bims-placeb 2025-11-16 papers

bims-placeb

Biomed News

on Placental cell biology

Issue of 2025–11–16
sixteen papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences

Capturing trophectoderm-like stem cells enables step-wisely remodeling of placental development.
Role of ferroptosis-related GPX4 signaling in the fusion of human trophoblast cells.
Extracellular vesicles derived from M1 macrophages deliver MPPED2 and regulate PI3K/AKT to suppress trophoblast autophagy and proliferation in recurrent spontaneous abortion.
Maternal Diet-Induced Excess Adiposity in Mice Disrupts Mid-Gestation Decidual Immune and Vascular Homeostasis Without Impairing Spiral Artery Remodeling.
Relative Expression of Peptidylarginine Deiminase 2 and Sex Steroid Receptors in XX and XY Mouse Placenta.
Placental Alterations in Autism Spectrum Disorder: An In Silico Approach to circRNA-miRNA-mRNA Networks.
Placental dysfunction and neonatal mortality induced by Salmonella Abortusequi in a murine model of pregestational infection.
Mechanism of miR-20b-5p targeting HIF-1α in regulating trophoblast function in recurrent spontaneous abortion.
Association between MRI-derived early second trimester placental physiology and birth weight percentiles in pregnancies without ischemic placenta disease (IPD).
Umbilical cord-derived exosomal miR-548 is involved in driving preeclampsia pathogenesis by Inhibiting trophoblast cells invasion.
Antenatal melatonin for cardiovascular deficits in fetal growth restriction.
Early female germline development in Xenopus laevis: Stem cells, nurse cells, and germline cysts.
The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.
Secondhand Smoke Exposure Timing Triggers Distinct Placental Responses in Mouse Pregnancy.
Trigonelline activates NRF2 and awakens dormant ovarian follicles to promote pregnancy in aging mice.
Distinct miRNA profiles in human amniotic tissue and its vesicular and non-vesicular secretome.

Protein Cell. 2025 Nov 10. pii: pwaf098. [Epub ahead of print]

Capturing trophectoderm-like stem cells enables step-wisely remodeling of placental development.

Xinyi Jia, Bing Peng, Hongjin Zhao, Chunhui Wang, Aibin He, Wei Tao, Peng Du.

  The trophectoderm produced from totipotent blastomeres initiates trophoblast development, while placental deficiencies can cause pregnancy disorders. Yet, a culture system that fully recapitulates the entire placenta development is still lacking, greatly limiting related studies. Here, we captured mouse trophectoderm-like stem cells (TELSCs), which can give rise to all trophoblast lineages and be applied to generate trophoblast organoids. We achieved the induction and maintenance of TELSCs from totipotent blastomere-like stem cells or early embryos through a Hippo-YAP/Notch-to-TGFβ1 signaling switch. At the molecular level, TELSCs resemble E4.5 trophectoderm and are distinct from all previously known trophoblast-like stem cells. Functionally, TELSCs can generate all trophoblast lineages in both teratoma and chimera assays. We further applied TELSCs to generate trophoblast organoids containing various mature trophoblasts and a self-renewing extraembryonic ectoderm (ExE)-like progenitor population. Interestingly, we observed transiently formed rosette-like structures that rely on Itgb1, which are essential to induce ExE-like progenitors and to generate organoids eventually. Thus, the capture of TELSCs enables comprehensive insights into placental development.

Keywords:  embryonic development; epigenetic; organoid; placenta; pregnancy; stem cell; totipotency; transcriptomic; trophectoderm; trophoblast

DOI:  https://doi.org/10.1093/procel/pwaf098
Sci Rep. 2025 Nov 11. 15(1): 39515

Role of ferroptosis-related GPX4 signaling in the fusion of human trophoblast cells.

Kanoko Yoshida, Kazuya Kusama, Shiho Sato, Yu Kawaguchi, Ayaka Horiuchi, Mikihiro Yoshie, Kazuhiro Tamura.

  The placenta is mainly composed of trophoblast cells which fuse to create multinucleated syncytiotrophoblasts in the process of syncytialization. Syncytiotrophoblasts secrete human chorionic gonadotropin (hCG) for maintaining pregnancy. Impaired syncytialization contributes to pregnancy complications such as preterm labor and fetal growth restriction. Ferroptosis, a form of regulated non-apoptotic cell death, is characterized by the iron-dependent accumulation of lipid peroxides. This process is triggered by inactivation of glutathione peroxidase 4 (GPX4)-dependent antioxidant system. During pregnancy, iron demand increases, accompanied by elevated transferrin expression in syncytiotrophoblasts. However, the physiological relevance of ferroptosis signaling in trophoblast fusion remains largely explored. To address the impact of ferroptosis signaling on syncytialization, forskolin-stimulated trophoblast BeWo cells were treated with GPX4 inhibitors RSL3, ML-210, or erastin. Both RSL3 and ML-210 increased hCGβ expression and increased the number of fusogenic cells, alongside elevated intracellular Fe2⁺ levels and lipid peroxidation. These effects were suppressed by deferoxamine, an iron chelator, and ferrostatin-1, a lipid peroxidation inhibitor, both of which significantly reduced hCGβ expression. Enrichment analyses with 1,306 transcripts upregulated by ML-210 indicated the involvement of oxidative stress and endoplasmic reticulum (ER) stress pathways. ML-210 further upregulated NRF2, HO-1 and KEAP1, along with ER stress markers. Inhibition of the ER stress sensors IRE1α and ATF6 attenuated hCGβ expression, implicating these pathways in the regulation of syncytialization. Collectively, these findings suggest that ferroptosis-related lipid peroxidation and iron signaling contribute to the regulation of trophoblast fusion, potentially physiological role in placental development.

Keywords:  Cell fusion; ER stress; Ferroptosis; GPX4; Trophoblast; hCG

DOI:  https://doi.org/10.1038/s41598-025-23372-6
Biol Reprod. 2025 Nov 11. pii: ioaf249. [Epub ahead of print]

Extracellular vesicles derived from M1 macrophages deliver MPPED2 and regulate PI3K/AKT to suppress trophoblast autophagy and proliferation in recurrent spontaneous abortion.

Cen Tang, Hongbo Qi.

   BACKGROUND: Increasing evidence suggests that the biological activity of trophoblasts and M1-type macrophages plays a crucial role in recurrent spontaneous abortion. However, detailed mechanistic studies on the intercellular communication between these two cells at the maternal-fetal interface are not clear.
METHODS: In this study, extracellular vesicles (EVs) were first isolated from the supernatant of M1 macrophages induced by THP-1 cells (M1-EVs), identified by transmission electron microscopy, exosome immunofluorescence uptake, and western blotting, and characterized by mRNA sequencing to screen for specific target genes by mRNA profiling. CCK8 and western blotting experiments were used to investigate the effects of M1-EVs on trophoblast proliferation and autophagy. Subsequently, target genes MPPED2 and PI3K/AKT signaling pathway were found by bioinformatics analysis of raw mRNA sequencing results. Western blotting and CCK8 experiments were used to reveal the potential mechanisms by which MPPED2 in M1-EVs regulates trophoblast function.
RESULTS: M1 macrophages induce inflammatory responses in the mother and fetus, and M1 macrophages inhibit trophoblast autophagy and proliferative capacity by secreting EVs. By mRNA transcriptome sequencing, MPPED2, among others, were identified as the most up-regulated mRNAs in M1-EVs-treated trophoblasts. Further functional experiments indicate that M1 macrophage-derived exosomes may regulate PI3K/AKT pathway activity by transferring MPPED2, leading to reduced autophagy and proliferation activity in trophoblasts.
CONCLUSION: Our findings suggest that MPPED2 from exosomes plays an important role in intercellular communication between M1 macrophages and the trophoblast, elucidating a novel mechanism by which M1 macrophages regulate trophoblast function and its role in recurrent spontaneous abortion.

Keywords:  Exosomes; M1 macrophages; Mpped2; Recurrent spontaneous abortion; Trophoblasts

DOI:  https://doi.org/10.1093/biolre/ioaf249
Acta Physiol (Oxf). 2025 Dec;241(12): e70130

Maternal Diet-Induced Excess Adiposity in Mice Disrupts Mid-Gestation Decidual Immune and Vascular Homeostasis Without Impairing Spiral Artery Remodeling.

Christian J Bellissimo, Erica Yeo, Tatiane A Ribeiro, Patrycja A Jazwiec, Chethana Ellewela, Jaskiran Bains, Ariana E Lewis, Katherine M Kennedy, Ali A Ashkar, Alexander G Beristain, Dawn M E Bowdish, Deborah M Sloboda.

   AIM: Maternal excess adiposity (i.e., overweight/obesity) is linked to impaired uteroplacental perfusion, compromised placental development, and increased risk of adverse pregnancy outcomes. Inflammation and immune dysregulation accompanying excess adiposity may disrupt leukocyte-mediated tissue remodeling and immunoregulation, contributing to placental dysfunction. However, the impacts of excess adiposity on populations of innate lymphoid cells and macrophages orchestrating these processes, and on the decidual microenvironment, remain understudied. Here, we used a mouse model of high-fat, high-sucrose (HFHS) diet-feeding to study the impacts of excess adiposity on decidual immune dynamics during placental development.
METHODS: Uteroplacental tissues were collected at mid-gestation (E10.5) from mice fed a control chow (CON) or HFHS diet before and during pregnancy. Multicolour flow cytometry was used to profile decidual leukocyte composition. Spiral artery remodeling was measured using (immuno)histochemistry. Multiplex immunoassays were used to compare systemic and decidual cytokine and growth factor levels. Comparative gene expression was measured in placental tissues using a NanoString nCounter array.
RESULTS: HFHS pregnancies had elevated decidual leukocyte abundance, with increased tissue-resident and conventional-like NK cells, and MHC-II+ macrophages. This was not associated with abnormal spiral artery remodeling but coincided with increased decidual proinflammatory cytokine and chemokine expression, and greater elevations in mediators of angiogenesis, endothelial activation, and coagulation. Despite this, placental gene expression was largely unaltered at mid-gestation.
CONCLUSION: These findings point towards decidual vascular inflammation and dysregulated angiogenesis during early placentation in pregnancies complicated by excess adiposity. This may stem from or induce shifts in resident immune cells, contributing to later placental dysfunction.

Keywords:  adiposity; decidua; decidual NK cells; decidual macrophages; high‐fat diet; obesity; placenta; pregnancy; reproductive immunology

DOI:  https://doi.org/10.1111/apha.70130
Int J Mol Sci. 2025 Oct 29. pii: 10523. [Epub ahead of print]26(21):

Relative Expression of Peptidylarginine Deiminase 2 and Sex Steroid Receptors in XX and XY Mouse Placenta.

Amanda Wewer, Autumn Bennitt, Emily Hinners, Morgan Helmich, Nathan Schnepp, Sean Pitcher, Agata M Parsons, Gerrit J Bouma.

  Although female (XX) and male (XY) placentas generally function the same, it is evident that there are sex-specific postnatal health outcomes following placental dysfunction and pregnancy complications. Although the underlying causes for these sex differences are unclear, it is postulated that differences in XX and XY placental function are involved due to sex chromosomes and/or sex steroids. Studies in breast and prostate cancer cells demonstrated a role for the citrullination enzyme peptidylarginine deiminase 2 (PAD2) in post-translational regulation of estrogen (ESR) and androgen receptor (AR) signaling. The goal of this study is to determine if PAD2 is present in mouse placentas and if XX versus XY differences exist in the relative level of PAD2. Fetuses and placentas were collected from three pregnant mice (C57BL6) at 14 days of gestation. Total RNA and protein were isolated from XX and XY placentas, and relative mRNA and protein were analyzed by real-time PCR and Western blot. AR and PAD2 levels were significantly higher in XY than in XX placentas. This study is the first to demonstrate XX and XY differences in PAD2 and AR in the placenta. It suggests a role for PAD2 regulation of androgen receptor signaling in the XY placenta.

Keywords:  PAD2; androgen receptor; estrogen receptor 1; fetus; peptidylarginine deiminase; placenta

DOI:  https://doi.org/10.3390/ijms262110523
Int J Dev Neurosci. 2025 Nov;85(7): e70064

Placental Alterations in Autism Spectrum Disorder: An In Silico Approach to circRNA-miRNA-mRNA Networks.

Brayan Braz-Barbosa, Carmem Gottfried, Júlio Santos-Terra.

  Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and repetitive behaviours with an aetiology involving genetic and environmental risk factors. Placental alterations, such as epigenetic DNA methylation and structural abnormalities, have been associated with ASD. Circular RNA (circRNA), covalently closed and highly stable molecules, play an epigenetic role by sequestering microRNA (miRNA) and modulating messenger RNA (mRNA) translation, forming posttranscriptional networks essential for gene expression. However, there is a lack of evidence in the literature regarding the involvement of circRNA, the placenta and ASD. To address this gap, the study aimed to map the interactions among circRNA, miRNA and mRNA, investigating their relevance to ASD and placental development using bioinformatics tools, such as circATLAS and miRTargetLink 2.0. The analysis identified 71 circRNA linked to ASD and 30 highly expressed in the placenta, which regulate pathways such as 'immune response,' 'gene transcription,' and 'replication,' and others previously associated with ASD, such as 'Notch and AKT signalling pathway'. Searches in the SFARI database revealed 11 relevant genes in the ASD group, nine in the placenta group and five shared genes (SRSF11, PSMD11, NOTCH1, CREBBP and TBL1X). Further analysis identified the interaction of the circRNA hsa-MAN1A2_0008 with miRNA associated with these genes. These findings suggest that highly expressed circRNA in the placenta regulate critical pathways for placental development and ASD aetiology, underscoring their role in linking placental alterations to ASD.

Keywords:  ASD; bioinformatics; circRNA; circRNA–miRNA–mRNA; placenta

DOI:  https://doi.org/10.1002/jdn.70064
Placenta. 2025 Nov 04. pii: S0143-4004(25)00738-6. [Epub ahead of print]172 139-149

Placental dysfunction and neonatal mortality induced by Salmonella Abortusequi in a murine model of pregestational infection.

Diana M Betancourt, Mariángeles Noto Llana, Ailín N Garófalo, Sebastián H Sarnacki, M Cristina Cerquetti, Nairobi Hernández Bridón, M Carolina Pustovrh, Mónica N Giacomodonato.

   INTRODUCTION: Salmonella Abortusequi is a host-restricted equine pathogen and a major cause of abortion in mares, threatening reproductive health and industry sustainability. This study was aimed to identify factors that adversely affect placental function, contributing to the development of fetal growth restriction (FGR) and neonatal mortality.
METHODS: CF1 virgin female mice received a pregestational intragastric dose of Salmonella Abortusequi (108 CFU/mouse). On gestational day 18 (GD18), pregnant females were sacrificed, and maternal tissues and fetoplacental units were collected. In a separate group, pregnancy proceeded to term for neonatal outcome assessment.
RESULTS: Salmonella Abortusequi infection impaired placental morphometry and efficiency, leading to FGR and increased neonatal mortality. Offspring from infected dams had persistently low body weight and 40.3 % mortality rate during the first postnatal week. Molecular detection of the invA gene confirmed bacterial presence in fetoplacental units at GD18 and prolonged persistence in maternal spleen and liver up to 90 days post-inoculation. Infection significantly reduced placental claudin-4 gene and protein expression, suggesting a disruption of placental barrier integrity.
DISCUSSION: This study demonstrates that a pregestational infection with Salmonella Abortusequi can exert long-term consequences not only on placental development and fetal growth, but also on neonatal viability and early postnatal development. Importantly, these findings highlight the potential impact of subclinical maternal infections as contributors to reproductive failure and early-life morbidity.

Keywords:  Fetal growth restriction; Neonatal mortality; Placenta; Placental morphometry; Pregnancy; Salmonella Abortusequi

DOI:  https://doi.org/10.1016/j.placenta.2025.11.002
Eur J Med Res. 2025 Nov 14. 30(1): 1119

Mechanism of miR-20b-5p targeting HIF-1α in regulating trophoblast function in recurrent spontaneous abortion.

Yihong Guo, Qiaoxian Wu, Lujing Chen, Yanyu Lai, Aizhen Fu.

   OBJECTIVE: Recurrent spontaneous abortion (RSA) is a major pregnancy complication with unclear pathogenesis. This study aims to investigate the role of miR-20b-5p and its downstream target HIF-1α in trophoblast function and RSA pathogenesis.
METHODS: Placental villous tissues from uRSA patients and healthy pregnant women were collected to assess trophoblast migration, invasion, apoptosis, and placental angiogenesis. The expression levels of miR-20b-5p and HIF-1α were analyzed using qPCR, Western blot, and immunohistochemistry. HTR-8/SVneo cells were transfected with miR-20b-5p mimics, si-miR-20b-5p, and si-HIF-1α to evaluate their effects on trophoblast function. Luciferase reporter assays were performed to confirm the regulatory relationship between miR-20b-5p and HIF-1α.
RESULTS: Trophoblast cells isolated from uRSA patients exhibited impaired trophoblast invasion and increased trophoblast apoptosis, accompanied by increased trophoblast apoptosis. miR-20b-5p was significantly upregulated, whereas HIF-1α expression was downregulated in uRSA placental tissues. Overexpression of miR-20b-5p inhibited trophoblast migration, invasion, and endothelial-like differentiation, while its knockdown enhanced these functions. HIF-1α was identified as a direct target of miR-20b-5p, and its knockdown partially reversed the effects of miR-20b-5p inhibition.
CONCLUSION: miR-20b-5p negatively regulates trophoblast function by targeting HIF-1α, contributing to trophoblast dysfunction and RSA pathogenesis. The miR-20b-5p/HIF-1α axis may serve as a potential therapeutic target for RSA.

Keywords:  HIF-1α; MiR-20b-5p; Recurrent spontaneous abortion; Trophoblast

DOI:  https://doi.org/10.1186/s40001-025-03308-6
Placenta. 2025 Nov 06. pii: S0143-4004(25)00739-8. [Epub ahead of print]172 120-130

Association between MRI-derived early second trimester placental physiology and birth weight percentiles in pregnancies without ischemic placenta disease (IPD).

Raymi O Ramirez, Jennifer J Kim, Precious Ann Fortes, Carla Janzen, Peggy Sullivan, Sherin U Devaskar, Kyunghyun Sung.

   INTRODUCTION: This study investigated whether placental structure and function, measured using multiparametric MRI (mpMRI) in early second trimester, are associated with birth weight percentiles. We focused on pregnancies without ischemic placental disease (IPD), excluding cases with preeclampsia, fetal growth restriction (FGR), small for gestational age (SGA), or placental abruption. Clinical and pathological moderators were also examined.
METHODS: In this prospective single-center cohort, 199 participants were recruited between 2017 and 2019. Placental MRI was performed at two gestational age (GA) windows: 14-16 weeks (w) and 19-24w. Placental volume, perfusion, and oxygenation were quantified and standardized to 16w for the first imaging timepoint and 20w for the second imaging timepoint. After excluding IPD cases, linear mixed-effects models were used to explore retrospective associations between MRI metrics and birth weight percentiles, adjusting for clinical and histopathological variables.
RESULTS: Early second trimester mpMRI showed significant associations between placental volume (positive association) and perfusion (negative association) as early as 16w GA to birthweight percentiles (p < 0.05). The nonlinear three-way interaction between the change of mpMRI parameters between 16w and 20w GA (Δ w GA) was consistently positively associated to birth weight percentiles regardless of clinical and pathological factors (p < 0.05).
DISCUSSION: Early second trimester mpMRI markers (volume and perfusion) at 16w and 20w GA are associated with birth weight outcomes, suggesting utility in early pregnancy monitoring. The three-way interaction between the mpMRI markers may serve as a composite marker for identifying variation in fetal growth trajectories.

Keywords:  BMI; Birth weight; Fetal sex; Hypoxic score; Imaging; Placenta; Regression

DOI:  https://doi.org/10.1016/j.placenta.2025.11.003
Hypertens Pregnancy. 2025 Dec 31. 44(1): 2579984

Umbilical cord-derived exosomal miR-548 is involved in driving preeclampsia pathogenesis by Inhibiting trophoblast cells invasion.

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

   BACKGROUND: Preeclampsia (PE) is a severe pregnancy-related disorder characterized by hypertension and end-organ manifestation, and remains a leading cause of perinatal maternal and fetal mortality and morbidity in developing countries. The pathogenesis of PE involves reduced uteroplacental blood flow and impaired trophoblast invasion; however, the role of exosomes in these processes is not fully understood.
METHODS: This study employed Transwell assay, wound healing assay, and CCK-8 assays to evaluate the effects of umbilical cord exosomes derived from women with PE (PE-exosomes) on trophoblast function. Additionally, miRNA sequencing, in vitro transfection, western blotting, RT-PCR amd FISH assays were used to investigate the involvement of the microRNA-548 (miR-548)/Ras homolog family member A (RhoA) axis. Statistical analysis was performed using t-tests, with a significance threshold of P < 0.01.
RESULTS: Expression levels of miR-548 were significantly elevated in PE-exosomes. Both treatment with PE-exosomes and the overexpression of miR-548 inhibited trophoblast invasion and proliferation. These effects were reversed by RhoA overexpression. Together, these findings suggest that PE-exosomes suppress trophoblast invasion via the miR-548/RhoA axis. In pregnant women with PE, high miR-548 expression levels were observed, and were positively correlated with blood pressure and proteinuria.
CONCLUSIONS: Elevated miR-548 levels may contribute to the development of PE, suggesting that miR-548 could serve as a novel diagnostic or therapeutic target for this condition.

Keywords:  Preeclampsia; RhoA; exosome; miR-548; trophoblast

DOI:  https://doi.org/10.1080/10641955.2025.2579984
J Physiol. 2025 Nov 13.

Antenatal melatonin for cardiovascular deficits in fetal growth restriction.

Charmaine R Rock, Tegan A White, Beth R Piscopo, Amy E Sutherland, Yen Pham, Connor Karozis, Fiona L Cousins, Emily J Camm, Suzanne L Miller, Beth J Allison.

  Fetal growth restriction (FGR) increases the risk of cardiovascular disease. FGR is linked to placental insufficiency and fetal hypoxemia, leading to oxidative stress and inflammation, which collectively influence the developmental programming of cardiovascular disease. This study assessed whether melatonin (MLT), a potent antioxidant and anti-inflammatory agent, could prevent cardiovascular deficits associated with FGR. Placental insufficiency was induced in ewes at 89 days of gestational age (dGA, term 148 dGA). Ewes were randomly allocated to control, FGR or FGR+MLT (i.v., 15 mg day-1, from 95 dGA to birth) groups. Lambs were delivered preterm at 136 dGA and assessed as newborn (24 h) and 4-week-old lambs. Vascular function was determined in femoral arteries using in vitro wire myography and vascular morphology as assessed in carotid and femoral arteries. Newborn FGR lambs were ∼30% smaller than control lambs with an increased brain-to-body weight ratio, indicative of brain sparing. Femoral endothelial function declined between ∼24 h after birth and 4 weeks in FGR lambs. By contrast, femoral arteries from newborn FGR+MLT lambs displayed transient endothelial dysfunction that improved by 4 weeks. However, these arteries showed elevated levels of oxidative stress and inflammation. Despite improving endothelial function, melatonin also disrupted the brain-sparing response in FGR lambs. Furthermore, by 4 weeks of age, melatonin treatment led to heightened oxidative stress and inflammatory markers in the peripheral vasculature, suggesting a potential trade-off between vascular benefits and systemic maladaptation. These findings highlight the complexity of melatonin's effects on the cardiovascular system and underscore the need for careful evaluation of its long-term safety and efficacy before clinical translation. KEY POINTS: Fetal growth restriction (FGR) significantly increases the lifelong risk of cardiovascular disease, and there are currently no targeted treatments to mitigate these risks. This study follows growth-restricted lambs from birth to 4 weeks of age (comparable to a 1-year-old human in terms of cardiovascular function) to characterise how FGR affects vascular development over time. FGR lambs exhibited progressive endothelial dysfunction in the femoral artery, but antenatal melatonin treatment restored endothelial function long-term despite the presence of vascular oxidative stress and inflammation. The brain-sparing response is a key adaptive mechanism for fetal survival, yet melatonin appears to dampen this response, highlighting the need for further investigation into its broader physiological effects.

Keywords:  brain sparing; cardiovascular; fetal growth restriction; melatonin

DOI:  https://doi.org/10.1113/JP288750
Proc Natl Acad Sci U S A. 2025 Nov 18. 122(46): e2522343122

Early female germline development in Xenopus laevis: Stem cells, nurse cells, and germline cysts.

Asya Davidian, Allan C Spradling.

  In Drosophila, germline cysts arise through synchronous mitotic divisions and acquire a polarized architecture organized by the fusome, which guides oocyte specification and supports meiotic progression. Similar cyst structures exist in nonmammalian vertebrate ovaries, but their polarity and function have remained uncertain. Using single-cell RNA sequencing and high-resolution imaging, we reconstructed the germ cell differentiation trajectory in Xenopus laevis and uncovered striking parallels with invertebrate and mouse cyst development. We identified a distinct germline stem cell (GSC) population marked by piwil4, low translational activity, and expression of neuronal-specific and transposon-silencing genes. Downstream from GSCs, during cyst development, an asymmetric fusome-like structure composed of stable microtubules forms a rosette-like connection between cystocytes and contains Golgi vesicles and endoplasmic reticulum, suggesting polarized trafficking. In contrast to previous claims, ~80% of cyst cells turned over rather than forming oocytes, consistent with a nurse cell fate. The striking parallels described here between cyst and fusome formation, polarization, cyst breakdown, and nurse-like cell turnover to produce relatively few oocytes argue that amphibian cysts have important functions in female gametogenesis.

Keywords:  Xenopus; germ cell; germline cyst; germline stem cell; ovary

DOI:  https://doi.org/10.1073/pnas.2522343122
Sci Adv. 2025 Nov 14. 11(46): eaea4660

The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.

Laura S Kremer, Zoe Golder, Tom Barton-Owen, Polyxeni Papadea, Camilla Koolmeister, Patrick F Chinnery, Nils-Göran Larsson.

Mammalian mitochondrial DNA (mtDNA) inheritance differs fundamentally from nuclear inheritance owing to exclusive maternal transmission, high mutation rate, and lack of recombination. Two key mechanisms shape this inheritance: the bottleneck, which drives stochastic transmission of maternal mtDNA variants, and purifying selection, which actively removes mutant mtDNA. Whether these mechanisms interact has been unresolved. To address this question, we generated a series of mouse models with random mtDNA mutations alongside alleles altering mtDNA copy number or decreasing autophagy. We demonstrate that tightening the mtDNA bottleneck increases heteroplasmic variance between individuals, causing lower mutational burden and nonsynonymous-to-synonymous ratios. In contrast, reduced autophagy weakens purifying selection, leading to decreased interoffspring heteroplasmic variance and increased mutational burden with higher nonsynonymous-to-synonymous ratios. These findings provide experimental evidence that the mtDNA bottleneck size modulates the efficacy of purifying selection. Our findings yield fundamental insights into the processes governing mammalian mtDNA transmission with direct implications for the origin and propagation of mtDNA mutations causing human disease.

DOI: https://doi.org/10.1126/sciadv.aea4660
Cells. 2025 Nov 05. pii: 1735. [Epub ahead of print]14(21):

Secondhand Smoke Exposure Timing Triggers Distinct Placental Responses in Mouse Pregnancy.

Archarlie Chou, Ethan Frank, Matt Reall, Olivia Hiatt, Logan Beck, Paul R Reynolds, Brett E Pickett, Juan A Arroyo.

  Secondhand smoke (SHS), found in about 57.6% of global public areas as a widespread environmental hazard, has been associated with negative effects during pregnancy, such as preeclampsia (PE) and intrauterine growth restriction (IUGR). Our research investigated the impact of SHS on placental issues in a C57BL/6 model that simulates PE and IUGR in mice. We administered SHS to pregnant mice through a nose-only delivery method, beginning either on embryonic day 12.5 (prior to spiral artery (SA) invasion; labeled SHS-6D) or day 14.5 (following SA invasion; labeled SHS-4D), continuing up to E18.5. Control animals received only ambient air. We employed bulk RNA sequencing to assess and describe changes in placental gene expression patterns. For the SHS-4D group, which mimicked IUGR, compared to untreated controls, results showed elevated levels of inflammation-related genes (IL11RA, CHI3L1) alongside likely interference in pathways for antibody-triggered complement activation, marked by reduced expression of C1QA, C1QB, and C1QC. Immune profiling also indicated decreased macrophage activity in the placentas of the SHS-4D group relative to those from normal pregnancies at term. In contrast, the SHS-6D versus control analysis revealed lowered expression of collagen-related genes (COL1A1, COL4A5, COL4A6, COL17A1). Additionally, SHS-6D exhibited higher levels of genes associated with cell-based lysis processes compared to SHS-4D. An evaluation of the existing literature revealed that nearly every differentially expressed gene (DEG) identified in our work has been reported in studies associated with SHS exposure. Yet, few of these DEGs are discussed alongside PE or IUGR in prior reports, highlighting gaps in knowledge about how SHS triggers these conditions. Overall, we determined that the timing of SHS exposure in pregnant mice results in unique patterns of gene regulation and involvement in biological pathways.

Keywords:  RNA-sequencing; intrauterine growth restriction; placental dysfunction; preeclampsia; secondhand smoke

DOI:  https://doi.org/10.3390/cells14211735
iScience. 2025 Nov 21. 28(11): 113717

Trigonelline activates NRF2 and awakens dormant ovarian follicles to promote pregnancy in aging mice.

Mahboobeh Amoushahi, Emil Hagen Ernst, Anders Heuck, Margit Dueholm, Erik Ernst, Karin Lykke-Hartmann.

  Aging ovaries exhibit increased oxidative stress, contributing to infertility through cellular and hormonal changes. Nuclear factor E2-related factor 2 (NRF2), a key transcription factor, regulates antioxidant responses. This study investigates NRF2 in dormant (primordial) ovarian follicles to determine if NRF2 activation accounts for primordial follicle activation. We show that trigonelline (TRG) transiently activates NRF2, promoting primordial follicle activation in the non-hormonal phase of follicle development. Indeed, TRG enhances egg quality in aged mice. In human ovarian tissues, TRG increased activation of primordial follicles, resulting in more primary and secondary follicles. Mechanistically, TRG induces NRF2 nuclear translocation and upregulates NRF2-responsive genes, including Egf. Elevated epidermal growth factor (EGF) levels activate EGF receptor (EGFR), increasing protein kinase B (AKT) phosphorylation, which leads to FOXO3A nuclear extrusion and primordial follicle activation. These findings demonstrate that transient NRF2 activation is sufficient to initiate primordial follicle activation and follicle growth and development.

Keywords:  Cell biology; Reproductive medicine

DOI:  https://doi.org/10.1016/j.isci.2025.113717
Front Cell Dev Biol. 2025 ;13 1692501

Distinct miRNA profiles in human amniotic tissue and its vesicular and non-vesicular secretome.

Nefertiti Chaves-Solano, Silvio Kau-Strebinger, Johannes Oesterreicher, Marianne Pultar, Wolfgang Holnthoner, Johannes Grillari, Simone Hennerbichler, Andreas Brandstetter, Andreas Spittler, Matthias Hackl, Susanne Wolbank, Asmita Banerjee, Adelheid Weidinger.

   Introduction: The human amniotic membrane (hAM) has largely been used in tissue regeneration and wound healing applications. A promising alternative to decellularized hAM or isolated cells is the usage of native viable hAM which contains and releases cell-derived bioactive factors that are known to enhance tissue regeneration. MicroRNAs (miRNAs) are known regulators of gene expression at post-transcriptional level and are important drivers of regeneration processes in several tissues. In this study, we characterized the miRNA profile of hAM tissue and its vesicular and non-vesicular secretome in the reflected and placental hAM as two spatially and physiologically distinct regions.
Methods: Extracellular vesicles were enriched from the secretome by size exclusion chromatography (SEC). Small RNAs were determined by Next Generation Sequencing in the conditioned medium and in tissue.
Results: After SEC, we identified predominantly small hAM-derived EVs (≤200 nm) expressing CD81. The highest percentage of miRNA relative to all mapped reads was found in tissue (15%-40%), while 2%-15% were protein-bound and 3%-6% associated with EVs. Unsupervised clustering revealed distinct clusters of miRNA expression according to sample fraction (EV-associated, protein-bound, and tissue) and amniotic regions (reflected, placental). Gene ontology analysis linked EV-associated and tissue miRNAs to (smooth) muscle proliferation, while protein-bound miRNAs were associated with connective tissue development, chondrocyte differentiation and glial cell proliferation. Furthermore, correlation analysis of tissue miRNAs and extracellular expression identified EV-associated and protein-bound miRNAs specifically released from the tissue.
Conclusion: These findings support the assumption that native viable hAM could serve as a miRNA source for applications in regenerative medicine.

Keywords:  extracellular vesicles; human amniotic membrane; miRNA; non-vesicular secretome; perinatal tissue; tissue regeneration; vesicular secretome

DOI:  https://doi.org/10.3389/fcell.2025.1692501