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

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Grijalva, Sandra
Cho, Hee Cheol
Choi, Bum-Rak
Fenton, Flavio H.
Levit, Rebecca D.
Xu, Chunhui
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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.
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