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

Abstract

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.

TPD7 inhibits the growth of cutaneous T cell lymphoma H9 cell through regulating IL‐2R signalling pathway

“…34 And, it was well recognized that CDC2, cyclinD1 and cyclinE are critical molecules in the regulation of cells from G1 phase into S phase. 35 Consistent with these, we observed a decrease in CDC2, cyclinB1, cyclinD1 and cyclinE level in H9 cells treated with TPD7 ( Figure 4).…”

Pericytes Contribute to Dysfunction in a Human 3D Model of Placental Microvasculature through VEGF‐Ang‐Tie2 Signaling

“…Given that our previous results suggested exogenous cytokines could positively influence vessel morphology (Figure 2e), tricultures and subsequent HPP-or HLF-HUVEC cocultures were grown in complete media until day 3 (to allow for initial EC coalescence) and subsequently switched to basal media + 1%FBS (Figure 3c). This proliferative capacity is reminiscent of increased proliferation of stromal cells derived from PE placentas, [33] and suggests that a balance between stromal cells types and their proliferative capacity may contribute to placental vascular growth and dysfunction, the mechanisms of which are not yet known, but are under current investigation. The seeding ratio of ECs to stromal cells was kept consistent for the triculture (5:1), but with 50% each of HPPs and HLFs (final ratio 5:0.5:0.5).…”

Is there a role for placental senescence in the genesis of obstetric complications and fetal growth restriction?

“…In preeclamptic placentas, the formation of telomere (or nuclear) aggregate (SAHF) is increased compared with placentas from normotensive women 24,28,106 The expression of senescence inducers p53, p21, and p16 are higher in pregnancy complicated by preeclampsia. 27,[107][108][109] Moreover, a high level of proinflammatory cytokine (IL-1b and IL-6) profile can be demonstrated in preeclampsia. 27,110 DNA oxidation as measured by the expression of 8-OHdG in preeclamptic placenta is higher than in the healthy placentas.…”