Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium
Paul J Brighton, Yojiro Maruyama, Katherine Fishwick, Pavle Vrljicak, Shreeya Tewary, Risa Fujihara, Joanne Muter, Emma S Lucas, Taihei Yamada, Laura Woods, Raffaella Lucciola, Yie Hou Lee, Satoru Takeda, Sascha Ott, Myriam Hemberger, Siobhan Quenby, Jan Joris Brosens, Paul J Brighton, Yojiro Maruyama, Katherine Fishwick, Pavle Vrljicak, Shreeya Tewary, Risa Fujihara, Joanne Muter, Emma S Lucas, Taihei Yamada, Laura Woods, Raffaella Lucciola, Yie Hou Lee, Satoru Takeda, Sascha Ott, Myriam Hemberger, Siobhan Quenby, Jan Joris Brosens
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.
Keywords: Endometrium; Immunosurveillance; Implantation; Senescence; human; human biology; medicine; receptivity; uterine natural killer cells.
Conflict of interest statement
No competing interests declared.
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References
- Acosta JC, O'Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, Fumagalli M, Da Costa M, Brown C, Popov N, Takatsu Y, Melamed J, d'Adda di Fagagna F, Bernard D, Hernando E, Gil J. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell. 2008;133:1006–1018. doi: 10.1016/j.cell.2008.03.038.
- Aird KM, Iwasaki O, Kossenkov AV, Tanizawa H, Fatkhutdinov N, Bitler BG, Le L, Alicea G, Yang TL, Johnson FB, Noma KI, Zhang R. HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci. The Journal of Cell Biology. 2016;215:325–334. doi: 10.1083/jcb.201608026.
- Al-Sabbagh M, Fusi L, Higham J, Lee Y, Lei K, Hanyaloglu AC, Lam EW, Christian M, Brosens JJ. NADPH oxidase-derived reactive oxygen species mediate decidualization of human endometrial stromal cells in response to cyclic AMP signaling. Endocrinology. 2011;152:730–740. doi: 10.1210/en.2010-0899.
- Barros F, Brosens J, Brighton P. Isolation and Primary Culture of Various Cell Types from Whole Human Endometrial Biopsies. Bio-Protocol. 2016;6:e2028. doi: 10.21769/BioProtoc.2028.
- Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry. 1976;72:248–254. doi: 10.1016/0003-2697(76)90527-3.
- Childs BG, Gluscevic M, Baker DJ, Laberge RM, Marquess D, Dananberg J, van Deursen JM. Senescent cells: an emerging target for diseases of ageing. Nature Reviews Drug Discovery. 2017;16:718–735. doi: 10.1038/nrd.2017.116.
- Chowdhury D, Lieberman J. Death by a thousand cuts: granzyme pathways of programmed cell death. Annual Review of Immunology. 2008;26:389–420. doi: 10.1146/annurev.immunol.26.021607.090404.
- de Keizer PL. The fountain of youth by targeting senescent cells? Trends in Molecular Medicine. 2017;23:6–17. doi: 10.1016/j.molmed.2016.11.006.
- de Ziegler D, Bergeron C, Cornel C, Medalie DA, Massai MR, Milgrom E, Frydman R, Bouchard P. Effects of luteal estradiol on the secretory transformation of human endometrium and plasma gonadotropins. The Journal of Clinical Endocrinology and Metabolism. 1992;74:322–331. doi: 10.1210/jcem.74.2.1730810.
- Demidenko ZN, Zubova SG, Bukreeva EI, Pospelov VA, Pospelova TV, Blagosklonny MV. Rapamycin decelerates cellular senescence. Cell Cycle. 2009;8:1888–1895. doi: 10.4161/cc.8.12.8606.
- Diep CH, Charles NJ, Gilks CB, Kalloger SE, Argenta PA, Lange CA. Progesterone receptors induce FOXO1-dependent senescence in ovarian cancer cells. Cell Cycle. 2013;12:1433–1449. doi: 10.4161/cc.24550.
- Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. PNAS. 1995;92:9363–9367. doi: 10.1073/pnas.92.20.9363.
- Drury JA, Tang AW, Turner MA, Quenby S. A rapid, reliable method for uNK cell density estimation. Journal of Reproductive Immunology. 2013;97:183–185. doi: 10.1016/j.jri.2012.12.002.
- Erlebacher A. Immunology of the maternal-fetal interface. Annual Review of Immunology. 2013;31:387–411. doi: 10.1146/annurev-immunol-032712-100003.
- Evans J, Salamonsen LA, Winship A, Menkhorst E, Nie G, Gargett CE, Dimitriadis E. Fertile ground: human endometrial programming and lessons in health and disease. Nature Reviews Endocrinology. 2016;12:654–667. doi: 10.1038/nrendo.2016.116.
- Funayama R, Saito M, Tanobe H, Ishikawa F. Loss of linker histone H1 in cellular senescence. The Journal of Cell Biology. 2006;175:869–880. doi: 10.1083/jcb.200604005.
- Gellersen B, Brosens JJ. Cyclic decidualization of the human endometrium in reproductive health and failure. Endocrine Reviews. 2014;35:851–905. doi: 10.1210/er.2014-1045.
- Groll JM, Usadi RS, Lessey BA, Lininger R, Young SL, Fritz MA. Effects of variations in serum estradiol concentrations on secretory endometrial development and function in experimentally induced cycles in normal women. Fertility and Sterility. 2009;92:2058–2061. doi: 10.1016/j.fertnstert.2009.06.018.
- Hanna J, Goldman-Wohl D, Hamani Y, Avraham I, Greenfield C, Natanson-Yaron S, Prus D, Cohen-Daniel L, Arnon TI, Manaster I, Gazit R, Yutkin V, Benharroch D, Porgador A, Keshet E, Yagel S, Mandelboim O. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nature Medicine. 2006;12:1065–1074. doi: 10.1038/nm1452.
- Hapangama DK, Kamal A, Saretzki G. Implications of telomeres and telomerase in endometrial pathology. Human Reproduction Update. 2017;23:166–187. doi: 10.1093/humupd/dmw044.
- Iannello A, Raulet DH. Immune surveillance of unhealthy cells by natural killer cells. Cold Spring Harbor Symposia on Quantitative Biology. 2013;78:249–257. doi: 10.1101/sqb.2013.78.020255.
- Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, Yee H, Zender L, Lowe SW. Senescence of activated stellate cells limits liver fibrosis. Cell. 2008;134:657–667. doi: 10.1016/j.cell.2008.06.049.
- Laws MJ, Taylor RN, Sidell N, DeMayo FJ, Lydon JP, Gutstein DE, Bagchi MK, Bagchi IC. Gap junction communication between uterine stromal cells plays a critical role in pregnancy-associated neovascularization and embryo survival. Development. 2008;135:2659–2668. doi: 10.1242/dev.019810.
- Lucas ES, Dyer NP, Fishwick K, Ott S, Brosens JJ. Success after failure: the role of endometrial stem cells in recurrent miscarriage. Reproduction. 2016a;152:R159–R166. doi: 10.1530/REP-16-0306.
- Lucas ES, Dyer NP, Murakami K, Lee YH, Chan YW, Grimaldi G, Muter J, Brighton PJ, Moore JD, Patel G, Chan JK, Takeda S, Lam EW, Quenby S, Ott S, Brosens JJ. Loss of Endometrial Plasticity in Recurrent Pregnancy Loss. Stem Cells. 2016b;34:346–356. doi: 10.1002/stem.2222.
- Marçais A, Cherfils-Vicini J, Viant C, Degouve S, Viel S, Fenis A, Rabilloud J, Mayol K, Tavares A, Bienvenu J, Gangloff YG, Gilson E, Vivier E, Walzer T. The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells. Nature Immunology. 2014;15:749–757. doi: 10.1038/ni.2936.
- Matjusaitis M, Chin G, Sarnoski EA, Stolzing A. Biomarkers to identify and isolate senescent cells. Ageing Research Reviews. 2016;29:1–12. doi: 10.1016/j.arr.2016.05.003.
- Mosteiro L, Pantoja C, Alcazar N, Marión RM, Chondronasiou D, Rovira M, Fernandez-Marcos PJ, Muñoz-Martin M, Blanco-Aparicio C, Pastor J, Gómez-López G, De Martino A, Blasco MA, Abad M, Serrano M. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science. 2016;354:aaf4445. doi: 10.1126/science.aaf4445.
- Muñoz-Espín D, Serrano M. Cellular senescence: from physiology to pathology. Nature Reviews Molecular Cell Biology. 2014;15:482–496. doi: 10.1038/nrm3823.
- Murakami K, Bhandari H, Lucas ES, Takeda S, Gargett CE, Quenby S, Brosens JJ, Tan BK. Deficiency in clonogenic endometrial mesenchymal stem cells in obese women with reproductive failure--a pilot study. PLoS One. 2013;8:e82582. doi: 10.1371/journal.pone.0082582.
- Paria BC, Lim H, Wang XN, Liehr J, Das SK, Dey SK. Coordination of differential effects of primary estrogen and catecholestrogen on two distinct targets mediates embryo implantation in the mouse. Endocrinology. 1998;139:5235–5246. doi: 10.1210/endo.139.12.6386.
- Park Y, Nnamani MC, Maziarz J, Wagner GP. Cis-regulatory evolution of forkhead box O1 (FOXO1), a terminal selector gene for decidual stromal cell identity. Molecular Biology and Evolution. 2016;33:3161–3169. doi: 10.1093/molbev/msw193.
- Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Research. 2001;29:45e–45. doi: 10.1093/nar/29.9.e45.
- Pohnke Y, Schneider-Merck T, Fahnenstich J, Kempf R, Christian M, Milde-Langosch K, Brosens JJ, Gellersen B. Wild-type p53 protein is up-regulated upon cyclic adenosine monophosphate-induced differentiation of human endometrial stromal cells. The Journal of Clinical Endocrinology & Metabolism. 2004;89:5233–5244. doi: 10.1210/jc.2004-0012.
- Rajagopalan S, Long EO. Cellular senescence induced by CD158d reprograms natural killer cells to promote vascular remodeling. PNAS. 2012;109:20596–20601. doi: 10.1073/pnas.1208248109.
- Ritschka B, Storer M, Mas A, Heinzmann F, Ortells MC, Morton JP, Sansom OJ, Zender L, Keyes WM. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes & Development. 2017;31:172–183. doi: 10.1101/gad.290635.116.
- Ruifrok AC, Johnston DA. Quantification of histochemical staining by color deconvolution. Analytical and Quantitative Cytology and Histology. 2001;23:291–299.
- Sadaie M, Salama R, Carroll T, Tomimatsu K, Chandra T, Young AR, Narita M, Pérez-Mancera PA, Bennett DC, Chong H, Kimura H, Narita M. Redistribution of the Lamin B1 genomic binding profile affects rearrangement of heterochromatic domains and SAHF formation during senescence. Genes & Development. 2013;27:1800–1808. doi: 10.1101/gad.217281.113.
- Saeed AI, Sharov V, White J, Li J, Liang W, Bhagabati N, Braisted J, Klapa M, Currier T, Thiagarajan M, Sturn A, Snuffin M, Rezantsev A, Popov D, Ryltsov A, Kostukovich E, Borisovsky I, Liu Z, Vinsavich A, Trush V, Quackenbush J. TM4: a free, open-source system for microarray data management and analysis. BioTechniques. 2003;34:374–378.
- Sagiv A, Biran A, Yon M, Simon J, Lowe SW, Krizhanovsky V. Granule exocytosis mediates immune surveillance of senescent cells. Oncogene. 2013;32:1971–1977. doi: 10.1038/onc.2012.206.
- Sagiv A, Burton DG, Moshayev Z, Vadai E, Wensveen F, Ben-Dor S, Golani O, Polic B, Krizhanovsky V. NKG2D ligands mediate immunosurveillance of senescent cells. Aging. 2016;8:328–344. doi: 10.18632/aging.100897.
- Salker MS, Nautiyal J, Steel JH, Webster Z, Sućurović S, Nicou M, Singh Y, Lucas ES, Murakami K, Chan YW, James S, Abdallah Y, Christian M, Croy BA, Mulac-Jericevic B, Quenby S, Brosens JJ. Disordered IL-33/ST2 activation in decidualizing stromal cells prolongs uterine receptivity in women with recurrent pregnancy loss. PLoS One. 2012;7:e52252. doi: 10.1371/journal.pone.0052252.
- Smith A, Tilling K, Nelson SM, Lawlor DA. Live-Birth Rate Associated With Repeat In Vitro Fertilization Treatment Cycles. Jama. 2015;314:2654–2662. doi: 10.1001/jama.2015.17296.
- Takano M, Lu Z, Goto T, Fusi L, Higham J, Francis J, Withey A, Hardt J, Cloke B, Stavropoulou AV, Ishihara O, Lam EW, Unterman TG, Brosens JJ, Kim JJ. Transcriptional cross talk between the forkhead transcription factor forkhead box O1A and the progesterone receptor coordinates cell cycle regulation and differentiation in human endometrial stromal cells. Molecular Endocrinology. 2007;21:2334–2349. doi: 10.1210/me.2007-0058.
- Team RC. Vienna, Austria: R Foundation for Statistical Computing; 2015.
- van Deursen JM. The role of senescent cells in ageing. Nature. 2014;509:439–446. doi: 10.1038/nature13193.
- Venables W. Ripley B. Modern Applied Statistics with S-Plus. 4th edn. Springer; 1997.
- Xiong S, Sharkey AM, Kennedy PR, Gardner L, Farrell LE, Chazara O, Bauer J, Hiby SE, Colucci F, Moffett A. Maternal uterine NK cell-activating receptor KIR2DS1 enhances placentation. Journal of Clinical Investigation. 2013;123:4264–4272. doi: 10.1172/JCI68991.
- Yuan X, Saravelos SH, Wang Q, Xu Y, Li TC, Zhou C. Endometrial thickness as a predictor of pregnancy outcomes in 10787 fresh IVF-ICSI cycles. Reproductive BioMedicine Online. 2016;33:197–205. doi: 10.1016/j.rbmo.2016.05.002.
- Zhang S, Lin H, Kong S, Wang S, Wang H, Wang H, Armant DR. Physiological and molecular determinants of embryo implantation. Molecular Aspects of Medicine. 2013;34:939–980. doi: 10.1016/j.mam.2012.12.011.
- Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, Dai HM, Ling YY, Stout MB, Pirtskhalava T, Giorgadze N, Johnson KO, Giles CB, Wren JD, Niedernhofer LJ, Robbins PD, Kirkland JL. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell. 2016;15:428–435. doi: 10.1111/acel.12445.
- Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, Palmer AK, Ikeno Y, Hubbard GB, Lenburg M, O'Hara SP, LaRusso NF, Miller JD, Roos CM, Verzosa GC, LeBrasseur NK, Wren JD, Farr JN, Khosla S, Stout MB, McGowan SJ, Fuhrmann-Stroissnigg H, Gurkar AU, Zhao J, Colangelo D, Dorronsoro A, Ling YY, Barghouthy AS, Navarro DC, Sano T, Robbins PD, Niedernhofer LJ, Kirkland JL. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015;14:644–658. doi: 10.1111/acel.12344.
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