iPSC-Derived Biological Pacemaker-From Bench to Bedside

Abstract

Induced pluripotent stem cell (iPSC)-derived biological pacemakers have emerged as an alternative to traditional electronic pacemakers for managing cardiac arrhythmias. While effective, electronic pacemakers face challenges such as device failure, lead complications, and surgical risks, particularly in children. iPSC-derived pacemakers offer a promising solution by mimicking the sinoatrial node's natural pacemaking function, providing a more physiological approach to rhythm control. These cells can differentiate into cardiomyocytes capable of autonomous electrical activity, integrating into heart tissue. However, challenges such as achieving cellular maturity, long-term functionality, and immune response remain significant barriers to clinical translation. Future research should focus on refining gene-editing techniques, optimizing differentiation, and developing scalable production processes to enhance the safety and effectiveness of these biological pacemakers. With further advancements, iPSC-derived pacemakers could offer a patient-specific, durable alternative for cardiac rhythm management. This review discusses key advancements in differentiation protocols and preclinical studies, demonstrating their potential in treating dysrhythmias.

Keywords: HCN channels; induced pluripotent stem cell; sinoatrial node.

Figure 1

iPSC-derived biological pacemaker and its clinical application.

Figure 2

SAN coupled-clock system: A coupled-clock system consists of a membrane clock and a calcium clock. The membrane clock generates diastolic depolarization through pacemaker currents facilitated by HCN channels and L-type and T-type calcium channels. In parallel, the calcium clock operates in synchrony with the membrane clock, releasing calcium from the sarcoplasmic reticulum (SR) via ryanodine receptors, which activate the sodium–calcium exchanger (NCX) to assist with cell depolarization. Subsequently, calcium is reabsorbed into the SR by SERCA, regulated by phospholamban, to prepare for the next cycle. These clocks function together to create spontaneous depolarizations, and their activity is modulated by the autonomic nervous system through β-adrenergic and muscarinic signals that influence kinases such as PKA and CAMKII. (SR: sarcoplasmic reticulum; NCX: sodium–calcium exchanger; SERCA: sarcoplasmic Ca²⁺-ATPase; PKA: protein kinase A; CAMKII: calmodulin-stimulated protein kinase II).

Figure 3

Strategy to develop pacemaker-like cells: (A) In the re-engineering strategy, virus vectors are utilized to enhance the expression of genes that encode ion channels within cardiomyocytes to induce automaticity. (B) Somatic reprogramming involves the overexpression of the T-box transcription factor TBX18 using virus vectors, transforming adult cardiac chamber cardiomyocytes into induced SAN-like cells. (C) A hybrid method employs cells such as fibroblasts to introduce ion channel genes to generate cardiac automaticity. (D) hESCs or iPSCs are differentiated with pharmacological manipulation to create SAN-like cells and transplanted into specific heart regions to integrate with the surrounding myocardium and establish biological pacing.