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Specialized blood vessels Notch up osteogenesis in engineered bone (Banfi Lab)
Bone regeneration is an area of acute medical need, but its clinical success is hampered by the need to ensure rapid vascularization of osteogenic grafts for their survival and proper tissue formation. Vascular Endothelial Growth Factor (VEGF) is the master regulator of vascular growth and during bone development angiogenesis and osteogenesis are physiologically coupled through so-called angiocrine factors produced by blood vessels. However, how to exploit this process for therapeutic bone regeneration remains a challenge.
Here, researchers from Basel University (Regenerative Angiogenesis group led by Dr. Andrea Banfi) found that VEGF signaling controls several processes at the crossroads of angiogenesis and osteogenesis in a dose-dependent manner. Fine-tuning of VEGF dose in the signaling microenvironment is the key to ensuring physiological coupling of vascular growth and bone formation in engineered grafts.
In collaboration with the Plastic and Reconstructive Surgery of Unispital Basel (Prof. Dirk J. Schaefer) and the Pritzker School of Molecular Engineering at the University of Chicago (Prof. Jeffrey A. Hubbell), here they rigorously dissected how VEGF dose over a 1’000-fold range regulates vascular invasion, bone formation and bone resorption under therapeutically relevant conditions in osteogenic grafts. This was made possible by a unique platform we previously optimized, whereby finely tuned signaling microenvironments can be generated by decoration of fibrin matrices with engineered growth factors.
Surprisingly, the harmonious coupling of angiogenesis and osteogenesis depends on a delicate equilibrium between opposing effects of the vascular master regulator VEGF. A narrow range of VEGF doses specifically activates Notch1 signaling in invading blood vessels, inducing a pro-osteogenic functional state called Type H endothelium, that promotes differentiation of surrounding mesenchymal progenitors. However, lower doses are ineffective and higher ones paradoxically inhibit both vascular invasion and bone formation.
These findings suggest an explanation for the apparent discrepancy between the biological functions and the therapeutic effects of VEGF and also bear translational relevance for the design of effective therapeutic strategies to engineer vascularized osteogenic grafts. Fibrin matrices decorated with engineered VEGF protein provide a highly tunable and clinically applicable platform to generate a controlled regenerative microenvironment.