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Proteasome-Dependent Regulation of Distinct Metabolic States During Long-Term Culture of Human iPSC-Derived Cardiomyocytes.

Circ Res 2019 06 20;125(1):90-103. Epub 2019 May 20.

From the Stanford Cardiovascular Institute (A.E., Y.D., S.S., H.C., Y.L., P.G., J.C.W.), Stanford University School of Medicine, CA.

Rationale: The immature presentation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is currently a challenge for their application in disease modeling, drug screening, and regenerative medicine. Long-term culture is known to achieve partial maturation of iPSC-CMs. However, little is known about the molecular signaling circuitries that govern functional changes, metabolic output, and cellular homeostasis during long-term culture of iPSC-CMs.

Objective: We aimed to identify and characterize critical signaling events that control functional and metabolic transitions of cardiac cells during developmental progression, as recapitulated by long-term culture of iPSC-CMs.

Methods And Results: We combined transcriptomic sequencing with pathway network mapping in iPSC-CMs that were cultured until a late time point, day 200, in comparison to a medium time point, day 90, and an early time point, day 30. Transcriptomic landscapes of long-term cultured iPSC-CMs allowed mapping of distinct metabolic stages during development of maturing iPSC-CMs. Temporally divergent control of mitochondrial metabolism was found to be regulated by cAMP/PKA (protein kinase A)- and proteasome-dependent signaling events. The PKA/proteasome-dependent signaling cascade was mediated downstream by Hsp90 (heat shock protein 90), which in turn modulated mitochondrial respiratory chain proteins and their metabolic output. During long-term culture, this circuitry was found to initiate upregulation of iPSC-CM metabolism, resulting in increased cell contractility that reached a maximum at the day 200 time point.

Conclusions: Our results reveal a PKA/proteasome- and Hsp90-dependent signaling pathway that regulates mitochondrial respiratory chain proteins and determines cardiomyocyte energy production and functional output. These findings provide deeper insight into signaling circuitries governing metabolic homeostasis in iPSC-CMs during developmental progression.

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June 2019
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