Engraftment of allogeneic iPS cell-derived cartilage organoid in a primate model of articular cartilage defect

Induced pluripotent stem cells (iPSCs) are a promising resource for allogeneic cartilage transplantation to treat articular cartilage defects that do not heal spontaneously and often progress to debilitating conditions, such as osteoarthritis. However, to the best of our knowledge, allogeneic cartilage transplantation into primate models has never been assessed. Here, we show that allogeneic iPSC-derived cartilage organoids survive and integrate as well as function as articular cartilage in a primate model of chondral defects in the knee joints. Histological analysis revealed that allogeneic iPSC-derived cartilage organoids in chondral defects elicited no immune reaction and directly contributed to the tissue repair for at least four months. iPSC-derived cartilage organoids integrated with the host native articular cartilage and prevented degeneration of the surrounding cartilage. Single-cell RNA-sequence analysis indicated that iPSC-derived cartilage organoids differentiated after transplantation, acquiring expression of PRG4 that is crucial for joint lubrication. Pathway analysis suggested the involvement of SIK3 inactivation, verified through molecular experiments. Our study outcomes suggest that allogeneic transplantation of iPSC-derived cartilage organoids may be clinically applicable for the treatment of patients with chondral defects of the articular cartilage. We performed a single cell (sc)RNA-seq transcriptome analysis of cynomolgus monkey iPS cells (cyiPSC) and cyiPSC-derived cartilage (pre-transplant cyiPS-Cart). We created chondral defects in articular cartilage in knee joints of cynomolgus monkeys. We transplanted allogeneic cyiPS-Cart or nothing. Four months after transplantation, articular cartilage (AC), transplanted cyiPS-Cart (post-transplanted cyiPS-Cart) and fibrous tissue (cyFT) formed in the chondral defects where nothing had been transplanted were harvested and subjected to scRNA-seq analysis.