Gene Regulatory Network Analysis of Decidual Stromal Cells and Natural Killer Cells.
Endometrium
Gene regulatory network
Transcription factor
Uterus
scRNA-seq
Journal
Reproductive sciences (Thousand Oaks, Calif.)
ISSN: 1933-7205
Titre abrégé: Reprod Sci
Pays: United States
ID NLM: 101291249
Informations de publication
Date de publication:
01 Aug 2024
01 Aug 2024
Historique:
received:
26
12
2023
accepted:
11
07
2024
medline:
2
8
2024
pubmed:
2
8
2024
entrez:
1
8
2024
Statut:
aheadofprint
Résumé
Human reproductive success relies on the proper differentiation of the uterine endometrium to facilitate implantation, formation of the placenta, and pregnancy. This process involves two critical types of decidual uterine cells: endometrial/decidual stromal cells (dS) and uterine/decidual natural killer (dNK) cells. To better understand the transcription factors governing the in vivo functions of these cells, we analyzed single-cell transcriptomics data from first-trimester terminations of pregnancy, and for the first time conducted gene regulatory network analysis of dS and dNK cell subpopulations. Our analysis revealed stromal cell populations that corresponded to previously described in vitro decidualized cells and senescent decidual cells. We discovered new decidualization driving transcription factors of stromal cells for early pregnancy, including DDIT3 and BRF2, which regulate oxidative stress protection. For dNK cells, we identified transcription factors involved in the immunotolerant (dNK1) subpopulation, including IRX3 and RELB, which repress the NFKB pathway. In contrast, for the less immunotolerant (dNK3) population we predicted TBX21 (T-bet) and IRF2-mediated upregulation of the interferon pathway. To determine the clinical relevance of our findings, we tested the overrepresentation of the predicted transcription factors target genes among cell type-specific regulated genes from pregnancy disorders, such as recurrent pregnancy loss and preeclampsia. We observed that the predicted decidualized stromal and dNK1-specific transcription factor target genes were enriched with the genes downregulated in pregnancy disorders, whereas the predicted dNK3-specific targets were enriched with genes upregulated in pregnancy disorders. Our findings emphasize the importance of stress tolerance pathways in stromal cell decidualization and immunotolerance promoting regulators in dNK differentiation.
Identifiants
pubmed: 39090334
doi: 10.1007/s43032-024-01653-1
pii: 10.1007/s43032-024-01653-1
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
Références
Vento-Tormo R, Efremova M, Botting RA, Turco MY, Vento-Tormo M, Meyer KB, Park J-E, Stephenson E, Polański K, Goncalves A, Gardner L, Holmqvist S, et al. Single-cell reconstruction of the early maternal–fetal interface in humans. Nature. 2018;563:347–53.
doi: 10.1038/s41586-018-0698-6
pubmed: 30429548
pmcid: 7612850
Wang W, Vilella F, Alama P, Moreno I, Mignardi M, Isakova A, Pan W, Simon C, Quake SR. Single-cell transcriptomic atlas of the human endometrium during the menstrual cycle. Nat Med. 2020;26:1644–53.
doi: 10.1038/s41591-020-1040-z
pubmed: 32929266
Brighton PJ, Maruyama Y, Fishwick K, Vrljicak P, Tewary S, Fujihara R, Muter J, Lucas ES, Yamada T, Woods L, Lucciola R, Hou Lee Y, et al (2017) Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium. Elife 6. https://doi.org/10.7554/eLife.31274 .
Muter J, Kong C-S, Brosens JJ. The role of decidual subpopulations in implantation. Menstruat Miscarriage Front Reprod Heal. 2021;3:804921.
doi: 10.3389/frph.2021.804921
Stadtmauer DJ, Wagner GP. Single-cell analysis of prostaglandin E2-induced human decidual cell in vitro differentiation: a minimal ancestral deciduogenic signal†. Biol Reprod. 2022;106:155–72.
doi: 10.1093/biolre/ioab183
pubmed: 34591094
Gellersen B, Brosens JJ. Cyclic decidualization of the human endometrium in reproductive health and failure. Endocr Rev. 2014;35:851–905.
doi: 10.1210/er.2014-1045
pubmed: 25141152
Marinić M, Mika K, Chigurupati S, Lynch VJ. Evolutionary transcriptomics implicates HAND2 in the origins of implantation and regulation of gestation length. Elife. 2021;10:1–52.
doi: 10.7554/eLife.61257
Lucas ES, Vrljicak P, Muter J, Diniz-da-Costa MM, Brighton PJ, Kong C-S, Lipecki J, Fishwick KJ, Odendaal J, Ewington LJ, Quenby S, Ott S, et al. Recurrent pregnancy loss is associated with a pro-senescent decidual response during the peri-implantation window. Commun Biol. 2020;3:37.
doi: 10.1038/s42003-020-0763-1
pubmed: 31965050
pmcid: 6972755
Li K, Wu Y, Li Y, Yu Q, Tian Z, Wei H, Qu K. Landscape and dynamics of the transcriptional regulatory network during natural killer cell differentiation. Genom Proteomics Bioinforma. 2020;18:501–15.
doi: 10.1016/j.gpb.2020.12.003
Strunz B, Bister J, Jönsson H, Filipovic I, Crona-Guterstam Y, Kvedaraite E, Sleiers N, Dumitrescu B, Brännström M, Lentini A, Reinius B, Cornillet M, et al Continuous human uterine NK cell differentiation in response to endometrial regeneration and pregnancy. Sci Immunol (2021): 6. https://doi.org/10.1126/sciimmunol.abb7800 .
Muter J, Lynch VJ, McCoy RC, Brosens JJ Human embryo implantation. Development (2023); 150. https://doi.org/10.1242/dev.201507 .
Chen P, Zhou L, Chen J, Lu Y, Cao C, Lv S, Wei Z, Wang L, Chen J, Hu X, Wu Z, Zhou X, et al. The immune atlas of human deciduas with unexplained recurrent pregnancy loss. Front Immunol (2021); 12. https://doi.org/10.3389/fimmu.2021.689019 .
Garrido-Gomez T, Castillo-Marco N, Clemente-Ciscar M, Cordero T, Muñoz-Blat I, Amadoz A, Jimenez-Almazan J, Monfort-Ortiz R, Climent R, Perales-Marin A, Simon C. Disrupted pgr-b and esr1 signaling underlies defective decidualization linked to severe preeclampsia. Elife 2021; 10. https://doi.org/10.7554/eLife.70753 .
Rytkönen KT, Adossa N, Mahmoudian M, Lönnberg T, Poutanen M, Elo LL. Cell type markers indicate distinct contributions of decidual stromal cells and natural killer cells in preeclampsia. Reproduction. 2022;164:V9–13.
doi: 10.1530/REP-22-0079
pubmed: 36111648
Aibar S, González-Blas CB, Moerman T, Huynh-Thu VA, Imrichova H, Hulselmans G, Rambow F, Marine J-C, Geurts P, Aerts J, van den Oord J, Atak ZK, et al. SCENIC: single-cell regulatory network inference and clustering. Nat Methods. 2017;14:1083–6.
doi: 10.1038/nmeth.4463
pubmed: 28991892
pmcid: 5937676
Wolf FA, Angerer P, Theis FJ. SCANPY: Large-scale single-cell gene expression data analysis. Genome Biol. 2018;19:1–5.
doi: 10.1186/s13059-017-1382-0
Hao Y, Hao S, Andersen-Nissen E, Mauck WM, Zheng S, Butler A, Lee MJ, Wilk AJ, Darby C, Zager M, Hoffman P, Stoeckius M, et al. Integrated analysis of multimodal single-cell data. Cell. 2021;184:3573-3587.e29.
doi: 10.1016/j.cell.2021.04.048
pubmed: 34062119
pmcid: 8238499
Rawlings TM, Makwana K, Taylor DM, Molè MA, Fishwick KJ, Tryfonos M, Odendaal J, Hawkes A, Zernicka-Goetz M, Hartshorne GM, Brosens JJ, Lucas ES. Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids. Elife 2021; 10. https://doi.org/10.7554/eLife.69603 .
Li T, Li X, Guo Y, Zheng G, Yu T, Zeng W, Qiu L, He X, Yang Y, Zheng X, Li Y, Huang H, et al. Distinct mRNA and long non-coding RNA expression profiles of decidual natural killer cells in patients with early missed abortion. FASEB J. 2020;34:14264–86.
doi: 10.1096/fj.202000621R
pubmed: 32915478
Tong J, Zhao W, Lv H, Li W-P, Chen Z-J, Zhang C. Transcriptomic profiling in human decidua of severe preeclampsia detected by RNA sequencing. J Cell Biochem. 2018;119:607–15.
doi: 10.1002/jcb.26221
pubmed: 28618048
Goolam M, Xypolita ME, Costello I, Lydon JP, DeMayo FJ, Bikoff EK, Robertson EJ, Mould AW. The transcriptional repressor Blimp1/PRDM1 regulates the maternal decidual response in mice. Nat Commun 2020; 11. https://doi.org/10.1038/s41467-020-16603-z .
Fullerton PT, Monsivais D, Kommagani R, Matzuk MM. Follistatin is critical for mouse uterine receptivity and decidualization. Proc Natl Acad Sci U S A. 2017;114:E4772–81.
doi: 10.1073/pnas.1620903114
pubmed: 28559342
pmcid: 5474784
Neff AM, Yu J, Taylor RN, Bagchi IC, Bagchi MK. Insulin signaling via progesterone-regulated insulin receptor substrate 2 is critical for human uterine decidualization. Endocrinol (United States) 2020; 161. https://doi.org/10.1210/endocr/bqz021 .
Grasso E, Gori S, Soczewski E, Fernández L, Gallino L, Vota D, Martínez G, Irigoyen M, Ruhlmann C, Lobo TF, Salamone G, Mattar R, et al. Impact of the Reticular Stress and Unfolded Protein Response on the inflammatory response in endometrial stromal cells. Sci Rep. 2018;8:12274.
doi: 10.1038/s41598-018-29779-8
pubmed: 30116009
pmcid: 6095878
Khorshed Alam SM, Konno T, Soares MJ. Identification of target genes for a prolactin family paralog in mouse decidua. Reproduction. 2015;149:625–32.
doi: 10.1530/REP-15-0107
Gouge J, Satia K, Guthertz N, Widya M, Thompson AJ, Cousin P, Dergai O, Hernandez N, Vannini A. Redox Signaling by the RNA Polymerase III TFIIB-Related Factor Brf2. Cell. 2015;163:1375–87.
doi: 10.1016/j.cell.2015.11.005
pubmed: 26638071
pmcid: 4671959
Tian J, Zhang C, Kang N, Wang J, Kong N, Zhou J, Wu M, Ding L, Sun H, Yan G, Sheng X. Attenuated monoamine oxidase a impairs endometrial receptivity in women with adenomyosis via downregulation of FOXO1†. Biol Reprod. 2021;105:1443–57.
doi: 10.1093/biolre/ioab182
pubmed: 34568943
Pavličev M, Wagner GP, Chavan AR, Owens K, Maziarz J, Dunn-Fletcher C, Kallapur SG, Muglia L, Jones H. Single-cell transcriptomics of the human placenta: inferring the cell communication network of the maternal-fetal interface. Genome Res. 2017;27:349–61.
doi: 10.1101/gr.207597.116
pubmed: 28174237
pmcid: 5340963
Zhang J, Le Gras S, Pouxvielh K, Faure F, Fallone L, Kern N, Moreews M, Mathieu AL, Schneider R, Marliac Q, Jung M, Berton A, et al. Sequential actions of EOMES and T-BET promote stepwise maturation of natural killer cells. Nat Commun 2021; 12. https://doi.org/10.1038/s41467-021-25758-2 .
Crespo ÂC, Mulik S, Dotiwala F, Ansara JA, Sen Santara S, Ingersoll K, Ovies C, Junqueira C, Tilburgs T, Strominger JL, Lieberman J. Decidual NK cells transfer granulysin to selectively kill bacteria in trophoblasts. Cell. 2020;182:1125-1139.e18.
doi: 10.1016/j.cell.2020.07.019
pubmed: 32822574
pmcid: 7484179
Liang Y, Lai S, Huang L, Li Y, Zeng S, Zhang S, Chen J, Deng W, Liu Y, Liang J, Xu P, Liu M, et al. JAZF1 safeguards human endometrial stromal cells survival and decidualization by repressing the transcription of G0S2. Commun Biol 2023; 6. https://doi.org/10.1038/s42003-023-04931-x .
Hamilton GS, Lysiak JJ, Watson AJ, Lala PK. Effects of colony stimulating factor-1 on human extravillous trophoblast growth and invasion. J Endocrinol. 1998;159:69–77.
doi: 10.1677/joe.0.1590069
pubmed: 9795343
Meggyes M, Miko E, Szigeti B, Farkas N, Szereday L. The importance of the PD-1/PD-L1 pathway at the maternal-fetal interface. BMC Pregnancy Childbirth. 2019;19:74.
doi: 10.1186/s12884-019-2218-6
pubmed: 30782114
pmcid: 6381664
Takenaka MC, Robson S, Quintana FJ. Regulation of the T Cell Response by CD39. Trends Immunol. 2016;37:427–39.
doi: 10.1016/j.it.2016.04.009
pubmed: 27236363
pmcid: 5215082
Chen J, He R, Sun W, Gao R, Peng Q, Zhu L, Du Y, Ma X, Guo X, Zhang H, Tan C, Wang J, et al. TAGAP instructs Th17 differentiation by bridging Dectin activation to EPHB2 signaling in innate antifungal response. Nat Commun 2020; 11. https://doi.org/10.1038/s41467-020-15564-7 .
Ju S, Zhu Y, Liu L, Dai S, Li C, Chen E, He Y, Zhang X, Lu B. Gadd45b and Gadd45g are important for anti-tumor immune responses. Eur J Immunol. 2009;39:3010–8.
doi: 10.1002/eji.200839154
pubmed: 19688743
pmcid: 3025293
Slattery K, Gardiner CM. NK cell metabolism and TGFβ – implications for immunotherapy. Front Immunol. 2019;10:2915.
doi: 10.3389/fimmu.2019.02915
pubmed: 31921174
pmcid: 6927492
Kawamura E, Hamilton GB, Miskiewicz EI, MacPhee DJ. Fermitin family homolog-2 (FERMT2) is highly expressed in human placental villi and modulates trophoblast invasion. BMC Dev Biol. 2018;18:19.
doi: 10.1186/s12861-018-0178-0
pubmed: 30382829
pmcid: 6211606
Zhou G, Winn E, Nguyen D, Kasten EP, Petroff MG, Hoffmann HM. Co-alterations of circadian clock gene transcripts in human placenta in preeclampsia. Sci Rep. 2022;12:17856.
doi: 10.1038/s41598-022-22507-3
pubmed: 36284122
pmcid: 9596722
Comerci CJ, Mace EM, Banerjee PP, Orange JS. CD2 promotes human natural killer cell membrane nanotube formation. PLoS One 2012; 7. https://doi.org/10.1371/journal.pone.0047664 .
Tang JJJ, Sung AP, Guglielmo MJ, Navarrete-Galvan L, Redelman D, Smith-Gagen J, Hudig D. Natural Killer (NK) Cell Expression of CD2 as a Predictor of Serial Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC). Antibodies (Basel, Switzerland). 2020;9:1–18.
Bono P, Rubin K, Higgins JMG, Hynes RO. Layilin, a novel integral membrane protein, is a hyaluronan receptor. Mol Biol Cell. 2001;12:891–900.
doi: 10.1091/mbc.12.4.891
pubmed: 11294894
pmcid: 32274
Kong CS, Ordoñez AA, Turner S, Tremaine T, Muter J, Lucas ES, Salisbury E, Vassena R, Tiscornia G, Fouladi-Nashta AA, Hartshorne G, Brosens JJ, et al. Embryo biosensing by uterine natural killer cells determines endometrial fate decisions at implantation. FASEB J. 2021;35:e21336.
doi: 10.1096/fj.202002217R
pubmed: 33749894
Li M, Thorne RF, Shi R, Zhang XD, Li J, Li J, Zhang Q, Wu M, Liu L. DDIT3 directs a dual mechanism to balance glycolysis and oxidative phosphorylation during glutamine deprivation. Adv Sci. 2021;8:e2003732.
doi: 10.1002/advs.202003732
Leitao B, Jones MC, Fusi L, Higham J, Lee Y, Takano M, Goto T, Christian M, Lam EW-F, Brosens JJ. Silencing of the JNK pathway maintains progesterone receptor activity in decidualizing human endometrial stromal cells exposed to oxidative stress signals. FASEB J. 2010;24:1541–51.
doi: 10.1096/fj.09-149153
pubmed: 20026682
pmcid: 2857868
Kajihara T, Jones M, Fusi L, Takano M, Feroze-Zaidi F, Pirianov G, Mehmet H, Ishihara O, Higham JM, Lam EW-F, Brosens JJ. Differential expression of FOXO1 and FOXO3a confers resistance to oxidative cell death upon endometrial decidualization. Mol Endocrinol 2006; 20:2444–2455. https://doi.org/10.1210/me.2006-0118 .
Muter J, Lucas ES, Chan Y-W, Brighton PJ, Moore JD, Lacey L, Quenby S, Lam EW-F, Brosens JJ. The clock protein period 2 synchronizes mitotic expansion and decidual transformation of human endometrial stromal cells. FASEB J 2015; 29:1603–14. https://doi.org/10.1096/fj.14-267195 .
Leitao BB, Jones MC, Brosens JJ. The SUMO E3-ligase PIAS1 couples reactive oxygen species-dependent JNK activation to oxidative cell death. FASEB J. 2011;25:3416–25.
doi: 10.1096/fj.11-186346
pubmed: 21676946
pmcid: 3177572
Erkenbrack EM, Maziarz JD, Griffith OW, Liang C, Chavan AR, Nnamani MC, Wagner GP. The mammalian decidual cell evolved from a cellular stress response. PLOS Biol. 2018;16:e2005594.
doi: 10.1371/journal.pbio.2005594
pubmed: 30142145
pmcid: 6108454
Brown RM, Wang L, Fu A, Kannan A, Mussar M, Bagchi IC, Jorgensen JS. Irx3 promotes gap junction communication between uterine stromal cells to regulate vascularization during embryo implantation. Biol Reprod. 2022;106:1000–10.
doi: 10.1093/biolre/ioac015
pubmed: 35138358
pmcid: 9113487
Whettlock EM, Von WE, Cuff AO, Browne B, Johnson MR, Male V. Dynamic changes in uterine NK cell subset frequency and function over the menstrual cycle and pregnancy. Front Immunol. 2022;13:880438.
doi: 10.3389/fimmu.2022.880438
pubmed: 35784314
pmcid: 9245422
Garrido-Gómez T, Castillo-Marco N, Cordero T, Simón C. Decidualization resistance in the origin of preeclampsia. Am J Obstet Gynecol. 2022;226:S886–94.
doi: 10.1016/j.ajog.2020.09.039
pubmed: 33007270
Pique-Regi R, Romero R, Tarca AL, Sendler ED, Xu Y, Garcia-Flores V, Leng Y, Luca F, Hassan SS, Gomez-Lopez N. Single cell transcriptional signatures of the human placenta in term and preterm parturition. Elife 2019; 8. https://doi.org/10.7554/eLife.52004 .