退行性软骨疾病的干细胞疗法因对透明软骨形成和维持的不完全了解而受到限制。人骨髓基质细胞/骨骼干细胞（hBMSC/SSC）在附着于透明质酸包被的纤维蛋白微珠（HyA-FMB）时产生稳定的透明软骨，但其机制仍不清楚。在体外，hBMSC/SSC/HyA-FMB 类器官在软骨形成分化早期表现出 BMP 信号减弱，随后软骨形成 IGFBP5 /MGP 细胞中 BMP 信号恢复。随后，建立了人诱导多能干细胞 (hiPSC) 衍生的巩膜细胞（BMP 抑制），然后用转化生长因子 β (TGF-β) -/BMP2 和生长分化因子 5 (GDF5) 处理（BMP 信号传导激活） 。单独的 TGF-β 会引起微弱的软骨形成反应，但 TGF-β/BMP2/GDF5 会导致 SOX9 聚集体（软骨球体）分层，并在体外高表达 COL2A1、ACAN 和 PRG4，而最低表达 COL10A1 和 ALP。虽然移植的 hBMSCs/SSCs/HyA-FMB 不能治愈免疫功能低下的啮齿类动物的关节软骨缺陷，但软骨球衍生细胞/HyA-FMB 形成的非肥大性软骨在体内持续至少 5 个月。

Stem cell therapies for degenerative cartilage disease are limited by an incomplete understanding of hyaline cartilage formation and maintenance. Human bone marrow stromal cells/skeletal stem cells (hBMSCs/SSCs) produce stable hyaline cartilage when attached to hyaluronic acid-coated fibrin microbeads (HyA-FMBs), yet the mechanism remains unclear. In vitro, hBMSC/SSC/HyA-FMB organoids exhibited reduced BMP signaling early in chondrogenic differentiation, followed by restoration of BMP signaling in chondrogenic IGFBP5 + /MGP + cells. Subsequently, human-induced pluripotent stem cell (hiPSC)-derived sclerotome cells were established (BMP inhibition) and then treated with transforming growth factor β (TGF-β) -/+ BMP2 and growth differentiation factor 5 (GDF5) (BMP signaling activation). TGF-β alone elicited a weak chondrogenic response, but TGF-β/BMP2/GDF5 led to delamination of SOX9 + aggregates (chondrospheroids) with high expression of COL2A1, ACAN, and PRG4 and minimal expression of COL10A1 and ALP in vitro. While transplanted hBMSCs/SSCs/HyA-FMBs did not heal articular cartilage defects in immunocompromised rodents, chondrospheroid-derived cells/HyA-FMBs formed non-hypertrophic cartilage that persisted until at least 5 months in vivo.