Access Type

Open Access Dissertation

Date of Award

January 2020

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Biomedical Engineering

First Advisor

Juri G. Gelovani

Abstract

The Center for Disease Control’s National Center for Health Statistics data for mortality from diseases of the heart show the age-adjusted death rate has fallen from almost 600 deaths in the 1950s to just over 190 deaths per 100,000 U.S. residents today. With the recognized limitations of pharmacotherapy of myocardial infarction (MI), cell-based therapies have been undergoing rapid development and clinical testing. However, there is still no consensus about cell types, delivery routes, dosing and treatment schedules and pretreatment conditioning of cells prior to administration. Furthermore, a fundamental question remains unanswered about the reasons for the poor capacity for myocardial tissue regeneration in humans (mammals in general) as compared to robust myocardial regeneration in lower vertebrates (i.e., axolotl [Ambystoma mexicanum] and zebrafish [Danio rerio]). This lack in understanding the mechanisms behind the cell-cycle of cardiomyocytes and or cardiac progenitor cells, both during times of normal homeostasis and after pathologic insults, is central to the lack of progress in stimulating the regeneration of cardiac tissue. To understand the differences in cardiac tissue response after an MI, developing a true model of ischemia-reperfusion injury in an animal known for epimorphic regeneration in the adult life stage will help reframe the direction of research in the field of tissue engineering and regenerative medicine in the field of cardiology. To understand how the axolotl will respond to an MI, this research focuses on two Specific Aims:

Specific Aim 1: Develop a cardiac injury model in the axolotl that mimics the pathophysiology of a myocardial infarction in the mammalian heart. Cardiac injury models used to study heart regeneration in lower vertebrates known for robust healing responses have used novel approaches to induce major cardiomyocyte death. However, these novel injury models do not recapitulate the cellular signaling mechanisms present during ischemia and ischemia-reperfusion injuries. Thus, to study the epimorphic regeneration of heart tissue in axolotls, a novel model of inducing ischemia needs to be developed.

Specific Aim 2: Determine the spatiotemporal progression of axolotl cardiac tissue histopathology over time. Once a novel cardiac injury model produces the expected pathophysiological tissue response, chronic follow-up of surviving animals will help develop the spatiotemporal response to an MI. Data on functional recovery will require the development of regular, non-invasive techniques for monitoring heart function. After long-term recovery, appropriate harvesting of heart samples for histologic study is required to determine if the axolotl can completely regenerate cardiac injuries after an MI.

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