title: Insights into mesenchymal stem cell aging: involvement of antioxidant defense and actin cytoskeleton.
abstract: Progenitor cells such as mesenchymal stem cells (MSCs) have elicited great hopes for therapeutic augmentation of physiological regeneration processes, e.g., for bone fracture healing. However, regeneration potential decreases with age, which raises questions about the efficiency of autologous approaches in elderly patients. To elucidate the mechanisms and cellular consequences of aging, the functional and proteomic changes in MSCs derived from young and old Sprague-Dawley rats were studied concurrently. We demonstrate not only that MSC concentration in bone marrow declines with age but also that their function is altered, especially their migratory capacity and susceptibility toward senescence. High-resolution two-dimensional electrophoresis of the MSC proteome, under conditions of in vitro self-renewal as well as osteogenic stimulation, identified several age-dependent proteins, including members of the calponin protein family as well as galectin-3. Functional annotation clustering revealed that age-affected molecular functions are associated with cytoskeleton organization and antioxidant defense. These proteome screening results are supported by lower actin turnover and diminished antioxidant power in aged MSCs, respectively. Thus, we postulate two main reasons for the compromised cellular function of aged MSCs: (a) declined responsiveness to biological and mechanical signals due to a less dynamic actin cytoskeleton and (b) increased oxidative stress exposure favoring macromolecular damage and senescence. These results, along with the observed similar differentiation potentials, imply that MSC-based therapeutic approaches for the elderly should focus on attracting the cells to the site of injury and oxidative stress protection, rather than merely stimulating differentiation.
authors.affiliation: Julius Wolff Institute and Center for Musculoskeletal Surgery Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Grit
authors.initials: G
authors.lastname: Kasper
authors.forename: Lei
authors.initials: L
authors.lastname: Mao
authors.forename: Sven
authors.initials: S
authors.lastname: Geissler
authors.forename: Albena
authors.initials: A
authors.lastname: Draycheva
authors.forename: Jessica
authors.initials: J
authors.lastname: Trippens
authors.forename: Jirko
authors.initials: J
authors.lastname: Kühnisch
authors.forename: Miriam
authors.initials: M
authors.lastname: Tschirschmann
authors.forename: Katharina
authors.initials: K
authors.lastname: Kaspar
authors.forename: Carsten
authors.initials: C
authors.lastname: Perka
authors.forename: Georg N
authors.initials: GN
authors.lastname: Duda
authors.forename: Joachim
authors.initials: J
authors.lastname: Klose
mesh_terms: D000199:Actins / Q000378:metabolism*; D000375:Aging / Q000502:physiology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015153:Blotting, Western; D002452:Cell Count; D002465:Cell Movement / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology*; D003599:Cytoskeleton / Q000378:metabolism*; D015180:Electrophoresis, Gel, Two-Dimensional; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000199:Actins; D000975:Antioxidants