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

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

doi:10.1101/368829

Cited by 43 publications

(145 citation statements)

References 77 publications

Supporting

Mentioning

141

Contrasting

Unclassified

Order By: Relevance

“…Explorative investigations indicated that the increase in eMSC in response to sitagliptin is biologically meaningful and associated with a significant reduction in senescent decidual cells. This conclusion is based on expression analysis of DIO2 and SCARA5, which are marker genes of decidual cells and senescent decidual cells, respectively [26]. DIO2 encodes iodothyronine deiodinase 2, which catalyses the conversion of prohormone thyroxine (T4) into bioactive triiodothyronine (T3).…”

Section: Discussionmentioning

confidence: 99%

“…However, these marker genes do not discriminate between decidual cells and senescent decidual cells [26]. By contrast, SCARA5 and DIO2 are marker genes of decidual cells and senescent decidual cells, respectively, both in vitro and in vivo [26]. PRL and IGFBP1 transcript levels were not significantly different in the second biopsy compared to the baseline biopsy in either the placebo or treatment group (Suppl.…”

Section: Explorative Investigations: Oral Sitagliptin Inhibits Decidumentioning

confidence: 97%

“…Induction of PRL and IGFBP1 expression is widely used to monitor the decidual response in cultured EnSC [12]. However, these marker genes do not discriminate between decidual cells and senescent decidual cells [26]. By contrast, SCARA5 and DIO2 are marker genes of decidual cells and senescent decidual cells, respectively, both in vitro and in vivo [26].…”

Section: Explorative Investigations: Oral Sitagliptin Inhibits Decidumentioning

confidence: 99%

“…Further, we demonstrated that decidual cells orchestrate the elimination of their senescent counterparts by secreting factors, such as interleukin 15 (IL-15) and C-X-C motif chemokine ligand 14 (CXCL14), involved in recruitment and activation of uterine NK cells [11], de facto curtailing tissue inflammation and facilitating transformation of the stroma into the decidua of pregnancy. Based on marker genes of decidual subsets identified by high-throughput single-cell RNAsequencing, we demonstrated that the midluteal endometrium in RPL is associated not only with eMSC deficiency but also excessive decidual senescence [26], an imbalance that arguably predisposes to the formation of a proinflammatory and intrinsically unstable placental-decidual interface in pregnancy.…”

Section: Introductionmentioning

confidence: 99%

“…Decidual cells but not senescent decidual cells are dependant on continuous progesterone signalling [26]. Consequently, in the absence of embryo implantation, falling ovarian progesterone production leads to a preponderance of senescent cells and activation of a cascade of events that result in tissue breakdown, bleeding and menstrual shedding of the superficial endometrial layer [27,28].…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background: Recurrent pregnancy loss (RPL) is associated with the loss of endometrial mesenchymal stem-like progenitor cells (eMSC). DPP4 inhibitors may increase homing and engraftment of bone marrow-derived cells to sites of tissue injury. Here, we evaluated the effect of the DPP4 inhibitor sitagliptin on eMSC in women with RPL, determined the impact on endometrial decidualization, and assessed the feasibility of a full-scale clinical trial. Methods: A double-blind, randomised, placebo-controlled feasibility trial on women aged 18 to 42 years with a history of 3 or more miscarriages, regular menstrual cycles, and no contraindications to sitagliptin. Thirtyeight subjects were randomised to either 100 mg sitagliptin daily for 3 consecutive cycles or identical placebo capsules. Computer generated, permuted block randomisation was used to allocate treatment packs. Colony forming unit (CFU) assays were used to quantify eMSC in midluteal endometrial biopsies. The primary outcome measure was CFU counts. Secondary outcome measures were endometrial thickness, study acceptability, and first pregnancy outcome within 12 months following the study. Tissue samples were subjected to explorative investigations. Findings: CFU counts following sitagliptin were higher compared to placebo only when adjusted for baseline CFU counts and age (RR: 1.52, 95% CI: 1.32À1.75, P<0.01). The change in CFU count was 1.68 in the sitagliptin group and 1.08 in the placebo group. Trial recruitment, acceptability, and drug compliance were high. There were no serious adverse events. Explorative investigations showed that sitagliptin inhibits the expression of DIO2, a marker gene of senescent decidual cells. Interpretation: Sitagliptin increases eMSCs and decreases decidual senescence. A large-scale clinical trial evaluating the impact of preconception sitagliptin treatment on pregnancy outcome in RPL is feasible and warranted. Funding: Tommy's Baby Charity.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Explorative Investigations: Oral Sitagliptin Inhibits Decidumentioning

confidence: 97%

Section: Explorative Investigations: Oral Sitagliptin Inhibits Decidumentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

Antiphospholipid Antibodies Increase Endometrial Stromal Cell Decidualization, Senescence, and Inflammation via Toll‐like Receptor 4, Reactive Oxygen Species, and p38 MAPK Signaling

Tong

Kayani

Jones

et al. 2022

Arthritis & Rheumatology

View full text Add to dashboard Cite

Objective Miscarriage affects 1 in 7 pregnancies, and antiphospholipid autoantibodies (aPLs) are one of the biggest risk factors for recurrent pregnancy loss. While aPLs target the endometrial stroma, little is known about their impact. Endometrial stromal cells (EnSCs) undergo decidualization each menstrual cycle, priming the uterus to receive implanting embryos. Thus, appropriate decidualization and EnSC function is key for establishment of a successful pregnancy. This study was undertaken to explore the effects of aPL on EnSC decidualization, senescence, and inflammation. Methods EnSCs under decidualizing conditions were exposed to aPL or control IgG alone or in the presence of either a Toll‐like receptor 4 (TLR‐4) antagonist, a p38 MAPK inhibitor, a reactive oxygen species (ROS) inhibitor, low molecular weight heparin (LMWH), or acetyl salicylic acid. Secretion of decidualization markers and inflammatory interleukin‐8 were quantified by enzyme‐linked immunosorbent assay, and senescence‐associated β‐galactosidase activity was evaluated. In a mouse model of decidualization, aPL or control IgG was administered, and uterine expression levels of decidualization and inflammatory markers were quantified by real‐time quantitative polymerase chain reaction. Results Antiphospholipid antibodies increased human EnSC decidualization, senescence, and inflammation. This phenotype was recapitulated in the mouse model. The decidualization and inflammatory responses were partially mediated by TLR‐4 and p38 MAPK, while the decidualization and senescence responses were ROS‐dependent. LMWH, commonly used to treat aPL‐positive women at risk of obstetric complications, reduced the ability of aPL to increase EnSC decidualization and inflammation. Conclusion These findings shed new light on the pathogenesis of pregnancy complications in women with aPLs and underscore the benefit of heparin in preventing pregnancy loss in this high‐risk population.

show abstract

Characterization of Highly Proliferative Decidual Precursor Cells During the Window of Implantation in Human Endometrium

et al. 2021

Self Cite

View full text Add to dashboard Cite

Pregnancy depends on the wholesale transformation of the endometrium, a process driven by differentiation of endometrial stromal cells (EnSC) into specialist decidual cells. Upon embryo implantation, decidual cells impart the tissue plasticity needed to accommodate a rapidly growing conceptus and invading placenta, although the underlying mechanisms are unclear. Here we characterize a discrete population of highly proliferative mesenchymal cells (hPMC) in midluteal human endometrium, coinciding with the window of embryo implantation. Single-cell transcriptomics demonstrated that hPMC express genes involved in chemotaxis and vascular transmigration. Although distinct from resident EnSC, hPMC also express genes encoding pivotal decidual transcription factors and markers, most prominently prolactin. We further show that hPMC are enriched around spiral arterioles, scattered throughout the stroma, and occasionally present in glandular and luminal epithelium. The abundance of hPMC correlated with the in vitro colony-forming unit activity of midluteal endometrium and, conversely, clonogenic cells in culture express a gene signature partially conserved in hPMC. Cross-referencing of single-cell RNA-sequencing data sets indicated that hPMC differentiate into a recently discovered decidual subpopulation in early pregnancy. Finally, we demonstrate that recurrent pregnancy loss is associated with hPMC depletion. Collectively, our findings characterize midluteal hPMC as novel decidual precursors that are likely derived from circulating bone marrow-derived mesenchymal stem/stromal cells and integral to decidual plasticity in pregnancy.

show abstract

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

Cited by 43 publications

References 77 publications

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

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

Antiphospholipid Antibodies Increase Endometrial Stromal Cell Decidualization, Senescence, and Inflammation via Toll‐like Receptor 4, Reactive Oxygen Species, and p38 MAPK Signaling

Characterization of Highly Proliferative Decidual Precursor Cells During the Window of Implantation in Human Endometrium

Contact Info

Product

Resources

About