Abstract
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.
Highlights
Human induced pluripotent stem cell technology is a groundbreaking step in the endeavor to model human disease in a controlled laboratory setting
Engineered Heart Muscle (EHM) is a mixed culture of large numbers of cardiomyocytes and fibroblasts that are embedded in extracellular matrix (ECM) gel
There was a CD90-positive, non-cardiomyocyte population derived as a byproduct of Wnt-mediated cardiac differentiation, previous work suggests that these CD90 positive cells are a mixed population likely to contain a mixture of different cell types, including fibroblasts and endothelial cells[23]
Summary
Human induced pluripotent stem cell (iPSC) technology is a groundbreaking step in the endeavor to model human disease in a controlled laboratory setting. EHM is a mixed culture of large numbers (millions) of cardiomyocytes and fibroblasts that are embedded in extracellular matrix (ECM) gel (e.g., collagen or fibrin) These cell-ECM constructs are formed within ring-shaped molds[7], embedded with rigid posts or cantilevers[8,9] or entangled into rigid mesh[2,10]. Each EHM typically requires hundreds of thousands or millions of cells to form[11], and producing these large cell numbers is challenging for many differentiated cell types, including iPS-CM, in the case of high-volume drug screening or disease modeling, where cardiomyocytes from several lines Fabricating EHM involves handling ECM materials, which limits the throughput with which devices can be manufactured, and considerably increases the difficulty of incorporating EHM into micro-fluidic organ-on-a-chip systems[5]
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