title: Outside-in integrin signalling regulates haematopoietic stem cell function via Periostin-Itgav axis.
abstract: Integrins play an important role in haematopoietic stem cell (HSC) maintenance in the bone marrow niche. Here, we demonstrate that Periostin (Postn) via interaction with Integrin-αv (Itgav) regulates HSC proliferation. Systemic deletion of Postn results in peripheral blood (PB) anaemia, myelomonocytosis and lymphopenia, while the number of phenotypic HSCs increases in the bone marrow. Postn-/-mice recover faster from radiation injury with concomitant loss of primitive HSCs. HSCs from Postn-/-mice show accumulation of DNA damage generally associated with aged HSCs. Itgav deletion in the haematopoietic system leads to a similar PB phenotype and HSC-intrinsic repopulation defects. Unaffected by Postn, Vav-Itgav-/-HSCs proliferate faster in vitro, illustrating the importance of Postn-Itgav interaction. Finally, the Postn-Itgav interaction inhibits the FAK/PI3K/AKT pathway in HSCs, leading to increase in p27Kip1 expression resulting in improved maintenance of quiescent HSCs. Together, we demonstrate a role for Itgav-mediated outside-in signalling in regulation of HSC proliferation and stemness.
authors.affiliation: Inter-departmental Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Satish
authors.identifier: 0000-0001-5176-1510
authors.initials: S
authors.lastname: Khurana
authors.affiliation: Inter-departmental Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Schouteden
authors.affiliation: Inter-departmental Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Javed K
authors.initials: JK
authors.lastname: Manesia
authors.affiliation: École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Albert
authors.initials: A
authors.lastname: Santamaria-Martínez
authors.affiliation: École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Joerg
authors.initials: J
authors.lastname: Huelsken
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Lacy-Hulbert
authors.affiliation: Inter-departmental Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Verfaillie
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004249:DNA Damage; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D019426:Integrases / Q000378:metabolism; D039564:Integrin alphaV / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D022423:Myeloid Cells / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D015815:Cell Adhesion Molecules; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019426:Integrases; D039564:Integrin alphaV; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C082838:Postn protein, mouse; C045073:Cre recombinase