Regenerative therapies are limited by unfavorable environments in aging and diseased tissues. A promising strategy to improve success is to balance inflammatory and anti-inflammatory signals and enhance endogenous tissue repair mechanisms. Here, we identified a conserved immune modulatory mechanism that governs the interaction between damaged retinal cells and immune cells to promote tissue repair. In damaged retina of flies and mice, Platelet-Derived Growth Factor (PDGF)-like signaling induced Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) in innate immune cells. MANF promoted alternative activation of innate immune cells, enhanced neuroprotection and tissue repair, and improved the success of photoreceptor replacement therapies. Thus, immune modulation is required during tissue repair and regeneration. This approach may improve the efficacy of stem-cell based regenerative therapies.

Retinal degeneration often results in the loss of light‐sensing photoreceptors, which leads to permanent vision loss. Generating transplantable retinal photoreceptors using human somatic cell‐derived induced pluripotent stem cells (iPSCs) holds promise to treat a variety of retinal degenerative diseases by replacing the damaged or dysfunctional native photoreceptors with healthy and functional ones. Establishment of effective methods to produce retinal cells including photoreceptors in chemically defined conditions using current Good Manufacturing Practice (cGMP)‐manufactured human iPSC lines is critical for advancing cell replacement therapy to the clinic. In this study, we used a human iPSC line (NCL‐1) derived under cGMP‐compliant conditions from CD34+ cord blood cells. The cells were differentiated into retinal cells using a small molecule‐based retinal induction protocol. We show that retinal cells including photoreceptors, retinal pigmented epithelial cells and optic cup‐like retinal organoids can be generated from the NCL‐1 iPSC line. Additionally, we show that following subretinal transplantation into immunodeficient host mouse eyes, retinal cells successfully integrated into the photoreceptor layer and developed into mature photoreceptors. This study provides strong evidence that transplantable photoreceptors can be generated from a cGMP‐manufactured human iPSC line for clinical applications. Stem Cells Translational Medicine 2018;7:210–219

Background: DEPTOR is a negative regulator of mTOR activity and thus plays a role in the regulation of cell metabolism and growth. Results: DEPTOR levels decrease upon differentiation of embryonic stem cells, and reduction of DEPTOR levels is sufficient to promote differentiation. Conclusion: DEPTOR is a stemness factor that regulates pluripotency. Significance: Manipulation of DEPTOR activity provides a means of influencing embryonic stem cell renewal and differentiation.

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