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8 January 2022 Myostatin increases human trophoblast cell invasion by upregulating N-cadherin via SMAD2/3-SMAD4 signaling
Faten AbdelHafez, Christian Klausen, Hua Zhu, Peter C.K. Leung
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Abstract

Placental insufficiency disorders are major obstetric complications that share a common phenomenon of poor placental trophoblast cell invasion and remodeling of uterine tissues. Myostatin is a transforming growth factor (TGF)-β superfamily member well known for its important role in muscle growth control. Myostatin is also produced in the placenta and has been shown to regulate some trophoblast functions. However, its roles in placental development are still poorly understood. In this study, we tested the hypothesis that myostatin increases trophoblast cell invasion by upregulating N-cadherin via SMAD2/3-SMAD4 signaling. Primary and immortalized (HTR8/SVneo) trophoblast cells were used as study models. Matrigel-coated transwell invasion assays were used to study the effects of recombinant human myostatin on trophoblast cell invasion. Reverse transcription quantitative real-time polymerase chain reaction and Western blot were used to measure myostatin effects on N-cadherin mRNA and protein levels, respectively. Small inhibitor molecules as well as siRNA-mediated knockdown were used to block myostatin receptor and downstream signaling, respectively. Data were analyzed either by unpaired Student T test or one-way analysis of variance followed by Newman Keuls test for multiple group comparisons. Myostatin significantly increased primary and HTR8/SVneo trophoblast cell invasion. Moreover, myostatin upregulated N-cadherin mRNA and protein levels in a time-dependent manner in both study models. These effects were blocked by inhibition of TGF-β type I receptors as well as siRNA-mediated knockdown of SMAD2/3 combined or common SMAD4. Importantly, myostatin-induced trophoblast cell invasion was abolished by knockdown of N-cadherin, SMAD2/3, or SMAD4. Myostatin may increase human trophoblast cell invasion by upregulating N-cadherin via SMAD2/3-SMAD4 signaling.

Summary Sentence Myostatin increases primary and immortalized human trophoblast cell invasion and N-cadherin production. N-cadherin upregulation is required for myostatin-induced invasion and is mediated by SMAD2/3-SMAD4 signaling.

Graphical Abstract

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© The Author(s) 2022. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Faten AbdelHafez, Christian Klausen, Hua Zhu, and Peter C.K. Leung "Myostatin increases human trophoblast cell invasion by upregulating N-cadherin via SMAD2/3-SMAD4 signaling," Biology of Reproduction 106(6), 1267-1277, (8 January 2022). https://doi.org/10.1093/biolre/ioab238
Received: 4 August 2021; Accepted: 21 December 2021; Published: 8 January 2022
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KEYWORDS
invasion
IUGR
myostatin
N-cadherin
placenta
placental insufficiency
preeclampsia
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