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Engineered Cardiac Tissues Generated in the Biowire™ II: A Platform for Human-Based Drug Discovery.

ABSTRACT: Recent advances in techniques to differentiate human induced pluripotent stem cells (hiPSCs) hold the promise of an unlimited supply of human derived cardiac cells from both healthy and disease populations. That promise has been tempered by the observation that hiPSC-derived cardiomyocytes (hiPSC-CMs) typically retain a fetal-like phenotype, raising concern about the translatability of the in vitro data obtained to drug safety, discovery and development studies. The Biowire™ II platform was used to generate 3D engineered cardiac tissues (ECTs) from hiPSC-CMs and cardiac fibroblasts. Long term electrical stimulation was employed to obtain ECTs that possess a phenotype like that of adult human myocardium including a lack of spontaneous beating, the presence of a positive force-frequency response from 1-4Hz and prominent post-rest potentiation. Pharmacology studies were performed in the ECTs to confirm the presence and functionality of pathways that modulate cardiac contractility in humans. Canonical responses were observed for compounds that act via the ?-adrenergic/cAMP-mediated pathway, e.g. isoproterenol and milrinone; the L-type calcium channel, e.g. FPL64176 and nifedipine; and indirectly effect intracellular Ca2+ concentrations, e.g. digoxin. Expected positive inotropic responses were observed for compounds that modulate proteins of the cardiac sarcomere, e.g. omecamtiv mecarbil and levosimendan. ECTs generated in the BiowireTM II platform display adult-like properties and have canonical responses to cardiotherapeutic and cardiotoxic agents that affect contractility in humans via a variety of mechanisms. These data demonstrate that this human-based model can be used to assess the effects of novel compounds on contractility early in the drug discovery and development process.

SUBMITTER: Feric NT

PROVIDER: S-EPMC6813749 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Engineered Cardiac Tissues Generated in the Biowire II: A Platform for Human-Based Drug Discovery.

Feric Nicole T NT Pallotta Isabella I Singh Rishabh R Bogdanowicz Danielle R DR Gustilo Marietta M MM Chaudhary Khuram W KW Willette Robert N RN Chendrimada Tim P TP Xu Xiaoping X Graziano Michael P MP Aschar-Sobbi Roozbeh R

Toxicological sciences : an official journal of the Society of Toxicology 20191101 1

Recent advances in techniques to differentiate human induced pluripotent stem cells (hiPSCs) hold the promise of an unlimited supply of human derived cardiac cells from both healthy and disease populations. That promise has been tempered by the observation that hiPSC-derived cardiomyocytes (hiPSC-CMs) typically retain a fetal-like phenotype, raising concern about the translatability of the in vitro data obtained to drug safety, discovery, and development studies. The Biowire II platform was used ...[more]

PMID: 31385592

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Project description:BACKGROUND:Delivery of stem cells to the failing heart is a promising therapeutic strategy. However, the improvement in cardiac function in animal studies has not fully translated to humans. To help bridge the gap between species, we investigated the effects of adult human cardiac stem cells (hCSCs) on contractile function of human engineered cardiac tissues (hECTs) as a species-specific model of the human myocardium. METHODS:Human induced pluripotent stem cell-derived cardiomyoctes (hCMs) were mixed with Collagen/Matrigel to fabricate control hECTs, with an experimental group of hCSC-supplemented hECT fabricated using a 9:1 ratio of hCM to hCSC. Functional testing was performed starting on culture day 6, under spontaneous conditions and also during electrical pacing from 0.25 to 1.0?Hz, measurements repeated at days 8 and 10. hECTs were then frozen and processed for gene analysis using a Nanostring assay with a cardiac targeted custom panel. RESULTS:The hCSC-supplemented hECTs displayed a twofold higher developed force vs. hCM-only controls by day 6, with approximately threefold higher developed stress and maximum rates of contraction and relaxation during pacing at 0.75?Hz. The spontaneous beat rate characteristics were similar between groups, and hCSC supplementation did not adversely impact beat rate variability. The increased contractility persisted through days 8 and 10, albeit with some decrease in the magnitude of the difference of the force by day 10, but with developed stress still significantly higher in hCSC-supplemented hECT; these findings were confirmed with multiple hCSC and hCM cell lines. The force-frequency relationship, while negative for both, control (-?0.687?Hz-?1; p?=?0.013 vs. zero) and hCSC-supplemented (-?0.233?Hz-?1;p?=?0.067 vs. zero) hECTs, showed a significant rectification in the regression slope in hCSC-supplemented hECT (p?=?0.011 vs. control). Targeted gene exploration (59 genes) identified a total of 14 differentially expressed genes, with increases in the ratios of MYH7/MHY6, MYL2/MYL7, and TNNI3/TNNI1 in hCSC-supplemented hECT versus controls. CONCLUSIONS:For the first time, hCSC supplementation was shown to significantly improve human cardiac tissue contractility in vitro, without evidence of proarrhythmic effects, and was associated with increased expression of markers of cardiac maturation. These findings provide new insights about adult cardiac stem cells as contributors to functional improvement of human myocardium.

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Engineered Cardiac Tissues Generated in the Biowire™ II: A Platform for Human-Based Drug Discovery.

Publications

Engineered Cardiac Tissues Generated in the Biowire II: A Platform for Human-Based Drug Discovery.

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