Engineered Cardiac Pacemaker Nodes Created by TBX18 Gene Transfer Overcome Source-Sink Mismatch

Area of Science:

• Cardiology
• Biomedical Engineering
• Stem Cell Biology

Background:

• The sinoatrial node (SAN) initiates heartbeats using rare pacemaker cells, but how they activate the larger heart muscle (myocardium) is unclear.
• The scarcity of native SAN pacemaker cells limits direct study of the 'source-sink mismatch' phenomenon in live cardiac tissue.
• Understanding SAN function is crucial for developing effective biological pacemakers.

Purpose of the Study:

• To engineer a functional model of the sinoatrial node (SAN) using induced pacemaker cells.
• To investigate the 'source-sink mismatch' principle in cardiac pacing.
• To establish a platform for engineering biological pacemakers for therapeutic applications.

Main Methods:

• Somatic gene transfer was used to induce TBX18 expression in cells, creating 3D cardiac pacemaker spheroids (sphTBX18).
• Engineered spheroids were co-cultured with cardiomyocytes to assess pacing and driving capabilities in vitro.
• Electrical coupling and physical separation were manipulated to mimic SAN design principles.

Main Results:

• TBX18 induced pacemaker spheroids (sphTBX18) demonstrated autonomous pacing and the ability to drive contraction of neighboring myocardium.
• Reduced electrical coupling and physical separation were identified as critical for effective pacing, recapitulating native SAN function.
• β-Adrenergic stimulation and electrical uncoupling enhanced the pacing and driving capacity of the engineered spheroids.

Conclusions:

• Engineered TBX18 spheroids provide a novel platform for studying SAN design principles and the source-sink relationship.
• This model successfully recapitulates key features of the native SAN, offering insights into cardiac electrophysiology.
• The study paves the way for improved engineering of biological pacemakers for clinical translation.