Erythropoietin facilitates definitive endodermal differentiation of mouse embryonic stem cells via activation of ERK signaling
Erythropoietin facilitates definitive endodermal differentiation of mouse embryonic stem cells via activation of ERK signaling
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DOI：
10.1152/ajpcell.00071.2016
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发表时间：
2017-05-01
影响因子：
5.5
通讯作者：
Tomizawa, Kazuhito
中科院分区：
文献类型：
--
作者：
Kaitsuka, Taku;Kobayashi, Kohei;Tomizawa, Kazuhito
从多能干细胞中获得的胰腺β细胞有望用于1型糖尿病的细胞替代疗法。采用几种策略来指导多能干细胞向胰腺分化。然而，临床应用的标准鉴别方法尚未建立。重要的是要开发更有效、更安全的方法来产生胰腺β细胞，而无需有毒或致突变化学物质。在本研究中，我们筛选了几种参与器官发育的内源性因子，以确定诱导胰腺分化效率的因子，并发现用促红细胞生成素（EPO）处理促进小鼠胚胎干细胞（ESCs）分化为定形内胚层。在分化的早期阶段，EPO处理显著增加了Sox 17基因的表达，作为定形内胚层的标志物。与EPO的经典功能相反，它不影响磷酸化JAK 2和STAT 5的水平，但刺激ERK 1/2和Akt的磷酸化。MEK抑制剂U 0126显著抑制EPO诱导的Sox 17表达。胚胎干细胞向定形内胚层分化是向胰腺和其他内胚层谱系分化的重要步骤。这项研究表明，EPO在胚胎内胚层发育中可能发挥作用，并成为指导胰腺β细胞等内胚层谱系分化的新试剂。
Artificially generated pancreatic beta-cells from pluripotent stem cells are expected for cell replacement therapy for type 1 diabetes. Several strategies are adopted to direct pluripotent stem cells toward pancreatic differentiation. However, a standard differentiation method for clinical application has not been established. It is important to develop more effective and safer methods for generating pancreatic beta-cells without toxic or mutagenic chemicals. In the present study, we screened several endogenous factors involved in organ development to identify the factor, which induced the efficiency of pancreatic differentiation and found that treatment with erythropoietin (EPO) facilitated the differentiation of mouse embryonic stem cells (ESCs) into definitive endoderm. At an early stage of differentiation, EPO treatment significantly increased Sox17 gene expression, as a marker of the definitive endoderm. Contrary to the canonical function of EPO, it did not affect the levels of phosphorylated JAK2 and STAT5, but stimulated the phosphorylation of ERK1/2 and Akt. The MEK inhibitor U0126 significantly inhibited EPO-induced Sox17 expression. The differentiation of ESCs into definitive endoderm is an important step for the differentiation into pancreatic and other endodermal lineages. This study suggests a possible role of EPO in embryonic endodermal development and a new agent for directing the differentiation into endodermal lineages like pancreatic beta-cells.