Activin A increases human trophoblast invasion by upregulating integrin β1 through ALK4

Zhu, Shiqin; Li, Zeyan; Cui, Linlin; Ban, Yanli; Leung, Peter C.K.; Li, Yan; Ma, Jinlong

doi:10.1096/fj.202001604r

Cited by 18 publications

(10 citation statements)

References 59 publications

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“…After being affected by mechanical forces, integrin binds to its ligands and mediates FAK, PI3K, AKT/PKB, and other signaling pathways that regulate cell proliferation, migration, and epithelial-mesenchymal transition [ 67 , 68 ]. By upregulating integrin-β1, the invasion of human trophoblasts can be promoted [ 69 ]. We also examined the expression of integrin-β1 of JAR cells on different regions and found no significant differences either between soft and inter or between inter and stiff, with stiff being slightly higher than soft ( Figure S4 ), and the expression of other subunits of integrin did not change significantly with substrate stiffness [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

Stiff Extracellular Matrix Promotes Invasive Behaviors of Trophoblast Cells

Cao

Tang

et al. 2023

Bioengineering

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The effect of extracellular matrix (ECM) stiffness on embryonic trophoblast cells invasion during mammalian embryo implantation remains largely unknown. In this study, we investigated the effects of ECM stiffness on various aspects of human trophoblast cell behaviors during cell–ECM interactions. The mechanical microenvironment of the uterus was simulated by fabricating polyacrylamide (PA) hydrogels with different levels of stiffness. The human choriocarcinoma (JAR) cell lineage was used as the trophoblast model. We found that the spreading area of JAR cells, the formation of focal adhesions, and the polymerization of the F-actin cytoskeleton were all facilitated with increased ECM stiffness. Significantly, JAR cells also exhibited durotactic behavior on ECM with a gradient stiffness. Meanwhile, stiffness of the ECM affects the invasion of multicellular JAR spheroids. These results demonstrated that human trophoblast cells are mechanically sensitive, while the mechanical properties of the uterine microenvironment could play an important role in the implantation process.

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Section: Discussionmentioning

confidence: 99%

Stiff Extracellular Matrix Promotes Invasive Behaviors of Trophoblast Cells

Cao

Tang

et al. 2023

Bioengineering

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“…Activin A plays important roles in regulating the biological behavior of trophoblasts. Previous studies have shown that activin A promotes human trophoblast invasion, as evidenced by a Transwell invasion assay in HTR8/SVneo cells [ 20 , 31 , 60 ]. The vascular channels of human utero-placental bed are lined by trophoblasts, which acquire the functional characteristics of vascular endothelial cells [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

“…Notably, among all human tissues and single cell types, fibronectin is most abundant in human placental tissue and extravillous trophoblasts [ 29 , 30 ]. According to the research of Zhu et al [ 31 ], transcriptome profiles of HTR8/SVneo trophoblast cells with and without activin A treatment show the most significant changes in the ECM interaction pathway. Moreover, in normal pregnancies, maternal circulating concentrations of both fibronectin [ 32 , 33 ] and activin A [ 34 , 35 ] tend to increase progressively throughout pregnancy.…”

Section: Introductionmentioning

confidence: 99%

Fibronectin mediates activin A-promoted human trophoblast migration and acquisition of endothelial-like phenotype

Lan,

Guo,

et al. 2024

Cell Commun Signal

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Background During human early placentation, a proportion of extravillous trophoblasts (EVTs) migrate to the maternal decidua, differentiating into endovascular EVTs to remodel spiral arteries and ensure the establishment of blood circulation at the maternal-fetal interface. Inadequate EVT migration and endovascular differentiation are closely associated with adverse pregnancy outcomes such as miscarriage. Activin A and fibronectin are both secretory molecules abundantly expressed at the maternal-fetal interface. Activin A has been reported to regulate EVT biological functions. However, whether fibronectin mediates activin A-promoted EVT migration and acquisition of endothelial-like phenotype as well as the underlying molecular mechanisms remain unknown. Additionally, the role of fibronectin in pregnancy establishment and maintenance warrants further investigation. Methods Primary and immortalized (HTR8/SVneo) human EVTs were used as in vitro study models. Cultured human first-trimester chorionic villous explants were utilized for ex vivo validation. A local fibronectin knockdown model in ICR mouse uteri, achieved by nonviral in vivo transfection with small interfering RNA (siRNA) targeting fibronectin 1 (si-Fn1), was employed to explore the roles of fibronectin in the establishment and maintenance of early pregnancy. Results Our results showed that activin A treatment significantly induced fibronectin 1 (FN1) mRNA expression and fibronectin protein production, which is essential for human trophoblast migration and endothelial-like tube formation. Both basal and activin A-upregulated fibronectin expression were abolished by the TGF-β type I receptor inhibitor SB431542 or siRNA-mediated knockdown of activin receptor-like kinase (ALK4) or SMAD4. Moreover, activin A-increased trophoblast migration and endothelial-like tube formation were attenuated following the depletion of fibronectin. Fibronectin knockdown via intrauterine siRNA administration reduced CD31 and cytokeratin 8 (CK8) expression at the maternal-fetal interface, resulting in a decrease in the number of implantation sites and embryos. Conclusions Our study demonstrates that activin A promotes trophoblast cell migration and acquisition of endothelial-like phenotype via ALK4-SMAD2/3-SMAD4-mediated fibronectin upregulation. Furthermore, through a local fibronectin knockdown model in mouse uteri, we found that the absence of fibronectin at the maternal-fetal interface impedes endovascular migration of trophoblasts and decidual vascularization, thereby interfering with early embryo implantation and the maintenance of pregnancy. These findings provide novel insights into placental development during early pregnancy establishment and contribute to the advancement of therapeutic approaches for managing pregnancy complications related to trophoblast dysfunction.

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“…Consequently, this process contributes to the induction of ECM stiffness, which has been associated with the pathogenesis of hypertension [86]. Apart from these findings, research has revealed that pregnancy-induced hypertension represents a notable form of hypertension attributable to a deficiency in activin A [127]. This deficiency exerts its influence by suppressing the ActRII/ALK4/SMAD2/3/4 signaling pathway, subsequently upregulating β1 integrin expression on trophoblasts [127].…”

Section: Pdgf-bbmentioning

confidence: 99%

Roles of Integrin in Cardiovascular Diseases: From Basic Research to Clinical Implications

Zhang,

et al. 2024

IJMS

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Cardiovascular diseases (CVDs) pose a significant global health threat due to their complex pathogenesis and high incidence, imposing a substantial burden on global healthcare systems. Integrins, a group of heterodimers consisting of α and β subunits that are located on the cell membrane, have emerged as key players in mediating the occurrence and progression of CVDs by regulating the physiological activities of endothelial cells, vascular smooth muscle cells, platelets, fibroblasts, cardiomyocytes, and various immune cells. The crucial role of integrins in the progression of CVDs has valuable implications for targeted therapies. In this context, the development and application of various integrin antibodies and antagonists have been explored for antiplatelet therapy and anti-inflammatory-mediated tissue damage. Additionally, the rise of nanomedicine has enhanced the specificity and bioavailability of precision therapy targeting integrins. Nevertheless, the complexity of the pathogenesis of CVDs presents tremendous challenges for monoclonal targeted treatment. This paper reviews the mechanisms of integrins in the development of atherosclerosis, cardiac fibrosis, hypertension, and arrhythmias, which may pave the way for future innovations in the diagnosis and treatment of CVDs.

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Activin A increases human trophoblast invasion by upregulating integrin β1 through ALK4

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 18 publications

References 59 publications

Stiff Extracellular Matrix Promotes Invasive Behaviors of Trophoblast Cells

Stiff Extracellular Matrix Promotes Invasive Behaviors of Trophoblast Cells

Fibronectin mediates activin A-promoted human trophoblast migration and acquisition of endothelial-like phenotype

Roles of Integrin in Cardiovascular Diseases: From Basic Research to Clinical Implications

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