{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:23:39Z","timestamp":1790645019182,"version":"4.1.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:00:00Z","timestamp":1778025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Chronic diabetic ulcers exhibit a dysregulated immune microenvironment characterized by aberrant leukocyte responses and dysfunctional fibroblast activation. Identifying molecular regulators of fibroblast-driven immune responses may provide therapeutic targets to restore effective wound repair in these chronic wounds.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Bulk RNA-seq (GSE199939) and scRNA-seq (GSE165816) datasets from human DFUs were integrated to identify alterations in MFGE8 expression in wound fibroblasts. These findings were validated by immunofluorescence staining and RT-qPCR in\n                      <jats:italic>db\/db<\/jats:italic>\n                      mouse wounds. Cytokine screening assays were performed to identify upstream regulators of MFGE8 dysregulation. The effects of MFGE8 on fibroblast immune activity were assessed by RT-qPCR, Western blotting, ELISA, and Transwell migration assays. To evaluate its therapeutic potential\n                      <jats:italic>in vivo<\/jats:italic>\n                      , a single-dose of MFGE8-prestimulatedd fibroblasts were locally delivered into\n                      <jats:italic>db\/db<\/jats:italic>\n                      mouse wounds, followed by wound healing assessment, immunofluorescence staining, and transcriptomic analysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MFGE8 was markedly downregulated in fibroblasts from DFUs. TNF-\u03b1 and IL-1\u03b1 robustly induced MFGE8 expression in dermal fibroblasts. Recombinant MFGE8 reprogrammed fibroblasts toward a pro-inflammatory phenotype, significantly increasing the expression of IL1B, IL6, CXCL8, CXCL1, and CCL2, and enhancing macrophage migration\n                      <jats:italic>in vitro<\/jats:italic>\n                      . In\n                      <jats:italic>db\/db<\/jats:italic>\n                      mice, MFGE8-prestimulated fibroblasts increased macrophage infiltration, activated inflammatory and pro-repair transcriptional programs, and accelerated wound closure.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings establish MFGE8 as a key regulator of fibroblast inflammatory competence and support a cell-based immunomodulatory strategy to promote healing in chronic diabetic wounds.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1810043","type":"journal-article","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T07:33:46Z","timestamp":1778052826000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["MFGE8-primed fibroblasts reprogram the immunosuppressed microenvironment to promote diabetic wound healing"],"prefix":"10.3389","volume":"14","author":[{"given":"Ling","family":"Pan","sequence":"first","affiliation":[{"name":"Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Nanjing, Jiangsu, China"]},{"name":"Department of Mycobacterium, Jiangsu Provincial Key Laboratory of Dermatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yejing","family":"Huang","sequence":"additional","affiliation":[{"name":"Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinfeng","family":"Wu","sequence":"additional","affiliation":[{"name":"Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongqing","family":"Li","sequence":"additional","affiliation":[{"name":"Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongsheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Nanjing, Jiangsu, China"]},{"name":"Department of Mycobacterium, Jiangsu Provincial Key Laboratory of Dermatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1016\/j.jid.2024.06.1281","article-title":"Integrated single-cell analysis reveals spatially and temporally dynamic heterogeneity in fibroblast states during wound healing","volume":"145","author":"Almet","year":"2025","journal-title":"J. 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