Combination Therapy of Stem Cell Derived Neural Progenitors and Drug Delivery of Anti-Inhibitory Molecules for Spinal Cord Injury

Acta Biomater, 2015 · DOI: 10.1016/j.actbio.2015.09.018 · Published: December 1, 2015

Spinal Cord Injury Regenerative Medicine Biomedical

Simple Explanation

This study investigates a combination therapy for spinal cord injury (SCI) using stem cell-derived neural progenitors (pMNs) and anti-inhibitory molecules (AIMS) delivered via fibrin scaffolds. The goal is to overcome the limitations of single therapies by addressing multiple obstacles to recovery simultaneously. The fibrin scaffolds were designed to provide sustained delivery of neurotrophic factors and anti-inhibitory molecules, while also encapsulating embryonic stem cell-derived progenitor motor neurons (pMNs). The in vitro studies confirmed that pMN viability was not affected by the sustained delivery systems. In a rat model of sub-acute SCI, the transplantation of pMNs alone led to cell survival, differentiation into neuronal cell types, axonal extension, and integration into host tissue. However, combining pMNs with sustained delivery of anti-inhibitory molecules resulted in reduced cell survival and increased macrophage infiltration.

Study Duration

2 weeks

Participants

Female Long-Evans rats, 250–275 g

Evidence Level

Not specified

Key Findings

1
pMN survival was not affected by the combination therapy with AIMS in vitro.
2
Fibrin scaffolds with AIMS decreased pMN survival in a sub-acute SCI model in vivo.
3
The combination of pMNs and/or GFs with AIMS did not decrease CSPGs compared to GFs alone or pMNs+GFs.

Research Summary

The study combined cell transplantation, neurotrophic factor delivery, and anti-inhibitory molecule delivery in fibrin scaffolds to treat spinal cord injury (SCI). The aim was to improve recovery by repopulating the cystic cavity and limiting inhibitory effects within the glial scar. Transplanting pMNs with sustained delivery of neurotrophic factors confirmed previous findings of cell survival and differentiation. However, combining AIMS with pMNs did not produce an additive effect; it decreased cell survival and failed to reduce CSPGs. The combination of AIMS and pMNs led to decreased cell survival, possibly due to an enhanced inflammatory response. Surviving cells could differentiate into neural cell fates and extend axons, but the overall negative impact on cell survival limited the efficacy of the cell transplants.

Practical Implications

Refinement of AIMS

Future research should focus on improving AIMS to decrease their effect on pMN survival and limit their impact on the inflammatory response.

Long-term Studies

Studying the long-term effects of combination therapies on functional recovery is crucial for understanding transplant incorporation into host tissue.

Optimized Delivery

Optimizing the delivery and activity of ChABC to effectively degrade CSPGs is essential for promoting axonal extension and synaptic connections.

Study Limitations

1
The two-week time point may limit the ability to measure significant differences between groups.
2
The increased CSPG deposition may occur after some axonal extension has already occurred.
3
The amount of active ChABC delivered may not have been large enough to elicit significant decreases in CSPGs.

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