{"doi":"10.1016/j.jid.2024.07.012","title":"SOX2-Dependent Wound Repair Signature Triggers Prohealing Outcome in Hyperglycemic Wounds","abstract":"Wound healing is underpinned by the transcriptional regulation of signaling pathways to coordinate proper tissue repair (Eming et al., 2014Eming S.A. Martin P. Tomic-Canic M. Wound repair and regeneration: Mechanisms, signaling, and translation.Science Translational Medicine. 2014; 6265sr6-sr6Crossref PubMed Scopus (2094) Google Scholar, Overmiller et al., 2022Overmiller A.M. Sawaya A.P. Hope E.D. Morasso M.I. Intrinsic Networks Regulating Tissue Repair: Comparative Studies of Oral and Skin Wound Healing.Cold Spring Harb Perspect Biol. 2022; 14PubMed Google Scholar). In a hyperglycemic state, the repair process becomes deregulated and may result in diabetic foot ulcers (DFUs) (Eming et al., 2014Eming S.A. Martin P. Tomic-Canic M. Wound repair and regeneration: Mechanisms, signaling, and translation.Science Translational Medicine. 2014; 6265sr6-sr6Crossref PubMed Scopus (2094) Google Scholar). We previously showed that induction of the oral pro-wound healing transcription factor SOX2 in skin can reprogram cutaneous keratinocytes and prime wounds for accelerated repair through upregulation of epidermal growth factor receptor (EGFR) ligands (Iglesias-Bartolome et al., 2018Iglesias-Bartolome R. Uchiyama A. Molinolo A.A. Abusleme L. Brooks S.R. Callejas-Valera J.L. et al.Transcriptional signature primes human oral mucosa for rapid wound healing.Science Translational Medicine. 2018; 10eaap8798Crossref PubMed Scopus (159) Google Scholar, Uchiyama et al., 2019Uchiyama A. Nayak S. Graf R. Cross M. Hasneen K. Gutkind J.S. et al.SOX2 Epidermal Overexpression Promotes Cutaneous Wound Healing via Activation of EGFR/MEK/ERK Signaling Mediated by EGFR Ligands.Journal of Investigative Dermatology. 2019; 1391809-20.e8Abstract Full Text Full Text PDF Scopus (34) Google Scholar). EGFR signaling plays a crucial role in skin integrity and normal wound healing, and its impairment has been implicated in DFUs (Berlanga-Acosta et al., 2017Berlanga-Acosta J. Fernández-Montequín J. Valdés-Pérez C. Savigne-Gutiérrez W. Mendoza-Marí Y. García-Ojalvo A. et al.Diabetic Foot Ulcers and Epidermal Growth Factor: Revisiting the Local Delivery Route for a Successful Outcome.BioMed Research International. 2017; 20172923759Crossref PubMed Scopus (45) Google Scholar, Bodnar, 2012Bodnar R.J. Epidermal Growth Factor and Epidermal Growth Factor Receptor: The Yin and Yang in the Treatment of Cutaneous Wounds and Cancer.Advances in Wound Care. 2012; 2: 24-29Crossref Google Scholar). Therefore, we decided to investigate the effect of SOX2 upregulation on wound healing with hyperglycemia. Combining tamoxifen (Tam)-inducible K14CreERTM/LSL-SOX2-IRES-GFP (epidermal SOX2-overexpressing) and streptozotocin (STZ)-treated (hyperglycemic) mouse models (Figure 1a), we determined that the mRNA levels of SOX2 were significantly increased in Tam-treated mice compared with vehicle (Veh)-treated mice in both the control and STZ-treated groups, with no significant difference detected between the Tam- and Tam STZ-treated groups or between the Veh- and Veh STZ-treated groups by a Kruskal-Wallis test with Dunn’s multiple comparisons test (Figure 1b). All animal studies were carried out according to the protocol approved by the Institutional Animal Care and Use Committee at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (protocol A022-01-01). Protein expression of SOX2 was detected in the epidermis via immunofluorescence (IF) staining in Tam- and Tam STZ-treated mice (Figure 1c). To assess the wound healing process, skin punch biopsies were obtained from age-matched SOX2-overexpressing (Tam and Tam STZ) and control mice (Veh and Veh STZ) mice, and external wound measurements were performed every 2 days for 8 days (Figure 1d). Tam- and Tam STZ-treated mice exhibited significantly greater wound closure at the 2- and 4-day time points compared to the Veh- and Veh STZ-treated groups, respectively, and Tam STZ-treated mice also exhibited significantly greater wound cl","journal":"Journal of Investigative Dermatology","year":2024,"id":473802,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9463,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":232203,"name":"Andrew P. Sawaya","orcid":"0000-0002-4675-3919","position":1,"is_corresponding":false},{"id":232208,"name":"Spencer Mehdizadeh","orcid":"0000-0003-4805-4262","position":2,"is_corresponding":false},{"id":218255,"name":"Stephen R. Brooks","orcid":"0000-0001-5592-5332","position":3,"is_corresponding":false},{"id":232207,"name":"Kowser Hasneen","orcid":"0000-0002-1023-9408","position":4,"is_corresponding":false},{"id":1109302,"name":"Subhashree Nayak","orcid":"0000-0002-7088-9461","position":5,"is_corresponding":false},{"id":318571,"name":"Andrew M. Overmiller","orcid":"0000-0002-3169-0556","position":6,"is_corresponding":false},{"id":232211,"name":"María I. Morasso","orcid":"0000-0002-9632-9593","position":7,"is_corresponding":false},{"id":1258189,"name":"C. O'Neill","orcid":"0000-0001-8825-8548","position":0,"is_corresponding":true}],"reference_count":21,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:06:04.967429Z","pmid":"39127091","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}