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Human dental pulp stem cells (hDPSCs) and their derived Exosomes (hDPSCs-Exos) have emerged as promising regenerative strategies. Therefore, the present study aimed to compare the regenerative capacity of hDPSCs versus their Exos on surgically induced defects in rats\u2019 submandibular SGs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Seventy-two male Sprague Dawley rats were randomly assigned to four groups (n=18). Group I (negative control): no surgical intervention. The remaining rats underwent a circular defect preparation on the right submandibular SG, then the dissected areas were injected circumferentially with different treatments according to group assignment. Group II (positive control): 1ml phosphate buffered saline (PBS). Group III (hDPSCs group): 1\u00d7105 hDPSCs suspended in 1ml PBS, and group IV (hDPSCs-Exos): hDPSCs-Exos (20\u00b5g\/ml) suspended in 1 ml PBS. Six rats from each group were euthanized at 3, 7, and 14 days postoperatively. Histological evaluation, immunohistochemical analysis (IHC) of Collagen-I (COL-I), and quantitative real time polymerase chain reaction (qRT-PCR) for aquaporin-5 (Aqua-5) gene expression were performed, followed by relevant statistical analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The positive control group showed marked acinar disorganization and fibrosis. The hDPSCs-treated group demonstrated partial regeneration, whereas the exosome-treated group showed near-normal architecture by day 14. Statistical analysis showed significant differences between groups as COL-I expression decreased significantly over time, with the lowest levels in the exosome group indicating tissue regeneration without fibrosis. Aqua-5 expression increased significantly, showing superior molecular restoration in the exosome group approaching negative control baselines by day 14 that raises hope toward functional recovery followed by hDPSCs and finally positive control groups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Both hDPSCs and their exosomes promote regeneration of surgically injured submandibular glands. The exosomes-treated group demonstrated superior structural and molecular recovery approaching normal architecture, supporting their potentiality as a safer and effective cell-free regenerative therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12903-026-09337-9","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T01:04:14Z","timestamp":1784682254000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Regenerative capacity of human dental pulp stem cells versus their exosomes on surgically induced submandibular gland defects in rats"],"prefix":"10.1186","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0994-7586","authenticated-orcid":false,"given":"Basma A","family":"Hammad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0434-1529","authenticated-orcid":false,"given":"Mohamed E","family":"Helal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2357-0810","authenticated-orcid":false,"given":"Laila E","family":"Amin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0987-8616","authenticated-orcid":false,"given":"Jilan","family":"Youssef","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8577-4301","authenticated-orcid":false,"given":"Rana","family":"El\u208bQashty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"issue":"17","key":"9337_CR1","doi-asserted-by":"publisher","first-page":"1909","DOI":"10.1200\/JCO.21.00449","volume":"39","author":"JL Geiger","year":"2021","unstructured":"Geiger JL, Ismaila N, Beadle B, Caudell JJ, Chau N, Deschler D, et al. 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All experimental procedures were performed in compliance with the protocol approved by the Ethical Committee: Mansoura University Animal Care and Use Committee (MU-ACUC), Mansoura University, Mansoura, Egypt, ID: MU-ACUC (DENT.Phd.24.11.13) following the guidelines of the Animal Research: Reporting of In Vivo Experiments (ARRIVE).For the isolation of human dental pulp stem cells, impacted third molars were extracted from patients attending the Oral Surgery department clinics at the Faculty of Dentistry, Mansoura University, Egypt, after acquiring informed consents in accordance with approval from the Ethical Committee of the faculty of dentistry, Mansoura University, Mansoura, Egypt and following the guidelines outlined by the Declaration of Helsinki.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"1332"}}