Treatment with a Gamma-Secretase Inhibitor Promotes Functional Recovery in Human iPSC- Derived Transplants for Chronic Spinal Cord Injury

Stem Cell Reports, 2018 · DOI: https://doi.org/10.1016/j.stemcr.2018.10.022 · Published: December 11, 2018

Spinal Cord Injury Regenerative Medicine

Simple Explanation

Spinal cord injury (SCI) often leads to permanent paralysis. This study explores a new approach using stem cells to regenerate damaged spinal cords, especially in the chronic phase after the injury when treatment is more challenging. The researchers used human induced pluripotent stem cells (hiPSC-NS/PCs) treated with a gamma-secretase inhibitor (GSI). GSI helps the stem cells mature into neurons. These cells were then transplanted into mice with chronic SCI. The results showed that GSI-treated stem cells promoted the regrowth of nerve fibers, remyelination (repairing the protective coating around nerves), and the formation of new connections between the transplanted cells and the host's nervous system, ultimately improving motor function.

Study Duration

3 months

Participants

Adult female NOD-SCID mice

Evidence Level

Not specified

Key Findings

1
GSI-treated hiPSC-NS/PCs led to enhanced axonal regrowth and remyelination in chronically injured spinal cords.
2
Inhibiting Notch signaling with GSI caused phosphorylation of p38 MAPK, a key molecule for axonal regeneration.
3
Transplanted hiPSC-NS/PC-derived mature neurons were GABAergic and integrated with the host neural circuitry, forming inhibitory synapses.

Research Summary

The study evaluated the efficacy of GSI-treated hiPSC-NS/PC transplantation in treating chronic SCI. The treatment resulted in significantly enhanced axonal regrowth, remyelination, inhibitory synapse formation, and reticulospinal tract fiber formation. GSI treatment promotes the phosphorylation of p38 MAPK, leading to axonal regrowth and improved motor function.

Practical Implications

Clinical Application

GSI treatment prior to transplantation is a simple and clinically applicable method that may be useful for enhancing the safety and efficacy of transplantation therapy in SCI.

Therapeutic Potential

GSI-treated hiPSC-NS/PCs have great potential to enhance spinal cord regeneration, even when transplantation is performed in the chronic phase.

Combination Therapy

Combination therapy involving GSI-treated cell transplantation and rehabilitative treadmill training may be an ideal treatment for the chronic phase of SCI.

Study Limitations

1
Other signaling molecules act as targets for GSI, so the possibility that GSI-induced inhibition of signaling pathways other than Notch contributed to axonal regrowth and remyelination cannot be ruled out.
2
Glial scar formation may limit the effects of axonal regrowth obtained from cell transplantation alone in chronically injured spinal cords.
3
Transplantation in the chronic stage resulted in slight improvement compared to the subacute phase, suggesting environmental modulation and graft cell modification may be important for successful therapy.

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