Time- and cell-specific activation of BMP signaling restrains chondrocyte hypertrophy
Stephen J. Gadomski,
Byron W.H. Mui,
Raphael Gorodetsky,
Sriram S. Paravastu,
Joseph Featherall,
Li Li,
Abigail Haffey,
Jae-Chun Kim,
Sergei A. Kuznetsov,
Kathryn Futrega,
Astar Lazmi-Hailu,
Randall K. Merling,
Daniel Martin,
Andrew W. McCaskie,
Pamela G. Robey
Affiliations
Stephen J. Gadomski
Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA; NIH Oxford-Cambridge Scholars Program in Partnership with Medical University of South Carolina, Charleston, SC 29425, USA; Wellcome-MRC Cambridge Stem Cell Institute, Cambridge CB2 0AW, UK
Byron W.H. Mui
Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA; Wellcome-MRC Cambridge Stem Cell Institute, Cambridge CB2 0AW, UK; NIH Oxford-Cambridge Scholars Program in Partnership with Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; NIH Medical Research Scholars Program, National Institutes of Health, Bethesda, MD 20892, USA
Raphael Gorodetsky
Lab of Biotechnology and Radiobiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Sriram S. Paravastu
Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA; NIH Medical Research Scholars Program, National Institutes of Health, Bethesda, MD 20892, USA
Joseph Featherall
Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA; NIH Medical Research Scholars Program, National Institutes of Health, Bethesda, MD 20892, USA
Li Li
National Institute of Dental and Craniofacial Research Imaging Core, National Institutes of Health, Bethesda, MD 20892, USA
Abigail Haffey
Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA; National Institute of Dental and Craniofacial Research Summer Internship Program, National Institutes of Health, Bethesda, MD 20892, USA
Jae-Chun Kim
Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA; National Institute of Dental and Craniofacial Research Summer Dental Student Program, National Institutes of Health, Bethesda, MD 20892, USA
Sergei A. Kuznetsov
Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA
Kathryn Futrega
Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA
Astar Lazmi-Hailu
Lab of Biotechnology and Radiobiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Randall K. Merling
Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA
Daniel Martin
Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, 35A Convent Drive, Room 1F-103, Bethesda, MD 20892, USA; Genomics and Computational Biology Core, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
Andrew W. McCaskie
Wellcome-MRC Cambridge Stem Cell Institute, Cambridge CB2 0AW, UK; Department of Surgery, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
Pamela G. Robey
Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA; Corresponding author
Summary: Stem cell therapies for degenerative cartilage disease are limited by an incomplete understanding of hyaline cartilage formation and maintenance. Human bone marrow stromal cells/skeletal stem cells (hBMSCs/SSCs) produce stable hyaline cartilage when attached to hyaluronic acid-coated fibrin microbeads (HyA-FMBs), yet the mechanism remains unclear. In vitro, hBMSC/SSC/HyA-FMB organoids exhibited reduced BMP signaling early in chondrogenic differentiation, followed by restoration of BMP signaling in chondrogenic IGFBP5+/MGP+ cells. Subsequently, human-induced pluripotent stem cell (hiPSC)-derived sclerotome cells were established (BMP inhibition) and then treated with transforming growth factor β (TGF-β) −/+ BMP2 and growth differentiation factor 5 (GDF5) (BMP signaling activation). TGF-β alone elicited a weak chondrogenic response, but TGF-β/BMP2/GDF5 led to delamination of SOX9+ aggregates (chondrospheroids) with high expression of COL2A1, ACAN, and PRG4 and minimal expression of COL10A1 and ALP in vitro. While transplanted hBMSCs/SSCs/HyA-FMBs did not heal articular cartilage defects in immunocompromised rodents, chondrospheroid-derived cells/HyA-FMBs formed non-hypertrophic cartilage that persisted until at least 5 months in vivo.
