» Articles » PMID: 35922863

Mesenchymal Stem Cell-derived Extracellular Vesicles Protect Retina in a Mouse Model of Retinitis Pigmentosa by Anti-inflammation Through MiR-146a-Nr4a3 Axis

Overview
Publisher Biomed Central
Date 2022 Aug 3
PMID 35922863
Authors
Affiliations
Soon will be listed here.
Abstract

Background: Retinitis pigmentosa is a rod-cone degenerative disease that induces irreversible vision loss. This study probed the protective capacity of mesenchymal stem cell-derived small EVs (MSC-EVs) on the retinas of rd10 mice and the underlying mechanism.

Methods: MSC-EVs were injected into the vitreous of rd10 mice at postnatal day 14 and P21; morphology and function were examined at P28. The mechanism of action was explored by using co-culture of photoreceptor cell line 661 W and microglia cell line BV2.

Results: Treatment with MSC-EVs increased the survival of photoreceptors and preserved their structure. Visual function, as reflected by optomotor and electroretinogram responses, was significantly enhanced in MSC-EVs-treated rd10 mice. Mechanistically, staining for Iba1, GFAP, F4/80, CD68 and CD206 showed that MSC-EVs suppressed the activation of microglial, Müller glial and macrophages. Furthermore, western blotting showed that the treatment inhibited the NF-κB pathway. RNA-seq and qPCR showed that MSC-EVs upregulated anti-inflammatory cytokines while downregulating pro-inflammatory cytokines. MSC-EVs application in vitro decreased the number of TUNEL-positive 661 W cells co-cultured with LPS-stimulated BV2, with similar impact on the cytokine expression as in vivo study. Genetic screening predicted miR-146a to be the downstream target of MSC-EVs, which was detected in MSC-EVs and upregulated in co-cultured 661 W cells and BV2 cells after MSC-EVs treatment. Upregulation of miR-146a by using its mimic decreased the expression of the transcription factor Nr4a3, and its downregulation inhibition promoted Nr4a3 expression in both 661 W and BV2 cells. Nr4a3 was further identified as the target gene of miR-146a by dual-luciferase assay. Furthermore, overexpressing miR-146a significantly decreased the expression of LPS-induced pro-inflammatory cytokines in BV2 cells.

Conclusions: MSC-EVs delays retinal degeneration in rd10 mice mainly by its anti-inflammatory effect via the miR-146a-Nr4a3axis. Hence, MSC-EVs may be used in the treatment of neurodegenerative diseases.

Citing Articles

Mesenchymal stem cells and mesenchymal stem cell-derived exosomes: a promising strategy for treating retinal degenerative diseases.

An W, Zhang W, Qi J, Xu W, Long Y, Qin H Mol Med. 2025; 31(1):75.

PMID: 39984849 PMC: 11846226. DOI: 10.1186/s10020-025-01120-w.


Human hair follicle-derived mesenchymal stem cells improve ovarian function in cyclophosphamide-induced POF mice.

Mo J, Hu H, Li P, Ye Y, Chen W, Chen L Stem Cell Res Ther. 2025; 16(1):67.

PMID: 39934888 PMC: 11816600. DOI: 10.1186/s13287-024-04097-1.


Diagnostic and Therapeutic Utility of Extracellular Vesicles in Ocular Disease.

Khristov V, Weber S, Caton-Darby M, Campbell G, Sundstrom J Int J Mol Sci. 2025; 26(2).

PMID: 39859553 PMC: 11765869. DOI: 10.3390/ijms26020836.


Ghrelin Induces Ferroptosis Resistance and M2 Polarization of Microglia to Alleviate Neuroinflammation and Cognitive Impairment in Alzheimer's Disease.

Guo Y, Zhao J, Liu X, Lu P, Liang F, Wang X J Neuroimmune Pharmacol. 2025; 20(1):6.

PMID: 39797928 DOI: 10.1007/s11481-024-10165-3.


Potential guidelines for cataract surgery and rehabilitation in visually impaired patients: Literature analysis.

Limoli P, Limoli C, Nebbioso M Aging Med (Milton). 2025; 7(6):802-812.

PMID: 39777090 PMC: 11702492. DOI: 10.1002/agm2.12386.


References
1.
Zhang L, Zhao L, Zhu W, Ding Y, Chen H, Chi N . miR-146a Mimics Ameliorates Traumatic Brain Injury Involving JNK and NF-κB Signaling Pathway. Neuromolecular Med. 2020; 22(4):484-492. DOI: 10.1007/s12017-020-08599-y. View

2.
Mead B, Ahmed Z, Tomarev S . Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Promote Neuroprotection in a Genetic DBA/2J Mouse Model of Glaucoma. Invest Ophthalmol Vis Sci. 2018; 59(13):5473-5480. PMC: 6735616. DOI: 10.1167/iovs.18-25310. View

3.
Zhao G, Liu F, Lan S, Li P, Wang L, Kou J . Large-scale expansion of Wharton's jelly-derived mesenchymal stem cells on gelatin microbeads, with retention of self-renewal and multipotency characteristics and the capacity for enhancing skin wound healing. Stem Cell Res Ther. 2015; 6:38. PMC: 4413550. DOI: 10.1186/s13287-015-0031-3. View

4.
Terrell D, Comander J . Current Stem-Cell Approaches for the Treatment of Inherited Retinal Degenerations. Semin Ophthalmol. 2019; 34(4):287-292. DOI: 10.1080/08820538.2019.1620808. View

5.
Lei B, Liu J, Yao Z, Xiao Y, Zhang X, Zhang Y . NF-κB-Induced Upregulation of miR-146a-5p Promoted Hippocampal Neuronal Oxidative Stress and Pyroptosis TIGAR in a Model of Alzheimer's Disease. Front Cell Neurosci. 2021; 15:653881. PMC: 8085266. DOI: 10.3389/fncel.2021.653881. View