Ageing is a complex process that results in the decline of physiological functions due to accumulation of damage in cells and tissues as well as due to reduced repair capacities. The regenerative power of stem and progenitor cells has been found to decline with age and to be influenced by the systemic environment. In particular, the osteogenic differentiation capacity of mesenchymal stem cells (MSCs) has been shown to decrease with age thereby contributing to decelerated bone formation and the development of osteopenia or osteoporosis. The objective of this study was to identify circulating factors of the aged systemic environment that influence the functionality of adult stem cells. In order to identify such factors, the microRNA content in serum of young versus elderly healthy individuals was analysed using quantitative PCR. Levels of hsa-miR-31-5p were found to be strongly induced in serum of elderly donors. As a possible source senescent endothelial cells that secrete exosomal miR-31-5p were identified in vitro, since it could be shown that exosomal miR-31-5p can be transferred to target cells such as MSCs. Subsequently, exosomes with elevated levels in miR-31-5p were harvested either from senescent endothelial cells or elderly donors, and used for treatment of MSCs prior and during osteogenic differentiation, resulting in slowed differentiation. The effect of the vesicles could be rescued by antagonistic miR-31-5p, and mimicked by delivery of miR-31-5p alone. One of the novel targets of miR-31-5p in this context is the WNT ligand FZD3 whose knock-down leads to a similar inhibition of osteogenic differentiation as miR-31-5p. In conclusion, we could identify a novel mechanism by which circulating microvesicles and their content might impact tissue physiology during ageing. Furthermore these data show that microvesicles might represent a source for biomarkers as well as therapeutic targets in age-related diseases like osteoporosis.
Disclosure: Johannes Grillari acts as scientific advisor to TAmiRNA GmbH and CSO of Evercyte GmbH. This work was supported by: EU-FP7 Health Project FRAILOMIC 305483; and EU-FP7 Health Project SYBIL 602300.