细胞向心肌发生（p38 开启）或神经发生（p38 关闭）的定向分化。在这项研究中，我们表明 p38α 敲除 ES 细胞不会分化为心脏、内皮、平滑肌和骨骼肌谱系。在这些细胞中重新表达 p38MAPK 部分挽救了它们的中胚层分化缺陷，并纠正了敲除细胞中高水平的自发神经发生。在分化过程中，用 p38MAPK 特异性抑制剂处理野生型 ES 细胞。这些实验使我们能够确定 p38MAPK 在中胚层谱系形成中具有 2 个早期独立的连续功能。此外，第一个功能与 p38MAPK 对 Brachyury（一种必需的中胚层特异性转录因子）表达的调节相关。总之，通过遗传和生化方法，我们证明 p38MAPK 活性对于 ES 细胞向心脏、内皮、平滑肌和骨骼肌中胚层谱系的定向分化是必需的。
