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 agedependent 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.

How do Mesenchymal Stem Cells Repair?

“…This however is still controversial. Other studies indicate that oxidative stress correlates with MSC senescence (145,146). These different results may be consequent to different ROS inductors, and consequently, different levels of ROS production and enviromental contributing factors envolved.…”

MicroRNA-141-3p plays a role in human mesenchymal stem cell aging by directly targeting ZMPSTE24

“…Adult stem cells present in mammalian organs are essential for tissue generation, maintenance and injury repair throughout adult life. Similar to other somatic cells, adult stem cells experience lifelong exposure to intrinsic and extrinsic factors, throughout the lifetime of the organism, which lead to an age-associated decline in their number and function (Janzen et al, 2006;Kasper et al, 2009;Rao and Mattson, 2001;Trosko, 2008).…”

What can proteomics teach us about bone marrow aging?

“…[17]. Kasper and colleagues compared the proteomic profile of young and old MSCs under osteogenic differentiation conditions and they ascribed the changed differentiating property of aged MSCs to the altered anti-oxidant defense and cytoskeleton dynamics [18]. Our group also found that the expression of peroxiredoxin-2, a member of the anti-oxidant system, declined during aging in the interstitial fluid of bone marrow [19].…”