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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,4,28]]},"abstract":"<jats:p>\n                    Limb loss remains a significant clinical challenge, but regenerative medicine approaches such as gene therapy offer a promising strategy to trigger endogenous regeneration programs. Optimal vector configurations and molecular targets for appendicular skeletal repair are not well defined. Here, we leveraged insights from species with a high endogenous capacity for appendage regeneration to design an enhancer-directed gene delivery platform that functions during mouse digit regeneration, a well-characterized model for partial limb regeneration in mammals. Single-cell RNA sequencing of zebrafish caudal fin regeneration, combined with expression data in regenerating salamander limbs and mouse digit tips, implicated the SP family of transcription factors as conserved, epidermally expressed mediators of appendage regrowth. Null mutants of\n                    <jats:italic toggle=\"yes\">Sp8<\/jats:italic>\n                    demonstrated impaired limb regeneration in salamanders, while conditional knockout of\n                    <jats:italic toggle=\"yes\">Sp6<\/jats:italic>\n                    and\/or\n                    <jats:italic toggle=\"yes\">Sp8<\/jats:italic>\n                    in the mouse basal epidermis resulted in defective bony digit tip regeneration, involving an IL-17-mediated osteoclastogenic program. Spatiotemporally focused expression of FGF8, a known target of SP factors, using a zebrafish-derived tissue regeneration enhancer element via adeno-associated viral vectors, could partially rescue digit tip regeneration in SP knockout mice and accelerate digit regeneration in wild-type mice. Our results demonstrate a contextual gene therapy approach to address limb loss based on genes like SP transcription factors conserved across multiple contexts of appendage regeneration.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2532804123","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T18:02:37Z","timestamp":1776189757000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":3,"title":["Enhancer-directed gene delivery for digit regeneration based on conserved epidermal factors"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9805-0632","authenticated-orcid":false,"given":"David A.","family":"Brown","sequence":"first","affiliation":[{"name":"Division of Plastic, Maxillofacial, and Oral Surgery, Department of Surgery, Duke University","place":["Durham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja K.","family":"Koll","sequence":"additional","affiliation":[{"name":"Division of Plastic, Maxillofacial, and Oral Surgery, Department of Surgery, Duke University","place":["Durham"]},{"name":"Department of Hand, Plastic and Reconstructive Surgery, Microsurgery, Burn Centre, Berufsgenossenschaftliche Klinik Ludwigshafen","place":["Ludwigshafen, Germany"]},{"name":"Medical Faculty of the University of Heidelberg","place":["Heidelberg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Brush","sequence":"additional","affiliation":[{"name":"School of Medicine, Duke University","place":["Durham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0858-1850","authenticated-orcid":false,"given":"Grant","family":"Darner","sequence":"additional","affiliation":[{"name":"School of Medicine, Duke 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of Plastic, Maxillofacial, and Oral Surgery, Department of Surgery, Duke University","place":["Durham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3850-3925","authenticated-orcid":false,"given":"David W.","family":"Wolfson","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Duke University School of Medicine","place":["Durham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor J.","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Surgery, Duke University","place":["Durham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1761-8566","authenticated-orcid":false,"given":"Sydney","family":"Jeffs","sequence":"additional","affiliation":[{"name":"School of Medicine, Duke 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A. Brown J. Ou K. D. Poss Data from \u201cEnhancer-directed gene delivery for digit regeneration based on conserved epidermal factors [scRNA-seq].\u201d NCBI GEO. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE309821. Deposited 14 November 2025.","DOI":"10.64898\/2025.12.01.691633"},{"key":"e_1_3_5_39_2","doi-asserted-by":"crossref","unstructured":"D. A. Brown J. Ou K. D. Poss Data from \u201cEnhancer-directed gene delivery for digit regeneration based on conserved epidermal factors [RNA-seq].\u201d NCBI GEO. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE309792. 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