Systemic Neutrophil Depletion Modulates the Migration and Fate of Transplanted Human Neural Stem Cells to Rescue Functional Repair

The Journal of Neuroscience, 2017 · DOI: 10.1523/JNEUROSCI.2785-16.2017 · Published: September 20, 2017

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

This study investigates how transplanted stem cells interact with their environment in the injured spinal cord and how this affects their ability to promote repair. Specifically, the researchers looked at how the timing of stem cell transplants affects their behavior and whether blocking a certain type of immune cell, neutrophils, could improve outcomes. They found that transplanting stem cells immediately after spinal cord injury led to the stem cells turning into a specific type of support cell (astrocytes) and not improving function. However, when neutrophils were blocked, the stem cells were able to promote functional recovery. These findings suggest that the inflammatory environment after spinal cord injury can prevent stem cell therapies from working effectively, and that targeting specific immune cells could improve the success of these treatments.

Study Duration

12-16 weeks post-SCI

Participants

Female NOD-scid mice (N = 16/group, 10 weeks old)

Evidence Level

Not specified

Key Findings

1
Acute transplantation of hCNS-SCns resulted in localized astroglial differentiation of donor cells near the lesion epicenter and failure to produce functional improvement.
2
Specific immunodepletion of neutrophils blocked hCNS-SCns astroglial differentiation near the lesion epicenter and rescued the capacity of these cells to restore function.
3
Anti-Ly6G treatment altered the localization of donor human cells near the lesion site and suggest a novel role for PMNs in modulating donor human cell behavior in the SCI microenvironment.

Research Summary

This study demonstrates that the timing of hCNS-SCns transplantation post-SCI affects the localization and differentiation of donor cells. Acute transplantation (0 dpi) resulted in astroglial differentiation and no functional improvement, while delayed transplantation (30 dpi) has previously been shown to result in neuronal and oligodendrocytic differentiation and functional improvements. Specific depletion of neutrophils (PMNs) via anti-Ly6G treatment after acute transplantation rescued the capacity of hCNS-SCns to improve locomotor function, suggesting that PMNs play a role in modulating donor cell fate and efficacy.

Practical Implications

Optimizing Cell Therapy

Targeting the inflammatory microenvironment, particularly neutrophils, could improve the efficacy of cell transplantation therapies for spinal cord injury.

Expanding Therapeutic Window

Modulating immune populations and inflammatory molecules may have clinical relevance as an approach to expand therapeutic window after SCI.

Localized Drug Delivery

Anti-Ly6G could be packaged into biodegradable materials for sustained local delivery at the lesion to avoid systemic PMN depletion and impairment of the overall systemic immune response.

Study Limitations

1
Study used an immunodeficient mouse model, which may not fully represent the human immune response after SCI.
2
The study focused on a specific time window based on PMN infiltration in rodent SCI models, which may differ in humans.
3
Further studies are needed to establish the relationships among PMN infiltration, activation/infiltration of other immune populations, and the recovery of CNS function.

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