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

文献类型：期刊论文

作者Chen, Guofang2; Xu, Xinxiu1,2; Zhang, Lihong2; Fu, Yanbin1; Wang, Min2; Gu, Haifeng2; Xie, Xin1,2
刊名CELL RESEARCH
出版日期2014-09
卷号24期号:9页码:1121-1136
ISSN号1001-0602
关键词sunitinib Sutent embryonic stem cell self-renewal iPSC VEGF autocrine
DOI10.1038/cr.2014.112
文献子类Article
英文摘要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 (HIF1 alpha) 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 HIF1 alpha 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.
WOS关键词ENDOPLASMIC-RETICULUM STRESS ; GROWTH-FACTOR RECEPTORS ; TUMOR-CELLS ; FACTOR-I ; DIFFERENTIATION ; EXPRESSION ; HYPOXIA ; ANGIOGENESIS ; HIF-1-ALPHA ; INHIBITOR
资助项目Chinese Academy of Sciences[XDA01040301] ; Ministry of Science and Technology of China[2009CB940900] ; Ministry of Science and Technology of China[2011CB965104] ; Ministry of Science and Technology of China[2011DFB30010] ; Ministry of Science and Technology of China[2012ZX09301001-005] ; Shanghai Commission of Science and Technology[12XD1402100]
WOS研究方向Cell Biology
语种英语
CSCD记录号CSCD:5240371
出版者INST BIOCHEMISTRY & CELL BIOLOGY
WOS记录号WOS:000344992900012
源URL[http://119.78.100.183/handle/2S10ELR8/276913]  
专题国家新药筛选中心
通讯作者Xie, Xin
作者单位1.Tongji Univ, Sch Life Sci & Technol, Shanghai Key Lab Signaling & Dis Res, Lab Receptor Based Biomed, Shanghai 200092, Peoples R China
2.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai 201203, Peoples R China;
推荐引用方式
GB/T 7714		 Chen, Guofang,Xu, Xinxiu,Zhang, Lihong,et al. Blocking autocrine VEGF signaling by sunitinib, an anti-cancer drug, promotes embryonic stem cell self-renewal and somatic cell reprogramming[J]. CELL RESEARCH,2014,24(9):1121-1136.
APA Chen, Guofang.,Xu, Xinxiu.,Zhang, Lihong.,Fu, Yanbin.,Wang, Min.,...&Xie, Xin.(2014).Blocking autocrine VEGF signaling by sunitinib, an anti-cancer drug, promotes embryonic stem cell self-renewal and somatic cell reprogramming.CELL RESEARCH,24(9),1121-1136.
MLA Chen, Guofang,et al."Blocking autocrine VEGF signaling by sunitinib, an anti-cancer drug, promotes embryonic stem cell self-renewal and somatic cell reprogramming".CELL RESEARCH 24.9(2014):1121-1136.

入库方式： OAI收割

来源：上海药物研究所

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