Circadian networks in human embryonic stem cell-derived cardiomyocytes

Pieterjan Dierickx, Marit W Vermunt, Mauro J Muraro, Menno P Creyghton, Pieter A Doevendans, Alexander van Oudenaarden, Niels Geijsen, Linda W Van Laake

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgaveArtikelWetenschappelijkpeer review

Samenvatting

Cell-autonomous circadian oscillations strongly influence tissue physiology and pathophysiology of peripheral organs including the heart, in which the circadian clock is known to determine cardiac metabolism and the outcome of for instance ischemic stress. Human pluripotent stem cells represent a powerful tool to study developmental processes in vitro, but the extent to which human embryonic stem (ES) cell-derived cardiomyocytes establish circadian rhythmicity in the absence of a systemic context is unknown. Here we demonstrate that while undifferentiated human ES cells do not possess an intrinsic functional clock, oscillatory expression of known core clock genes emerges spontaneously during directed cardiac differentiation. We identify a set of clock-controlled output genes that contain an oscillatory network of stress-related transcripts. Furthermore, we demonstrate that this network results in a time-dependent functional response to doxorubicin, a frequently used anti-cancer drug with known cardiotoxic side effects. Taken together, our data provide a framework from which the effect of oscillatory gene expression on cardiomyocyte physiology can be modeled in vitro, and demonstrate the influence of a functional clock on experimental outcome.

Originele taal-2Engels
Pagina's (van-tot)1199-1212
Aantal pagina's14
TijdschriftEMBO Reports
Volume18
Nummer van het tijdschrift7
DOI's
StatusGepubliceerd - jul 2017

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