Aged‐vascular niche hinders osteogenesis of mesenchymal stem cells through paracrine repression of Wnt‐axis

Abstract

Age‐induced decline in osteogenic potential of bone marrow mesenchymal stem cells (BMSCs) potentiates osteoporosis and increases the 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 boosts the osteogenic potential of BMSCs through de‐repression and activation of the Wnt‐signaling, respectively. Our results demonstrate that the vascular niche significantly contributes to osteogenesis defects in aging and pave the ground for microRNA‐based therapies of bone loss in elderly.

Premature aging effects on COVID-19 pathogenesis: new insights from mouse models

“…Aging, together with other aging-related diseases, are identi ed to be major risk factors for severe COVID19 11 . Since HGPS share several phenotypes with accelerated aging especially atherosclerosis, osteoporosis, and cardiovascular diseases 5,33,34 , one would assume a severe COVID19-like phenotype from HGPS after viral infection. However, beyond our expectation, HGPS/hACE2 mice only experienced mild pathological outcomes compared to the young and aged mice, indicating that Progeria syndrome cases may not be susceptible to SARS-CoV-2.…”

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