Elsevier

Current Opinion in Neurobiology

Volume 27, August 2014, Pages 103-109
Current Opinion in Neurobiology

Axonal growth and connectivity from neural stem cell grafts in models of spinal cord injury

https://doi.org/10.1016/j.conb.2014.03.010Get rights and content

Highlights

  • Grafted neural stem cells extend high numbers of axons over long distances after spinal cord injury.

  • Graft derived axons make synaptic connections with host neurons.

  • Host supraspinal axons regenerate into and make connections with grafted neurons.

  • Grafted neurons serve as functional relays to improve behavioral outcomes.

Spinal cord injury (SCI) damages both gray matter and white matter, but white matter damage is responsible for the vast majority of the subsequent functional loss. Neural stem cells (NSCs) have been investigated as a means of improving outcomes after SCI, either through neuroprotective properties that limit secondary damage or by direct cell replacement. This review will focus on cell replacement strategies, and the ability of multipotent NSCs to form new functional synaptic relays across sites of even severe SCI. The ability of these early stage neurons to extend axons from the lesion site in large numbers and over long distances constitutes an important mechanism underlying their potential to promote neural repair.

Introduction

Spinal cord injury (SCI) results in the death of neurons at the injury site and the loss of axons that carry signals to and from the brain. Axons of the injured adult central nervous system (CNS) exhibit little ability to spontaneously regenerate, often resulting in permanent functional deficits below the level of injury [1]. For more than a decade, neural stem cells (NSCs) or neural precursor cells (NPCs) have been an attractive cell source for the treatment of SCI, because they have the potential to replace lost neurons and glia, and to restore disrupted connectivity at lesion sites. Recently we have come to appreciate that grafts of NSCs to spinal cord lesion sites are able to extend numerous new axons into the host spinal cord for long distances, and to receive inputs from injured host axons. On the basis of this bi-directional growth of axons and establishment of reciprocal synapses, NSCs form new relays between separated segments of the spinal cord after injury (Fig. 1).

NSCs or NPCs can be isolated from the developing CNS, or derived from pluripotent stem cells, including embryonic stem (ES) cells or induced pluripotent stem (iPS) cells. Here, we systematically review NSC transplantation studies in SCI research, with an emphasis on axonal growth and connectivity between transplanted and injured host neurons. We conclude by discussing future challenges in the field of NSC transplantation for SCI.

Section snippets

Axonal projections arising from neural stem cell grafts

There is an extensive history of CNS tissue grafting in models of SCI [2•, 3, 4]. Early studies demonstrated axonal projections from grafted tissue into host for distances as long as 4–5 mm, using both anterograde and retrograde axonal labeling techniques [3]. Intrinsic cellular markers and reporters, such as green fluorescent protein (GFP) and alkaline phosphatase (AP), may be more reliable methods for labeling axons emerging from neural implants than tracer injections. These cell-intrinsic

Connectivity and function of axons arising from neural stem cell grafts

Several studies have reported connectivity and functional recovery after grafting various types of NSCs to sites of SCI, although the strength of evidence supporting these reports varies across studies. The first study that grafted mouse ES cell-derived NSCs to a site of contusive rat SCI reported functional recovery, but provided no detailed mechanism [32]. However, only 8% of grafted cells became neurons in this study, and there was no labeling of neuronal processes. Another study also

Axonal projection and connectivity from host neurons into neural stem cell grafts

The outgrowth and connectivity of grafted NSCs is only one component of neuronal relay formation. A complete neuronal relay also relies on ingrowth and connectivity of host axons with grafted neurons. Several studies have reported regeneration of adult host axons, including rubrospinal, reticulospinal, raphespinal, propriospinal, and sensory axons, into grafts of embryonic spinal cord tissue or ES cell-derived NSCs placed in sites of SCI [3, 4, 7••, 10, 37••, 38]. However, the distance and

Future perspectives

Axonal growth from NSCs and the potential formation of new functional neuronal relays across lesion sites offers new hope for SCI treatment. Several challenges remain. The modest growth and regeneration of adult host axons into the NSC grafts is one challenge, since the intrinsic growth capacity of adult neurons is greatly reduced [41]. Enhancing the intrinsic adult neuronal growth state [42•, 43•] or provision of neurotrophic factors in regions of lesioned axon terminals [44] could enhance

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was funded by grants from the Veterans Administration, NIH (NS09881), the Craig H. Neilsen Foundation, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the California Institute for Regenerative Medicine.

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