Induced Pacemaker Spheroids As A Model To Reverse-Engineer The Native Sinoatrial Node

Background: The sinoatrial node (SAN) has intricate architecture, which facilitates the spontaneous action potentials generated from the SAN to pace and drive the neighboring myocardium. We sought to create an engineered SAN that recapitulates the native SAN’s ability to overcome source-sink mismatch. We hypothesized spheroids consisting of induced pacemaker cells (iPM) can pace and drive surrounding quiescent myocardium. Methods: The iPMs were created by singular expression of a transcription factor, TBX18, to neonatal rat ventricular myocytes as we have previously demonstrated. The iPM or GFP-spheroids (control) were created by subjecting the NRVMs to the AggreWell™ plate at 1000 cells/well, and cultured for three days in suspension. Spheroids consisted of 90% NRVM and 10% cardiac fibroblast. Results: iPM-spheroids demonstrated spontaneous pacing at 145±26 bpm compared to 66±1 bpm (p=6.5770E-9) of control, GFP-spheroids. When one iPM-spheroid was surrounded by a monolayer of quiescent NRVMs (iPM:NRVM=1:...