image: (A) t-distribution random neighborhood embedding (t-SNE) plots from human placental single-cell RNA sequencing data showing the various trophoblast lineages and the trophoblastic ectoderm (TE). (B) The number of subtypes of each trophoblast lineage. (C) Annotation of the DESC method and the expression distribution of known marker genes for each lineage or cell type (HLA-G, EVT marker; CYP19A1, STB marker; CDH1, villous CTB marker; CDX2, TE marker). (D) The Venn diagram illustrating the genes that are expressed in each of the five EVT subtypes in the gene set maps. (E) Biaxial scatter plots of WIPF1 expression patterns in different trophoblast lineages and TE. (F) The violin plots showing the expression of WIPF1 in the four major trophoblast lineages. CTB, cytotrophoblast; EVT, extravillous trophoblast; STB, syncytiotrophoblast; HLA-G, human leukocyte antigen-G; CYP19A1, cytochrome P450 family 19 subfamily A member 1; CDH1, cadherin 1; CDX2, caudal type homeobox 2; WIPF1, WAS/WASL interacting protein family member 1.
Credit: Cong Li, Shengya Wang, Jing Tang, Xin Luo, Luxing Ge, Youlong Xie, Lijuan Fu, Lingling Ruan, Enoch Appiah Adu-Gyamfi, Fangfang Li, Yingxiong Wang, Hongbo Qi, Yubin Ding
Successful placental development, critical in pregnancy and fetal growth, hinges on effective extravillous trophoblast (EVT) invasion. Conversely, impaired EVT invasion is linked consistently with recurrent spontaneous abortions (RSA). Elucidating the mechanisms underlying EVT invasion may facilitate the development of improved therapeutic strategies for RSA.
In a recent study published in the Genes & Diseases journal, researchers from Chongqing Medical University, State University of New York at Albany, and Changsha Medical University provide mechanistic insights into EVT invasion and the pathogenesis of RSA.
Single-cell RNA-sequencing data of the human early feto–maternal interface and deep embedding for single-cell clustering (DESC) analysis identified five EVT subtypes. Differentially expressed genes, like placental growth factor (PGF), caveolin 1 (CAV1), laminin subunit alpha 4 (LAMA4), Epstein-Barr virus induced 3 (EBI3), and tetraspanin-30 (CD63), involved in regulating EVT functioning, were found to be expressed in four subtypes. In contrast, WAS/WASL interacting protein family member 1 (WIPF1), a key regulator of cytoskeletal dynamics, was expressed in all five subtypes, suggesting that WIPF1 might be a novel gene regulating human EVTs.
Further experiments showed that WIPF1 is expressed exclusively in the EVTs of the human placenta, promotes trophoblast cell migration and invasion, and regulates podosome formation in EVTs. Mechanistically, WIPF1 co-localizes with cortactin (a podosome marker protein) and interacts with ACTN4 to modulate actin polymerization during podosome formation and podosome-mediated matrix degradation by invading trophoblasts. Additionally, WIPF1 interacts with actin-related proteins, WASL and ACTN1, which facilitate lamellipodia formation, thus enhancing EVT migration and invasion.
Molecular docking and further experimental validation revealed that the R54A mutation disrupts the WIPF1-ACTN4 interaction, highlighting that the WIPF1-ACTN4 interaction, particularly at the R54A site, plays a critical role in regulating podosome function and EVT invasion.
Insufficient EVT invasion is a hallmark of RSA; consequently, the authors observed that WIPF1 was down-regulated in RSA placental villi of both mice and humans. Downregulation of WIPF1 was accompanied by a decrease in MMP2 expression, resulting in impaired trophoblast invasion and contributing to RSA pathogenesis.
In conclusion, this study showed that WIPF1 interacts with ACTN4, particularly at the R54A site, and interacts with WASL and ACTN1 to regulate podosome formation and EVT invasion, while its decrease contributes to RSA pathogenesis, thus highlighting it as a pivotal factor in EVT invasion.
Reference
Title of the original paper: Unraveling the role of the WIPF1/ACTN4 complex in podosome formation of human placental EVTs: Insights into recurrent spontaneous abortion
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101665
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