Human iPSC-derived cardiac microphysiological system with sympathetic innervation
Description: The proposed research seeks to unravel the nuanced interplay between sympathetic neurons (SNs) and cardiac electrophysiology (EP) within arrhythmogenic cardiomyopathy (ACM) contexts using a microphysiological system (MPS). While existing studies highlight SNs' role in arrhythmogenesis, a distinct gap remains in comprehending the exact influence of SNs on cardiac EP during disease states. This necessitates an advanced cardiac model that reflects the intricate role of SNs during cardiac development in vivo, where SN innervation augments the functional electrical synchrony in cardiomyocytes through the regulation of gap junction protein expression. The study is partitioned into two main aims. Aim one intends to understand the role of sympathetic innervation on electrical interactions within cardiac organoids derived from human pluripotent stem cells (hiPSCs-CO). The underlying hypothesis posits that SN innervation amplifies functional electrical connectivity in cardiomyocytes. To test this, the study employs organoids paired with optogenetically modified hiPSCs-SNs, and the cardiac EP indicators are monitored via 3D MEA. The primary metrics include the conduction vector (CV) and beating period (BP), comparing a sympathetic innervated group against a non-innervated one, with a positive control group administered with a Rotigaptide, a gap junction protein agonist. Aim two investigates the potential disruptions of cardiac EP caused by specifications of ACM-derived hiPSC-SNs. It is hypothesized that ACM-specific-hiPSC-SNs induce EP aberrations in cardiac organoids derived from either isogenic-gene-corrected or healthy iPSCs. Given ACM's association with desmosomal mutations in cardiomyocytes and the presence of desmosome-like structures in diverse mammalian nervous systems, the study will juxtapose DSG2 mutation-afflicted ACM-hiPSCs with their gene-corrected counterparts, seeking to discern the impact of ACM-hiPSC-SNs on EP. In essence, this research will provide a mechanistic understanding of SN specifications and their impact on cardiac EP that could unveil critical elements for novel therapeutic avenues aimed at ACM.
Funder: American Heart Association
Amount: $67,390
Funding type: training
Funder scheme: Predoctoral Fellowship
Start date: 2024-01-01
End date: 2025-04-14
Investigators: Byunggik Kim, Byunggik Kim
Institution: Johns Hopkins University School of Medicine
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Funded outputs count: 3
Funder award ID: 24PRE1242036
OpenAlex ID: G3516826013