{
  "abstract": "Background\n\nMesenchymal stem cells (MSCs) within the shoulder joint serve as a critical progenitor pool for regenerating the fibrocartilaginous enthesis during rotator cuff repair. However, the chondrogenic potential of MSCs across distinct rotator cuff sites, along with the underlying molecular mechanisms, remains to be elucidated.Methods\n\nWe performed a comparative analysis of human subacromial bursa-derived MSCs (sMSCs) and rotator cuff enthesis-derived MSCs (rMSCs). By integrating functional chondrogenic assays with longitudinal bulk and single-cell RNA sequencing, we reconstructed source-specific differentiation trajectories and identified key regulatory drivers.Results\n\nrMSCs exhibited superior chondrogenic potency compared to sMSCs. Transcriptional profiling identified a region-specific pro-chondrogenic module in rMSCs driven by the transcription factor SIX2. Single-cell atlas construction revealed that tissue origin dictates lineage fate: rMSCs were enriched for a high-potency SIX2⁺ progenitor population that differentiated into metabolic-active S100A2⁺ chondrocytes. Conversely, sMSCs were dominated by DPP4⁺ progenitors that preferentially bifurcated into an aberrant CXCL8⁺ inflammatory trajectory. Mechanistically, we demonstrated that SIX2 acted as a competency factor, coordinating early proliferative expansion with late-stage matrix assembly and, crucially, active suppression of inflammatory signaling. Accordingly, lentiviral overexpression of SIX2 in sMSCs was sufficient to rescue their chondrogenic defects and rewire their trajectory toward a regenerative phenotype.Conclusions\n\nOur findings define the transcriptional hierarchy of shoulder-resident progenitors, identifying SIX2 as a master regulator that couples chondrogenesis with immune evasion. This establishes a molecular framework for precision cell sourcing and rational design of lineage-specific therapies.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Orthopedics and Trauma, Peking University People's Hospital, Beijing, China. jujiabao@bjmu.edu.cn.",
    "Department of Dermatology and Venereology, Peking University First Hospital, Beijing, China.",
    "Department of Orthopedics and Trauma, Peking University People's Hospital, Beijing, China.",
    "Department of Orthopedics and Trauma, Peking University People's Hospital, Beijing, China. shoulderchen@126.com.",
    "Department of Orthopedics and Trauma, Peking University People's Hospital, Beijing, China. hailin@bjmu.edu.cn."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Jiabao Ju"
    },
    {
      "affs": [
        1
      ],
      "name": "Pingping Lin"
    },
    {
      "affs": [
        2
      ],
      "name": "Dingxiao Xue"
    },
    {
      "affs": [
        2
      ],
      "name": "Hao Lu"
    },
    {
      "affs": [
        2
      ],
      "name": "Yuhui Kou"
    },
    {
      "affs": [
        2
      ],
      "name": "Mingtai Ma"
    },
    {
      "affs": [
        2
      ],
      "name": "Ming Yang"
    },
    {
      "affs": [
        3
      ],
      "name": "Jianhai Chen"
    },
    {
      "affs": [
        4
      ],
      "name": "Hailin Xu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0defxwd7t2wzz.bib",
  "cited_by": 0,
  "doi": "10.1007/s10565-026-10251-7",
  "fulltext_url": "https://europepmc.org/articles/PMC13719724",
  "id": "0defxwd7t2wzz",
  "issns": [
    "0742-2091",
    "1573-6822"
  ],
  "landing_url": "https://europepmc.org/article/MED/42957914",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
    [
      "openalex",
      "2716|Mesenchymal stem cell research"
    ]
  ],
  "openalex": "W7172283615",
  "pdf_url": "https://europepmc.org/articles/PMC13719724?pdf=render",
  "pmcid": "PMC13719724",
  "pmid": "42957914",
  "published": "2026-08-03",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/0defxwd7t2wzz.ris",
  "sources": [
    {
      "first_seen": "2026-11-01T00:20:47Z",
      "native_id": "MED:42957914",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42957914"
    },
    {
      "first_seen": "2026-11-02T12:23:38Z",
      "native_id": "PMC13719724",
      "source": "pmc",
      "url": "https://doi.org/10.1007/s10565-026-10251-7"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2716|Mesenchymal stem cell research",
      "subfield": "human-genetics"
    }
  ],
  "title": "Single-cell dissection of shoulder-derived mesenchymal stem cells reveals source-specific progenitor heterogeneity and a SIX2-driven chondrogenic program.",
  "title_text": "Single-cell dissection of shoulder-derived mesenchymal stem cells reveals source-specific progenitor heterogeneity and a SIX2-driven chondrogenic program.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T12:20:44Z",
  "url": "https://research.draconitic.com/paper/0defxwd7t2wzz",
  "venue": "Cell biology and toxicology",
  "versions": []
}