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.

Highlights

  • Beginning in the early stages of development, vascular and neural networks are intimately linked in the central nervous system (CNS)

  • Exploiting the intrinsic interaction between neural and vascular cells holds great potential for directing axon growth in regenerative applications designed for repair and restoring connectivity in the CNS

  • Our results demonstrate that microvessels guide axon growth from both neural progenitors in vitro and infiltrating neurites in vivo

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Summary

Introduction

Beginning in the early stages of development, vascular and neural networks are intimately linked in the central nervous system (CNS). Vascular and neural systems are patterned in parallel and exhibit spatial proximity and alignment throughout the central and peripheral nervous systems[5,6,7,8,9,10]. In addition to their structural association, the function of these two systems is closely intertwined. Conduits delivered to the site of a spinal cord injury (SCI) that are permissive to regenerating axons[23,24,25,26] provide a means to interrogate the effect of vascular orientation on the direction of axon growth. Transplantation of the scaffolds into a cervical hemisection SCI rat model provides validation of the efficacy of vascular-guided axon growth in vivo

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