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Nat Commun. 2018 Sep 7;9(1):3634. doi: 10.1038/s41467-018-05573-y.

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

Author information

1
Department of Orthopaedic Surgery, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, 90033, USA.
2
Department of Stem Cell Research and Regenerative Medicine, USC, Los Angeles, CA, 90033, USA.
3
Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, 90095, USA.
4
Department of Biological Chemistry, UCLA, Los Angeles, CA, 90095, USA.
5
Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, Los Angeles, CA, 90095, USA.
6
Department of Molecular, Cell and Developmental Biology, UCLA, Los Angeles, CA, 90095, USA.
7
Institute of Molecular and Cell Biology, University of Tartu, Tartu, 51010, Estonia.
8
InVitro Cell Research, LLC, Cockeysville, MD, 21030, USA.
9
Departments of Orthopedic Surgery & Biochemistry and Molecular Biology, Center of Regenerative Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
10
Department of Orthopaedic Surgery, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA.
11
Computer Science Department, University of California, Los Angeles, CA, 90095, USA.
12
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, 90095, USA.
13
Molecular Biology Institute, University of California, Los Angeles, CA, 90095, USA.
14
Department of Orthopaedic Surgery, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, 90033, USA. evseenko@usc.edu.
15
Department of Stem Cell Research and Regenerative Medicine, USC, Los Angeles, CA, 90033, USA. evseenko@usc.edu.
16
Department of Orthopaedic Surgery, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA. evseenko@usc.edu.

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.

PMID:
30194383
PMCID:
PMC6128860
DOI:
10.1038/s41467-018-05573-y
[Indexed for MEDLINE]
Free PMC Article

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