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Trophoblast survival signaling during human placentation requires HIF-induced transcription of HSP70

Chandni V. Jain, Philip Jessmon, Charbel T. Barrak, Alan D. Bolnik, Brian A. Kilburn, Michael Hertz, D. Randall Armant
doi: https://doi.org/10.1101/043851
Chandni V. Jain
1Departments of Phyiology, Wayne State University School of Medicine, Detroit, Michigan, USA
2Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
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Philip Jessmon
2Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
3Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan, USA
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Charbel T. Barrak
2Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
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Alan D. Bolnik
2Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
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Brian A. Kilburn
2Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
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Michael Hertz
2Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
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D. Randall Armant
2Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
3Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan, USA
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  • For correspondence: d.armant@wayne.edu
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Abstract

Survival of trophoblast cells in the low oxygen environment of human placentation requires metalloproteinase-mediated shedding of HBEGF and downstream signaling. A matrix metalloproteinase (MMP) antibody array and quantitative RT-PCR revealed upregulation of MMP2 post-transcriptionally in human first trimester HTR-8/SVneo trophoblast cells and placental explants exposed to 2% O2. Specific MMP inhibitors established the requirement for MMP2 in HBEGF shedding and upregulation. Hypoxia inducible factors, HIF1A and EPAS1 (HIF2A), accumulated at 2% O2, and HIF target genes were identified by next-generation sequencing of RNA from trophoblast cells cultured at 2% O2 for 0, 1, 2 and 4 hrs. Of nine genes containing HIF-response elements upregulated at 1 hour, only HSPA6 (HSP70B’) remained elevated after 4 hours. The HSP70 chaperone inhibitor VER155008 blocked upregulation of both MMP2 and HBEGF at 2% O2, and increased apoptosis. However, both HBEGF upregulation and apoptosis were rescued by exogenous MMP2. We propose that MMP2-mediated shedding of HBEGF, initiated by HSP70, contributes to trophoblast survival at the low O2 levels encountered during the first trimester, and is essential for successful pregnancy outcomes.

Summary Statement Trophoblast survival during human placentation, when oxygenation is minimal, required HIF-induced transcription of HSP70, which mediated MMP2 accumulation and the transactivation of anti-apoptotic ERBB signaling by HBEGF shedding.

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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 4.0 International license.
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Posted March 15, 2016.
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Trophoblast survival signaling during human placentation requires HIF-induced transcription of HSP70
Chandni V. Jain, Philip Jessmon, Charbel T. Barrak, Alan D. Bolnik, Brian A. Kilburn, Michael Hertz, D. Randall Armant
bioRxiv 043851; doi: https://doi.org/10.1101/043851
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Trophoblast survival signaling during human placentation requires HIF-induced transcription of HSP70
Chandni V. Jain, Philip Jessmon, Charbel T. Barrak, Alan D. Bolnik, Brian A. Kilburn, Michael Hertz, D. Randall Armant
bioRxiv 043851; doi: https://doi.org/10.1101/043851

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