MSX1+PDGFRAlow limb mesenchyme-like cells as an efficient stem cell source for human cartilage regeneration.

Degenerative bone disorders have a significant impact on global health, and regeneration of articular cartilage remains a challenge. Existing cell therapies using mesenchymal stromal cells (MSCs) have shown limited efficacy, highlighting the necessity for alternative stem cell sources. Here, we have identified and characterized MSX1⁺ mesenchymal progenitor cells in the developing limb bud with remarkable osteochondral-regenerative and microenvironment-adaptive capabilities. Single-cell sequencing further revealed the presence of two major cell compositions within the MSX1⁺ cells, where a distinct PDGFRA^low subset retained the strongest osteochondral competency and could efficiently regenerate articular cartilage in vivo. Furthermore, a strategy was developed to generate MSX1⁺PDGFRA^low limb mesenchyme-like (LML) cells from human pluripotent stem cells that closely resembled their mouse counterparts, which were bipotential in vitro and could directly regenerate damaged cartilage in a mouse injury model. Together, our results indicated that MSX1⁺PDGFRA^low LML cells might be a prominent stem cell source for human cartilage regeneration.