title: Surface topography regulates wnt signaling through control of primary cilia structure in mesenchymal stem cells.
abstract: The primary cilium regulates cellular signalling including influencing wnt sensitivity by sequestering β-catenin within the ciliary compartment. Topographic regulation of intracellular actin-myosin tension can control stem cell fate of which wnt is an important mediator. We hypothesized that topography influences mesenchymal stem cell (MSC) wnt signaling through the regulation of primary cilia structure and function. MSCs cultured on grooves expressed elongated primary cilia, through reduced actin organization. siRNA inhibition of anterograde intraflagellar transport (IFT88) reduced cilia length and increased active nuclear β-catenin. Conversely, increased primary cilia assembly in MSCs cultured on the grooves was associated with decreased levels of nuclear active β-catenin, axin-2 induction and proliferation, in response to wnt3a. This negative regulation, on grooved topography, was reversed by siRNA to IFT88. This indicates that subtle regulation of IFT and associated cilia structure, tunes the wnt response controlling stem cell differentiation.
authors.affiliation: Institute of Bioengineering and School of Engineering and Materials Science, Queen Mary University of London, Bancroft Road, Mile End, London E1 4NS, UK.
authors.forename: R J
authors.initials: RJ
authors.lastname: McMurray
authors.affiliation: Institute of Bioengineering and School of Engineering and Materials Science, Queen Mary University of London, Bancroft Road, Mile End, London E1 4NS, UK.
authors.forename: A K T
authors.initials: AK
authors.lastname: Wann
authors.affiliation: Institute of Bioengineering and School of Engineering and Materials Science, Queen Mary University of London, Bancroft Road, Mile End, London E1 4NS, UK.
authors.forename: C L
authors.initials: CL
authors.lastname: Thompson
authors.affiliation: Institute of Bioengineering and Institute of Cellular and Molecular Sciences, Blizard Institute, Barts and The London School of Medicine and Dentistry Queen Mary University of London, 4 Newark Street London, E1 2AT, UK.
authors.forename: J T
authors.initials: JT
authors.lastname: Connelly
authors.affiliation: Institute of Bioengineering and School of Engineering and Materials Science, Queen Mary University of London, Bancroft Road, Mile End, London E1 4NS, UK.
authors.forename: M M
authors.initials: MM
authors.lastname: Knight
mesh_terms: D008841:Actin Cytoskeleton / Q000502:physiology; D000577:Amides / Q000494:pharmacology; D060466:Axin Protein / Q000096:biosynthesis; D001854:Bone Marrow Cells / Q000502:physiology; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D002923:Cilia / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000502:physiology; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D009218:Myosins / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D013312:Stress, Physiological; D013499:Surface Properties; D025521:Tumor Suppressor Proteins / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000502:physiology*; D060509:Wnt3A Protein / Q000378:metabolism*; D051176:beta Catenin / Q000096:biosynthesis; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C491761:AXIN2 protein, human; D000577:Amides; D060466:Axin Protein; D004791:Enzyme Inhibitors; C098623:IFT88 protein, human; D011725:Pyridines; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; C555510:WNT3A protein, human; D060509:Wnt3A Protein; D051176:beta Catenin; C108830:Y 27632; D054460:rho-Associated Kinases; D009218:Myosins