Membrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOR
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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-022-34363-w |
| _version_ | 1827928554173628416 |
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| author | 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 Mustafa K. Khokha |
| author_facet | 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 Mustafa K. Khokha |
| author_sort | Emily Sempou |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T06:10:24Z |
| format | Article |
| id | doaj.art-58862aeb53a640a4ba563a0187c09257 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T06:10:24Z |
| publishDate | 2022-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-58862aeb53a640a4ba563a0187c092572023-06-11T11:17:45ZengNature PortfolioNature Communications2041-17232022-11-0113111710.1038/s41467-022-34363-wMembrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOREmily Sempou0Valentyna Kostiuk1Jie Zhu2M. Cecilia Guerra3Leonid Tyan4Woong Hwang5Elena Camacho-Aguilar6Michael J. Caplan7David Zenisek8Aryeh Warmflash9Nick D. L. Owens10Mustafa K. Khokha11Pediatric Genomics Discovery Program, Departments of Pediatrics and Genetics, Yale University School of MedicinePediatric Genomics Discovery Program, Departments of Pediatrics and Genetics, Yale University School of MedicineDepartment of Cellular and Molecular Physiology, Yale University School of MedicineDepartments of Biosciences and Bioengineering Rice UniversityPediatric Genomics Discovery Program, Departments of Pediatrics and Genetics, Yale University School of MedicinePediatric Genomics Discovery Program, Departments of Pediatrics and Genetics, Yale University School of MedicineDepartments of Biosciences and Bioengineering Rice UniversityDepartment of Cellular and Molecular Physiology, Yale University School of MedicineDepartment of Cellular and Molecular Physiology, Yale University School of MedicineDepartments of Biosciences and Bioengineering Rice UniversityDepartment of Clinical and Biomedical Sciences, University of ExeterPediatric Genomics Discovery Program, Departments of Pediatrics and Genetics, Yale University School of MedicineAbstract 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.https://doi.org/10.1038/s41467-022-34363-w |
| spellingShingle | 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 Mustafa K. Khokha Membrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOR Nature Communications |
| title | Membrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOR |
| title_full | Membrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOR |
| title_fullStr | Membrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOR |
| title_full_unstemmed | Membrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOR |
| title_short | Membrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOR |
| title_sort | membrane potential drives the exit from pluripotency and cell fate commitment via calcium and mtor |
| url | https://doi.org/10.1038/s41467-022-34363-w |
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