Dysfunction of Shh signaling activates autophagy to inhibit trophoblast motility in recurrent miscarriage

Recurrent miscarriage: Malfunctioning molecular signals Impairments in a signaling process in embryological development process are linked to problems in early pregnancy that can cause recurrent miscarriages, an insight that could suggest new targets for preventive treatment. The signaling process, named after two of its key proteins, Shh and Gli, controls sequences of gene activation and repression that are vital for the early development of the placenta and embryo. Songying Zhang and colleagues at Zhejiang University School of Medicine, Hangzhou, China, examined placental tissues from normal but aborted pregnancies and from patients with recurrent miscarriage. In the latter group, they found that dysfunctional Shh/Gli signaling impaired the activity of cells needed to form the placenta, and reduced blood vessel formation. The dysfunction also increased the destruction of cell components in these cells. 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.

Automated summary

Recurrent miscarriage is associated with dysfunction in the signaling process, specifically the Shh/Gli pathway, which impairs the activity of cells needed for placental formation and reduces blood vessel formation. This study suggests that targeting the Shh pathway and autophagy could be potential therapeutic strategies for recurrent miscarriage.