Miniaturized iPS-Cell-Derived Cardiac Muscles for Physiologically Relevant Drug Response Analyses.
Tissue engineering approaches have the potential to increase the physiologic relevance of human iPS-derived cells, such as cardiomyocytes (iPS-CM). However, forming Engineered Heart Muscle (EHM) typically requires >1 million cells per tissue. Existing miniaturization strategies involve complex approaches not amenable to mass production, limiting the ability to use EHM for iPS-based disease modeling and drug screening. Micro-scale cardiospheres are easily produced, but do not facilitate assembly of elongated muscle or direct force measurements. Here we describe an approach that combines features of EHM and cardiospheres: Micro-Heart Muscle (μHM) arrays, in which elongated muscle fibers are formed in an easily fabricated template, with as few as 2,000 iPS-CM per individual tissue. Within μHM, iPS-CM exhibit uniaxial contractility and alignment, robust sarcomere assembly, and reduced variability and hypersensitivity in drug responsiveness, compared to monolayers with the same cellular composition. μHM mounted onto standard force measurement apparatus exhibited a robust Frank-Starling response to external stretch, and a dose-dependent inotropic response to the β-adrenergic agonist isoproterenol. Based on the ease of fabrication, the potential for mass production and the small number of cells required to form μHM, this system provides a potentially powerful tool to study cardiomyocyte maturation, disease and cardiotoxicology in vitro.
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.|Department of Pediatrics, University of California, San Francisco, CA 94143.
Nathaniel
N
Huebsch
Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, California 94720, USA.|Department of Materials Science and Engineering, University of California at Berkeley, Berkeley, California 94720, USA.
Peter
P
Loskill
Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, California 94720, USA.
Nikhil
N
Deveshwar
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.
C Ian
CI
Spencer
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.|Department of Pediatrics, University of California, San Francisco, CA 94143.
Luke M
LM
Judge
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.
Mohammad A
MA
Mandegar
University of California, San Francisco, Schools of Pharmacy and Medicine, Department of Bioengineering and Therapeutic Sciences, San Francisco, CA 94158.
Cade B
CB
Fox
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.|Institute of Cardiovascular Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.|Faculty of Pharmacy, Zagazig University, EL-Sharkiak, Egypt.
Tamer M A
TM
Mohamed
Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, California 94720, USA.|Department of Materials Science and Engineering, University of California at Berkeley, Berkeley, California 94720, USA.
Zhen
Z
Ma
Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, California 94720, USA.|Department of Materials Science and Engineering, University of California at Berkeley, Berkeley, California 94720, USA.
Anurag
A
Mathur
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.
Alice M
AM
Sheehan
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.
Annie
A
Truong
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.
Mike
M
Saxton
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.
Jennie
J
Yoo
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.|Department of Pediatrics, University of California, San Francisco, CA 94143.
Deepak
D
Srivastava
University of California, San Francisco, Schools of Pharmacy and Medicine, Department of Bioengineering and Therapeutic Sciences, San Francisco, CA 94158.
Tejal A
TA
Desai
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.
Po-Lin
PL
So
Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, California 94720, USA.|Department of Materials Science and Engineering, University of California at Berkeley, Berkeley, California 94720, USA.
Kevin E
KE
Healy
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.|Departments of Medicine, and Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158.
Bruce R
BR
Conklin
D002454:Cell Differentiation; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D012518:Sarcomeres; D017154:Stromal Cells