Abstract
The retinal pigment epithelium (RPE), the outermost layer of the retina, provides essential support to both the neural retina and choroid. Additionally, the RPE is highly active in modulating functions of immune cells such as microglia, which migrate to the subretinal compartment during aging and age-related degeneration. Recently, studies have highlighted the important roles of microRNA (miRNA) in the coordination of general tissue maintenance as well as in chronic inflammatory conditions. In this study, we analyzed the miRNA profiles in extracellular vesicles (EVs) released by the RPE, and identified and validated miRNA species whose expression levels showed age-dependent changes in the EVs. Using co-culture of RPE and retinal microglia, we further demonstrated that miR-21 was transferred between the two types of cells, and the increased miR-21 in microglia influenced the expression of genes downstream of the p53 pathway. These findings suggest that exosome-mediated miRNA transfer is a signaling mechanism that contributes to the regulation of microglia function in the aging retina.
Highlights
Postmitotic cells, such as neurons and the retinal pigment epithelium (RPE), tend to accumulate macromolecular damage and degenerate early in the aging process [1,2]
PE-derived exosomal miRNAs in modulating mIincrtohgelicaul rfruenncttisotun.dWy, ewfeouexnadmthinaetdagthede rRoPleEscoefllRs PinEc-rdeearsievdedtheexroesloeamsealomf aiRsNelAecstiivnemseotdouf lmatiiRnNg As micirnogthlieailrfuexnocstioomn.eWs. eUfsoiungndmtihRa-t2a1gaesdaRpPrEocoefl-losfi-ncocrnecaespetdatphperroealecahs,ewoef adesemleocntisvtreastetdotfhmatiRmNiRA-s21incan theibreextroasnosmfeersre. dUsbientgwmeeinR-R21PEasaandprmooifc-roofg-clioan, caenpdt athpepreoleavchat,ewdemdieRm-2o1nsctornatedntthinatmmiciRro-2g1liacaanffbeected trangsefneerrexdpbretswsieoenninRPthEeapn5d3mpiactrhowglaiya., aTnhde tfhinedeilnegvsatseudggmeisRt -t2h1atcoenxtoesnotmine-mmiecdroiagtleida amffieRcNteAd gtreannesfer expcraenssbioenainsigthnealpin53g pmaethchwaanyi.sTmhreefilantdedintgos cshurgogneisctitnhfalat mexmosaotmione-mduerdiniagteRdPmEiaRgNinAg.transfer can be a signaling mechanism related to chronic inflammation during RPE aging
Findings from our current study suggest that the transferring of miRNAs via RPE-derived exosomes can be a regulatory mechanism that modulates the functional status of the subretinal microglia
Summary
Postmitotic cells, such as neurons and the retinal pigment epithelium (RPE), tend to accumulate macromolecular damage and degenerate early in the aging process [1,2]. In addition to the intrinsic mechanisms of these cells, in neuronal tissue like the retina, the rate of aging and the progression of degeneration are strongly influenced by the surrounding microenvironment and cell–cell interactions. As transferrable genetic materials between different cell types, microRNAs (miRNAs) play important roles in modulating inflammation associated with organism longevity and tissue aging [5,6,7]. AAthgwe-areylsateredlactheadngtoes aogfimngiR[N16A].pIrnofiolecus lhaarvteisbseueens,rempoiRrtNedAisnare varionuvsoltvisesdueisnabnodthorpghanysi[o1l2o–g1i5c]a,lapnrdomceisRseNsA, ssuccahn asstrolingghlty/dinarflkueandcaepctaotmiopnon[1e7n]tsanofdmciarjcoardsiagnarlhinygthm path[1w8a],yasnrdelmateadnytodaisgeinasge[1p6r]o.cIenssoecsu[l1a9r–ti2s3s]u,eins,cmluidRiNngAasgaer-ereinlavtoeldvemdaicnublaorthdepgheynseiorlaotgioicna(lApMrocDe)ss[2e4s,]. It suchisafsoluignhdt/tdhaartkmadiRapNtaAtisoenx[i1s7t]inanedxocisrocamdeiasn, arnhdytehxmos[1o8m],aalnmdimRNanAysdcisaenasbeepdroelcievsesreesd[1t9o–r2e3c],ipinieclnutdcienlgls as ages-rieglnaatelidnmg macouleacrudlegse[n2e5r–a2t7io].n (AMD) [24]. DUsbientgwmeeinR-R21PEasaandprmooifc-roofg-clioan, caenpdt athpepreoleavchat,ewdemdieRm-2o1nsctornatedntthinatmmiciRro-2g1liacaanffbeected trangsefneerrexdpbretswsieoenninRPthEeapn5d3mpiactrhowglaiya., aTnhde tfhinedeilnegvsatseudggmeisRt -t2h1atcoenxtoesnotmine-mmiecdroiagtleida amffieRcNteAd gtreannesfer expcraenssbioenainsigthnealpin53g pmaethchwaanyi.sTmhreefilantdedintgos cshurgogneisctitnhfalat mexmosaotmione-mduerdiniagteRdPmEiaRgNinAg.transfer can be a signaling mechanism related to chronic inflammation during RPE aging PE-derived exosomal miRNAs in modulating mIincrtohgelicaul rfruenncttisotun.dWy, ewfeouexnadmthinaetdagthede rRoPleEscoefllRs PinEc-rdeearsievdedtheexroesloeamsealomf aiRsNelAecstiivnemseotdouf lmatiiRnNg As micirnogthlieailrfuexnocstioomn.eWs. eUfsoiungndmtihRa-t2a1gaesdaRpPrEocoefl-losfi-ncocrnecaespetdatphperroealecahs,ewoef adesemleocntisvtreastetdotfhmatiRmNiRA-s21incan theibreextroasnosmfeersre. dUsbientgwmeeinR-R21PEasaandprmooifc-roofg-clioan, caenpdt athpepreoleavchat,ewdemdieRm-2o1nsctornatedntthinatmmiciRro-2g1liacaanffbeected trangsefneerrexdpbretswsieoenninRPthEeapn5d3mpiactrhowglaiya., aTnhde tfhinedeilnegvsatseudggmeisRt -t2h1atcoenxtoesnotmine-mmiecdroiagtleida amffieRcNteAd gtreannesfer expcraenssbioenainsigthnealpin53g pmaethchwaanyi.sTmhreefilantdedintgos cshurgogneisctitnhfalat mexmosaotmione-mduerdiniagteRdPmEiaRgNinAg.transfer can be a signaling mechanism related to chronic inflammation during RPE aging
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