PhD Dissertation - Daniel Levy

Thursday, February 29, 2024
12:30 p.m.
AJC 3104 (3rd Floor conference room)
Rachel Chang
301 405 8268
rachel53@umd.edu

Title: Investigation and development of induced pluripotent stem cell derived extracellular vesicle-based therapeutics

 

Committee members:

Dr. Steve Jay, Chair

Dr. Gregg Duncan

Dr. Catherine Kuo

Dr. Erika Moore

Dr. Zhengguo Xiao, Dean's Representative

 

Abstract:

Due to their complex, multicomponent nature, extracellular vesicle (EV)-based therapeutics have arisen as an intriguing option for treatment of complex diseases that require the simultaneous modulation of distinct pathways. Due to their inherent regenerative properties, mesenchymal stem cell (MSC)-derived EVs have been the most heavily investigated and utilized in clinical trials for diseases including acute respiratory distress syndrome, wound healing and many more. While pre-clinical studies have demonstrated promise for such EV-based therapeutics, source cell limitations act as a hurdle to the widespread clinical translation of MSC EV therapies. MSCs and other cells reported to produce therapeutic EVs (cardiac progenitor cells, neural stem cells, etc.) have limited expansion capabilities ex vivo before cellular senescence, therefore limiting the amount of therapeutic EVs that can be produced by a single cell line. Due to these limited expansion capabilities, alternative, self-renewing therapeutic EV source cells are needed. One such source cell is induced pluripotent stem cells (iPSCs), which possess self-renewing capabilities. However, the baseline bioactivity of iPSC EVs have yet to be rigorously evaluated; in our work, we report for the first time that iPSC EVs possess robust anti-inflammatory properties in addition to confirming previous reports of their ability to promote vascularization in a murine diabetic wound healing model. Building off these baseline results, we sought to augment iPSC EV potency by utilizing genetic approaches to load of bioactive RNAs including microRNA (miRNA) and long non-coding RNA (lncRNA) into iPSC EVs. In our miRNA loading studies, we effectively demonstrate that the natural biogenesis pathways of miRNA can be probed to facilitate export of bioactive miRNAs to secreted EVs, thereby enhancing their anti-inflammatory bioactivity. Lastly, we utilize a genetic engineering approach to enhance active sorting of lncRNAs into secreted EVs and test their therapeutic potential in a murine colitis model. The work described in this dissertation provides a foundation towards the clinical translation of iPSC EV-based therapeutics by benchmarking them against more established therapeutic EV sources (iPSC-derived MSC EVs) and developing strategies to enhance their bioactivity via RNA cargo loading.


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