Potential therapeutic strategies for photoreceptor degeneration: the path to restore vision.

Photoreceptors (PRs), as the most abundant and light-sensing cells of the neuroretina, are responsible for converting light into electrical signals that can be interpreted by the brain. PR degeneration, including morphological and functional impairment of these cells, causes significant diminution of the retina's ability to detect light, with consequent loss of vision. Recent findings in ocular regenerative medicine have opened promising avenues to apply neuroprotective therapy, gene therapy, cell replacement therapy, and visual prostheses to the challenge of restoring vision. However, successful visual restoration in the clinical setting requires application of these therapeutic approaches at the appropriate stage of the retinal degeneration. In this review, firstly, we discuss the mechanisms of PR degeneration by focusing on the molecular mechanisms underlying cell death. Subsequently, innovations, recent developments, and promising treatments based on the stage of disorder progression are further explored. Then, the challenges to be addressed before implementation of these therapies in clinical practice are considered. Finally, potential solutions to overcome the current limitations of this growing research area are suggested. Overall, the majority of current treatment modalities are still at an early stage of development and require extensive additional studies, both pre-clinical and clinical, before full restoration of visual function in PR degeneration diseases can be realized.

Potential neuroprotective effect of stem cells from apical papilla derived extracellular vesicles enriched by lab-on-chip approach during retinal degeneration.

Retinal degeneration (RD) is recognized as a frequent cause of visual impairments, including inherited (Retinitis pigmentosa) and degenerative (age-related macular) eye diseases. Dental stem cells (DSCs) have recently demonstrated a promising neuroprotection potential for ocular diseases through a paracrine manner carried out by extracellular vesicles (EVs). However, effective isolation of EVs is still challenging, and isolation methods determine the composition of enriched EVs and the subsequent biological and functional effects. In the present study, we assessed two enrichment methods (micro-electromechanical systems and ultrafiltration) to isolate the EVs from stem cells from apical papilla (SCAP). The size distribution of the corresponding isolates exhibited the capability of each method to enrich different subsets of EVs, which significantly impacts their biological and functional effects. We confirmed the neuroprotection and anti-inflammatory capacity of the SCAP-EVs in vitro. Further experiments revealed the possible therapeutic effects of subretinal injection of SCAP-EVs in the Royal College of Surgeons (RCS) rat model. We found that EVs enriched by the micro-electromechanical-based device (MEMS-EVs) preserved visual function, reduced retinal cell apoptosis, and prevented thinning of the outer nuclear layer (ONL). Interestingly, the effect of MEMS-EVs was extended to the retinal ganglion cell/retinal nerve fiber layer (GCL/RNFL). This study supports the use of the microfluidics approach to enrich valuable subsets of EVs, together with the choice of SCAP as a source to derive EVs for cell-free therapy of RD.

Scaffold free retinal pigment epithelium sheet engineering using modified alginate-RGD hydrogel.

Tissue-specific extracellular matrix (ECM) plays a critical role in cell survival and homeostasis, which are particularly essential for directing differentiation of different complex tissues such as retina. However, ECM maintenance should be considered to design an effective therapeutic strategy for retina regeneration. To achieve this, cell sheet engineering has emerged as a growing approach to closely reconstruct basal membrane of cells through a scaffold-free manner. Several irreversible sight-threatening diseases are characterized by the dysfunction and lose of retinal pigment epithelium (RPE), leading to vision loss and eventually total blindness in patients. According to impressive developments in achievement of RPE from human embryonic stem cells (hESCs), we obtained RPE cells without any extrinsic factors in a co-culture system, and cultured them on a temporary alginate hydrogel substrate. Subsequently, Arg-Gly-Asp (RGD) peptide was superficially immobilized on the upper layer of hydrogel to improve cell attachment before harvesting sheet layer. RPE cell sheet layer was released by treating pre-seeded hydrogels with sodium citrate as a calcium chelating agent and characterized in both in vitro and in vivo models. RPE sheets formed tight junction and expressed high levels of retina structural markers such as ZO-1, Bestrophin and Collagen type IV. One week after in vivo transplantation of RPE sheet, cells survived in the subretinal space, indicating that our harvesting method is non-invasive. To sum up, we introduced a unique scaffold-free method for RPE cell sheet engineering, which can find potential use for future therapeutic purposes.