Stem Cell Markers LGR5, LGR4 and Their Immediate Signalling Partners are Dysregulated in Preeclampsia
Leucine-rich repeat-containing G protein-coupled receptors 5/4 (LGR5/LGR4) are critical stem cell markers in epithelial tissues including intestine. They agonise wingless-related integration site (WNT) signalling. Until now, LGR5/LGR4 were uncharacterised in placenta, where analogous functions may e...
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| creator | Wong, Georgia P Hartmann, Sunhild Nonn, Olivia Cannon, Ping Nguyen, Tuong-Vi Kandel, Manju de Alwis, Natasha Murphy, Ciara N Pritchard, Natasha Dechend, Ralf Hannan, Natalie J Tong, Stephen Simmons, David G Kaitu'u-Lino, Tu'uhevaha J |
| description | Leucine-rich repeat-containing G protein-coupled receptors 5/4 (LGR5/LGR4) are critical stem cell markers in epithelial tissues including intestine. They agonise wingless-related integration site (WNT) signalling. Until now, LGR5/LGR4 were uncharacterised in placenta, where analogous functions may exist. We characterised LGR5/LGR4, their ligands/targets in human placenta, with further assessments on dysregulation in preeclampsia/fetal growth restriction (FGR). LGR5 mRNA was unaltered in first trimester (n = 11), preterm (n = 9) and term (n = 11) placental lysate. LGR5 was enriched in human trophoblast stem cells (hTSCs) and downregulated with differentiation to extravillous trophoblasts (p |
| doi_str_mv | 10.1007/s12015-024-10831-2 |
| format | Article |
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They agonise wingless-related integration site (WNT) signalling. Until now, LGR5/LGR4 were uncharacterised in placenta, where analogous functions may exist. We characterised LGR5/LGR4, their ligands/targets in human placenta, with further assessments on dysregulation in preeclampsia/fetal growth restriction (FGR). LGR5 mRNA was unaltered in first trimester (n = 11), preterm (n = 9) and term (n = 11) placental lysate. LGR5 was enriched in human trophoblast stem cells (hTSCs) and downregulated with differentiation to extravillous trophoblasts (p < 0.0215) and syncytiotrophoblasts (p < 0.0350). In situ hybridisation localised LGR5 to unique, proliferative MKI67 + mononuclear trophoblasts underlying syncytium which concurred with proposed progenitor identities in single-cell transcriptomics. LGR5 expression was significantly reduced in placentas from early-onset preeclampsia (p < 0.0001, n = 81 versus n = 19 controls), late-onset preeclampsia (p = 0.0046, n = 20 versus n = 33 controls) and FGR (p = 0.0031, n = 34 versus n = 17 controls). LGR4 was elevated in first trimester versus preterm and term placentas (p = 0.0412), in placentas with early-onset preeclampsia (p = 0.0148) and in FGR (p = 0.0417). Transcriptomic analysis and in vitro hTSC differentiation to both trophoblast lineages suggested LGR4 increases with differentiation. Single-nucleus RNA sequencing of placental villous samples supported LGR5 and LGR4 localisation findings. Hypoxia/proinflammatory cytokine treatment modelling elements experienced by the placenta in placental insufficiency pathogenesis did not significantly alter LGR5/LGR4. Ligands R-spondins 1/3/4, and neutralising targets ring finger protein 43 (RNF43) and zinc and ring finger 3 (ZNRF3) were also reduced in placentas from preeclamptic pregnancies. This study is the first to describe LGR5/LGR4 and their signalling partner expression in human placenta. Their dysregulations in the preeclamptic placenta allude to disruptions to integral trophoblast stem cell function/differentiation that may occur during placental development related to WNT signalling.</description><identifier>ISSN: 2629-3277</identifier><identifier>EISSN: 2629-3277</identifier><identifier>DOI: 10.1007/s12015-024-10831-2</identifier><identifier>PMID: 39688759</identifier><language>eng</language><publisher>United States</publisher><ispartof>Stem cell reviews and reports, 2024-12</ispartof><rights>2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0003-4131-0008</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39688759$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wong, Georgia P</creatorcontrib><creatorcontrib>Hartmann, Sunhild</creatorcontrib><creatorcontrib>Nonn, Olivia</creatorcontrib><creatorcontrib>Cannon, Ping</creatorcontrib><creatorcontrib>Nguyen, Tuong-Vi</creatorcontrib><creatorcontrib>Kandel, Manju</creatorcontrib><creatorcontrib>de Alwis, Natasha</creatorcontrib><creatorcontrib>Murphy, Ciara N</creatorcontrib><creatorcontrib>Pritchard, Natasha</creatorcontrib><creatorcontrib>Dechend, Ralf</creatorcontrib><creatorcontrib>Hannan, Natalie J</creatorcontrib><creatorcontrib>Tong, Stephen</creatorcontrib><creatorcontrib>Simmons, David G</creatorcontrib><creatorcontrib>Kaitu'u-Lino, Tu'uhevaha J</creatorcontrib><title>Stem Cell Markers LGR5, LGR4 and Their Immediate Signalling Partners are Dysregulated in Preeclampsia</title><title>Stem cell reviews and reports</title><addtitle>Stem Cell Rev Rep</addtitle><description>Leucine-rich repeat-containing G protein-coupled receptors 5/4 (LGR5/LGR4) are critical stem cell markers in epithelial tissues including intestine. They agonise wingless-related integration site (WNT) signalling. Until now, LGR5/LGR4 were uncharacterised in placenta, where analogous functions may exist. We characterised LGR5/LGR4, their ligands/targets in human placenta, with further assessments on dysregulation in preeclampsia/fetal growth restriction (FGR). LGR5 mRNA was unaltered in first trimester (n = 11), preterm (n = 9) and term (n = 11) placental lysate. LGR5 was enriched in human trophoblast stem cells (hTSCs) and downregulated with differentiation to extravillous trophoblasts (p < 0.0215) and syncytiotrophoblasts (p < 0.0350). In situ hybridisation localised LGR5 to unique, proliferative MKI67 + mononuclear trophoblasts underlying syncytium which concurred with proposed progenitor identities in single-cell transcriptomics. LGR5 expression was significantly reduced in placentas from early-onset preeclampsia (p < 0.0001, n = 81 versus n = 19 controls), late-onset preeclampsia (p = 0.0046, n = 20 versus n = 33 controls) and FGR (p = 0.0031, n = 34 versus n = 17 controls). LGR4 was elevated in first trimester versus preterm and term placentas (p = 0.0412), in placentas with early-onset preeclampsia (p = 0.0148) and in FGR (p = 0.0417). Transcriptomic analysis and in vitro hTSC differentiation to both trophoblast lineages suggested LGR4 increases with differentiation. Single-nucleus RNA sequencing of placental villous samples supported LGR5 and LGR4 localisation findings. Hypoxia/proinflammatory cytokine treatment modelling elements experienced by the placenta in placental insufficiency pathogenesis did not significantly alter LGR5/LGR4. Ligands R-spondins 1/3/4, and neutralising targets ring finger protein 43 (RNF43) and zinc and ring finger 3 (ZNRF3) were also reduced in placentas from preeclamptic pregnancies. This study is the first to describe LGR5/LGR4 and their signalling partner expression in human placenta. Their dysregulations in the preeclamptic placenta allude to disruptions to integral trophoblast stem cell function/differentiation that may occur during placental development related to WNT signalling.</description><issn>2629-3277</issn><issn>2629-3277</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNpNkE9Lw0AQxRdRbKn9Ah5kjx6Mzv5vjlK1FioW23vYbCZ1NUnjbnLotzdFBS8zw-P3Hrwh5JLBLQMwd5FxYCoBLhMGM8ESfkLGXPM0EdyY03_3iExj_AAALkAOnnMyEqmezYxKxwQ3HdZ0jlVFX2z4xBDpavGmbo5TUtsUdPuOPtBlXWPhbYd043eNrSrf7Ojahq45WmxA-nCIAXd9NTAF9Q1dB0RX2bqN3l6Qs9JWEae_e0K2T4_b-XOyel0s5_erpFU6TZRyDrTTxkDJdJ5zUSptHBcGXIqlZlJzMegsF7LQApEVEnLpVCmkwRTEhFz_xLZh_9Vj7LLaRzd0sw3u-5iJISHlSio5oFe_aJ8PzbI2-NqGQ_b3GfENQN9k_w</recordid><startdate>20241217</startdate><enddate>20241217</enddate><creator>Wong, Georgia P</creator><creator>Hartmann, Sunhild</creator><creator>Nonn, Olivia</creator><creator>Cannon, Ping</creator><creator>Nguyen, Tuong-Vi</creator><creator>Kandel, Manju</creator><creator>de Alwis, Natasha</creator><creator>Murphy, Ciara N</creator><creator>Pritchard, Natasha</creator><creator>Dechend, Ralf</creator><creator>Hannan, Natalie J</creator><creator>Tong, Stephen</creator><creator>Simmons, David G</creator><creator>Kaitu'u-Lino, Tu'uhevaha J</creator><scope>NPM</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-4131-0008</orcidid></search><sort><creationdate>20241217</creationdate><title>Stem Cell Markers LGR5, LGR4 and Their Immediate Signalling Partners are Dysregulated in Preeclampsia</title><author>Wong, Georgia P ; Hartmann, Sunhild ; Nonn, Olivia ; Cannon, Ping ; Nguyen, Tuong-Vi ; Kandel, Manju ; de Alwis, Natasha ; Murphy, Ciara N ; Pritchard, Natasha ; Dechend, Ralf ; Hannan, Natalie J ; Tong, Stephen ; Simmons, David G ; Kaitu'u-Lino, Tu'uhevaha J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p569-55cc06c6770f16bb23f567c2370c9ef6146236bb1b34d63ee1d40b4c5f347e903</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wong, Georgia P</creatorcontrib><creatorcontrib>Hartmann, Sunhild</creatorcontrib><creatorcontrib>Nonn, Olivia</creatorcontrib><creatorcontrib>Cannon, Ping</creatorcontrib><creatorcontrib>Nguyen, Tuong-Vi</creatorcontrib><creatorcontrib>Kandel, Manju</creatorcontrib><creatorcontrib>de Alwis, Natasha</creatorcontrib><creatorcontrib>Murphy, Ciara N</creatorcontrib><creatorcontrib>Pritchard, Natasha</creatorcontrib><creatorcontrib>Dechend, Ralf</creatorcontrib><creatorcontrib>Hannan, Natalie J</creatorcontrib><creatorcontrib>Tong, Stephen</creatorcontrib><creatorcontrib>Simmons, David G</creatorcontrib><creatorcontrib>Kaitu'u-Lino, Tu'uhevaha J</creatorcontrib><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Stem cell reviews and reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wong, Georgia P</au><au>Hartmann, Sunhild</au><au>Nonn, Olivia</au><au>Cannon, Ping</au><au>Nguyen, Tuong-Vi</au><au>Kandel, Manju</au><au>de Alwis, Natasha</au><au>Murphy, Ciara N</au><au>Pritchard, Natasha</au><au>Dechend, Ralf</au><au>Hannan, Natalie J</au><au>Tong, Stephen</au><au>Simmons, David G</au><au>Kaitu'u-Lino, Tu'uhevaha J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Stem Cell Markers LGR5, LGR4 and Their Immediate Signalling Partners are Dysregulated in Preeclampsia</atitle><jtitle>Stem cell reviews and reports</jtitle><addtitle>Stem Cell Rev Rep</addtitle><date>2024-12-17</date><risdate>2024</risdate><issn>2629-3277</issn><eissn>2629-3277</eissn><abstract>Leucine-rich repeat-containing G protein-coupled receptors 5/4 (LGR5/LGR4) are critical stem cell markers in epithelial tissues including intestine. They agonise wingless-related integration site (WNT) signalling. Until now, LGR5/LGR4 were uncharacterised in placenta, where analogous functions may exist. We characterised LGR5/LGR4, their ligands/targets in human placenta, with further assessments on dysregulation in preeclampsia/fetal growth restriction (FGR). LGR5 mRNA was unaltered in first trimester (n = 11), preterm (n = 9) and term (n = 11) placental lysate. LGR5 was enriched in human trophoblast stem cells (hTSCs) and downregulated with differentiation to extravillous trophoblasts (p < 0.0215) and syncytiotrophoblasts (p < 0.0350). In situ hybridisation localised LGR5 to unique, proliferative MKI67 + mononuclear trophoblasts underlying syncytium which concurred with proposed progenitor identities in single-cell transcriptomics. LGR5 expression was significantly reduced in placentas from early-onset preeclampsia (p < 0.0001, n = 81 versus n = 19 controls), late-onset preeclampsia (p = 0.0046, n = 20 versus n = 33 controls) and FGR (p = 0.0031, n = 34 versus n = 17 controls). LGR4 was elevated in first trimester versus preterm and term placentas (p = 0.0412), in placentas with early-onset preeclampsia (p = 0.0148) and in FGR (p = 0.0417). Transcriptomic analysis and in vitro hTSC differentiation to both trophoblast lineages suggested LGR4 increases with differentiation. Single-nucleus RNA sequencing of placental villous samples supported LGR5 and LGR4 localisation findings. Hypoxia/proinflammatory cytokine treatment modelling elements experienced by the placenta in placental insufficiency pathogenesis did not significantly alter LGR5/LGR4. Ligands R-spondins 1/3/4, and neutralising targets ring finger protein 43 (RNF43) and zinc and ring finger 3 (ZNRF3) were also reduced in placentas from preeclamptic pregnancies. This study is the first to describe LGR5/LGR4 and their signalling partner expression in human placenta. Their dysregulations in the preeclamptic placenta allude to disruptions to integral trophoblast stem cell function/differentiation that may occur during placental development related to WNT signalling.</abstract><cop>United States</cop><pmid>39688759</pmid><doi>10.1007/s12015-024-10831-2</doi><orcidid>https://orcid.org/0000-0003-4131-0008</orcidid></addata></record> |
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| title | Stem Cell Markers LGR5, LGR4 and Their Immediate Signalling Partners are Dysregulated in Preeclampsia |
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