Preclinical long-term safety of intraspinal transplantation of human dorsal spinal GABA neural progenitor cells

iScience, 2023 · DOI: https://doi.org/10.1016/j.isci.2023.108306 · Published: November 17, 2023

Spinal Cord Injury Neurology Regenerative Medicine & Stem Cells

Simple Explanation

This study investigates the long-term safety of transplanting human spinal cord cells into rats. The goal is to see if these cells can help treat spinal cord injuries. Researchers tracked the cells for a year to check for any problems. The transplanted cells developed into neurons and astrocytes and integrated into the rat's spinal cord. The rats' sensorimotor functions remained normal, even when the human neurons were stimulated or suppressed. These findings suggest that using human spinal neuron transplants to treat spinal cord injuries could be safe. This work is a step towards testing this treatment in human clinical trials.

Study Duration

1 year

Participants

39 adult female athymic nude rats

Evidence Level

Not specified

Key Findings

1
Human spinal GABA neurons survived long-term and fully matured in the rat spinal cord after transplantation, differentiating into neurons and astrocytes.
2
The transplanted human dorsal spinal GABA neurons integrated into rat neural circuits, forming synapses with rat interneurons, motor neurons, and afferent sensory terminals.
3
Intraspinal transplantation of human ESC-derived dorsal spinal GABA NPCs was safe in the long term, with no impairment of sensorimotor function observed.

Research Summary

This study demonstrated the long-term fate and safety of human ESC-derived dorsal spinal dI4/dILA NPCs in adult naive rat spinal cords over 1 year. The majority of differentiated human neurons were PTF1A+, suggesting that they faithfully preserved spinal dI4/dILA identity in vivo. Although mature human neurons and astrocytes survived long-term and integrated into the rat spinal cord, the sensorimotor function of rats was not impaired by cell transplantation.

Practical Implications

Clinical Translation

The findings represent a significant step toward the clinical translation of human spinal neuron transplantation for treating SCI, suggesting potential for future clinical trials.

Refined cell therapies

For precisely reconstructing damaged circuits after SCI, subtypes of molecularly defined neurons might be optimal over a mixture of unspecified populations.

Long-term safety

The study verifies the long-term safety of human ESC-derived dorsal spinal dI4/dILA NPCs in the spinal cord, which is crucial for considering clinical applications.

Study Limitations

1
Further long-term studies in SCI rats and even in NHPs are clearly needed to definitively validate their fate, efficacy, and safety before initiating any clinical trials.
2
Immunoelectron microscopy, virus tracing and electrophysiology studies, although relatively technically hard, are needed to faithfully prove that grafted human neurons are functionally integrated into host neural circuits.
3
The study was conducted in naive adult rats, which may not fully represent the conditions of a spinal cord injury environment.

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