Abstract
Tissue-specific gene expression defines cellular identity and function, but knowledge of early human development is limited, hampering application of cell-based therapies. Here we profiled 5 distinct cell types at a single fetal stage, as well as chondrocytes at 4 stages in vivo and 2 stages during in vitro differentiation. Network analysis delineated five tissue-specific gene modules; these modules and chromatin state analysis defined broad similarities in gene expression during cartilage specification and maturation in vitro and in vivo, including early expression and progressive silencing of muscle- and bone-specific genes. Finally, ontogenetic analysis of freshly isolated and pluripotent stem cell-derived articular chondrocytes identified that integrin alpha 4 defines 2 subsets of functionally and molecularly distinct chondrocytes characterized by their gene expression, osteochondral potential in vitro and proliferative signature in vivo. These analyses provide new insight into human musculoskeletal development and provide an essential comparative resource for disease modeling and regenerative medicine.
Highlights
Tissue-specific gene expression defines cellular identity and function, but knowledge of early human development is limited, hampering application of cell-based therapies
We have previously demonstrated that lineage-committed chondrocytes are formed fourteen days after mesodermal induction of PSCs24 in vitro, and to better assess how well this process reflected human development we profiled the transcriptomes of these cells compared to cells allowed to mature for 60 days in culture
Our results demonstrate a surprising amount of transcriptional “noise” following cartilage specification in vivo, with genes of multiple musculoskeletal lineages undergoing progressive silencing with development
Summary
Tissue-specific gene expression defines cellular identity and function, but knowledge of early human development is limited, hampering application of cell-based therapies. This coordinated analysis allowed us to identify integrin alpha 4 (ITGA4) as a marker of distinct chondrocyte subsets within adult articular cartilage, as cells which coexpress bone morphogenetic protein receptor 1b (BMPR1B) possess osteochondral potential in vitro, are enriched for the skeletal progenitor markers SOX9, GLI1 and RUNX2, and have a transcriptional program suggesting increased proliferative capacity in vivo Taken together, these data sets provide a unique resource to understand human skeletogenesis and importantly may contribute to the development of future tissue engineering and regenerative medicine applications
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