Département de chimie-biochimie and Centre BioMed, Université du Québec à Montréal, Montreal, Quebec, Canada.
Stem Cells Dev. 2013 Jul 15;22(14):2003-16. doi: 10.1089/scd.2012.0209. Epub 2013 Apr 1.
All-trans-retinoic acid (atRA) is an essential signaling molecule in embryonic development. It regulates cell differentiation by activating nuclear retinoic acid receptors (RAR) and retinoid-X receptors (RXR), which both control gene expression. In addition, atRA could act in the cytoplasm by modulating the activity of mitogen-activated protein kinases (MAPK) ERK and p38, which also have a role in cell differentiation. AtRA can induce the differentiation of P19 embryonic carcinoma stem cells into adipocytes, cardiomyocytes, and skeletal muscle cells, concurrently, in the same culture. We postulated that combinations of atRA, atRA analogs exhibiting selectivity for RAR or RXR, and inhibitors of ERK and p38 signaling (ERKi and p38i) could be used to favor one mesodermal fate over the others in the P19 model. In a first series of experiments, we replaced atRA by an agonist of RXR (LG100268) or RAR (TTNPB) to preferentially stimulate one group of receptors over the other. LG100268 was as adipogenic and myogenic as atRA, whereas TTNPB strongly induced adipogenesis, but not myogenesis. ERKi enhanced the myogenic action of atRA, and p38i increased both adipogenesis and myogenesis. In a second series of experiments, we combined atRA with an RAR or RXR antagonist (RARatg or RXRatg) to preferentially deactivate each receptor group in turn. The combinations atRA+RXRatg and atRA+RARatg, including or not ERKi, had similar mesodermal actions as atRA. In contrast, there was no myogenesis with atRA+RXRatg+p38i treatment, and there were no myogenesis and no adipogenesis with the atRA+RARatg+p38i combination. Overall, the results indicate that p38 has a role in mesodermal differentiation that depends on the retinoid context. Indeed, p38 in conjunction with RXR is important in myogenesis, and p38 and RAR in adipogenesis. Under the conditions tested, it was possible to stimulate adipogenesis with a block on myogenesis, whereas increased myogenesis was accompanied by adipogenesis.
全反式视黄酸（atRA）是胚胎发育中必不可少的信号分子。它通过激活核视黄酸受体（RAR）和视黄醇-X 受体（RXR）来调节细胞分化，这两种受体都控制着基因的表达。此外，atRA 还可以通过调节丝裂原活化蛋白激酶（MAPK）ERK 和 p38 的活性在细胞质中发挥作用，这两种激酶也在细胞分化中发挥作用。atRA 可以诱导 P19 胚胎癌细胞向脂肪细胞、心肌细胞和骨骼肌细胞分化，同时在同一培养物中进行。我们假设，atRA、对 RAR 或 RXR 具有选择性的 atRA 类似物以及 ERK 和 p38 信号通路的抑制剂（ERKi 和 p38i）的组合可以用于在 P19 模型中促进一种中胚层命运而不是其他命运。在一系列实验中，我们用 RXR 激动剂（LG100268）或 RAR 激动剂（TTNPB）代替 atRA，以优先刺激一组受体而不是另一组。LG100268 与 atRA 一样具有脂肪生成和肌生成作用，而 TTNPB 强烈诱导脂肪生成，但不诱导肌生成。ERKi 增强了 atRA 的肌生成作用，而 p38i 增加了脂肪生成和肌生成。在一系列实验中，我们将 atRA 与 RAR 或 RXR 拮抗剂（RARatg 或 RXRatg）联合使用，以依次优先失活每组受体。atRA+RXRatg 和 atRA+RARatg 组合，包括或不包括 ERKi，与 atRA 具有相似的中胚层作用。相反，用 atRA+RXRatg+p38i 处理没有肌生成，而用 atRA+RARatg+p38i 组合没有肌生成和脂肪生成。总之，这些结果表明 p38 在中胚层分化中起作用，这取决于视黄酸的背景。事实上，p38 与 RXR 一起在肌生成中很重要，而 p38 和 RAR 在脂肪生成中很重要。在测试的条件下，有可能通过阻止肌生成来刺激脂肪生成，而增加肌生成伴随着脂肪生成。
