Oct 29, 2018

Engineered developmental niche enables predictive phenotypic screening in human dystrophic cardiomyopathy

BioRxiv : the Preprint Server for Biology
Jesse MacadangdangDeok-Ho Kim

Abstract

Directed differentiation of human pluripotent stem cells (hPSCs) into cardiomyocytes typically produces cells with structural, functional, and biochemical properties that most closely resemble those present in the fetal heart. Here we establish an in vitro engineered developmental cardiac niche to produce matured hPSC-derived cardiomyocytes (hPSC-CMs) with enhanced sarcomere development, electrophysiology, contractile function, mitochondrial capacity, and a more mature transcriptome. When this developmental cardiac niche was applied to dystrophin mutant hPSC-CMs, a robust disease phenotype emerged, which was not observed in non-matured diseased hPSC-CMs. Matured dystrophin mutant hPSC-CMs exhibited a greater propensity for arrhythmia as measured via beat rate variability, most likely due to higher resting cytosolic calcium content. Using a custom nanopatterned microelectrode array platform to screen functional output in hPSC-CMs exposed to our engineered developmental cardiac niche, we identified calcium channel blocker, nitrendipine, mitigated hPSC-CM arrhythmogenic behavior and correctly identified sildenafil as a false positive. Taken together, we demonstrate our developmental cardiac niche platform enables robust hPSC-CM ma...Continue Reading

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Mentioned in this Paper

Microelectrodes
Calcium [EPC]
Sarcomeres
DMD gene
Nitrendipine
Pluripotent Stem Cells
Cutaneous Mastocytosis
Calcium
Biologic Development
Cell Differentiation Process

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