Regenerating Corticospinal Axons Innervate Phenotypically Appropriate Neurons within Neural Stem Cell Grafts

Cell Rep, 2019 · DOI: 10.1016/j.celrep.2019.01.099 · Published: February 26, 2019

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

Neural progenitor cell grafts can help to repair spinal cord injuries by forming new connections. These grafts develop into different types of spinal cord neurons, similar to those found in a healthy spinal cord. When damaged motor nerve fibers grow into these grafts, they connect to the correct type of nerve cells, which are important for controlling movement. This happens naturally, without needing extra help to guide the nerve fibers. Human neural stem cells, when grafted into a primate spinal cord, also develop into diverse spinal cord neurons, and regenerating motor axons connect appropriately.

Study Duration

2 weeks to 6 months

Participants

42 adult female Fischer 344 rats, 4 male rhesus macaques

Evidence Level

Not specified

Key Findings

1
Spinal neural progenitor grafts adopt diverse spinal motor and sensory interneuronal fates, representing most neuronal subtypes of the intact spinal cord.
2
Host corticospinal motor axons regenerating into neural progenitor grafts innervate appropriate pre-motor interneurons, based on trans-synaptic tracing with herpes simplex virus.
3
A human spinal neural progenitor cell graft to a non-human primate also received topographically appropriate corticospinal axon regeneration.

Research Summary

Neural progenitor cell grafts form new relays across sites of spinal cord injury (SCI). Host corticospinal motor axons regenerating into neural progenitor grafts innervate appropriate pre-motor interneurons, based on trans-synaptic tracing with herpes simplex virus. Thus, grafted spinal neural progenitor cells give rise to a variety of neuronal progeny that are typical of the normal spinal cord; remarkably, regenerating injured adult corticospinal motor axons spontaneously locate appropriate motor domains in the heterogeneous, developing graft environment, without a need for additional exogenous guidance.

Practical Implications

Simplifying Clinical Translation

The finding that regenerating host corticospinal axons locate appropriate neuronal targets within grafts without exogenous guidance may simplify the clinical translation of neural stem cell therapies for spinal cord injury.

Understanding Axonal Guidance

This research provides insights into the mechanisms guiding axonal regeneration and target selection, potentially informing strategies to enhance neural repair.

Optimizing Graft Composition

Characterizing the neuronal subtype fates of grafted cells can help optimize graft composition to promote more effective functional integration and recovery after spinal cord injury.

Study Limitations

1
The study acknowledges that most tdTomato-labeled neurons did not co-localize with any fate-specific neuronal markers, potentially due either to polysynaptic transmission or to HSV cytotoxicity.
2
The authors mention that they did not quantify mature sensory interneuronal markers because most of them are not expressed exclusively by spinal sensory interneurons.
3
Preliminary nature of primate findings, with only one primate having corticospinal axon tracing data.

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