title: Vesicular Galectin-3 levels decrease with donor age and contribute to the reduced osteo-inductive potential of human plasma derived extracellular vesicles.
abstract: Aging results in a decline of physiological functions and in reduced repair capacities, in part due to impaired regenerative power of stem cells, influenced by the systemic environment. In particular osteogenic differentiation capacity (ODC) of mesenchymal stem cells (MSCs) has been shown to decrease with age, thereby contributing to reduced bone formation and an increased fracture risk. Searching for systemic factors that might contribute to this age related decline of regenerative capacity led us to investigate plasma-derived extracellular vesicles (EVs). EVs of the elderly were found to inhibit osteogenesis compared to those of young individuals. By analyzing the differences in the vesicular content Galectin-3 was shown to be reduced in elderly-derived vesicles. While overexpression of Galectin-3 resulted in an enhanced ODC of MSCs, siRNA against Galectin-3 reduced osteogenesis. Modulation of intravesicular Galectin-3 levels correlated with an altered osteo-inductive potential indicating that vesicular Galectin-3 contributes to the biological response of MSCs to EVs. By site-directed mutagenesis we identified a phosphorylation-site on Galectin-3 mediating this effect. Finally, we showed that cell penetrating peptides comprising this phosphorylation-site are sufficient to increase ODC in MSCs. Therefore, we suggest that decrease of Galectin-3 in the plasma of elderly contributes to the age-related loss of ODC.
authors.affiliation: Christian Doppler Laboratory for Biotechnology of Skin Aging, Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, 1190 Vienna, Austria.|Evercyte GmbH, 1190 Vienna, Austria.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Weilner
authors.affiliation: Christian Doppler Laboratory for Biotechnology of Skin Aging, Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, 1190 Vienna, Austria.
authors.forename: Verena
authors.initials: V
authors.lastname: Keider
authors.affiliation: Christian Doppler Laboratory for Biotechnology of Skin Aging, Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, 1190 Vienna, Austria.
authors.forename: Melanie
authors.initials: M
authors.lastname: Winter
authors.affiliation: Christian Doppler Laboratory for Biotechnology of Skin Aging, Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, 1190 Vienna, Austria.
authors.forename: Eva
authors.initials: E
authors.lastname: Harreither
authors.affiliation: Christian Doppler Laboratory for Biotechnology of Skin Aging, Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, 1190 Vienna, Austria.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Salzer
authors.affiliation: Christian Doppler Laboratory for Biotechnology of Skin Aging, Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, 1190 Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Weiss
authors.affiliation: Christian Doppler Laboratory for Biotechnology of Skin Aging, Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, 1190 Vienna, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schraml
authors.affiliation: Department of Nanobiotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, 1190 Vienna, Austria.
authors.forename: Paul
authors.initials: P
authors.lastname: Messner
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: Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, 1200 Vienna, Austria.|Austrian Cluster for Tissue Regeneration, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Hildner
authors.affiliation: Red Cross Blood Transfusion Service of Upper Austria, Austria.|Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, 1200 Vienna, Austria.|Austrian Cluster for Tissue Regeneration, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Gabriel
authors.affiliation: Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, 1200 Vienna, Austria.|Austrian Cluster for Tissue Regeneration, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Redl
authors.affiliation: Christian Doppler Laboratory for Biotechnology of Skin Aging, Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, 1190 Vienna, Austria.|Evercyte GmbH, 1190 Vienna, Austria.
authors.forename: Regina
authors.initials: R
authors.lastname: Grillari-Voglauer
authors.affiliation: Christian Doppler Laboratory for Biotechnology of Skin Aging, Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences Vienna, 1190 Vienna, Austria.|Evercyte GmbH, 1190 Vienna, Austria.|Austrian Cluster for Tissue Regeneration, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Grillari
mesh_terms: D000328:Adult; D000367:Age Factors; D000375:Aging / Q000097:blood / Q000378:metabolism*; D001798:Blood Proteins; D057846:Cell-Penetrating Peptides / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D016922:Cellular Senescence; D015536:Down-Regulation; D000067128:Extracellular Vesicles / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D037502:Galectin 3 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D037161:Galectins; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010012:Osteogenesis / Q000187:drug effects; D010766:Phosphorylation; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D055815:Young Adult
chemical_list: D001798:Blood Proteins; D057846:Cell-Penetrating Peptides; D037502:Galectin 3; D037161:Galectins; C428445:LGALS3 protein, human
keywords: Galectin-3; aging; bone; extracellular vesicles; osteogenic differentiation