WNT signaling determines tumorigenicity and function of ESC-derived retinal progenitors

被引：74

作者：

Cui, Lu ^{[1
,2
,3
,4
,5
]}

Guan, Yuan ^{[1
,2
,3
,4
]}

Qu, Zepeng ^{[1
,2
,5
]}

Zhang, Jingfa ^{[3
,4
]}

Liao, Bing ^{[1
,2
,5
]}

Ma, Bo ^{[6
]}

Qian, Jiang ^{[6
]}

Li, Dangsheng ^{[2
]}

Li, Weiye ^{[7
]}

Xu, Guo-Tong ^{[3
,4
]}

Jin, Ying ^{[1
,2
,5
]}

机构：

[1] Shanghai Jiao Tong Univ, Sch Med, Inst Hlth Sci, Key Lab Stem Cell Biol, Shanghai 200030, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai, Peoples R China

[3] Tongji Univ, Shanghai Peoples Hosp 10, Dept Ophthalmol, Sch Med, Shanghai 200092, Peoples R China

[4] Tongji Univ, Sch Med, Tongji Eye Inst, Shanghai 200092, Peoples R China

[5] Shanghai Jiao Tong Univ, Sch Med, Dept Mol Dev Biol, Shanghai 200030, Peoples R China

[6] Fudan Univ, Dept Ophthalmol, Eye Ear Nose Throat Hosp, Shanghai 200433, Peoples R China

[7] Drexel Univ, Coll Med, Dept Ophthalmol, Media, PA USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2013年 / 123卷 / 04期

基金：

国家高技术研究发展计划(863计划);

关键词：

EMBRYONIC STEM-CELLS; PHOTORECEPTOR PRECURSORS; SODIUM IODATE; NESTIN GENE; GENERATION; DISEASE; MICE; EXPRESSION; MOUSE; MODEL;

D O I：

10.1172/JCI65048

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

100103 [病原生物学]; 100218 [急诊医学];

摘要：

Tumor formation constitutes a major obstacle to the clinical application of embryonic stem cell-derived (ESC-derived) cells. In an attempt to find major extracellular signaling and intrinsic factors controlling tumorigenicity and therapeutic functionality of transplanted ESC-derived retinal progenitor cells (ESC-RPCs), we evaluated multiple kinds of ESC-RPCs in a mouse retinal degeneration model and conducted genome-wide gene expression profiling. We identified canonical WNT signaling as a critical determinant for the tumorigenicity and therapeutic function of ESC-RPCs. The function of WNT signaling is primarily mediated by TCF7, which directly induces expression of Sox2 and Nestin. Inhibition of WNT signaling, over-expression of dominant-negative Tcf7, and silencing Tcf7, Sox2, or Nestin all resulted in drastically reduced tumor formation and substantially improved retinal integration and visual preservation in mice. These results demonstrate that the WNT signaling cascade plays a critical role in modulating the tumorigenicity and functionality of ESC-derived progenitors.

引用

页码：1647 / 1661

页数：15

共 39 条

[1]

Neurally selected embryonic stem cells induce tumor formation after long-term survival following engraftment into the subretinal space [J].