{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T20:01:30Z","timestamp":1792094490058,"version":"4.4.0"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T00:00:00Z","timestamp":1740960000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Age-related macular degeneration (AMD) is a leading cause of vision loss in those over 60\u202fyears of age. Although there are limited interventions that may prevent the development or progression of disease, more efficacious treatments are required. Short-pulsed laser treatment shows promise in delaying progression of early disease. This work details how nanosecond laser influences the retinal pigment epithelium (RPE), the principal cell type implicated in AMD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>C57BL\/6J mice (3-month-old) underwent monocular nanosecond laser treatment to assess short-term RPE response, while 9-month-old C57BL\/6J and ApoEnull mice were similarly treated and longer-term responses investigated after 3\u202fmonths. Human tissue was also obtained after 2 nanosecond laser treatments (1\u202fmonth apart). RPE proliferation was assessed using bromodeoxyuridine and RPE gene change explored using qPCR and RNAseq. Melanin and lipofuscin content were quantified using histological techniques.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Nanosecond laser induced RPE proliferation in treated and fellow mouse eyes, with monolayer repair occurring within 3\u202fdays. This was replicated in human tissue, albeit over a longer duration (1\u20134\u202fweeks). Wildtype animals showed no overt change in RPE gene expression after short or longer post-treatment durations, while laser treated ApoEnull animals showed increased <jats:italic>Mertk<\/jats:italic> and <jats:italic>Pedf<\/jats:italic> expression, and a reduced number of dysregulated aging genes in treated and fellow eyes after 3\u202fmonths. Furthermore, melanin and lipofuscin content were restored to wildtype levels in laser-treated ApoEnull RPE, while melanolipofuscin granules were reduced within treated regions of human RPE.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This work shows nanosecond laser stimulates RPE proliferation and results in an improved cellular phenotype. These data provide a biological basis for the prophylactic use of nanosecond lasers in AMD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2025.1516900","type":"journal-article","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T07:03:49Z","timestamp":1740985429000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Nanosecond laser induces proliferation and improved cellular health within the retinal pigment epithelium"],"prefix":"10.3389","volume":"12","author":[{"given":"Andrew I.","family":"Jobling","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Findlay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Greferath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirstan A.","family":"Vessey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satya","family":"Gunnam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Morrison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gene","family":"Venables","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robyn H.","family":"Guymer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica L.","family":"Fletcher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,3]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1459","DOI":"10.1016\/S0140-6736(22)02609-5","article-title":"Age-related macular degeneration","volume":"401","author":"Guymer","year":"2023","journal-title":"Lancet"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1152\/physrev.00021.2004","article-title":"The retinal pigment epithelium in visual function","volume":"85","author":"Strauss","year":"2005","journal-title":"Physiol Rev"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.preteyeres.2006.12.002","article-title":"Ion channels in the RPE","volume":"26","author":"Wimmers","year":"2007","journal-title":"Prog Retin Eye Res"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1038\/177174a0","article-title":"Synthesis and bleaching of rhodopsin","volume":"177","author":"Wald","year":"1956","journal-title":"Nature"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1083\/jcb.42.2.392","article-title":"Participation of the retinal pigment epithelium in the rod outer segment renewal process","volume":"42","author":"Young","year":"1969","journal-title":"J Cell Biol"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1016\/S0140-6736(18)31550-2","article-title":"Age-related macular degeneration","volume":"392","author":"Mitchell","year":"2018","journal-title":"Lancet"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1009599","DOI":"10.3389\/fnins.2022.1009599","article-title":"Exploring the pathogenesis of age-related macular degeneration: a review of the interplay between retinal pigment epithelium dysfunction and the innate immune system","volume":"16","author":"Wong","year":"2022","journal-title":"Front Neurosci"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1001\/archopht.1973.01000050208006","article-title":"Drusen and disciform macular detachment and degeneration","volume":"90","author":"Gass","year":"1973","journal-title":"Arch Ophthalmol"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"484","DOI":"10.3390\/jcm10030484","article-title":"Subthreshold Nano-second Laser treatment and age-related macular degeneration","volume":"10","author":"Cohn","year":"2021","journal-title":"J Clin Med"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"2305","DOI":"10.1167\/iovs.12-11203","article-title":"Retinal damage profiles and neuronal effects of laser treatment: comparison of a conventional photocoagulator and a novel 3-nanosecond pulse laser","volume":"54","author":"Wood","year":"2013","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1096\/fj.14-262444","article-title":"Nanosecond laser therapy reverses pathologic and molecular changes in age-related macular degeneration without retinal damage","volume":"29","author":"Jobling","year":"2015","journal-title":"FASEB J"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1002\/lsm.20022","article-title":"Influence of pulse duration and pulse number in selective RPE laser treatment","volume":"34","author":"Framme","year":"2004","journal-title":"Lasers Surg Med"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"024001","DOI":"10.1117\/1.1896969","article-title":"Boiling nucleation on melanosomes and microbeads transiently heated by nanosecond and microsecond laser pulses","volume":"10","author":"Neumann","year":"2005","journal-title":"J Biomed Opt"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/j.oret.2016.12.001","article-title":"Subthreshold nanosecond Laser intervention in intermediate age-related macular degeneration: study design and baseline characteristics of the Laser in early stages of age-related macular degeneration study (report number 1)","volume":"1","author":"Lek","year":"2017","journal-title":"Ophthalmol Retina"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1016\/j.ophtha.2018.09.015","article-title":"Intervention in early stages of age-related macular degeneration study, subthreshold nanosecond Laser intervention in age-related macular degeneration: the LEAD randomized controlled clinical trial","volume":"126","author":"Guymer","year":"2019","journal-title":"Ophthalmology"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1167\/tvst.8.6.11","article-title":"Selective retina therapy reduces Bruch's membrane thickness and retinal pigment epithelium pathology in age-related macular degeneration mouse models","volume":"8","author":"Tode","year":"2019","journal-title":"Transl Vis Sci Technol"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1167\/tvst.7.3.2","article-title":"Thermal stimulation of the retina reduces Bruch's membrane thickness in age related macular degeneration mouse models","volume":"7","author":"Tode","year":"2018","journal-title":"Transl Vis Sci Technol"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"4471","DOI":"10.1073\/pnas.89.10.4471","article-title":"Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells","volume":"89","author":"Piedrahita","year":"1992","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1111\/ceo.12247","article-title":"Nanosecond-laser application in intermediate AMD: 12-month results of fundus appearance and macular function","volume":"42","author":"Guymer","year":"2014","journal-title":"Clin Experiment Ophthalmol"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1320","DOI":"10.1016\/j.ophtha.2016.02.009","article-title":"Correlation of histologic features with in vivo imaging of reticular Pseudodrusen","volume":"123","author":"Greferath","year":"2016","journal-title":"Ophthalmology"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"3350","DOI":"10.1167\/iovs.13-11831","article-title":"A naturally occurring mouse model of achromatopsia: characterization of the mutation in cone transducin and subsequent retinal phenotype","volume":"54","author":"Jobling","year":"2013","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1006\/abio.1999.4085","article-title":"Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro","volume":"270","author":"Winer","year":"1999","journal-title":"Anal Biochem"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1038\/s41596-018-0103-9","article-title":"Pathway enrichment analysis and visualization of omics data using g: profiler, GSEA, Cytoscape and EnrichmentMap","volume":"14","author":"Reimand","year":"2019","journal-title":"Nat Protoc"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1670","DOI":"10.1016\/j.ajpath.2017.04.016","article-title":"Loss of function of P2X7 receptor scavenger activity in aging mice: a novel model for investigating the early pathogenesis of age-related macular degeneration","volume":"187","author":"Vessey","year":"2017","journal-title":"Am J Pathol"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"e29245","DOI":"10.1371\/journal.pone.0029245","article-title":"Zinc deficiency leads to lipofuscin accumulation in the retinal pigment epithelium of pigmented rats","volume":"6","author":"Julien","year":"2011","journal-title":"PLoS One"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1167\/iovs.61.5.35","article-title":"Autofluorescent granules of the human retinal pigment epithelium: phenotypes, intracellular distribution, and age-related topography","volume":"61","author":"Bermond","year":"2020","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"2928","DOI":"10.1167\/iovs.11-8585","article-title":"Laser-mediated activation of human retinal pigment epithelial cells and concomitant release of matrix metalloproteinases","volume":"53","author":"Zhang","year":"2012","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1167\/iovs.17-23098","article-title":"Nanosecond Laser treatment for age-related macular degeneration does not induce focal vision loss or new vessel growth in the retina","volume":"59","author":"Vessey","year":"2018","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"e0141597","DOI":"10.1371\/journal.pone.0141597","article-title":"Comparison of mouse and human retinal pigment epithelium gene expression profiles: potential implications for age-related macular degeneration","volume":"10","author":"Bennis","year":"2015","journal-title":"PLoS One"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1186\/1471-2164-10-164","article-title":"Functional annotation of the human retinal pigment epithelium transcriptome","volume":"10","author":"Booij","year":"2009","journal-title":"BMC Genomics"},{"key":"ref31","first-page":"1235","article-title":"Transcriptome networks in the mouse retina: an exon level BXD RI database","volume":"21","author":"King","year":"2015","journal-title":"Mol Vis"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1016\/j.bbrc.2015.07.120","article-title":"Identification and characterization of proliferative retinopathy-related long noncoding RNAs","volume":"465","author":"Zhou","year":"2015","journal-title":"Biochem Biophys Res Commun"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"2368","DOI":"10.1080\/15548627.2022.2034131","article-title":"Treatments targeting autophagy ameliorate the age-related macular degeneration phenotype in mice lacking APOE (apolipoprotein E)","volume":"18","author":"Vessey","year":"2022","journal-title":"Autophagy"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/S0014-4835(02)00247-6","article-title":"Loss of melanin from human RPE with aging: possible role of melanin photooxidation","volume":"76","author":"Sarna","year":"2003","journal-title":"Exp Eye Res"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1016\/S0167-4943(02)00012-2","article-title":"Potential role of retinal pigment epithelial lipofuscin accumulation in age-related macular degeneration","volume":"34","author":"Katz","year":"2002","journal-title":"Arch Gerontol Geriatr"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"7085","DOI":"10.1167\/iovs.14-16246","article-title":"Human adult retinal pigment epithelial stem cell-derived RPE monolayers exhibit key physiological characteristics of native tissue","volume":"56","author":"Blenkinsop","year":"2015","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"3486","DOI":"10.1167\/iovs.16-19508","article-title":"Retinal pigment epithelium responses to selective retina therapy in mouse eyes","volume":"57","author":"Kim","year":"2016","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1167\/iovs.17-23163","article-title":"Release of different cell mediators during retinal pigment epithelium regeneration following selective retina therapy","volume":"59","author":"Richert","year":"2018","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1186\/s12886-021-02188-8","article-title":"Selective retina therapy and thermal stimulation of the retina: different regenerative properties - implications for AMD therapy","volume":"21","author":"Richert","year":"2021","journal-title":"BMC Ophthalmol"},{"key":"ref41","first-page":"18","article-title":"A culture model of development reveals multiple properties of RPE tight junctions","volume":"3","author":"Ban","year":"1997","journal-title":"Mol Vis"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"4555","DOI":"10.1167\/iovs.12-11572","article-title":"Disruption of cell-cell junctions and induction of pathological cytokines in the retinal pigment epithelium of light-exposed mice","volume":"54","author":"Narimatsu","year":"2013","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1111\/ceo.13931","article-title":"Physiological response of the retinal pigmented epithelium to 3-ns pulse laser application, in vitro and in vivo","volume":"49","author":"Wood","year":"2021","journal-title":"Clin Experiment Ophthalmol"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"2319","DOI":"10.1167\/iovs.12-11204","article-title":"Glial cell and inflammatory responses to retinal laser treatment: comparison of a conventional photocoagulator and a novel, 3-nanosecond pulse laser","volume":"54","author":"Chidlow","year":"2013","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1093\/jleuko\/qiac016","article-title":"Ocular immune privilege and retinal pigment epithelial cells","volume":"113","author":"Du","year":"2023","journal-title":"J Leukoc Biol"},{"key":"ref46","first-page":"570","article-title":"Microscopic mammalian retinal pigment epithelium lesions induce widespread proliferation with differences in magnitude between center and periphery","volume":"16","author":"von Leithner","year":"2010","journal-title":"Mol Vis"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1007\/s00417-011-1673-1","article-title":"Epidermal growth factor: the driving force in initiation of RPE cell proliferation","volume":"249","author":"Steindl-Kuscher","year":"2011","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"e1007939","DOI":"10.1371\/journal.pgen.1007939","article-title":"Regeneration of the zebrafish retinal pigment epithelium after widespread genetic ablation","volume":"15","author":"Hanovice","year":"2019","journal-title":"PLoS Genet"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1007\/s003470070020","article-title":"Effect of octreotide combined with growth factors on proliferation of RPE cells in vitro","volume":"97","author":"Amann","year":"2000","journal-title":"Ophthalmologe"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"5164","DOI":"10.1167\/iovs.16-20736","article-title":"Bone marrow-derived cell recruitment to the neurosensory retina and retinal pigment epithelial cell layer following subthreshold retinal phototherapy","volume":"58","author":"Caballero","year":"2017","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"100031","DOI":"10.1016\/j.cytox.2020.100031","article-title":"Modulation of inflammatory processes by thermal stimulating and RPE regenerative laser therapies in age related macular degeneration mouse models","volume":"2","author":"Richert","year":"2020","journal-title":"Cytokine X"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1007\/s12013-015-0675-8","article-title":"Biological modulation of mouse RPE cells in response to subthreshold diode micropulse Laser treatment","volume":"73","author":"Li","year":"2015","journal-title":"Cell Biochem Biophys"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"2295","DOI":"10.1007\/s10103-015-1809-3","article-title":"Effects of low-level laser irradiation on proliferation and functional protein expression in human RPE cells","volume":"30","author":"Dang","year":"2015","journal-title":"Lasers Med Sci"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"150","DOI":"10.3389\/fnagi.2020.00150","article-title":"APOE Alleles and Diet in Brain Aging and Alzheimer's Disease","volume":"12","author":"Yassine","year":"2020","journal-title":"Front Aging Neurosci"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1002\/humu.20957","article-title":"Age-related macular degeneration and functional promoter and coding variants of the apolipoprotein E gene","volume":"30","author":"Fritsche","year":"2009","journal-title":"Hum Mutat"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1002\/humu.20288","article-title":"Apolipoprotein (APOE) gene is associated with progression of age-related macular degeneration (AMD)","volume":"27","author":"Baird","year":"2006","journal-title":"Hum Mutat"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1167\/iovs.63.1.23","article-title":"Autofluorescent organelles within the retinal pigment epithelium in human donor eyes with and without age-related macular degeneration","volume":"63","author":"Bermond","year":"2022","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1016\/j.oret.2019.07.008","article-title":"Secondary and exploratory outcomes of the subthreshold nanosecond laser intervention randomized trial in age-related macular degeneration: a LEAD study report","volume":"3","author":"Wu","year":"2019","journal-title":"Ophthalmol Retina"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2025.1516900\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T07:03:53Z","timestamp":1740985433000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2025.1516900\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,3]]},"references-count":58,"alternative-id":["10.3389\/fmed.2025.1516900"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2025.1516900","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,3]]},"article-number":"1516900"}}