Overexpression of miR-210-3p Impairs Extravillous Trophoblast Functions Associated with Uterine Spiral Artery Remodeling

Hayder, Heyam; Fu, Guodong; Nadeem, Lubna; O’Brien, Jacob A.; Lye, Stephen J.; Peng, Chun

doi:10.3390/ijms22083961

Cited by 23 publications

(28 citation statements)

References 79 publications

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“…For example, achaete-scute family BHLH transcription factor 2 (ASCL2) was confirmed as a critical and conserved regulator of the invasive trophoblast cell lineage and ASCL2 expression was especially prominent in the endovascular EVT population [ 186 ]. Besides, it was demonstrated that also microRNAs are capable of influencing endoarterial trophoblast differentiation and spiral artery remodeling [ 20 , 80 ]. In these studies, the authors usually do not stratify/differentiate between endoarterial, endovenous and endolymphatic trophoblasts.…”

Section: Extravillous Trophoblast Subpopulations and Trophoblast Inva...mentioning

confidence: 99%

Early human trophoblast development: from morphology to function

Gauster

Moser

Wernitznig

et al. 2022

Cell. Mol. Life Sci.

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Human pregnancy depends on the proper development of the embryo prior to implantation and the implantation of the embryo into the uterine wall. During the pre-implantation phase, formation of the morula is followed by internalization of blastomeres that differentiate into the pluripotent inner cell mass lineage, while the cells on the surface undergo polarization and differentiate into the trophectoderm of the blastocyst. The trophectoderm mediates apposition and adhesion of the blastocyst to the uterine epithelium. These processes lead to a stable contact between embryonic and maternal tissues, resulting in the formation of a new organ, the placenta. During implantation, the trophectoderm cells start to differentiate and form the basis for multiple specialized trophoblast subpopulations, all of which fulfilling specific key functions in placentation. They either differentiate into polar cells serving typical epithelial functions, or into apolar invasive cells that adapt the uterine wall to progressing pregnancy. The composition of these trophoblast subpopulations is crucial for human placenta development and alterations are suggested to result in placenta-associated pregnancy pathologies. This review article focuses on what is known about very early processes in human reproduction and emphasizes on morphological and functional aspects of early trophoblast differentiation and subpopulations.

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Section: Extravillous Trophoblast Subpopulations and Trophoblast Inva...mentioning

confidence: 99%

Early human trophoblast development: from morphology to function

Gauster

Moser

Wernitznig

et al. 2022

Cell. Mol. Life Sci.

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“…Recently, we reported that miR-218-5p induces enEVT differentiation and increases IL1β expression ( 28 ). On the other hand, miR-210-3p inhibits the acquisition of an enEVT phenotype and also reduces IL1β expression ( 53 ). In this study, we showed that IL1β increased the expression of several enEVT differentiation-associated markers, such as ITGA1, ITGA5, CDH5, and PECAM1.…”

Section: Discussionmentioning

confidence: 99%

miR-218-5p Induces Interleukin-1β and Endovascular Trophoblast Differentiation by Targeting the Transforming Growth Factor β-SMAD2 Pathway

et al. 2022

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The acquisition of an endovascular trophoblast (enEVT) phenotype is essential for normal placental development and healthy pregnancy. MicroRNAs (miRNAs) are small noncoding RNAs that play critical roles in regulating gene expression. We have recently reported that miR-218-5p promotes enEVT differentiation and spiral artery remodeling in part by targeting transforming growth factor β2 (TGFβ2). We also identified IL1B, which encodes interleukin 1β (IL1β), as one of the most highly upregulated genes by miR-218-5p. In this study, we investigated how miR-218-5p regulates IL1B expression and IL1β secretion and the potential role of IL1β in enEVT differentiation. Using two cell lines derived from extravillous trophoblasts (EVTs), HTR-8/SVneo and Swan 71, we found that stable overexpression of miR-218-5p precursor, mir-218-1, or transient transfection of miR-218-5p mimic, significantly increased IL1B mRNA and IL1β protein levels in cells and conditioned media. We also showed that miR-218-5p directly interacted with SMAD2 3’UTR and reduced SMAD2 at mRNA and protein levels. Knockdown of SMAD2 induced IL1B expression and attenuated the inhibitory effect of TGFβ2 on IL1B expression. On the other hand, overexpression of SMAD2 reduced IL1β levels and blocked the stimulatory effects of miR-218-5p on IL1B expression, trophoblast migration and endothelial-like network formation. In addition, treatment of trophoblasts with IL1β induced the formation of endothelial-like networks and the expression of enEVT markers in a dose-dependent manner. These results suggest that miR-218-5p inhibits the TGFβ/SMAD2 pathway to induce IL1β and enEVT differentiation. Finally, low doses of IL1β also inhibited the expression of miR-218-5p, suggesting the existence of a negative feedback regulatory loop. Taken together, our findings suggest a novel interactive miR-218-5p/TGFβ/SMAD2/IL1β signaling nexus that regulates enEVT differentiation.

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“…For instance, miR-373-3p has been proved to suppress migration and invasion of trophoblasts by targeting CD44 and Radixin, 31 and Hayder et al. 21 highlighted that miR-210-3p upregulation could damage USAR-related biological functions of extravillous trophoblasts. In contrast, Jiang et al.…”

Section: Discussionmentioning

confidence: 99%

“…For example, according to Ma et al., miR-486-5p expressed in exosomes secreted by human placental microvascular endothelial cells could suppress proliferation and migration of trophoblasts through inhibiting IGF1, 20 and Hayder et al. 21 revealed that miR-210-3p could intensify USAR (uterine spiral artery remodeling)-related trophoblast dysfunction. In addition, Su et al.…”

Section: Introductionmentioning

confidence: 99%