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Cell Res:维持胚胎干细胞的自我更新并促进重编程的方法

摘要 : 中科院上海分院药物研究所谢欣研究组发现,激活LIF-STAT通路或抑制TGFb/ERK等促进分化的通路可以有效促进胚胎干细胞的自我更新,并使得胚胎干细胞的体外培养得以实现。相关文章发表于2014年8月22日的《Cell Research》杂志上。
Cell Res:维持胚胎干细胞的自我更新并促进重编程的方法






Blocking autocrine VEGF signaling by sunitinib, an anti-cancer drug,promotes embryonic stem cell self-renewal and somatic cellreprogramming

Guofang Chen, Xinxiu Xu, Lihong Zhang, Yanbin Fu, Min Wang, Haifeng Gu & Xin Xie

Maintaining the self-renewal of embryonic stem cells (ESCs) could be achieved by activating the extrinsic signaling, i.e., the use of leukemia inhibitory factor (LIF), or blocking the intrinsic differentiation pathways, i.e., the use of GSK3 and MEK inhibitors (2i). Here we found that even in medium supplemented with LIF, mESCs still tend to differentiate toward meso-endoderm lineages after long-term culture and the culture spontaneously secretes vascular endothelial growth factors (VEGFs). Blocking VEGF signaling with sunitinib, an anti-cancer drug and a receptor tyrosine kinase (RTK) inhibitor mainly targeting VEGF receptors (VEGFRs), is capable of maintaining the mESCs in the undifferentiated state without the need for feeder cells or LIF. Sunitinib facilitates the derivation of mESCs from blastocysts, and the mESCs maintained in sunitinib-containing medium remain pluripotent and are able to contribute to chimeric mice. Sunitinib also promotes iPSC generation from MEFs with only Oct4. Knocking down VEGFR2 or blocking it with neutralizing antibody mimicks the effect of sunitinib, indicating that blocking VEGF/VEGFR signaling is indeed beneficial to the self-renewal of mESCs. We also found that hypoxia-inducible factor alpha (HIF1α) and endoplasmic reticulum (ER) stress are involved in the production of VEGF in mESCs. Blocking both pathways inhibits the expression of VEGF and prevents spontaneous differentiation of mESCs. Interestingly, LIF may also exert its effect by downregulating HIF1α and ER stress pathways and subsequent VEGF expression. These results indicate the existence of an intrinsic differentiation pathway in mESCs by activating the autocrine VEGF signaling. Blocking VEGF signaling with sunitinib or other small molecules help to maintain the mESCs in the ground state of pluripotency.

来源: 中科院 浏览次数:93


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