Long-Distance Growth and Connectivity of Neural Stem Cells After Severe Spinal Cord Injury

Cell, 2012 · DOI: 10.1016/j.cell.2012.08.020 · Published: September 14, 2012

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

The study investigates the ability of neural stem cells (NSCs) to promote axonal regeneration after severe spinal cord injury in rats. NSCs were grafted into the injury site within a fibrin matrix containing growth factors to enhance survival and integration. The grafted NSCs differentiated into various cell types, including neurons that extended axons over remarkably long distances within the host spinal cord. These newly grown axons formed connections (synapses) with the host's existing neurons. The research also found that this axonal growth and functional recovery were partially dependent on a cellular signaling pathway called mTOR. Additionally, human neural stem cells showed similar growth capabilities, suggesting potential translational relevance for treating spinal cord injuries in humans.

Study Duration

9 weeks

Participants

Adult Fischer 344 rats (n=55) and athymic nude rats (n=12)

Evidence Level

Not specified

Key Findings

1
Neural stem cells, when grafted into sites of complete spinal cord transection, differentiated into neurons and extended axons over remarkably long distances (up to 25 mm) in both rostral and caudal directions.
2
These graft-derived axons formed functional synapses with host neurons, contributing to the formation of novel relay circuits across the site of injury, which improved electrophysiological activity and functional outcomes such as hindlimb locomotion.
3
The mTOR signaling pathway was found to play a significant role in the axonal growth of the grafted neurons, as inhibiting mTOR reduced axonal outgrowth. Furthermore, human neural stem cells exhibited similar growth and functional recovery properties, indicating translational potential.

Research Summary

Neural stem cells (NSCs) expressing GFP were embedded into fibrin matrices containing growth factor cocktails and grafted to sites of severe spinal cord injury. Grafted cells differentiated into multiple cellular phenotypes, including neurons, which extended large numbers of axons over remarkable distances. Extending axons formed abundant synapses with host cells. Properties intrinsic to early stage neurons can overcome the inhibitory milieu of the injured adult spinal cord to mount remarkable axonal growth resulting in formation of novel relay circuits that significantly improve function.

Practical Implications

Therapeutic Potential

The study suggests that neural stem cell transplantation, combined with supportive matrices and growth factors, holds promise as a therapeutic strategy for severe spinal cord injuries.

Clinical Translation

The successful use of human neural stem cells, already in clinical trials for ALS, further supports the translational potential of this approach.

Overcoming CNS Inhibition

The findings indicate that properties intrinsic to early-stage neurons can overcome the inhibitory environment of the adult CNS, paving the way for novel strategies to promote axonal regeneration.

Study Limitations

1
The study was primarily conducted in rats, and further research is needed to confirm these findings in larger animal models and humans.
2
The long-term survival and functional stability of the grafted cells and newly formed circuits need to be evaluated over extended periods.
3
The precise mechanisms underlying the mTOR-dependent axonal growth and the interactions between grafted and host cells require further investigation.

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