JunB/Cyclin-D1 imbalance in placental mesenchymal stromal cells derived from preeclamptic pregnancies with fetal-placental compromise

Nuzzo, Anna Maria; Giuffrida, Domenica; Zenerino, Cristian; Piazzese, Annalisa; Olearo, Elena; Todros, Tullia; Rolfo, Alessandro

doi:10.1016/j.placenta.2014.04.001

Cited by 18 publications

(18 citation statements)

References 34 publications

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“…During early placentation, mesenchymal cells represent the structural support for the forming primary villi and drive placental capillary network establishment. 13 Our recent findings on JunB-mediated inhibition of Cyclin D1 in preeclamptic PDMSCs 10 lead to the hypothesis that PE-PDMSCs, as previously demonstrated for the trophoblast, may present defects that could cause/contribute to the aberrant placenta development of preeclamptic placentae. 7 The Activating Protein 1 (AP-1) family member JunB is well known as a cell division inhibitor 14,15 and senescence inducer.…”

Section: Introductionmentioning

confidence: 61%

“… 20,21 Besides the trophoblast, mesenchymal stromal cells resident in both chorionic villi and decidua are actively involved in the impaired placenta development typical of PE. 9,10,22-24 In line with PE trophoblast, we previously reported that chorionic PE-PDMSCs are characterized by JunB-mediated Cyclin D1 downregulation, 10 stressing the importance of preeclampsia-related G1/S transition anomalies. In the present study, we added another important piece to the intricate puzzle of PE pathogenesis, describing a significant increase of p16 INK4α and p18 INK4C in preeclamptic PDMSCs.…”

Section: Discussionmentioning

confidence: 95%

“…We previously demonstrated that JunB overexpression in PE-PDMSCs affects cell cycle progression by inducing Cyclin-D1 downregulation. 10 We next investigated the expression of p16 INK4A , p18 INK4C , CDK4 and CDK6 in normal and PE-PDMSCs in order to complete the characterization of the G1/S regulatory pathway headed by Cyclin D1. We showed that Cyclin D1 post-translational inhibitors p16 INK4A (p = 0.01, 1.73 Fold Increase) and p18 INK4C (p = 0.04, 2.74 Fold Increase) mRNA levels were significantly higher in PE- relative to normal PDMSCs ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We recently reported that the AP-1 family member JunB specifically controls Cyclin D1 transcriptional regulation in PDMSCs. 10 The modulation of Cyclin D1 as well as Cyclin D1 inhibitors is one of the most common strategies used by MSC to face adverse conditions. 41 In the placental context, it could be used by normal PDMSCs to counteract spontaneous apoptosis associated with trophoblast proliferation, thus maintaining tissue homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“… 7 The Activating Protein 1 (AP-1) family member JunB is well known as a cell division inhibitor 14,15 and senescence inducer. 15 JunB is able to inhibit the G1/S phase transition by inducing Cyclin-D1 downregulation 10 and promoting the expression of the cell-cycle kinase inhibitor p16 INK4A . 15 Importantly, the G1/S phase is cooperatively regulated by CDK 4 and 6 whose activities are in turn constrained by CKIs p16 INK4A and p18 INK4C , that specifically inhibit the formation of CDKs-Cyclin D1 complexes.…”

Section: Introductionmentioning

confidence: 99%

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Altered expression of G1/S phase cell cycle regulators in placental mesenchymal stromal cells derived from preeclamptic pregnancies with fetal-placental compromise

Nuzzo

Giuffrida

Masturzo³

et al. 2016

Cell Cycle

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Herein, we evaluated whether Placental Mesenchymal Stromal Cells (PDMSCs) derived from normal and Preeclamptic (PE) placentae presented differences in the expression of G1/S-phase regulators p16INK4A, p18INK4C, CDK4 and CDK6. Finally, we investigated normal and PE-PDMSCs paracrine effects on JunB, Cyclin D1, p16INK4A, p18INK4C, CDK4 and CDK6 expressions in physiological term villous explants.PDMSCs were isolated from physiological (n = 20) and PE (n = 24) placentae. Passage three normal and PE-PDMSC and conditioned media (CM) were collected after 48h. Physiological villous explants (n = 60) were treated for 72h with normal or PE-PDMSCs CM. Explants viability was assessed by Lactate Dehydrogenase Cytotoxicity assay. Cyclin D1 localization was evaluated by Immuofluorescence (IF) while JunB, Cyclin-D1 p16INK4A, p18INK4C, CDK4 and CDK6 levels were assessed by Real Time PCR and Western Blot assay.We reported significantly increased p16INK4A and p18INK4C expression in PE- relative to normal PDMSCs while no differences in CDK4 and CDK6 levels were detected. Explants viability was not affected by normal or PE-PDMSCs CM. Normal PDMSCs CM increased JunB, p16INK4 and p18INK4C and decreased Cyclin-D1 in placental tissues. In contrast, PE-PDMSCs CM induced JunB downregulation and Cyclin D1 increase in placental explants. Cyclin D1 IF staining showed that CM treatment targeted mainly the syncytiotrophoblast.We showed Cyclin D1-p16INK4A/p18INK4C altered pathway in PE-PDMSCs demonstrating an aberrant G1/S phase transition in these pathological cells. The abnormal Cyclin D1-p16INK4A/p18INK4C expression in explants conditioned by PE-PDMSCs media suggest a key contribution of mesenchymal cells to the altered trophoblast cell cycle regulation typical of PE pregnancies with fetal-placental compromise.

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Section: Introductionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Altered expression of G1/S phase cell cycle regulators in placental mesenchymal stromal cells derived from preeclamptic pregnancies with fetal-placental compromise

Nuzzo

Giuffrida

Masturzo³

et al. 2016

Cell Cycle

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Low‐dose aspirin reduces hypoxia‐induced sFlt1 release via the JNK/AP‐1 pathway in human trophoblast and endothelial cells

Lin

Zhang

et al. 2019

Journal Cellular Physiology

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Pre‐eclampsia (PE) is a serious hypertensive disorder of pregnancy that remains a leading cause of perinatal and maternal morbidity and mortality worldwide. Placental ischemia/hypoxia and the secretion of soluble fms‐like tyrosine kinase 1 (sFlt1) into maternal circulation are involved in the pathogenesis of PE. Although low‐dose aspirin (LDA) has beneficial effects on the prevention of PE, the exact mechanisms of action of LDA, particularly on placental dysfunction, and sFlt1 release, have not been well investigated. This study aimed to determine whether LDA exists the protective effects on placental trophoblast and endothelial functions and prevents PE‐associated sFlt1 release. First, we observed that LDA mitigated hypoxia‐induced trophoblast apoptosis, showed positive effects on trophoblast cells migration and invasion activity, and increased the tube‐forming activity of human umbilical vein endothelial cells (HUVECs). In addition, LDA decreased hypoxia‐induced sFlt1 production, and the c‐Jun NH2‐terminal kinase/activator protein‐1 (JNK/AP‐1) pathway was shown to mediate the induction of sFlt1. Moreover, the transcription factor AP‐1 was confirmed to regulate the Flt1 gene expression by directly binding to the Flt1 promoter in luciferase assays. The result of chromatin immunoprecipitation assays further demonstrated that LDA could directly decrease the expression of the transcription factor AP‐1, and thus decrease sFlt1 production. Finally, the effects of LDA on sFlt1 production were proved in human placental explants. Taken together, our data show the protective effects of LDA against trophoblast and endothelial cell dysfunction and reveal that the LDA‐mediated inhibition of sFlt1 via the JNK/AP‐1 pathway may be a potential cellular/molecular mechanism for the prevention of PE.

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Human leukocyte antigen HLA-C, HLA-G, HLA-F, and HLA-E placental profiles are altered in early severe preeclampsia and preterm birth with chorioamnionitis

Dunk

Bucher

Zhang

et al. 2022

American Journal of Obstetrics and Gynecology

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JunB/Cyclin-D1 imbalance in placental mesenchymal stromal cells derived from preeclamptic pregnancies with fetal-placental compromise

Cited by 18 publications

References 34 publications

Altered expression of G1/S phase cell cycle regulators in placental mesenchymal stromal cells derived from preeclamptic pregnancies with fetal-placental compromise

Altered expression of G1/S phase cell cycle regulators in placental mesenchymal stromal cells derived from preeclamptic pregnancies with fetal-placental compromise

Low‐dose aspirin reduces hypoxia‐induced sFlt1 release via the JNK/AP‐1 pathway in human trophoblast and endothelial cells

Human leukocyte antigen HLA-C, HLA-G, HLA-F, and HLA-E placental profiles are altered in early severe preeclampsia and preterm birth with chorioamnionitis

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