title: Cross-talk between TGF-beta/SMAD and integrin signaling pathways in regulating hypertrophy of mesenchymal stem cell chondrogenesis under deferral dynamic compression.
abstract: The molecular mechanisms of mechanotransduction in regulating mesenchymal stem cell (MSC) chondrogenesis are not fully understood and represent an area of growing investigation. In this study, human MSC was subjected to chondrogenic differentiation in chitosan-coated poly L-lactide-co-ɛ-caprolactone scaffolds under free swelling or deferral dynamic compression conditions. The effect of deferral dynamic compression to MSC chondrogenesis and late stage hypertrophy development was investigated, and the involvement of TGF-β/SMAD pathway and integrin β1 signaling was analyzed. Deferral dynamic compression enhanced cartilage formation and suppressed chondrocyte hypertrophy. Differential cell morphology and cytoskeletal organization were induced under dynamic compression, together with the activation of TGF-β/Activin/Nodal and suppression of the BMP/GDP signaling. This was accompanied by the repression of integrin/FAK/ERK signaling in the non-hypertrophic cells when compared to the free swelling samples. Inhibition studies blocking TGF-β/Activin/Nodal signaling heightened hypertrophy, activate BMP/SMAD1/5/8 and integrin signaling, while inhibition of integrin-ECM interaction suppressed hypertrophy and activate TGF-β/SMAD2/3 in the free-swelling samples. This study demonstrates the roles of TGF-β/SMAD and integrin signaling, and suggests cross-talk between these two signaling pathways, in regulating the compression-driven hypertrophy development.
authors.affiliation: Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, Level 11, 1E Kent Ridge Road, Singapore 119288, Singapore.
authors.forename: Tianting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore.
authors.forename: Feng
authors.initials: F
authors.lastname: Wen
authors.affiliation: School of Chemical and Biomedical Engineering, Nanyang Technological University, 62 Nanyang Drive, Singapore 637459, Singapore.
authors.forename: Yingnan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, Level 11, 1E Kent Ridge Road, Singapore 119288, Singapore.
authors.forename: Graham Seow Hng
authors.initials: GS
authors.lastname: Goh
authors.affiliation: Department of Biomedical Engineering, College of Engineering, Peking University, Beijing 100871, PR China.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Ge
authors.affiliation: School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore.
authors.forename: Lay Poh
authors.initials: LP
authors.lastname: Tan
authors.affiliation: Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, Level 11, 1E Kent Ridge Road, Singapore 119288, Singapore; Tissue Engineering Program, Life Sciences Institute, National University of Singapore, DSO (Kent Ridge) Building, #04-01, 27 Medical Drive, Singapore 117510, Singapore. Electronic address: james_hui@nuhs.edu.sg.
authors.forename: James Hoi Po
authors.initials: JH
authors.lastname: Hui
authors.affiliation: Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, Level 11, 1E Kent Ridge Road, Singapore 119288, Singapore; Tissue Engineering Program, Life Sciences Institute, National University of Singapore, DSO (Kent Ridge) Building, #04-01, 27 Medical Drive, Singapore 117510, Singapore. Electronic address: lsiyz@nus.edu.sg.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000502:physiology*; D020219:Chondrogenesis / Q000502:physiology*; D019245:Compressive Strength / Q000502:physiology; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D020239:Receptor Cross-Talk / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D051785:Smad Proteins / Q000378:metabolism*; D013314:Stress, Mechanical; D023822:Tissue Engineering / Q000295:instrumentation / Q000379:methods; D054457:Tissue Scaffolds; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D019012:Integrin beta1; D051785:Smad Proteins; D016212:Transforming Growth Factor beta
keywords: Chondrogenesis; Dynamic compression; Integrin β signaling; Mesenchymal stem cells; TGF/SMAD signaling