title: Proteasome activation enhances stemness and lifespan of human mesenchymal stem cells.
abstract: The age-associated decline of adult stem cell function contributes to the physiological failure of homeostasis during aging. The proteasome plays a key role in the maintenance of proteostasis and its failure is associated with various biological phenomena including senescence and aging. Although stem cell biology has attracted intense attention, the role of proteasome in stemness and its age-dependent deterioration remains largely unclear. By employing both Wharton's-Jelly- and Adipose-derived human adult mesenchymal stem cells (hMSCs), we reveal a significant age-related decline in proteasome content and peptidase activities, accompanied by alterations of proteasomal complexes. Additionally, we show that senescence and the concomitant failure of proteostasis negatively affects stemness. Remarkably, the loss of proliferative capacity and stemness of hMSCs can be counteracted through proteasome activation. At the mechanistic level, we demonstrate for the first time that Oct4 binds at the promoter region of β2 and β5 proteasome subunits and thus possibly regulates their expression. A firm understanding of the mechanisms regulating proteostasis in stem cells will pave the way to innovative stem cell-based interventions to improve healthspan and lifespan.
authors.affiliation: National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry & Biotechnology, 48 Vas. Constantinou Ave., Athens 11635, Greece; Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, Panepistimiopolis, 15701 Athens, Greece.
authors.forename: Marianna
authors.initials: M
authors.lastname: Kapetanou
authors.affiliation: National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry & Biotechnology, 48 Vas. Constantinou Ave., Athens 11635, Greece. Electronic address: nikichon@eie.gr.
authors.forename: Niki
authors.initials: N
authors.lastname: Chondrogianni
authors.affiliation: Biohellenika Biotechnology Company, 57001 Thessaloniki, Greece.
authors.forename: Spyros
authors.initials: S
authors.lastname: Petrakis
authors.affiliation: Biohellenika Biotechnology Company, 57001 Thessaloniki, Greece; Department of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Koliakos
authors.affiliation: National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry & Biotechnology, 48 Vas. Constantinou Ave., Athens 11635, Greece. Electronic address: sgonos@eie.gr.
authors.forename: Efstathios S
authors.initials: ES
authors.lastname: Gonos
mesh_terms: D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D004789:Enzyme Activation; D015870:Gene Expression; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism
chemical_list: D021122:Protein Subunits; D046988:Proteasome Endopeptidase Complex
keywords: Aging; Differentiation; Pluripotency; Proteasome; Proteostasis; Senescence; Stem cells; Stemness