{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:27:24Z","timestamp":1783488444098,"version":"3.55.0"},"reference-count":24,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T00:00:00Z","timestamp":1661731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005972","name":"German Cancer Aid","doi-asserted-by":"publisher","award":["70113135"],"award-info":[{"award-number":["70113135"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"German Cancer Aid","doi-asserted-by":"publisher","award":["RU821\/8-1"],"award-info":[{"award-number":["RU821\/8-1"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["70113135"],"award-info":[{"award-number":["70113135"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["RU821\/8-1"],"award-info":[{"award-number":["RU821\/8-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Purpose: Precise molecular and cellular mechanisms of radiation-induced dermatitis are incompletely understood. Histone variant H2A.J is associated with cellular senescence and modulates senescence-associated secretory phenotype (SASP) after DNA-damaging insults, such as ionizing radiation (IR). Using ex vivo irradiated cultured foreskin, H2A.J was analyzed as a biomarker of radiation-induced senescence, potentially initiating the inflammatory cascade of radiation-induced skin injury. Methods: Human foreskin explants were collected from young donors, irradiated ex vivo with 10 Gy, and cultured in air-liquid interphase for up to 72 h. At different time-points after ex vivo IR exposure, the foreskin epidermis was analyzed for proliferation and senescence markers by immunofluorescence and immunohistochemical staining of sectioned tissue. Secretion of cytokines was measured in supernatants by ELISA. Using our mouse model with fractionated in vivo irradiation, H2A.J expression was analyzed in epidermal stem\/progenitor cell populations localized in different regions of murine hair follicles (HF). Results: Non-vascularized foreskin explants preserved their tissue homeostasis up to 72 h (even after IR exposure), but already non-irradiated foreskin epithelium expressed high levels of H2A.J in all epidermal layers and secreted high amounts of cytokines. Unexpectedly, no further increase in H2A.J expression and no obvious upregulation of cytokine secretion was observed in the foreskin epidermis after ex vivo IR. Undifferentiated keratinocytes in murine HF regions, by contrast, revealed low H2A.J expression in non-irradiated skin and significant radiation-induced H2A.J upregulations at different time-points after IR exposure. Based on its staining characteristics, we presume that H2A.J may have previously underestimated the importance of the epigenetic regulation of keratinocyte maturation. Conclusions: Cultured foreskin characterized by highly keratinized epithelium and specific immunological features is not an appropriate model for studying H2A.J-associated tissue reactions during radiation-induced dermatitis.<\/jats:p>","DOI":"10.3390\/ijms23179830","type":"journal-article","created":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T21:01:31Z","timestamp":1661806891000},"page":"9830","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Cultured Human Foreskin as a Model System for Evaluating Ionizing Radiation-Induced Skin Injury"],"prefix":"10.3390","volume":"23","author":[{"given":"Yanick","family":"Hippchen","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Saarland University Medical Center, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2826-8741","authenticated-orcid":false,"given":"Gargi","family":"Tewary","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Saarland University Medical Center, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Saarland University Medical Center, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zo\u00e9","family":"Schmal","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Saarland University Medical Center, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Meessen","sequence":"additional","affiliation":[{"name":"Department of Urology, Klinikum Saarbr\u00fccken, 66119 Saarbr\u00fccken, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1122-1557","authenticated-orcid":false,"given":"Jan","family":"Palm","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Saarland University Medical Center, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3882-7903","authenticated-orcid":false,"given":"Claudia E.","family":"R\u00fcbe","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Saarland University Medical Center, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e825","DOI":"10.1016\/j.clbc.2018.06.015","article-title":"Radiation-induced Skin Toxicity in Breast Cancer Patients: A Systematic Review of Randomized Trials","volume":"18","author":"Yee","year":"2018","journal-title":"Clin. Breast Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"12489","DOI":"10.3390\/ijms222212489","article-title":"Structural and Functional Changes and Possible Molecular Mechanisms in Aged Skin","volume":"22","author":"Lee","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1126\/science.1253734","article-title":"Mammalian skin cell biology: At the interface between laboratory and clinic","volume":"346","author":"Watt","year":"2014","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.semcdb.2013.12.007","article-title":"Regionalisation of the skin","volume":"25\u201326","author":"Johansson","year":"2014","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Lemos, M.P., Lama, J.R., Karuna, S.T., Fong, Y., Montano, S.M., Ganoza, C., Gottardo, R., Sanchez, J., and McElrath, M.J. (2014). The inner foreskin of healthy males at risk of HIV infection harbors epithelial CD4+ CCR5+ cells and has features of an inflamed epidermal barrier. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0108954"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.jdermsci.2014.02.003","article-title":"Human in vitro skin organ culture as a model system for evaluating DNA repair","volume":"74","author":"Liu","year":"2014","journal-title":"J. Dermatol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"247","DOI":"10.3389\/fgene.2018.00247","article-title":"Biomarkers of Cellular Senescence and Skin Aging","volume":"9","author":"Wang","year":"2018","journal-title":"Front. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nrc3960","article-title":"Forging a signature of in vivo senescence","volume":"15","author":"Sharpless","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1172\/JCI64098","article-title":"Cellular senescence and the senescent secretory phenotype: Therapeutic opportunities","volume":"123","author":"Tchkonia","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"14995","DOI":"10.1038\/ncomms14995","article-title":"Histone variant H2A.J accumulates in senescent cells and promotes inflammatory gene expression","volume":"8","author":"Contrepois","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Isermann, A., Mann, C., and R\u00fcbe, C. (2020). Histone Variant H2A.J Marks Persistent DNA Damage and Triggers the Secretory Phenotype in Radiation-Induced Senescence. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239130"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/s41514-021-00060-z","article-title":"Human skin aging is associated with increased expression of the histone variant H2A.J in the epidermis","volume":"7","author":"Schuler","year":"2021","journal-title":"npj Aging Mech. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1038\/nm.3643","article-title":"Emerging interactions between skin stem cells and their niches","volume":"20","author":"Hsu","year":"2014","journal-title":"Nat. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1038\/s41586-019-1085-7","article-title":"Stem cell competition orchestrates skin homeostasis and ageing","volume":"568","author":"Liu","year":"2019","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1038\/nrm.2016.76","article-title":"Epigenetic control of adult stem cell function","volume":"17","author":"Avgustinova","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1111\/exd.13872","article-title":"Epigenetic control in skin development, homeostasis and injury repair","volume":"28","author":"Kang","year":"2019","journal-title":"Exp. Dermatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1053\/j.gastro.2012.09.057","article-title":"Mice That Express Human Interleukin-8 Have Increased Mobilization of Immature Myeloid Cells, Which Exacerbates Inflammation and Accelerates Colon Carcinogenesis","volume":"144","author":"Asfaha","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/nri3646","article-title":"Mechanisms regulating skin immunity and inflammation","volume":"14","author":"Pasparakis","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"111525","DOI":"10.1016\/j.mad.2021.111525","article-title":"Faces of cellular senescence in skin aging","volume":"198","author":"Ho","year":"2021","journal-title":"Mech. Ageing Dev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1667\/RR2524.1","article-title":"Transcriptional Response ofEx VivoHuman Skin to Ionizing Radiation: Comparison Between Low- and High-Dose Effects","volume":"177","author":"Albrecht","year":"2012","journal-title":"Radiat. Res."},{"key":"ref_21","first-page":"133","article-title":"Unraveling Immune-Epithelial Interactions in Skin Homeostasis and Injury","volume":"93","author":"Mansfield","year":"2020","journal-title":"Yale J. Biol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"14684","DOI":"10.1038\/ncomms14684","article-title":"Defining stem cell dynamics and migration during wound healing in mouse skin epidermis","volume":"8","author":"Aragona","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/nrm3272","article-title":"A family business: Stem cell progeny join the niche to regulate homeostasis","volume":"13","author":"Hsu","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.radonc.2019.04.021","article-title":"DNA damage accumulation during fractionated low-dose radiation compromises hippocampal neurogenesis","volume":"137","author":"Schmal","year":"2019","journal-title":"Radiother. Oncol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/17\/9830\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:19:50Z","timestamp":1760141990000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/17\/9830"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,29]]},"references-count":24,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["ijms23179830"],"URL":"https:\/\/doi.org\/10.3390\/ijms23179830","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,29]]}}}