Activation of the Hippo/TAZ pathway is required for menstrual stem cells to suppress myofibroblast and inhibit transforming growth factor β signaling in human endometrial stromal cells.

STUDY QUESTION: Can menstrual stem cells (MenSCs) inhibit myofibroblast differentiation and reverse transforming growth factor β (TGFβ)-mediated activation of myofibroblast phenotypes in human endometrial stromal cells (ESCs)?

SUMMARY ANSWER: MenSCs suppressed endometrial myofibroblast differentiation and reversed TGFβ-mediated activation of myofibroblast phenotypes, which might be associated with activation of the Hippo/TAZ pathway.

WHAT IS KNOWN ALREADY: The potential effect of MenSCs as a cell therapy include attenuation of intrauterine adhesions, but the underlying mechanisms by which MenSCs exerts these effects are not entirely understood.

STUDY DESIGN, SIZE, DURATION: We evaluated the antagonistic effects of MenSCs on myofibroblast differentiation as well as the broader effect of the Hippo/TAZ signaling pathway on TGFβ-mediated induction of myofibroblast gene expression. The study design was based on a cohort of clinical proliferative phase endometrial samples obtained from three healthy premenopausal females with regular menstrual cycles.

PARTICIPANTS/MATERIALS, SETTING, METHODS: ESCs were cocultured with MenSCs or in MenSC-conditioned medium. Fibrotic markers (αSMA, collagen I, CTGF and fibronectin) as well as proliferation and wound-healing abilities were evaluated. Components of the Hippo/TAZ pathway (TAZ, p-TAZ, MOB1, p-MOB1, LATS1 and p-LATS1) were also investigated. Cell Counting Kit 8, wound healing assay, real-time PCR, western blotting, immunofluorescence and shRNA knockdown approaches were used to validate the findings.

MAIN RESULTS AND THE ROLE OF CHANCE: MenSCs inhibited myofibroblast activation, resulting in more rapid proliferation of ESCs. MenSCs downregulated the expression of myofibroblast markers αSMA and collagen I and promoted endometrial wound healing. Coculture with MenSCs also attenuated the TGFβ-mediated increase in expression of fibrotic marker genes αSMA, collagen I, CTGF and fibronectin, and restored the wound-healing ability inhibited by TGFβ. MenSCs induced Hippo/TAZ pathway activation, resulting in nuclear export and cytoplasmic retention of TAZ. TAZ inhibition was demonstrated to have similar effects even in the absence of MenSCs, and inhibition of TAZ was sufficient to attenuate TGFβ-mediated myofibroblast activation.

LARGE SCALE DATA: N/A.

LIMITATIONS, REASONS FOR CAUTION: This study included only in vitro experiments. Thus, additional data from in vivo experiments are needed in a future study.

WIDER IMPLICATIONS OF THE FINDINGS: The Hippo/TAZ pathway may be an important therapeutic target for endometrial fibrosis.

STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Natural Science Foundation of China (No. 81601236) and Zhejiang Provincial Natural Science Foundation of China (LY19H040009). None of the authors has any competing interests to declare.