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The lack of effective treatment for OA creates a need for the development of new therapeutic approaches that may rely on stem cells including mesenchymal stem\/stromal cells (MSCs) and their derivatives such as extracellular vesicles (EVs). The objective of this study was to evaluate the impact of MSCs derived from adipose tissue (AT-MSCs) and umbilical cord (UC-MSCs) and their EVs on cartilage-bone injury in vivo, to identify the specimen with the highest regenerative potential for further clinical applications in patients with OA. Humanized pigs underwent cartilage-bone injuries followed by intraarticular administration of products containing AT-MSCs, UC-MSCs, AT-MSC-EVs or UC-MSC-EVs mixed with hyaluronic acid (HA) or HA alone (for comparison). After 6-m follow-up, almost-fully-healed cartilage-bone defects were observed in the AT-MSC- and UC-MSC-treated pigs, and the defects were filled primarily with hyaline cartilage. In AT-MSC-EV- and UC-MSC-EV-treated pigs, a partial cartilage-bone tissue repair was observed, and the defects were filled primarily with fibrocartilage. The control pigs demonstrated limited regeneration capacity. The microcomputed tomography parameters of the subchondral bone indicated the ongoing progression of OA in controls, whereas in the MSC- and MSC-EV-treated pigs, the parameters indicated the cessation of OA progression. Moreover, no serious side effects were observed after the administration of products containing MSCs or MSC-EVs. The results indicate the safety and regenerative activity of MSCs on injured tissues, which favors not only the healing and improvement of bone structure but also the formation of hyaline cartilage. Superior tissue repair was observed after the administration of products containing AT-MSCs. The treatment of OA with MSC-EVs needs further standardization.<\/jats:p>\n          <jats:p>\n            <jats:bold>Graphical Abstract<\/jats:bold>\n          <\/jats:p>","DOI":"10.1007\/s12015-025-10853-4","type":"journal-article","created":{"date-parts":[[2025,5,17]],"date-time":"2025-05-17T03:24:14Z","timestamp":1747452254000},"page":"1075-1095","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Evaluation of the Safety and Regenerative Potential of Human Mesenchymal Stem Cells and Their Extracellular Vesicles in a Transgenic Pig Model of Cartilage-Bone Injury In Vivo \u2013 Preclinical Study"],"prefix":"10.1007","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8088-6221","authenticated-orcid":false,"given":"Anna","family":"\u0141ab\u0119d\u017a-Mas\u0142owska","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5579-4870","authenticated-orcid":false,"given":"Jaros\u0142aw","family":"Wieczorek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6411-8034","authenticated-orcid":false,"given":"Maciej","family":"Mierzwi\u0144ski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9511-9498","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Seku\u0142a-Stryjewska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4475-187X","authenticated-orcid":false,"given":"Sylwia","family":"Noga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6836-4738","authenticated-orcid":false,"given":"Jolanta","family":"Rajca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3575-5641","authenticated-orcid":false,"given":"Piotr","family":"Duda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5777-9591","authenticated-orcid":false,"given":"Katarzyna","family":"Milian-Ciesielska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9956-1593","authenticated-orcid":false,"given":"El\u017cbieta","family":"Karnas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6298-2853","authenticated-orcid":false,"given":"Katarzyna","family":"Kmiotek-Caller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4901-9621","authenticated-orcid":false,"given":"Agnieszka","family":"Szkaradek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5523-1215","authenticated-orcid":false,"given":"Zbigniew","family":"Madeja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3027-9984","authenticated-orcid":false,"given":"Krzysztof","family":"Ficek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1544-1733","authenticated-orcid":false,"given":"Jacek","family":"Jura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6814-6127","authenticated-orcid":false,"given":"Ewa","family":"Zuba-Surma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,17]]},"reference":[{"key":"10853_CR1","unstructured":"Kaplan, W., Wirtz, V. 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Written informed consent was obtained from the patients for participation in the study, for the use of biological material, and for the publication of the results before the adipose tissue was harvested.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"Human umbilical cords were provided by Polish Stem Cell Bank LLC, with permission from the Polish Ministry of Health (MZ-PZ-TSZ-025-15906-36\/AB\/14), obtained based on the approval of the appropriate Bioethics Committee. Written informed consent was obtained for participation in the study, for the use of biological material and for the publication of results from umbilical cord donors. The Material Transfer Agreement (free of charge) was signed by the Polish Stem Cell Bank and Jagiellonian University.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"The authors declare that they have no conflicts of interest.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of Interest\/Competing Interests"}},{"value":"The authors declare that they have not used generative AI in the preparation of this manuscript.","order":7,"name":"Ethics","group":{"name":"EthicsHeading","label":"Use of AI"}}]}}