bims-placeb 2025-12-14 papers

Cell Mol Life Sci. 2025 Dec 10.

TCF7L2 is essential for the differentiation and invasive function of human extravillous trophoblast.

Joudi Salamah, Elisha Cheeran, Brandt Beck, Zaineb Ahmad, Bum-Kyu Lee.

Extravillous trophoblasts (EVTs) play essential roles in placental development by anchoring the placenta, invading the maternal decidua, and remodeling spiral arteries. TCF7L2 is known to be expressed in human placental tissues and EVTs, and it controls EVT motility. However, the targets of TCF7L2 in trophoblasts and the mechanism by which it contributes to early trophoblast differentiation are largely unknown. Here, using trophoblast stem cells (TSCs), we investigate the expression patterns of TCF7L2 during trophoblast lineage differentiation, revealing that its expression gradually elevates throughout EVT formation. Loss-of-function studies uncover that TCF7L2 is implicated in the proliferation of TSCs and is essential for EVT formation. Conversely, overexpression of TCF7L2 hinders TSC differentiation into STs. We identify TCF7L2 binding sites across the genome in TSCs and EVTs. Integrative analyses of TCF7L2 targets with global gene expression profiles unveil that TCF7L2 facilitates EVT formation by directly activating extracellular matrix organization while suppressing genes linked to the cell cycle. Moreover, overlap analyses of TCF7L2 targets with those of other EVT factors reveal that TCF7L2 collaborates with other EVT factors to promote EVT formation. In summary, our findings highlight context-specific functions of TCF7L2 in the trophoblast lineage.

Keywords: Extravillous trophoblast; Placental development; TCF7L2 transcription factor; Trophoblast lineage differentiation; Trophoblast stem cells

DOI: https://doi.org/10.1007/s00018-025-05991-4

Front Cell Dev Biol. 2025 ;13 1661952

Cis-regulatory elements operating in the trophoblast.

Terezia Vcelkova, Paulina A Latos.

The placenta is vital for supporting embryonic development and ensuring a successful pregnancy. Its diverse functions are carried out by specialized trophoblast cell types, including the progenitor cytotrophoblast, the multinucleated syncytiotrophoblast, and the invasive extravillous trophoblast. The distinct identities of these cells are governed by tightly regulated gene expression programs, controlled by transcription factors and cis-regulatory elements, particularly enhancers and silencers. They integrate spatiotemporal cues to modulate transcriptional activity and establish cell-type-specific gene expression profiles. Disruptions of these regulatory mechanisms can impair placental development and function, contributing to pregnancy complications. In this review, we explore the interplay between TFs and CREs in trophoblast lineage specification and function, with a focus on enhancers and silencers. We provide an overview of human placental development, describe commonly used in vitro models, and discuss recent technological advances that have deepened our understanding of transcriptional regulation in the placenta.

Keywords: enhancers; gene regulation; placenta; silencers; trophoblast

DOI: https://doi.org/10.3389/fcell.2025.1661952

Biol Reprod. 2025 Dec 08. pii: ioaf273. [Epub ahead of print]

Metabolism and homeostasis of energy in trophoblast cells of the placenta: from development to disease.

Nirvay Sah, Kent Thornburg, Jaroslav Slamecka, Francesca Soncin.

The placenta is a highly metabolic organ essential for fetal growth by mediating nutrient transport, hormone production, and immunological regulation. These functions depend on continuous and efficient ATP supply, primarily generated through glycolysis and oxidative phosphorylation. However, due to high turnover of ATP and multi-step de novo synthesis, these pathways may not always meet the rapid and localized energy demands of trophoblast cells. The phosphagen system, comprising creatine kinase (CK), creatine (Cr), and phosphocreatine (PCr), provides a rapid ATP-buffering mechanism, yet its role in placental biology remains poorly understood. This review synthesizes current knowledge on ATP production and buffering across trophoblast subtypes drawing from in vitro, ex vivo, and transcriptomic studies. We highlight emerging data on the contribution of the Cr-CK-PCr system to ATP homeostasis in trophoblasts and its dynamic regulation across gestation. Dysregulation of this system, including altered creatine metabolism and CK expression, is observed in pregnancy disorders such as preeclampsia, fetal growth restriction, and gestational diabetes. We also examine evidence from animal models supporting maternal creatine supplementation as a potential strategy to enhance placental efficiency and fetal outcomes. Finally, we propose that new models, including trophoblast stem cells and organoids, could be leveraged in the future to further elucidate creatine's role in early placental development and disease. A deeper understanding of placental energy metabolism and buffering may reveal new therapeutic avenues to improve maternal-fetal health.

Keywords: ATP; Creatine; Placenta; Trophoblast

DOI: https://doi.org/10.1093/biolre/ioaf273

Genesis. 2025 Dec;63(6): e70034

Generation of Tpbpα-iCre-EGFP Knock-In Mice for Trophoblast Subtype-Specific Gene Manipulation.

Shaoqiang Ban, Chang'e Mu, Mengqi Gu, Yinan Wang, Han Cai, Shuangbo Kong, Haibin Wang, Jinhua Lu.

The placenta plays an essential role during pregnancy in mammals, with the placental endocrine trophoblast subtypes secreting many growth factors and cytokines to promote fetal growth and maternal adaptation. These endocrine cells, including trophoblast giant cells (TGCs), glycogen trophoblast cells (GlyTs) and spongiotrophoblast cells (SpTs), are mainly derived from Tpbpα-positive (Tpbpα+) trophoblast cells primarily located in the ectoplacental cone (EPC) and later junctional zone (JZ) of the mouse placenta. However, the mechanism driving Tpbpα+ trophoblast cell differentiation and the functions of the factors secreted by these endocrine cells remain largely unknown. In the present study, we generated the Tpbpα-iCre-EGFP knock-in mice with codon-improved Cre recombinase (iCre) inserted into the endogenous locus of the Tpbpα gene. To examine the specificity and efficiency of iCre recombinase, we crossed the Tpbpα-iCre-EGFP mice with ROSA26Sortm9(CAG-tdTomato)Hze reporter mice. The co-expression of EGFP and Td-tomato was detected obviously in the EPC at E8.5 and E9.5, and in the JZ at E13.5. Meanwhile, employing lineage tracing and in situ hybridization, we demonstrated that Tpbpα+ trophoblast cells could differentiate into SpTs, GlyTs, maternal blood canal (C)-TGCs, parietal (P)-TGCs, and spiral artery-associated (Spa)-TGCs. In addition, no Tpbpα expression or iCre recombinase activity was detected in other organs examined, indicating the specificity of the iCre activity in placental trophoblast cells. In summary, we successfully generated the Tpbpα-iCre-EGFP knock-in mice with enhanced Cre recombinase for modulating specific genes and investigating their functions during pregnancy.

Keywords: Tpbpα‐iCre‐EGFP ; mice; placenta

DOI: https://doi.org/10.1002/dvg.70034