Title:
Improving the therapeutic functionality of child cardiac progenitor cells by spherical aggregation

dc.contributor.advisor Davis, Michael E.
dc.contributor.author Trac, David
dc.contributor.committeeMember Brewster, Luke P.
dc.contributor.committeeMember Goudy, Steven L.
dc.contributor.committeeMember Maxwell, Joshua T.
dc.contributor.committeeMember Xu, Chunhui
dc.contributor.department Biomedical Engineering (Joint GT/Emory Department)
dc.date.accessioned 2020-05-20T16:55:58Z
dc.date.available 2020-05-20T16:55:58Z
dc.date.created 2019-05
dc.date.issued 2019-03-25
dc.date.submitted May 2019
dc.date.updated 2020-05-20T16:55:58Z
dc.description.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.
dc.description.degree Ph.D.
dc.format.mimetype application/pdf
dc.identifier.uri http://hdl.handle.net/1853/62652
dc.language.iso en_US
dc.publisher Georgia Institute of Technology
dc.subject Exosome
dc.subject Progenitor cell
dc.subject Congenital heart disease
dc.subject Partial least squares regression
dc.subject Systems biology
dc.subject Right ventricular heart failure
dc.title Improving the therapeutic functionality of child cardiac progenitor cells by spherical aggregation
dc.type Text
dc.type.genre Dissertation
dspace.entity.type Publication
local.contributor.advisor Davis, Michael E.
local.contributor.corporatename Wallace H. Coulter Department of Biomedical Engineering
local.contributor.corporatename College of Engineering
relation.isAdvisorOfPublication fab83195-e1b0-4b5e-933d-5b97a14b945a
relation.isOrgUnitOfPublication da59be3c-3d0a-41da-91b9-ebe2ecc83b66
relation.isOrgUnitOfPublication 7c022d60-21d5-497c-b552-95e489a06569
thesis.degree.level Doctoral
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