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Junctional epidermolysis bullosa (JEB) is a hereditary skin disorder characterised by severe skin fragility and aberrant granulation tissue formation, caused by loss-of-function variants in basement membrane proteins, including laminin-332. We developed JEB-like organotypic (OT) cultures with distinct fibroblast subpopulations and explored their role in an inducible JEB in vivo disease model, mimicking key features of the human disease. Mechanistically, papillary fibroblasts are highly increased in the granulation tissue of blistered JEB skin, promoting pathological \u03b1v\u03b26 integrin and TGF\u03b2 signalling in JEB keratinocytes. Treatment with the TGF\u03b2 receptor inhibitor RepSox not only normalised aberrant cell proliferation, differentiation, and cytokine signalling in JEB OTs but also reduced aberrant granulation tissue formation and skin blistering in laminin-332-depleted mice. Collectively, our study reveals that papillary fibroblasts promote JEB pathogenesis through increasing \u03b1v\u03b26 integrin and TGF\u03b2 signalling and disruption of these pathological signalling interactions significantly improved skin health and regeneration in JEB.<\/jats:p>","DOI":"10.1038\/s44321-026-00475-9","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T09:03:23Z","timestamp":1783501403000},"page":"3175-3199","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Dermal papillary fibroblasts promote persistent granulation tissue formation in junctional epidermolysis bullosa"],"prefix":"10.1038","volume":"18","author":[{"given":"Mohammad R A","family":"Khan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priya","family":"Garcha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktorija","family":"Lapinska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4483-7357","authenticated-orcid":false,"given":"Yuanjinze","family":"Nie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4808-0337","authenticated-orcid":false,"given":"Ilaria","family":"Di Girolamo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8654-0291","authenticated-orcid":false,"given":"Christina","family":"Philippeos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edel A","family":"O\u2019Toole","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0494-2295","authenticated-orcid":false,"given":"John F","family":"Marshall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8504-1738","authenticated-orcid":false,"given":"Gernot","family":"Walko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A","family":"McGrath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"Reynolds","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9151-5154","authenticated-orcid":false,"given":"Fiona M","family":"Watt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0504-9922","authenticated-orcid":false,"given":"Matthew","family":"Caley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6050-2860","authenticated-orcid":false,"given":"Emanuel","family":"Rognoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"475_CR1","unstructured":"Alhajj M, Goyal A (2022). 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