{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T07:08:19Z","timestamp":1767337699199,"version":"3.37.3"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2020,2,13]],"date-time":"2020-02-13T00:00:00Z","timestamp":1581552000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100011781","name":"Shriners Hospitals for Children","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011781","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Engineered skin substitutes (ESS) containing autologous fibroblasts and keratinocytes provide stable wound closure in patients with large, full-thickness burns, but are limited by hypopigmentation due to absence of added melanocytes. DNA damage caused by ultraviolet radiation (UV) increases risk for skin cancer development. In human skin, melanocytes provide pigmentation that protects skin from UV-induced DNA damage. This study investigated whether inclusion of human melanocytes (hM) affects the response of ESS to UV in vivo. Specifically, pigmentation and formation of cyclobutane pyrimidine dimers (CPDs), the most prevalent UV-induced DNA photoproduct, were analyzed. Three groups of ESS were prepared with fibroblasts and keratinocytes, \u00b1 melanocytes, and grafted orthotopically to immunodeficient mice: ESS without melanocytes (ESS-hM), ESS with light skin-derived (Caucasian) melanocytes (ESS+hM-L), and ESS with dark skin-derived (African-American) melanocytes (ESS+hM-D). Pigmentation of ESS+hM-L and ESS+hM-D increased significantly after grafting; pigmentation levels were significantly different among groups. Mean melanocyte densities in ESS+hM-L and ESS+hM-D were similar to each other and to densities in normal human skin. After 8 weeks in vivo, grafts were irradiated with 135 mJ\/cm2 UV; non-UV-treated mice served as controls. UV modestly increased pigmentation in the ESS+hM groups. UV significantly increased CPD levels in ESS-hM, and levels in ESS-hM were significantly greater than in ESS+hM-L or ESS+hM-D. The results demonstrate that light or dark melanocytes in ESS decreased UV-induced DNA damage. Therefore, melanocytes in ESS play a photoprotective role. Protection against UV-induced DNA damage is expected to reduce skin cancer risk in patients grafted with ESS containing autologous melanocytes.<\/jats:p>","DOI":"10.1093\/jbcr\/iraa029","type":"journal-article","created":{"date-parts":[[2020,2,13]],"date-time":"2020-02-13T10:53:24Z","timestamp":1581591204000},"page":"751-760","source":"Crossref","is-referenced-by-count":25,"title":["Light or Dark Pigmentation of Engineered Skin Substitutes Containing Melanocytes Protects Against Ultraviolet Light-Induced DNA Damage In Vivo"],"prefix":"10.1093","volume":"41","author":[{"given":"Dorothy M","family":"Supp","sequence":"first","affiliation":[{"name":"Research Department, Shriners Hospitals for Children \u2013 Cincinnati, Ohio"},{"name":"Research Department, Shriners Hospitals for Children \u2013 Cincinnati, Ohio"},{"name":"Center for Stem Cell & Organoid Medicine (CuSTOM), Cincinnati Children\u2019s Hospital Medical Center, Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer M","family":"Hahn","sequence":"first","affiliation":[{"name":"Research Department, Shriners Hospitals for Children \u2013 Cincinnati, Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher M","family":"Lloyd","sequence":"first","affiliation":[{"name":"Department of Surgery, University of Cincinnati, College of Medicine, Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly A","family":"Combs","sequence":"first","affiliation":[{"name":"Research Department, Shriners Hospitals for Children \u2013 Cincinnati, Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Viki B","family":"Swope","sequence":"first","affiliation":[{"name":"Department of Dermatology, University of Cincinnati, College of Medicine, Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zalfa","family":"Abdel-Malek","sequence":"first","affiliation":[{"name":"Department of Dermatology, University of Cincinnati, College of Medicine, Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven T","family":"Boyce","sequence":"first","affiliation":[{"name":"Research Department, Shriners Hospitals for Children \u2013 Cincinnati, Ohio"},{"name":"Department of Surgery, University of Cincinnati, College of Medicine, Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,2,13]]},"reference":[{"key":"2020070310340434300_CIT0001","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s41038-016-0027-y","article-title":"Skin tissue engineering advances in severe burns: review and therapeutic applications","volume":"4","author":"Chua","year":"2016","journal-title":"Burns Trauma"},{"key":"2020070310340434300_CIT0002","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1016\/S0140-6736(13)61093-4","article-title":"Burns in children: standard and new treatments","volume":"383","author":"Jeschke","year":"2014","journal-title":"Lancet"},{"key":"2020070310340434300_CIT0003","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.addr.2017.06.012","article-title":"Advances in keratinocyte delivery in burn wound care","volume":"123","author":"Ter Horst","year":"2018","journal-title":"Adv Drug Deliv Rev"},{"key":"2020070310340434300_CIT0004","first-page":"2059513117696324","article-title":"Increased burn healing time is associated with higher Vancouver Scar Scale score","volume":"3","author":"Finlay","year":"2017","journal-title":"Scars Burn Heal"},{"key":"2020070310340434300_CIT0005","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1111\/wrr.12748","article-title":"A systematic review: current trends and take rates of cultured epithelial autografts in the treatment of patients with burn injuries","volume":"27","author":"Lo","year":"2019","journal-title":"Wound Repair Regen"},{"key":"2020070310340434300_CIT0006","first-page":"821","article-title":"Cultured skin substitutes reduce requirements for harvesting of skin autograft for closure of excised, full-thickness burns","volume":"60","author":"Boyce","year":"2006","journal-title":"J Trauma"},{"key":"2020070310340434300_CIT0007","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1097\/00004630-199920060-00006","article-title":"Cultured skin substitutes combined with Integra to replace native skin autograft and allograft for closure of full-thickness burns","volume":"20","author":"Boyce","year":"1999","journal-title":"J Burn Care Rehabil"},{"key":"2020070310340434300_CIT0008","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1097\/BCR.0000000000000401","article-title":"Randomized, paired-site comparison of autologous engineered skin substitutes and split-thickness skin graft for closure of extensive, full-thickness burns","volume":"38","author":"Boyce","year":"2017","journal-title":"J Burn Care Res"},{"key":"2020070310340434300_CIT0009","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1046\/j.1523-1747.2002.01717.x","article-title":"Vitamin C regulates keratinocyte viability, epidermal barrier, and basement membrane in vitro, and reduces wound contraction after grafting of cultured skin substitutes","volume":"118","author":"Boyce","year":"2002","journal-title":"J Invest Dermatol"},{"key":"2020070310340434300_CIT0010","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1046\/j.1524-475X.2002.10607.x","article-title":"Regulation of cutaneous pigmentation by titration of human melanocytes in cultured skin substitutes grafted to athymic mice","volume":"10","author":"Swope","year":"2002","journal-title":"Wound Repair Regen"},{"key":"2020070310340434300_CIT0011","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1111\/pcmr.12609","article-title":"Restoration of cutaneous pigmentation by transplantation to mice of isogeneic human melanocytes in dermal-epidermal engineered skin substitutes","volume":"30","author":"Boyce","year":"2017","journal-title":"Pigment Cell Melanoma Res"},{"key":"2020070310340434300_CIT0012","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1016\/j.burns.2017.03.023","article-title":"Assessment of burn-specific health-related quality of life and patient scar status following burn","volume":"43","author":"Oh","year":"2017","journal-title":"Burns"},{"key":"2020070310340434300_CIT0013","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1111\/1523-1747.ep12371676","article-title":"Melanin reduces ultraviolet-induced DNA damage formation and killing rate in cultured human melanoma cells","volume":"101","author":"Kobayashi","year":"1993","journal-title":"J Invest Dermatol"},{"key":"2020070310340434300_CIT0014","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1046\/j.1523-1747.1998.00178.x","article-title":"Supranuclear melanin caps reduce ultraviolet induced DNA photoproducts in human epidermis","volume":"110","author":"Kobayashi","year":"1998","journal-title":"J Invest Dermatol"},{"key":"2020070310340434300_CIT0015","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1111\/j.1600-0749.2006.00315.x","article-title":"Melanin content and MC1R function independently affect UVR-induced DNA damage in cultured human melanocytes","volume":"19","author":"Hauser","year":"2006","journal-title":"Pigment Cell Res"},{"key":"2020070310340434300_CIT0016","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1096\/fj.02-0865fje","article-title":"UV-induced DNA damage and melanin content in human skin differing in racial\/ethnic origin","volume":"17","author":"Tadokoro","year":"2003","journal-title":"FASEB J"},{"key":"2020070310340434300_CIT0017","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S1011-1344(01)00245-7","article-title":"Biological consequences of cyclobutane pyrimidine dimers","volume":"65","author":"Vink","year":"2001","journal-title":"J Photochem Photobiol B"},{"key":"2020070310340434300_CIT0018","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1039\/C7PP00395A","article-title":"Formation of UV-induced DNA damage contributing to skin cancer development","volume":"17","author":"Cadet","year":"2018","journal-title":"Photochem Photobiol Sci"},{"key":"2020070310340434300_CIT0019","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s00383-018-4384-4","article-title":"Induction of angiogenic and inflammation-associated dermal biomarkers following acute UVB exposure on bio-engineered pigmented dermo-epidermal skin substitutes in vivo","volume":"35","author":"Micka-Michalak","year":"2019","journal-title":"Pediatr Surg Int"},{"key":"2020070310340434300_CIT0020","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1002\/term.2519","article-title":"UVB exposure of a humanized skin model reveals unexpected dynamic of keratinocyte proliferation and Wnt inhibitor balancing","volume":"12","author":"Michalczyk","year":"2018","journal-title":"J Tissue Eng Regen Med"},{"key":"2020070310340434300_CIT0021","doi-asserted-by":"crossref","first-page":"e0213325","DOI":"10.1371\/journal.pone.0213325","article-title":"Identification of Merkel cells associated with neurons in engineered skin substitutes after grafting to full thickness wounds","volume":"14","author":"Hahn","year":"2019","journal-title":"PLoS One"},{"key":"2020070310340434300_CIT0022","first-page":"365","article-title":"Methods for the serum-free culture of keratinocytes and transplantation of collagen-GAG-based skin substitutes","volume":"18","author":"Boyce","year":"1999","journal-title":"Methods Mol Med"},{"issue":"Pt 11","key":"2020070310340434300_CIT0023","doi-asserted-by":"crossref","first-page":"2349","DOI":"10.1242\/jcs.115.11.2349","article-title":"Human melanocortin 1 receptor variants, receptor function and melanocyte response to UV radiation","volume":"115","author":"Scott","year":"2002","journal-title":"J Cell Sci"},{"key":"2020070310340434300_CIT0024","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1111\/j.1600-0749.2006.00325.x","article-title":"Increased expression of integrins and decreased apoptosis correlate with increased melanocyte retention in cultured skin substitutes","volume":"19","author":"Swope","year":"2006","journal-title":"Pigment Cell Res"},{"key":"2020070310340434300_CIT0025","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1177\/0963689719857657","article-title":"Collagen VII expression is required in both keratinocytes and fibroblasts for anchoring fibril formation in bilayer engineered skin substitutes","volume":"28","author":"Supp","year":"2019","journal-title":"Cell Transplant"},{"key":"2020070310340434300_CIT0026","doi-asserted-by":"crossref","first-page":"3850","DOI":"10.1096\/fj.10-158485","article-title":"Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation","volume":"24","author":"Kadekaro","year":"2010","journal-title":"FASEB J"},{"key":"2020070310340434300_CIT0027","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.1002\/term.2959","article-title":"Impact of ultraviolet radiation on dermal and epidermal DNA damage in a human pigmented bilayered skin substitute","volume":"13","author":"Goyer","year":"2019","journal-title":"J Tissue Eng Regen Med"},{"key":"2020070310340434300_CIT0028","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1111\/exd.12570","article-title":"Characterization of pigmented dermo-epidermal skin substitutes in a long-term in vivo assay","volume":"24","author":"B\u00f6ttcher-Haberzeth","year":"2015","journal-title":"Exp Dermatol"},{"key":"2020070310340434300_CIT0029","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1136\/bmj.1.4869.1016","article-title":"The number of melanocytes in human epidermis","volume":"1","author":"Szabo","year":"1954","journal-title":"Br Med J"},{"key":"2020070310340434300_CIT0030","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1111\/j.1365-2133.1996.tb01505.x","article-title":"Hyperpigmentation of human skin grafted on to athymic nude mice: immunohistochemical study","volume":"135","author":"Matsumoto","year":"1996","journal-title":"Br J Dermatol"},{"key":"2020070310340434300_CIT0031","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/j.1600-0625.1997.tb00140.x","article-title":"The expression of cytokines, growth factors and ICAM-1 in the healing of human cutaneous xenografts on nude mice","volume":"6","author":"Matsumoto","year":"1997","journal-title":"Exp Dermatol"},{"key":"2020070310340434300_CIT0032","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1097\/BCR.0000000000000224","article-title":"A primer on pigmentation","volume":"36","author":"Greenhalgh","year":"2015","journal-title":"J Burn Care Res"},{"key":"2020070310340434300_CIT0033","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s40257-017-0333-6","article-title":"Postinflammatory hyperpigmentation: epidemiology, clinical presentation, pathogenesis and treatment","volume":"19","author":"Kaufman","year":"2018","journal-title":"Am J Clin Dermatol"},{"key":"2020070310340434300_CIT0034","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1093\/jbcr\/iry045","article-title":"Pigmentation diathesis of hypertrophic scar: an examination of known signaling pathways to elucidate the molecular pathophysiology of injury-related dyschromia","volume":"40","author":"Carney","year":"2019","journal-title":"J Burn Care Res"},{"key":"2020070310340434300_CIT0035","article-title":"Exogenous keratinocyte growth factor is not required for pigmentation of skin substitutes with three isogeneic cell types","author":"Boyce","year":"2019","journal-title":"Tissue Eng Part A"},{"key":"2020070310340434300_CIT0036","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1016\/j.jaad.2017.06.009","article-title":"Reference values for skin microanatomy: a systematic review and meta-analysis of ex vivo studies","volume":"77","author":"Xu","year":"2017","journal-title":"J Am Acad Dermatol"},{"key":"2020070310340434300_CIT0037","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1111\/1523-1747.ep12265342","article-title":"The relationship of skin color, UVB-induced erythema, and melanogenesis","volume":"84","author":"Shono","year":"1985","journal-title":"J Invest Dermatol"},{"key":"2020070310340434300_CIT0038","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.taap.2003.08.019","article-title":"Toxic effects of ultraviolet radiation on the skin","volume":"195","author":"Matsumura","year":"2004","journal-title":"Toxicol Appl Pharmacol"},{"key":"2020070310340434300_CIT0039","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1016\/j.bpj.2008.10.030","article-title":"UVA generates pyrimidine dimers in DNA directly","volume":"96","author":"Jiang","year":"2009","journal-title":"Biophys J"},{"key":"2020070310340434300_CIT0040","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1126\/science.1256022","article-title":"Photochemistry. Chemiexcitation of melanin derivatives induces DNA photoproducts long after UV exposure","volume":"347","author":"Premi","year":"2015","journal-title":"Science"},{"key":"2020070310340434300_CIT0041","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1111\/pcmr.12381","article-title":"Dark CPDs and photocarcinogenesis: the party continues after the lights go out","volume":"28","author":"Abdel-Malek","year":"2015","journal-title":"Pigment Cell Melanoma Res"}],"container-title":["Journal of Burn Care &amp; Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jbcr\/advance-article-pdf\/doi\/10.1093\/jbcr\/iraa029\/32849462\/iraa029.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jbcr\/article-pdf\/41\/4\/751\/33460567\/iraa029.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jbcr\/article-pdf\/41\/4\/751\/33460567\/iraa029.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,15]],"date-time":"2022-10-15T12:43:03Z","timestamp":1665837783000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbcr\/article\/41\/4\/751\/5735316"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,13]]},"references-count":41,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,2,13]]},"published-print":{"date-parts":[[2020,7,3]]}},"URL":"https:\/\/doi.org\/10.1093\/jbcr\/iraa029","relation":{},"ISSN":["1559-047X","1559-0488"],"issn-type":[{"type":"print","value":"1559-047X"},{"type":"electronic","value":"1559-0488"}],"subject":[],"published-other":{"date-parts":[[2020,7]]},"published":{"date-parts":[[2020,2,13]]}}}