{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T18:02:55Z","timestamp":1784311375508,"version":"3.55.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"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>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Keloid is a fibroproliferative scar with marked ethnic disparities, disproportionately affecting Asian and Black populations. Single-cell RNA sequencing (scRNA-seq) studies have mapped keloid pathology, but cross-study differences complicate generalization. We performed a meta-analysis to identify composition and transcriptional programs associated with keloid across ethnicities.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We aggregated human skin scRNA-seq datasets containing keloid and healthy samples with documented ethnicity (Asian, Black, White). After quality control and batch integration (scVI\/scANVI), we annotated cell types and subtypes. Differential abundance was estimated with scCODA, Milo, and propeller. Pseudobulk differential expression was meta-analyzed using random-effects models. Ligand-receptor signaling was inferred with CellChat\/NicheNet.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The harmonized atlas comprised 112 donors, 147 samples, and 487,293 cells from 8 studies. Keloid demonstrated higher proportions of vascular endothelial cells and fibroblasts across all methods. Ethnicity-stratified analysis revealed endothelial expansion in Asian and Black relative to White populations, while fibroblast expansion was greater in White keloids. Endothelial subtyping showed increased post-capillary venules and arteriolar states. Fibroblast analysis revealed expansion of mesenchymal\/ADAM12\n                      <jats:sup>+<\/jats:sup>\n                      and pro-inflammatory populations. Meta-analysis implicated TGF-\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \/SMAD, integrin\/FAK, and YAP\/TAZ mechanotransduction pathways as candidate pathogenic programs warranting functional validation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Cross-study synthesis identifies shared and ethnicity-stratified endothelial and fibroblast programs in keloid. Expansion of post-capillary venules and ADAM12\n                      <jats:sup>+<\/jats:sup>\n                      fibroblasts provides candidate therapeutic targets pending functional validation and a framework for understanding ethnic disparities in keloid formation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1751725","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T17:06:04Z","timestamp":1784307964000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A multi-dataset single-cell meta-analysis of human keloid skin across Asian, Black and White populations reveals endothelial and mesenchymal programs linked to ethnic disparities"],"prefix":"10.3389","volume":"13","author":[{"given":"Ziad","family":"Alkouz","sequence":"first","affiliation":[{"name":"Dermatology Hospital of Southern Medical University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Dermatology Hospital of Southern Medical University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ala'a Al","family":"Suwait","sequence":"additional","affiliation":[{"name":"Dermatology Hospital of Southern Medical University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rehab","family":"Alhejairi","sequence":"additional","affiliation":[{"name":"Dermatology Hospital of Southern Medical University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenmei","family":"Liu","sequence":"additional","affiliation":[{"name":"Dermatology Hospital of Southern Medical University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyu","family":"Gu","sequence":"additional","affiliation":[{"name":"Dermatology Hospital of Southern Medical University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Yang","sequence":"additional","affiliation":[{"name":"Dermatology Hospital of Southern Medical University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"S3","DOI":"10.1097\/DSS.0000000000000819","article-title":"Keloids and hypertrophic scars: pathophysiology, classification, and treatment","volume":"43","author":"Berman","year":"2017","journal-title":"Dermatologic Surg"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"606","DOI":"10.3390\/ijms18030606","article-title":"Keloid and hypertrophic scars are the result of chronic inflammation in the reticular dermis","volume":"18","author":"Ogawa","year":"2017","journal-title":"Int J Mol Sci"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.matbio.2016.01.013","article-title":"Keloids: the paradigm of skin fibrosis - pathomechanisms and treatment","volume":"51","author":"Andrews","year":"2016","journal-title":"Matrix Biol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"225","DOI":"10.2340\/00015555-2498","article-title":"Burden of keloid disease: a cross-sectional health-related quality of life assessment","volume":"97","author":"Bijlard","year":"2017","journal-title":"Acta Derm Venereol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"S50","DOI":"10.1016\/j.jisp.2016.10.024","article-title":"Current understanding of the genetic causes of keloid formation","volume":"18","author":"Glass","year":"2017","journal-title":"J Investig Dermatol Symp Proc"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1111\/bjd.13826","article-title":"Epidemiology of keloids in normally pigmented Africans and African people with albinism: population-based cross-sectional survey","volume":"173","author":"Kiprono","year":"2015","journal-title":"Br J Dermatol"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1007\/s00403-014-1491-5","article-title":"Keloid incidence in Asian people and its comorbidity with other fibrosis-related diseases: a nationwide population-based study","volume":"306","author":"Sun","year":"2014","journal-title":"Arch Dermatol Res"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"360","DOI":"10.3389\/fcell.2020.00360","article-title":"The keloid disorder: heterogeneity, histopathology, mechanisms and models","volume":"8","author":"Limandjaja","year":"2020","journal-title":"Front Cell Dev Biol"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jccw.2016.10.001","article-title":"Novel insights on understanding of keloid scar: article review","volume":"7","author":"Mari","year":"2016","journal-title":"J Am Coll Clin Wound Spec"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1111\/j.1742-481X.2012.01118.x","article-title":"Are keloid and hypertrophic scar different forms of the same disorder? A fibroproliferative skin disorder hypothesis based on keloid findings","volume":"11","author":"Huang","year":"2014","journal-title":"Int Wound J"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1111\/j.1524-475X.2009.00553.x","article-title":"Molecular dissection of abnormal wound healing processes resulting in keloid disease","volume":"18","author":"Shih","year":"2010","journal-title":"Wound Repair Regen"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1007\/s00403-009-0952-8","article-title":"Keloid scarring: bench and bedside","volume":"301","author":"Seifert","year":"2009","journal-title":"Arch Dermatol Res"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.14670\/HH-11-624","article-title":"Functional histopathology of keloid disease","volume":"30","author":"Jumper","year":"2015","journal-title":"Histol 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testing for differences in cell type proportions in single cell data","volume":"38","author":"Phipson","year":"2022","journal-title":"Bioinformatics"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1186\/s12859-016-1323-z","article-title":"variancePartition: interpreting drivers of variation in complex gene expression studies","volume":"17","author":"Hoffman","year":"2016","journal-title":"BMC Bioinformatics"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v036.i03","article-title":"Conducting meta-analyses in R with the metafor package","volume":"36","author":"Viechtbauer","year":"2010","journal-title":"J Stat Softw"},{"key":"ref47","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":"ref48","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1038\/s41592-019-0667-5","article-title":"NicheNet: modeling intercellular communication by linking ligands to target genes","volume":"17","author":"Browaeys","year":"2020","journal-title":"Nat Methods"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1038\/nri3298","article-title":"HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes","volume":"12","author":"Girard","year":"2012","journal-title":"Nat Rev Immunol"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1097\/00000372-200410000-00006","article-title":"Histopathological differential diagnosis of keloid and hypertrophic scar","volume":"26","author":"Lee","year":"2004","journal-title":"Am J Dermatopathol"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"1685","DOI":"10.1016\/j.biocel.2008.01.025","article-title":"Cellular roles of ADAM12 in health and 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