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

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Paul J Brighton ◽  
Yojiro Maruyama ◽  
Katherine Fishwick ◽  
Pavle Vrljicak ◽  
Shreeya Tewary ◽  
...  
Keyword(s):  
Natural Killer ◽  
Embryo Implantation ◽  
Critical Role ◽  
Human Endometrium ◽  
Dependent Manner ◽  
Endometrial Stromal Cells ◽  
Uterine Natural Killer Cells ◽  
Decidual Cells ◽  
Unk Cells ◽  
Uterine Natural Killer

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.

scholarly journals Clearance of senescent decidual cells by uterine natural killer cells drives endometrial remodeling during the window of implantation

2017 ◽  
Author(s):  
Paul J Brighton ◽  
Yojiro Maruyama ◽  
Katherine Fishwick ◽  
Pavle Vrljicak ◽  
Shreeya Tewary ◽  
...  
Keyword(s):  
Natural Killer ◽  
Embryo Implantation ◽  
Critical Role ◽  
Dependent Manner ◽  
Endometrial Stromal Cells ◽  
Uterine Natural Killer Cells ◽  
Decidual Cells ◽  
Unk Cells ◽  
Dependent Growth ◽  
Uterine Natural Killer

SummaryIn 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.

scholarly journals Involvement of uterine natural killer cells in the natural selection of human embryos at implantation

2020 ◽  
Author(s):  
Chow-Seng Kong ◽  
Alexandra Almansa Ordoñez ◽  
Sarah Turner ◽  
Tina Tremaine ◽  
Joanne Muter ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Natural Killer ◽  
Cell Activity ◽  
Human Embryos ◽  
Endometrial Stromal Cells ◽  
Uterine Natural Killer Cells ◽  
Decidual Cells ◽  
Unk Cells ◽  
Unk Cell ◽  
Uterine Natural Killer

AbstractDecidualizing endometrial stromal cells (EnSC) critically determine the maternal response to an implanting conceptus, triggering either menstruation-like disposal of low-fitness embryos or creating an environment that promotes further development. However, the mechanism that couples maternal recognition of low-quality embryos to tissue breakdown remains poorly understood. Recently, we demonstrated that successful transition of the cycling endometrium to a pregnancy state requires selective elimination of pro-inflammatory senescent decidual cells by activated uterine natural killer (uNK) cells. Here we report that uNK cells express CD44, the canonical hyaluronan (HA) receptor, and demonstrate that high-molecular weight HA (HMWHA) inhibits uNK cell-mediated killing of senescent decidual cells. By contrast, low-molecular weight HA (LMWHA) did not attenuate uNK cell activity in co-culture experiments. Killing of senescent decidual cells by uNK cells was also inhibited upon exposure to medium conditioned by IVF embryos that failed to implant, but not successful embryos. Embryo-mediated inhibition of uNK cell activity was reversed by recombinant hyaluronidase 2 (HYAL2), which hydrolyses HMWHA. We further report a correlation between the levels of HYAL2 secretion by human blastocysts, morphological scores, and implantation potential. Taken together, the data suggest a pivotal role for uNK cells in embryo biosensing and endometrial fate decisions at implantation.

scholarly journals Proliferation of Uterine Natural Killer Cells Is Induced by Human Chorionic Gonadotropin and Mediated via the Mannose Receptor

Endocrinology ◽  
2009 ◽  
Vol 150 (6) ◽  
pp. 2882-2888 ◽  
Author(s):  
Nicole Kane ◽  
Rodney Kelly ◽  
Philippa T. K. Saunders ◽  
Hilary O. D. Critchley
Keyword(s):  
Natural Killer ◽  
Mannose Receptor ◽  
Lh Receptor ◽  
Uterine Natural Killer Cells ◽  
Unk Cells ◽  
The Impact ◽  
Insight Into ◽  
Unk Cell ◽  
Uterine Natural Killer

The endometrial lining of the human uterus contains a population of phenotypically distinct (CD56bright, CD16dim), tissue-specific, natural killer [uterine natural killer (uNK)] cells that play a key role in the establishment of a successful pregnancy. An increase in the number of endometrial uNK cells occurs when the conceptus implants, and there is a further increase during the early stages of placentation. Here, we describe studies that have identified human chorionic gonadotrophin (hCG), a glycoprotein synthesized by the preimplantation conceptus, as a novel regulator of uNK cell proliferation. The impact of hCG on uNK cells was mediated via the mannose receptor (CD206) rather than by the classical hCG/LH receptor that was not expressed. The mannose receptor and hCG were colocalized on the surface of uNK cells, and proliferation did not occur if cells were incubated with deglycosylated hCG or intact hCG in the presence of excess d-Mannose. These novel observations provide new insight into the endocrine-immune dialogue that exists between the conceptus and immune cells within the receptive endometrium, and have implications for the role of uNK cell-trophoblast interactions and pregnancy outcome.

1.  Heme Oxygenase‐1 Enzyme Deficiency Affects Uterine Natural Killer Cell Function During Murine Pregnancy 

2017 ◽  
Author(s):  
Tracy Zhang
Keyword(s):  
Natural Killer ◽  
Heme Oxygenase ◽  
Cell Function ◽  
Recurrent Miscarriage ◽  
Embryo Implantation ◽  
Killer Cell ◽  
Implantation Site ◽  
Heme Oxygenase 1 ◽  
Unk Cells ◽  
Uterine Natural Killer

Recurrent miscarriage is a condition that affects 1% of all women, and rejection of the fetus by the mother's immune system is thought to be one of the underlying causes. The mechanisms of maternal tolerance vital to a successful pregnancy are not well understood; however, uterine natural killer (uNK) cells are implicated as they comprise over 70% of immune cells in the uterus during early pregnancy. Heme oxygenase‐1 (HO‐1) is an enzyme that is known to be immunosuppressive. Moreover, mice missing HO‐1 have extremely high abortion rates. This study is the first to analyze the effects of HO‐1 deficiency specifically on uNK cells. We posit that an absence of HO‐1 affects normal uNK cell‐mediated immunosuppression, and also possibly their ability to modify uterine spiral arteries supplying blood to the fetus. Our study analyzed embryos from mice lacking or deficient in HO‐1 on days 8, 10, and 12 of pregnancy. Both number of uNK cells and degree of vascularization were analyzed using immunohistochemistry staining. We observed a significantly higher number of uNK cells in one area of the embryo implantation site and a significantly lower number of cells in another, suggesting the uNK cells are failing to localize properly. Analysis of vascularization is currently ongoing. Since women with multiple miscarriages have been shown to down‐regulate HO‐1, confirmation that absence of HO‐1 leads to implantation site abnormalities could pave the way for future clinical treatments.  

scholarly journals The Role of Decidual Subpopulations in Implantation, Menstruation and Miscarriage

2021 ◽  
Vol 3 ◽  
Author(s):  
Joanne Muter ◽  
Chow-Seng Kong ◽  
Jan J. Brosens
Keyword(s):  
Stromal Cells ◽  
Acute Stress ◽  
Embryo Implantation ◽  
Recurrence Risk ◽  
Tissue Remodelling ◽  
Endometrial Stromal Cells ◽  
Decidual Cells ◽  
Unk Cells ◽  
Acute Stress Response

In each menstrual cycle, the endometrium becomes receptive to embryo implantation while preparing for tissue breakdown and repair. Both pregnancy and menstruation are dependent on spontaneous decidualization of endometrial stromal cells, a progesterone-dependent process that follows rapid, oestrogen-dependent proliferation. During the implantation window, stromal cells mount an acute stress response, which leads to the emergence of functionally distinct decidual subsets, reflecting the level of replication stress incurred during the preceding proliferative phase. Progesterone-dependent, anti-inflammatory decidual cells (DeC) form a robust matrix that accommodates the conceptus whereas pro-inflammatory, progesterone-resistant stressed and senescent decidual cells (senDeC) control tissue remodelling and breakdown. To execute these functions, each decidual subset engages innate immune cells: DeC partner with uterine natural killer (uNK) cells to eliminate senDeC, while senDeC co-opt neutrophils and macrophages to assist with tissue breakdown and repair. Thus, successful transformation of cycling endometrium into the decidua of pregnancy not only requires continuous progesterone signalling but dominance of DeC over senDeC, aided by recruitment and differentiation of circulating NK cells and bone marrow-derived decidual progenitors. We discuss how the frequency of cycles resulting in imbalanced decidual subpopulations may determine the recurrence risk of miscarriage and highlight emerging therapeutic strategies.

scholarly journals α-actin Down Regulation and Perforin Loss in Uterine Natural Killer Cells From LPS-Treated Pregnant Mice

2015 ◽  
pp. 427-432 ◽  
Author(s):  
B. ZAVAN ◽  
A. M. DO AMARANTE-PAFFARO ◽  
V. A. PAFFARO
Keyword(s):  
Natural Killer ◽  
Cell Types ◽  
Normal Pregnancy ◽  
Down Regulation ◽  
Uterine Arteries ◽  
Uterine Natural Killer Cells ◽  
Unk Cells ◽  
Pregnant Mice ◽  
Unk Cell ◽  
Uterine Natural Killer

One of the most abundant immunologic cell types in early decidua is the uterine natural killer (UNK) cell that despite the presence of cytoplasmic granules rich in perforin and granzymes does not degranulate in normal pregnancy. UNK cells are important producers of angiogenic factors that permit normal dilation of uterine arteries to provide increased blood flow for the growing feto-placental unit. Gram-negative bacteria lipopolysaccharide (LPS) administration can trigger an imbalance of pro-inflammatory and anti-inflammatory cytokines impairing the normal immune cells activity as well as uterine homeostasis. The present study aimed to evaluate by immunohistochemistry the reactivity of perforin and α-actin on UNK cell from LPS-treated pregnant mice. For the first time, we demonstrate that LPS injection in pregnant mice causes α-actin down regulation, concomitantly with perforin loss in UNK cells. This suggests that LPS alters UNK cell migration and activates cytotoxic granule release.

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