Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have emerged as an exciting new tool for cardiac research and can serve as a preclinical platform for drug development and disease modeling studies. However, these aspirations are limited by current culture methods in which hPSC-CMs resemble fetal human cardiomyocytes in terms of structure and function. Herein we provide a novel in vitro platform that includes patterned extracellular matrix with physiological substrate stiffness and is amenable to both mechanical and electrical analysis. Micropatterned lanes promote the cellular and myofibril alignment of hPSC-CMs while the addition of micropatterned bridges enable formation of a functional cardiac syncytium that beats synchronously over a large two-dimensional area. We investigated the electrophysiological properties of the patterned cardiac constructs and showed they have anisotropic electrical impulse propagation, as occurs in the native myocardium, with speeds 2x faster in the primary direction of the pattern as compared to the transverse direction. Lastly, we interrogated the mechanical function of the pattern constructs and demonstrated the utility of this platform in recording the strength of cardiomyocyte contractions. This biomimetic platform with electrical and mechanical readout capabilities will enable the study of cardiac disease and the influence of pharmaceuticals and toxins on cardiomyocyte function. The platform also holds potential for high throughput evaluation of drug safety and efficacy, thus furthering our understanding of cardiovascular disease and increasing the translational use of hPSC-CMs.
Bibliographical noteFunding Information:
J. C. Makielski, L. L. Eckhardt, A. V. Glukhov, T. J. Kamp, and W. C. Crone contributed to the conception of and funding acquisition for the study. B. N. Napiwocki, J. Zhang, R. Vaidyanathan, J. C. Makielski, L. L. Eckhardt, A. V. Glukhov, T. J. Kamp, and W. C. Crone contributed to methodological development of the study. B. N. Napiwocki and D. Lang had primary responsibility for conducting the experiments, data acquisition, curation, and analysis, with assistance from A. Stempien, J. Zhang, and R. Vaidyanathan. T. J. Kamp, and W. C. Crone had lead roles in project oversight. B. N. Napiwocki drafted the manuscript, with assistance from T. J. Kamp and W. C. Crone. All authors edited and reviewed the manuscript. This study was funded by the University of Wisconsin‐Madison through the Karen Thompson Medhi Professorship (W. C. Crone), the Graduate School (W. C. Crone), and a UW2020 grant from the Office of the Vice Chancellor for Research and Graduate Education with funding from the Wisconsin Alumni Research Foundation (T. J. Kamp, J. C. Makielski, L. L. Eckhardt, A. V. Glukhov, W. C. Crone). Funding from NIH U01HL134764 (T. J. Kamp), NSF EEC‐1648035 (T. J. Kamp), NSF 1743346 (T. J. Kamp).
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- anisotropic conduction
- human pluripotent stem cell-derived cardiomyocytes
- microcontact printing
- substrate stiffness
PubMed: MeSH publication types
- Journal Article