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Long-term connectivity between spinal cord tissue transplants and the injured phrenic motor network
Dissertation

Long-term connectivity between spinal cord tissue transplants and the injured phrenic motor network

Adam Aaron Hall
Doctor of Philosophy (Ph.D.), Drexel University
Nov 2025
DOI:
https://doi.org/10.17918/00011228
pdf
Hall_Adam_202511.77 MB
PDF Embargoed Access, Embargo ends: 31 Dec 2026

Abstract

Connectivity Phrenic motor networks Respiration Spinal cord injuries Cell Transplantation Electromyography
Impaired breathing is a severe consequence of cervical spinal cord injury (SCI), leading to morbidity and mortality. While some recovery is possible with current treatments, responses are limited. Fetal spinal cord (FSC) transplants enriched in spinal interneurons offer a promising approach to reconstruct neural circuits and promote functional recovery. Previous studies have demonstrated that embryonic (E)13.5 spinal cord transplants differentiate into diverse populations of spinal interneurons and glial cells. These cells establish donor-host connectivity that supports functional recovery one month after transplantation. However, the long-term stability of these connections and their contribution to recovery remain largely unexplored. To investigate the long-term stability and functional impact of FSC transplants in SCI repair, E13.5 FSC tissue was transplanted into adult rats one week after a cervical contusion injury. Donor-host synaptic integration was assessed using transsynaptic pseudorabies virus (PRV) tracing at 1- and 12- months post-transplantation, while phrenic recovery was evaluated via diaphragm electromyography (dEMG). At 1-month post-transplantation, PRV tracing revealed robust donor-host synaptic integration, which paralleled significant restoration of diaphragm activity. Other aspects of transplant composition such as transplant survival and neuronal presence did not correlate with recovery. However, by 12 months, donor-derived connectivity was substantially reduced, accompanied by a marked decline in dEMG activity, indicating a progressive loss of functional recovery. At this stage continued diaphragm activity was correlated with more robust transplant composition including donor-host connectivity and neuronal presence. These findings highlight a critical limitation in the long-term efficacy of FSC transplants and underscore the need for strategies to sustain donor-host connectivity and preserve functional benefits in SCI repair such as activity. Additionally, while FSC transplants provide valuable insights into neural repair, human SpIN-rich organoids derived from induced pluripotent stem cells (iPSCs) offer a complementary, human-relevant model for studying SCI repair. These organoids may help bridge the gap between preclinical animal models and clinical applications, providing translational insights into donor-host interactions and the potential for human-specific therapeutic strategies.

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