Blocking autocrine VEGF signaling by sunitinib, an anti-cancer drug, promotes embryonic stem cell selfrenewal and somatic cell reprogramming

• Published in: 细胞研究：英文版 2014 (9), p.1121-1136
• Main Author: Guofang Chen Xinxiu Xu Lihong Zhang Yanbin Fu Min Wang Haifeng Gu Xin Xie
• Format: Article
• Language: English
• Subjects: VEGF; 信号; 抗癌药物; 胚胎干细胞; 自分泌; 自我更新; 血管内皮生长因子; 重编程
• ISSN: 1001-0602; 1748-7838

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 ty- rosine 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 contrib- ute 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 HIFla 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.