{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T10:56:38Z","timestamp":1790852198009,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,24]]},"group-title":"Physiology","reference-count":39,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["P01 HL107147"],"award-info":[{"award-number":["P01 HL107147"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,27]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Type 2 diabetes mellitus (T2DM) is a chronic disorder associated with obesity and hyperglycemia. T2DM is linked to significant clinical complications such as delayed wound healing and diabetic foot ulcers. Tumor necrosis factor-stimulated gene 6 (TSG-6) is a protein with multiple functions including regulation of cytokine binding to glycosaminoglycans in extracellular matrices and on vascular endothelial walls. Loss of TSG-6 in knockout mice increases skin inflammation and delays wound healing. Here, in both a genetic model (\n                  <jats:italic>db\/db<\/jats:italic>\n                  mice) and a dietary model that simulates human T2DM (mice treated with a high-fat diet [HFD] and streptozotocin [STZ]), we observed sustained hyperglycemia and a reproducible delay in wound closure. TSG-6 expression was markedly reduced in diabetic skin in these models, both before injury and post wounding. HFD+STZ diabetic mouse wounds showed elevated levels of pro-inflammatory cytokines (IL-6, TNF-\u03b1, and MIP-1\u03b1) and lower levels of the anti-inflammatory cytokine IL-10, relative to normoglycemic mice. Re-introduction of TSG-6 protein into the wounds normalized healing rates, corrected abnormal cytokine expression levels, and increased macrophage accumulation in dermal and adipose compartments. Thus, T2DM is associated with reduced levels of TSG-6 in diabetic skin, which contributes to the pro-inflammatory milieu and the delay in wound closure.\n                <\/jats:p>","DOI":"10.64898\/2026.09.19.752893","type":"posted-content","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:00:17Z","timestamp":1790312417000},"source":"Crossref","is-referenced-by-count":0,"title":["Abnormally low expression of tumor necrosis factor stimulated gene 6 (TSG-6) in obese type 2 diabetic mice contributes to altered inflammation and delayed cutaneous wound healing"],"prefix":"10.64898","author":[{"given":"Minou","family":"Alipour","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Cleveland Clinic Research Institute, Cleveland OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Offenberger","sequence":"additional","affiliation":[{"name":"Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Anand","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Cleveland Clinic Research Institute, Cleveland OH"},{"name":"Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland OH"},{"name":"Department of Dermatology, Medical Specialty Institute, Cleveland Clinic, Cleveland OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Cleveland Clinic Research Institute, Cleveland OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Stenina-Adognravi","sequence":"additional","affiliation":[{"name":"Department of Heart, Blood, and Kidney Research, Cleveland Clinic, Cleveland OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3690-8382","authenticated-orcid":false,"given":"Edward V.","family":"Maytin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Cleveland Clinic Research Institute, Cleveland OH"},{"name":"Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland OH"},{"name":"Department of Dermatology, Medical Specialty Institute, Cleveland Clinic, Cleveland OH"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100103051097000_2026.09.19.752893v2.1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.52.2.542"},{"issue":"1","key":"2026100103051097000_2026.09.19.752893v2.2","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1186\/s13287-020-01621-x","article-title":"Adipose stem cells isolated from diabetic mice improve cutaneous wound healing in streptozotocin-induced diabetic mice","volume":"11","year":"2020","journal-title":"Stem Cell Res Ther"},{"key":"2026100103051097000_2026.09.19.752893v2.3","doi-asserted-by":"publisher","DOI":"10.1186\/s13047-020-00383-2"},{"key":"2026100103051097000_2026.09.19.752893v2.4","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.13462"},{"key":"2026100103051097000_2026.09.19.752893v2.5","doi-asserted-by":"publisher","DOI":"10.2174\/1573399815666191024085838"},{"key":"2026100103051097000_2026.09.19.752893v2.6","doi-asserted-by":"crossref","unstructured":"Chini J , DeMarco N , Mitchell DV , McCright SJ , Shen KM , Pandey D , et al. CD9 regulates macrophage-mediated remodeling of adipose tissue in obesity. JCI Insight 2026;11(6).","DOI":"10.1172\/jci.insight.193837"},{"key":"2026100103051097000_2026.09.19.752893v2.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2018.01.011"},{"issue":"10","key":"2026100103051097000_2026.09.19.752893v2.8","doi-asserted-by":"crossref","first-page":"4344","DOI":"10.1167\/iovs.17-21506","article-title":"Mesenchymal Stem Cells Promote Diabetic Corneal Epithelial Wound Healing Through TSG-6-Dependent Stem Cell Activation and Macrophage Switch","volume":"58","year":"2017","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2026100103051097000_2026.09.19.752893v2.9","doi-asserted-by":"publisher","DOI":"10.2337\/db12-0227"},{"key":"2026100103051097000_2026.09.19.752893v2.10","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-019-00749-0"},{"key":"2026100103051097000_2026.09.19.752893v2.11","doi-asserted-by":"publisher","DOI":"10.1038\/nri2925"},{"key":"2026100103051097000_2026.09.19.752893v2.12","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1300194"},{"key":"2026100103051097000_2026.09.19.752893v2.13","doi-asserted-by":"crossref","unstructured":"Fang WC , Lan CE . The Epidermal Keratinocyte as a Therapeutic Target for Management of Diabetic Wounds. Int J Mol Sci 2023;24(5).","DOI":"10.3390\/ijms24054290"},{"key":"2026100103051097000_2026.09.19.752893v2.14","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63754-6"},{"key":"2026100103051097000_2026.09.19.752893v2.15","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.223545"},{"key":"2026100103051097000_2026.09.19.752893v2.16","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/416254"},{"key":"2026100103051097000_2026.09.19.752893v2.17","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.26.6.1790"},{"key":"2026100103051097000_2026.09.19.752893v2.18","doi-asserted-by":"publisher","DOI":"10.2337\/dc15-0536"},{"key":"2026100103051097000_2026.09.19.752893v2.19","doi-asserted-by":"crossref","first-page":"100037","DOI":"10.1016\/j.mbplus.2020.100037","article-title":"The role of extracellular matrix in the pathophysiology of diabetic wounds","volume":"6-7","year":"2020","journal-title":"Matrix Biol Plus"},{"key":"2026100103051097000_2026.09.19.752893v2.20","doi-asserted-by":"crossref","unstructured":"Huynh P , Phie J , Krishna SM , Golledge J . Systematic review and meta-analysis of mouse models of diabetes-associated ulcers. BMJ Open Diabetes Res Care 2020;8(1).","DOI":"10.1136\/bmjdrc-2019-000982"},{"key":"2026100103051097000_2026.09.19.752893v2.21","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.10.5.1982"},{"key":"2026100103051097000_2026.09.19.752893v2.22","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.molimm.2022.11.008","article-title":"An update on the role of tumor necrosis factor alpha stimulating gene-6 in inflammatory diseases","volume":"152","year":"2022","journal-title":"Mol Immunol"},{"key":"2026100103051097000_2026.09.19.752893v2.23","doi-asserted-by":"crossref","first-page":"108605","DOI":"10.1016\/j.intimp.2022.108605","article-title":"IL-25 improves diabetic wound healing through stimulating M2 macrophage polarization and fibroblast activation","volume":"106","year":"2022","journal-title":"Int Immunopharmacol"},{"key":"2026100103051097000_2026.09.19.752893v2.24","doi-asserted-by":"crossref","first-page":"918223","DOI":"10.3389\/fimmu.2022.918223","article-title":"Fibroblasts: Immunomodulatory factors in refractory diabetic wound healing","volume":"13","year":"2022","journal-title":"Front Immunol"},{"key":"2026100103051097000_2026.09.19.752893v2.25","doi-asserted-by":"publisher","DOI":"10.2337\/dci22-0043"},{"key":"2026100103051097000_2026.09.19.752893v2.26","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.00407"},{"key":"2026100103051097000_2026.09.19.752893v2.27","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M800019-JLR200"},{"key":"2026100103051097000_2026.09.19.752893v2.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2008.02.026"},{"key":"2026100103051097000_2026.09.19.752893v2.29","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.55.02.06.db05-1103"},{"key":"2026100103051097000_2026.09.19.752893v2.30","first-page":"476969","article-title":"Wound healing in mice with high-fat diet- or ob gene-induced diabetes-obesity syndromes: a comparative study","volume":"2010","year":"2010","journal-title":"Exp Diabetes Res"},{"issue":"6","key":"2026100103051097000_2026.09.19.752893v2.31","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1002\/cbf.3424","article-title":"The link between advanced glycation end products and apoptosis in delayed wound healing","volume":"37","year":"2019","journal-title":"Cell Biochem Funct"},{"key":"2026100103051097000_2026.09.19.752893v2.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2020.04.015"},{"key":"2026100103051097000_2026.09.19.752893v2.33","first-page":"701738","article-title":"Hyperglycemia-Induced Changes in Hyaluronan Contribute to Impaired Skin Wound Healing in Diabetes: Review and Perspective","volume":"2015","year":"2015","journal-title":"Int J Cell Biol"},{"key":"2026100103051097000_2026.09.19.752893v2.34","doi-asserted-by":"crossref","unstructured":"Sun Y , Song L , Zhang Y , Wang H , Dong X . Adipose stem cells from type 2 diabetic mice exhibit therapeutic potential in wound healing. Stem Cell Res Ther 2020;11.","DOI":"10.1186\/s13287-020-01817-1"},{"key":"2026100103051097000_2026.09.19.752893v2.35","doi-asserted-by":"publisher","DOI":"10.2337\/diab.37.9.1163"},{"issue":"1","key":"2026100103051097000_2026.09.19.752893v2.36","doi-asserted-by":"crossref","first-page":"14840","DOI":"10.1038\/s41598-022-18281-x","article-title":"High-fat diet causes mechanical allodynia in the absence of injury or diabetic pathology","volume":"12","year":"2022","journal-title":"Sci Rep"},{"key":"2026100103051097000_2026.09.19.752893v2.37","first-page":"1323315","article-title":"Current knowledge of morbidities and direct costs related to diabetic foot disorders: a literature review","volume":"14","year":"2023","journal-title":"Front Endocrinol (Lausanne"},{"key":"2026100103051097000_2026.09.19.752893v2.38","doi-asserted-by":"publisher","DOI":"10.7150\/thno.29766"},{"issue":"2","key":"2026100103051097000_2026.09.19.752893v2.39","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/nprot.2013.002","article-title":"The mouse excisional wound splinting model, including applications for stem cell transplantation","volume":"8","year":"2013","journal-title":"Nature Protocols"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.19.752893","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T10:05:26Z","timestamp":1790849126000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.09.19.752893"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,24]]},"references-count":39,"URL":"https:\/\/doi.org\/10.64898\/2026.09.19.752893","relation":{},"subject":[],"published":{"date-parts":[[2026,9,24]]},"subtype":"preprint"}}