PROVEC · Promoting Osteogenesis through Vascular Endothelial Cells

The skeletal system and its vasculature form a functional unit with great relevance in health, regeneration, and disease. Our recent work has provided fundamental insights into the organization of the bone vasculature in mouse, its changes during aging, the heterogeneity and functional specialization of bone capillaries and endothelial cells, the regulation of these properties by Notch and hypoxia-inducible factor signaling, and the crosstalk with osteoblast lineage cells. Most importantly, we found that the manipulation of ECs in the aging animal can trigger the expansion of osteoprogenitors and thereby induce bone formation. PROVEC will now systemically identify and characterize endothelial cell subpopulations, their gene expression and functional properties in the healthy, aging, diseased and regenerating skeletal system. Preclinical models will establish whether endothelial cells are involved in the response to therapeutic treatments aiming at osteoblasts or osteoclasts, or if the modulation of ECs alone is sufficient to generate beneficial effects. Finally, PROVEC will investigate whether cultured mouse and human ECs can be endowed with beneficial properties to enhance bone formation in 3D organoid cultures and after transplantation into mice, which will be monitored by imaging in living animals.To achieve its ambitions aims, PROVEC will use a powerful combination of mouse genetics, disease models, genetic fate mapping, RNA-seq and single cell sequencing, computational biology, confocal and 2-photon microscopy, micro-CT imaging, pharmacological treatments, and cell biology methods to establish if and how vascular endothelial cells can be used to increase bone mineral density in preclinical models.The successful completion of PROVEC would be highly relevant for diseases such as osteoporosis, which affects around 27.5 million patients in the EU, generates annual costs of about 37 billion Euros, and for which we currently lack appropriate treatments.