Paracrine effects of intraocularly implanted cells on degenerating retinas in mice

Abstract

Background: Retinal degeneration is a leading cause of blindness in the world; its etiology is complex and involves genetic defects and stress-associated aging. In addition to gene therapies for known genetically defective retinal degeneration, cellular therapies have been widely explored for restoring vision in both preclinical animal models and clinical trials. Stem cells of distinct tissue sources and their derived lineages have been tested for treating retinal degeneration; most of them were reported to be effective to some extent in restoring/improving deteriorated vision. Whether this visual improvement is due to a functional integration of grafted cells to substitute for lost retinal neurons in recipients or due to their neuroprotective and neurotrophic effects to retain recipient functional neurons, or both, is still under debate. Methods: We compared the results of subretinal transplantation of various somatic cell types, such as stem cells and differentiated cells, into Rho P23H/+ mice, a retinal degeneration model for human retinitis pigmentosa (RP) by evaluating their optokinetic response (OKR) and retinal histology. We identified some paracrine factors in the media that cultured cells secreted by western blotting (WB) and functionally evaluated the vascular endothelial growth factor Vegfa for its potential neurotrophic and neuroprotective effects on the neuroretina of model animals by intravitreal injection of VEGF antibody. Results: We found that live cells, regardless of whether they were stem cells or differentiated cell types, had a positive effect on improving degenerating retinas after subretinal transplantation; the efficacy depended on their survival duration in the host tissue. A few paracrine factors were identified in cell culture media; Vegfa was the most relevant neurotrophic and neuroprotective factor identified by our experiments to extend neuron survival duration in vivo. Conclusions: Cellular therapy-produced benefits for remediating retinal degeneration are mostly, if not completely, due to a paracrine effect of implanted cells on the remaining host retinal neurons.

Comparison of retinal degeneration treatment with four types of different mesenchymal stem cells, human induced pluripotent stem cells and RPE cells in a rat retinal degeneration model

“…Consistent with the previous studies [33,37,52,65], RCS rats or other animal models of RD, which underwent a progressive retinal degeneration, can be halted by stem cell-based therapy. Our study confirmed the protective effect of different stem cells and hiPSC-RPE cells on RCS rats with various degrees, and figured out the most effective stem cell-based therapy for RD that is the subretinal transplantation of hiPSC-RPE cells.…”

Biotechnology and Biomaterial-Based Therapeutic Strategies for Age-Related Macular Degeneration. Part II: Cell and Tissue Engineering Therapies

“…In the majority of the preclinical trials with dissociated cells suspensions for photoreceptor regeneration, the transplanted cells fail to survive or to functionally integrate with the host tissue; despite some positive results none of the attempted approaches achieved a significant restoration of the visual function ( Gamm and Wong, 2015 ; Canto-Soler et al, 2016 ; Zarbin, 2016 ). Furthermore, it is not known to which extent the observed improvements are due to the capability of the grafted cells of replacing the lost retinal tissue; to the secretion of protective and regenerative factors that protect the retinal neurons, or by both of them ( Liu et al, 2020 ).…”

“…This material transfer is bidirectional and, interestingly, it is independent of the source of implanted stem cells ( Singh et al, 2016 ; Ortin-Martinez et al, 2017 ; Waldron et al, 2018 ). It seems that the therapeutic effects are due more to neurotrophic and neuroprotective function, rather than functional integration in the diseased retina ( Liu et al, 2020 ). These facts raise the need to reevaluate all up-to-day photoreceptor transplant studies, characterizing the relative contribution to vision restoration based on material transfer and donor integration.…”

First steps for the development of silk fibroin-based 3D biohybrid retina for age-related macular degeneration (AMD)

“…Stem cells from different tissue sources and their derived lineages have been tested to treat retinal degeneration. Currently, it is not known whether visual improvement by cell therapy is due to the fact that the grafted cells are capable of replacing lost retinal neurons; or due to the secretion, by these cellular implants, of neuroprotective and neurotrophic factors that protect the host retina; or both causes [110].…”