scholarly journals Menin directs regionalized decidual transformation through epigenetically setting PTX3 as an obstacle balancing FGF and BMP signaling

2021 ◽  
Author(s):  
Haibin Wang ◽  
Mengying Liu ◽  
Wenbo Deng ◽  
Lu Tang ◽  
Meng Liu ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Stromal Cell ◽  
Terminal Differentiation ◽  
Underlying Mechanism ◽  
Bmp Signaling ◽  
Dependent Manner ◽  
Pregnancy Failure ◽  
Genome Wide ◽  
Decidual Cells ◽  
In Pregnancy

Abstract During programmed decidualization in rodents, uterine stromal cells undergo extensive cellular and molecular reprograming into morphologically and functionally distinct decidual cells, forming the discrete regions defined as the primary decidual zone (PDZ), the secondary decidual zone (SDZ) and the layer of undifferentiated stromal cells respectively. However, the underlying mechanism governing this spatiotemporal specificity of decidualization remains elusive. Here, we demonstrated that uterine deletion of Men1, a key component of the MLL1/2 histone methyltransferase complex, disrupted the terminal differentiation of stromal cells, resulting in chaotic decidualization and pregnancy failure. Genome-wide epigenetic profile reveals that Men1 distribution in chromatin recapitulates the enrichment of transcription active modification H3K4me3 orchestrating spatiotemporal decidualization of stromal cells. Further transcriptomic investigation demonstrates that Men1 directly regulated the expression of PTX3, an extra-cellular trap for FGF2, in a H3K4me3 dependent manner in decidual cells. Decreased Ptx3 upon Men1 ablation leads to aberrant activation of ERK1/2 in the SDZ due to the unrestrained FGF2 signal emanated from undifferentiated stromal cells, which blunt BMP2 induction and stromal cell differentiation during decidualization. In brief, our study provides genetic evidence and molecular mechanism for epigenetic rewiring mediated decidual regionalization by Men1 and shed new light in pregnancy maintenance.

scholarly journals Oxytocin Inhibits T-Type Calcium Current of Human Decidual Stromal Cells

2005 ◽  
Vol 90 (7) ◽  
pp. 4191-4197 ◽  
Author(s):  
Bo Liu ◽  
Stephen J. Hill ◽  
Raheela N. Khan
Keyword(s):  
Stromal Cells ◽  
Calcium Current ◽  
Elective Cesarean Section ◽  
Dependent Manner ◽  
Uterine Contractility ◽  
Patch Clamp Technique ◽  
Concentration Dependent Manner ◽  
Inactivation Curve ◽  
Decidual Cells ◽  
Elective Cesarean

Abstract Context: Little is known about the crosstalk between the decidua and myometrium in relation to human labor. The hormone oxytocin (OT) is considered to be a key mediator of uterine contractility during parturition, exerting some of its effects through calcium channels. Objective: The objective was to characterize the effect of OT on the T-type calcium channel in human decidual stromal cells before and after the onset of labor. Design: The nystatin-perforated patch-clamp technique was used to record inward T-type calcium current (ICa(T)) from acutely dispersed decidual stromal cells obtained from women at either elective cesarean section [CS (nonlabor)] or after normal spontaneous vaginal delivery [SVD (labor)]. Setting: These studies took place at the University of Nottingham Medical School. Results: I Ca(T) of both SVD and CS cells were blocked by nickel (IC50 of 5.6 μm) and cobalt chloride (1 mm) but unaffected by nifedipine (10 μm). OT (1 nm to 3.5 μm) inhibited ICa(T) of SVD cells in a concentration-dependent manner, with a maximal inhibition of 79.0% compared with 26.2% in decidual cells of the CS group. OT-evoked reduction of ICa(T) was prevented by preincubation with the OT antagonist L371,257 in the SVD but not CS group. OT, in a concentration-dependent manner, displaced the steady-state inactivation curve for ICa(T) to the left in the SVD group with no significant effect on curves of the CS group. Conclusion: Inhibition of ICa(T) by OT in decidual cells obtained during labor may signify important functional remodeling of uterine signaling during this period.

scholarly journals The Role of Interleukin-11 in Pregnancy Involves Up-Regulation of α2-Macroglobulin Gene through Janus Kinase 2-Signal Transducer and Activator of Transcription 3 Pathway in the Decidua

2006 ◽  
Vol 20 (12) ◽  
pp. 3240-3250 ◽  
Author(s):  
Lei Bao ◽  
Sangeeta Devi ◽  
Jennifer Bowen-Shauver ◽  
Susan Ferguson-Gottschall ◽  
Lorraine Robb ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Janus Kinase ◽  
Abnormal Development ◽  
Trophoblast Invasion ◽  
Signal Transducer ◽  
Janus Kinase 2 ◽  
Double Mutation ◽  
Α2 Macroglobulin ◽  
Decidual Cells ◽  
In Pregnancy

Abstract IL-11 expressed by endometrial stromal cells is crucial for normal pregnancy. IL-11 receptor α (IL-11Rα) null mice are infertile due to abnormal development of the placenta. In these mice, the mesometrial decidual tissue, which is the site of trophoblast invasion, thins and disappears at mid-pregnancy. Degeneration of the decidua is accompanied by uncontrolled trophoblast invasion. In this report, we show, using IL-11Rα null mice, that a defect in IL-11 signaling in the decidua leads to severe down-regulation of α2-macroglobulin (α2-MG), a metalloproteinase inhibitor crucial for limiting trophoblast invasion. We also present evidence, using uterine stromal cells that decidualize in culture, that IL-11 robustly stimulates the endogenous α2-MG expression and enhances α2-MG promoter activity. Serial 5′ deletion and internal deletion of the promoter reveal two important signal transducer and activator of transcription (Stat) binding sites. Mutation of either one of these motifs decreases IL-11 stimulation, whereas double mutation prevents IL-11 action. We also found that IL-11 activates Janus kinase 2 (Jak2) and induces rapid phosphorylation, nuclear translocation, and promoter binding activity of Stat3 in decidual cells, whereas Jak1, Tyk2, and Stat5 activities are not affected. In addition, Jak2 inhibitor totally prevents α2-MG expression in decidual cells. Taken together, results of this investigation provide, at least in part, an explanation for the overinvasiveness of the trophoblast in IL-11Rα null mice and reveal, for the first time, that IL-11 signals through the Jak2/Stat3 pathway in decidual cells to stimulate the expression of α2-MG, a protease inhibitor essential for normal placentation in pregnancy.

scholarly journals The Role of Pannexin3-Modified Human Dental Pulp-Derived Mesenchymal Stromal Cells in Repairing Rat Cranial Critical-Sized Bone Defects

2017 ◽  
Vol 44 (6) ◽  
pp. 2174-2188 ◽  
Author(s):  
Fangfang Song ◽  
Hualing Sun ◽  
Liyuan Huang ◽  
Dongjie Fu ◽  
Cui Huang
Keyword(s):  
Osteogenic Differentiation ◽  
Signaling Pathway ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Dental Pulp ◽  
Underlying Mechanism ◽  
Bone Defects ◽  
Dependent Manner ◽  
Alizarin Red ◽  
Human Dental Pulp

Background/Aims: Human dental pulp-derived mesenchymal stromal cells (hDPSCs) are promising seed cells for tissue engineering due to their easy accessibility and multi-lineage differentiation. Pannexin3 (Panx3) plays crucial roles during bone development and differentiation. The aim of the present study was to investigate the effect of Panx3 on osteogenesis of hDPSCs and the underlying mechanism. Methods: Utilizing qRT-PCR, Western blot, and immunohistochemistry, we explored the change of Panx3 during osteogenic differentiation of hDPSCs. Next, hDPSCs with loss (Panx3 knockdown) and gain (Panx3 overexpression) of Panx3 function were developed to investigate the effects of Panx3 on osteogenic differentiation of hDPSC and the underlying mechanism. Finally, a commercial β-TCP scaffold carrying Panx3-modified hDPSCs was utilized to evaluate bone defect repair. Results: Panx3 was upregulated during osteogenic differentiation in a time-dependent manner. Panx3 overexpression promoted osteogenic differentiation of hDPSCs, whereas depletion of Panx3 resulted in a decline of differentiation, evidenced by upregulated expression of mineralization-related markers, increased alkaline phosphatase (ALP) activity, and enhanced ALP and Alizarin red staining. Panx3 was found to interact with the Wnt/β-catenin signaling pathway, forming a negative feedback loop. However, Wnt/β-catenin did not contribute to enhancement of osteogenic differentiation as observed in Panx3 overexpression. Moreover, Panx3 promoted osteogenic differentiation of hDPSCs via increasing ERK signaling pathway. Micro-CT and histological staining results showed that Panx3-modified hDPSCs significantly improved ossification of critical-sized bone defects. Conclusion: These findings suggest that Panx3 is a crucial modulator of hDPSCs differentiation.

scholarly journals Cyclin G1 inhibits the proliferation of mouse endometrial stromal cell in decidualization

2017 ◽  
Vol 69 (1) ◽  
pp. 71-81
Author(s):  
Qian Xu ◽  
Dong-zhi Yuan ◽  
Sheng Zhang ◽  
Ting Qu ◽  
Shi-mao Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Embryo Implantation ◽  
Negative Regulator ◽  
Cell Cycle Regulators ◽  
Cyclin G1 ◽  
Decidual Cells

Uterine stromal cell decidualization is a dynamic physiological process in which cell proliferation, differentiation and apoptosis are orchestrated and occur in a temporal and cell-specific manner. This process is important for successful embryo implantation. Many cell-cycle regulators are involved in decidualization. The protein cyclin G1 is a unique regulator of the cell cycle with dual functions in cell proliferation. It was reported that cyclin G1 is expressed in mouse uterine stromal cells during the period of peri-implantation. To prove the function of cyclin G1 in mouse uterine stromal cells during this period, immunohistochemistry was used to stain mouse uterine tissues on days 4-8 of pregnancy. The results showed obvious spatial and temporal expression of cyclin G1 in uterine stromal cells, and that it is expressed in the cells of the primary decidual zone (PDZ) on day 5 and secondary decidual zone (SDZ) on days 6 and 7, when the stromal cells experienced active proliferation and differentiation was initiated. Applying the decidualization model of cultured primary stromal cells in vitro, we further revealed that the expression of cyclin G1 is associated with decidualization of stromal cells induced by medroxyprogesterone acetate (MPA) and estradiol-17? (E2). RNA interference was used for the knockdown of cyclin G1 in the induced decidual cells. Flow cytometry analysis indicated that the proportion of cells in the S stage was increased, and decreased in the G2/M phase. Our study indicates that cyclin G1, as a negative regulator of the cell cycle, plays an important role in the process of decidualization in mouse uterine stromal cells by inhibiting cell-cycle progression.

DHT and testosterone, but not DHEA or E2, differentially modulate IGF-I, IGFBP-2, and IGFBP-3 in human prostatic stromal cells

2006 ◽  
Vol 290 (5) ◽  
pp. E952-E960 ◽  
Author(s):  
Hanh Le ◽  
Julia T. Arnold ◽  
Kimberly K. McFann ◽  
Marc R. Blackman
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Mrna Expression ◽  
Protein Secretion ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Time Dependent ◽  
Dependent Manner ◽  
Igf I ◽  
Igfbp 3

Prostate cancer is one of the four most common cancers in the United States, affecting one of six men. Increased serum levels of androgens and IGF-I are associated with an augmented risk of prostate cancer. Dihydrotestosterone (DHT) and testosterone (T) stimulate prostate cancer cell growth, development, and function, whereas the effects of DHT and T in prostate stromal cells, and of dehydroepiandrosterone (DHEA) in prostate cancer or stromal cells, are uncertain. We investigated the actions of DHT, T, DHEA, and estradiol (E2) on insulin-like growth factor (IGF)-I, IGF-II, IGF-I receptor (R), IGF-binding protein (IGFBP)-2, IGFBP-3, and IGFBP-5 in primary cultures of human prostatic stromal cells by assessing cell proliferation, mRNA expression, and protein secretion by MTT growth assay, quantitative real-time PCR, and ELISA, respectively. DHT and T each increased IGF-I (7-fold) and decreased IGFBP-3 (2-fold) mRNA expression and protein secretion in a dose- and time-dependent manner and increased IGFBP-2 (2-fold) mRNA in a dose- and time-dependent manner. DHEA and E2did not significantly alter these measures. Flutamide abolished the DHT-modulated increases in IGF-I and IGFBP-2, suggesting that the influences of DHT and T on these measures were androgen receptor mediated. None of the four steroids significantly affected IGF-IR, IGF-II, or IGFBP-5 mRNA levels or stromal cell proliferation. The effects of DHT on IGF-I, IGFBP-2, and IGFBP-3 were more pronounced in stromal cultures that did not express desmin. These data suggest that DHT and T promote prostate growth partly via modulation of the stromal cell IGF axis, with potential paracrine effects on prostate epithelial cells.

scholarly journals Mesenchymal-Stromal Cell-like Melanoma-Associated Fibroblasts Increase IL-10 Production by Macrophages in a Cyclooxygenase/Indoleamine 2,3-Dioxygenase-Dependent Manner

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6173
Author(s):  
Uğur Çakır ◽  
Anna Hajdara ◽  
Balázs Széky ◽  
Balázs Mayer ◽  
Sarolta Kárpáti ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Mesenchymal Stromal Cell ◽  
Stromal Cell ◽  
Tumor Stroma ◽  
Melanoma Cells ◽  
Dependent Manner ◽  
Intimate Contact ◽  
Indoleamine 2,3 Dioxygenase ◽  
Treatment Naïve

Melanoma-associated fibroblasts (MAFs) are integral parts of melanoma, providing a protective network for melanoma cells. The phenotypical and functional similarities between MAFs and mesenchymal stromal cells (MSCs) prompted us to investigate if, similarly to MSCs, MAFs are capable of modulating macrophage functions. Using immunohistochemistry, we showed that MAFs and macrophages are in intimate contact within the tumor stroma. We then demonstrated that MAFs indeed are potent inducers of IL-10 production in various macrophage types in vitro, and this process is greatly augmented by the presence of treatment-naïve and chemotherapy-treated melanoma cells. MAFs derived from thick melanomas appear to be more immunosuppressive than those cultured from thin melanomas. The IL-10 increasing effect is mediated, at least in part, by cyclooxygenase and indoleamine 2,3-dioxygenase. Our data indicate that MAF-induced IL-10 production in macrophages may contribute to melanoma aggressiveness, and targeting the cyclooxygenase and indoleamine 2,3-dioxygenase pathways may abolish MAF–macrophage interactions.

scholarly journals Interleukin 11 Signaling Components Signal Transducer and Activator of Transcription 3 (STAT3) and Suppressor of Cytokine Signaling 3 (SOCS3) Regulate Human Endometrial Stromal Cell Differentiation

Endocrinology ◽  
2006 ◽  
Vol 147 (8) ◽  
pp. 3809-3817 ◽  
Author(s):  
Evdokia Dimitriadis ◽  
Chelsea Stoikos ◽  
Yee-Lee Tan ◽  
Lois A. Salamonsen
Keyword(s):  
Stromal Cells ◽  
Stromal Cell ◽  
Ex Vivo ◽  
Cytokine Signaling ◽  
Endometrial Stromal Cell ◽  
Ex Vivo Model ◽  
Human Endometrial Stromal Cell ◽  
Decidual Cells ◽  
Signaling Components ◽  
Socs3 Mrna

The differentiation of endometrial stromal cells into decidual cells (decidualization) is critical for embryo implantation, but the mechanisms remain poorly defined. Numerous paracrine agents including IL-11 promote human endometrial stromal cell (HESC) decidualization. IL-11 signaling is transduced by the signal transducers and activators of transcription (STAT) proteins. Suppressors of cytokine signaling (SOCS) proteins are stimulated in response to cytokine-inducible STAT phosphorylation, acting in a negative-feedback mechanism to hinder cytokine receptor activity. This study examined the role of IL-11 signal transduction components in HESC decidualization in an ex vivo model. Cells were induced to differentiate with estrogen plus medroxyprogesterone acetate (E+P) or cAMP (assessed by prolactin secretion) and resulted in increased STAT3 and SOCS3. E+P maximally stimulated STAT3, whereas cAMP maximally stimulated SOCS3 during decidualization, suggesting E+P and cAMP differentially regulated the signaling components. IL-11 stimulated the phosphorylation (p) of STAT3 and SOCS3 mRNA and protein. Antiprogestin (onapristone) added to decidualizing cells attenuated STAT3 protein but increased SOCS3 mRNA and protein, suggesting regulation via both ligand-dependent and -independent progesterone-receptor pathways. SOCS3 overexpression in HESC reduced IL-11-induced pSTAT3 and retarded decidualization, indicating that SOCS3 is a critical regulator of differentiation. Immunoreactive pSTAT3 and SOCS3 were all present in decidualized stromal cells, epithelial cells, and leukocytes in human endometrium. These data support a role for IL-11 via pSTAT3 and SOCS3 in initiating and progressing decidualization.

scholarly journals Stromal cell–mediated glycolytic switch in CLL cells involves Notch-c-Myc signaling

Blood ◽  
2015 ◽  
Vol 125 (22) ◽  
pp. 3432-3436 ◽  
Author(s):  
Regina Jitschin ◽  
Martina Braun ◽  
Mirjeta Qorraj ◽  
Domenica Saul ◽  
Katarina Le Blanc ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Glucose Metabolism ◽  
Signaling Pathway ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Dependent Manner ◽  
Key Points

Key Points Stromal cells promote a glycolytic switch in CLL cells in a Notch-c-Myc signaling-dependent manner. Targeting glucose metabolism or the Notch-c-Myc signaling pathway could be exploited to breach stromal cell–mediated CLL drug resistance.

scholarly journals Ionizing radiation–induced expression of INK4a/ARF in murine bone marrow–derived stromal cell populations interferes with bone marrow homeostasis

Blood ◽  
2012 ◽  
Vol 119 (3) ◽  
pp. 717-726 ◽  
Author(s):  
Cynthia L. Carbonneau ◽  
Geneviève Despars ◽  
Shanti Rojas-Sutterlin ◽  
Audrey Fortin ◽  
Oanh Le ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Ionizing Radiation ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Cell Populations ◽  
Dependent Manner ◽  
Murine Bone Marrow ◽  
Genetic Manipulations ◽  
Residual Damage ◽  
Radiation Induced

Abstract Alterations of the BM microenvironment have been shown to occur after chemoradiotherapy, during aging, and after genetic manipulations of telomere length. Nevertheless, whether BM stromal cells adopt senescent features in response to these events is unknown. In the present study, we provide evidence that exposure to ionizing radiation (IR) leads murine stromal BM cells to express senescence markers, namely senescence-associated β-galactosidase and increased p16INK4a/p19ARF expression. Long (8 weeks) after exposure of mice to IR, we observed a reduction in the number of stromal cells derived from BM aspirates, an effect that we found to be absent in irradiated Ink4a/arf-knockout mice and to be mostly independent of the CFU potential of the stroma. Such a reduction in the number of BM stromal cells was specific, because stromal cells isolated from collagenase-treated bones were not reduced after IR. Surprisingly, we found that exposure to IR leads to a cellular nonautonomous and Ink4a/arf-dependent effect on lymphopoiesis. Overall, our results reveal the distinct sensitivity of BM stromal cell populations to IR and suggest that long-term residual damage to the BM microenvironment can influence hematopoiesis in an Ink4a/arf-dependent manner.

scholarly journals Interleukin (IL)-1β Regulation of IL-1β and IL-1 Receptor Antagonist Expression in Cultured Human Endometrial Stromal Cells1

2001 ◽  
Vol 86 (3) ◽  
pp. 1387-1393 ◽  
Author(s):  
Hong-Yuan Huang ◽  
Yan Wen ◽  
Jan S. Kruessel ◽  
Francisco Raga ◽  
Yung-Kuei Soong ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Internal Standard ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Cellular Interactions ◽  
Intracellular Protein ◽  
Protein Levels ◽  
Quantitative Ratio

The interleukin (IL)-1 system is a major regulator of local cellular interactions during embryonic implantation. Because IL-1β and IL receptor antagonist (IL-1ra) are both expressed in human endometrium, we hypothesized that an appropriate ratio of IL-1β to IL-1ra might favor the process of embryo implantation. Therefore, we investigated IL-1 regulation of the quantitative ratio of IL-1β/IL-1ra messenger RNA (mRNA) expression in human endometrial stromal cells using quantitative competitive PCR, as well as intracellular protein expression after stromal cell solubilization. Confluent stromal cell cultures were stimulated with human IL-1β (0–1000 IU/mL) for 24 h. After 24 h, total RNA was extracted, reverse transcribed, and coamplified by PCR with a defined amount of internal standard. The quantitative ratio was determined by the density of target to the internal standard. After culture with IL-1β for 24 and 48 h, stromal cells were solubilized, and the intracellular protein levels of IL-1β and IL-1ra were measured by enzyme-linked immunosorbent assay. The IL-1β and IL-1ra mRNA were both up-regulated, and IL-1R tI mRNA was down-regulated, by IL-1β in a dose-dependent manner. The quantitative ratio of IL-1β to IL-1ra mRNA was constant with the presence of increasing concentrations of IL-1β (1–1000 IU/mL). IL-1β and IL-1ra protein was not detected in conditioned media of cultures before addition of IL-1β. IL-1β and IL-1ra protein levels increased with increasing amounts of IL-1β after solubilization of stromal cells. The IL-1β was detectable after 12 h of culture, in comparison with IL-1ra, which was detectable after 24 h of IL-1β stimulation. These results suggest that IL-1 may play a crucial role in embryo-maternal interaction by regulating stromal cell expression of IL-1β and IL-1ra, resulting in an appropriate ratio during the process of embryonic implantation.

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