Author ORCID Identifier

https://orcid.org/0000-0001-5023-8197

Year of Publication

2021

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department/School/Program

Physiology

First Advisor

Dr. John C. Gensel

Second Advisor

Dr. Kathryn Saatman

Abstract

Spinal cord injury (SCI) is devastating and often leaves the injured individual with persistent dysfunction. The injury persists because humans have poor wound repair and there are no pharmacologic treatments to induce wound repair after SCI. The continued efforts to discover therapeutic targets and develop treatments heavily relies on animal models. The purpose of this project is to develop and study novel mammalian models of SCI to provide insights for the development and effective implementation of SCI therapies.

Lab mice (Mus musculus) are a powerful tool for recapitulating the progression and persistent damage evident in human SCI, but our insight to naturally occurring wound repair because Mus recover poorly from SCI without intervention. Some non-mammalian species and neonates, on the other hand, can be used to identify therapeutic targets because they naturally regenerate spinal tissues. Unfortunately, translating therapeutic targets from non-mammalian or neonatal models to humans is onerous due to their phylogenetic and developmental disparity from adult mammals. One aspect of this project investigates SCI in the African spiny mouse (Acomys cahirinus), a rodent species with robust wound repair. In this investigation, I have identified enhanced functional recovery and tissue integrity in Acomys compared to Mus. Further investigations show that Acomys respond to injury with a dampened inflammatory and fibrotic scarring response, including a decrease in cells with fibroblast markers. The association of dampened inflammatory and fibrotic scarring responses with enhanced tissue integrity and functional recovery in the subacute window after SCI suggests that inhibiting subacute inflammatory and fibroblast proliferation and activation may be an effective strategy for inducing endogenous functional repair in the mammalian spinal cord. Further studies of SCI in Acomys can continue to illuminate the mechanism of endogenous repair in the mammalian spinal cord.

Effectively implementing therapies depends on accurately understanding the nature of the injury, which is doubly important in SCI because it is inherently heterogeneous. Several studies have suggested that the specific biomechanics of the initial SCI can influence overall outcomes of injury and perhaps even the secondary cellular responses to injury. While we have a broad understanding of these influences in SCI, the particular aspects of injury biomechanics and secondary injury responses have not been thoroughly investigated. In another aspect of my project, I investigation how subsequent compression affects the overall outcomes and inflammatory responses in Mus contusion SCI. This study identifies a unique injury progression specific to compression injuries, manifesting as a proportional increase in pathological macrophages, exacerbated tissue pathology, and a premature cessation of functional recovery in the subacute recovery window. Insights from this study provide strong rationale for the effectiveness of immunomodulatory therapies, particularly in SCI that involves sustained compression.

The novel mammalian models of SCI developed in this project point toward a strong influence of cellular dynamics in the subacute window after compression SCI. Insights across these studies can be applied to advance therapeutic development and to inform the effective application of these therapies.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2021.341

Funding Information

This study was supported by the National Institutes of Health through 5T32 NS077889 from 2018-2019 and through F31 NS110264-O1A1 from 2019-2020.

Available for download on Friday, August 12, 2022

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