Abstract
BackgroundInduced pluripotent stem cells (iPSC) provide an unlimited patient-specific cell source for regenerative medicine. Adult cells have had limited success in cartilage repair, but juvenile chondrocytes (from donors younger than 13 years of age) have been identified to generate superior cartilage. With this perspective, the aim of these studies was to compare the human iPSC-derived chondrocytes (hiChondrocytes) to adult and juvenile chondrocytes and identify common molecular factors that govern their function.MethodsPhenotypic and functional characteristics of hiChondrocytes were compared to juvenile and adult chondrocytes. Analyses of global gene expression profiling, independent gene expression, and loss-of-function studies were utilized to test molecular factors having a regulatory effect on hiChondrocytes and juvenile chondrocyte function.ResultsHere, we report that the iPSC-derived chondrocytes mimic juvenile chondrocytes in faster cell proliferation and resistance to IL-1β compared to adult chondrocytes. Whole genome transcriptome analyses revealed unique ECM factors and immune response pathways to be enriched in both juvenile and iPSC-derived chondrocytes as compared to adult chondrocytes. Loss-of-function studies demonstrated that CD24, a cell surface receptor enriched in both juvenile chondrocytes and hiChondrocytes, is a regulatory factor in both faster proliferation and resistance to proinflammatory cues in these chondrocyte populations.ConclusionsOur studies identify that hiChondrocytes mimic juvenile chondrocytes for the dual advantage of faster proliferation and a reduced response to the inflammatory cytokine IL-1β. While developmental immaturity of iPSC-derived cells can be a challenge for tissues like muscle and brain, our studies demonstrate that it is advantageous for a tissue like cartilage that has limited regenerative ability in adulthood.
Highlights
Induced pluripotent stem cells provide an unlimited patient-specific cell source for regenerative medicine
Resistance to IL-1β in hiChondrocytes and juvenile chondrocytes compared to adult chondrocytes We have recently reported that cluster of differentiation 24 (CD24), which has previously been shown to modulate innate immunity [25], regulates differential response of juvenile and adult chondrocytes to inflammatory cues in an NF-κB-dependent manner [26]
This study is fundamentally interesting because it provides an exemplar for how the developmental immaturity of hiPSCderived cells can be an advantage for generating a tissue like cartilage with poor regenerative capability in adulthood in contrast to tissues like heart and brain, where such a developmental immaturity is a bottleneck
Summary
Induced pluripotent stem cells (iPSC) provide an unlimited patient-specific cell source for regenerative medicine. Adult cells have had limited success in cartilage repair, but juvenile chondrocytes (from donors younger than 13 years of age) have been identified to generate superior cartilage. With this perspective, the aim of these studies was to compare the human iPSC-derived chondrocytes (hiChondrocytes) to adult and juvenile chondrocytes and identify common molecular factors that govern their function. Recent reports have suggested that juvenile chondrocytes from donors younger than 13 years old have a potential for superior cartilage regeneration compared to adult chondrocytes [5,6,7]. A major challenge to the widespread clinical use of juvenile cartilage or chondrocytes is the limited donor availability
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