WNT signaling determines tumorigenicity and function of ESC-derived retinal progenitors
Lu Cui, … , Guo-Tong Xu, Ying Jin
Lu Cui, … , Guo-Tong Xu, Ying Jin
Published March 25, 2013
Citation Information: J Clin Invest. 2013;123(4):1647-1661. https://doi.org/10.1172/JCI65048.
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Research Article

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

Abstract

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, overexpression 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.

Authors

Lu Cui, Yuan Guan, Zepeng Qu, Jingfa Zhang, Bing Liao, Bo Ma, Jiang Qian, Dangsheng Li, Weiye Li, Guo-Tong Xu, Ying Jin

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Figure 5

The expression level of TCF7 is directly linked to the state of ESC-RPCs and eye tumor formation in vivo.

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The expression level of TCF7 is directly linked to the state of ESC-RPCs...
(A) FCM analysis to compare the percentage of ESC-RPCs expressing SOX2, PAX6, RAX, OTX2, and CRX, respectively, between shControl and shTcf7-ESC-RPCs. (B) FCM analysis to compare the percentage of P-RPCs expressing PCNA, SOX2, PAX6, RAX, OTX2, and CRX, respectively, between vector-infected and fTcf7-infected P-RPCs in the presence of WNT3A protein. (C and D) Immunofluorescence staining with antibodies against glutamine synthetase (GS) and BrdU in retinae injected with lentiviral fTCF7 and WNT3A protein. Retinae injected with lentiviral EGFP plus recombination WNT3A protein and the medium were used as controls. Scale bar: 50 μm (C); 250 μm (D).