Transforming Growth Factor Beta1 is Required for Embryo Implantation and Decidualizaion in Mouse and its Dysregulation Leads to Miscarriage in Humans

Abstract

Background: Embryo implantation is a crucial event in pregnancy establishment and is a two way dialogue between implanting blastocyst and maternal uterus and involves various cellular messengers that orchestrate this event. Transforming growth factor beta1 (TGF-β1) is a key regulatory molecule involved in proper implantation and decidualization via SMAD3 dependent pathway. Inappropriate molecular cross talk of conceptus and maternal endometrium facilitates early rejection of fetus and results in early miscarriage (EM).

Objective: To elucidate the role of TGF-β1 in pathogenesis of EM.

Methods: To achieve the given objective, in-vivo intra-luminal delivery of TGF-β1activation inhibitor in mouse uterus, ELISA, RT-PCR and western blotting were used.

Results: We found that inhibition of TGF-β1 liberation by monensin sodium reduced embryo implantation in mouse uterus. Further, embryo implantation and decidualization biomarkers STAT3, BMP2 and prolactin (PRL) were compromised after TGF-β1 liberation inhibition. The ovarian steroids estrogen and progesterone receptors (ER and PR) were also evaluated and found downregulated PR-A after TGF-β1 inhibition whereas, there is an increased expression of ER-α.

Thereafter, we translated our rodent based research findings of TGF-β1 requirement for embryo implantation and pregnancy establishment to human scenario by evaluation of TGF-β1 and its signaling in decidual tissue from patients with early miscarriage (EM). Our immunoblot results showed that although, there is no significant difference active form of TGF-β1 while its downstream signaling molecule SMAD3 expression was significantly downregulated (p value<0.001, N=10) in EM patients. Similarly, STAT3 is significantly decreased in EM patients (p value <0.01, N=10) than control.

Conclusion: Present study for the first time showed that dysregulation of TGFβ1 signaling in decidua under pathogenesis of EM. These findings indicate that optimum level of TGF-β1 and its downstream signaling molecules may play essential role in the decidua during early pregnancy and dysregulated in the EM case.