Photoreceptor protection by mesenchymal stem cell transplantation identifies exosomal MiR-21 as a therapeutic for retinal degeneration

Abstract

Photoreceptor apoptosis is recognized as one key pathogenesis of retinal degeneration, the counteraction of which represents a promising approach to safeguard visual function. Recently, mesenchymal stem cell transplantation (MSCT) has demonstrated immense potential to treat ocular disorders, in which extracellular vesicles (EVs), particularly exosomes, have emerged as effective ophthalmological therapeutics. However, whether and how MSCT protects photoreceptors against apoptotic injuries remains largely unknown. Here, we discovered that intravitreal MSCT counteracted photoreceptor apoptosis and alleviated retinal morphological and functional degeneration in a mouse model of photoreceptor loss induced by N-methyl-N-nitrosourea (MNU). Interestingly, effects of MSCT were inhibited after blockade of exosomal generation by GW4869 preconditioning. Furthermore, MSC-derived exosomal transplantation (EXOT) effectively suppressed MNU-provoked photoreceptor injury. Notably, therapeutic efficacy of MSCT and EXOT on MNU-induced retinal degeneration was long-lasting as photoreceptor preservance and retinal maintenance were detected even after 1–2 months post to injection for only once. More importantly, using a natural occurring retinal degeneration model caused by a nonsense mutation of Phosphodiesterase 6b gene (Pde6bmut), we confirmed that MSCT and EXOT prevented photoreceptor loss and protected long-term retinal function. In deciphering therapeutic mechanisms regarding potential exosome-mediated communications, we identified that miR-21 critically maintained photoreceptor viability against MNU injury by targeting programmed cell death 4 (Pdcd4) and was transferred from MSC-derived exosomes in vivo for functional regulation. Moreover, miR-21 deficiency aggravated MNU-driven retinal injury and was restrained by EXOT. Further experiments revealed that miR-21 mediated therapeutic effects of EXOT on MNU-induced photoreceptor apoptosis and retinal dysfunction. These findings uncovered the efficacy and mechanism of MSCT-based photoreceptor protection, indicating exosomal miR-21 as a therapeutic for retinal degeneration.

Evaluation of the Diagnostic Potential of a Plasma Exosomal miRNAs Panel for Gastric Cancer

“…For blockade of SGC-7901 cell line generation of exosomes ( 20 ), 10-μM GW4869 (Sigma-Aldrich, USA) was applied in SGC-7901 culture for 24 h, which was initially dissolved in DMSO into a stock solution of 5 mM and was diluted in culture media. The effects of GW4869 on SGC-7901 biological functions were determined after wash-out procedures.…”

The role of miRNA in retinal ganglion cell health and disease

“…In mouse models of photoreceptor degeneration, MSC and MSC-derived exosomes were sufficient in preventing cellular degeneration and functional deterioration. Interestingly, exosomes isolated from MSC of miR-21 knockout mice were no longer therapeutically efficacious (Deng et al, 2020). miR-155 is associated with retinal inflammation following injury and its expression in glial cells is up-regulated in response to stress.…”

Small extracellular vesicles from menstrual blood-derived mesenchymal stem cells (MenSCs) as a novel therapeutic impetus in regenerative medicine

“…Currently, the similarity of therapeutic mechanisms between MenSC-derived and other sources of small EVs is mainly due to the secretion of effective bioactive molecules and production of miRNAs [163]. The miR-21, miR-27a, miR-196a, and miR-206 are abundant in EVs from BM-MSCs and are responsible for pro-regenerative and immunomodulatory effects [164][165][166]; miR-20, miR-21, miR-23a, miR-125b, miR-326, and miR-145 are profuse in EVs from UC-MSCs and are responsible for mediation of apoptosis, regulation of autophagy, inhibition of neddylation, and suppression of myofibroblast differentiation [167][168][169]; let-7, miR148a, miR378, and miR532-5p are abundant in EVs from AD-MSCs and are responsible for angiogenesis, cellular transport, apoptosis, and proteolysis [170,171]; and let-7 and miR21 are abundant in EVs from MenSCs and are responsible for regulating mitochondrial-DNA damage and enhancing cell survival rate [134,146]. Several studies explored MSC-derived small EVs signaling pathways [64,160,172,173], supporting that a thorough database of small EVs from MenSCs is needed to further assess their therapeutic potential.…”