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

Despite considerable advances in the etiology and treatment of IUAs, the cellular and molecular mechanisms underlying the development of IUAs remain unclear. Furthermore, no efficient therapy has been developed so far to prevent IUAs’ recurrence. Further research efforts must focus on elucidating the molecular mechanisms underlying endometrial fibrosis and strategies to reverse fibrogenesis. Recent advancements in the field of Hippo signaling have suggested its important role in fibrous diseases. Hippo signaling does not act alone but is involved in cross talk with Wnt and TGF-β signaling components [ Figure 1 ]. The interaction among these pathways is the reason why inhibition of a single molecular target often does not achieve the desired therapeutic effect. Our findings not only contribute to the current knowledge on the pathogenesis of endometrial fibrosis, but also highlight the necessity to develop highly specific inhibitors that target the protein–protein interactions at the intersection of multiple signaling pathways. Cross talk among the Hippo, Wnt, and TGF-β signaling pathways. TGF-β: Transforming growth factor-β. This work was supported by grants from the National Natural Science Foundation of China (No. 81601236 and No. 81471505). There are no conflicts of interest.

Recent studies have implicated the Hippo pathway and its transcriptional effectors, TAZ and YAP, as necessary for tissue fibrosis and myofibroblast activation.[ 12 ] The Hippo/TAZ signaling pathway has been proven to play a major role in regulating the epithelial–mesenchymal transition (EMT), to promote the expression of α-smooth muscle actin (α-SMA) and connective tissue growth factor (CTGF),[ 35 36 ] and to regulate the growth and differentiation of stem cells. As a contact inhibitory signaling pathway, the Hippo/TAZ pathway is related to cell differentiation and organ size control.[ 25 ] It is widely believed that the Hippo/TAZ pathway is activated when cells enter the differentiation phase or when an organ approaches its final size, which in turn inhibits cell proliferation and regulates the EMT. TAZ is an important transducer of the Hippo pathway that modulates the EMT and cell proliferation. Activated TAZ translocates from the cytoplasm into the nucleus and binds with various transcription factors, such as TEAD and Smads. TAZ has been suggested to regulate the expression of α-SMA and CTGF.[ 35 36 37 ] Activation of the Hippo pathway leads to TAZ phosphorylation and limits cytoplasmic retention,[ 37 ] which in turn inhibits TAZ-induced cell proliferation and the EMT process. EMT has been well established as the key mechanism that mediates fibrosis during tissue repair. The most advanced form of EMT is the epithelial/fibroblast–myofibroblast transition, during which epithelial and stromal cells acquire a myofibroblast phenotype and is characterized by the expression of α-SMA and increased secretion of collagen I.[ 38 39 ] The mesenchymal–epithelial transition (MET), the reverse process of EMT, is known to be crucial in counteracting fibrotic processes.[ 40 ] The balance between EMT and MET critically determines the convalescence of organ fibrosis. A previous study reported that promotion of MET and reversal of EMT could relieve liver fibrosis.[ 40 ] EMT and MET were also demonstrated to be involved in the fibrosis of pelvic endometriosis,[ 41 ] conversion of endometriotic stromal cells into myofibroblasts, and the upregulation of α-SMA and collagen I.[ 39 ] Notably, the Hippo signaling pathway was also demonstrated to play a role in the development and progression of endometriosis, which modulates endometrial stromal cell activity through transcriptional regulation of CTGF.[ 42 ]

More than half a century has passed since Asherman[ 1 ] first described the frequency, etiology, and symptoms of intrauterine adhesion (IUA) in 1948. Since then, a numerous studies addressing the etiology and treatment of IUAs have been conducted. IUA refers to the destruction of the basal layer of the endometrium and is attributed to multiple causes.[ 2 ] These lead to adhesion between the uterine walls, which in turn results in clinical manifestations, such as amenorrhea, hypomenorrhea, pelvic pain, infertility, and habitual abortion.[ 3 4 ] IUAs generally occur after curettage and various forms of hysteroscopic surgery, including hysteroscopic resection of multiple fibroids and resection of the septa.[ 5 ] The primary causes of IUA include trauma to the basal layer of the endometrium and uterine infections.[ 6 ] Histologically, IUA is defined as the condition in which the endometrium becomes fibrosed, which leads to impaired endometrium function, uterine cavity deformation, and stenosis.[ 2 ] In IUA, the endometrial stroma is mainly replaced by large fibrous tissues. IUA is characterized by the destruction of the border between the basal and functional layers of the endometrium. In addition, the functional layer no longer responds to hormone stimulation, and fibrous scarring occurs across the uterine cavity. Vascularity might be abundant and may comprise thin-walled and dilated vessels; however, in most cases, the tissues become avascular.[ 7 ] Fibrosis may limit uterine myometrial activity and reduce the perfusion of estrogen and progesterone, eventually resulting in atrophy.[ 7 ] The treatments for IUAs include adhesiolysis and preventing the recurrence of adhesion. The primary objective of treatment is to restore the normal shape and volume of the uterine cavity, and the secondary goals of intervention include the treatment of associated symptoms (i.e., infertility and amenorrhea) and prevention of recurrence of adhesion.[ 8 ] With the application of intrauterine devices and antibiotics, the probability of recurrence of uterine cavity adhesion after treatment is gradually reduced.[ 9 ] In the near future, improvements in infertility outcomes, including pregnancy rates, and live birth rates are expected to serve as the primary indicators for defining complete resolution of IUAs. However, for patients with moderate-to-severe IUAs, recurrence of adhesion after hysteroscopic adhesiolysis still has a high incidence and remains difficult to treat. Moreover, the effects of IUA treatment on reproductive outcomes remain to be established. Intrauterine devices and high doses of estrogen therapy are often used to prevent the recurrence of uterine adhesions and to promote endometrial repair.[ 7 10 ] However, it is worth noting that estrogen therapy alone has poor efficacy and is usually accompanied by adverse effects, which significantly limit its widespread application. Endometrial fibrosis has been implicated in the development of IUA. Thus, the prevention of endometrial fibrosis is fundamental to IUA treatment. The Hippo signaling pathway has been previously demonstrated to participate in the fibrogenesis of various organs and cross talks with other signaling pathways, such as the transforming growth factor-β (TGF-β) and Wnt/β-catenin signaling pathways, through a variety of mechanisms.[ 11 12 ] In this review, we discuss the role of the Hippo pathway in endometrial fibrosis in IUAs and focus on the mechanisms by which the Hippo pathway integrates and interacts with other signaling pathways.