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

Overview

Journal Stem Cell Res Ther

Publisher Biomed Central

Date 2022 Aug 3

PMID 35922863

Authors

Jia Zhang

Pengdong Li

Guifang Zhao

Siqi He

Di Xu

Weijie Jiang

Qian Peng

Zhaohui Li

Zhongjian Xie

Han Zhang

Ying Xu

Ling Qi

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

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

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

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

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

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

Gomes C, Cunha C, Nascimento F, Ribeiro J, Vaz A, Brites D . Cortical Neurotoxic Astrocytes with Early ALS Pathology and miR-146a Deficit Replicate Gliosis Markers of Symptomatic SOD1G93A Mouse Model. Mol Neurobiol. 2018; 56(3):2137-2158. DOI: 10.1007/s12035-018-1220-8. View

Chang B, Hawes N, Pardue M, German A, Hurd R, Davisson M . Two mouse retinal degenerations caused by missense mutations in the beta-subunit of rod cGMP phosphodiesterase gene. Vision Res. 2007; 47(5):624-33. PMC: 2562796. DOI: 10.1016/j.visres.2006.11.020. View

Bian B, Zhao C, He X, Gong Y, Ren C, Ge L . Exosomes derived from neural progenitor cells preserve photoreceptors during retinal degeneration by inactivating microglia. J Extracell Vesicles. 2020; 9(1):1748931. PMC: 7191912. DOI: 10.1080/20013078.2020.1748931. View

Roche S, Wyse-Jackson A, Byrne A, Ruiz-Lopez A, Cotter T . Alterations to retinal architecture prior to photoreceptor loss in a mouse model of retinitis pigmentosa. Int J Dev Biol. 2016; 60(4-6):127-39. DOI: 10.1387/ijdb.150400tc. View

10.

Park H, Huang X, Lu C, Cairo M, Zhou X . MicroRNA-146a and microRNA-146b regulate human dendritic cell apoptosis and cytokine production by targeting TRAF6 and IRAK1 proteins. J Biol Chem. 2014; 290(5):2831-41. PMC: 4317016. DOI: 10.1074/jbc.M114.591420. View

11.

Safe S, Jin U, Morpurgo B, Abudayyeh A, Singh M, Tjalkens R . Nuclear receptor 4A (NR4A) family - orphans no more. J Steroid Biochem Mol Biol. 2015; 157:48-60. PMC: 4618773. DOI: 10.1016/j.jsbmb.2015.04.016. View

12.

Duan S, Wang F, Cao J, Wang C . Exosomes Derived from MicroRNA-146a-5p-Enriched Bone Marrow Mesenchymal Stem Cells Alleviate Intracerebral Hemorrhage by Inhibiting Neuronal Apoptosis and Microglial M1 Polarization. Drug Des Devel Ther. 2020; 14:3143-3158. PMC: 7425091. DOI: 10.2147/DDDT.S255828. View

13.

Nakano M, Kubota K, Kobayashi E, Chikenji T, Saito Y, Konari N . Bone marrow-derived mesenchymal stem cells improve cognitive impairment in an Alzheimer's disease model by increasing the expression of microRNA-146a in hippocampus. Sci Rep. 2020; 10(1):10772. PMC: 7330036. DOI: 10.1038/s41598-020-67460-1. View

14.

Yu B, Shao H, Su C, Jiang Y, Chen X, Bai L . Exosomes derived from MSCs ameliorate retinal laser injury partially by inhibition of MCP-1. Sci Rep. 2016; 6:34562. PMC: 5043341. DOI: 10.1038/srep34562. View

15.

Zhao G, Liu F, Liu Z, Zuo K, Wang B, Zhang Y . MSC-derived exosomes attenuate cell death through suppressing AIF nucleus translocation and enhance cutaneous wound healing. Stem Cell Res Ther. 2020; 11(1):174. PMC: 7212595. DOI: 10.1186/s13287-020-01616-8. View

16.

Zhu J, Cifuentes H, Reynolds J, Lamba D . Immunosuppression via Loss of IL2rγ Enhances Long-Term Functional Integration of hESC-Derived Photoreceptors in the Mouse Retina. Cell Stem Cell. 2017; 20(3):374-384.e5. DOI: 10.1016/j.stem.2016.11.019. View

17.

Mead B, Tomarev S . Extracellular vesicle therapy for retinal diseases. Prog Retin Eye Res. 2020; 79:100849. PMC: 9460937. DOI: 10.1016/j.preteyeres.2020.100849. View

18.

Deng C, Hu C, Ling S, Zhao N, Bao L, Zhou F . Photoreceptor protection by mesenchymal stem cell transplantation identifies exosomal MiR-21 as a therapeutic for retinal degeneration. Cell Death Differ. 2020; 28(3):1041-1061. PMC: 7937676. DOI: 10.1038/s41418-020-00636-4. View

19.

Mead B, Tomarev S . Bone Marrow-Derived Mesenchymal Stem Cells-Derived Exosomes Promote Survival of Retinal Ganglion Cells Through miRNA-Dependent Mechanisms. Stem Cells Transl Med. 2017; 6(4):1273-1285. PMC: 5442835. DOI: 10.1002/sctm.16-0428. View

20.

Riazifar M, Pone E, Lotvall J, Zhao W . Stem Cell Extracellular Vesicles: Extended Messages of Regeneration. Annu Rev Pharmacol Toxicol. 2016; 57:125-154. PMC: 5360275. DOI: 10.1146/annurev-pharmtox-061616-030146. View