title: Loss of fibronectin from the aged stem cell niche affects the regenerative capacity of skeletal muscle in mice.
abstract: Age-related changes in the niche have long been postulated to impair the function of somatic stem cells. Here we demonstrate that the aged stem cell niche in skeletal muscle contains substantially reduced levels of fibronectin (FN), leading to detrimental consequences for the function and maintenance of muscle stem cells (MuSCs). Deletion of the gene encoding FN from young regenerating muscles replicates the aging phenotype and leads to a loss of MuSC numbers. By using an extracellular matrix (ECM) library screen and pathway profiling, we characterize FN as a preferred adhesion substrate for MuSCs and demonstrate that integrin-mediated signaling through focal adhesion kinase and the p38 mitogen-activated protein kinase pathway is strongly de-regulated in MuSCs from aged mice because of insufficient attachment to the niche. Reconstitution of FN levels in the aged niche remobilizes stem cells and restores youth-like muscle regeneration. Taken together, we identify the loss of stem cell adhesion to FN in the niche ECM as a previously unknown aging mechanism.
authors.affiliation: Nestlé Institute of Health Sciences (NIHS), Campus École Polytechnique Fédérale de Lausanne, École Polytechnique Fédérale de Lausanne Innovation Park, Lausanne, Switzerland.|École Polytechnique Fédérale de Lausanne, Doctoral Program in Biotechnology and Bioengineering, Lausanne, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Lukjanenko
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
authors.forename: M Juliane
authors.initials: MJ
authors.lastname: Jung
authors.affiliation: Nestlé Institute of Health Sciences (NIHS), Campus École Polytechnique Fédérale de Lausanne, École Polytechnique Fédérale de Lausanne Innovation Park, Lausanne, Switzerland.
authors.forename: Nagabhooshan
authors.initials: N
authors.lastname: Hegde
authors.affiliation: Nestlé Institute of Health Sciences (NIHS), Campus École Polytechnique Fédérale de Lausanne, École Polytechnique Fédérale de Lausanne Innovation Park, Lausanne, Switzerland.
authors.forename: Claire
authors.identifier: 0000-0001-5482-6236
authors.initials: C
authors.lastname: Perruisseau-Carrier
authors.affiliation: Nestlé Institute of Health Sciences (NIHS), Campus École Polytechnique Fédérale de Lausanne, École Polytechnique Fédérale de Lausanne Innovation Park, Lausanne, Switzerland.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Migliavacca
authors.affiliation: Department of Embryology, Carnegie Institution of Washington, Baltimore, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Rozo
authors.affiliation: Nestlé Institute of Health Sciences (NIHS), Campus École Polytechnique Fédérale de Lausanne, École Polytechnique Fédérale de Lausanne Innovation Park, Lausanne, Switzerland.
authors.forename: Sonia
authors.initials: S
authors.lastname: Karaz
authors.affiliation: Nestlé Institute of Health Sciences (NIHS), Campus École Polytechnique Fédérale de Lausanne, École Polytechnique Fédérale de Lausanne Innovation Park, Lausanne, Switzerland.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jacot
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Department of Embryology, Carnegie Institution of Washington, Baltimore, USA.
authors.forename: Liangji
authors.initials: L
authors.lastname: Li
authors.affiliation: Nestlé Institute of Health Sciences (NIHS), Campus École Polytechnique Fédérale de Lausanne, École Polytechnique Fédérale de Lausanne Innovation Park, Lausanne, Switzerland.
authors.forename: Sylviane
authors.identifier: 0000-0003-2434-8733
authors.initials: S
authors.lastname: Metairon
authors.affiliation: Nestlé Institute of Health Sciences (NIHS), Campus École Polytechnique Fédérale de Lausanne, École Polytechnique Fédérale de Lausanne Innovation Park, Lausanne, Switzerland.
authors.forename: Frederic
authors.initials: F
authors.lastname: Raymond
authors.affiliation: Nestlé Institute of Health Sciences (NIHS), Campus École Polytechnique Fédérale de Lausanne, École Polytechnique Fédérale de Lausanne Innovation Park, Lausanne, Switzerland.
authors.forename: Umji
authors.initials: U
authors.lastname: Lee
authors.affiliation: Nestlé Institute of Health Sciences (NIHS), Campus École Polytechnique Fédérale de Lausanne, École Polytechnique Fédérale de Lausanne Innovation Park, Lausanne, Switzerland.
authors.forename: Federico
authors.initials: F
authors.lastname: Sizzano
authors.affiliation: Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute Regenerative Medicine Program, Ottawa, Canada.|Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: David H
authors.initials: DH
authors.lastname: Wilson
authors.affiliation: Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute Regenerative Medicine Program, Ottawa, Canada.|Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Nicolas A
authors.initials: NA
authors.lastname: Dumont
authors.affiliation: Nestlé Institute of Health Sciences (NIHS), Campus École Polytechnique Fédérale de Lausanne, École Polytechnique Fédérale de Lausanne Innovation Park, Lausanne, Switzerland.
authors.forename: Alessio
authors.initials: A
authors.lastname: Palini
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
authors.affiliation: Nestlé Institute of Health Sciences (NIHS), Campus École Polytechnique Fédérale de Lausanne, École Polytechnique Fédérale de Lausanne Innovation Park, Lausanne, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Steiner
authors.affiliation: Nestlé Institute of Health Sciences (NIHS), Campus École Polytechnique Fédérale de Lausanne, École Polytechnique Fédérale de Lausanne Innovation Park, Lausanne, Switzerland.
authors.forename: Patrick
authors.identifier: 0000-0002-1274-247X
authors.initials: P
authors.lastname: Descombes
authors.affiliation: Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute Regenerative Medicine Program, Ottawa, Canada.|Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rudnicki
authors.affiliation: Department of Embryology, Carnegie Institution of Washington, Baltimore, USA.
authors.forename: Chen-Ming
authors.initials: CM
authors.lastname: Fan
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: von Maltzahn
authors.affiliation: Nestlé Institute of Health Sciences (NIHS), Campus École Polytechnique Fédérale de Lausanne, École Polytechnique Fédérale de Lausanne Innovation Park, Lausanne, Switzerland.
authors.forename: Jerome N
authors.initials: JN
authors.lastname: Feige
authors.affiliation: Nestlé Institute of Health Sciences (NIHS), Campus École Polytechnique Fédérale de Lausanne, École Polytechnique Fédérale de Lausanne Innovation Park, Lausanne, Switzerland.
authors.forename: C Florian
authors.initials: CF
authors.lastname: Bentzinger
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012038:Regeneration / Q000235:genetics*; D055153:Stem Cell Niche; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D005353:Fibronectins; D016023:Integrins; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases