ArticleProceedings of the National Academy of Sciences of the United States of America2021
Placental trophoblast syncytialization potentiates macropinocytosis via mTOR signaling to adapt to reduced amino acid supply.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 129 citations in OpenAlex.
- Cellular PrPThe Journal of general virology · 2026Article
- Metabolic Reprogramming at the Maternal-Fetal Interface: Insights from Decidual Stromal Cells and Trophoblasts in Healthy Pregnancy Versus Recurrent Pregnancy Loss.International journal of molecular sciences · 2026Review
- Understanding Intracellular Transport Impairments in Maternal Protein Restriction: A Scoping Review of DOHaD-Driven Cellular Biology Perspective.Cell biochemistry and biophysics · 2026Article
- Targeting the GSK-3β/mTOR axis: a novel pharmacological strategy for preeclampsia prevention and treatment.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- The Effects of L-Citrulline on the Apparent Digestion and Metabolism of Nutrients, Blood Hormone Levels, Amino Acid Metabolism and the Diversity of Faecal Microbiota in Mares in the Later Stage of Pregnancy.Life (Basel, Switzerland) · 2026Article
- Tim1 Deficiency Mediates Gestational Hyperglycemia-Related Syncytiotrophoblast Dysfunction and Fetal Growth Restriction.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Placental Steroid Hormones in Preeclampsia: Multilayered Regulation of Endocrine Pathogenesis.Endocrine reviews · 2026Review
- Metabolic control of feto-placental development and pregnancy outcomes.Nature reviews. Endocrinology · 2026Review
- CRISPRi Screening Identifies EssentialInternational journal of molecular sciences · 2026Article
- The Impact of Monkeypox Virus Infection on Pregnancy Outcome: Clinical Features and Potential Pathogenic Mechanisms.Journal of immunology research · 2026Review
- Maternal milk fat globule membrane enriched gutGut microbes · 2025Article
- Maternal Nutritional Status Governs Fetal Development by Modulating Imprinting Gene GAB1-Mediated Trophoblast Differentiation in the Placenta.Cell proliferation · 2025Article
- Mapping the placental galectin-3 interactome identifies CD9 and ITGB1 as functional glycoprotein counterreceptors during syncytialization.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Maternal stressors disrupt mouse placental proteome and fetal brain development in a sex-specific fashion through inflammation and oxidative stress.Molecular psychiatry · 2025Article
- Macropinocytosis fuels osteoclast differentiation in bone-related diseases.Journal of orthopaedic translation · 2025Article
- Effects of selective serotonin reuptake inhibitors on the placenta†.Biology of reproduction · 2025Review
- Lactate shuttle between cytotrophoblast and syncytiotrophoblast in the placenta enhances ferroptosis resistance and maintains placental homeostasis: implications for early pregnancy loss.Cell communication and signaling : CCS · 2025Article
- The human placenta and its role in reproductive outcomes revisited.Physiological reviews · 2025Review
- Acid sphingomyelinase is a gatekeeper of placental labyrinthine architecture and function.Development (Cambridge, England) · 2025Article
- AMPK: Accumulating Evidence in Support of its role in Dual Regulation of Vascular Function and Metabolism During Human Pregnancy.Acta physiologica (Oxford, England) · 2025Review
2 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
During pregnancy, the appropriate allocation of nutrients between the mother and the fetus is dominated by maternal-fetal interactions, which is primarily governed by the placenta. The syncytiotrophoblast (STB) lining at the outer surface of the placental villi is directly bathed in maternal blood and controls feto-maternal exchange. The STB is the largest multinucleated cell type in the human body, and is formed through syncytialization of the mononucleated cytotrophoblast. However, the physiological advantage of forming such an extensively multinucleated cellular structure remains poorly understood. Here, we discover that the STB uniquely adapts to nutrient stress by inducing the macropinocytosis machinery through repression of mammalian target of rapamycin (mTOR) signaling. In primary human trophoblasts and in trophoblast cell lines, differentiation toward a syncytium triggers macropinocytosis, which is greatly enhanced during amino acid shortage, induced by inhibiting mTOR signaling. Moreover, inhibiting mTOR in pregnant mice markedly stimulates macropinocytosis in the syncytium. Blocking macropinocytosis worsens the phenotypes of fetal growth restriction caused by mTOR-inhibition. Consistently, placentas derived from fetal growth restriction patients display: 1) Repressed mTOR signaling, 2) increased syncytialization, and 3) enhanced macropinocytosis. Together, our findings suggest that the unique ability of STB to undergo macropinocytosis serves as an essential adaptation to the cellular nutrient status, and support fetal survival and growth under nutrient deprivation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.