Aged vascular niche hinders osteogenesis of mesenchymal stem cells through  paracrine repression of Wnt-axis
Age-induced decline in osteogenic potential of bone marrow mesenchymal stem cells (BMSCs) potentiates osteoporosis and increases risk for bone fractures. Despite epidemiology studies reporting concurrent development of vascular- and bone diseases in the elderly, the underlying mechanisms for the vascular-bone cross-talk in aging are largely unknown. In this study, we show that accelerated endothelial aging deteriorates bone tissue through paracrine repression of Wnt-driven-axis in BMSCs. Here, we utilize physiologically aged mice in conjunction with our transgenic endothelial progeria mouse model (Hutchinson-Gilford progeria syndrome; HGPS) that displays hallmarks of an aged bone marrow vascular niche. We find bone defects associated with diminished BMSC osteogenic differentiation that implicate the existence of angiocrine factors with long-term inhibitory effects. microRNA-transcriptomics of HGPS-patient plasma combined with aged-vascular niche analyses in progeria mice reveal abundant secretion of Wnt-repressive microRNA-31-5p. Moreover, we show that inhibition of microRNA-31-5p as well as selective Wnt-activator CHIR99021 boost the osteogenic potential of BMSCs through de-repression and activation of the Wnt-signalling, respectively. Our results demonstrate that the vascular niche significantly contributes to osteogenesis defects in aging and pave ground for microRNA-based therapies of bone loss in elderly. Overall design: To screen for microRNAs that are physiologically relevant for HGPS patients and possibly aging population, we obtained plasma samples from HGPS patients and corresponding unaffected controls that were kindly provided by Progeria Research Foundation (PRF). Selma Osmanagic-Myers harbors PRF approved “Material Transfer Agreement” and Application and Agreement for Cells, DNA or Tissue HGPS and control plasma samples (11/12/2019). PRF harbors ethical approval for human research from Rhode Island Hospital's Institutional Review Board, for which all donors have given consent. We then performed gene expression profiling analysis of HGPS plasma samples and those from unaffected controls. Comparative gene expression profiling analysis of RNA-Seq data for HGPS plasma samples (194p, 230, 204) and unaffected (612, 648p, 555)