scholarly journals Downregulation of Dickkopf-1 Augments the Therapeutic Effects of Endometrial Regenerative Cells on Experimental Colitis

2020 ◽  
Author(s):  
Dingding Yu ◽  
Yiming Zhao ◽  
Yonghao Hu ◽  
Dejun Kong ◽  
Wang Jin ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Tap Water ◽  
Body Weight Loss ◽  
Experimental Colitis ◽  
Underlying Mechanism ◽  
Therapeutic Effects ◽  
Endometrial Regenerative Cells ◽  
Tnf Α ◽  
Regenerative Cells ◽  
Dickkopf 1

Abstract Background We have demonstrated that endometrial regenerative cells (ERCs) are mesenchymal-like stromal cells and can attenuate experimental colitis, however, its underlying mechanism needs further investigation. Dickkopf-1 (DKK1), a glucoprotein secreted by mesenchymal stromal cells (MSCs), is a classical inhibitor of Wnt/β-catenin pathway which is closely associated with the development of colitis. Therefore, the objective of this study was to investigate whether ERCs could also secret DKK1, and whether the downregulation of DKK1 (DKK1 low -ERCs) would enhance the therapeutic effects of ERCs in attenuation of experimental colitis. Methods BALB/c mice were given 3% dextran sodium sulfate (DSS) for 7 consecutive days and free tap water for 3 days sequentially to induce experimental colitis. Unmodified ERCs, IL-1β-treated ERCs (DKK1 low -ERCs) and glucocorticoid-treated ERCs (DKK1 high -ERCs) were injected (1 million/mouse/day, i.v. ) on day 2, 5 and 8 respectively. Colonic and splenic samples were harvested on day 10 after DSS-induction. Results It was found that DKK1 low -ERC treatment markedly attenuated colonic damage, body weight loss and colon-length shortening in colitis mice. Compared with other treatments, cell populations of CD4 + IL-4 + Th2, CD4 + CD25 + FOXP3 + Treg, and CD68 + CD206 + macrophages in spleens were also significantly upregulated in DKK1 low -ERC group ( p < 0.05). In addition, lower expression of pro-inflammatory (TNF-α and IFN-γ), but higher levels of anti-inflammatory cytokines (IL-4 and IL-10) and β-catenin were detected in colons in DKK1 low -ERC group ( p < 0.01 vs. other groups). Conclusions DKK1 low -ERCs display augmented immunoregulatory ability and therapeutic effects in DSS-induced colitis.

scholarly journals Downregulation of Dickkopf-1 Augments the Therapeutic Effects of Endometrial Regenerative Cells on Experimental Colitis

2020 ◽  
Author(s):  
Dingding Yu ◽  
Yiming Zhao ◽  
Yonghao Hu ◽  
Dejun Kong ◽  
Wang Jin ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Tap Water ◽  
Body Weight Loss ◽  
Experimental Colitis ◽  
Underlying Mechanism ◽  
Therapeutic Effects ◽  
Endometrial Regenerative Cells ◽  
Tnf Α ◽  
Regenerative Cells ◽  
Dickkopf 1

Abstract Background We have demonstrated that endometrial regenerative cells (ERCs) are mesenchymal-like stromal cells and can attenuate experimental colitis, however, its underlying mechanism needs further investigation. Dickkopf-1 (DKK1), a glucoprotein secreted by mesenchymal stromal cells (MSCs), is a classical inhibitor of Wnt/β-catenin pathway which is closely associated with the development of colitis. Therefore, the objective of this study was to investigate whether ERCs could also secret DKK1, and whether the downregulation of DKK1 (DKK1low-ERCs) would enhance the therapeutic effects of ERCs in attenuation of experimental colitis. Methods BALB/c mice were given 3% dextran sodium sulfate (DSS) for 7 consecutive days and free tap water for 3 days sequentially to induce experimental colitis. Unmodified ERCs, IL-1β-treated ERCs (DKK1low-ERCs) and glucocorticoid-treated ERCs (DKK1high-ERCs) were injected (1 million/mouse/day, i.v.) on day 2, 5 and 8 respectively. Colonic and splenic samples were harvested on day 10 after DSS-induction. Results It was found that DKK1low-ERC treatment markedly attenuated colonic damage, body weight loss and colon-length shortening in colitis mice. Compared with other treatments, cell populations of CD4+IL-4+Th2, CD4+CD25+FOXP3+Treg, and CD68+CD206+macrophages in spleens were also significantly upregulated in DKK1low-ERC group (p < 0.05). In addition, lower expression of pro-inflammatory (TNF-α and IFN-γ), but higher levels of anti-inflammatory cytokines (IL-4 and IL-10) and β-catenin were detected in colons in DKK1low-ERC group (p < 0.01 vs. other groups). Conclusions DKK1low-ERCs display augmented immunoregulatory ability and therapeutic effects in DSS-induced colitis.

scholarly journals IL-1β pre-stimulation enhances the therapeutic effects of endometrial regenerative cells on experimental colitis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Dingding Yu ◽  
Yiming Zhao ◽  
Hongda Wang ◽  
Dejun Kong ◽  
Wang Jin ◽  
...  
Keyword(s):  
Tap Water ◽  
Treatment Strategies ◽  
Body Weight Loss ◽  
Experimental Colitis ◽  
Treated Group ◽  
Current Treatment ◽  
Th2 Cells ◽  
Therapeutic Effects ◽  
Endometrial Regenerative Cells ◽  
Regenerative Cells

Abstract Background Ulcerative colitis (UC) is a chronic, relapsing, and non-specific inflammatory bowel disease, and the current treatment strategies were mainly used to relieve symptoms or for maintenance. Endometrial regenerative cells (ERCs) are mesenchymal-like stromal cells and have been demonstrated to alleviate multiple immune-dysregulation diseases. Pro-inflammatory stimuli were reported to enhance the immunosuppressive functions of ERCs, but the mechanism underlined is not fully understood. Here, we have designed this study to investigate the therapeutic effects of IL-1β-primed ERCs in the attenuation of experimental colitis. Methods BALB/c mice were given 3% dextran sodium sulfate (DSS) for 7 consecutive days and free tap water for 3 days sequentially to induce experimental colitis. PBS (200 μL), ERCs, and IL-1β-primed ERCs (10ng/mL, 48 h) were injected (1 million/mouse/day, i.v.) on day 2, 5, and 8, respectively. Colonic and splenic samples were harvested on day 10 after DSS induction. Results It was found that IL-1β-primed ERC treatment markedly attenuated colonic damage, body weight loss, and colon length shortening in colitis mice. Compared with other treatments, cell populations of CD4+IL-4+Th2 cells, CD4+CD25+FOXP3+ regulatory T cells (Tregs), and CD68+CD206+ macrophages in spleens were also significantly upregulated in the IL-1β-primed ERC-treated group (p < 0.05). In addition, lower expression of pro-inflammatory (IFN-γ, IL-17, TNF-α, and IL-6), but higher levels of anti-inflammatory cytokines (IL-4 and IL-10) were detected in colons in the IL-1β-primed ERC-treated group (p < 0.05 vs. other groups). Importantly, we also found that different generations of ERCs had an overall lower secretion of Dickkopf-1 (DKK1) by IL-1β pre-stimulation (p < 0.05) and a higher expression of β-catenin in colonic and splenic tissues after the administration of IL-1β-primed ERCs. Conclusions This study has demonstrated that IL-1β pre-stimulation effectively downregulated DKK1 expression in ERCs, which in turn promoted the wnt/β-catenin pathway activation in colonic and splenic tissues. Consequently, IL-1β-primed ERCs exhibited an enhanced therapeutic effect in the attenuation of DSS-induced colitis.

scholarly journals Stromal Cell-Derived Factor-1 Enhances the Therapeutic Effects of Human Endometrial Regenerative Cells in a Mouse Sepsis Model

2020 ◽  
Vol 2020 ◽  
pp. 1-14 ◽  
Author(s):  
Wang Jin ◽  
Yiming Zhao ◽  
Yonghao Hu ◽  
Dingding Yu ◽  
Xiang Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stromal Cells ◽  
Tissue Damage ◽  
Stromal Cell ◽  
Therapeutic Effects ◽  
Sepsis Model ◽  
Endometrial Regenerative Cells ◽  
Regenerative Cells ◽  
Stromal Cell Derived Factor ◽  
Mouse Sepsis Model

Endometrial regenerative cells (ERCs) are mesenchymal-like stromal cells obtained from human menstrual blood, whose positive therapeutic effects have been validated in several experimental models. Stromal cell-derived factor-1 (SDF-1), the ligand for CXCR4, plays an important role in the migration of mesenchymal stromal cells. The purpose of this study was to investigate the role of the SDF-1/CXCR4 pathway in the therapeutic effects of ERCs in a mouse sepsis model. Through preexperiment and confirmation, wild-type C57BL/6 mice were intraperitoneally injected with 10 mg/kg lipopolysaccharide (LPS). The therapeutic effects of ERCs with different pretreatments were evaluated by assessing sepsis-related symptoms, detecting tissue damage and measuring levels of inflammatory and oxidative stress-related factors. The in vitro experiments demonstrated that there was a much higher CXCR4 expression on ERCs when they were cocultured with SDF-1. The ex vivo experiment results showed that SDF-1 expression significantly increased in mouse tissues. Further experiments also confirmed that, compared with the unmodified ERC treatment group, SDF-1 pretreatment significantly enhanced the therapeutic effects of ERCs on alleviating sepsis symptoms, ameliorating pathological changes, reducing Bax level, and increasing Bcl-2 and PCNA expressions in mouse liver tissues. Furthermore, it was also found that SDF-1-pretreated ERCs contributed to reducing the levels of proinflammatory cytokines (TNF-α, IL-1β) and increasing the levels of anti-inflammatory factors (IL-4, IL10) in mouse serum, liver, and lung. Moreover, SDF-1-pretreated ERCs could also significantly decrease the levels of iNOS and MDA and increase the expression of Nrf2, HO-1, and SOD in liver tissues. Taken together, these results indicate that SDF-1 pretreatment plays a key role in improving the therapeutic effects of ERCs in alleviating sepsis-related symptoms, reducing tissue damage, regulating inflammatory imbalance, and relieving oxidative stress in a mouse sepsis model, which provides more possibilities for the clinical application of ERCs in sepsis and relevant diseases.

scholarly journals Effects of Guchang Capsule on Dextran Sulphate Sodium-Induced Experimental Ulcerative Colitis in Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Baoshan Liu ◽  
Tong Liu ◽  
Xiaohong Wang ◽  
Xin Zheng ◽  
Hong Wang ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Body Weight Loss ◽  
Experimental Colitis ◽  
Intestinal Disease ◽  
Therapeutic Effects ◽  
Dextran Sulphate ◽  
Chinese Materia Medica ◽  
Dextran Sulphate Sodium ◽  
Underlying Mechanisms

Guchang capsule (GC) is a Chinese materia medica standardized product extracted from 15 Chinese traditional medical herbs and it has been clinically used in the treatment of intestinal disease. In this study, in order to extend the research of GC in intestinal disease, we were aiming to evaluate potential effects of GC on dextran sulphate sodium- (DSS-) induced murine experimental colitis and to elucidate the underlying mechanisms. GC treatment attenuated DSS-induced body weight loss and reduced the mortality. Moreover, GC treatment prevented DSS-induced colonic pathological damage; meanwhile it inhibited proinflammatory cytokines production in colon tissues.In vitro, GC significantly reduced LPS-induced proinflammatory cytokines production via inhibiting the activation of NF-κB in macrophage cells, and the expressions of several long noncoding RNAs (lncRNAs) which were reported in regulating NF-κB signaling pathway were obviously affected by adding GC into culture medium. In conclusion, our data suggested that administration of GC exhibits therapeutic effects on DSS-induced colitis partially through regulating the expression of NF-κB related lncRNAs in infiltrating immune cells.

scholarly journals Endometrial regenerative cells as a novel cell therapy attenuate experimental colitis in mice

2014 ◽  
Vol 12 (1) ◽  
Author(s):  
Yongcheng Lv ◽  
Xiaoxi Xu ◽  
Bai Zhang ◽  
Guangying Zhou ◽  
Hongyue Li ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Experimental Colitis ◽  
Endometrial Regenerative Cells ◽  
Regenerative Cells

scholarly journals Comparison of endometrial regenerative cells and bone marrow stromal cells

2012 ◽  
Vol 10 (1) ◽  
pp. 207 ◽  
Author(s):  
Huan Wang ◽  
Ping Jin ◽  
Marianna Sabatino ◽  
Jiaqiang Ren ◽  
Sara Civini ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Marrow Stromal Cells ◽  
Endometrial Regenerative Cells ◽  
Regenerative Cells

scholarly journals SCM-198 Prevents Endometriosis By Reversing Low Autophagy Levels Of Endometriotic Stromal Cells Via Inhibiting TNF-Α-Aromatase-Estrogen-Erα Pathway And Promoting PR Expression

2022 ◽  
Author(s):  
Yikong Lin ◽  
Yunyun Li ◽  
Yue Li ◽  
Dajin Li ◽  
Xiaolin Wang ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Estrogen Signaling ◽  
Therapeutic Effects ◽  
Rna Seq ◽  
Pharmacological Activities ◽  
Endometrial Stromal Cells ◽  
Tnf Α ◽  
The Relationship

Abstract Background: Endometriosis (EMS), an estrogen-dependent disease, is characterized by dysregulated inflammation and increased estrogen in ectopic lesions. However, the crosstalk and pathogenic mechanism of inflammation and estrogen has not been fully explored. SCM-198 is the synthetic form of leonurine with multiple pharmacological activities. Whether SCM-198 could inhibit the progress of EMS by regulating inflammation and estrogen signaling remains unknown. Methods: The therapeutic effects and potential mechanisms of SCM-198 on EMS were analyzed by establishing EMS mice models and performing RNA-seq assay. ELISA was performed to detect estrogen and TNF-α concentration in normal endometrial stromal cells (nESCs) and ectopic endometrial stromal cells (eESCs), with or without SCM-198 treatment. Western blotting, RNA silencing and plasmid overexpression were utilized to analyze the relationship among inflammation, endocrine and autophagy as well as the regulation of SCM-198 on inflammation-endocrine-autophagy axis. Results: Increased estrogen-ERα signaling and decreased PR expression co-led to the hypo-autophagy state in eESCs, which further inhibited the apoptosis of eESCs. Highly expressed TNF-α in eESCs enhanced low-autophagy mediated anti-apoptosis effect by activating aromatase-estrogen-ERα signaling. SCM-198 inhibited the growth of ectopic lesions in EMS mouse model and promoted the apoptosis of eESCs both in vivo and in vitro. The apoptosis effect of SCM-198 on eESCs were realized by upregulating the autophagy level via inhibiting TNF-α activated aromatase-estrogen-ERα signaling and increasing PR expression. Conclusion: Inflammation facilitated the progress of EMS by disturbing estrogen regulatory axis. SCM-198 restrained the growth of EMS by regulating inflammation-endocrine-autophagy axis.

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