Differentiating induced pluripotent stem cells into articular chondrocytes: advances, challenges, and future directions

Cartilage injury and osteoarthritis-associated degeneration remain major clinical challenges because articular cartilage is avascular, aneural, and alymphatic, leaving it with limited intrinsic capacity for repair. Current clinical strategies, including microfracture, osteochondral grafting, autologous chondrocyte implantation, and mesenchymal stem cell-based approaches, can relieve symptoms and partially restore tissue architecture. However, these approaches, particularly mesenchymal stem cell-based therapies, often produce fibrocartilage rather than durable hyaline cartilage and do not reliably reproduce the long-term mechanical competence or molecular identity of native articular cartilage. Induced pluripotent stem cells (iPSCs) have emerged as a promising alternative cell source for cartilage regeneration because they combine unlimited self-renewal with the capacity to generate patient-specific or allogeneic chondroprogenitors, articular chondrocytes, cartilage organoids, and engineered cartilage constructs. iPSC-derived chondrocytes also provide versatile platforms for modeling osteoarthritis and genetic skeletal disorders, performing genome editing, testing disease-modifying drugs, and developing personalized tissue-engineering systems. Nevertheless, clinical translation remains limited by protocol variability, incomplete lineage specification, hypertrophic differentiation, residual pluripotent cells, immune compatibility, tumorigenic risk, biomechanical immaturity, and the need for scalable Good Manufacturing Practice-compliant manufacturing. This review summarizes the developmental principles and molecular signaling networks that guide iPSC chondrogenesis, compares current differentiation and tissue-engineering strategies, and discusses therapeutic applications and key barriers that must be addressed to achieve safe, reproducible, and clinically effective iPSC-based cartilage repair.