Blood vessels heal nerve injury

The enigma of nerve regeneration has intrigued scientists for over a century: why do nerves in the brain or spinal cord fail to regenerate, while those connecting with peripheral tissues undergo repair?  This dichotomy remains a mystery and can hardly be attributed to a single factor, although it is increasingly evident that the unique characteristics of nerve tissue play a crucial role in determining its regenerative capacity

A team of San Raffaele researchers, headed by Dario Bonanomi, group leader of the Molecular Neurobiology laboratory in the Division of Neuroscience, has unveiled a new and unexpected role for blood vessels in the healing process. The study –published in Neuron–defines the properties of vascular endothelial cells that organize a polarized scaffold within the wound of injured peripheral nerves. The research demonstrates that the newly formed vasculature plays a pivotal role in instructing the reconfiguration of the lesion site, establishing a microenvironment conducive to nerve regeneration. 

The importance of angiogenesis

Angiogenesis, the formation of new capillaries from existing blood vessels, is a crucial process in wound healing and tissue regeneration. While the adult endothelium is typically inactive, injury rapidly triggers angiogenesis to supply oxygen and nutrients to the damaged area. Neovessels play a key role in supporting the inflammatory response and facilitating tissue growth and remodeling.

“A balance in both the magnitude and duration of angiogenesis is essential for effective healing, as inadequate vascularization leads to chronic wounds, while excessive growth results in disorganized and leaky capillaries, contributing to fibrosis and impairing the overall repair process”, explains Dario Bonanomi.

Despite its significance, the molecular mechanisms underlying wound angiogenesis are incompletely understood.

p3lab_coverCompartimentalized nerve scar


How blood vessels help nerve repair

San Raffaele researchers discovered that new blood vessels that grow in the wound immediately after peripheral nerve damage are guided to form a highly organized 3D framework that is critical for shaping the architecture of nerve tissue.

“We show that an orderly system of stromal tubes is constructed ad hoc across the wound under the influence of blood vessels to promote nerve repair and safeguard the newly grown fibers. These tubular structures are absent in the healthy nerve and are very stable, suggesting that they indelibly mark the wound ", says Ganesh Bhat, first author of the study. The mesenchymal tubes form a blood-tissue barrier, effectively preventing harmful substances and cells derived from the circulatory system from reaching the delicate regrowing nerve fibers.

Of particular interest is the observation that, unlike injuries to the brain or spinal cord that result in a permanent scar hindering fiber regeneration, peripheral nerve wounds undergo substantial structural remodeling orchestrated by vessels. This reshaping process gives rise to the formation of mesenchymal barrier compartments that provide preferential corridors for axon regeneration while simultaneously exerting a prolonged protective effect on these fibers.

“We propose that this precisely engineered scar is possible in the regenerating peripheral nerve but not in the central nervous system, due to differences in the way vessels form and respond to damage in these tissues. Finding strategies to guide vascular growth in the brain or spinal cord, similar to what is observed in the peripheral nerve, could open new opportunities for applications in regenerative medicine”, concludes Bonanomi.