| First Author | Pocock MW | Year | 2025 |
| Journal | Nat Cardiovasc Res | Volume | 4 |
| Issue | 7 | Pages | 821-840 |
| PubMed ID | 40562874 | Mgi Jnum | J:392750 |
| Mgi Id | MGI:8289250 | Doi | 10.1038/s44161-025-00669-3 |
| Citation | Pocock MW, et al. (2025) Maturation of human cardiac organoids enables complex disease modeling and drug discovery. Nat Cardiovasc Res 4(7):821-840 |
| abstractText | Maturation of human pluripotent stem (hPS) cell-derived cardiomyocytes is critical for their use as a model system. Here we mimic human heart maturation pathways in the setting of hPS cell-derived cardiac organoids (hCOs). Specifically, transient activation of 5' AMP-activated protein kinase and estrogen-related receptor enhanced cardiomyocyte maturation, inducing expression of mature sarcomeric and oxidative phosphorylation proteins, and increasing metabolic capacity. hCOs generated using the directed maturation protocol (DM-hCOs) recapitulate cardiac drug responses and, when derived from calsequestrin 2 (CASQ2) and ryanodine receptor 2 (RYR2) mutant hPS cells exhibit a pro-arrhythmia phenotype. These DM-hCOs also comprise multiple cell types, which we characterize and benchmark to the human heart. Modeling of cardiomyopathy caused by a desmoplakin (DSP) mutation resulted in fibrosis and cardiac dysfunction and led to identifying the bromodomain and extra-terminal inhibitor INCB054329 as a drug mitigating the desmoplakin-related functional defect. These findings establish DM-hCOs as a versatile platform for applications in cardiac biology, disease and drug screening. |
