Mapping molecular landmarks of human skeletal ontogeny and pluripotent stem cell-derived articular chondrocytes

• Published in: Nature communications Vol. 9; no. 1; pp. 3634 - 16
• Main Authors: Ferguson, Gabriel B., Van Handel, Ben, Bay, Maxwell, Fiziev, Petko, Org, Tonis, Lee, Siyoung, Shkhyan, Ruzanna, Banks, Nicholas W., Scheinberg, Mila, Wu, Ling, Saitta, Biagio, Elphingstone, Joseph, Larson, A. Noelle, Riester, Scott M., Pyle, April D., Bernthal, Nicholas M., Mikkola, Hanna KA, Ernst, Jason, van Wijnen, Andre J., Bonaguidi, Michael, Evseenko, Denis
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07-09-2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 13/107; 38/15; 38/91; 631/136/819; 631/337/2019; Animals; Biocompatibility; Biomarkers - metabolism; Biomedical materials; Cartilage; Chondrocytes; Chondrocytes - metabolism; Chondrogenesis; Chromatin; Epigenesis, Genetic; Fetal Development; Fetuses; Gene expression; Gene Expression Profiling; Histone Code; Humanities and Social Sciences; Humans; Kinases; Mice; Modules; multidisciplinary; Muscles; Myoblasts - metabolism; Network analysis; Ontogeny; Osteoblasts - metabolism; Pluripotency; Regenerative medicine; Science; Science (multidisciplinary); Sequence Analysis, RNA; Stem cells; Swine; Tenocytes - metabolism; Tissue engineering; Transcription, Genetic; Transcriptome
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05573-y

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.
Human development provides a roadmap for advancing pluripotent stem cell-based regenerative therapies. Here the authors mapped human skeletogenesis using RNA sequencing on 5 cell types from a single foetal stage as well as chondrocytes at 4 stages in vivo and 2 stages during in vitro differentiation.