Clinical translation of stem cell therapies for heart disease requires electrical integration of transplanted cardiomyocytes. Generation of electrically matured human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) is critical for electrical integration. Here, we found that hiPSC-derived endothelial cells (hiPSC-ECs) promoted the expression of selected maturation markers in hiPSC-CMs. Using tissue-embedded stretchable mesh nanoelectronics, we achieved a long-term stable map of human three-dimensional (3D) cardiac microtissue electrical activity. The results revealed that hiPSC-ECs accelerated the electrical maturation of hiPSC-CMs in 3D cardiac microtissues. Machine learning–based pseudotime trajectory inference of cardiomyocyte electrical signals further revealed the electrical phenotypic transition path during development. Guided by the electrical recording data, single-cell RNA sequencing identified that hiPSC-ECs promoted cardiomyocyte subpopulations with a more mature phenotype, and multiple ligand-receptor interactions were up-regulated between hiPSC-ECs and hiPSC-CMs, revealing a coordinated multifactorial mechanism of hiPSC-CM electrical maturation. Collectively, these findings show that hiPSC-ECs drive hiPSC-CM electrical maturation via multiple intercellular pathways.
Induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs) capture patient‐specific genotype–phenotype relationships, as well as cell‐to‐cell variability of cardiac electrical activity Computational modelling and simulation provide a high throughput approach to reconcile multiple datasets describing physiological variability, and also identify vulnerable parameter regimes We have developed a whole‐cell model of iPSC‐CMs, composed of single exponential voltage‐dependent gating variable rate constants, parameterized to fit experimental iPSC‐CM outputs We have utilized experimental data across multiple laboratories to model experimental variability and investigate subcellular phenotypic mechanisms in iPSC‐CMs This framework links molecular mechanisms to cellular‐level outputs by revealing unique subsets of model parameters linked to known iPSC‐CM phenotypes
There is a profound need to develop a strategy for predicting patient‐to‐patient vulnerability in the emergence of cardiac arrhythmia. A promising
- NSF-PAR ID:
- 10458201
- Publisher / Repository:
- Wiley-Blackwell
- Date Published:
- Journal Name:
- The Journal of Physiology
- Volume:
- 597
- Issue:
- 17
- ISSN:
- 0022-3751
- Page Range / eLocation ID:
- p. 4533-4564
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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