Overactivated sonic hedgehog signaling aggravates intrauterine adhesion via inhibiting autophagy in endometrial stromal cells

Cheng Wei,Yinli Zhang,Wenzhi Xu,Lingling Jiang,Yibin Pan,Shiqian Xu,Yingyi Zhang,Xiaona Lin,Yanling Zhang,Songying Zhang,Weijie Yang,Yongdong Dai,Libing Shi

doi:10.1038/s41419-020-02956-2

Cheng Wei, Yinli Zhang + Show 11 more

Open Access

https://doi.org/10.1038/s41419-020-02956-2

Copy DOI

Abstract

Autophagy can be dynamically induced in response to stresses and is an essential, ubiquitous intracellular recycling system that impacts the fate of damaged resident cells, thereby influencing wound healing. Endometrial fibrosis is a form of abnormal wound healing that causes intrauterine adhesion (IUA) and infertility. We previously demonstrated that overactivated sonic hedgehog (SHH) signaling exacerbated endometrial fibrosis, but the role of autophagy in this process is still unknown. Here, we report that impaired autophagy participates in SHH pathway-induced endometrial fibrosis. Endometrial stroma-myofibroblast transition accompanied by autophagy dysfunction was present in both endometrial biopsies of IUA patients and Amhr2cre/+R26-SmoM2+/− (AM2) transgenic mouse. Mechanistically, SHH pathway negatively regulated autophagy through pAKT-mTORC1 in a human endometrial stromal cell line (T-HESCs). Furthermore, SHH pathway-mediated fibrosis was partly counteracted by autophagy modulation in both T-HESCs and the murine IUA model. Specifically, the impact of SHH pathway inhibition (GANT61) was reversed by the pharmacological autophagy inhibitor chloroquine (CQ) or RNA interference of autophagy-related gene ATG5 or ATG7. Similar results were obtained from the murine IUA model treated with GANT61 and CQ. Moreover, promoting autophagy with rapamycin reduced fibrosis in the AM2 IUA model to baseline levels. In summary, defective autophagy is involved in SHH pathway-driven endometrial fibrosis, suggesting a potential novel molecular target for IUA treatment.

Highlights

The human endometrium is a highly dynamic tissue that serves as a “fertile ground” for embryo implantation and placenta development[1]
Because the transcriptional activator GLI2 is elevated in the stroma of intrauterine adhesion (IUA) tissues[28], and autophagy dysfunction was evident in the study described above, we further explored the relationship between sonic hedgehog (SHH) signaling and autophagy in a human endometrial stromal cell line, T-HESCs
We propose for the first time that impaired autophagy participates in SHH pathway-driven endometrial fibrosis (Fig. 6), which is supported by integrated data from an endometrial stromal cell line, murine IUA models, endometrial stroma-specific transgenic mouse, and clinical IUA samples

Summary

Introduction

The human endometrium is a highly dynamic tissue that serves as a “fertile ground” for embryo implantation and placenta development[1]. Wei et al Cell Death and Disease (2020)11:755 the predominant origin of myofibroblasts in multiple organic fibrosis[7,8,9]. Autophagy is a highly conserved degradation and recycling system within cells that is gentle under physiological conditions and reacts adaptively to various stimuli[10,11]. Autophagy initiates the formation of autophagosomes sequestering unnecessary elements, followed by fusion with lysosomes to form autolysosomes and degradation by lysosomal hydrolases[12]. This process saves energy and removes toxicant, thereby facilitating cellular adaptation to stress[12], whether it is beneficial or harmful for an organism is strongly contextdependent[13]. Studies have reported that disrupting autophagy-related genes (ATG5, ATG4B, and MAP1S) leads to fibrotic protein accumulation in the kidney[14,15] and lung[16], whereas the role of autophagy in endometrial fibrosis is still unclear

Methods

Results

Conclusion