Key result
Adding epicardial cells to pacemaker organoids boosts SHOX2+ cell yield to 20% vs 16% in controls.
Absolute Event Rate: 20% vs 16%
Integrating epicardial cells into human iPSC-derived pacemaker organoids better recapitulates the cellular heterogeneity and spatial patterning of the native sinoatrial node.
Introduction: The sinoatrial node (SAN) is heterogeneous and comprises pacemaker cells (PCs), atrial cardiomyocytes (ACMs), transitional zone (TZ) cells, and stromal cells. Epicardial cells (Epics) serve as a major source of nonmyocytes, contributing to SAN development and function. To better understand the patterning of Epics, we modeled the SAN with human iPSC-derived SAN-like organoids (SANOs). Hypothesis: Integrating pacemaker organoids with Epics (Epi-SANOs) better recapitulate the cellular heterogeneity of the SAN. Approach: WTC11 hiPSCs were differentiated to Epics or to ACMs and PCs. Control SANOs were generated from hiPSC-derived ACMs and PCs at d15. Epi-SANOs are generated by combining ACMs and PCs with Epics at a 1:1 ratio at d15. Single-cell RNA sequencing was performed at d15 prior to organoid formation and at d20, d25, and d30 (5, 10, and 15 days after organoid formation). Results: Atrial differentiation led to 75% ACMs, 11% PCs, 1% ventricular cardiomyocytes, and 13% nonmyocytes at d15. Epicardial differentiation was highly efficient with 99% WT1+/TBX18+ Epics at d15. As anticipated, fibroblast (FB) population was higher in Epi-SANOs than in control SANOs from d20 to d30. Surprisingly, the SHOX2+ PC content was higher in Epi-SANOs (20%) than in control SANOs (16%) at d30, despite that half of all cells were Epics in Epi-SANOs at d15. Native SAN is delineated into the head, tail, and TZ regions. When compared to the native SAN single-cell transcriptome, most PCs in control SANOs were mapped to TZ cells. In contrast, Epi-SANOs’ PCs were identified as the SAN head and tail cells. Trajectory analysis indicated that Epics gave rise to PCs as well as stromal cells via epithelial-mesenchymal transition (EMT). Consistent with the transition of Epics to PCs and FBs, Epi-SANOs exhibited stronger cell-cell interactions among PCs, FBs, and Epics than control SANOs, facilitated by the recruitment of AGRN and NRG signaling, key EMT mediators. Conclusion: Epics may directly contribute to PCs in the developing SAN, particularly in its head and tail. Our data support further investigation into the functional role of Epics in sinus rhythm by modeling the SAN with pacemaker organoids.
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Koakutsu et al. (2025) studied this question. Integration of pacemaker organoids with epicardial cells (Epi-SANOs) vs. Control SANOs was evaluated on SHOX2+ pacemaker cell content at day 30. Integrating pacemaker organoids with epicardial cells increased SHOX2+ pacemaker cell content to 20% versus 16% in controls, better recapitulating native sinoatrial node heterogeneity.
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