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GLUT3 and PKM2 regulate OCT4 expression and support the hypoxic culture of human embryonic stem cells

Human embryonic stem cells (hESCs) have the capacity to differentiate into all cell types and thus have great potential for regenerative medicine. hESCs cultured at low oxygen tensions are more pluripotent and display an increased glycolytic rate but how this is regulated is unknown. This study ther...

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Autores principales: Christensen, David R., Calder, Philip C., Houghton, Franchesca D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671001/
https://www.ncbi.nlm.nih.gov/pubmed/26639784
http://dx.doi.org/10.1038/srep17500
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author Christensen, David R.
Calder, Philip C.
Houghton, Franchesca D.
author_facet Christensen, David R.
Calder, Philip C.
Houghton, Franchesca D.
author_sort Christensen, David R.
collection PubMed
description Human embryonic stem cells (hESCs) have the capacity to differentiate into all cell types and thus have great potential for regenerative medicine. hESCs cultured at low oxygen tensions are more pluripotent and display an increased glycolytic rate but how this is regulated is unknown. This study therefore aimed to investigate the regulation of glucose metabolism in hESCs and whether this might impact OCT4 expression. In contrast to the glucose transporter GLUT1, GLUT3 was regulated by environmental oxygen and localised to hESC membranes. Silencing GLUT3 caused a reduction in glucose uptake and lactate production as well as OCT4 expression. GLUT3 and OCT4 expression were correlated suggesting that hESC self-renewal is regulated by the rate of glucose uptake. Surprisingly, PKM2, a rate limiting enzyme of glycolysis displayed a nuclear localisation in hESCs and silencing PKM2 did not alter glucose metabolism suggesting a role other than as a glycolytic enzyme. PKM2 expression was increased in hESCs cultured at 5% oxygen compared to 20% oxygen and silencing PKM2 reduced OCT4 expression highlighting a transcriptional role for PKM2 in hESCs. Together, these data demonstrate two separate mechanisms by which genes regulating glucose uptake and metabolism are involved in the hypoxic support of pluripotency in hESCs.
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spelling pubmed-46710012015-12-11 GLUT3 and PKM2 regulate OCT4 expression and support the hypoxic culture of human embryonic stem cells Christensen, David R. Calder, Philip C. Houghton, Franchesca D. Sci Rep Article Human embryonic stem cells (hESCs) have the capacity to differentiate into all cell types and thus have great potential for regenerative medicine. hESCs cultured at low oxygen tensions are more pluripotent and display an increased glycolytic rate but how this is regulated is unknown. This study therefore aimed to investigate the regulation of glucose metabolism in hESCs and whether this might impact OCT4 expression. In contrast to the glucose transporter GLUT1, GLUT3 was regulated by environmental oxygen and localised to hESC membranes. Silencing GLUT3 caused a reduction in glucose uptake and lactate production as well as OCT4 expression. GLUT3 and OCT4 expression were correlated suggesting that hESC self-renewal is regulated by the rate of glucose uptake. Surprisingly, PKM2, a rate limiting enzyme of glycolysis displayed a nuclear localisation in hESCs and silencing PKM2 did not alter glucose metabolism suggesting a role other than as a glycolytic enzyme. PKM2 expression was increased in hESCs cultured at 5% oxygen compared to 20% oxygen and silencing PKM2 reduced OCT4 expression highlighting a transcriptional role for PKM2 in hESCs. Together, these data demonstrate two separate mechanisms by which genes regulating glucose uptake and metabolism are involved in the hypoxic support of pluripotency in hESCs. Nature Publishing Group 2015-12-07 /pmc/articles/PMC4671001/ /pubmed/26639784 http://dx.doi.org/10.1038/srep17500 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Christensen, David R.
Calder, Philip C.
Houghton, Franchesca D.
GLUT3 and PKM2 regulate OCT4 expression and support the hypoxic culture of human embryonic stem cells
title GLUT3 and PKM2 regulate OCT4 expression and support the hypoxic culture of human embryonic stem cells
title_full GLUT3 and PKM2 regulate OCT4 expression and support the hypoxic culture of human embryonic stem cells
title_fullStr GLUT3 and PKM2 regulate OCT4 expression and support the hypoxic culture of human embryonic stem cells
title_full_unstemmed GLUT3 and PKM2 regulate OCT4 expression and support the hypoxic culture of human embryonic stem cells
title_short GLUT3 and PKM2 regulate OCT4 expression and support the hypoxic culture of human embryonic stem cells
title_sort glut3 and pkm2 regulate oct4 expression and support the hypoxic culture of human embryonic stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671001/
https://www.ncbi.nlm.nih.gov/pubmed/26639784
http://dx.doi.org/10.1038/srep17500
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