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Jay McKinney
BME PhD Thesis Defense Presentation
Date: Thursday, July 29, 2021
Time: 11:00 AM
Location (In-Person): Children's Healthcare of Atlanta Seminar Room – EBB Krone
Location (Remote): https://bluejeans.com/855153310/6250
Committee Members:
Nick Willett, PhD (Advisor, Emory University)
Levi Wood, PhD (Co-advisor, Georgia Institute of Technology)
Rebecca Levit, MD (Emory University)
Peng Qiu, PhD (Georgia Institute of Technology)
Melissa Kinney, PhD (University of Wisconsin – Madison)
Ron June, PhD (Montana State University)
Title: Identification of critical quality attributes of human Mesenchymal Stromal Cells as Osteoarthritis therapeutics
Abstract: Osteoarthritis (OA) is the most prevalent chronic disease of the joints and leads to degeneration of articular cartilage surfaces. While physical therapy and weight loss have demonstrated improved functionality in patients with OA, current drugs are limited to providing symptomatic relief. Thus, there is a notable need for the development of a disease modifying drug for OA. Mesenchymal stromal cells (MSC) offer a promising treatment strategy for OA due to the regenerative and immunomodulatory capacity these cells possess. MSC therapeutics for cartilage regeneration have been widely studied, in both the pre-clinical and clinical environment. While these pre-clinical studies have shown improved cartilage repair with MSC treatment, effective translation into the clinic has been limited by numerous factors ranging from high variability and heterogeneity of MSCs to poor understanding of critical quality and potency attributes. Prior research has demonstrated that therapeutic potency varies in MSCs isolated from different human donors for treatment of other disease states; however, this donor heterogeneity remains understudied for MSCs as OA therapeutics. This absence of identified critical factors motivates the overall objective of this thesis to identify critical quality attributes (CQAs) of human MSCs (hMSCs) that are related to the therapeutic efficacy of hMSCs for treatment of OA. The overarching hypothesis is that a profile of hMSC secreted cytokines, ribonucleic acid (RNA) transcripts, and intracellular signaling phospho-proteins can be identified that relate to the therapeutic efficacy of hMSCs for treatment of OA. To address this hypothesis, we utilized clinically relevant cellular therapeutics in hMSCs to establish the efficacy of the paracrine signaling properties of these cells as the major therapeutic mechanism of action in OA, relative to direct cell engraftment. We then assessed hMSC donor heterogeneity to identify secreted cytokines, RNA transcripts, and intracellular signaling phospho-proteins expressed by these cells that relate to the therapeutic efficacy of hMSCs for treatment of OA. Finally, the knowledge of key secreted cytokines identified were used to determine the underlying intracellular signaling pathways modulating hMSC therapeutic paracrine signaling in OA. Overall, this thesis increases the fundamental knowledge of hMSCs as therapeutics for use in OA and provides a novel pharmacological intervention strategy that has clinical translation potential.
