{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T14:19:33Z","timestamp":1762957173373,"version":"3.41.2"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T00:00:00Z","timestamp":1684454400000},"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. Mol. Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Age-related macular degeneration (AMD), an ever-increasing ocular disease, has become one of the leading causes of irreversible blindness. Recent advances in single-cell genomics are improving our understanding of the molecular mechanisms of AMD. However, the pathophysiology of this multifactorial disease is complicated and still an ongoing challenge. To better understand disease pathogenesis and identify effective targets, we conducted an in-depth analysis of the single-cell transcriptome of AMD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The cell expression specificity of the gene (CESG) was selected as an index to identify the novel cell markers. A computational framework was designed to explore the cell-specific TF regulatory loops, containing the interaction of gene pattern signatures, transcription factors regulons, and differentially expressed genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Three potential novel cell markers were <jats:italic>DNASE1L3<\/jats:italic> for endothelial cells, <jats:italic>ABCB5<\/jats:italic> for melanocytes, and <jats:italic>SLC39A12<\/jats:italic> for RPE cells detected. We observed a notable change in the cell abundance and crosstalk of fibroblasts cells, melanocytes, schwann cells, and T\/NK cells between AMD and controls, representing a complex cellular ecosystem in disease status. Finally, we identified six cell type related and three disease-associated ternary loops and elaborated on the robust association between key immune-pathway and AMD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>In conclusion, this study facilitates the optimization of screening for AMD-related receptor ligand pathways and proposes to further improve the interpretability of disease associations from single-cell data. It illuminated that immune-related regulation paths could be used as potential diagnostic markers for AMD, and in the future, also as therapeutic targets, providing insights into AMD diagnosis and potential interventions.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnmol.2023.1173123","type":"journal-article","created":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T05:14:26Z","timestamp":1684473266000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["In-depth mining of single-cell transcriptome reveals the key immune-regulated loops in age-related macular degeneration"],"prefix":"10.3389","volume":"16","author":[{"given":"Wencan","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guosi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyan","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Youyuan","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianzhong","family":"Su","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liangde","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1693","DOI":"10.1016\/j.ophtha.2020.06.020","article-title":"Integrating metabolomics, genomics, and disease pathways in age-related macular degeneration: the EYE-RISK consortium","volume":"127","author":"Acar","year":"2020","journal-title":"Ophthalmology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1038\/nmeth.4463","article-title":"SCENIC: single-cell regulatory network inference and clustering","volume":"14","author":"Aibar","year":"2017","journal-title":"Nat. Methods"},{"key":"B3","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1002\/humu.23395","article-title":"Mutation update of transcription factor genes FOXE3, HSF4, MAF, and PITX3 causing cataracts and other developmental ocular defects","volume":"39","author":"Anand","year":"2018","journal-title":"Hum. Mutat."},{"key":"B4","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1001\/jama.2020.5576","article-title":"Current perspective on age-related macular degeneration","volume":"324","author":"Chakravarthy","year":"2020","journal-title":"JAMA"},{"key":"B5","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/s41572-021-00265-2","article-title":"Age-related macular degeneration","volume":"7","author":"Fleckenstein","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"B6","doi-asserted-by":"publisher","first-page":"P1459","DOI":"10.1016\/S0140-6736(22)02609-5","article-title":"Age-related macular degeneration","volume":"401","author":"Guymer","year":"2023","journal-title":"Lancet"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.04.048","article-title":"Integrated analysis of multimodal single-cell data","author":"Hao","year":"2021","journal-title":"Cell 184"},{"key":"B8","doi-asserted-by":"publisher","first-page":"W57","DOI":"10.1093\/nar\/gkv395","article-title":"i-cisTarget 2015 update: generalized cis-regulatory enrichment analysis in human, mouse and fly","volume":"43","author":"Imrichova","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"0071","DOI":"10.4172\/2155-9570.S2-007","article-title":"Immuno-modulatory effect of IFN-gamma in AMD and its role as a possible target for therapy","volume":"2","author":"Jiang","year":"2013","journal-title":"J. Clin. Exp. Ophthalmol. Suppl."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell-cell communication using CellChat","volume":"12","author":"Jin","year":"2021","journal-title":"Nat. Commun."},{"key":"B11","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.preteyeres.2018.11.003","article-title":"Stemming retinal regeneration with pluripotent stem cells","volume":"69","author":"Jin","year":"2019","journal-title":"Prog. Retin. Eye Res."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20190730","article-title":"Single-cell profiling reveals an endothelium-mediated immunomodulatory pathway in the eye choroid","author":"Lehmann","year":"2020","journal-title":"J. Exp. Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"4902","DOI":"10.1038\/s41467-019-12780-8","article-title":"Single-cell transcriptomic atlas of the human retina identifies cell types associated with age-related macular degeneration","volume":"10","author":"Menon","year":"2019","journal-title":"Nat. Commun."},{"key":"B14","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":"B15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0080223","article-title":"DNase gamma is the effector endonuclease for internucleosomal DNA fragmentation in necrosis","author":"Mizuta","year":"2013","journal-title":"PLoS ONE"},{"key":"B16","doi-asserted-by":"publisher","first-page":"6666506","DOI":"10.1155\/2021\/6666506","article-title":"MicroRNA-27a promotes oxidative-induced RPE cell death through targeting FOXO1","volume":"2021","author":"Ren","year":"2021","journal-title":"Biomed. Res. Int."},{"key":"B17","doi-asserted-by":"publisher","first-page":"618598","DOI":"10.3389\/fcell.2020.618598","article-title":"Secreted phosphoprotein 1 expression in retinal mononuclear phagocytes links murine to human choroidal neovascularization","volume":"8","author":"Schlecht","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1111\/aos.12650","article-title":"Nutritional supplements in age-related macular degeneration","volume":"93","author":"Schmidl","year":"2015","journal-title":"Acta Ophthalmol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"3592","DOI":"10.1093\/bioinformatics\/btaa183","article-title":"projectR: an R\/Bioconductor package for transfer learning via PCA, NMF, correlation and clustering","volume":"36","author":"Sharma","year":"2020","journal-title":"Bioinformatics"},{"key":"B20","doi-asserted-by":"publisher","first-page":"513","DOI":"10.3238\/arztebl.2020.0513","article-title":"The diagnosis and treatment of age-related macular degeneration","volume":"117","author":"Stahl","year":"2020","journal-title":"Dtsch. Arztebl. Int."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2019.04.004","article-title":"Decomposing cell identity for transfer learning across cellular measurements, platforms, tissues, and species","author":"Stein-O'brien","year":"2019","journal-title":"Cell Syst. 8"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1436","DOI":"10.1016\/j.celrep.2018.10.045","article-title":"Revealing the critical regulators of cell identity in the mouse cell atlas","volume":"25","author":"Suo","year":"2018","journal-title":"Cell Rep."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl4896","article-title":"The Tabula Sapiens: a multiple-organ, single-cell transcriptomic atlas of humans","author":"Tabula Sapiens","year":"2022","journal-title":"Science"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1255","DOI":"10.3390\/ijms24021255","article-title":"The LIV-1 subfamily of zinc transporters: from origins to present day discoveries","volume":"24","author":"Taylor","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1016\/j.mcna.2021.01.003","article-title":"Age-related macular degeneration","volume":"105","author":"Thomas","year":"2021","journal-title":"Med. Clin. North Am."},{"key":"B26","doi-asserted-by":"publisher","first-page":"24100","DOI":"10.1073\/pnas.1914143116","article-title":"Single-cell transcriptomics of the human retinal pigment epithelium and choroid in health and macular degeneration","volume":"116","author":"Voigt","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B27","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.bbrc.2017.08.052","article-title":"ABCB5 promotes melanoma metastasis through enhancing NF-kappaB p65 protein stability","volume":"492","author":"Wang","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B28","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.preteyeres.2018.11.008","article-title":"Wnt signaling in vascular eye diseases","volume":"70","author":"Wang","year":"2019","journal-title":"Prog. Retin. Eye Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"e106","DOI":"10.1016\/S2214-109X(13)70145-1","article-title":"Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis","volume":"2","author":"Wong","year":"2014","journal-title":"Lancet Glob. Health"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaf1443","article-title":"Targeting factor D of the alternative complement pathway reduces geographic atrophy progression secondary to age-related macular degeneration","author":"Yaspan","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"D721","DOI":"10.1093\/nar\/gky900","article-title":"CellMarker: a manually curated resource of cell markers in human and mouse","volume":"47","author":"Zhang","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1128","DOI":"10.1016\/j.jhep.2021.06.023","article-title":"Single-cell RNA-sequencing atlas reveals an MDK-dependent immunosuppressive environment in ErbB pathway-mutated gallbladder cancer","volume":"75","author":"Zhang","year":"2021","journal-title":"J. Hepatol."}],"container-title":["Frontiers in Molecular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2023.1173123\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T05:14:34Z","timestamp":1684473274000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2023.1173123\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,19]]},"references-count":32,"alternative-id":["10.3389\/fnmol.2023.1173123"],"URL":"https:\/\/doi.org\/10.3389\/fnmol.2023.1173123","relation":{},"ISSN":["1662-5099"],"issn-type":[{"type":"electronic","value":"1662-5099"}],"subject":[],"published":{"date-parts":[[2023,5,19]]},"article-number":"1173123"}}