title: TGFβ1 - induced recruitment of human bone mesenchymal stem cells is mediated by the primary cilium in a SMAD3-dependent manner.
abstract: The recruitment of mesenchymal stem cells (MSCs) is a crucial process in the development, maintenance and repair of tissues throughout the body. Transforming growth factor-β1 (TGFβ1) is a potent chemokine essential for the recruitment of MSCs in bone, coupling the remodelling cycle. The primary cilium is a sensory organelle with important roles in bone and has been associated with cell migration and more recently TGFβ signalling. Dysregulation of TGFβ signalling or cilia has been linked to a number of skeletal pathologies. Therefore, this study aimed to determine the role of the primary cilium in TGFβ1 signalling and associated migration in human MSCs. In this study we demonstrate that low levels of TGFβ1 induce the recruitment of MSCs, which relies on proper formation of the cilium. Furthermore, we demonstrate that receptors and downstream signalling components in canonical TGFβ signalling localize to the cilium and that TGFβ1 signalling is associated with activation of SMAD3 at the ciliary base. These findings demonstrate a novel role for the primary cilium in the regulation of TGFβ signalling and subsequent migration of MSCs, and highlight the cilium as a target to manipulate this key pathway and enhance MSC recruitment for the treatment of skeletal diseases.
authors.affiliation: Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.|Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland.|Department of Mechanical, Aeronautical and Biomedical Engineering, University of Limerick, Limerick, Ireland.
authors.forename: Marie-Noëlle
authors.initials: MN
authors.lastname: Labour
authors.affiliation: Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.|Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland.|Advanced Materials and Bioengineering Research Centre, Trinity College Dublin &RCSI, Dublin 2, Ireland.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Riffault
authors.affiliation: Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Søren T
authors.initials: ST
authors.lastname: Christensen
authors.affiliation: Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.|Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland.|Department of Mechanical, Aeronautical and Biomedical Engineering, University of Limerick, Limerick, Ireland.|Advanced Materials and Bioengineering Research Centre, Trinity College Dublin &RCSI, Dublin 2, Ireland.
authors.forename: David A
authors.initials: DA
authors.lastname: Hoey
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D002923:Cilia / Q000187:drug effects / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C098623:IFT88 protein, human; D018125:Receptors, Transforming Growth Factor beta; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins