The Fates of Mesenchymal Stem Cells and Perivascular Cells in Eye Disease
Ray, Howard, Biomedical Engineering - School of Engineering and Applied Science, University of Virginia
Yates, Paul, UPG-MD-OPTH Ophthalmology, University of Virginia
Degenerative eye diseases, such as diabetic retinopathy, threaten the vision of millions of people across the world. Current treatment strategies, such as small molecule therapy and laser photocoagulation, attempt to slow the breakdown of diseased tissue, but fail to regenerate damaged ocular tissue. Furthermore, these clinical interventions are often destructive, leaving patients with few safe and viable treatment options. The use of adult mesenchymal stem cells (MSCs) in the treatment of ocular diseases could be a novel approach to addressing these issues. Mesenchymal stem cells are regarded as multipotent, pro-angiogenic, and immunomodulatory cells that, when locally delivered, could potentially regenerate healthy ocular tissue through multiple modes of action. However, questions remain about the origin and cellular function of MSCs due to discrepancies across studies, which make it difficult to predict therapeutic efficacy. Also, recent delivery of MSCs into the eyes of human patients has led to detrimental side-effects, including vision loss, further demonstrating a poor understanding of the innate behavior of MSCs. To fully appreciate a MSC-based therapy for ocular diseases, we need a refined understanding of both MSC in vitro and in vivo cell behavior. Thus, the overall goal of this work was to (i) investigate the cell fates of MSCs once delivered into eye diseases, and (ii) determine if these fates also correspond with those found in the endogenous, perivascular MSC population that is activated in the wound healing of ocular disease. Throughout this thesis, we develop and apply novel statistical models, transgenic mice, and preclinical eye injury models to ascertain MSC bioactivity and cellular differentiation into specific cell types. The work presented in this thesis highlights: (i) determining the proclivity of adipose-derived mesenchymal stem cells to adopt a perivascular support position in ischemic retinal neovascularization, (ii) evaluating adipose vascular smooth muscle cells and pericytes as a newly defined source of mesenchymal stem cells that improve retinal vascular growth, while (iii) also identifying retinal vascular smooth muscle cells and pericytes as a contributor to retinal fibrosis, and (iv) demonstrating mesenchymal stem cells as a potential cell source to replace damaged corneal endothelial cells in cornea injury. Taken together, this work provides insight on the complexity of MSCs and promotes the strategic engineering of these cells to provide both a safe and effective therapy for eye diseases.
PHD (Doctor of Philosophy)
mesenchymal stem cells, diabetic retinopathy, pericytes, vascular smooth muscle cells, fibrosis, cornea endothelium
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