1. Time- and cell-specific activation of BMP signaling restrains chondrocyte hypertrophy.
- Author
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Gadomski SJ, Mui BWH, Gorodetsky R, Paravastu SS, Featherall J, Li L, Haffey A, Kim JC, Kuznetsov SA, Futrega K, Lazmi-Hailu A, Merling RK, Martin D, McCaskie AW, and Robey PG
- Abstract
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 ., Competing Interests: P.G.R., S.A.K., R.G., A.H.-L., and J.F. have a patent on the hyaluronic-acid-coated fibrin microbeads (US Patent #1094021).- Published
- 2024
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