Introduction: Mesenchymal stem cells (MSCs) counteract the decline of physiologic functions but their regenerative power decreases with age. In particular osteogenic differentiation capacity of MSCs has been shown to decrease with age thereby contributing to slowed down bone formation and osteoporosis. While much is known about cellular aging of MSCs, little is known about extrinsic factors influencing their functionality. Here we set out to identify circulating factors of the aged systemic environment that influence osteogenesis
Results: While searching for influential factors extracellular vesicles (EVs) were found. Exposition of MSCs to EVs isolated from plasma of human elderly donors failed to induce osteogenesis compared to EVs of young donors raising the question which age-dependent vesicularly secreted components impact on the differentiation capacity. We identified vesicular galectin-3 as an influential component. Overexpression of galectin-3 in MSCs was shown to boost osteogenic differentiation capacity while reducing its protein expression by siRNA inhibited osteogenesis in vitro. Moreover intracellular galectin-3 levels of MSCs correlated with their osteogenic differentiation potential. Next we could demonstrate that plasma as well as vesicular galectin-3 levels were reduced in elderly human donors compared to young donors and that vesicular galectin-3 levels indeed impact on osteogenic differentiation capacity of MSCs. Finally nano-CT scan on galectin-3 knock out mice revealed a previously unknown reduction of femoral cortical as well as trabecular thickness compared to WT littermates.
Conclusion: We could demonstrate that the composition of circulating EVs changes with age and that they deliver factors impacting on the osteogenic differentiation capacity of MSCs. Among other factors vesicular galectin-3 was shown to be enriched within EVs isolated from young human donors and to enhance osteogenesis. Reduction in vesicular galectin-3 plasma levels with age might lead to a reduced uptake of galectin-3 by MSC and therefore contribute to impaired osteogenesis with age.
17 May 2014 - 20 May 2014