PhD Student/Junior Researcher Institute of Cytology Russian Academy of Science, Saint Petersburg City, Russia
Abstract: The processes of angiogenesis and osteogenesis are intrinsically linked, with a complex interplay between endothelial and osteogenic cells governing the delicate balance of bone homeostasis and mineralization. The aim of this study was to investigate and expand our understanding of the paracrine and juxtacrine mechanisms that mediate crosstalk between endothelial cells (EC) and osteoblasts (OB) in the context of osteogenic cell differentiation in vitro. To distinguish these two types of interaction, we co-cultured OB and EC directly to activate juxtacrine signaling (direct co-culture) or separated them by a membrane penetrable to paracrine factors, but not to cells (indirect co-culture). We have determined that the presence or absence of direct contact between OB and EC during the induction of osteogenic differentiation can lead to either osteoinductive or osteosuppressive effects. Our proteotranscriptomic analysis showed that the osteosuppressive effect is associated with the action of paracrine factors secreted by EC, while the osteoinductive properties of EC are mediated by the Notch signaling pathway, which can only be activated by physical contact of EC with OB. Indeed, upon direct co-cultivation, the knockdown of Notch1 and Notch3 receptors in EC has an inhibitory effect on osteogenic differentiation of OB, whereas activation of Notch by the intracellular domain of either Notch1 or Notch3 in EC has an inductive effect on osteogenic differentiation of OB. This represents a new and important discovery, as it reveals previously unknown crosstalk between EC and OB mediated by dynamic regulation of Notch1 and Notch3 signaling.
Funding Source: The work was carried out with financial support from the Russian Science Foundation (project number 23-15-00320)
