bims-placeb Biomed News
on Placental cell biology
Issue of 2026–01–18
seven papers selected by
Carlos M Guardia, National Institute of Environmental Health Sciences
  1. Dihydroorotate dehydrogenase (DHODH) regulates trophoblast syncytialization through organelle stress-induced cellular senescence.
  2. Efficient Fluorescent Labeling of Human Trophoblast Stem Cells via a CRISPR/Cas9-Mediated Knock-In Approach in a Safe Harbor Locus.
  3. Nicotinamide Riboside Mitigates Antiphospholipid Antibody-Induced Dysfunction in Human Trophoblast Cells.
  4. Evolution and expression of glial cells missing (GCM1 and GCM2) in monotremes suggest an ancient role in reproduction.
  5. Adeno-associated viral vector-mediated gene delivery and shRNA knockdown in primary human cytotrophoblasts.
  6. The Secretome of Human Trophoblast Stem Cells Attenuates Senescence-Associated Traits.
  7. The impact of obesity on placental vascular development and function.
  1. FEBS Open Bio. 2026 Jan 16.
    Dihydroorotate dehydrogenase (DHODH) regulates trophoblast syncytialization through organelle stress-induced cellular senescence.
    Kanoko Yoshida, Kazuya Kusama, Ayaka Horiuchi, Yu Kawaguchi, Atsuya Tsuru, Mikihiro Yoshie, Kazuhiro Tamura.
      Trophoblast syncytialization is essential for placental function, and its dysregulation contributes to hypertensive disorders of pregnancy (HDPs), which compromise maternal and fetal health. Reduced expression of mitochondrial dihydroorotate dehydrogenase (DHODH) was observed in early-onset HDP placentas in our previous study. Experiments using human trophoblast stem cells demonstrated that DHODH inhibition impairs syncytialization and induces cellular senescence via mitochondrial and endoplasmic reticulum stress, elevating sFlt1/PlGF levels, a hallmark of placental dysfunction in HDPs. Mitochondrial activators quercetin and riboflavin partially reversed these effects. Our findings suggest that DHODH may be a key regulator of trophoblast differentiation by linking organelle stress to cellular senescence.
    Keywords:  Hypertensive disorder of pregnancy; cellular senescence; dihydroorotate dehydrogenase; human trophoblast stem cells; mitochondrial dysfunction; syncytialization
    DOI:  https://doi.org/10.1002/2211-5463.70194
  2. Bio Protoc. 2026 Jan 05. 16(1): e5561
    Efficient Fluorescent Labeling of Human Trophoblast Stem Cells via a CRISPR/Cas9-Mediated Knock-In Approach in a Safe Harbor Locus.
    Hengshan Zhang, Jie Zhou, Morgan Orsolini, Anthony Zhao, Askar Takhirov, Danny J Schust.
      Labeling cells with reporter genes allows researchers to visually identify specific cells and observe how they interact with each other in dynamic biological systems. Even though various labeling methods are now available, a specific description of gene knock-in labeling methods for human trophoblast stem cells (hTSCs) has not been reported. Here, we present a streamlined protocol for labeling hTSCs with the green fluorescent protein (GFP) reporter gene via CRISPR/Cas9-mediated knock-in of the gene into the adeno-associated virus site 1 (AAVS1) safe harbor locus. A commonly used hTSC cell line, CT29, was transfected with a dual plasmid system encoding the Cas9 endonuclease and an AAVS1-targeted guide RNA in one plasmid and a donor plasmid encoding a puromycin resistance gene and GFP reporter gene flanked by AAVS1 homology arms. Puromycin-resistant clonal cells were isolated, and AAVS1 integration was confirmed via PCR and sequencing of the PCR products. The labeled cells are proliferative and can give rise to extravillous cytotrophoblast cells (EVT) and the syncytiotrophoblast (ST). To our knowledge, this is the first report using the CRISPR/Cas9 system for AAVS1 integration of a reporter gene in human trophoblast stem cells. It provides an efficient tool to facilitate the study of human trophoblast development and function in co-culture systems and will be highly useful in developing clinical gene therapy-related plasmid constructs. Key features • First report to constitutively express a fluorescent label in hTSCs by applying a CRISPR/Cas9 knock-in approach and an AAVS1 safe harbor locus. • Provides an efficient tool to facilitate the study of human trophoblast development and function, particularly in heterologous co-culture systems. • Offers an approach for developing clinical gene therapy-related plasmid constructs that allow insertion of therapeutic genes without associated disruption of essential genes. • Widely applicable approach to label other human cell lines.
    Keywords:  AAVS1; CRISPR/Cas9; Gene labeling; Knock-in; Placenta; Stem cells; Trophoblast; hTSCs
    DOI:  https://doi.org/10.21769/BioProtoc.5561
  3. Am J Reprod Immunol. 2026 Jan;95(1): e70205
    Nicotinamide Riboside Mitigates Antiphospholipid Antibody-Induced Dysfunction in Human Trophoblast Cells.
    Abigail C Fischer, Hanah M Georges, Deidre M Jones, Lawrence W Chamley, Vikki M Abrahams.
       PROBLEM: Obstetric antiphospholipid syndrome (APS) is characterized by the presence of circulating anti-phospholipid antibodies (aPL), which disrupt early placentation and contribute to adverse pregnancy outcomes including pregnancy loss and preterm birth. aPL, specifically those targeting beta 2 glycoprotein 1 (β2GPI), interact with placental trophoblast cells and induce inflammation, disrupt angiogenic factor production, and reduce cell migration. In addition, aPL have been shown to promote a state of oxidative stress in trophoblast cells and in APS patients. This study aimed to investigate if the antioxidant, nicotinamide riboside (NR), could mitigate the negative effects of aPL on trophoblast cells.
    METHOD OF STUDY: The human first-trimester trophoblast cell line, Sw.71, was treated with or without aPL in the presence or absence of NR. Trophoblast supernatants were measured by ELISA for pro-inflammatory cytokines/chemokines and angiogenic factors. Cell migration was measured using a two-chamber colorimetric assay. ROS production was measured using a fluorescence assay.
    RESULTS: NR blocked aPL-induced trophoblast inflammation and ROS production, and reversed the effects of aPL on trophoblast angiogenic factor production. However, NR was unable to rescue aPL-induced trophoblast migratory dysfunction.
    CONCLUSION: NR mitigated some, but not all, aPL-induced trophoblast dysfunction. This provides new insight into the role of antioxidant therapies on aPL-induced pregnancy complications, and a possible new avenue of managing obstetric APS to explore further.
    DOI:  https://doi.org/10.1111/aji.70205
  4. Open Biol. 2025 Dec 01. pii: 250083. [Epub ahead of print]15(12):
    Evolution and expression of glial cells missing (GCM1 and GCM2) in monotremes suggest an ancient role in reproduction.
    Isabella Wilson, Diana Demiyah Mohd Hamdan, Rachel van der Ploeg, Tahlia Perry, Frank Grützner.
      The glial cells missing (GCM) genes were first discovered in Drosophila and encode transcription factors important for gliogenesis. In placental mammals, GCM1 regulates several genes that are important for early placenta development, while its paralogue GCM2 is important for parathyroid gland development. The egg-laying monotremes, which represent the most diverged extant mammalian lineage, undergo a short period of intrauterine development and form a simple placenta. To gain more insight into the evolution of GCM genes, we analysed the sequence, expression and genomic localization of GCM1 and GCM2 genes in the platypus and echidna. We found that the chromosomal localization of GCM1 changed after the divergence of therian mammals, coinciding with the evolution of a complex placenta. Expression analysis revealed the presence of GCM transcripts in male and female monotreme gonads, as well as expression of GCM1 in the female reproductive tract. GCM-binding sites in target genes associated with placental development in therian mammals were also present in the monotremes and the chicken. Together, this suggests that the role of GCM1 in reproduction emerged early in mammalian evolution.
    Keywords:  GCM; glial cells missing; monotreme; placenta; placental evolution; reproductive evolution
    DOI:  https://doi.org/10.1098/rsob.250083
  5. Placenta. 2026 Jan 10. pii: S0143-4004(26)00014-7. [Epub ahead of print]174 254-258
    Adeno-associated viral vector-mediated gene delivery and shRNA knockdown in primary human cytotrophoblasts.
    Hiromichi Yamamoto, Masato Tamari, Seiji Wada, Hironori Takahashi, Hiromi Yoshida-Komiya, Hirohisa Saito, Hideaki Morita, Kenji Matsumoto, Kenichiro Motomura.
      The placenta is essential for fetal growth and the maintenance of pregnancy. Primary human cytotrophoblasts (CTBs) provide a physiologically relevant model of this transient organ, yet their use has been limited by the difficulty of genetic manipulation. Recombinant adeno-associated virus (AAV) vectors, widely used to modulate gene expression in other systems, offer low immunogenicity, low cytotoxicity, and high efficiency in primary cells. Here, we provide proof of concept of an AAV-mediated gene delivery approach for primary CTBs. This platform enables in-depth, cell-biological studies to elucidate molecular mechanisms of human placental biology and pathology.
    Keywords:  Adeno-associated virus vector; Cytotrophoblast; In vitro model; Pregnancy; Primary culture; Syncytiotrophoblast; Transduction
    DOI:  https://doi.org/10.1016/j.placenta.2026.01.005
  6. Aging Cell. 2026 Feb;25(2): e70368
    The Secretome of Human Trophoblast Stem Cells Attenuates Senescence-Associated Traits.
    Kotb Abdelmohsen, Jennifer L Martindale, Martina Rossi, Chang Hoon Shin, Apala Pal, Rachel Munk, Martin Salamini-Montemurri, Mirko Baranzini, Ethan M Arends, Maja Mustapic, Yuta Lee, Jau-Nan Lee, Sicco H Popma, Justin Hu, Nathan Duda, Carlos J Nogueras-Ortiz, Dimitrios Kapogiannis, Chang-Yi Cui, Myriam Gorospe.
      Senescent cells display indefinite growth arrest and a pro-inflammatory, senescence-associated secretory phenotype (SASP). As the accumulation of senescent cells in tissues with age plays detrimental roles in age-related pathologies, there is much interest in finding therapeutic strategies to eliminate them or suppress the SASP. In this study, we investigated the impact of the secretome and extracellular vesicles (EVs) derived from human trophoblast stem cells (hTSCs) on senescent human fibroblasts. We found that the hTSC conditioned medium (hTSC-CM), and in particular the EVs (hTSC-EVs), significantly reduced the levels of mRNAs encoding SASP factors and the secretion of SASP factors including CXCL1, IL8, and GDF15. Proteomic analysis of hTSC-CM and EVs indicated an enrichment in proteins involved in cell adhesion, tissue repair, and remodeling of the extracellular matrix (ECM). Furthermore, incubation of senescent cells with hTSC-EVs attenuated DNA damage and inflammatory signaling, at least in part by suppressing the function of NF-κB, a major transcriptional regulator of the SASP program. Our findings underscore the value of hTSC-CM and EVs therein in therapeutic approaches directed at senescent cells.
    Keywords:  SASP; aging; cellular senescence; extracellular vesicles (EVs); human trophoblast stem cells; inflammation; secretome; senotherapeutics
    DOI:  https://doi.org/10.1111/acel.70368
  7. Mol Hum Reprod. 2026 Jan 13. pii: gaag002. [Epub ahead of print]
    The impact of obesity on placental vascular development and function.
    Isha Ramanlal, Joanna L James, Anna L Boss.
      Maternal obesity is complicating an increasing number of pregnancies globally and is associated with a heightened risk of adverse obstetric and fetal outcomes. The placenta, which mediates maternal-fetal exchange, is postulated to be a key mediator of these outcomes. The development of the extensively branched placental vascular network, driven by spatial and temporal regulation of angiogenic cues, is critical to ensure efficient exchange capacity. In maternal obesity, the placenta exhibits lipotoxicity, inflammation, and a range of cellular stresses, which may impair angiogenic signalling and endothelial metabolism, thereby disrupting vascular development. Understanding the timing and nature of obesity-induced disruptions to placental vascular development is important to improve clinical monitoring, inform the development of targeted interventions to improve fetal outcomes, and reduce obesity-associated pregnancy complications. This review synthesises the current literature on the impact of maternal obesity on the placental vasculature, considering how changes in vascular architecture, angiogenic factors, and endothelial cell metabolism intersect to lead to dysfunction. Furthermore, we propose a conceptual framework to explain how distinct combinations of placental alterations may underlie the heightened risk of divergent fetal growth outcomes (both pathologically large and small babies) commonly observed in obese pregnancies.
    Keywords:  Placenta; angiogenesis; endothelial cell metabolism; endothelial cells; fetal growth; inflammation; lipotoxicity; maternal obesity; stress; vasculature
    DOI:  https://doi.org/10.1093/molehr/gaag002
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