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Low oxygen enhances trophoblast column growth by potentiating the extravillous lineage and promoting LOX activity

Jenna Treissman, Victor Yuan, Jennet Baltayeva, Hoa T. Le, Barbara Castellana, View ORCID ProfileWendy P. Robinson, View ORCID ProfileAlexander G. Beristain
doi: https://doi.org/10.1101/669796
Jenna Treissman
1The British Columbia Children’s Hospital Research Institute, Vancouver, Canada.
2Department of Obstetrics & Gynecology, The University of British Columbia, Vancouver, Canada.
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Victor Yuan
1The British Columbia Children’s Hospital Research Institute, Vancouver, Canada.
3Department of Medical Genetics, The University of British Columbia, Vancouver, Canada.
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Jennet Baltayeva
1The British Columbia Children’s Hospital Research Institute, Vancouver, Canada.
2Department of Obstetrics & Gynecology, The University of British Columbia, Vancouver, Canada.
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Hoa T. Le
1The British Columbia Children’s Hospital Research Institute, Vancouver, Canada.
2Department of Obstetrics & Gynecology, The University of British Columbia, Vancouver, Canada.
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Barbara Castellana
1The British Columbia Children’s Hospital Research Institute, Vancouver, Canada.
2Department of Obstetrics & Gynecology, The University of British Columbia, Vancouver, Canada.
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Wendy P. Robinson
1The British Columbia Children’s Hospital Research Institute, Vancouver, Canada.
3Department of Medical Genetics, The University of British Columbia, Vancouver, Canada.
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  • ORCID record for Wendy P. Robinson
Alexander G. Beristain
1The British Columbia Children’s Hospital Research Institute, Vancouver, Canada.
2Department of Obstetrics & Gynecology, The University of British Columbia, Vancouver, Canada.
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  • ORCID record for Alexander G. Beristain
  • For correspondence: aberista@mail.ubc.ca
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ABSTRACT

Early placental development and the establishment of the invasive trophoblast lineage take place within a low oxygen environment. However, conflicting and inconsistent findings have obscured the role of oxygen in regulating invasive trophoblast differentiation. In this study, the effect of hypoxic, normoxic, and atmospheric oxygen on invasive extravillous pathway progression was examined using a human placental explant model. Here, we show that exposure to low oxygen enhances extravillous column outgrowth and promotes the expression of genes that align with extravillous trophoblast (EVT) lineage commitment. By contrast, super-physiological atmospheric levels of oxygen promote trophoblast proliferation while simultaneously stalling EVT progression. Low oxygen-induced EVT differentiation coincided with elevated transcriptomic levels of lysyl oxidase (LOX) in trophoblast anchoring columns, where functional experiments established a role for LOX activity in promoting EVT column outgrowth. The findings of this work support a role for low oxygen in potentiating the differentiation of trophoblasts along the extravillous pathway. Additionally, these findings generate insight into new molecular processes controlled by oxygen during early placental development.

Summary Statement Low oxygen promotes extravillous trophoblast differentiation

Footnotes

  • The original bioRxiv submission was through a concurrent submission to a peer reviewed journal. As such, supplementary figures and tables were not able to be uploaded from the journal submission site to bioRxiv for this manuscript. The purpose of this revision is the uploading of 4 supplemental figures (Supplemental Figures 1-4) and 4 supplemental tables (Supplemental Tables 1-4) directly related to the manuscript.

  • Abbreviations

    BAPN
    β-aminopropionitrile
    BrdU
    Bromodeoxyuridine
    CM
    Conditioned media
    CTB
    Cytotrophoblast
    DAP
    1,5-diaminopentane
    DCT
    Distal column trophoblast
    DGE
    Differential gene expression
    ECM
    Extracellular matrix
    EVT
    Extravillous trophoblast
    FDR
    False discovery rate
    GO
    Gene ontology
    HIF1A
    Hypoxia inducible factor 1 A
    HLA-G
    Human leukocyte antigen G
    Hr
    Hour
    IF
    Immunofluorescence
    LOX
    Lysyl oxidase
    PCA
    Principal component analysis
    PCT
    Proximal column trophoblast
    PEG10
    Paternally expressed gene 10
    scRNA-seq
    single cell RNA sequencing
    SCT
    Syncytiotrophoblast
    UMAP
    Uniform manifold approximation and projection
    vCTB
    Villous cytotrophoblast
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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    Posted June 13, 2019.
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    Low oxygen enhances trophoblast column growth by potentiating the extravillous lineage and promoting LOX activity
    Jenna Treissman, Victor Yuan, Jennet Baltayeva, Hoa T. Le, Barbara Castellana, Wendy P. Robinson, Alexander G. Beristain
    bioRxiv 669796; doi: https://doi.org/10.1101/669796
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    Low oxygen enhances trophoblast column growth by potentiating the extravillous lineage and promoting LOX activity
    Jenna Treissman, Victor Yuan, Jennet Baltayeva, Hoa T. Le, Barbara Castellana, Wendy P. Robinson, Alexander G. Beristain
    bioRxiv 669796; doi: https://doi.org/10.1101/669796

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