Trophoblast survival signaling during human placentation requires HSP70 activation of MMP2-mediated HBEGF shedding
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 firs...
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creator | Jain, Chandni V Jessmon, Philip Barrak, Charbel T Bolnick, Alan D Kilburn, Brian A Hertz, Michael Armant, D Randall |
description | 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 villous explants exposed to 2% O
2
. Specific MMP inhibitors established the requirement for MMP2 in HBEGF shedding and upregulation. Because
α
-amanitin inhibited the upregulation of HBEGF, differentially expressed genes were identified by next-generation sequencing of RNA from trophoblast cells cultured at 2% O
2
for 0, 1, 2 and 4 h. Nine genes, all containing HIF-response elements, were upregulated at 1 h, but only HSPA6 (HSP70B’) remained elevated at 2–4 h. The HSP70 chaperone inhibitor VER 155008 blocked upregulation of both MMP2 and HBEGF at 2% O
2
, and increased apoptosis. However, both HBEGF upregulation and apoptosis were rescued by exogenous MMP2. Proximity ligation assays demonstrated interactions between HSP70 and MMP2, and between MMP2 and HBEGF, supporting the concept that MMP2-mediated shedding of HBEGF, initiated by HSP70, contributes to trophoblast survival at the low O
2
concentrations encountered during the first trimester, and is essential for successful pregnancy outcomes. Trophoblast survival during human placentation, when oxygenation is minimal, required HSP70 activity, which mediated MMP2 accumulation and the transactivation of anti-apoptotic ERBB signaling by HBEGF shedding. |
doi_str_mv | 10.1038/cdd.2017.104 |
format | Article |
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2
. Specific MMP inhibitors established the requirement for MMP2 in HBEGF shedding and upregulation. Because
α
-amanitin inhibited the upregulation of HBEGF, differentially expressed genes were identified by next-generation sequencing of RNA from trophoblast cells cultured at 2% O
2
for 0, 1, 2 and 4 h. Nine genes, all containing HIF-response elements, were upregulated at 1 h, but only HSPA6 (HSP70B’) remained elevated at 2–4 h. The HSP70 chaperone inhibitor VER 155008 blocked upregulation of both MMP2 and HBEGF at 2% O
2
, and increased apoptosis. However, both HBEGF upregulation and apoptosis were rescued by exogenous MMP2. Proximity ligation assays demonstrated interactions between HSP70 and MMP2, and between MMP2 and HBEGF, supporting the concept that MMP2-mediated shedding of HBEGF, initiated by HSP70, contributes to trophoblast survival at the low O
2
concentrations encountered during the first trimester, and is essential for successful pregnancy outcomes. Trophoblast survival during human placentation, when oxygenation is minimal, required HSP70 activity, which mediated MMP2 accumulation and the transactivation of anti-apoptotic ERBB signaling by HBEGF shedding.</description><identifier>ISSN: 1350-9047</identifier><identifier>EISSN: 1476-5403</identifier><identifier>DOI: 10.1038/cdd.2017.104</identifier><identifier>PMID: 28731464</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/106 ; 13/2 ; 13/51 ; 38/1 ; 38/77 ; 38/90 ; 38/91 ; 631/337 ; 631/80 ; 82/80 ; Amanitin ; Apoptosis ; Biochemistry ; Biomedical and Life Sciences ; Cell Biology ; Cell Cycle Analysis ; Cell Line ; Cell Movement ; Cells, Cultured ; ErbB protein ; Explants ; Female ; Gelatinase A ; Genes ; Heparin-binding EGF-like Growth Factor - metabolism ; HSP70 Heat-Shock Proteins - metabolism ; Hsp70 protein ; Humans ; Life Sciences ; Matrix metalloproteinase ; Matrix Metalloproteinase 2 - metabolism ; Metalloproteinase ; Original Paper ; Oxygenation ; Placenta ; Placentation ; Polymerase chain reaction ; Post-transcription ; Pregnancy ; Regulatory sequences ; Ribonucleic acid ; RNA ; Shedding ; Stem Cells ; Survival ; Transcription ; Trophoblasts - cytology ; Up-Regulation</subject><ispartof>Cell death and differentiation, 2017-10, Vol.24 (10), p.1772-1783</ispartof><rights>Macmillan Publishers Limited, part of Springer Nature. 2017</rights><rights>Copyright Nature Publishing Group Oct 2017</rights><rights>Copyright © 2017 Macmillan Publishers Limited, part of Springer Nature. 2017 Macmillan Publishers Limited, part of Springer Nature.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c450t-89434905cf4c2fa6a287dbfc3833c325ce51cce813553a4045a1d845e548971a3</citedby><cites>FETCH-LOGICAL-c450t-89434905cf4c2fa6a287dbfc3833c325ce51cce813553a4045a1d845e548971a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596420/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596420/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28731464$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jain, Chandni V</creatorcontrib><creatorcontrib>Jessmon, Philip</creatorcontrib><creatorcontrib>Barrak, Charbel T</creatorcontrib><creatorcontrib>Bolnick, Alan D</creatorcontrib><creatorcontrib>Kilburn, Brian A</creatorcontrib><creatorcontrib>Hertz, Michael</creatorcontrib><creatorcontrib>Armant, D Randall</creatorcontrib><title>Trophoblast survival signaling during human placentation requires HSP70 activation of MMP2-mediated HBEGF shedding</title><title>Cell death and differentiation</title><addtitle>Cell Death Differ</addtitle><addtitle>Cell Death Differ</addtitle><description>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 villous explants exposed to 2% O
2
. Specific MMP inhibitors established the requirement for MMP2 in HBEGF shedding and upregulation. Because
α
-amanitin inhibited the upregulation of HBEGF, differentially expressed genes were identified by next-generation sequencing of RNA from trophoblast cells cultured at 2% O
2
for 0, 1, 2 and 4 h. Nine genes, all containing HIF-response elements, were upregulated at 1 h, but only HSPA6 (HSP70B’) remained elevated at 2–4 h. The HSP70 chaperone inhibitor VER 155008 blocked upregulation of both MMP2 and HBEGF at 2% O
2
, and increased apoptosis. However, both HBEGF upregulation and apoptosis were rescued by exogenous MMP2. Proximity ligation assays demonstrated interactions between HSP70 and MMP2, and between MMP2 and HBEGF, supporting the concept that MMP2-mediated shedding of HBEGF, initiated by HSP70, contributes to trophoblast survival at the low O
2
concentrations encountered during the first trimester, and is essential for successful pregnancy outcomes. Trophoblast survival during human placentation, when oxygenation is minimal, required HSP70 activity, which mediated MMP2 accumulation and the transactivation of anti-apoptotic ERBB signaling by HBEGF shedding.</description><subject>13/106</subject><subject>13/2</subject><subject>13/51</subject><subject>38/1</subject><subject>38/77</subject><subject>38/90</subject><subject>38/91</subject><subject>631/337</subject><subject>631/80</subject><subject>82/80</subject><subject>Amanitin</subject><subject>Apoptosis</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Cell Biology</subject><subject>Cell Cycle Analysis</subject><subject>Cell Line</subject><subject>Cell Movement</subject><subject>Cells, Cultured</subject><subject>ErbB protein</subject><subject>Explants</subject><subject>Female</subject><subject>Gelatinase A</subject><subject>Genes</subject><subject>Heparin-binding EGF-like Growth Factor - metabolism</subject><subject>HSP70 Heat-Shock Proteins - metabolism</subject><subject>Hsp70 protein</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Matrix metalloproteinase</subject><subject>Matrix Metalloproteinase 2 - metabolism</subject><subject>Metalloproteinase</subject><subject>Original Paper</subject><subject>Oxygenation</subject><subject>Placenta</subject><subject>Placentation</subject><subject>Polymerase chain reaction</subject><subject>Post-transcription</subject><subject>Pregnancy</subject><subject>Regulatory sequences</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Shedding</subject><subject>Stem Cells</subject><subject>Survival</subject><subject>Transcription</subject><subject>Trophoblasts - cytology</subject><subject>Up-Regulation</subject><issn>1350-9047</issn><issn>1476-5403</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNptkc1P3DAQxa2qVfkot54rS730QGAc23FyqUQRsJVAIBXO1qzt7Bpl42AnK_W_r9OliFY9jUfz8_MbP0I-MjhhwOtTY-1JCUzlTrwh-0yoqpAC-Nt85hKKBoTaIwcpPQJApZrqPdkra8WZqMQ-ifcxDOuw7DCNNE1x67fY0eRXPXa-X1E7xbmspw32dOjQuH7E0YeeRvc0-egSXfy4U0DRjPnq70lo6c3NXVlsnPU4OksX3y6uLmlaO2uz2AfyrsUuuaPnekgeLi_uzxfF9e3V9_Oz68IICWNRN4KLBqRphSlbrDCbtsvW8Jpzw0tpnGTGuDovKTkKEBKZrYV0UtSNYsgPyded7jAts5XZecROD9FvMP7UAb3-e9L7tV6FrZayqUQJWeDLs0AMT5NLo974ZFzXYe_ClDRrylICByUy-vkf9DFMMf_hTHHFKyF5lanjHWViSCm69sUMAz2HqXOYeg4zd7Pop9cLvMB_0stAsQPSMKfk4qtX_yf4CxxSqeE</recordid><startdate>20171001</startdate><enddate>20171001</enddate><creator>Jain, Chandni V</creator><creator>Jessmon, Philip</creator><creator>Barrak, Charbel T</creator><creator>Bolnick, Alan D</creator><creator>Kilburn, Brian A</creator><creator>Hertz, Michael</creator><creator>Armant, D Randall</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20171001</creationdate><title>Trophoblast survival signaling during human placentation requires HSP70 activation of MMP2-mediated HBEGF shedding</title><author>Jain, Chandni V ; Jessmon, Philip ; Barrak, Charbel T ; Bolnick, Alan D ; Kilburn, Brian A ; Hertz, Michael ; Armant, D Randall</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c450t-89434905cf4c2fa6a287dbfc3833c325ce51cce813553a4045a1d845e548971a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>13/106</topic><topic>13/2</topic><topic>13/51</topic><topic>38/1</topic><topic>38/77</topic><topic>38/90</topic><topic>38/91</topic><topic>631/337</topic><topic>631/80</topic><topic>82/80</topic><topic>Amanitin</topic><topic>Apoptosis</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Cell Biology</topic><topic>Cell Cycle Analysis</topic><topic>Cell Line</topic><topic>Cell Movement</topic><topic>Cells, Cultured</topic><topic>ErbB protein</topic><topic>Explants</topic><topic>Female</topic><topic>Gelatinase A</topic><topic>Genes</topic><topic>Heparin-binding EGF-like Growth Factor - metabolism</topic><topic>HSP70 Heat-Shock Proteins - metabolism</topic><topic>Hsp70 protein</topic><topic>Humans</topic><topic>Life Sciences</topic><topic>Matrix metalloproteinase</topic><topic>Matrix Metalloproteinase 2 - metabolism</topic><topic>Metalloproteinase</topic><topic>Original Paper</topic><topic>Oxygenation</topic><topic>Placenta</topic><topic>Placentation</topic><topic>Polymerase chain reaction</topic><topic>Post-transcription</topic><topic>Pregnancy</topic><topic>Regulatory sequences</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>Shedding</topic><topic>Stem Cells</topic><topic>Survival</topic><topic>Transcription</topic><topic>Trophoblasts - cytology</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jain, Chandni V</creatorcontrib><creatorcontrib>Jessmon, Philip</creatorcontrib><creatorcontrib>Barrak, Charbel T</creatorcontrib><creatorcontrib>Bolnick, Alan D</creatorcontrib><creatorcontrib>Kilburn, Brian A</creatorcontrib><creatorcontrib>Hertz, Michael</creatorcontrib><creatorcontrib>Armant, D Randall</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>ProQuest Health and Medical</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biological Sciences</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest Biological Science Journals</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell death and differentiation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jain, Chandni V</au><au>Jessmon, Philip</au><au>Barrak, Charbel T</au><au>Bolnick, Alan D</au><au>Kilburn, Brian A</au><au>Hertz, Michael</au><au>Armant, D Randall</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Trophoblast survival signaling during human placentation requires HSP70 activation of MMP2-mediated HBEGF shedding</atitle><jtitle>Cell death and differentiation</jtitle><stitle>Cell Death Differ</stitle><addtitle>Cell Death Differ</addtitle><date>2017-10-01</date><risdate>2017</risdate><volume>24</volume><issue>10</issue><spage>1772</spage><epage>1783</epage><pages>1772-1783</pages><issn>1350-9047</issn><eissn>1476-5403</eissn><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 villous explants exposed to 2% O
2
. Specific MMP inhibitors established the requirement for MMP2 in HBEGF shedding and upregulation. Because
α
-amanitin inhibited the upregulation of HBEGF, differentially expressed genes were identified by next-generation sequencing of RNA from trophoblast cells cultured at 2% O
2
for 0, 1, 2 and 4 h. Nine genes, all containing HIF-response elements, were upregulated at 1 h, but only HSPA6 (HSP70B’) remained elevated at 2–4 h. The HSP70 chaperone inhibitor VER 155008 blocked upregulation of both MMP2 and HBEGF at 2% O
2
, and increased apoptosis. However, both HBEGF upregulation and apoptosis were rescued by exogenous MMP2. Proximity ligation assays demonstrated interactions between HSP70 and MMP2, and between MMP2 and HBEGF, supporting the concept that MMP2-mediated shedding of HBEGF, initiated by HSP70, contributes to trophoblast survival at the low O
2
concentrations encountered during the first trimester, and is essential for successful pregnancy outcomes. Trophoblast survival during human placentation, when oxygenation is minimal, required HSP70 activity, which mediated MMP2 accumulation and the transactivation of anti-apoptotic ERBB signaling by HBEGF shedding.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28731464</pmid><doi>10.1038/cdd.2017.104</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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subjects | 13/106 13/2 13/51 38/1 38/77 38/90 38/91 631/337 631/80 82/80 Amanitin Apoptosis Biochemistry Biomedical and Life Sciences Cell Biology Cell Cycle Analysis Cell Line Cell Movement Cells, Cultured ErbB protein Explants Female Gelatinase A Genes Heparin-binding EGF-like Growth Factor - metabolism HSP70 Heat-Shock Proteins - metabolism Hsp70 protein Humans Life Sciences Matrix metalloproteinase Matrix Metalloproteinase 2 - metabolism Metalloproteinase Original Paper Oxygenation Placenta Placentation Polymerase chain reaction Post-transcription Pregnancy Regulatory sequences Ribonucleic acid RNA Shedding Stem Cells Survival Transcription Trophoblasts - cytology Up-Regulation |
title | Trophoblast survival signaling during human placentation requires HSP70 activation of MMP2-mediated HBEGF shedding |
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