Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium

• Published in: eLife 2017-12, Vol.6
• Main Authors: Brighton, Paul J, Maruyama, Yojiro, Fishwick, Katherine, Vrljicak, Pavle, Tewary, Shreeya, Fujihara, Risa, Muter, Joanne, Lucas, Emma S, Yamada, Taihei, Woods, Laura, Lucciola, Raffaella, Hou Lee, Yie, Takeda, Satoru, Ott, Sascha, Hemberger, Myriam, Quenby, Siobhan, Brosens, Jan Joris
• Format: Article
• Language: English
• Subjects: Biotechnology industries; Cell cycle; Cell Differentiation; Cells, Cultured; Cellular Senescence; Cyclic adenosine monophosphate; Decidua; Decidua - cytology; Decidua - metabolism; Embryo; Embryos; Endometrium; Endometrium - cytology; Endometrium - metabolism; Estrogens; Exocytosis; Female; Forkhead Box Protein O1 - metabolism; Forkhead protein; FOXO1 protein; Gene Expression Regulation; Homeostasis; Human Biology and Medicine; Humans; Immunosurveillance; Implantation; Inflammation; Interleukin 15; Interleukin 8; Interleukin-15 - metabolism; Interleukin-8 - metabolism; Killer cells; Killer Cells, Natural - cytology; Killer Cells, Natural - metabolism; Medical research; Menstruation; Mesenchyme; Natural killer cells; Obstetrics; Ovulation; Phenols (Class of compounds); Progesterone; receptivity; Senescence; Sex hormones; Signal Transduction; Software industry; Stem cells; Stromal cells; Stromal Cells - cytology; Stromal Cells - metabolism; uterine natural killer cells; Uterus; Uterus - cytology; Uterus - metabolism
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.31274

In cycling human endometrium, menstruation is followed by rapid estrogen-dependent growth. Upon ovulation, progesterone and rising cellular cAMP levels activate the transcription factor Forkhead box O1 (FOXO1) in endometrial stromal cells (EnSCs), leading to cell cycle exit and differentiation into decidual cells that control embryo implantation. Here we show that FOXO1 also causes acute senescence of a subpopulation of decidualizing EnSCs in an IL-8 dependent manner. Selective depletion or enrichment of this subpopulation revealed that decidual senescence drives the transient inflammatory response associated with endometrial receptivity. Further, senescent cells prevent differentiation of endometrial mesenchymal stem cells in decidualizing cultures. As the cycle progresses, IL-15 activated uterine natural killer (uNK) cells selectively target and clear senescent decidual cells through granule exocytosis. Our findings reveal that acute decidual senescence governs endometrial rejuvenation and remodeling at embryo implantation, and suggest a critical role for uNK cells in maintaining homeostasis in cycling endometrium.