Advanced Role of Hippo Signaling in Endometrial Fibrosis: Implications for Intrauterine Adhesion

Objective: Intrauterine adhesion (IUA) is a major health problem that causes infertility, menstrual irregularities, and recurrent pregnancy losses in women. Unfortunately, treatments for IUA are limited, and there are currently no effective strategies for preventing 1UA recurrence. In this review, we introduced the role of Hippo signaling in the normal endometrium and IUA and described the mechanisms by which the Hippo pathway integrates with the Wnt and transforming growth factor-beta (TGF-beta) signaling pathways to form an intricate network governing the development of fibrosis. Data Sources: Original research articles in English that were published until July 2017 were collected from the PubMed database. Study Selection: Literature search was conducted using the search terms "endometrial fibrosis OR fibrosis AND or OR intrauterine adhesion OR Asherman syndrome OR IUA," "Hippo AND or OR Hippo/TAZ," "TGF-beta," and "Wnt." Related original research articles were included in the comprehensive analysis. Results: Endometrial fibrosis is recognized as a key pathological event in the development of IUA, which is characterized by epithelial/fibroblast-myofibroblast transition. Myofibroblasts play crucial roles in the pathogenesis of fibrous scarring, and myofibroblast differentiation can be triggered by multiple signaling pathways. Hippo signaling is a critical regulator of the epithelial/ fibroblast-myofibroblast transition and alpha-smooth muscle actin, which exhibits a specific spatiotemporal expression in the endometrium. Conclusions: Hippo signaling plays a critical role in fibrous diseases and participates in cross talks with Wnt and TGF-beta signaling. Our findings not only contributed to knowledge on the pathogenesis of endometrial fibrosis, but can also serve as a useful resource for developing specific molecular inhibitors for UA treatment and prevention.