PMID- 33835684
OWN - NLM
STAT- MEDLINE
DCOM- 20211004
LR  - 20211004
IS  - 1582-4934 (Electronic)
IS  - 1582-1838 (Print)
IS  - 1582-1838 (Linking)
VI  - 25
IP  - 10
DP  - 2021 May
TI  - Extracellular vesicle-derived microRNA-18b ameliorates preeclampsia by enhancing 
      trophoblast proliferation and migration via Notch2/TIM3/mTORC1 axis.
PG  - 4583-4595
LID - 10.1111/jcmm.16234 [doi]
AB  - Preeclampsia (PE), a common disorder of pregnancy, is characterized by 
      insufficient trophoblast migration and inadequate vascular remodelling, such that 
      promotion of trophoblast proliferation might ameliorate PE. In the current study, 
      we sought to study the underlying mechanism of extracellular vesicle (EV)-derived 
      microRNA-18 (miR-18b) in PE. Human umbilical cord mesenchymal stem cells 
      (HUCMSCs) isolated from placental tissues were verified through osteogenic, 
      adipogenic and chondrogenic differentiation assays. Bioinformatics analyses and 
      dual-luciferase reporter gene assay were adopted to confirm the targeting 
      relationship between miR-18b and Notch2. The functional roles of EV-derived 
      miR-18b and Notch2 in trophoblasts were determined using loss- and 
      gain-of-function experiments, and trophoblast proliferation and migration were 
      assayed using CCK-8 and Transwell tests. In vivo experiments were conducted to 
      determine the effect of EV-derived miR-18b, Notch2 and TIM3/mTORC1 in a rat model 
      of PE, with monitoring of blood pressure and urine proteinuria. TUNEL staining 
      was conducted to observe the cell apoptosis of placental tissues of PE rats. We 
      found down-regulated miR-18b expression, and elevated Notch2, TIM3 and mTORC1 
      levels in the placental tissues of PE patients compared with normal placenta. 
      miR-18b was delivered to trophoblasts and targeted Notch2 and negatively its 
      expression, whereas Notch2 positively mediated the expression of TIM3/mTORC1. 
      EV-derived miR-18b or Notch2 down-regulation enhanced trophoblast proliferation 
      and migration in vitro and decreased blood pressure and 24 hours urinary protein 
      in PE rats by deactivating the TIM3/mTORC1 axis in vivo. In summary, EV-derived 
      miR-18b promoted trophoblast proliferation and migration via down-regulation of 
      Notch2-dependent TIM3/mTORC1.
CI  - (c) 2021 The Authors. Journal of Cellular and Molecular Medicine published by 
      Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
FAU - Yang, Zhongmei
AU  - Yang Z
AD  - Department of Obstetrics and Gynecology, Sichuan Academy of Medical Sciences & 
      Sichuan Provincial People's Hospital, Chengdu, China.
AD  - Department of Obstetrics and Gynecology, The First Affiliated Hospital of 
      Chongqing Medical University, Chongqing, China.
FAU - Shan, Nan
AU  - Shan N
AD  - Department of Obstetrics and Gynecology, The First Affiliated Hospital of 
      Chongqing Medical University, Chongqing, China.
FAU - Deng, Qinyin
AU  - Deng Q
AD  - Department of Obstetrics and Gynecology, Sichuan Academy of Medical Sciences & 
      Sichuan Provincial People's Hospital, Chengdu, China.
FAU - Wang, Yujue
AU  - Wang Y
AD  - Department of Obstetrics and Gynecology, Sichuan Academy of Medical Sciences & 
      Sichuan Provincial People's Hospital, Chengdu, China.
FAU - Hou, Yan
AU  - Hou Y
AD  - Department of Obstetrics and Gynecology, Sichuan Academy of Medical Sciences & 
      Sichuan Provincial People's Hospital, Chengdu, China.
FAU - Mei, Jie
AU  - Mei J
AD  - Department of Obstetrics and Gynecology, Sichuan Academy of Medical Sciences & 
      Sichuan Provincial People's Hospital, Chengdu, China.
FAU - Wu, Zhao
AU  - Wu Z
AUID- ORCID: 0000-0001-8545-7373
AD  - Department of Obstetrics and Gynecology, Sichuan Academy of Medical Sciences & 
      Sichuan Provincial People's Hospital, Chengdu, China.
LA  - eng
GR  - Q19071/Youth Innovation Scientific research projects of Sichuan Medical 
      association/
GR  - 2020LY03/clinical research and translation fund of Sichuan Provincial People's 
      Hospital/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210409
PL  - England
TA  - J Cell Mol Med
JT  - Journal of cellular and molecular medicine
JID - 101083777
RN  - 0 (HAVCR2 protein, human)
RN  - 0 (Hepatitis A Virus Cellular Receptor 2)
RN  - 0 (MIRN18 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (NOTCH2 protein, human)
RN  - 0 (Receptor, Notch2)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Cell Movement
MH  - Cell Proliferation
MH  - Extracellular Vesicles/*genetics
MH  - Female
MH  - *Gene Expression Regulation
MH  - Hepatitis A Virus Cellular Receptor 2/genetics/*metabolism
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 1/genetics/*metabolism
MH  - Mesenchymal Stem Cells/metabolism/pathology
MH  - MicroRNAs/*genetics
MH  - Pre-Eclampsia/genetics/metabolism/pathology/*prevention & control
MH  - Pregnancy
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptor, Notch2/genetics/*metabolism
MH  - Trophoblasts/metabolism/pathology
MH  - Tumor Cells, Cultured
MH  - Umbilical Cord/metabolism/pathology
PMC - PMC8107107
OTO - NOTNLM
OT  - MicroRNA-18b
OT  - Rapamycin complex 1
OT  - T-cell immunoglobulin and mucin domain-containing protein 3
OT  - extracellular vesicle
OT  - migration
OT  - notch receptor 2
OT  - preeclampsia
OT  - proliferation
OT  - trophoblast
COIS- The authors declare that they have no conflicts of interests.
EDAT- 2021/04/10 06:00
MHDA- 2021/10/05 06:00
PMCR- 2021/05/01
CRDT- 2021/04/09 13:04
PHST- 2020/10/27 00:00 [revised]
PHST- 2020/04/07 00:00 [received]
PHST- 2020/11/21 00:00 [accepted]
PHST- 2021/04/10 06:00 [pubmed]
PHST- 2021/10/05 06:00 [medline]
PHST- 2021/04/09 13:04 [entrez]
PHST- 2021/05/01 00:00 [pmc-release]
AID - JCMM16234 [pii]
AID - 10.1111/jcmm.16234 [doi]
PST - ppublish
SO  - J Cell Mol Med. 2021 May;25(10):4583-4595. doi: 10.1111/jcmm.16234. Epub 2021 Apr 
      9.