# Development of a high throughput microtissue model for integrative analysis of contractile function and biomechanical stress in iPSC-derived cardiomyocytes

> **NIH NIH R03** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $78,000

## Abstract

ABSTRACT
Cardiomyopathies, including hypertrophic (HCM) and dilated (DCM) cardiomyopathy, are conditions in which
heart muscle dysfunction may lead to arrhythmias and heart failure. Cardiomyopathies are most commonly
caused by variants in sarcomere genes that encode contractile proteins. The immediate effect of these genetic
variants is perturbation of contractile function. However, a clear understanding of how the thousands of different
variants in individual sarcomere genes differentially affect contractile function to cause HCM and DCM has not
been attained. Furthermore, traditional systems have not been able to efficiently study the interaction between
genetic variants affecting contractile function and varying levels of biomechanical workload that models the in
vivo state. Cardiomyocytes differentiated from induced pluripotent stem cells (iPSC-CMs) are a promising model
system that allow the study of HCM- and DCM-causing mutations in a human cell context, but the capacity of
this model system for contractile analysis has been limited because of technical and biologic hurdles. My
preliminary data shows that an optimized bioengineered platform enables generation of contracting micrometer-
scale 2-dimensional heart muscle tissues (referred to as M2D) on an elastomer substrate. M2D tissues exhibit
coordinated, uniaxial contraction, robust myofibrillar alignment, and expected responses to contractile
agonists/antagonists. In addition, my preliminary data shows that the M2D tissues are amenable to modified
RNA transfection, enabling >90% mutant replacement of contractile proteins. I hypothesize that the M2D
technology will enable mechanistic determination of dysregulated contractile velocity and workload relationships
in cardiomyopathy patient iPSCMs compared to controls, and, moreover, that these analyses will enable
subclassification of contractile defects due to thick vs. thin filament mutations that will predict responses to
pharmacologic modulation of contractile function. The first aim tests the capacity of the M2D system to
discriminate contractile dysregulation in patient iPSCM muscle tissues with thick (MYH7, MYBPC3) vs thin
(TNNT2) filament sarcomere gene variants in a total of 10 patient iPSC lines, as compared to controls. Modified
RNA transfections will be used as additional models since we are able to achieve very high transfection
efficiencies in the M2D system. Both myofibrillar alignment and contractile function will be quantified using
custom analysis tools. Sensitivity of contractile function to calcium concentration will also be assessed in both
patient and control muscle tissues. The second aim will test whether thick vs. thin filament variant iPSCMs have
a differential reversal of contractile dysregulation with the myosin inhibitor Myk-461. The implementation of the
M2D technology to interrogate contractile function in the presence of sarcomere gene variants will be
transformative for precision analysis of patient-specific he...

## Key facts

- **NIH application ID:** 10312792
- **Project number:** 5R03HL148465-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** ADAM S HELMS
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $78,000
- **Award type:** 5
- **Project period:** 2020-12-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312792

## Citation

> US National Institutes of Health, RePORTER application 10312792, Development of a high throughput microtissue model for integrative analysis of contractile function and biomechanical stress in iPSC-derived cardiomyocytes (5R03HL148465-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10312792. Licensed CC0.

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