Harnessing neurovascular interaction to guide axon growth

Abstract

Regulating the intrinsic interactions between blood vessels and nerve cells has the potential to enhance repair and regeneration of the central nervous system. Here, we evaluate the efficacy of aligned microvessels to induce and control directional axon growth from neural progenitor cells in vitro and host axons in a rat spinal cord injury model. Interstitial fluid flow aligned microvessels generated from co-cultures of cerebral-derived endothelial cells and pericytes in a three-dimensional scaffold. The endothelial barrier function was evaluated by immunostaining for tight junction proteins and quantifying the permeability coefficient (~10−7 cm/s). Addition of neural progenitor cells to the co-culture resulted in the extension of Tuj-positive axons in the direction of the microvessels. To validate these findings in vivo, scaffolds were transplanted into an acute spinal cord hemisection injury with microvessels aligned with the rostral-caudal direction. At three weeks post-surgery, sagittal sections indicated close alignment between the host axons and the transplanted microvessels. Overall, this work demonstrates the efficacy of exploiting neurovascular interaction to direct axon growth in the injured spinal cord and the potential to use this strategy to facilitate central nervous system regeneration.

Advances in Biomaterial‐Based Spinal Cord Injury Repair

“…These microvessel‐laden scaffolds stimulate neural differentiation and guide axon growth and neurite infiltration close to the microvasculature, both in vitro and in vivo. [ 163 ] Moreover, the transplantation of human cerebral microvascular endothelial cells, HCMEC/D3‐, laden self‐assembling peptide hydrogel at the contusion injury site in the subacute phase, supports the formation of microvessels with BSCB‐integrity and host axon growth in an HCMEC/D3 density‐dependent manner. [ 164 ] Interestingly, in SCI rats with endothelial cell transplantation, more serotonergic‐specific axons were observed at the lesion site at a low cell density.…”

The Use of Tissue Engineering to Fabricate Perfusable 3D Brain Microvessels in vitro

“…Vasculogenic approaches involve culturing endothelial cells and pericytes within a hydrogel and allowing for the formation of microvessels over time. This strategy has been used to create capillary scale BBB-forming microvessels within collagen/hyaluronan composite hydrogels ( Partyka et al, 2019 ; Tran et al, 2020 ). Similar to the angiogenic method, the vasculogenic protocol prohibits patterning of complex topologies since the structures are formed spontaneously.…”

The Influence of Neuron-Extrinsic Factors and Aging on Injury Progression and Axonal Repair in the Central Nervous System

“…The vascular and nervous system are closely juxtaposed, and endothelial cells respond to similar patterning cues as growth cones (Adams and Eichmann, 2010). There is increasing interest in taking advantage of this interaction to control axon regeneration by controlling vascular patterning after SCI (Partyka et al, 2019;Tran et al, 2020). Endothelial cells secrete vascular endothelial growth factor (VEGF), which promotes cell survival and axonal outgrowth (Sondell et al, 1999).…”