Background: 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 decline 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 affect 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. Consequently, the question raised which vesicularly secreted components impact on the differentiation capacity of MSCs. We identified vesicular Galectin-3 as an influential component and could demonstrate that plasma as well as vesicular Galectin-3 levels decline with age in humans. Supportingly 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. Finally, we could show that high vesicular Galectin-3 levels indeed contribute to the pro-osteogenic effect of extracellular vesicles from young individuals.
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. Therefore, reduced vesicular Galectin-3 plasma levels with age might lead to a decreased uptake of Galectin-3 by MSCs and therefore contribute to impaired osteogenesis with age.
Disclosure: The authors declared no competing interests. A patent application describing Galectin-3 as a therapeutic target in deranged bone metabolism has been filed. This work was supported by the European Union (Frailomics and Sybill).