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Retinal photoreceptor degeneration occurs frequently in several neurodegenerative retinal diseases such as age-related macular degeneration, retinitis pigmentosa, or genetic retinal diseases related to the photoreceptors. Despite the impact on daily life and the social and economic consequences, there is no cure for these diseases. Considering this, cell-based therapy may be an optimal therapeutic option. This study evaluated the neuroprotective in vitro potential of a secretome of human bone marrow mesenchymal stem cells (MSCs) for retinal photoreceptors in vitro. We analyzed the photoreceptor morphologic changes and the paracrine factors secreted by human bone marrow MSCs in a physically separated co-culture with degenerated neuroretinas, using organotypic neuroretinal cultures. The results showed that the secretome of human bone marrow MSCs had a neuroprotective effect over the neuroretinal general organization and neuropreserved the photoreceptors from degeneration probably by secretion of neuroprotective proteins. The study of the expression of 1,000 proteins showed increased paracrine factors secreted by MSCs that could be crucial in the neuroprotective effect of the stem cell secretome over in vitro retinal degeneration. The current results reinforce the hypothesis that the paracrine effect of the human bone marrow MSCs may slow photoreceptor neurodegeneration and be a therapeutic option in retinal photoreceptor degenerative diseases., This work was supported by grants from Fondo Europeo de Desarrollo Regional (FEDER) and Consejería de Educación from Junta de Castilla y León, Spain (grant VA077P17), and from the Spanish Health Institute Carlos III (ISCIII) (grants PI17/01930 and CB16/12/00400). The Proteomics Unit belongs to ProteoRed (PRB3-ISCIII) supported by grant PT17/0019/0023, of the PEI+D+I 2017-2020, funded by ISCIII and FEDER. R.U.-M. was supported by FEDER and Consejería de Educación from Junta de Castilla y León, Spain (grant VA077P17); K.P.-N. was supported by Fundación Carolina, Madrid, Spain; and I.F.-B. was supported by Centro en Red de Medicina Regenerativa y Terapia Celular, Junta de Castilla y León, Spain.

Retinal degenerations are the leading causes of irreversible visual loss worldwide. Many pathologies included under this umbrella involve progressive degeneration and ultimate loss of the photoreceptor cells, with age-related macular degeneration and inherited and ischemic retinal diseases the most relevant. These diseases greatly impact patients' daily lives, with accompanying marked social and economic consequences. However, the currently available treatments only delay the onset or slow progression of visual impairment, and there are no cures for these photoreceptor diseases. Therefore, new therapeutic strategies are being investigated, such as gene therapy, optogenetics, cell replacement, or cell-based neuroprotection. Specifically, stem cells can secrete neurotrophic, immunomodulatory, and anti-angiogenic factors that potentially protect and preserve retinal cells from neurodegeneration. Further, neuroprotection can be used in different types of retinal degenerative diseases and at different disease stages, unlike other potential therapies. This review summarizes stem cell-based paracrine neuroprotective strategies for photoreceptor degeneration, which are under study in clinical trials, and the latest preclinical studies. Effective retinal neuroprotection could be the next frontier in photoreceptor diseases, and the development of novel neuroprotective strategies will address the unmet therapeutic needs.