{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:41:54Z","timestamp":1781106114724,"version":"3.54.1"},"reference-count":61,"publisher":"National Academy of Sciences","issue":"29","license":[{"start":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T00:00:00Z","timestamp":1752451200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"HHS | NIH | National Eye Institute","doi-asserted-by":"publisher","award":["R01 EY029748"],"award-info":[{"award-number":["R01 EY029748"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"publisher","award":["Catalyst Award"],"award-info":[{"award-number":["Catalyst Award"]}],"id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"publisher","award":["unrestricted funds"],"award-info":[{"award-number":["unrestricted funds"]}],"id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001608","name":"EyeSight Foundation of Alabama","doi-asserted-by":"publisher","award":["unrestricted funds"],"award-info":[{"award-number":["unrestricted funds"]}],"id":[{"id":"10.13039\/100001608","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,7,22]]},"abstract":"<jats:p>The retinal pigment epithelium (RPE) is the metabolic gatekeeper to the photoreceptors, thus playing many essential roles in healthy vision. Under certain conditions, RPE cells may transdifferentiate and migrate from the RPE layer. Ectopic RPE cells are potential signal sources for hyperreflective foci, prominent clinically visible biomarkers in age-related macular degeneration, which causes central vision loss globally. Applying multiple imaging modalities including ex vivo optical coherence tomography, autofluorescence microscopy, and imaging mass spectrometry (IMS) to human retina tissue, we compared lipid profiles in ectopic and orthotopic RPE cells. Our results showed that ectopic RPE cells share some molecular signatures with normal RPE cells as revealed through autofluorescence imaging and IMS. In both orthotopic and ectopic RPE cells, IMS detected phosphatidylglycerol, PG 36:2, and several triacylglycerols containing long-chain fatty acids. GM3 gangliosides (40:1, 42:1, and 42:2) were also detected in ectopic RPE cells with differences in abundance in different populations of ectopic RPE cells. Lactosylceramide (LacCer 44:5) and glucosylceramide (GlcCer 44:5) were found exclusively in ectopic RPE cells. In contrast, ectopic RPE did not exhibit signals of phosphatidylinositols (PI) (PI32:0, PI32:1, PI34:1, and PI34:2) normally detected in RPE cells. Near-single-cell resolution IMS results suggest that RPE transdifferentiation, with loss of normal functions and gain of new functions like migration, may be linked to altered metabolism of glycosphingolipids and PIs.<\/jats:p>","DOI":"10.1073\/pnas.2503191122","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T19:01:31Z","timestamp":1752519691000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["Glycolipids implicated as mediators of clinically visible retinal pigment epithelial migration in age-related macular degeneration"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9993-1889","authenticated-orcid":false,"given":"Zhen","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Mass Spectrometry Research Center, Vanderbilt University","place":["Nashville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3866-0923","authenticated-orcid":false,"given":"David M. G.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Mass Spectrometry Research Center, Vanderbilt University","place":["Nashville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey D.","family":"Messinger","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham","place":["Birmingham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9769-1538","authenticated-orcid":false,"given":"Christine A.","family":"Curcio","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham","place":["Birmingham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3959-1712","authenticated-orcid":false,"given":"Kevin L.","family":"Schey","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Mass Spectrometry Research Center, Vanderbilt University","place":["Nashville"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,7,14]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.oret.2020.12.009"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1159\/000342159"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2008.12.039"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajo.2017.02.017"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.oret.2017.07.020"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1097\/IAE.0b013e318217ffc7"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2013.05.029"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.62.10.34"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2008.10.006"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00417-012-1928-5"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2019.05.016"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaophthalmol.2020.1376"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.oret.2023.12.006"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2012.07.004"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2012.10.018"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.oret.2020.05.001"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2017.08.019"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0007945"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajo.2011.08.041"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-03529-8"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.12-9813"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2010.08.010"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.15-16432"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-023-02699-9"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.63.13.5"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajo.2016.02.002"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.18-24132"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-024-04995-1"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202302491R"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41433-022-02016-3"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2018.09.045"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7063"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1021\/ac970888i"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1021\/jasms.0c00119"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4835(86)90045-X"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.3390\/nu15143096"},{"key":"e_1_3_4_37_2","first-page":"1222","article-title":"Transcriptional factors associated with epithelial-mesenchymal transition in choroidal neovascularization","volume":"17","author":"Hirasawa M.","year":"2011","unstructured":"M. Hirasawa , Transcriptional factors associated with epithelial-mesenchymal transition in choroidal neovascularization. Mol. Vis. 17, 1222\u20131230 (2011).","journal-title":"Mol. Vis."},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.19-26949"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.16-19816"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.63.11.24"},{"key":"e_1_3_4_41_2","first-page":"BIO211","article-title":"Activated retinal pigment epithelium, an optical coherence tomography biomarker for progression in age-related macular degeneration","volume":"58","author":"Curcio C. A.","year":"2017","unstructured":"C. A. Curcio, E. C. Zanzottera, T. Ach, C. Balaratnasingam, K. B. Freund, Activated retinal pigment epithelium, an optical coherence tomography biomarker for progression in age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 58, BIO211\u2013BIO226 (2017).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"e_1_3_4_42_2","first-page":"267","article-title":"Phenotypic variation of retinal pigment epithelium in age-related macular degeneration","volume":"43","author":"Guidry C.","year":"2002","unstructured":"C. Guidry, N. E. Medeiros, C. A. Curcio, Phenotypic variation of retinal pigment epithelium in age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 43, 267\u2013273 (2002).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201439333"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20120189"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0902368106"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0168794"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.491431"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10719-006-7920-8"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2023.06.004"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4835(76)90198-6"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells9040866"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200407058"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.3906\/biy-2004-108"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.5487\/TR.2008.24.1.001"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200701078"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells12020207"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-3084(01)00132-3"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1080\/02713683.2024.2343334"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom13030546"},{"key":"e_1_3_4_60_2","article-title":"Ex vivo OCT-based multimodal imaging of human donor eyes for research into age-related macular degeneration","volume":"195","author":"Messinger J. D.","year":"2023","unstructured":"J. D. Messinger, , Ex vivo OCT-based multimodal imaging of human donor eyes for research into age-related macular degeneration. J. Vis. Exp. 195 (2023), 10.3791\/65240.","journal-title":"J. Vis. Exp."},{"key":"e_1_3_4_61_2","author":"Wang Z.","unstructured":"Z. Wang, Data from \u201cGlycolipids implicated as mediators of clinically visible retinal pigment epithelial migration in age-related macular degeneration.\u201d Harvard Dataverse. https:\/\/doi.org\/10.7910\/DVN\/HIVYWA. Deposited 1 July 2025.","journal-title":"migration"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2503191122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T19:02:03Z","timestamp":1752519723000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2503191122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,14]]},"references-count":61,"journal-issue":{"issue":"29","published-print":{"date-parts":[[2025,7,22]]}},"alternative-id":["10.1073\/pnas.2503191122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2503191122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,14]]},"assertion":[{"value":"2025-02-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2503191122"}}