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2. Uncoupling of circadian and other maternal cues in decidualizing endometrial cells

Author

Muter, Joanne

Subjects
618.3, QM Human anatomy, RJ Pediatrics
Abstract

The differentiation of human endometrial stromal cells (HESCs) into specialised decidual cells prepares the endometrium for embryonic implantation. The biochemical and morphological transformation of these cells is highly temporally regulated in order to define a transient period of endometrial receptivity. Currently, the involvement of circadian machinery, and clock dependent pathways in this process are not fully understood. Firstly, analysis of circadian rhythms in HESCs revealed a consistent loss of oscillations in clock components upon decidualization. Down-regulation of Period 2 (PER2) expression, apparent in the early stages of differentiation, was shown to be sufficient to cause this aperiodicity. In turn, temporal suppression of PER2 expression was achieved via reduced CLOCK binding to a non-canonical Ebox enhancer in the PER2 promoter. RNA sequencing analysis upon premature PER2 knockdown revealed a disorganised decidual phenotype in which cell cycle and mitotic regulators were perturbed. As such, PER2 acts to uncouple the endometrium from circadian oscillations during decidualization. Secondly, the gene PRIP-1 was shown to be PER2 dependent in undifferentiated HESCs. Endometrial expression of PRIP-1 was induced and maintained upon decidualization by the post-ovulatory rise in progesterone. Analysis of Ca2+ fluxes demonstrated the ability of PRIP-1 to act as a chelator of IP3 signalling. Additionally, PRIP-1, via its regulation of the AKT pathway, is shown to be an anti-apoptotic regulator in decidual HESCs. Together, these results indicate PRIP-1 functions as a molecular switch in response to progesterone signalling. High PRIP-1 levels during differentiation enable AKT and IP3 mediated cell survival, whilst declining levels upon P4 withdrawal leads to decidual apoptosis. In summary, I provide a novel paradigm whereby both PER2 and PRIP-1 act to uncouple the endometrium from various signalling inputs, enabling an autonomous decidual response. Asynchrony in these pathways can lead to a cascade of events resulting in an array of adverse pregnancy complications.

Published
2015

13. EndoTime: non-categorical timing estimates for luteal endometrium

Author

Lipecki, Julia, primary, Mitchell, Andrew E, additional, Muter, Joanne, additional, Lucas, Emma S, additional, Makwana, Komal, additional, Fishwick, Katherine, additional, Odendaal, Joshua, additional, Hawkes, Amelia, additional, Vrljicak, Pavle, additional, Brosens, Jan J, additional, and Ott, Sascha, additional

Published
2022
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18. EndoTime: Non-categorical timing estimates for luteal endometrium

Author

Lipecki, Julia, primary, Mitchell, Andrew E, additional, Muter, Joanne, additional, Lucas, Emma S, additional, Makwana, Komal, additional, Fishwick, Katherine, additional, Odendaal, Joshua, additional, Hawkes, Amelia, additional, Vrljicak, Pavle, additional, Brosens, Jan J, additional, and Ott, Sascha, additional

Published
2021
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19. Embryo biosensing by uterine natural killer cells determines endometrial fate decisions at implantation

Author

Kong, Chow‐Seng, primary, Ordoñez, Alexandra Almansa, additional, Turner, Sarah, additional, Tremaine, Tina, additional, Muter, Joanne, additional, Lucas, Emma S., additional, Salisbury, Emma, additional, Vassena, Rita, additional, Tiscornia, Gustavo, additional, Fouladi‐Nashta, Ali A., additional, Hartshorne, Geraldine, additional, Brosens, Jan J., additional, and Brighton, Paul J., additional

Published
2021
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22. Involvement of uterine natural killer cells in the natural selection of human embryos at implantation

Author

Kong, Chow-Seng, primary, Ordoñez, Alexandra Almansa, additional, Turner, Sarah, additional, Tremaine, Tina, additional, Muter, Joanne, additional, Lucas, Emma S., additional, Salisbury, Emma, additional, Vassena, Rita, additional, Fouladi-Nashta, Ali A., additional, Tiscornia, Gustavo, additional, Hartshorne, Geraldine, additional, Brosens, Jan J., additional, and Brighton, Paul J., additional

Published
2020
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25. Impact of sitagliptin on endometrial mesenchymal stem-like progenitor cells: A randomised, double-blind placebo-controlled feasibility trial

Author

Tewary, Shreeya, primary, Lucas, Emma S., additional, Fujihara, Risa, additional, Kimani, Peter K., additional, Polanco, Angela, additional, Brighton, Paul J., additional, Muter, Joanne, additional, Fishwick, Katherine J., additional, Da Costa, Maria José Minhoto Diniz, additional, Ewington, Lauren J., additional, Lacey, Lauren, additional, Takeda, Satoru, additional, Brosens, Jan J., additional, and Quenby, Siobhan, additional

Published
2020
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26. Erratum: EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association (Nucleic acids research (2018) 46 15 (7662-7674))

Author

Paredes, Roberto, Schneider, Marion, Stevens, Adam, White, Daniel J., K Williamson, Andrew J., Muter, Joanne, Pearson, Stella, Kelly, James R., Connors, Kathleen, Wiseman, Daniel H., Chadwick, John A., Löffler, Harald, Teng, Hsiang Ying, Lovell, Simon, Unwin, Richard, van de Vrugt, Henri J., Smith, Helen, Kustikova, Olga, Schambach, Axel, P Somervaille, Tim C., Pierce, Andrew, Whetton, Anthony D., and Meyer, Stefan

Published
2018

28. Impact of Sitagliptin on Endometrial Mesenchymal Stem-Like Progenitor Cells: A Randomised, Double-Blind Placebo-Controlled Feasibility Trial

Author

Tewary, Shreeya, primary, Lucas, Emma S., additional, Fujihara, Risa, additional, Kimani, Peter K., additional, Polanco, Angela, additional, Brighton, Paul J., additional, Muter, Joanne, additional, Fishwick, Katherine J., additional, Diniz Da Costa, Maria José Minhoto, additional, Ewington, Lauren J., additional, Lacey, Lauren, additional, Takeda, Satoru, additional, Brosens, Jan, additional, and Quenby, Siobhan, additional

Published
2019
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30. Acquired cross linker resistance associated with a novel spliced BRCA2 protein variant for molecular phenotyping of BRCA2 disruption

Author

Meyer, Stefan, Stevens, Adam, Paredes, Roberto, Schneider, Marion, Walker, Michael J, Williamson, Andrew J K, Gonzalez-Sanchez, Maria-Belen, Smetsers, Stephanie, Dalal, Vineet, Teng, Hsiang Ying, White, Daniel J, Taylor, Sam, Muter, Joanne, Pierce, Andrew, de Leonibus, Chiara, Rockx, Davy A P, Rooimans, Martin A, Spooncer, Elaine, Stauffer, Stacey, Biswas, Kajal, Godthelp, Barbara, Dorsman, Josephine, Clayton, Peter E, Sharan, Shyam K, Whetton, Anthony D, Pediatric surgery, Surgery, Human genetics, CCA - Cancer biology and immunology, and Amsterdam Reproduction & Development (AR&D)

Subjects
Transcription, Genetic, endocrine system diseases, RNA Splicing, Genes, BRCA2, Breast Neoplasms, Mice, Cell Line, Tumor, Animals, Humans, Genetic Predisposition to Disease, skin and connective tissue diseases, neoplasms, BRCA2 Protein, Ovarian Neoplasms, Manchester Cancer Research Centre, ResearchInstitutes_Networks_Beacons/mcrc, Exons, Introns, female genital diseases and pregnancy complications, Alternative Splicing, Leukemia, Myeloid, Acute, Fanconi Anemia, Phenotype, Drug Resistance, Neoplasm, Mutation, Original Article, Female, Neoplasm Recurrence, Local, K562 Cells, DNA Damage
Abstract

BRCA2 encodes a protein with a fundamental role in homologous recombination that is essential for normal development. Carrier status of mutations in BRCA2 is associated with familial breast and ovarian cancer, while bi-allelic BRCA2 mutations can cause Fanconi anemia (FA), a cancer predisposition syndrome with cellular cross-linker hypersensitivity. Cancers associated with BRCA2 mutations can acquire chemo-resistance on relapse. We modeled acquired cross-linker resistance with an FA-derived BRCA2-mutated acute myeloid leukemia (AML) platform. Associated with acquired cross-linker resistance was the expression of a functional BRCA2 protein variant lacking exon 5 and exon 7 (BRCA2 δE5+7), implying a role for BRCA2 splicing for acquired chemo-resistance. Integrated network analysis of transcriptomic and proteomic differences for phenotyping of BRCA2 disruption infers impact on transcription and chromatin remodeling in addition to the DNA damage response. The striking overlap with transcriptional profiles of FA patient hematopoiesis and BRCA mutation associated ovarian cancer helps define and explicate the â € BRCAness' profile.

Published
2017

31. EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association

Author

Paredes, Roberto, primary, Schneider, Marion, additional, Stevens, Adam, additional, White, Daniel J, additional, K. Williamson, Andrew J, additional, Muter, Joanne, additional, Pearson, Stella, additional, Kelly, James R, additional, Connors, Kathleen, additional, Wiseman, Daniel H, additional, Chadwick, John A, additional, Löffler, Harald, additional, Teng, Hsiang Ying, additional, Lovell, Simon, additional, Unwin, Richard, additional, van de Vrugt, Henri J, additional, Smith, Helen, additional, Kustikova, Olga, additional, Schambach, Axel, additional, P. Somervaille, Tim C, additional, Pierce, Andrew, additional, Whetton, Anthony D, additional, and Meyer, Stefan, additional

Published
2018
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32. Recurrent pregnancy loss is associated with a pro-senescent decidual response during the peri-implantation window

Author

Lucas, Emma S, primary, Vrljicak, Pavle, additional, Muter, Joanne, additional, Diniz-da-Costa, Maria M, additional, Brighton, Paul J, additional, Kong, Chow-Seng, additional, Lipecki, Julia, additional, Fishwick, Katherine, additional, Odendaal, Joshua, additional, Ewington, Lauren J., additional, Quenby, Siobhan, additional, Ott, Sascha, additional, and Brosens, Jan J, additional

Published
2018
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35. Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium

Author

Brighton, Paul J, primary, Maruyama, Yojiro, additional, Fishwick, Katherine, additional, Vrljicak, Pavle, additional, Tewary, Shreeya, additional, Fujihara, Risa, additional, Muter, Joanne, additional, Lucas, Emma S, additional, Yamada, Taihei, additional, Woods, Laura, additional, Lucciola, Raffaella, additional, Hou Lee, Yie, additional, Takeda, Satoru, additional, Ott, Sascha, additional, Hemberger, Myriam, additional, Quenby, Siobhan, additional, and Brosens, Jan Joris, additional

Published
2017
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36. Author response: Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium

Author

Brighton, Paul J, primary, Maruyama, Yojiro, additional, Fishwick, Katherine, additional, Vrljicak, Pavle, additional, Tewary, Shreeya, additional, Fujihara, Risa, additional, Muter, Joanne, additional, Lucas, Emma S, additional, Yamada, Taihei, additional, Woods, Laura, additional, Lucciola, Raffaella, additional, Hou Lee, Yie, additional, Takeda, Satoru, additional, Ott, Sascha, additional, Hemberger, Myriam, additional, Quenby, Siobhan, additional, and Brosens, Jan Joris, additional

Published
2017
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37. Clearance of senescent decidual cells by uterine natural killer cells drives endometrial remodeling during the window of implantation

Author

Brighton, Paul J, primary, Maruyama, Yojiro, additional, Fishwick, Katherine, additional, Vrljicak, Pavle, additional, Tewary, Shreeya, additional, Fujihara, Risa, additional, Muter, Joanne, additional, Lucas, Emma S, additional, Yamada, Taihei, additional, Woods, Laura, additional, Lucciola, Raffaella, additional, Lee, Yie Hou, additional, Takeda, Satoru, additional, Ott, Sascha, additional, Hemberger, Myriam, additional, Quenby, Siobhan, additional, and Brosens, Jan J, additional

Published
2017
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40. Loss of Endometrial Plasticity in Recurrent Pregnancy Loss

Author

Lucas, Emma S., primary, Dyer, Nigel P., additional, Murakami, Keisuke, additional, Hou Lee, Yie, additional, Chan, Yi-Wah, additional, Grimaldi, Giulia, additional, Muter, Joanne, additional, Brighton, Paul J., additional, Moore, Jonathan D., additional, Patel, Gnyaneshwari, additional, Chan, Jerry K.Y., additional, Takeda, Satoru, additional, Lam, Eric W-F., additional, Quenby, Siobhan, additional, Ott, Sascha, additional, and Brosens, Jan J., additional

Published
2015
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43. Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

Author

Anderson, Beverley H., Kasher, Paul R., Mayer, Josephine, Szynkiewicz, Marcin, Jenkinson, Emma M., Bhaskar, Sanjeev S., Urquhart, Jill E., Daly, Sarah B., Dickerson, Jonathan E., O'Sullivan, James, Leibundgut, Elisabeth Oppliger, Muter, Joanne, Abdel-Salem, Ghada M. H., Babul-Hirji, Riyana, Baxter, Peter, Berger, Andrea, Bonafe, Luisa, Brunstom-Hernandez, Janice E., Buckard, Johannes A., Chitayat, David, Chong, Wui K., Cordelli, Duccio M., Ferreira, Patrick, Fluss, Joel, Forrest, Ewan H., Franzoni, Emilio, Garone, Caterina, Hammans, Simon R., Houge, Gunnar, Hughes, Imelda, Jacquemont, Sebastien, Jeannet, Pierre-Yves, Jefferson, Rosalind J., Kumar, Ram, Kutschke, Georg, Lundberg, Staffan, Lourenco, Charles M., Mehta, Ramesh, Naidu, Sakkubai, Nischal, Ken K., Nunes, Luis, Ounap, Katrin, Philippart, Michel, Prabhakar, Prab, Risen, Sarah R., Schiffmann, Raphael, Soh, Calvin, Stephenson, John B. P., Stewart, Helen, Stone, Jon, Tolmie, John L., van der Knaap, Marjo S., Vieira, Jose P., Vilain, Catheline N., Wakeling, Emma L., Wermenbol, Vanessa, Whitney, Andrea, Lovell, Simon C., Meyer, Stefan, Livingston, John H., Baerlocher, Gabriela M., Black, Graeme C. M., Rice, Gillian I., Crow, Yanick J., Anderson, Beverley H., Kasher, Paul R., Mayer, Josephine, Szynkiewicz, Marcin, Jenkinson, Emma M., Bhaskar, Sanjeev S., Urquhart, Jill E., Daly, Sarah B., Dickerson, Jonathan E., O'Sullivan, James, Leibundgut, Elisabeth Oppliger, Muter, Joanne, Abdel-Salem, Ghada M. H., Babul-Hirji, Riyana, Baxter, Peter, Berger, Andrea, Bonafe, Luisa, Brunstom-Hernandez, Janice E., Buckard, Johannes A., Chitayat, David, Chong, Wui K., Cordelli, Duccio M., Ferreira, Patrick, Fluss, Joel, Forrest, Ewan H., Franzoni, Emilio, Garone, Caterina, Hammans, Simon R., Houge, Gunnar, Hughes, Imelda, Jacquemont, Sebastien, Jeannet, Pierre-Yves, Jefferson, Rosalind J., Kumar, Ram, Kutschke, Georg, Lundberg, Staffan, Lourenco, Charles M., Mehta, Ramesh, Naidu, Sakkubai, Nischal, Ken K., Nunes, Luis, Ounap, Katrin, Philippart, Michel, Prabhakar, Prab, Risen, Sarah R., Schiffmann, Raphael, Soh, Calvin, Stephenson, John B. P., Stewart, Helen, Stone, Jon, Tolmie, John L., van der Knaap, Marjo S., Vieira, Jose P., Vilain, Catheline N., Wakeling, Emma L., Wermenbol, Vanessa, Whitney, Andrea, Lovell, Simon C., Meyer, Stefan, Livingston, John H., Baerlocher, Gabriela M., Black, Graeme C. M., Rice, Gillian I., and Crow, Yanick J.

Abstract

Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous gamma H2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the alpha-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-alpha primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.

Published
2012
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44. Phosphorylation of the Leukemic Oncoprotein EVI1 on Serine 196 Modulates DNA Binding, Transcriptional Repression and Transforming Ability

Author

White, Daniel J., primary, Unwin, Richard D., additional, Bindels, Eric, additional, Pierce, Andrew, additional, Teng, Hsiang-Ying, additional, Muter, Joanne, additional, Greystoke, Brigit, additional, Somerville, Tim D., additional, Griffiths, John, additional, Lovell, Simon, additional, Somervaille, Tim C. P., additional, Delwel, Ruud, additional, Whetton, Anthony D., additional, and Meyer, Stefan, additional

Published
2013
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45. Loss of Endometrial Plasticity in Recurrent Pregnancy Loss.

Author

Lucas, Emma S., Dyer, Nigel P., Murakami, Keisuke, Hou Lee, Yie, Chan, Yi-Wah, Grimaldi, Giulia, Muter, Joanne, Brighton, Paul J., Moore, Jonathan D., Patel, Gnyaneshwari, Chan, Jerry K.Y., Takeda, Satoru, Lam, Eric W-F., Quenby, Siobhan, Ott, Sascha, and Brosens, Jan J.

Subjects
MENSTRUATION, HUMAN reproduction, STROMAL cells
Abstract

Menstruation drives cyclic activation of endometrial progenitor cells, tissue regeneration, and maturation of stromal cells, which differentiate into specialized decidual cells prior to and during pregnancy. Aberrant responsiveness of human endometrial stromal cells (HESCs) to deciduogenic cues is strongly associated with recurrent pregnancy loss (RPL), suggesting a defect in cellular maturation. MeDIP-seq analysis of HESCs did not reveal gross perturbations in CpG methylation in RPL cultures, although quantitative differences were observed in or near genes that are frequently deregulated in vivo. However, RPL was associated with a marked reduction in methylation of defined CA-rich motifs located throughout the genome but enriched near telomeres. Non-CpG methylation is a hallmark of cellular multipotency. Congruently, we demonstrate that RPL is associated with a deficiency in endometrial clonogenic cell populations. Loss of epigenetic stemness features also correlated with intragenic CpG hypomethylation and reduced expression of HMGB2, coding high mobility group protein 2. We show that knockdown of this sequence-independent chromatin protein in HESCs promotes senescence and impairs decidualization, exemplified by blunted time-dependent secretome changes. Our findings indicate that stem cell deficiency and accelerated stromal senescence limit the differentiation capacity of the endometrium and predispose for pregnancy failure. S tem C ells 2016;34:346-356 [ABSTRACT FROM AUTHOR]

Published
2016
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46. Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

Author

Anderson, Beverley H, primary, Kasher, Paul R, additional, Mayer, Josephine, additional, Szynkiewicz, Marcin, additional, Jenkinson, Emma M, additional, Bhaskar, Sanjeev S, additional, Urquhart, Jill E, additional, Daly, Sarah B, additional, Dickerson, Jonathan E, additional, O'Sullivan, James, additional, Leibundgut, Elisabeth Oppliger, additional, Muter, Joanne, additional, Abdel-Salem, Ghada M H, additional, Babul-Hirji, Riyana, additional, Baxter, Peter, additional, Berger, Andrea, additional, Bonafé, Luisa, additional, Brunstom-Hernandez, Janice E, additional, Buckard, Johannes A, additional, Chitayat, David, additional, Chong, Wui K, additional, Cordelli, Duccio M, additional, Ferreira, Patrick, additional, Fluss, Joel, additional, Forrest, Ewan H, additional, Franzoni, Emilio, additional, Garone, Caterina, additional, Hammans, Simon R, additional, Houge, Gunnar, additional, Hughes, Imelda, additional, Jacquemont, Sebastien, additional, Jeannet, Pierre-Yves, additional, Jefferson, Rosalind J, additional, Kumar, Ram, additional, Kutschke, Georg, additional, Lundberg, Staffan, additional, Lourenço, Charles M, additional, Mehta, Ramesh, additional, Naidu, Sakkubai, additional, Nischal, Ken K, additional, Nunes, Luís, additional, Õunap, Katrin, additional, Philippart, Michel, additional, Prabhakar, Prab, additional, Risen, Sarah R, additional, Schiffmann, Raphael, additional, Soh, Calvin, additional, Stephenson, John B P, additional, Stewart, Helen, additional, Stone, Jon, additional, Tolmie, John L, additional, van der Knaap, Marjo S, additional, Vieira, Jose P, additional, Vilain, Catheline N, additional, Wakeling, Emma L, additional, Wermenbol, Vanessa, additional, Whitney, Andrea, additional, Lovell, Simon C, additional, Meyer, Stefan, additional, Livingston, John H, additional, Baerlocher, Gabriela M, additional, Black, Graeme C M, additional, Rice, Gillian I, additional, and Crow, Yanick J, additional

Published
2012
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48. Uncoupling of circadian and other maternal cues in decidualizing endometrial cells

Author

Muter, Joanne

Subjects
QM, RJ
Abstract

The differentiation of human endometrial stromal cells (HESCs) into specialised decidual cells prepares the endometrium for embryonic implantation. The biochemical and morphological transformation of these cells is highly temporally regulated in order to define a transient period of endometrial receptivity. Currently, the involvement of circadian machinery, and clock dependent pathways in this process are not fully understood. Firstly, analysis of circadian rhythms in HESCs revealed a consistent loss of oscillations in clock components upon decidualization. Down-regulation of Period 2 (PER2) expression, apparent in the early stages of differentiation, was shown to be sufficient to cause this aperiodicity. In turn, temporal suppression of PER2 expression was achieved via reduced CLOCK binding to a non-canonical Ebox enhancer in the PER2 promoter. RNA sequencing analysis upon premature PER2 knockdown revealed a disorganised decidual phenotype in which cell cycle and mitotic regulators were perturbed. As such, PER2 acts to uncouple the endometrium from circadian oscillations during decidualization.\ud \ud Secondly, the gene PRIP-1 was shown to be PER2 dependent in undifferentiated HESCs. Endometrial expression of PRIP-1 was induced and maintained upon decidualization by the post-ovulatory rise in progesterone. Analysis of Ca2+ fluxes demonstrated the ability of PRIP-1 to act as a chelator of IP3 signalling. Additionally, PRIP-1, via its regulation of the AKT pathway, is shown to be an anti-apoptotic regulator in decidual HESCs. Together, these results indicate PRIP-1 functions as a molecular switch in response to progesterone signalling. High PRIP-1 levels during differentiation enable AKT and IP3 mediated cell survival, whilst declining levels upon P4 withdrawal leads to decidual apoptosis.\ud \ud In summary, I provide a novel paradigm whereby both PER2 and PRIP-1 act to uncouple the endometrium from various signalling inputs, enabling an autonomous decidual response. Asynchrony in these pathways can lead to a cascade of events resulting in an array of adverse pregnancy complications.

49. The endoplasmic reticulum protein HSPA5/BiP is essential for decidual transformation of human endometrial stromal cells.

Author

Fernández L, Kong CS, Alkhoury M, Tryfonos M, Brighton PJ, Rawlings TM, Muter J, Gori MS, Leirós CP, Lucas ES, Brosens JJ, and Ramhorst R

Subjects
Humans, Female, Cellular Senescence, Cell Differentiation, Cells, Cultured, Gene Knockdown Techniques, Adult, Endoplasmic Reticulum metabolism, Endoplasmic Reticulum Chaperone BiP metabolism, Stromal Cells metabolism, Decidua metabolism, Decidua cytology, Heat-Shock Proteins metabolism, Heat-Shock Proteins genetics, Endoplasmic Reticulum Stress, Endometrium metabolism, Endometrium cytology
Abstract

Decidualization denotes the process of inflammatory reprogramming of endometrial stromal cells (EnSC) into specialized decidual cells (DC). During this process, EnSC are subjected to endoplasmic reticulum (ER) stress as well as acute cellular senescence. Both processes contribute to the proinflammatory mid-luteal implantation window and their dysregulation has been implicated in reproductive failure. Here, we evaluated the link between ER stress, decidual differentiation and senescence. In-silico analysis identified HSPA5 gene, codifying the ER chaperone BiP, as a potentially critical regulator of cell fate divergence of decidualizing EnSC into anti-inflammatory DC and pro-inflammatory senescent decidual cells (snDC). Knockdown of HSPA5 in primary EnSC resulted both in decreased expression of DC marker genes and attenuated induction of senescence associated β-galactosidase activity, a marker of snDC. Stalling of the decidual reaction upon HSPA5 knockdown was apparent at 8 days of differentiation and was preceded by the upregulation of ER stress associated proteins IRE1α and PERK. Further, HSPA5 knockdown impaired colony-forming unit activity of primary EnSC, indicative of loss of cellular plasticity. Together, our results point to a key role for HSPA5/BiP in decidual transformation of EnSCs and highlight the importance of constraining ER stress levels during this process., (© 2024. The Author(s).)

Published
2024
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