Dissertations and Theses
Date of Award
tendinopathy, exosomes, miRNA, miR-221-5p
Tendinopathy, characterized by degeneration and chronic inflammation, is a significant clinical burden. Current treatments focus on symptom management but do not sufficiently address its underlying pathology; however, stem cell-based approaches aimed at repairing diseased tissues may overcome this limitation. Therapeutic effects of stem cells may be due in part to paracrine actions, including some mediated by exosomes – extracellular vesicles secreted by cells that play a role in cell communication. MicroRNA (miRNA), small non-coding RNA carried by exosomes, are likely responsible for many exosome effects. Exosomes and miRNA therapies show promise in treating diseases such as cancer and arthritis, but there is no exosome or miRNA product yet available for clinical use, and development of new treatments face many translational hurdles.
Previous studies in our lab reported that Ex3D, exosomes secreted by tendon stem/progenitor cells (TSPCs) grown on a specialized scaffold, showed efficacy in tendinopathy. However, TSPCs are not feasible for clinical use due to donor site morbidity. Therefore, in the first major part of this thesis, the first objective was to test the hypothesis that MSCs derived from a readily available source – adipose tissue – would demonstrate efficacy in treating an animal model of tendinopathy. The second objective was to advance Ex3D toward FDA compliance, beginning with developing the scaffold.
We found that adipose-derived stem cells (ADSCs) produced Ex3D that mitigated major histopathological features of tendinopathy as assessed by modified Movin score. The effects on ultimate load and modulus of the tendon tissue, and pain-related behavior (plantar hypersensitivity of the animals) were also examined. This study established the feasibility of using ADSC-derived Ex3D as a therapy for tendinopathy. Furthermore, the new design and prototype of a machine-made scaffold for consistency and scalability is presented.
In the search for the mechanism of Ex3D’s therapeutic effects, our lab previously identified miRNA (miR)-221-5p as a molecular component that shared targets with Ex3D in vitro. Thus, in the second major part of this thesis, the first objective was to test the hypothesis that miR-221-5p exerts a therapeutic effect in an animal model of tendinopathy. The second objective was to begin the process of engineering a miR-221-5p drug product by examining chemical modifications designed to improve its cellular delivery.
We found that miR-221-5p mitigated histological features of tendinopathy and may improve pain behaviors compared to placebo, showing potential to be developed for future clinical use. Furthermore, modifications to the backbone and addition of cholesterol to miR-221-5p may enhance its uptake and stability in vitro and in vivo, while preserving its intended biological activity.
Together, this thesis presents two innovative approaches for tendinopathy, with evidence of therapeutic efficacy for both ADSC-derived Ex3D and miR-221-5p. In consideration of translational hurdles facing the development of these promising therapeutics, this thesis takes the first steps toward compliance with FDA regulations. As there is currently no FDA-approved treatment using exosomes or miRNA, developing either strategy would be highly innovative and significant for any disease including tendinopathy.
Wang Ilaltdinov, Angela, "Exosome- and Microrna-based Therapeutic Approach for Tendinopathy" (2022). CUNY Academic Works.
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