{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T00:16:56Z","timestamp":1793146616807,"version":"4.5.0"},"reference-count":36,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["21K16312"],"award-info":[{"award-number":["21K16312"]}]},{"name":"JSPS KAKENHI","award":["18K08160"],"award-info":[{"award-number":["18K08160"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Interstitial lung disease associated with connective tissue disease (CTD-ILD) is a severe condition characterized by inflammation and progressive lung fibrosis, with limited treatment options. Previous studies have demonstrated the anti-inflammatory and antifibrotic properties of human umbilical cord-derived mesenchymal stem cells (huMSCs), suggesting their potential as novel therapeutic agents. Therefore, we investigated the dose-dependent therapeutic effects of huMSCs on CTD-ILD. A bleomycin-induced mouse model of interstitial lung disease, in which female C57BL\/6J mice developed diffuse pulmonary lesions following continuous subcutaneous infusion of bleomycin, was used. Mice subsequently received intravenous huMSCs at doses of 1.0 \u00d7 103, 1.0 \u00d7 104, or 1.0 \u00d7 105 cells. The medium dose (1.0 \u00d7 104 cells) showed the most pronounced effects on pulmonary fibrosis and collagen deposition, while significantly suppressing pro-inflammatory cytokines, including interleukin-1\u03b2 and interleukin-6; however, this effect was not consistent across all measured outcomes. The treatment also enhanced beneficial matrix remodeling by downregulating TIMP-1 and upregulating MMP-9 expression. Furthermore, huMSC administration modulated macrophage polarization and inhibited the pro-inflammatory M1 phenotype. These findings highlight the therapeutic potential of huMSCs for CTD-ILD and underscore the importance of dose optimization to balance efficacy and safety.<\/jats:p>","DOI":"10.3390\/ijms262010016","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T08:34:26Z","timestamp":1760517266000},"page":"10016","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Evaluating the Dose-Dependent Effects of Human Umbilical Cord-Derived Mesenchymal Stem Cells in a Preclinical Model of Interstitial Lung Disease"],"prefix":"10.3390","volume":"26","author":[{"given":"Takuya","family":"Kotani","sequence":"first","affiliation":[{"name":"Department of Internal Medicine (IV), Division of Rheumatology, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8049-1943","authenticated-orcid":false,"given":"Takashi","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Legal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Osaka, Japan"},{"name":"Laboratory of Microbial Informatics, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki 567-0085, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryota","family":"Masutani","sequence":"additional","affiliation":[{"name":"Division of Central Laboratory, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satsuki","family":"Uemura","sequence":"additional","affiliation":[{"name":"School of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shogo","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (IV), Division of Rheumatology, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayasu","family":"Suzuka","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (IV), Division of Rheumatology, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Ikemoto","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (IV), Division of Rheumatology, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0065-929X","authenticated-orcid":false,"given":"Tohru","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (IV), Division of Rheumatology, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/S0140-6736(12)61079-4","article-title":"Interstitial lung disease in connective tissue disorders","volume":"380","author":"Fischer","year":"2012","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1007\/s00408-020-00383-w","article-title":"Connective tissue disease-related interstitial lung disease: Prevalence, patterns, predictors, prognosis, and treatment","volume":"198","author":"Jeganathan","year":"2020","journal-title":"Lung"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Vacchi, C., Sebastiani, M., Cassone, G., Cerri, S., Della Casa, G., Salvarani, C., and Manfredi, A. 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