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 April 1, 2013; First 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 3

DKK1 treatment drives ESC-RPCs into a more P-RPC–like state.

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DKK1 treatment drives ESC-RPCs into a more P-RPC–like state. (A) The neu...
(A) The neural retinal thickness on H&E-stained sections is shown. The bar chart shows the quantitative analysis of the corresponding staining. n, the number of animals; RPE, retinal pigment epithelium. (B) A typical image of integrated DKK1-ESC-RPCsEGFP (green) in the SI-damaged retina. (C) The magnified image of the rectangle shown in B, with OPSIN staining (red). The OPSIN staining is not shown in B for the clarity of donor cell integration. The typical morphology of integrated donor cells: the nucleus (black arrow), outer process (white arrow), IS (white arrowhead), and OS (black arrowhead). (D) Therapeutic effects were monitored by ERG examination. n = 10 for each group. (E) Immunostaining for proliferation markers and SOX2 in ESC-RPCs with or without DKK1 treatment. Bar charts show the quantitative analysis of the corresponding staining. (F) FCM analysis shows the changes in the percentage of ESC-RPCs expressing SOX2, PAX6, RAX, and CRX, respectively, after DKK1 treatment. IgG was applied as a negative control. DAPI is shown in gray. Data are shown as mean ± SD; ANOVA (A and D), t test (E); **P < 0.01. Scale bar: 50 μm (A and E); 25 μm (B and C).