Endometrial extracellular matrix rigidity and IFNτ ensure the establishment of early pregnancy through activation of YAP

Abstract

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Extracellular matrix stiffness mediates uterine repair via the Rap1a/ARHGAP35/RhoA/F-actin/YAP axis

“…As we demonstrated above, the dynamic biomechanical nature of endometrial remodeling and the endometrial cell regeneration that occur during the repair of physiological or pathological uterine lesions are remarkable, but the mechanism by which cells in the endometrial cellular niche respond to mechanical cues remains unclear. We previously showed that YAP, as a sensor of chemical and mechanical cues, participates in the establishment of pregnancy [ 25 ]. Therefore, we speculate that YAP is involved in the conversion of mechanical signals to chemical cues during the uterine repair process.…”

“…Of note, cell proliferation was not completely suppressed, and it remains unclear whether this was due to incomplete inhibition or whether other cues that are independent of F-actin are involved in the repair of the endometrium. For example, the classical Hippo-YAP pathway is regulated by chemical signals, and the WNT signaling pathway regulates stem cell activation and proliferation[ 25 , 33 , 34 ]. Together, these data indicate that blocking the mechanotransduction pathway leads to prolongation of the time required for uterine repair.…”

“…The endometrium is an organ that is sensitive to mechanical force and to mechanical cues that regulate internal tension and external force. Our previous study and other data suggested that mechanotransduction is involved in the physiological and pathological processes that occur in the uterus, including embryo implantation, the development of uterine fibroids, and childbirth [ 25 , 38 ]. We now show that uterine injury results in a loss of EEC polarity and in breakage of TJs and AJs between cells and that GO terms related to mechanotransduction and mechanical force formation are activated and are accompanied by actin polymerization and high expression during the repair phase.…”

“…Mouse endometrial stromal cells (ESCs) were isolated and cultured as previously described [ 25 ]. In brief, uterine horns were harvested from mice and finely chopped using scalpel blades.…”

“…2D culture on hydrogels with high (40 kPa) or low (1 kPa) stiffness was performed as described elsewhere [ 25 ]. In brief, 10 μg/mL bovine fibrinogen (Solarbio, Beijing, China) was used to coat hydrogels activated with Sulfo-SANPAH (Thermo Fisher Scientific, USA) according to the needs of the cells.…”