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Hypoxia induces a transcriptional early primitive streak signature in pluripotent cells enhancing spontaneous elongation and lineage representation in gastruloids

View ORCID ProfileNatalia López-Anguita, Seher Ipek Gassaloglu, Maximilian Stötzel, Marina Typou, Iiris Virta, Sara Hetzel, René Buschow, Burak Koksal, Derya Atilla, Ronald Maitschke-Rajasekharan, Rui Chen, Alexandra L. Mattei, Ivan Bedzhov, David Meierhofer, Alexander Meissner, Jesse V. Veenvliet, Aydan Bulut-Karslioglu
doi: https://doi.org/10.1101/2021.07.21.452906
Natalia López-Anguita
1Max Planck Institute for Molecular Genetics, Berlin, Germany
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  • ORCID record for Natalia López-Anguita
Seher Ipek Gassaloglu
1Max Planck Institute for Molecular Genetics, Berlin, Germany
2Charite Molecular Medicine, Berlin, Germany
3Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
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Maximilian Stötzel
1Max Planck Institute for Molecular Genetics, Berlin, Germany
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Marina Typou
1Max Planck Institute for Molecular Genetics, Berlin, Germany
4Medical School of the Democritus University of Thrace, Greece
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Iiris Virta
1Max Planck Institute for Molecular Genetics, Berlin, Germany
2Charite Molecular Medicine, Berlin, Germany
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Sara Hetzel
1Max Planck Institute for Molecular Genetics, Berlin, Germany
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René Buschow
1Max Planck Institute for Molecular Genetics, Berlin, Germany
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Burak Koksal
5Bilkent University, Ankara, Turkey
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Derya Atilla
6Istanbul Technical University, Istanbul, Turkey
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Ronald Maitschke-Rajasekharan
1Max Planck Institute for Molecular Genetics, Berlin, Germany
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Rui Chen
7Max Planck Institute for Molecular Biomedicine, Münster, Germany
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Alexandra L. Mattei
1Max Planck Institute for Molecular Genetics, Berlin, Germany
8Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA
9Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
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Ivan Bedzhov
7Max Planck Institute for Molecular Biomedicine, Münster, Germany
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David Meierhofer
1Max Planck Institute for Molecular Genetics, Berlin, Germany
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Alexander Meissner
1Max Planck Institute for Molecular Genetics, Berlin, Germany
9Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
10Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Jesse V. Veenvliet
1Max Planck Institute for Molecular Genetics, Berlin, Germany
3Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
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Aydan Bulut-Karslioglu
1Max Planck Institute for Molecular Genetics, Berlin, Germany
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  • For correspondence: Aydan.karslioglu@molgen.mpg.de
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ABSTRACT

The cellular microenvironment together with intrinsic regulators shapes stem cell identity and differentiation capacity. Mammalian early embryos are exposed to hypoxia in vivo and appear to benefit from hypoxic culture in vitro. Yet, components of the hypoxia response and how their interplay impacts stem cell transcriptional networks and lineage choices remain poorly understood. Here we investigated the molecular effects of acute and prolonged hypoxia on distinct embryonic and extraembryonic stem cell types as well as the functional impact on differentiation potential. We find a temporal and cell type-specific transcriptional response including an early primitive streak signature in hypoxic embryonic stem (ES) cells. Using a 3D gastruloid differentiation model, we show that hypoxia-induced T expression enables symmetry breaking and axial elongation in the absence of exogenous WNT activation. Importantly, hypoxia also modulates T levels in conventional gastruloids and enhances representation of endodermal and neural markers. Mechanistically, we identify Hif1α as a central factor that mediates the transcriptional response to hypoxia in balance with epigenetic and metabolic rewiring. Our findings directly link the microenvironment to stem cell function and provide a rationale supportive of applying physiological conditions in models of embryo development

Competing Interest Statement

The authors have declared no competing interest.

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Posted July 22, 2021.
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Hypoxia induces a transcriptional early primitive streak signature in pluripotent cells enhancing spontaneous elongation and lineage representation in gastruloids
Natalia López-Anguita, Seher Ipek Gassaloglu, Maximilian Stötzel, Marina Typou, Iiris Virta, Sara Hetzel, René Buschow, Burak Koksal, Derya Atilla, Ronald Maitschke-Rajasekharan, Rui Chen, Alexandra L. Mattei, Ivan Bedzhov, David Meierhofer, Alexander Meissner, Jesse V. Veenvliet, Aydan Bulut-Karslioglu
bioRxiv 2021.07.21.452906; doi: https://doi.org/10.1101/2021.07.21.452906
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Hypoxia induces a transcriptional early primitive streak signature in pluripotent cells enhancing spontaneous elongation and lineage representation in gastruloids
Natalia López-Anguita, Seher Ipek Gassaloglu, Maximilian Stötzel, Marina Typou, Iiris Virta, Sara Hetzel, René Buschow, Burak Koksal, Derya Atilla, Ronald Maitschke-Rajasekharan, Rui Chen, Alexandra L. Mattei, Ivan Bedzhov, David Meierhofer, Alexander Meissner, Jesse V. Veenvliet, Aydan Bulut-Karslioglu
bioRxiv 2021.07.21.452906; doi: https://doi.org/10.1101/2021.07.21.452906

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