BMP4/Smad1 Signalling Promotes Spinal Dorsal Column Axon Regeneration and Functional Recovery After Injury

Molecular Neurobiology, 2019 · DOI: https://doi.org/10.1007/s12035-019-1555-9 · Published: March 28, 2019

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

This research investigates how activating the BMP4/Smad1 pathway can help spinal cord axons regenerate and restore function after injury in rats. The study found that when dorsal root ganglion neurons (DRGN) are in an environment that promotes regeneration, the BMP4/Smad1 signaling pathway is more active. By delivering BMP4 directly to the injured spinal cord, the researchers were able to stimulate axon regeneration and improve functional recovery in rats, even with the presence of spinal cord cavities.

Study Duration

6 weeks

Participants

Adult female Sprague-Dawley rats (180–250 g)

Evidence Level

Not specified

Key Findings

1
BMP4 peptide promoted significant DRGN survival and disinhibited neurite outgrowth in vitro.
2
AAV-BMP4 delivery in vivo stimulated DC axon regeneration and functional recovery in a model that cavitates.
3
Activation of the BMP4/Smad1 pathway is a potential therapeutic target in the search for axon regenerative signalling pathways in the CNS.

Research Summary

The study investigated the contribution of the BMP4/Smad1 pathway in promoting long-tract DRGN axon regeneration after DC injury in a rat model that cavitates. BMP4 and Smad1 mRNA and protein were highly upregulated in both regenerating paradigms whilst expression levels of the BMP4 suppressor Noggin were attenuated. AAV8-mediated delivery of BMP4 in the rat in vivo promoted DC axon regeneration and electrophysiological, sensory and locomotor improvements after DC injury, despite the presence of cavities.

Practical Implications

Therapeutic Target

The BMP4/Smad1 pathway is a potential therapeutic target for spinal cord injury patients.

Delivery Method

Non-viral delivery vectors can be used to safely deliver BMP4 and activate the BMP/Smad1 signaling pathway.

Combination Therapy

Combining AAV8-BMP4 with a Noggin antagonist may further enhance DC axon regeneration and functional recovery.

Study Limitations

1
Although we used AAV8 to deliver BMP4, which is not considered translational since transgenes were injected 1 week before DC injury
2
Our electrophysiological data recorded cord dorsum potentials, which not only measured dorsal column activity but may have detected signals from diverse sources.
3
The functional deficits using the DC injury model are mild

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