Modeling axonal regeneration by changing cytoskeletal dynamics in stem cell‑derived motor nerve organoids

Scientific Reports, 2022 · DOI: 10.1038/s41598-022-05645-6 · Published: January 28, 2022

Simple Explanation

The study creates a model of motor nerve cells using human stem cells to study how nerve fibers (axons) degenerate and regenerate. This model allows researchers to visualize and quantify the effects of oxidative stress on motor axons, which are particularly vulnerable in neurodegenerative diseases. The researchers exposed the nerve cell model to oxidative stress, mimicking conditions in diseases like ALS. They observed axon degeneration, including retraction and fragmentation. They then tested drugs that affect the cell's internal scaffolding (cytoskeleton) and found some could help the axons regenerate. The findings suggest that manipulating the cytoskeleton, specifically actin and microtubules, can improve axon regeneration after injury. This model can be used for drug screening to find treatments that promote nerve repair in motor neuron diseases.

Study Duration

Not specified

Participants

Human induced pluripotent stem cells (hiPSCs)

Evidence Level

In vitro study using stem cell-derived motor nerve organoids

Key Findings

1
Motor nerve organoids derived from human pluripotent stem cells (hPSCs) can be efficiently generated and exhibit characteristics of mature motor neurons.
2
Oxidative stress induced by hydrogen peroxide (H2O2) leads to quantifiable axon degeneration in both 2D and 3D motor nerve models.
3
Pharmacological modulation of cytoskeletal dynamics, particularly with Y-27632 (ROCK inhibitor) and TSA (HDAC inhibitor), promotes axon regeneration after oxidative stress.

Research Summary

The study establishes a motor nerve organoid model from human pluripotent stem cells to investigate axonal degeneration and regeneration under oxidative stress conditions. The model demonstrates that oxidative stress induces axon degeneration, characterized by growth cone collapse, axon retraction, and fragmentation, which can be quantified. Pharmacological interventions targeting cytoskeletal dynamics, specifically actin and microtubule stabilization, enhance axon regeneration, suggesting potential therapeutic strategies for motor neuron diseases.

Practical Implications

Drug Screening

The motor nerve organoid model can be used for high-throughput drug screening to identify compounds that promote axon regeneration and protect against neurodegeneration.

Disease Modeling

The model allows for patient-specific disease modeling to study the mechanisms of motor neuron diseases and test personalized therapeutic approaches.

Therapeutic Development

The findings suggest that targeting cytoskeletal dynamics could be a promising therapeutic strategy for promoting axon regeneration and treating motor neuron diseases.

Study Limitations

1
The model is an in vitro system and may not fully replicate the complexity of the in vivo environment.
2
The study focuses on oxidative stress as a primary driver of axon degeneration, while other factors may also contribute to motor neuron diseases.
3
The long-term effects and potential toxicity of the pharmacological interventions were not assessed.

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