TGFbeta signaling hyperactivation-induced tumorigenicity during the derivation of neural progenitors from mouse ESCs

	TGFbeta signaling hyperactivation-induced tumorigenicity during the derivation of neural progenitors from mouse ESCs
	Yang Xianfa1,2 ; Wang Ran 1; Wang Xiongjun 3; Cai Guoqing 1; Qian Yun 1; Feng Su 1; Tan Fangzhi2 ; Chen Kun 3; Tang Ke 3; Huang Xingxu2 ; Jing Naihe1,2 ; Qiao Yunbo 3
	2018
发表期刊	JOURNAL OF MOLECULAR CELL BIOLOGY
ISSN	1674-2788
卷号	10 期号:3 页码:216-228
发表状态	已发表
摘要	Clinical therapies of pluripotent stem cells (PSCs)-based transplantation have been hindered by frequent development of teratomas or tumors in animal models and clinical patients. Therefore, clarifying the mechanism of carcinogenesis in stem cell therapy is of great importance for reducing the risk of tumorigenicity. Here we differentiate Oct4-GFP mouse embryonic stem cells (mESCs) into neural progenitor cells (NPCs) and find that a minority of Oct4+ cells are continuously sustained at Oct4+ state. These cells can be enriched and proliferated in a standard ESC medium. Interestingly, the differentiation potential of these enriched cells is tightly restricted with much higher tumorigenic activity, which are thus defined as differentiation-resistant ESCs (DR-ESCs). Transcriptomic and epigenomic analyses show that DR-ESCs are characterized by primordial germ cell-like gene signatures (Dazl, Rec8, Stra8, Blimpl, etc.) and specific epigenetic patterns distinct from mESCs. Moreover, the DR-ESCs possess germ cell potential to generate Sycp3+ haploid cells and are able to reside in sperm-free spermaduct induced by busulfan. Finally, we find that TGFbeta signaling is overactivated in DR-ESCs, and inhibition of TGFbeta signaling eliminates the tumorigenicity of mESC-derived NPCs by inducing the full differentiation of DR-ESCs. These data demonstrate that these TGFbeta-hyperactivated germ cell-like DR-ESCs are the main contributor for the tumorigenicity of ESCs-derived target cell therapy and that inhibition of TGFbeta signaling in ESC-derived NPC transplantation could drastically reduce the risk of tumor development.
关键词	embryonic stem cells differentiation-resistant ESCs tumorigenicity germ cell TGFbeta signaling
收录类别	CSCD
语种	英语
资助项目	National Natural Science Foundation of China ; the Strategic Priority Research Program of the Chinese Academy of Sciences ; the National Key Basic Research and Development Program of China ; the National Natural Science Foundation of China ; supported in part by the Hundred Talent Program of Guangzhou University and the
WOS研究方向	Life Sciences & Biomedicine - Other Topics
WOS类目	BIOLOGY
CSCD记录号	CSCD:6283096
原始文献类型	Article
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/34202
专题	iHuman研究所_PI研究组_钟桂生组生命科学与技术学院_PI研究组_黄行许组生命科学与技术学院_特聘教授组_景乃禾组生命科学与技术学院_博士生
共同第一作者	Wang Ran; Wang Xiongjun
通讯作者	Jing Naihe; Qiao Yunbo
作者单位	1.State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai 200031, China 2.School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China 3.Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou 510006, China
第一作者单位	生命科学与技术学院
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Yang Xianfa,Wang Ran,Wang Xiongjun,et al. TGFbeta signaling hyperactivation-induced tumorigenicity during the derivation of neural progenitors from mouse ESCs[J]. JOURNAL OF MOLECULAR CELL BIOLOGY,2018,10(3):216-228.
APA	Yang Xianfa.,Wang Ran.,Wang Xiongjun.,Cai Guoqing.,Qian Yun.,...&Qiao Yunbo.(2018).TGFbeta signaling hyperactivation-induced tumorigenicity during the derivation of neural progenitors from mouse ESCs.JOURNAL OF MOLECULAR CELL BIOLOGY,10(3),216-228.
MLA	Yang Xianfa,et al."TGFbeta signaling hyperactivation-induced tumorigenicity during the derivation of neural progenitors from mouse ESCs".JOURNAL OF MOLECULAR CELL BIOLOGY 10.3(2018):216-228.