Derivation of Isogenic Mesodermal and Ectomesodermal Chondrocytes from Human Induced Pluripotent Stem Cells for Articular Cartilage Regeneration

Generating phenotypic chondrocytes from human pluripotent stem cells through driving developmental lineage-specific differentiation remains to be of great interest in the field of cartilage regeneration. In this study, we derived chondrocytes from human induced pluripotent stem cells (hiPSCs) along the mesodermal or ectomesodermal lineages to prepare isogenic mesodermal cell-derived chondrocytes (MC-Chs) or neural crest cell-derived chondrocytes (NCC-Chs), respectively, and further evaluated differences in their cellular and molecular characteristics and cartilage repair capabilities. Our results showed that both lineage-derived chondrocytes expressed hyaline cartilage-associated markers and were capable of forming hyaline cartilage-like tissue ectopically and at joint defects. Moreover, NCC-Chs showed the absence of markers of hypertrophic chondrocytes and revealed a closer morphological resemblance to articular chondrocytes and a greater capability of producing glycosaminoglycans and collagen type 2 at cartilage defects compared to MC-Chs. It was found that the profile of global transcript expression of NCC-Chs more closely resembled that of native chondrocytes (NCs) than that of MC-Chs. Induced by additional growth factors identified through the analysis of transcriptome comparison to NCs, both MC-Chs and NCC-Chs showed a further increase in the phenotype of hyaline cartilage chondrocytes. Results of this study reveal differences in cellular and molecular characteristics and cartilage repair capabilities between isogenic hiPSC-derived MC-Chs and NCC-Chs and demonstrate that chondrocytes derived from hiPSCs along the ectomesodermal lineage are a potential cell source for articular cartilage regeneration.