title: Secreted microvesicular miR-31 inhibits osteogenic differentiation of mesenchymal stem cells.
abstract: Damage to cells and tissues is one of the driving forces of aging and age-related diseases. Various repair systems are in place to counteract this functional decline. In particular, the property of adult stem cells to self-renew and differentiate is essential for tissue homeostasis and regeneration. However, their functionality declines with age (Rando, 2006). One organ that is notably affected by the reduced differentiation capacity of stem cells with age is the skeleton. Here, we found that circulating microvesicles impact on the osteogenic differentiation capacity of mesenchymal stem cells in a donor-age-dependent way. While searching for factors mediating the inhibitory effect of elderly derived microvesicles on osteogenesis, we identified miR-31 as a crucial component. We demonstrated that miR-31 is present at elevated levels in the plasma of elderly and of osteoporosis patients. As a potential source of its secretion, we identified senescent endothelial cells, which are known to increase during aging in vivo (Erusalimsky, 2009). Endothelial miR-31 is secreted within senescent cell-derived microvesicles and taken up by mesenchymal stem cells where it inhibits osteogenic differentiation by knocking down its target Frizzled-3. Therefore, we suggest that microvesicular miR-31 in the plasma of elderly might play a role in the pathogenesis of age-related impaired bone formation and that miR-31 might be a valuable plasma-based biomarker for aging and for a systemic environment that does not favor cell-based therapies whenever osteogenesis is a limiting factor.
authors.affiliation: Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, Muthgasse 18, 1190, Vienna, Austria.|Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, Donaueschingenstrasse 13, A-1200, Vienna, Austria.|Evercyte GmbH, Muthgasse 18, 1190, Vienna, Austria.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Weilner
authors.affiliation: Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, Muthgasse 18, 1190, Vienna, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schraml
authors.affiliation: Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, Muthgasse 18, 1190, Vienna, Austria.|ACIB, Muthgasse 18, 1190, Vienna, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Wieser
authors.affiliation: Department of NanoBiotechnology, Vienna Institute of BioTechnology, University of Natural Resources and Life Sciences Vienna, Vienna, Austria.
authors.forename: Paul
authors.initials: P
authors.lastname: Messner
authors.affiliation: Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, Muthgasse 18, 1190, Vienna, Austria.|Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, Donaueschingenstrasse 13, A-1200, Vienna, Austria.
authors.forename: Karl
authors.initials: K
authors.lastname: Schneider
authors.affiliation: Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, Muthgasse 18, 1190, Vienna, Austria.|Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, Donaueschingenstrasse 13, A-1200, Vienna, Austria.
authors.forename: Klemens
authors.initials: K
authors.lastname: Wassermann
authors.affiliation: Institute of Biomedical Aging Research, Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Lucia
authors.initials: L
authors.lastname: Micutkova
authors.affiliation: Children's Cancer Research Institute (CCRI), St. Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Klaus
authors.initials: K
authors.lastname: Fortschegger
authors.affiliation: Department of Medicine and Aged Care, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia.|Department of Human Movement Sciences, MOVE Research Institute Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Maier
authors.affiliation: Department of public health and center for healthy aging, university of Copenhagen, Denmark.
authors.forename: Rudi
authors.initials: R
authors.lastname: Westendorp
authors.affiliation: Department of Medicine 2, St. Vincent Hospital, 1060, Vienna, Austria.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Resch
authors.affiliation: Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, Donaueschingenstrasse 13, A-1200, Vienna, Austria.|Austrian Cluster for Tissue Regeneration, Vienna, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: Wolbank
authors.affiliation: Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, Donaueschingenstrasse 13, A-1200, Vienna, Austria.|Austrian Cluster for Tissue Regeneration, Vienna, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Redl
authors.affiliation: Institute of Biomedical Aging Research, Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Pidder
authors.initials: P
authors.lastname: Jansen-Dürr
authors.affiliation: Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Pietschmann
authors.affiliation: Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, Muthgasse 18, 1190, Vienna, Austria.|Evercyte GmbH, Muthgasse 18, 1190, Vienna, Austria.|ACIB, Muthgasse 18, 1190, Vienna, Austria.
authors.forename: Regina
authors.initials: R
authors.lastname: Grillari-Voglauer
authors.affiliation: Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, Muthgasse 18, 1190, Vienna, Austria.|Evercyte GmbH, Muthgasse 18, 1190, Vienna, Austria.|Austrian Cluster for Tissue Regeneration, Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Grillari
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000375:Aging / Q000097:blood; D002454:Cell Differentiation; D055252:Cell-Derived Microparticles / Q000378:metabolism* / Q000648:ultrastructure; D016922:Cellular Senescence; D042783:Endothelial Cells / Q000378:metabolism; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010012:Osteogenesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060149:Tetraspanin 30 / Q000378:metabolism
chemical_list: C105574:FZD3 protein, human; D051157:Frizzled Receptors; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D060149:Tetraspanin 30
keywords: MicroRNA; aging; mesenchymal stem cells; microvesicles; osteogenic differentiation; senescence-associated secretory phenotype