Circadian networks in human embryonic stem cell-derived cardiomyocytes
Pieterjan Dierickx1,2,3, Marit W Vermunt4, Mauro J Muraro4
1Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands p.dierickx@hubrecht.eu l.w.vanlaake@umcutrecht.nl.
Insights
Human embryonic stem cell-derived cardiomyocytes develop a functional circadian clock during differentiation. This intrinsic clock influences their response to cardiotoxic drugs like doxorubicin, impacting experimental outcomes.
Area of Science:
- Cardiovascular Biology
- Chronobiology
- Stem Cell Biology
Background:
- Circadian rhythms govern heart physiology and disease, influencing metabolism and stress response.
- Human pluripotent stem cells offer a model for studying cardiac development in vitro.
- The presence and function of circadian clocks in human embryonic stem cell-derived cardiomyocytes remain largely uncharacterized.
Purpose of the Study:
- To investigate the emergence and function of circadian rhythms in human embryonic stem cell-derived cardiomyocytes.
- To determine if these cells possess an intrinsic functional clock during differentiation.
- To explore the impact of circadian oscillations on cardiomyocyte responses to external stimuli.
Main Methods:
- Directed differentiation of human embryonic stem cells into cardiomyocytes.
- Analysis of core clock gene expression patterns during differentiation.
- Identification and characterization of clock-controlled output genes.
- Assessment of time-dependent functional responses to doxorubicin exposure.
Main Results:
- Undifferentiated human embryonic stem cells lack an intrinsic functional clock.
- Spontaneous oscillatory expression of core clock genes occurs during cardiac differentiation.
- A network of stress-related transcripts is regulated by the emerging circadian clock.
- Doxorubicin-induced cardiotoxicity exhibits time-dependent functional responses.
Conclusions:
- Human embryonic stem cell-derived cardiomyocytes acquire a functional circadian clock during differentiation.
- The intrinsic circadian clock influences cardiomyocyte physiology and response to cardiotoxic agents.
- This model system allows in vitro investigation of circadian gene expression effects on cardiomyocyte function and drug responses.
Abstract:
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.
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