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WNT signaling determines tumorigenicity and function of ESC-derived retinal progenitors
Lu Cui1,2,3, Yuan Guan1,2, Zepeng Qu1,3, Jingfa Zhang2, Bing Liao1,3, Bo Ma4, Jiang Qian4, Dangsheng Li5, Weiye Li6, Guo-Tong Xu2 and Ying Jin1,3
The unique properties of embryonic stem cells (ESCs), unlimited self-renewal and pluripotency, make them an attractive cell source for the treatment of various degenerative diseases. However, the same properties also present a major hurdle for their clinical application. Tumor formation has been reported in the transplantation of ESC derivatives despite predifferentiation or presorting (1–6), raising a safety concern for the therapeutic use of ESC-derived cell products in humans. On the other hand, transplantation of photoreceptor precursors in neonatal mice repaired retinal defect efficiently without development of any tumors (7, 8), which emphasizes the critical role of the developmental stage of donor cells in determining the cell fate following transplantation. Thus, steering ESCs to an appropriate state could be an important step for safe and effective cell therapies.
To date, ESCs from the mouse, monkey, and human have been successfully differentiated into retinal cells in vitro (9–13). Sasai’s group developed an efficient induction of retinal precursors by culturing mouse ESCs under a serum-free suspension condition (SFEB culture) and obtained high percentages of differentiated cells expressing key eye-field transcription factors (12–14). However, mechanisms governing efficient generation of various types of retinal cells and the optical cups from ESCs in vitro as well as their application potential in vivo, in regards to the functional integration and safety, are not clearly elucidated.
In an attempt to find major extracellular signaling and intrinsic factors controlling tumorigenicity and therapeutic effects of ocular transplanted ESC-derived retinal progenitor cells (ESC-RPCs), we identified the canonical WNT signaling-activated TCF7-SOX2-NESTIN cascade as a critical determinant for the consequence of ESC-RPC transplantation: whether tumors would form as well as whether successful integration into the host retina and prevention of the visual defect would be achieved. Canonical WNT signaling is known to play a key role in cell fate determination for various cell lineages, and its inappropriate activation is frequently associated with cancers (15–17). It has also been shown to promote proliferation of isolated retinal stem cells (18) and retina regeneration in adult mammals (19). However, the correlation between WNT signaling in ESC-derived donor cells and their therapeutic effect as well as tumorigenicity after transplantation in a disease model remains unexamined. In addition, factor(s) that mediate the function of WNT signaling in the control of cell fate commitment remain elusive. In this study, we link the activity of WNT signaling to the tumorigenic potential of ESC-RPCs and provide the experimental evidence for transcriptional factor TCF7 to regulate expression of SOX2 and NESTIN, two important genes actively engaged in the neural development and tumor formation. The tumorigenic and therapeutic effect of transplanted ESC-RPCs is determined in a well-studied sodium iodate–induced (SI-induced) mouse retinal degeneration model (20, 21). We also show that the expression of TCF7, SOX2, and NESTIN is closely associated in mouse neonatal retinae. These findings open new avenues to define and manipulate ESC-derived donor cells prior to transplantation for safe and effective cell therapies.
