MTA3 regulates differentiation of human cytotrophoblast stem cells

Horii, Mariko; Moretto-Zita, Matteo; Nelson, Katelyn N.; Li, Yingchun; Parast, Mana M.

doi:10.1016/j.placenta.2015.07.122

Cited by 7 publications

(6 citation statements)

References 15 publications

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“…In pre-eclampsia, the levels of MTA-3 appear to be reduced [ 35 ]. Therefore, when Horii et al generated MTA-3 stable knockdown in choriocarcinoma JEG-3 cells using shRNA, there was a 60% decrease in hCG secretion in the knockdown models compared to control, and migration was increased by 1.8-fold [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

Elucidating the Pathogenesis of Pre-eclampsia Using In Vitro Models of Spiral Uterine Artery Remodelling

et al. 2017

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Purpose of ReviewThe aim of the study is to perform a critical assessment of in vitro models of pre-eclampsia using complementary human and cell line-based studies. Molecular mechanisms involved in spiral uterine artery (SUA) remodelling and trophoblast functionality will also be discussed.Recent FindingsA number of proteins and microRNAs have been implicated as key in SUA remodelling, which could be explored as early biomarkers or therapeutic targets for prevention of pre-eclampsia.SummaryVarious 2D and 3D in vitro models involving trophoblast cells, endothelial cells, immune cells and placental tissue were discussed to elucidate the pathogenesis of pre-eclampsia. Nevertheless, pre-eclampsia is a multifactorial disease, and the mechanisms involved in its pathogenesis are complex and still largely unknown. Further studies are required to provide better understanding of the key processes leading to inappropriate placental development which is the root cause of pre-eclampsia. This new knowledge could identify novel biomarkers and treatment strategies.

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Section: Introductionmentioning

confidence: 99%

Elucidating the Pathogenesis of Pre-eclampsia Using In Vitro Models of Spiral Uterine Artery Remodelling

et al. 2017

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“…1 A). Owing to the recent finding that CTB proliferation and trophoblast stemness are responsible for early placental development [ 24 , 25 ], we next explored the role of ACTN4 in trophoblast proliferation. This was accomplished by treatment of the first trimester villous explants with a siRNA that specifically targeted the mRNA of ACTN4.…”

Section: Resultsmentioning

confidence: 99%

Alpha‐actinin‐4 is essential for maintaining normal trophoblast proliferation and differentiation during early pregnancy

Peng

Liu

et al. 2021

Reprod Biol Endocrinol

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Background Proper differentiation of trophoblasts in the human placenta is essential for a successful pregnancy, whereas abnormal regulation of this process may lead to adverse pregnancy outcomes, especially preeclampsia (PE). However, the underlying mechanism of trophoblast differentiation remains unclear. Previous studies have reported the involvement of alpha-actinin-4 (ACTN4) in the actin cytoskeleton dynamics and motility. Hence, we hypothesized that ACTN4 may act as an important regulator in the normal proliferation and differentiation of trophoblasts during early pregnancy. Method: To test this hypothesis, we collected villous tissues from women undergoing a legal pregnancy termination during 6–10 weeks of gestation and explanted them for cell culture and siRNA transfection. We also obtained placental tissues from PE patients and healthy pregnant women and isolated the primary cytotrophoblast (CTB) cells. The expression of ACTN4 in the CTBs of placental villi and during the differentiation of CTBs into STBs was detected by immunofluorescence, immunohistochemistry (IHC), and EdU proliferation assays. Besides, villous explant, Matrigel invasion, transwell migration assay, and Wound-healing assay were performed to identify the possible role of ACTN4 in the outgrowth of explants and the invasion, migration, and proliferation of cell column trophoblasts (CCTs). Western blot analysis was carried out to compare the protein expression level of AKT, Snail activities, and epithelial-to-mesenchymal transition (EMT) in the villi or HTR8/SVneo cells with ACTN4 knockdown. Results ACTN4 was highly expressed in CTB cells and interstitial extravillous trophoblast (iEVT) cells but not found in the syncytiotrophoblast (STB) cells in the first trimester villi. Downregulation of ACTN4 led to reduced trophoblast proliferation and explant outgrowth ex vivo, as well as iEVT invasion and migration in vitro due to disrupt of actin filaments organization. Such ACTN4 inhibition also decreased AKT and Snail activities and further impeded the EMT process. In addition, ACTN4 expression was found to be downregulated in the iEVTs from preeclamptic placentas. Conclusions Our findings suggest that ACTN4 may act as an important regulator of trophoblast proliferation and differentiation during early pregnancy, and dysregulation of this protein may contribute to preeclampsia pathogenesis.

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“…Dynamic reconstruction of epigenome happens in the trophoblast differentiation and function and chromatin remodeling proteins such as MTA3 are known to play important roles in this process [ 19 ]. MTA3 is a subunit of NuRD complex and is involved in the regulation of villous trophoblast differentiation and fusion [ 15 , 16 ]. In this study, we showed inhibition of MTA3 correlates with increased trophoblast invasion and up-regulated invasion-related genes MMP2 , MMP9 , and Snail in EVT cells.…”

Section: Discussionmentioning

confidence: 99%

“…In our previous study, we showed MTA3 regulates trophoblast gene expression in villous trophoblast [ 15 ]. A recent report identified MTA3 functions in stem cells [ 16 ]; MTA3 regulates the differentiation of cytotrophoblast stem cells into EVT cells [ 16 ]. However, the role of MTA3 and its related mechanisms in EVT, especially EVT invasion, is still largely unknown.…”

Section: Introductionmentioning

confidence: 99%

MTA3 Regulates Extravillous Trophoblast Invasion Through NuRD Complex

Chen

Khoo

Leach

et al. 2017

AIMS Medical Science

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Extravillous trophoblast (EVT) invasion is required for remodeling uterine tertiary arteries and placenta development during pregnancy. Compromised EVT invasion may contribute to the pathology of placenta-related diseases. Metastasis -associated protein 3 (MTA3) is one of the subunits of nucleosome remodeling and deacetylation (NuRD) complex that represses transcription in a histone deacetylase-dependent manner. MTA3 is reported to be down-regulated in preeclamptic placentas, suggesting its potential role in EVT invasion. Here, we investigate the role of MTA3 in EVT invasion by studying its molecular mechanisms in EVT cells. First, we confirmed MTA3 expression in the EVT cells in human placenta using immunohistochemistry. We then used lentivirus-mediated MTA3 short hairpin RNA (shRNA) to knock down MTA3 expression in EVT-derived HTR8/SVneo cells and found higher invasion capacity in MTA3 knockdown cells. Using quantitative real-time PCR, we showed higher expression of invasion-related genes matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), and transcription factor Snail in MTA3 knockdown compared with control cells. Co-immunoprecipitation-Western blot assay showed the protein-protein interaction of histone deacetylase 1 (HDAC1), a subunit of NuRD, with MTA3 in HTR8/SVneo cells. Co-immunoprecipitation-Mass spectrometry assay further identified 71 proteins interacting with MTA3, including NuRD subunits, heterochromatin proteins, epigenetics modifiers and transcription factors. This result not only indicated the involvement of NuRD complex in MTA3’s function, but also demonstrated the complicated multiple co-players in MTA3 and NuRD complex mediated transcription repression in EVT. In summary, our data demonstrates that MTA3 regulates EVT invasion and related gene expression via NuRD complex in EVT.

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MTA3 regulates differentiation of human cytotrophoblast stem cells

Cited by 7 publications

References 15 publications

Elucidating the Pathogenesis of Pre-eclampsia Using In Vitro Models of Spiral Uterine Artery Remodelling

Elucidating the Pathogenesis of Pre-eclampsia Using In Vitro Models of Spiral Uterine Artery Remodelling

Alpha‐actinin‐4 is essential for maintaining normal trophoblast proliferation and differentiation during early pregnancy

MTA3 Regulates Extravillous Trophoblast Invasion Through NuRD Complex

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