Injured adult motor and sensory axons regenerate into appropriate organotypic domains of neural progenitor grafts

Nature Communications, 2018 · DOI: 10.1038/s41467-017-02613-x · Published: January 26, 2018

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

Neural progenitor cell (NPC) transplantation holds significant promise for treating neurological disorders. The success of this approach may hinge on the establishment of connections between the host and the graft. This study reveals that when spinal cord NPCs are grafted into an injured adult rat spinal cord, they spontaneously organize into structures resembling the dorsal horn, a region of the spinal cord responsible for processing sensory information. Injured adult sensory axons readily regenerate into these graft-derived structures, while corticospinal axons, which transmit motor signals, tend to avoid them. This suggests that injured axons retain the ability to recognize and connect with appropriate targets within the grafts.

Study Duration

6 Weeks

Participants

119 rats

Evidence Level

Not specified

Key Findings

1
Spinal cord NPCs transplanted into the injured adult spinal cord can differentiate into multiple subtypes of neurons with distinct lineage identities.
2
Dissociated NPC grafts self-assemble neuronal clusters with laminar organization of distinct dorsal spinal cord interneuronal subtypes, recapitulating the laminar cytoarchitecture of the intact spinal cord dorsal horn.
3
Injured host motor and sensory axons selectively innervate graft tissue domains populated with specific neuronal subtypes and avoid domains populated with inappropriate targets.

Research Summary

This study investigates whether adult, injured host axons regenerating into neural progenitor cell (NPC) grafts form appropriate connections. Spinal cord NPCs were grafted into the injured adult rat spinal cord, and the researchers observed the self-assembly of organotypic, dorsal horn-like domains. Key findings included that these domains are extensively innervated by regenerating adult host sensory axons and avoided by corticospinal axons. Moreover, host axon regeneration into grafts increases significantly after enrichment with appropriate neuronal targets. The study concludes that injured adult axons retain the ability to recognize appropriate targets and avoid inappropriate targets within neural progenitor grafts, suggesting that restoration of complex circuitry after SCI may be achievable.

Practical Implications

Targeted SCI Therapy

The findings suggest that cell transplantation approaches can be optimized for neurological disease and injury by promoting the integration of regenerated host axons into new, functionally relevant neural circuits.

Graft Engineering

Spatial engineering of grafts may be required to enhance the ability of corticospinal and other functionally important axonal systems to encounter their appropriate graft-derived neuronal targets.

Circuit Restoration

The intrinsic programming of injured adult corticospinal neurons to spontaneously seek out and synapse onto their normal target neuron subtypes within grafts offers potential for the restoration of lost function after spinal cord injury.

Study Limitations

1
The extent to which graft-derived neurons integrate into host neural circuitry toward the ultimate goal of restoring lost function is still unclear.
2
The possibility that the formation of ectopic sensory foci may result in adverse outcomes requires further investigation.
3
A complete characterization of distinct neural subtypes populating these grafts, as well as the array of complex relay circuits that might spontaneously arise is needed.

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