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

Abstract

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.

Senescent cells: Living or dying is a matter of NK cells

“…Replication stress of rapid endometrial growth during the proliferative phase induces senescence in a pool of decidualizing endometrial stromal cells (EnSCs). The transcription factor FOXO1, inducing cell cycle exit of EnSCs, not only drives differentiation into decidual cells but also forces a pool of EnSCs to enter senescence, that in turn, is supported in an autocrine/paracrine way by the secretion of IL‐8 by the senescent decidual cells themselves . The SASP of senescent decidual cells encompasses IL‐8, IL‐6, and CXCL1 secretion, supporting the transient inflammatory state observed during decidualization.…”

“…Accordingly, NK cells target senescent EnSCs only after decidualization, when IL‐15 levels support NK cell activity. Also in this setting, NK cells eliminate senescent cells through perforin‐ and granzyme‐containing granule exocytosis upon NKG2D engagement . Efficacy of senescent decidual cell removal by uterine NK cells regulates endometrial remodeling and assures homeostasis in cycling endometrium (Fig.…”

Preconception resveratrol intake against infertility: Friend or foe?

“…Resveratrol has anti‐inflammatory actions that may suppress embryo implantation directly. The decidualization of endometrial stromal cells does not entail only cellular differentiation; the alteration requires a combination of differentiation and apoptosis/senescence . In fact, decidual cells secrete proapoptotic factors during the decidualization of HESCs .…”

“…In fact, decidual cells secrete proapoptotic factors during the decidualization of HESCs . In in vitro primary cultures, the decidualization of HESCs induces senescence‐associated β‐galactosidase (SAβG) activity and increases expressions of major senescent markers, including p16 and p53 . Decidual cells secrete inflammatory mediators associated with endometrial receptivity, through acute cellular senescence.…”

“…Decidual cells secrete inflammatory mediators associated with endometrial receptivity, through acute cellular senescence. In addition, pro‐senescent decidual cells are cleared by uterine natural killer (uNK) cells (the most abundant immune cells in the decidualized endometrium) for remodeling and rejuvenating the environment . A suppressor of cellular senescence, the mTOR inhibitor rapamycin inhibits SAβG‐positive cells, expression of senescent markers, and decidualization, leading to reduced expression of decidual marker genes, PRL and IGFBP1 .…”