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This study aimed to elucidate the effect of Treg cell-derived exosomes (Treg-Exos), particularly those carrying microRNA-21 (miR-21), on the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) and periodontal tissue regeneration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>After co-culturing Treg cells or Treg-Exos with PDLSCs respectively in vitro, the osteogenic differentiation of treated PDLSCs was assessed through Alkaline phosphatase (ALP) activity, Alizarin Red staining, and the expression of osteogenic markers runt-related transcription factor 2 (Runx-2) and Osterix. The functional role of miR-21 in Treg-Exos was assessed via gain- and loss-of-function experiments, involving transfection of Treg cells with miR-21 mimics or inhibitors. In vivo, a mice periodontal defect model was established via silk ligation and Porphyromonas gingivalis inoculation. Subsequently, Treg-Exos were locally administered into defects to assess their potential in promoting periodontal tissue regeneration. The regenerative efficacy was evaluated using micro-CT and histological analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Treg cell levels were significantly elevated in periodontitis patients compared to healthy controls. Both Treg cells and Treg-Exos markedly promoted the osteogenic differentiation of PDLSCs in vitro, as evidenced by increased ALP activity, enhanced mineralization, and upregulated Runx-2\/Osterix expression. Exosomes derived from miR-21-overexpressing Treg cells further promoted PDLSC osteogenesis, whereas exosomes with miR-21 knockdown exhibited an inhibitory effect. In vivo, Treg-Exos injection alleviated periodontal damage and improved tissue morphology compared to PBS controls, as demonstrated by micro-CT and histological analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Treg cell-derived exosomal miR-21 promotes the osteogenic differentiation of PDLSCs, enhancing periodontal tissue regeneration in vivo, suggesting that Treg cells and their exosomal miR-21 may serve as promising therapeutic targets for periodontitis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12903-025-06770-0","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T09:55:15Z","timestamp":1758880515000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Treg cell-derived exosomal miR-21 promotes osteogenic differentiation of periodontal ligament stem cells"],"prefix":"10.1186","volume":"25","author":[{"given":"Yu","family":"Xia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Feng","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,26]]},"reference":[{"issue":"1","key":"6770_CR1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/s12010-022-04127-9","volume":"195","author":"RR Ray","year":"2023","unstructured":"Ray RR. 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Gene. 2018;666:116\u201322.","journal-title":"Gene"}],"container-title":["BMC Oral Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12903-025-06770-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12903-025-06770-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12903-025-06770-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T10:04:06Z","timestamp":1758881046000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcoralhealth.biomedcentral.com\/articles\/10.1186\/s12903-025-06770-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,26]]},"references-count":50,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["6770"],"URL":"https:\/\/doi.org\/10.1186\/s12903-025-06770-0","relation":{},"ISSN":["1472-6831"],"issn-type":[{"value":"1472-6831","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,26]]},"assertion":[{"value":"8 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 September 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This work was approved by the Ethics Committee of the Chinese PLA General Hospital (No. 309202406063203). Clinical samples were obtained from the Eighth Medical Center of the PLA General Hospital with informed consent from participants. Female C57BL\/6 mice (8\u201312 weeks old) were sourced from the Laboratory Animal Center at the Eighth Medical Center of Chinese PLA General Hospital (Beijing, China). The work had been reported in line with the ARRIVE guidelines 2.0.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1465"}}