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It is characterized by articular cartilage degradation and inflammation, leading to joint pain and disability. Osteoarthritis is incurable and the patients may eventually need joint replacement. An emerging treatment is mesenchymal stromal cells (MSCs), with over two hundred clinical trials being registered. However, the outcomes of these trials have fallen short of the expectation, due to heterogeneity of MSCs and uncertain mechanisms of action. It is generally believed that MSCs exert their function mainly by secreting immunomodulatory and trophic factors. Here we used knee osteoarthritis mouse model to assess the therapeutic effects of MSCs isolated from the white adipose or dermal adipose tissue of <jats:italic>Prrx1-Cre; R26<\/jats:italic><jats:sup><jats:italic>tdTomato<\/jats:italic><\/jats:sup> mice and <jats:italic>Dermo1-Cre; R26<\/jats:italic><jats:sup><jats:italic>tdTomato<\/jats:italic><\/jats:sup> mice. We found that the <jats:italic>Prrx1<\/jats:italic>-lineage MSCs from the white adipose tissues showed the greatest in vitro differentiation potentials among the four MSC groups and single cell profiling showed that the <jats:italic>Prrx1<\/jats:italic>-lineage MSCs contained more stem cells than the <jats:italic>Dermo1<\/jats:italic> counterpart. Only the <jats:italic>Prrx1<\/jats:italic>-lineage cells isolated from white adipose tissues showed long-term therapeutic effectiveness on early-stage osteoarthritis models. Mechanistically, <jats:italic>Prrx1<\/jats:italic>-lineage MSCs differentiated into Col2<jats:sup>+<\/jats:sup> chondrocytes and replaced the damage cartilage, activated Col1 expressing in resident chondrocytes, and inhibited synovial inflammation. Transcriptome analysis showed that the articular chondrocytes derived from injected MSCs expressed immunomodulatory cytokines, trophic factors, and chondrocyte-specific genes. Our study identified a MSC population genetically marked by <jats:italic>Prrx1<\/jats:italic> that has great multipotentiality and can differentiate into chondrocytes to replace the damaged cartilage.<\/jats:p>","DOI":"10.1038\/s41536-024-00358-y","type":"journal-article","created":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T09:13:50Z","timestamp":1711962830000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Comparison studies identify mesenchymal stromal cells with potent regenerative activity in osteoarthritis treatment"],"prefix":"10.1038","volume":"9","author":[{"given":"Hongshang","family":"Chu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoyang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenlin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Yue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijuan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3913-1062","authenticated-orcid":false,"given":"Baojie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2070-0085","authenticated-orcid":false,"given":"Feng","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,1]]},"reference":[{"key":"358_CR1","doi-asserted-by":"publisher","first-page":"eadd3702","DOI":"10.1126\/scisignal.add3702","volume":"15","author":"M Pacifici","year":"2022","unstructured":"Pacifici, M. 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