LIF is a common cytokine used to support the self-renewal of mESCs. Here researchers from Shanghai Institute of Materia Medica,CAS and Tongji University  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.

Researchers 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.

This work is published online by Cell Research (August 22, 2014; doi:10.1038/cr.2014.113)
This research was supervised by Professor XIE Xin . First authors are CHEN Guofang  of Shanghai Institute of Materia Medica,CAS and XU Xinxiu of Tongji University. This work was supported by grants from the Chinese Academy of Sciences, the Ministry of Science and Technology of China, and the Natural Science Foundation of China.

Original article: http://www.nature.com/cr/journal/vaop/ncurrent/pdf/cr2014112a.pdf