Despite the concern of tumorigenic potential, stem cell–based therapy still holds the most promise to restore lost vision in patients with retinal diseases, due to our extensive knowledge of retinal development (10
). To date, a number of protocols have been developed for differentiation of mature retinal cells, including photoreceptors, by a stepwise treatment with defined factors (3
). Notably, the rates of tumor formation and successful host integration vary among different reports, even using a same selective marker. Cui et al. selected SOX1.EGFP–positive neural progenitor cells first and then obtained ESC-RPCs and subsequent photoreceptor precursors by adding small molecule inhibitors. Unlike most other groups, they did not choose DKK1 as a common factor to direct ESCs to retinal progenitors and found a high rate of neural tumor formation following ocular injection as a result (5
). Thus, a more in-depth comparison between P-RPCs and ESC-RPCs, such as assessment of epigenetic signatures using genome-wide tools (11
), will be required to optimize differentiation conditions and to make progress toward translational applications.
As an alternative to ESC-RPCs or P-RPCs for cell therapy, pluripotent stem cells could be differentiated into more mature, lineage-restricted stem cells, such as neural stem cells, to reduce tumorigenicity (12
). However, as Cui et al. discuss, donor cells might lose desired functions and the ability to integrate to host retina by prolonged differentiation. Thus, it will be critical to identify the appropriate stage of ESC-derived cells and ensure the balance between safety and efficiency (13
). It remains to be seen how broadly the approach to retinal progenitor cell differentiation by the WNT pathway modulation can be applied to differentiation of other tissue or cell types. Nevertheless, predifferentiation of ESCs in vitro to a desired cell population before transplantation both to ensure efficiency of transplantation as well as to minimize the risk of tumor formation may be a good general strategy in stem cell therapy.