{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T14:47:09Z","timestamp":1791730029556,"version":"4.3.4"},"reference-count":34,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T00:00:00Z","timestamp":1771977600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["JP22K10221 and JP25K13149"],"award-info":[{"award-number":["JP22K10221 and JP25K13149"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Tissue Engineering Part A"],"abstract":"<jats:p>\n                    Sj\u00f6gren\u2019s disease (SjD) is a debilitating autoimmune disorder characterized by progressive salivary gland destruction, for which current therapies are merely palliative. Novel therapeutic approaches focusing on immunomodulation are therefore urgently needed. Extracellular vesicles from dental pulp stem cells (DPSC-EVs) have emerged as a promising cell-free platform for systemic immunomodulation. Here, we investigated the therapeutic efficacy of DPSC-EVs in a nonobese diabetic mouse model of SjD to elucidate the mechanistic basis for their superior immunomodulatory potential compared with bone-marrow-derived EVs (BMMSC-EVs). A single intravenous administration of DPSC-EVs significantly recovered salivary gland function, accompanied by a marked reduction in serum autoantibodies and glandular inflammation. DPSC-EVs preferentially accumulate in the spleen and are internalized by F4\/80\n                    <jats:sup>+<\/jats:sup>\n                    macrophages. This interaction triggered a dual modulation of transforming growth factor (TGF)-\u03b2\/Smad signaling: (i) direct delivery of a higher TGF-\u03b21 payload, initiating signaling and (ii) concurrent downregulation of the NEDD4L E3 ubiquitin ligase, which amplified and sustained the signal by inhibiting phosphorylated Smad2\/3 degradation. Thus, DPSC-EVs exert their therapeutic effects by systemically targeting splenic macrophages to orchestrate a powerful, dual-mode activation of an immunoregulatory pathway. This study established DPSC-EVs as a highly promising, cell-free immunomodulatory therapy for SjD, offering a clear pathway for clinical translation.\n                  <\/jats:p>","DOI":"10.1177\/19373341261426389","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T07:16:14Z","timestamp":1772090174000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["DPSC-EVs Drive Functional Recovery in Sj\u00f6gren\u2019s Disease by Systemic Immunomodulation"],"prefix":"10.1177","author":[{"given":"Tatsuya","family":"Kawado","sequence":"first","affiliation":[{"name":"Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Ogata","sequence":"additional","affiliation":[{"name":"Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan."},{"name":"Dent-craniofacial Development and Regeneration Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masafumi","family":"Moriyama","sequence":"additional","affiliation":[{"name":"Section of Oral and Maxillofacial Surgery, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Yoshioka","sequence":"additional","affiliation":[{"name":"Department of Hygiene, Kitasato University School of Medicine, Sagamihara, Japan."},{"name":"Department of Pharmacy Gifu, University of Medical Science, Kani, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiko","family":"Yano","sequence":"additional","affiliation":[{"name":"Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayu","family":"Matsumura","sequence":"additional","affiliation":[{"name":"Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiji","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shintaro","family":"Kawano","sequence":"additional","affiliation":[{"name":"Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, 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