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AngioBone Report Summary

Project ID: 339409
Funded under: FP7-IDEAS-ERC
Country: Germany

Mid-Term Report Summary - ANGIOBONE (Angiogenic growth, specialization, ageing and regenerationof bone vessels)

Our research is concerned with the organization, growth and molecular regulation of the vasculature in the skeletal system and its interactions with bone-forming cells. In the first half of the project, we have resolved many fundamental questions regarding the functional roles of blood vessels and ECs in the skeletal system. In particular, we have demonstrated the existence of two distinct but interconnected capillary subsets with specific properties. Metaphyseal and endosteal capillaries in proximity of compact bone express high levels of the markers CD31 and Endomucin (Emcn), mediate most of the angiogenic growth of the local vasculature and support perivascular Osterix-expressing osteoprogenitor cells, which give rise to bone-forming osteoblasts. In contrast, the dense, highly branched capillary network of the bone marrow cavity in the diaphysis, which corresponds to the sinusoidal vasculature described in the literature, is surrounded by densely packed hematopoietic cells and lacks association with Osterix+ osteoprogenitors (Kusumbe et al. 2014, Nature 507:323-328). As arteries in postnatal long bone terminate only in the capillary subsets located in the metaphysis and endosteum but do not connect to diaphyseal vessels, distinct metabolic environments with strong differences in oxygenation are generated.
Moreover, our work has provided unexpected insights into the molecular regulation of bone angiogenesis. Angiogenesis in bone requires Notch and hypoxia-inducible factor signaling. Genetic inactivation of the endothelium of postnatal mice did not only impair bone vessel morphology and growth, but also led to reduced osteogenesis, shortening of long bones, chondrocyte defects, loss of trabeculae and decreased bone mass. We also uncovered extensive age-related changes in the bone vasculature, which led to the loss of the capillary subtype supporting perivascular osteoprogenitor cells and thereby reduced osteogenesis (Kusumbe et al. 2014, Nature 507:323-328; Ramasamy et al. 2014, Nature 507:376-380).
Blood vessels in bone are not only important for osteogenesis but also provide a vascular niche microenvironment for hematopoietic stem cells (HSCs). We could recently provide new insights into the organization of vascular HSC niches in the bone marrow (Kusumbe et al. 2016, Nature 532:380-4; Itkin et al. 2016, Nature 532:323-8). The activation of Notch signaling led to the expansion of HSC niches in bone, which involved increases in CD31-positive capillaries and platelet-derived growth factor receptor-β (PDGFRβ)-positive perivascular cells, arteriole formation and elevated levels of cellular stem cell factor. In ageing mice, niche-forming vessels in the skeletal system were strongly reduced, but could be restored by activation of endothelial Notch signaling (Kusumbe et al. 2016, Nature 532:380-4). In a parallel study (Itkin et al. 2016, Nature 532:323-8) led by our collaboration partner Tsvee Lapidot (Weizmann Institute, Israel), we contributed to the characterization of different vessel subtypes and the role of reactive oxygen species (ROS) in bone marrow. Together, these findings indicate that vascular HSC niches are part of complex, age-dependent microenvironments involving multiple cell populations and vessel subtypes.
Taken together, the ERC-funded research has already led to significant technological improvements and fundamental conceptual insights, which form the basis of the work planned for the second half of the project.

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