Placental trophoblast syncytialization potentiates macropinocytosis via mTOR signaling to adapt to reduced amino acid supply
- 5 January 2021
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 118 (3)
- https://doi.org/10.1073/pnas.2017092118
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.Keywords
Funding Information
- National Key Research and Development Program of China (2018YFC1004100)
- National Key Research and Development Program of China (2016YFC1000200)
- National Key Research and Development Program of China (2018YFC1004400)
- National Key Research and Development Program of China (2016YFC1000401)
- National Key Research and Development Program of China (2017YFC1001404)
- National Natural Science Foundation of China (81730040)
- National Natural Science Foundation of China (81971414)
- National Natural Science Foundation of China (31800986)
- Natural Sciences Foundation of Fujian Province (2020J06003)
This publication has 47 references indexed in Scilit:
- Macropinocytosis of protein is an amino acid supply route in Ras-transformed cellsNature, 2013
- Trophoblast FusionAdvances in Experimental Medicine and Biology, 2011
- Ragulator-Rag Complex Targets mTORC1 to the Lysosomal Surface and Is Necessary for Its Activation by Amino AcidsCell, 2010
- Mechanisms of EndocytosisAnnual Review of Biochemistry, 2009
- Defining MacropinocytosisTraffic, 2009
- Intrauterine restriction (IUGR)jpme, 2008
- TOR Signaling in Growth and MetabolismCell, 2006
- Trophoblast invasionHuman Fertility, 2004
- Class I MHC presentation of exogenous soluble antigen via macropinocytosis in bone marrow macrophagesImmunity, 1995
- Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products.The Journal of Experimental Medicine, 1995