Astrocytes derived from glial-restricted precursors promote spinal cord repair

Jeannette E Davies,Margot Mayer-Proschel,Christoph Proschel,Stephen Ja Davies,Mark Noble,Carol Huang

doi:10.1186/jbiol35

Jeannette E Davies, Margot Mayer-Proschel + Show 4 more

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https://doi.org/10.1186/jbiol35

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Abstract

BackgroundTransplantation of embryonic stem or neural progenitor cells is an attractive strategy for repair of the injured central nervous system. Transplantation of these cells alone to acute spinal cord injuries has not, however, resulted in robust axon regeneration beyond the sites of injury. This may be due to progenitors differentiating to cell types that support axon growth poorly and/or their inability to modify the inhibitory environment of adult central nervous system (CNS) injuries. We reasoned therefore that pre-differentiation of embryonic neural precursors to astrocytes, which are thought to support axon growth in the injured immature CNS, would be more beneficial for CNS repair.ResultsTransplantation of astrocytes derived from embryonic glial-restricted precursors (GRPs) promoted robust axon growth and restoration of locomotor function after acute transection injuries of the adult rat spinal cord. Transplantation of GRP-derived astrocytes (GDAs) into dorsal column injuries promoted growth of over 60% of ascending dorsal column axons into the centers of the lesions, with 66% of these axons extending beyond the injury sites. Grid-walk analysis of GDA-transplanted rats with rubrospinal tract injuries revealed significant improvements in locomotor function. GDA transplantation also induced a striking realignment of injured tissue, suppressed initial scarring and rescued axotomized CNS neurons with cut axons from atrophy. In sharp contrast, undifferentiated GRPs failed to suppress scar formation or support axon growth and locomotor recovery.ConclusionPre-differentiation of glial precursors into GDAs before transplantation into spinal cord injuries leads to significantly improved outcomes over precursor cell transplantation, providing both a novel strategy and a highly effective new cell type for repairing CNS injuries.

Highlights

Transplantation of embryonic stem or neural progenitor cells is an attractive strategy for repair of the injured central nervous system
Regeneration of endogenous dorsal column axons Transplantation of glial-restricted precursor (GRP)-derived astrocytes (GDAs) into stab-wound lesions of the dorsal column white matter pathways of adult rat spinal cord (Figure 1a-c) resulted in the growth of the majority of the cut ascending dorsal column axons into the lesion center (Figures 2 and 3a), with 66% of these axons extending further beyond the lesion site into adjacent white matter (Figures 2 and 3a,b,e,f)
In order to minimize labeling of spared axons, a discrete population of ascending axons aligned with the lesion site was traced en passage with a single biotinylated dextran amine (BDA) injection caudal to GDA-transplanted or control stab injuries of the right-hand dorsal column cuneate and gracile white matter pathways (Figure 1c; see the Glossary box for an explanation of terms)

Summary

Introduction

Transplantation of embryonic stem or neural progenitor cells is an attractive strategy for repair of the injured central nervous system. Transplants of some cell types have provided more benefit than others, the general lack of significant axon regeneration beyond sites of injury has led to the combination of cellular transplant strategies with delivery of neurotrophic factors, treatments designed to override or degrade the scar, and/or with the use of biomaterials to offer both potential substrates and organized tissue structures [16,17]. Such combinations have resulted in varying degrees of successful axon regeneration

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