Decreased Autophagy Impairs Decidualization of Human Endometrial Stromal Cells: A Role for ATG Proteins in Endometrial Physiology.

Ana Cecilia Mestre Citrinovitz,Ariane Germeyer,Thomas Strowitzki

doi:10.3390/ijms20123066

Ana Cecilia Mestre Citrinovitz, Ariane Germeyer + Show 1 more

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https://doi.org/10.3390/ijms20123066

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Abstract

During the menstrual cycle, the endometrium undergoes cyclic changes of cellular proliferation, differentiation, and death, an essential preparation of the endometrium for its interaction with the implanting embryo. In particular, the differentiation of endometrial stromal cells, named decidualization, ensures the formation of a proper feto-maternal interface for a regulated trophoblast invasion and correct placental orientation and growth. Interestingly, autophagy, an intracellular degradation process of great importance for the maintenance of cellular homeostasis, plays an important role in cell proliferation, differentiation, and growth. In the endometrium, increased detection of autophagy markers correlates with the progression of the menstrual cycle. However, until now, it was unknown whether autophagy contributes to the proper function of the endometrium. In this study, we show that autophagy is increased during in vitro decidualization of human endometrial stromal cells. Furthermore, we demonstrate that the knockdowns of two important autophagy-related (ATG) proteins, ATG7 and ATG5, impaired decidualization, confirming a positive role of these proteins and of autophagy for the correct decidualization of human endometrial stromal cells. In conclusion, in this work, we describe a previously unknown functional connection between autophagy and endometrial physiology.

Highlights

The inner lining of the uterus, known as the endometrium, undergoes cyclic rounds of cellular proliferation, differentiation, and death defining each stage of the menstrual cycle
We demonstrate that the knockdowns of two important ATG proteins, ATG7 and ATG5, impair decidualization confirming a positive role of these ATG proteins and of autophagy for the correct decidualization of human endometrial stromal cells
The first goal of this study was to evaluate whether autophagic flux (AF) is modified during the decidualization of t-HESC, a cell line that has a normal response to decidual stimulation [20]

Summary

Introduction

The inner lining of the uterus, known as the endometrium, undergoes cyclic rounds of cellular proliferation, differentiation, and death defining each stage of the menstrual cycle These cyclic changes in cellular fate are tightly regulated by plasma levels of the ovarian steroid hormones, progesterone (P) and estradiol (E), and by the activation and crosstalk with the signaling pathway of cyclic adenosine monophosphate (cAMP) [1,2,3]. Two of the main secretory products of decidual cells are prolactin (PRL) and Insulin-like growth factor binding protein 1 (IGFBP1). Both proteins are commonly used as decidualization markers [2,7]

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