Laminins Regulate Placentation and Pre-eclampsia: Focus on Trophoblasts and Endothelial Cells

Liu, Min; Yin, Yangxue; Yu, Hongbiao; Zhou, Rong

doi:10.3389/fcell.2020.00754

Cited by 14 publications

(6 citation statements)

References 78 publications

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“…Laminins are in the basement membrane protein family and prior studies have shown that laminins are engaged in placental development and regulate placental trophoblast cell functions. 12 LAMC2 is a unique subunit of heterotrimeric glycoprotein laminin-5, located on chromosome 1q25-q31. 13 Mounting evidences indicated LAMC2 is involved in the development and maintenance of embryonic differentiated tissues, affecting the differentiation, migration and adhesion, as well as the phenotype and survival of normal and tumor cells, and is expected to a promising cancer biomarker.…”

Section: Introductionmentioning

confidence: 99%

“…Hence, it is imperative to identify the relevant proteins and pathways affecting placental implantation for further prediction and intervention. Laminins are in the basement membrane protein family and prior studies have shown that laminins are engaged in placental development and regulate placental trophoblast cell functions 12 . LAMC2 is a unique subunit of heterotrimeric glycoprotein laminin‐5, located on chromosome 1q25‐q31 13 .…”

Section: Introductionmentioning

confidence: 99%

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Overexpressed LAMC2 promotes trophoblast over‐invasion through the PI3K/Akt/MMP2/9 pathway in placenta accreta spectrum

Wang

Liu

Zhao

et al. 2022

J of Obstet and Gynaecol

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Background Placenta accreta spectrum (PAS) is an ongoing major iatrogenic public health challenge with devastating obstetric complications, but its underlying molecular pathogenesis remains poorly illuminated. LAMC2 is reported to regulate tumor cells proliferation and invasion, yet has not been explored in placenta trophoblast cells. This study investigated LAMC2 expression and its contribution in the etiology of PAS. Methods Quantitative polymerase chain reaction, western blot, and immunohistochemistry were performed to detect the expression of LAMC2 in placentas. Cell proliferation, invasion, migration, and apoptosis were monitored by CCK8 assay, wound healing assay, transwell invasion assay, and flow cytometry assay. Western blot was conducted to confirm the pertinent proteins level of PI3K/Akt/MMP2/9 pathway in HTR8/SVneo cells. Results LAMC2 was predominantly expressed in placental villous syncytiotrophoblasts and cytotrophoblasts. LAMC2 mRNA and protein expression were substantially upregulated in placental tissues with PAS compared to those with pernicious placenta previa without PAS. LAMC2 overexpression eminently boosted HTR8/SVneo cells proliferation, invasion, and migration, but inhibited apoptosis, accompanied by elevated protein expression of MMP2, MMP9, and phosphorylated Akt (pAkt). Knockdown of LAMC2 yielded the converse results. Additionally, when treated with LY294002, the effects of LAMC2 overexpression on proliferation, migration, invasion, and apoptosis of HTR8/SVneo cells were abolished and concomitantly the elevated pAkt, MMP2, and MMP9 proteins induced by LAMC2 overexpression were eliminated. Conclusion Our study highlighted the involvement of LAMC2 in the pathogenesis of PAS by activating the PI3K/Akt/MMP2/9 signaling pathway to stimulate trophoblast over‐invasion. These findings provide a new target for the diagnosis and disease stratification of PAS.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Overexpressed LAMC2 promotes trophoblast over‐invasion through the PI3K/Akt/MMP2/9 pathway in placenta accreta spectrum

Wang

Liu

Zhao

et al. 2022

J of Obstet and Gynaecol

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“…Placental pathology is associated with changes to ECM composition. Specifically, there is a relationship between altered ECM and preeclampsia [ 68–70 ], with decreased placental laminin [ 68–70 ], the collagen IV to laminin ratio altered [ 71 ], and fibronectin reduced around the fetal vessels in the villi [ 72 ]. We previously showed in our growth-restricted reduced uteroplacental perfusion pressure (RUPP) mouse placenta study (an animal model of preeclampsia) that collagen was reduced in the RUPP placentae [ 10 ], and in a separate study that maternal exposure to Δ9-THC during pregnancy alters the placental fetal blood spaces and vessel-associated expression of collagen IV [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

Extracellular Matrix Influences Gene Expression and Differentiation of Mouse Trophoblast Stem Cells

Natale

Kotadia

Gustin

et al. 2023

Stem Cells and Development

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Trophoblast stem (TS) cells were first isolated from the mouse placenta; however, little is known about their maintenance and niche in vivo. TS cells, like other stem cells, have a unique microenvironment in which the extracellular matrix (ECM) is a component. Placental pathology is associated with ECM change. However, how these changes and the individual ECM components impact the maintenance or differentiation of TS cells has not been established. This study identified which ECM component(s) maintain the greatest expression of markers associated with undifferentiated mouse trophoblast stem (mTS) cells and which alter the profile of markers of differentiation based on mRNA analysis. mTS cells cultured on individual ECM components and subsequent quantitative polymerase chain reaction analysis revealed that laminin promoted the expression of markers associated with undifferentiated TS cells, fibronectin promoted gene expression associated with syncytiotrophoblast (SynT) layer II cells, and collagen IV promoted the expression of genes associated with differentiated trophoblast. To investigate whether pathological placental ECM influenced the expression of genes associated with different trophoblast subtypes, the mouse model of streptozotocin (STZ)-induced pancreatic β cell ablation and diabetes was used. Female mice administered STZ (blood glucose ≥300 mg/dL) or control (blood glucose ≤150 mg/dL) were mated. Placental pathology at embryonic day (E)14.5 was confirmed with reduced fetal blood space area, reduced expression of the pericyte marker αSMA, and decreased expression of ECM proteins. mTS cells cultured on ECM isolated from STZ placenta were associated with reduced expression of undifferentiated mTS markers and increased expression of genes associated with terminally differentiated trophoblast [ Gcm-1 and SynA (SynT) and junctional zone Tpbpa and Prl2c2 ]. Altogether, these results support the value of using ECM isolated from the placenta as a tool for understanding trophoblast contribution to placental pathology.

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“…The role for BCAM interaction with laminin cannot be ignored here as well, as this interaction may establish an extracellular matrix progenitor cell niche. Laminin has been shown to be necessary for proper trophoblast implantation, placental perfusion, and angiogenesis 53 . The inclusion of laminin in Matrigel used in organoid culture may provide signaling through integrins expressed on the cytotrophoblast cell surface to induce BCAM expression, explaining this observation in our BCAM lo organoids.…”

Section: Discussionmentioning

confidence: 99%

Cell trajectory modeling identifies a primitive trophoblast state defined by BCAM enrichment

Shannon

Baltayeva

Castellana

et al. 2021

Preprint

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The establishment and function of the human placenta is dependent on specialized cells called trophoblasts. Progenitor cytotrophoblasts (CTBs) differentiate along one of two cellular trajectories: the villous or extravillous pathways. CTBs committed to the villous pathway fuse with neighboring CTBs forming the outer multinucleated syncytiotrophoblast layer (SCT), while CTBs committed to the extravillous pathway develop into multi-layered cell columns that anchor the placenta to uterine tissue. At distal column sites, column CTBs differentiate into invasive extravillous trophoblasts (EVT) that facilitate uterine remodeling of spiral arteries and modulate the maternal immune response to fetal antigen. Unfortunately, little is known about the cellular and molecular processes controlling human trophoblast stem cell maintenance and differentiation into these critical trophoblast sub-lineages. To address this, our laboratory established a single cell RNA sequencing (scRNA-seq) dataset from first trimester placentas to identify molecular programs and cell states important in trophoblast progenitor establishment, renewal, and differentiation. Using this dataset, eight distinct trophoblast states were identified, representing progenitor cytotrophoblasts, intermediate column CTBs, syncytiotrophoblast progenitors, and terminally differentiated EVT. Lineage trajectory analysis identified a CTB origin that was reproduced in human trophoblast stem cell organoids. Heightened expression of basal cell adhesion molecule (BCAM) defined this primitive state, where CTBs selected for high levels of surface BCAM expression generated larger clonally-derived organoids than did CTB counterparts expressing lower levels of BCAM. Together, this work resolves complex gene networks within human trophoblast progenitor cells, and identifies BCAM as marker that defines an up-stream progenitor origin.

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Laminins Regulate Placentation and Pre-eclampsia: Focus on Trophoblasts and Endothelial Cells

Cited by 14 publications

References 78 publications

Overexpressed LAMC2 promotes trophoblast over‐invasion through the PI3K/Akt/MMP2/9 pathway in placenta accreta spectrum

Overexpressed LAMC2 promotes trophoblast over‐invasion through the PI3K/Akt/MMP2/9 pathway in placenta accreta spectrum

Extracellular Matrix Influences Gene Expression and Differentiation of Mouse Trophoblast Stem Cells

Cell trajectory modeling identifies a primitive trophoblast state defined by BCAM enrichment

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