WNT signaling determines tumorigenicity and function of ESC-derived retinal progenitors
Lu Cui, Yuan Guan, Zepeng Qu, Jingfa Zhang, Bing Liao, Bo Ma, Jiang Qian, Dangsheng Li, Weiye Li, Guo-Tong Xu, Ying Jin
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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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 7

Canonical WNT signaling does not only define the cell fate of transplanted ESC-derived retinal progenitors but is also closely associated with early development of the mouse retina.

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Canonical WNT signaling does not only define the cell fate of transplant...
(A) Immunofluorescence staining for the expression of fTCF7 and SOX2 in the retina of a Nestin.EGFP transgenic mouse from P1 to P30. DAPI is shown in gray. The asterisks indicate the nonspecific staining. ONBL, outer neuroblastic layer. Scale bar: 50 μm. (B) Representative Western blots of β-catenin, fTCF7, TCF7, SOX2, NESTIN, and PCNA proteins in mouse retina from E14 to adult. (C) The proposed model explains how canonical WNT signaling determines the proliferation and differentiation state of ESC-derived progenitors via TCF7 to regulate the expression of Sox2 and Nestin in vitro, controlling tumorigenesis and functional visual preservation in a disease model. The potential targets to block the pathway are indicated. β-cat, β-catenin.