Authors
Laura A Sherer, Abigail Nagle, Mary Papadaki, Seby Edassery, Tim McMillen, Dasom Yoo, Lauren D'Amico, Daniel Brambila-Diaz, Lucy Maynard, Mark Qiao, Jennifer Davis, Michael Regnier, Jonathan A Kirk
Published in
Circulation research. Jul 09, 2026. Epub Jul 09, 2026.
Abstract
Understanding the mechanisms of cardiomyocyte development is critical for fulfilling the potential of induced pluripotent stem cell-derived cardiomyocytes. Although myocyte development is known to depend on internal and external mechanical cues, further investigation is required to understand the contributions of different signals and how they are integrated together to generate an adult cardiomyocyte. Here, we address this gap by examining the role of calcium-activated contractility in sarcomere formation and maturation and its influence on the induced pluripotent stem cell-derived cardiomyocyte response to nanopatterns.
We generated induced pluripotent stem cells with homozygous D65A cTnC (cardiac troponin C) substitutions. This engineered cTnC cannot bind to calcium at site II, resulting in tropomyosin blocking strong myosin binding to the thin filament and inhibiting sarcomere contraction. The induced pluripotent stem cells were differentiated into cardiomyocytes and matured in culture over 60 days. Cells were characterized via imaging, metabolic assays, and calcium transient analysis. Proteomes were examined using mass spectrometry throughout differentiation and maturation. We also replated partially matured cardiomyocytes onto nanopatterned surfaces to investigate how external mechanical signals affect maturation in contractile versus noncontractile cells.
Surprisingly, we found that sarcomeres formed in the D65A cTnC cardiomyocytes, though these sarcomeres were underdeveloped and disorganized. The D65A cardiomyocytes also exhibited significant proteomic maturation defects and abnormal calcium transients. Replating the noncontractile cardiomyocytes onto nanopatterns improved several structural and proteomic maturation metrics. In contrast, wild-type maturation did not benefit from the introduction of nanopatterns.
Calcium-activated contractility is dispensable for sarcomerogenesis but critical for cardiomyocyte maturation. In noncontractile, D65A cTnC cardiomyocytes, nanopatterns enhanced maturation, suggesting that external mechanical cues may partially compensate for defective contractility. However, nanopatterns did not facilitate wild-type maturation, suggesting that maturity may reduce the efficacy of nanopatterns. In addition to these novel findings, these mass spectrometry data sets cataloging induced pluripotent stem cell-derived cardiomyocyte maturation represent a useful resource for the cardiovascular research community.
PMID:
42422954
Bibliographic data and abstract were imported from PubMed on 09 Jul 2026.
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