Therapeutic effects of mesenchymal stem cells-derived extracellular vesicles' miRNAs on retinal regeneration: a review

Abstract

Extracellular vesicles (EVs), which consist of microvesicles and exosomes, are secreted from all cells to transform vital information in the form of lipids, proteins, mRNAs and small RNAs such as microRNAs (miRNAs). Many studies demonstrated that EVs' miRNAs have effects on target cells. Numerous people suffer from the blindness caused by retinal degenerations. The death of retinal neurons is irreversible and creates permanent damage to the retina. In the absence of acceptable cures for retinal degenerative diseases, stem cells and their paracrine agents including EVs have become a promising therapeutic approach. Several studies showed that the therapeutic effects of stem cells are due to the miRNAs of their EVs. Considering the effects of microRNAs in retinal cells development and function and studies which provide the possible roles of mesenchymal stem cells-derived EVs miRNA content on retinal diseases, we focused on the similarities between these two groups of miRNAs that could be helpful for promoting new therapeutic techniques for retinal degenerative diseases.

Keywords: Extracellular vesicles; Mesenchymal stem cells; Retina; miRNA.

Fig. 1

MiRNA synthesis pathway. Biogenesis of miRNA begins with transcription of a miRNA gene (Canonical pathway) or the intron region of a protein-coding gene (Mirtron pathway) mainly by RNA polymerase II, and sometimes by RNA polymerase III in the nucleus. Canonical pathway: The sequences from miRNA genes transcription self-anneal and make hairpin-like structures called primary miRNAs (pri-miRNAs). Pri-miRNAs are being cut by DGCR8/Drosha complex and become pre-miRNAs. Mirtron pathway: Pre-miRNAs which are the result of intron regions of protein-coding genes are not dependent on Drosha complex. They are divided by spliceosome from the primary transcript of mRNAs. Then, they will self-anneal and become pre-miRNAs directly. All Pre-miRNAs from both pathways leave the nucleus and enter the cytoplasm by Exportin-5. There, the pre-miRNAs are cleaved by the Dicer/TRBP complex, yielding an about 22 nucleotides long miRNA: miRNA* duplex molecule. Then, this molecule will be loaded into the Argonaute (Ago) part of RNA-induced silencing complex (RISC). After discarding one of the strands, the other one will remain in the RISC and binds to 3’ untranslated regions of target mRNAs. miRNAs binding to target mRNAs lead to their translational repression, deadenylation and cleavage

Fig. 2

MiRNAs enriched in retinal cells which are also present in MSC-EVs

Fig. 3

MSC-EVs’ miRNAs with studied effects on retinal cells. ILM, inner limiting membrane; GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; IS, inner segment of photoreceptors; OS, outer segment of photoreceptors; RPE, retinal pigment epithelium. General effects of miRNAs on retinal cells: ¹differentiaition, ²function, ³survival & apoptosis reduction, ⁴development & growth, ⁵reprogramming, ⁶maturation, ⁷proliferation, ⁸protection & maintenance, ⁹dedifferentiation