Generation of functional posterior spinal motor neurons from hPSCs‑derived human spinal cord neural progenitor cells

Cell Regeneration, 2023 · DOI: https://doi.org/10.1186/s13619-023-00159-6 · Published: March 2, 2023

Regenerative Medicine Neurology Genetics

Simple Explanation

Spinal motor neuron deficiency leads to disorders like ALS and spinal cord injury, which are currently incurable. This study aims to generate functional spinal motor neurons from human pluripotent stem cells (hPSCs). The researchers established human spinal cord neural progenitor cells (hSCNPCs) from hPSCs via neuromesodermal progenitors (NMPs). These hSCNPCs can be expanded for up to 40 passages and differentiated into posterior spinal motor neurons. A co-culture system mimicking the neuromuscular junction (NMJ) formation was developed. This involves co-culturing neural and muscular cells, providing potential avenues for modeling neuromuscular diseases.

Study Duration

Not specified

Participants

Human pluripotent stem cells (hPSCs)

Evidence Level

Not specified

Key Findings

1
The study established a protocol for generating hSCNPCs from hPSCs through high-purity hNMPs, showing molecular properties of the spinal cord.
2
hSCNPCs can be passaged up to 40 times in vitro and efficiently differentiated into homogeneous spinal motor neurons with posterior spinal cord identities.
3
The derived spinal motor neurons exhibited functional maturity and could form neuromuscular junction (NMJ)-like structures when co-cultured with muscle fibers.

Research Summary

This study successfully differentiated hPSCs into self-renewal hSCNPCs through hNMPs, expressing homogeneous pan-NPC markers and spinal cord specific markers. The hSCNPCs could be further differentiated into high-purity motor neurons with posterior spinal cord regional identity and electrophysiological maturity. Co-culture of hSCNPCs-derived spinal motor neurons with C2C12-derived muscle fibers formed NMJ-like structures in vitro, providing a model for studying neuromuscular junctions.

Practical Implications

Disease Modeling

The developed hSCNPCs and NMJ-like structures offer a valuable in vitro model for studying spinal cord injuries and motor neuron diseases like ALS and SMA.

Regenerative Medicine

The ability to generate expandable and functional posterior spinal motor neurons holds potential for cell transplantation therapies to restore functional neural circuits in vivo.

Drug Discovery

The high-purity motor neurons and NMJ model can be used for high-throughput drug screening to identify potential therapeutic agents for neuromuscular disorders.

Study Limitations

1
The study primarily focuses on in vitro experiments, and further in vivo validation is needed to confirm the therapeutic potential.
2
The co-culture system uses C2C12 cells, which are a mouse myoblast cell line, and may not fully represent human muscle physiology.
3
The study acknowledges that the spinal motor neurons, while producing robust single bursts, do not readily form complex microcircuit assemblies in the in vitro culture system.

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