Abstract
In early pregnancy, the placenta anchors the conceptus and supports embryonic development and survival. This study aimed to investigate the underlying functions of Shh signaling in recurrent miscarriage (RM), a serious disorder of pregnancy. In the present study, Shh and Gli2 were mainly observed in cytotrophoblasts (CTBs), Ptch was mainly observed in syncytiotrophoblasts (STBs), and Smo and Gli3 were expressed in both CTBs and STBs. Shh signaling was significantly impaired in human placenta tissue from recurrent miscarriage patients compared to that of gestational age-matched normal controls. VEGF-A and CD31 protein levels were also significantly decreased in recurrent miscarriage patients. Furthermore, inhibition of Shh signaling impaired the motility of JAR cells by regulating the expression of Gli2 and Gli3. Intriguingly, inhibition of Shh signaling also triggered autophagy and autolysosome accumulation. Additionally, knockdown of BECN1 reversed Gant61-induced motility inhibition. In conclusion, our results showed that dysfunction of Shh signaling activated autophagy to inhibit trophoblast motility, which suggests the Shh pathway and autophagy as potential targets for RM therapy.
Highlights
In mammals, after zygote division and development into blastocysts, the outer cells of blastocysts become polarized and differentiate, first into trophoblasts and further to form the placenta
Cytokeratin 7 (CK7), a marker of trophoblasts, was Attenuating Sonic hedgehog (Shh) signaling inhibited trophoblast motility and placental angiogenesis To study the role of Shh signaling in trophoblast motility, Matrigel cell invasion, and transwell cell migration assays were performed
We investigated the effect of cyclopamine or recombinant human Shh on JAR cell viability
Summary
After zygote division and development into blastocysts, the outer cells of blastocysts become polarized and differentiate, first into trophoblasts and further to form the placenta. The inner cells of blastocysts divide to form the inner cell masses, which further differentiate to form the embryo proper. The human placenta serves as the feto-maternal material exchange barrier and protective shield to give rise to fetal development. Trophoblast progenitor cells differentiate into cytotrophoblasts (CTBs). CTBs either differentiate into invasive lineages to yield extravillous trophoblasts (EVTs) or undergo cell fusion to yield. The integrated proliferation and differentiation of all these trophoblast lineages are essential for normal placental development. Aberrant trophoblast development is usually associated with severe pregnancy complications, including miscarriage, preeclampsia, and intrauterine growth restriction[6,7,8]
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