GDF8 Promotes the Cell Invasiveness in Human Trophoblasts by Upregulating the Expression of Follistatin-Like 3 Through the ALK5-SMAD2/3 Signaling Pathway.

Jiamin Xie,Hua Zhu,Hsun-Ming Chang,Peter C K Leung,Minyue Dong,Christian Klausen

doi:10.3389/fcell.2020.573781

Abstract

Growth differentiation factor 8 (GDF8) and its antagonist follistatin-like 3 (FSTL3) are expressed in the placenta during early pregnancy. These two factors may have a role to play in the regulation of normal placentation. However, whether GDF8 can regulate the expression of FSTL3 in human trophoblasts remains to be elucidated. In this study, we aimed to investigate the effects of GDF8 on the expression of FSTL3 and the underlying molecular mechanisms using human trophoblasts as a study model. Our results showed that GDF8 significantly upregulates the expression and production of FSTL3, which further promotes cell invasiveness in immortalized extravillous cytotrophoblast cells and primary extravillous cytotrophoblast cells obtained from human first-trimester placentae. Additionally, using an siRNA-mediated knockdown approach, we found that this regulatory effect is most likely mediated by the ALK5-Sma- and Mad-related protein (SMAD)2/3-induced signaling pathway. These findings deepen our understanding of the functional roles of GDF8 and FSTL3 in the regulation of cell invasiveness of trophoblasts.

Highlights

Trophoblasts play key roles in the regulation of embryo development and implantation, as well as in the maintenance of normal pregnancy (Staun-Ram and Shalev, 2005)
It has been reported that the expression of Growth differentiation factor 8 (GDF8) is significantly higher in early and preterm placentae compared with the term placentae; this phenomenon is most likely correlated to its trophoblast invasion ability (Peiris and Mitchell, 2012)
In this follow-up study, we demonstrated that GDF8 promotes the expression and production of follistatin-like 3 (FSTL3) in human trophoblasts, including an immortalized cell line and cultured primary extravillous cytotrophoblasts isolated from the first-trimester placenta

Summary

Introduction

Trophoblasts play key roles in the regulation of embryo development and implantation, as well as in the maintenance of normal pregnancy (Staun-Ram and Shalev, 2005). These cells influence multiple physiological and pathological conditions by releasing various factors into the placental and maternal circulation (Bischof and Campana, 2000). Inadequate remodeling of maternal arteries or improper trophoblast invasion can result in insufficient uterine placental perfusion and induce several pregnancy-related complications, including preeclampsia and fetal growth restriction (Redman and Sargent, 2005; Burton et al, 2009). Excessive trophoblast invasion may lead to placenta creta (accreta, increta, and percreta) or gestational trophoblastic diseases (Allias et al, 2015; Silva and Serakides, 2016)

Objectives

Methods

Results

Conclusion