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There is now a CONTENT FREEZE for Mercury while we switch to a new platform. It began on Friday, March 10 at 6pm and will end on Wednesday, March 15 at noon. No new content can be created during this time, but all material in the system as of the beginning of the freeze will be migrated to the new platform, including users and groups. Functionally the new site is identical to the old one. webteam@gatech.edu
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David Trac
Biomedical Engineering PhD Thesis Defense
Date: Tuesday, January 22nd, 2019
Time: 10:00am - 12:00pm
Location: Room E260, Health Sciences Research Building (HSRB), Emory University
Advisor:
Michael E. Davis, PhD
Committee Members:
Luke Brewster, MD, PhD
Steven Goudy, MD
Joshua T. Maxwell, PhD
Chunhui Xu, PhD
Title: Improving the Therapeutic Functionality of Child Cardiac Progenitor Cells by Spherical Aggregation
Abstract:
Congenital heart disease can lead to life-threatening right ventricular heart failure (RVHF). Advances in surgical management have led to improved survival of patients born with CHD, creating a new population of older CHD patients at significant risk for RVHF. New regenerative medicine and stem cell-based therapies for the treatment of RVHF are promising. But older CPCs, starting as early as 1 year old, have a reduced ability to repair the heart. The goal of this thesis was to determine whether the aggregation of child (1 to 5-year-old) CPCs into scaffold-free spheres could improve CPC reparative effects. We hypothesized that the close mechanical contact between CPCs within a 3-dimensional structure would enhance Notch signaling, a known regulator of CPC fate.In our studies, we show that aggregating child (≥1-year-old) CPCs into spheroids activates Notch signaling and improves endothelial differentiation. We also show that aggregated child CPCs have an improved ability to repair the RV in a RVHF rat model, likely by stimulating angiogenesis and reducing right ventricular hypertrophy and fibrosis. While aggregated child CPCs contributed some endothelial cells via direct differentiation, exosomes released by CPCs seemed to play a much larger role in RV repair. To further evaluate CPC exosome function, we used partial least squares regression to model CPC exosome miRNA content and mapped the signals to putative biological responses from in vitro experiments. Using an unbiased approach, we reduced the model and successfully made a priori predictions of in vitro responses from additional biological cues. Moreover, we demonstrated the ability of the in vitro model to perform predictions on biological responses to exosome treatment in vivo. By modelling exosome function, we can identify optimal CPC donor profiles with strong predicted in vivo response and use these predictions to develop better, patient-specific therapeutics. While a Phase I study of CPC therapy in children with hypoplastic left heart syndrome is underway (NCT03406884), there is a potential for rapid translation of this therapy to the clinic, especially in patients that do not respond to traditional cell therapy.
