title: Primary cilium-associated genes mediate bone marrow stromal cell response to hypoxia.
abstract: Currently there is intense interest in using mesenchymal stem cells (MSC) for therapeutic interventions in many diseases and conditions. To accelerate the therapeutic use of stem cells we must understand how they sense their environment. Primary cilia are an extracellular sensory organelle present on most growth arrested cells that transduce information about the cellular environment into cells, triggering signaling cascades that have profound effects on development, cell cycle, proliferation, differentiation and migration. Migrating cells likely encounter differing oxygen tensions, therefore we investigated the effect of oxygen tension on cilia. Using bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) we found that oxygen tension significantly affected the length of cilia in primary BMSCs. Chronic exposure to hypoxia specifically down-regulated genes involved in hedgehog signaling and re-localized the Smo and Gli2 proteins to cilia. Investigating the effects of chemotactic migration on cilia, we observed significantly longer cilia in migrating cells which was again, strongly influenced by oxygen tension. Finally, using computational modeling we identified links between migration and ciliation signaling pathways, characterizing the novel role of HSP90 and PI3K signaling in regulating BMSC cilia length. These findings enhance our current understanding of BMSC adaptions to hypoxia and advance our knowledge of BMSC biology and cilia regulation.
authors.affiliation: Systems Biology Ireland, Regenerative Medicine Institute (REMEDI), National University of Ireland, Galway, Ireland; Regenerative Medicine Institute (REMEDI), National University of Ireland, Galway, Ireland. Electronic address: james.brown@nuigalway.ie.
authors.forename: James A L
authors.initials: JA
authors.lastname: Brown
authors.affiliation: Systems Biology Ireland, Conway Institute, University College Dublin (UCD), Dublin, Ireland. Electronic address: tapesh.santra@gmail.com.
authors.forename: Tapesh
authors.initials: T
authors.lastname: Santra
authors.affiliation: Centre for Microscopy and Imaging, Anatomy Department, National University of Ireland, Galway, Ireland. Electronic address: peter.owens@nuigalway.ie.
authors.forename: Peter
authors.initials: P
authors.lastname: Owens
authors.affiliation: Regenerative Medicine Institute (REMEDI), National University of Ireland, Galway, Ireland. Electronic address: aline.morrison@nuigalway.ie.
authors.forename: Aline M
authors.initials: AM
authors.lastname: Morrison
authors.affiliation: Systems Biology Ireland, Regenerative Medicine Institute (REMEDI), National University of Ireland, Galway, Ireland; Regenerative Medicine Institute (REMEDI), National University of Ireland, Galway, Ireland. Electronic address: frank.barry@nuigalway.ie.
authors.forename: Frank
authors.initials: F
authors.lastname: Barry
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects / Q000235:genetics; D002867:Chromones / Q000494:pharmacology; D002923:Cilia / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology; D030541:Databases, Genetic; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012118:Resorcinols / Q000494:pharmacology; D015398:Signal Transduction; D055153:Stem Cell Niche; D013997:Time Factors
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D018932:Chemokine CCL2; D002867:Chromones; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D012118:Resorcinols; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D058539:Phosphatidylinositol 3-Kinase; D010100:Oxygen