nature

当前位置: Nature » 分子生物学 » 正文

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

中科院上海药物所谢欣研究组发现即使在LIF存在的条件下,小鼠胚胎干细胞还是很容易自发向中内胚层分化,并且分泌VEGF。利用靶向受体型络氨酸激酶的抗肿瘤药物舒尼替尼(Sunitinib,Sutent)抑制VEGF受体(VEGFRs)即可有效防止胚胎干细胞的自发分化,并在无LIF和滋养层细胞的条件下促进干细胞自我更新。舒尼替尼也可以促进Oct4一因子诱导的体细胞重编程效率。敲除或利用抗体抑制VEGFR2可以模拟舒尼替尼的作用,促进干细胞自我更新。

进一步研究显示缺氧诱导因子HIF1a和内质网应激促进胚胎干细胞分泌VEGF,抑制这两条通路都对干性维持有利。有趣的是LIF也会下调上述通路,提示LIF维持干性的作用不止是激活STAT3。

上述研究显示胚胎干细胞存在一条自分泌VEGF并诱导自发分化的通路,利用小分子化合物抑制该通路可以有效维持干细胞的自我更新。

本研究工作是在谢欣研究员指导下完成。论文第一作者为来自中科院上海药物研究所的陈国芳同学及来自同济大学生命科学与技术学院的许新秀同学。本研究工作得到中科院干细胞先导专项,科技部重大科学研究计划及国家自然科学基金的支持。

原文摘要:

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

热门文章TOP

RSS订阅 - 填写您的邮件地址,订阅我们的精彩内容: - 网站地图
网站联系电话:020-87540820 备案号:粤ICP备11050685号-8 增值电信业务经营许可证:粤B2-20120479
©2011-2015 生物帮 All rights reserved.