In principle, differentiated cardiomyocytes derived from hESCs and hiPSCs are ideal model systems in which to study the physiological effects of disease and aging. However, hESC/hiPSC-derived cardiomyocytes characteristically exhibit electrical and mechanical properties of early fetal, rather than adult, cells. Although a few growt factor-like molecules are reported to have a maturational effect, little is known about the precise physiological effects or how the molecules can be used to improve the utility of hiPSC/hESC-derived cardiomyocytes to model aging and disease. The goal of this R21 proposal is to identify and characterize such molecules, based on preliminary data that endothelial cells normally produce maturation-inducing factors. Data are presented showing the development of instrumentation and software for high-throughput assessment of electrophysiological maturation. Using this technology, we provide preliminary evidence that endothelial cells (ECs) promote electrical and ion channel profile maturation of hiPSC/ESC-derived cardiomyocytes through the production of factors that accumulate in conditioned media.
The specific aims of this proposal are to: 1) define EC-induced maturation by functional expression of ion channels and pumps, drug sensitivity profiling, action potential and calcium handling metrics, 2) determine if ECs also promote maturation of contractile apparatus structure and function, and 3) use the electrical and mechanical metrics from Aims 1 and 2 as quantitative metrics to identify and characterize the effects of EC-derived maturation factor(s). The identification of signals that promote cardiomyocyte maturation should lead to improved methods for deriving functional cardiomyocytes that will be enabling for studies of aging and disease. Beyond the high- risk/high-yield scope of the R21 project, we have established collaborations to evaluate whether the maturational factors indeed enhance the utility of hiPSC-cardiomyocytes as models for drug risk assessment and disease.

Public Health Relevance

This project will identify and characterize proteins and genes that direct physiological maturation of heart muscle cells from stem cells. Heart muscle cells produced from stem cells typically lack electrical and mechanical properties of adult cardiomyocytes that are important for research and clinical applications. The findings will constitute a conceptual advance since little is known about the specific molecules that drive physiological maturation, and the molecules themselves will increase the utility of stem cell-derived cardiomyocytes for research and translational applications.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21AG043917-02
Application #
8851826
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Kohanski, Ronald A
Project Start
2013-07-15
Project End
2015-06-30
Budget Start
2014-08-15
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
$193,750
Indirect Cost
$68,750
Name
University of California San Diego
Department
Engineering (All Types)
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093