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