Title:
Engineering cardiac biological pacemaker tissues to dissect source-sink mismatch in the heart

dc.contributor.advisor Cho, Hee Cheol
dc.contributor.advisor Choi, Bum-Rak
dc.contributor.advisor Fenton, Flavio H.
dc.contributor.advisor Levit, Rebecca D.
dc.contributor.advisor Xu, Chunhui
dc.contributor.author Grijalva, Sandra
dc.contributor.department Biomedical Engineering (Joint GT/Emory Department)
dc.date.accessioned 2021-01-11T17:05:51Z
dc.date.available 2021-01-11T17:05:51Z
dc.date.created 2019-12
dc.date.issued 2019-10-01
dc.date.submitted December 2019
dc.date.updated 2021-01-11T17:05:51Z
dc.description.abstract Each and every heartbeat is initiated from, and driven by, the pacemaker cells in the sinoatrial node (SAN). More than 10 billion cardiac myocytes and non-myocytes make up the heart, but remarkably, it takes only a few thousand pacemaker (<10,000) cells to pace-and-drive the entire heart. Although we have a general understanding of how individual cardiac pacemaker cells beat automatically, there is a lack of understanding in how a few pacemaker cells can drive the beating of the entire heart. This problem, known as a “source-sink mismatch”, is a fundamental concept that has been difficult to study due to it being painfully low-throughput to study these pacemaker cells. Recently, we have demonstrated conversion of ventricular cardiomyocytes to induced pacemaker cells (iPMs) by singular expression of TBX18. In this thesis we develop a cardiac pacemaker tissue model of the SAN by exploiting the de novo iPMs. We have examined four design principles of the native SAN, i) number of iPMs required to pace a given number of neighboring ventricular myocytes, ii) influence of autonomic nervous system on pacemaking, iii) role of non-myocyte population in pacemaking, and iv) the need for exit pathways. Our 3D model uses patterned cardiac spheroids, by 3D –printed silicone mold stenciling techniques. We have created a population of iPMs co-cultured with ventricular cardiomyocytes. The major readout is fast, high-resolution optical mapping using a calcium dye. This work demonstrates the ability to reverse-engineer the SAN (eSAN) to i) provide the mechanistic insights on generating sinus rhythm at the tissue level, ii) exploit the insights gained to better engineer biological pacemakers.
dc.description.degree Ph.D.
dc.format.mimetype application/pdf
dc.identifier.uri http://hdl.handle.net/1853/64030
dc.language.iso en_US
dc.publisher Georgia Institute of Technology
dc.subject biological pacemaker, sinoatrial node tissue model
dc.title Engineering cardiac biological pacemaker tissues to dissect source-sink mismatch in the heart
dc.type Text
dc.type.genre Dissertation
dspace.entity.type Publication
local.contributor.advisor Fenton, Flavio H.
local.contributor.advisor Cho, Hee Cheol
local.contributor.corporatename Wallace H. Coulter Department of Biomedical Engineering
local.contributor.corporatename College of Engineering
relation.isAdvisorOfPublication 3e5085f8-dda4-423c-bdea-0739e3566037
relation.isAdvisorOfPublication 4a5f8a3b-8962-432f-add2-b4447d5fe8c1
relation.isOrgUnitOfPublication da59be3c-3d0a-41da-91b9-ebe2ecc83b66
relation.isOrgUnitOfPublication 7c022d60-21d5-497c-b552-95e489a06569
thesis.degree.level Doctoral
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