bims-placeb 2025-09-14 papers

Reproduction. 2025 Oct 01. pii: e250160. [Epub ahead of print]170(4):

Sex-specific alterations in placental mitochondria, oxidative damage and apoptosis in mice of advanced maternal age.

Jessica Dalton-O'Reilly, Alexander E P Heazell, Susan Greenwood, Mark Dilworth, Michelle Desforges.

In brief: Advanced maternal age (AMA) is associated with adverse pregnancy outcomes, particularly those associated with placental dysfunction. This study showed that in a mouse model of AMA, male but not female fetuses had increased placental apoptosis and lipid peroxidation, as well as increased mitochondrial content, suggesting that the placentas of male fetuses in AMA mothers adapt to be able to deliver sufficient energy to the fetus.
Abstract: Although advanced maternal age (AMA) increases the risk of fetal growth restriction (FGR) and stillbirth, the mechanisms leading to the placental dysfunction observed in AMA are unknown. Mitochondrial function declines and oxidative stress increases with age. Furthermore, FGR, of which placental dysfunction is a major cause, is associated with alterations in respiratory function of placental mitochondria. Therefore, this study aimed to examine placental mitochondrial function, oxidative stress, and apoptosis in AMA mice using respirometry and immunohistochemistry. Relative to young mice (12-16 weeks), AMA mice (36-42 weeks) demonstrated reduced weight in both female and male fetuses, but placental alterations occurred in a sex-specific manner. In AMA, lipid peroxidation and apoptosis were increased in the placental junctional zone (Jz) and labyrinth zone (Lz) of male but not female fetuses. Placental mitochondrial content was significantly increased in the Lz and Jz of male fetuses and the Lz of female fetuses in AMA. When normalised to sample mitochondrial content, complex I + II-linked respiration, electron transfer capacity, and complex IV activity were significantly reduced in the Jz of male fetuses and Lz of female fetuses in AMA. However, when normalised to protein content, no differences were observed in placentas of female fetuses; in the Lz of male fetuses, complex I-linked respiration was increased and complex IV activity was reduced. Collectively, these findings suggest that the observed increase in mitochondrial content could be an adaptation by the placenta to maintain appropriate bioenergetic capacity and that oxidative damage may contribute to placental dysfunction in male fetuses in AMA pregnancies.

Keywords: apoptosis; fetal growth restriction; mitochondria; oxidative stress; placenta; pregnancy

DOI: https://doi.org/10.1530/REP-25-0160

Stem Cell Reports. 2025 Sep 03. pii: S2213-6711(25)00241-3. [Epub ahead of print] 102637

Trophoblast stem cell derivation from naive and primed hPSC enables ELF5 functional analysis.

Joonas Sokka, Ella Lapinsuo, Jouni Kvist, Sami Jalil, Masahito Yoshihara, Jere Weltner, Fredrik Lanner, Juha Kere, Diego Balboa, Timo Otonkoski, Ras Trokovic.

Human pluripotent stem cells (hPSCs) are valuable tools for studying placental biology, yet their differentiation into bona fide trophoblast stem cells (TSCs) remains challenging. In this study, we established and thoroughly compared naive and primed-derived TSC-like cells with primary human TSCs derived from pre-implantation blastocyst and first-trimester placenta. Comprehensive analyses confirmed expression of trophoblast lineage-specific genes and typical placental features. Detailed transcriptional analyses revealed that naive-derived TSC-like cells resembled embryo and placenta-derived cell lines and differentiated faster and more directly into TSC than primed-derived cells. We used these TSC-like models to study the role of ELF5, a transcription factor indispensable for maintenance and differentiation in mouse TSC. In contrast to the mouse, knockout and knockdown experiments revealed that ELF5 is dispensable for human TSC-like cells self-renewal and differentiation. Our study provides valuable transcriptional data and highlights the utility of hPSC-derived TSC-like cells for modeling the placenta and studying gene function.

Keywords: C19MC; CRISPR-Cas9; ELF5; early embryon annotation; embryonic stem cell; induced pluripotent stem cell; pluripotent stem cell; single cell RNA sequencing; transcriptomics; trophoblast; trophoblast stem cell

DOI: https://doi.org/10.1016/j.stemcr.2025.102637

Nat Commun. 2025 Sep 12. 16(1): 8267

Matrix directs trophoblast differentiation in a bioprinted organoid model of early placental development.

Claire Richards, Hao Chen, Matthew O'Rourke, Ashley Bannister, Grace Owen, Alexander Volkerling, Arnab Ghosh, Catherine A Gorrie, David Gallego-Ortega, Amy L Bottomley, Matthew P Padula, Kristine C McGrath, Louise Cole, Philip M Hansbro, Lana McClements.

Trophoblast organoids can provide crucial insights into mechanisms of placentation, however their potential is limited by highly variable extracellular matrices unable to reflect in vivo tissues. Here, we present a bioprinted placental organoid model, generated using the first trimester trophoblast cell line, ACH-3P, and a synthetic polyethylene glycol (PEG) matrix. Bioprinted or Matrigel-embedded organoids differentiate spontaneously from cytotrophoblasts into two major subtypes: extravillous trophoblasts (EVTs) and syncytiotrophoblasts (STBs). Bioprinted organoids are driven towards EVT differentiation and show close similarity with early human placenta or primary trophoblast organoids. Inflammation inhibits proliferation and STBs within bioprinted organoids, which aspirin or metformin (0.5 mM) cannot rescue. We reverse the inside-out architecture of ACH-3P organoids by suspension culture with STBs forming on the outer layer of organoids, reflecting placental tissue. Our bioprinted methodology is applicable to trophoblast stem cells. We present a high-throughput, automated, and tuneable trophoblast organoid model that reproducibly mimics the placental microenvironment in health and disease.

DOI: https://doi.org/10.1038/s41467-025-62996-0

Am J Reprod Immunol. 2025 Sep;94(3): e70101

Maternal-Fetal Interface Cell Dysfunction in Patients With Preeclampsia Revealed via Single-Cell RNA Sequencing.

Songyuan Xiao, Yiling Ding, Ling Yu, Yali Deng, Yang Zhou, Mei Peng, Weisi Lai, Yanting Nie, Wen Zhang.

PROBLEM: Preeclampsia (PE) is a leading cause of perinatal maternal and fetal mortality. Clinical and pathological studies suggest that placental and decidual cell dysfunction may contribute to this condition. However, the pathogenesis of PE remains poorly understood. Therefore, this study aims to investigate the heterogeneous changes in cell types within placental and decidual tissue isolated from cesarean sections using single-cell sequencing.
METHOD OF STUDY: Patients included those diagnosed with PE (n = 3) and normal pregnancy (NP) (n = 3). Overall, 32 279 cells (PE: 16.575; NP: 15 704) were identified across nine cell types, including villous cytotrophoblast (VCT), syncytiotrophoblast (SCT), extravillous trophoblasts (EVT), endothelial cells, neutrophil, Hofbauer cells, T cells, dendritic cells (DC), macrophages, fibroblasts, and B cells. VCT and T cells subclusters and pseudotime were analyzed. The in vivo and in vitro experiments are focused on the invasion ability of EVT.
RESULTS: Using gene set variation analysis (GSVA) for differential expression genes, cell-reclustering, and pseudotime analysis, the VCT in patients with PE showed a tendency to differentiate toward SCT instead of EVT. And the invasive ability of PE EVT cells was declined by decreased expression of the invasion-related gene TMEM200A. Additionally, the impaired immune environment of T-cell differentiation into CD8+T cells instead of Treg cells is the main change related to PE.
CONCLUSIONS: These findings suggest that understanding how T cell differentiation occurs in the early stage of pregnancy and how the predominantly CD8+T cell-driven immune environment influences VCT differentiation are crucial for elucidating the pathogenesis of PE.

Keywords: VCT; immunity; maternal‐fetal interface; preeclampsia; single‐cell RNA sequencing

DOI: https://doi.org/10.1111/aji.70101

Sci Rep. 2025 Sep 09. 15(1): 32387

RO8191, a new compound for initiating embryo implantation in mice.

Junlan Shu, Jumpei Terakawa, Sota Takikawa, Satoko Osuka, Ayako Muraoka, Jiali Ruan, Atsuo Iida, Junya Ito, Eiichi Hondo.

During early pregnancy in mice, leukemia inhibitory factor (LIF) regulates embryo implantation by activating the JAK/STAT3 signaling pathway. The STAT3 pathway has been recognized to play a critical role in embryo implantation; however, it remains unclear whether STAT3 activation alone is sufficient to induce implantation. In this study, we investigated the effects of RO8191, a potential STAT3 activator, on embryo implantation through a series of studies with different mouse models. We found that RO8191 can induce embryo implantation and decidual reaction by activating STAT3, but not STAT1, signaling in both epithelial and stromal compartments in delayed implantation models. Furthermore, RO8191 was able to rescue implantation and establish pregnancy even in uterine epithelial-specific Lifr conditional knockout (cKO) mice, which exhibit infertility due to implantation failure. In contrast, in uterine epithelial-specific Stat3 or Gp130 conditional knockout (cKO) mice, which also show embryo implantation failure, RO8191 induces only a partial decidual response. These results suggest that STAT3, Gp130 and LIFR each play distinct roles in embryo implantation and development. Although the detailed mechanisms underlying RO8191's action remain to be elucidated, our findings provide insights supporting its potential application in treating recurrent implantation failure.

Keywords: Implantation; Mice; RO8191; STAT3; Uterus

DOI: https://doi.org/10.1038/s41598-025-18471-3