PMID- 33402432 OWN - NLM STAT- MEDLINE DCOM- 20210512 LR - 20221005 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 118 IP - 3 DP - 2021 Jan 19 TI - Placental trophoblast syncytialization potentiates macropinocytosis via mTOR signaling to adapt to reduced amino acid supply. LID - 10.1073/pnas.2017092118 [doi] LID - e2017092118 AB - 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. FAU - Shao, Xuan AU - Shao X AUID- ORCID: 0000-0003-0352-1648 AD - State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China. AD - Stem Cell and Regenerative Medicine Innovation Institute, Chinese Academy of Sciences, 100101 Beijing, China. AD - University of Chinese Academy of Sciences, 101408 Beijing, China. FAU - Cao, Guangming AU - Cao G AUID- ORCID: 0000-0002-5601-6605 AD - Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Capital Medical University, 100020 Beijing, China. FAU - Chen, Dunjin AU - Chen D AUID- ORCID: 0000-0002-1839-3469 AD - Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, 510150 Guangzhou, China. FAU - Liu, Juan AU - Liu J AD - State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China. AD - University of Chinese Academy of Sciences, 101408 Beijing, China. FAU - Yu, Bolan AU - Yu B AD - Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, 510150 Guangzhou, China. FAU - Liu, Ming AU - Liu M AD - State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China. FAU - Li, Yu-Xia AU - Li YX AUID- ORCID: 0000-0003-3231-2271 AD - State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China. FAU - Cao, Bin AU - Cao B AUID- ORCID: 0000-0003-2516-790X AD - Fujian Provincial Key Laboratory of Reproductive Health Research, School of Medicine, Xiamen University, 361102 Xiamen, China; caobin19@xmu.edu.cn ysadovsky@mwri.magee.edu wangyl@ioz.ac.cn. FAU - Sadovsky, Yoel AU - Sadovsky Y AUID- ORCID: 0000-0003-2969-6737 AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213; caobin19@xmu.edu.cn ysadovsky@mwri.magee.edu wangyl@ioz.ac.cn. AD - Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15219. FAU - Wang, Yan-Ling AU - Wang YL AUID- ORCID: 0000-0002-9448-7803 AD - State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China; caobin19@xmu.edu.cn ysadovsky@mwri.magee.edu wangyl@ioz.ac.cn. AD - Stem Cell and Regenerative Medicine Innovation Institute, Chinese Academy of Sciences, 100101 Beijing, China. AD - University of Chinese Academy of Sciences, 101408 Beijing, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Amino Acids) RN - 0 (ERVFRD-1 protein, human) RN - 0 (Pregnancy Proteins) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.1 (ribosomal protein S6 kinase, 70kD, polypeptide 1) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - AMP-Activated Protein Kinases/genetics/metabolism MH - *Adaptation, Physiological MH - Amino Acids/deficiency MH - Animals MH - Cell Line MH - Cell Nucleus/genetics/metabolism MH - Chorionic Villi/metabolism MH - Female MH - Fetal Growth Retardation/genetics/*metabolism/pathology MH - Gene Expression Regulation MH - Humans MH - Maternal-Fetal Exchange/*physiology MH - Mice MH - Pinocytosis/*genetics MH - Pregnancy MH - Pregnancy Proteins/*genetics/metabolism MH - Primary Cell Culture MH - Ribosomal Protein S6 Kinases, 70-kDa/genetics/metabolism MH - Signal Transduction MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases/antagonists & inhibitors/*genetics/metabolism MH - Trophoblasts/cytology/*metabolism PMC - PMC7826386 OTO - NOTNLM OT - amino acid shortage OT - fetal growth OT - mTOR OT - macropinocytosis OT - placental syncytiotrophoblast COIS- The authors declare no competing interest. EDAT- 2021/01/07 06:00 MHDA- 2021/05/13 06:00 PMCR- 2021/07/05 CRDT- 2021/01/06 05:38 PHST- 2021/01/06 05:38 [entrez] PHST- 2021/01/07 06:00 [pubmed] PHST- 2021/05/13 06:00 [medline] PHST- 2021/07/05 00:00 [pmc-release] AID - 2017092118 [pii] AID - 202017092 [pii] AID - 10.1073/pnas.2017092118 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2021 Jan 19;118(3):e2017092118. doi: 10.1073/pnas.2017092118.