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
The Department of Obstetrics, Gynaecology and Newborn Health/Mercy Hospital for Women, University of Melbourne, 163 Studley Road, Heidelberg, Victoria, 3084, Australia.
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
Stem Cell Rev Rep. 2025 Apr;21(3):872-896. doi: 10.1007/s12015-024-10831-2. Epub 2024 Dec 17.
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.
富含亮氨酸重复序列的G蛋白偶联受体5/4（LGR5/LGR4）是包括肠道在内的上皮组织中的关键干细胞标志物。它们激活无翅相关整合位点（WNT）信号通路。到目前为止，LGR5/LGR4在胎盘（可能存在类似功能）中尚未被描述。我们对LGR5/LGR4及其在人胎盘中的配体/靶点进行了表征，并对先兆子痫/胎儿生长受限（FGR）中的失调进行了进一步评估。LGR5 mRNA在孕早期（n = 11）、早产（n = 9）和足月（n = 11）胎盘裂解物中未发生改变。LGR5在人滋养层干细胞（hTSCs）中富集，并随着向绒毛外滋养层细胞（p < 0.0215）和合胞体滋养层细胞（p < 0.0350）的分化而下调。原位杂交将LGR5定位到合胞体下方独特的、增殖性的MKI67 +单核滋养层细胞，这与单细胞转录组学中提出的祖细胞身份一致。在早发型先兆子痫（p < 0.0001，81例对19例对照）、晚发型先兆子痫（p = 0.0046，20例对33例对照）和FGR（p = 0.0031，34例对17例对照）的胎盘中，LGR5表达显著降低。与早产和足月胎盘相比，LGR4在孕早期胎盘中升高（p = 0.0412），在早发型先兆子痫胎盘中升高（p = 0.0148），在FGR胎盘中升高（p = 0.0417）。转录组分析以及体外hTSC向两种滋养层谱系的分化表明，LGR4随着分化而增加。胎盘绒毛样本的单核RNA测序支持LGR5和LGR4的定位结果。胎盘功能不全发病机制中胎盘所经历的缺氧/促炎细胞因子处理模型元素并未显著改变LGR5/LGR4。在先兆子痫妊娠的胎盘中，配体R-spondins 1/3/4以及中和靶点环指蛋白43（RNF43）和锌指环指蛋白3（ZNRF3）也减少。本研究首次描述了LGR5/LGR4及其信号伴侣在人胎盘中的表达。它们在先兆子痫胎盘中的失调暗示了在与WNT信号相关的胎盘发育过程中，可能发生的滋养层干细胞功能/分化的破坏。
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