Mesenchymal stem cell transplantation improves chronic colitis-associated complications through inhibiting the activity of toll-like receptor-4 in mice

Niu, Guo chao; Liu, Lei; Zheng, Libo; Zhang, Hong; Shih, David Q.; Zhang, Xiaolan

doi:10.1186/s12876-018-0850-7

Cited by 16 publications

(6 citation statements)

References 42 publications

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“…MSC are considered as a potential therapy for IBD and other autoimmune diseases [ 26 ]. Previously, our study found that injection of stem cells can improve colitis and its associated complications in mice [ 27 ]. Accumulating studies also revealed that the effects of anti-inflammatory and immunosuppression were mainly contributed by exosome secretion [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

A novel therapeutic approach for inflammatory bowel disease by exosomes derived from human umbilical cord mesenchymal stem cells to repair intestinal barrier via TSG-6

et al. 2021

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Background Exosomes as the main therapeutic vectors of mesenchymal stem cells (MSC) for inflammatory bowel disease (IBD) treatment and its mechanism remain unexplored. Tumor necrosis factor-α stimulated gene 6 (TSG-6) is a glycoprotein secreted by MSC with the capacities of tissue repair and immune regulation. This study aimed to explore whether TSG-6 is a potential molecular target of exosomes derived from MSCs (MSCs-Exo) exerting its therapeutic effect against colon inflammation and repairing mucosal tissue. Methods Two separate dextran sulfate sodium (DSS) and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced IBD mouse models were intraperitoneally administered MSCs-Exo extracted from human umbilical cord MSC (hUC-MSC) culture supernatant. Effects of MSCs-Exo on intestinal inflammation, colon barrier function, and proportion of T cells were investigated. We explored the effects of MSCs-Exo on the intestinal barrier and immune response with TSG-6 knockdown. Moreover, recombinant human TSG-6 (rhTSG-6) was administered exogenously and colon inflammation severity in mice was evaluated. Results Intraperitoneal injection of MSCs-Exo significantly ameliorated IBD symptoms and reduced mortality rate. The protective effect of MSCs-Exo on intestinal barrier was demonstrated evidenced by the loss of goblet cells and intestinal mucosa permeability, thereby improving the destruction of tight junctions (TJ) structures and microvilli, as well as increasing the expression of TJ proteins. Microarray analysis revealed that MSCs-Exo administration downregulated the level of pro-inflammatory cytokines and upregulated the anti-inflammatory cytokine in colon tissue. MSCs-Exo also modulated the response of Th2 and Th17 cells in the mesenteric lymph nodes (MLN). Reversely, knockdown of TSG-6 abrogated the therapeutic effect of MSCs-Exo on mucosal barrier maintenance and immune regulation, whereas rhTSG-6 administration showed similar efficacy to that of MSCs-Exo. Conclusions Our findings suggested that MSCs-Exo protected against IBD through restoring mucosal barrier repair and intestinal immune homeostasis via TSG-6 in mice.

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Section: Discussionmentioning

confidence: 99%

A novel therapeutic approach for inflammatory bowel disease by exosomes derived from human umbilical cord mesenchymal stem cells to repair intestinal barrier via TSG-6

et al. 2021

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“…Of course, these effects depend, to a large extent, on the time and concentration of the administered MSCs [39]. Upon transplantation, MSCs can inhibit the intestinal endotoxemia and liver inflammation via the LPS/TLR4 pathway, and improve chronic colitis-related hepatobiliary complications [40].…”

Section: Discussionmentioning

confidence: 99%

Impact of miR-223-3p and miR-2909 on inflammatory factors IL-6, IL-1ß, and TNF-α, and the TLR4/TLR2/NF-κB/STAT3 signaling pathway induced by lipopolysaccharide in human adipose stem cells

Niu

Zhao

et al. 2019

PLoS ONE

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MicroRNAs (miRNAs) are small non-coding RNA molecules that play an important role in the regulation of gene expression related to inflammatory responses. Human adipose stem cells are characterized by pluripotent differentiation potential and isolated from adipose tissues. These cells regulate inflammation mainly by interacting with immune cells and affecting the secretion of immune factors; details of this interaction are currently unknown. In the current study, we successfully established an acute inflammation model and a chronic inflammation model involving adipose stem cells. We used high-throughput miRNA microarray analysis to identify miRNAs that were significantly (p < 0.05) differentially expressed during both acute and chronic inflammation. Lipopolysaccharide (LPS) significantly (p < 0.05) reduced the expression of miR-223-3P and miR-2909, while promoting the production of pro-inflammatory cytokines, interleukin (IL) 6, IL-1β, and tumor necrosis factor (TNF)-α via the Toll-like receptor (TLR) 4/TLR2/nuclear factor (NF)-κB/signal transducer and activator of transcription (STAT) 3 signaling pathway in human adipose stem cells. Further, miR-223-3P expression was significantly (p < 0.05) reduced in human adipose stem cells during activation by IL-6 stimulation. The inducible down-regulation of miR-223-3P resulted in the activation of STAT3, which was directly targeted by miR-223-3P. STAT3 directly targeted TLR4 and TLR2, promoting the production of the pro-inflammatory cytokine, IL-6, and formed a positive feedback loop to regulate IL-6 levels. Similarly, TNF-α significantly (p < 0.05) increased the expression of miR-223-3p, with LPS and TLR4/TLR2/NF-κB/STAT3 forming a negative feedback loop to regulate TNF-α levels. In addition, miR-2909, which depends on NF-κB, targeted Krueppel-like factor (KLF) 4 to regulate the levels of pro-inflammatory cytokines, IL-6, IL-1β, and TNF-α. We conclude that miR-223-3p and miR-2909 form a complex regulatory network with pro-inflammatory factors and signaling pathways in adipose stem cells stimulated by LPS. These findings will inform the development of therapies against autoimmune and inflammatory diseases.

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“…TLR4 activates the endotoxin-induced innate immune system and the NF-κB pathway, further stimulating the expression of pro-inflammatory factors (45). MSCs reduce the level of TLR4, leading to the reduction of pro-inflammatory factors and alleviating intestinal inflammatory response (46). A previous study has demonstrated that MSCs inhibited the proliferation and activation of cluster of differentiation (CD)4 + T cells and the differentiation of CD4+ T cells into Th1 and Th17 cells (47).…”

Section: Discussionmentioning

confidence: 99%

Protective effect and mechanism of mesenchymal stem cells on heat stroke induced intestinal injury

Wang¹,

Deng

Yuan³

et al. 2020

Exp Ther Med

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Heat stroke (HS) is considered to be a severe systemic inflammatory reaction disease that is caused by high fever. The mortality of HS is high worldwide due to the lack of effective treatments. Presently, mesenchymal stem cells (MSCs) have been demonstrated to serve roles in inflammation and immune regulation. Therefore, the current study aimed to investigate the protective effect and mechanism of MSCs against the HS-induced inflammatory response and organ dysfunction. A rat model of HS was induced by a high-temperature environment and treated with MSCs via tail veins. The levels of molecular markers of organ function, inflammatory factors and chemokines were examined at days 1, 7, 14 and 28. Histological staining was performed on the intestines of rats and control groups, and the Chiu's scores of the two groups were compared. The results revealed that MSCs injection significantly reduced the mortality and inhibited the circulatory inflammatory response. Additionally, main organ function, such as in the liver and kidney, were significantly improved following MSCs infusion in HS rats. Furthermore, MSCs treatment significantly improved edema, necrosis and villus exfoliation of intestinal mucosa, and reduced the inflammatory response of intestinal tissue. These results indicated that MSC infusion had therapeutic effects on HS of rats by regulating the circulatory and intestinal inflammatory response. Moreover, MSCs may be able to protect organ function and promote tissue repair in HS. The results of the current study indicated that MSCs may be used as a potential method to treat HS and the resulting organ dysfunction.

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Mesenchymal stem cell transplantation improves chronic colitis-associated complications through inhibiting the activity of toll-like receptor-4 in mice

Cited by 16 publications

References 42 publications

A novel therapeutic approach for inflammatory bowel disease by exosomes derived from human umbilical cord mesenchymal stem cells to repair intestinal barrier via TSG-6

A novel therapeutic approach for inflammatory bowel disease by exosomes derived from human umbilical cord mesenchymal stem cells to repair intestinal barrier via TSG-6

Impact of miR-223-3p and miR-2909 on inflammatory factors IL-6, IL-1ß, and TNF-α, and the TLR4/TLR2/NF-κB/STAT3 signaling pathway induced by lipopolysaccharide in human adipose stem cells

Protective effect and mechanism of mesenchymal stem cells on heat stroke induced intestinal injury

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