Membrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOR

Emily Sempou, Valentyna Kostiuk, Jie Zhu, M. Cecilia Guerra, Leonid Tyan, Woong Hwang, Elena Camacho-Aguilar, Michael J. Caplan, David Zenisek, Aryeh Warmflash, Nick D. L. Owens and Mustafa K. Khokha ()
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Emily Sempou: Yale University School of Medicine
Valentyna Kostiuk: Yale University School of Medicine
Jie Zhu: Yale University School of Medicine
M. Cecilia Guerra: Departments of Biosciences and Bioengineering Rice University
Leonid Tyan: Yale University School of Medicine
Woong Hwang: Yale University School of Medicine
Elena Camacho-Aguilar: Departments of Biosciences and Bioengineering Rice University
Michael J. Caplan: Yale University School of Medicine
David Zenisek: Yale University School of Medicine
Aryeh Warmflash: Departments of Biosciences and Bioengineering Rice University
Nick D. L. Owens: University of Exeter
Mustafa K. Khokha: Yale University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Transitioning from pluripotency to differentiated cell fates is fundamental to both embryonic development and adult tissue homeostasis. Improving our understanding of this transition would facilitate our ability to manipulate pluripotent cells into tissues for therapeutic use. Here, we show that membrane voltage (Vm) regulates the exit from pluripotency and the onset of germ layer differentiation in the embryo, a process that affects both gastrulation and left-right patterning. By examining candidate genes of congenital heart disease and heterotaxy, we identify KCNH6, a member of the ether-a-go-go class of potassium channels that hyperpolarizes the Vm and thus limits the activation of voltage gated calcium channels, lowering intracellular calcium. In pluripotent embryonic cells, depletion of kcnh6 leads to membrane depolarization, elevation of intracellular calcium levels, and the maintenance of a pluripotent state at the expense of differentiation into ectodermal and myogenic lineages. Using high-resolution temporal transcriptome analysis, we identify the gene regulatory networks downstream of membrane depolarization and calcium signaling and discover that inhibition of the mTOR pathway transitions the pluripotent cell to a differentiated fate. By manipulating Vm using a suite of tools, we establish a bioelectric pathway that regulates pluripotency in vertebrates, including human embryonic stem cells.

Date: 2022
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DOI: 10.1038/s41467-022-34363-w

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