Date of Award
Winter 2-23-2024
Embargo Period
3-1-2029
Document Type
Dissertation - MUSC Only
Degree Name
Doctor of Philosophy (PhD)
Department
Molecular and Cellular Biochemistry and Pathobiology
Additional Department
Regenerative Medicine and Cell Biology
College
College of Graduate Studies
Additional College
College of Medicine
First Advisor
Ying Mei
Second Advisor
Donald Menick
Third Advisor
Jeffrey Jones
Fourth Advisor
Daniel Judge
Fifth Advisor
R. Amanda LaRue
Sixth Advisor
Hai Yao
Abstract
In the context of excessive inflammation, cardiovascular complications such as arrhythmias, functional deficits, vascular dysfunction and fibrosis have all been reported. However, characterizing these pathologies has remained challenging given the complex interplay of cytokines, immune cells, and the affected tissue. Given the immune system’s known roles in remodeling post ischemic injury, preclinical efforts have been directed towards minimizing excessive fibrosis and immune cell infiltration. To facilitate the healing process and spare the myocardium from pathological remodeling and functional decline, cellular transplantation therapies have been employed, with the intent to either replace damaged cardiomyocytes, or provide a continued source of healing factors to the affected area. However, the inability to produce universally transplantable organoids capable of avoiding immune rejection has limited advances in engineering approaches aimed at regenerating damaged human myocardium.
Animal models and 2D cultures of human cells have been employed to study the effects of cytokines, immune cells, and infectious insults on the heart, but their translational impact has been limited due to interspecies differences, cell-cell communication, and the significance of three-dimensional tissue organization. To this end, our lab has developed human cardiac organoids for disease modeling and regenerative medicine. Given their ability to recapitulate key hallmarks of myocardial infarctions and drug induced cardiotoxicity and the intrinsic inflammatory properties of the cell types composing the organoids, we hypothesized these human cardiac organoids would provide a suitable platform to model myocardial inflammation. We further hypothesized the vasculature in our cardiac organoids could be leveraged to engineer a vascularized cardiac microtissue. In doing so, the vascular network would address current limitations such as nutrient accessibility and enable the incorporation of immune cells. Finally, we hypothesized that engineering T cells, or the organoid graft to abrogate the host immune response would prolong organoid survival time to increase their therapeutic benefit. In the enclosed dissertation, we illustrate these human cardiac organoids have the potential to model inflammatory conditions such as the acute cardiac injuries induced by COVID-19 Cytokine Storm, to be engineered into a perfusable microtissue, and show that multiple immune engineering approaches have the potential to augment cellular transplantation therapies in the context of cardiac regeneration post myocardial infarction.
Recommended Citation
Arhontoulis, Dimitrios Chrisovalantou, "Next Generation Human Cardiac Organoids: Modeling Inflammatory Diseases and Engineering Their Protection in vivo" (2024). MUSC Theses and Dissertations. 838.
https://medica-musc.researchcommons.org/theses/838
Rights
Copyright is held by the author. All rights reserved.