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

iScience (Aug 2024)

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

Journal volume & issue: Vol. 27, no. 8
p. 110537

Abstract

Read online

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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

About the journal

Abstract

Keywords