In the course of the project, we have generated substantial insights into the heterogeneity, molecular properties and functional specialization of bone endothelial cells and other cell populations in the skeletal system.
Specifically, we have been able to show that the Hippo pathway is an important regulator of angiogenic blood vessel growth in bone and trabecular bone formation by regulating hypoxia-inducible factor signaling (Sivaraj et al., eLife 2020). We also showed that Notch signaling plays important roles in bone angiogenesis and osteogenesis, which can be therapeutically utilized in mice as a preclinical model (Xu, Dinh et al, eLife 2022; Remark et al., Bone Res. 2023). Furthermore, we discovered that vessel-associated bone mesenchymal stromal cells are regionally specialized and that a subset of these cells mediates chondrocyte resorption during developmental bone growth and fracture healing (Sivaraj et al., Cell Reports 2021; Sivaraj et al., Nature Commun. 2022). While blood vessels are coupled to the progenitors of bone-forming cells during fracture healing in long bone, the same is not the case in skull (Bixel et al., Nature Commun., accepted for publication). Skull bone marrow is also functionally different from long bone and is subjected to lifelong expansion (Koh et al., under revision). All these papers utilized single cell RNA-sequencing to analyze the properties of different cell populations in bone, which is also the topic of another earlier publication (Tikhonova et al., Nature 2019). More recently, we have used single cell RNA-sequencing and mouse genetics for the identification of another blood vessel subtype associated with remodeling bone (Mohanakrishnan et al., final revision). Furthermore, we demonstrated that certain blood vessels protect bone and marrow against fibrosis (Sivaraj, Majev et al., Nature CVR, accepted for publication).
In the context of the functional specialization of bone endothelial cells, we showed that a subset of Apelin-expressing cells promotes vessel and bone marrow regeneration after irradiation (Chen et al., Cell Stem Cell 2019). The function of bone marrow also relies of vessel-associated nerve fibers and the neurotransmitter dopamine (Liu et al., Blood 2021; Deng et al., FASEB Journal 2022). Furthermore, we showed that the development of fetal bone marrow relies on signals from arterial endothelial cells (Liu et al., Nature Commun. 2022).
Taken together, research in PROVEC has discovered many fundamental properties of the bone vasculature and its interactions with other cell types with relevance for fracture healing, regeneration, fibrosis and age-related bone loss. These results will form the basis for future preclinical and translational research addressing the function of blood vessels in health and disease.
