Physiologic mechanics drive contractile development in stem cell derived cardiac muscle to model genetic heart disease

Abstract:
Disorganized mechanics and immaturity of stem cell derived cardiomyocytes have been hurdles to reproducible applications for regenerative medicine or disease modeling. We developed a platform of micron-scale cardiac muscle bundles to control biomechanics in arrays of thousands of purified, independently contracting cardiac muscle strips on two-dimensional elastomer substrates. By defining geometry and workload in this reductionist platform, we show that myofibrillar alignment and auxotonic contractions at physiologic workload drive maturation of contractile function, calcium handling, and electrophysiology. Using transcriptomics, reporter hPSC-CMs, and quantitative immunofluorescence, these cardiac muscle bundles can be used to parse orthogonal cues in early development, including contractile force, calcium load, and metabolic signals. Additionally, the resultant organized biomechanics facilitates automated extraction of contractile kinetics from brightfield microscopy imaging, increasing the accessibility, reproducibility, and throughput of pharmacologic testing. Our lab is working toward applications of this system to understand human cardiomyopathies caused by variants that affect cardiomyocyte structure and function.

Bio:
Dr. Helms is a physician-scientist in the Division of Cardiovascular Medicine at the University of Michigan. He co-directs the Inherited Cardiomyopathy and Arrhythmia Clinic. His lab studies genetic cardiomyopathy using stem cell derived cardiomyocyte and mouse models. 

Zoom Link: https://umich.zoom.us/j/96508834308

Organized by:
Dr. Brendon Baker,
Assistant Professor, Biomedical Engineering

Dr. David Nordsletten,
Associate Professor, Department of Biomedical Engineering and Cardiac Surgery