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TLR4 Modulates Senescence and Paracrine Action in Placental Mesenchymal Stem Cells via Inhibiting Hedgehog Signaling Pathway in Preeclampsia
Preeclampsia (PE) is a heterogeneous disease closely associated with the accelerated senescence of the placentas. Placental mesenchymal stem cells (PMSCs) modulate placental development, which is abnormally senescent in PE together with abnormal paracrine. Both pivotal in the placenta development, T...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9214654/ https://www.ncbi.nlm.nih.gov/pubmed/35757501 http://dx.doi.org/10.1155/2022/7202837 |
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author | Zhong, Yanqi Zhang, Yang Liu, Weifang Zhao, Yin Zou, Li Liu, Xiaoxia |
author_facet | Zhong, Yanqi Zhang, Yang Liu, Weifang Zhao, Yin Zou, Li Liu, Xiaoxia |
author_sort | Zhong, Yanqi |
collection | PubMed |
description | Preeclampsia (PE) is a heterogeneous disease closely associated with the accelerated senescence of the placentas. Placental mesenchymal stem cells (PMSCs) modulate placental development, which is abnormally senescent in PE together with abnormal paracrine. Both pivotal in the placenta development, Toll-like receptor 4 (TLR4) and Hedgehog (HH) pathway are also tightly involved in regulating cellular senescence. This study was aimed at demonstrating that TLR4/HH pathway modulated senescence of placentas and PMSCs in vitro and in vivo. Preeclamptic and normal PMSCs were isolated. Smoothed agonist (SAG) and cyclopamine were used to activate and inhibit HH pathway, respectively. Lipopolysaccharide (LPS) was used to activate TLR4 in vitro and establish the classic PE-like rat model. qRT-PCR, Western blotting, and immunofluorescence were used to detect the expression of TLR4 and HH components (SHH, SMO, and Gli1). Cellular biological function such as proliferation, apoptosis, and migration was compared. Cell cycle analysis, β-galactosidase staining, and the protein expressions of p16 and p53 were detected to analyze the cellular senescence. The secretion levels of human matrix metalloproteinase 9 (MMP-9) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured in the conditioned medium. Cell migration, invasion, and tube formation were analyzed in HTR8/SVneo cells or human umbilical vein endothelial cells (HUVECs). Our study demonstrated that activation of TLR4 accelerated senescence of PMSCs via suppressing HH pathway both in vitro and in vivo, accompanied by the detrimental paracrine to impair the uterine spiral artery remodeling and placental angiogenesis. Meanwhile, induction of HH pathway could alleviate PE-like manifestations, improve pregnancy outcomes, and ameliorate multiorgan injuries, suggesting that strengthening the HH pathway may serve as a potential therapy in PE. |
format | Online Article Text |
id | pubmed-9214654 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Hindawi |
record_format | MEDLINE/PubMed |
spelling | pubmed-92146542022-06-23 TLR4 Modulates Senescence and Paracrine Action in Placental Mesenchymal Stem Cells via Inhibiting Hedgehog Signaling Pathway in Preeclampsia Zhong, Yanqi Zhang, Yang Liu, Weifang Zhao, Yin Zou, Li Liu, Xiaoxia Oxid Med Cell Longev Research Article Preeclampsia (PE) is a heterogeneous disease closely associated with the accelerated senescence of the placentas. Placental mesenchymal stem cells (PMSCs) modulate placental development, which is abnormally senescent in PE together with abnormal paracrine. Both pivotal in the placenta development, Toll-like receptor 4 (TLR4) and Hedgehog (HH) pathway are also tightly involved in regulating cellular senescence. This study was aimed at demonstrating that TLR4/HH pathway modulated senescence of placentas and PMSCs in vitro and in vivo. Preeclamptic and normal PMSCs were isolated. Smoothed agonist (SAG) and cyclopamine were used to activate and inhibit HH pathway, respectively. Lipopolysaccharide (LPS) was used to activate TLR4 in vitro and establish the classic PE-like rat model. qRT-PCR, Western blotting, and immunofluorescence were used to detect the expression of TLR4 and HH components (SHH, SMO, and Gli1). Cellular biological function such as proliferation, apoptosis, and migration was compared. Cell cycle analysis, β-galactosidase staining, and the protein expressions of p16 and p53 were detected to analyze the cellular senescence. The secretion levels of human matrix metalloproteinase 9 (MMP-9) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured in the conditioned medium. Cell migration, invasion, and tube formation were analyzed in HTR8/SVneo cells or human umbilical vein endothelial cells (HUVECs). Our study demonstrated that activation of TLR4 accelerated senescence of PMSCs via suppressing HH pathway both in vitro and in vivo, accompanied by the detrimental paracrine to impair the uterine spiral artery remodeling and placental angiogenesis. Meanwhile, induction of HH pathway could alleviate PE-like manifestations, improve pregnancy outcomes, and ameliorate multiorgan injuries, suggesting that strengthening the HH pathway may serve as a potential therapy in PE. Hindawi 2022-06-14 /pmc/articles/PMC9214654/ /pubmed/35757501 http://dx.doi.org/10.1155/2022/7202837 Text en Copyright © 2022 Yanqi Zhong et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Zhong, Yanqi Zhang, Yang Liu, Weifang Zhao, Yin Zou, Li Liu, Xiaoxia TLR4 Modulates Senescence and Paracrine Action in Placental Mesenchymal Stem Cells via Inhibiting Hedgehog Signaling Pathway in Preeclampsia |
title | TLR4 Modulates Senescence and Paracrine Action in Placental Mesenchymal Stem Cells via Inhibiting Hedgehog Signaling Pathway in Preeclampsia |
title_full | TLR4 Modulates Senescence and Paracrine Action in Placental Mesenchymal Stem Cells via Inhibiting Hedgehog Signaling Pathway in Preeclampsia |
title_fullStr | TLR4 Modulates Senescence and Paracrine Action in Placental Mesenchymal Stem Cells via Inhibiting Hedgehog Signaling Pathway in Preeclampsia |
title_full_unstemmed | TLR4 Modulates Senescence and Paracrine Action in Placental Mesenchymal Stem Cells via Inhibiting Hedgehog Signaling Pathway in Preeclampsia |
title_short | TLR4 Modulates Senescence and Paracrine Action in Placental Mesenchymal Stem Cells via Inhibiting Hedgehog Signaling Pathway in Preeclampsia |
title_sort | tlr4 modulates senescence and paracrine action in placental mesenchymal stem cells via inhibiting hedgehog signaling pathway in preeclampsia |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9214654/ https://www.ncbi.nlm.nih.gov/pubmed/35757501 http://dx.doi.org/10.1155/2022/7202837 |
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