Human umbilical cord mesenchymal stem cell-derived extracellular vesicles alleviated silica induced lung inflammation and fibrosis in mice via circPWWP2A/miR-223–3p/NLRP3 axis

Hou, Lin; Zhu, Zhaohui; Jiang, Fuyang; Zhao, Jing; Jia, Qiyue; Jiang, Qiyue; Wang, Hongwei; Xue, Wenming; Lin, Tian

doi:10.1016/j.ecoenv.2023.114537

Cited by 26 publications

(13 citation statements)

References 47 publications

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“…A similar study found that UC-MSC-EVs reduced liver brosis in rat models by inhibiting hepatic stellate cell activation [57]. Furthermore, EVs derived from human UC-MSCs have shown potential in preventing and ameliorating pulmonary brosis, with miR-223-3p acting as a key therapeutic effector [32]. Administration of MSC culture supernatant signi cantly reduced the degree of luminal stricture in the rectum and mitigated myo broblast activation and hypertrophy of the muscularis propria in pigs [58].…”

Section: Discussionmentioning

confidence: 89%

“…A previous study has found that therapeutic factors were distributed within the soluble fraction and EV fraction of the secretome, implying that both secretome fractions work synergistically to promote skeletal muscle regeneration [50]. MSC secretome and EVs have anti-brotic properties via transferring anti-brogenic growth factors, cytokines, and miRNAs, including HGF, TGF-β3, IL-10, MFGE-8, miR-27b, and miR-223-3p [31,32,[51][52][53]. They can also block the TGF-β1/Smad2/3 signaling pathway, which inhibits the transition of dermal broblasts to myo broblasts [54,55].…”

Section: Discussionmentioning

confidence: 99%

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Human umbilical cord/placenta-derived mesenchymal stem cell secretome attenuates intestinal fibrosis

Choi

Kim

et al. 2023

Preprint

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Background: A significant unmet need in inflammatory bowel disease is the lack of anti-fibrotic agents targeting intestinal fibrosis. This study aimed to investigate the anti-fibrogenic properties and mechanisms of the secretome of human umbilical cord/placenta-derived mesenchymal stem cells (UC/PL-scrtm) in a murine intestinal fibrosis model and human primary intestinal myofibroblasts (HIMFs). Methods:UC/PL-scrtm was concentrated by 15 times using a 3 kDa cut-off filter. C57BL/6 mice aged 7 weeks old were randomly assigned to one of four groups: 1) control, 2) dextran sulfate sodium (DSS), 3) DSS + secretome (late-phase treatment), and 4) DSS + secretome (early-phase treatment). Chronic DSS colitis and intestinal fibrosis was induced by three cycles of DSS administration. One DSS cycle consisted of 7 d oral DSS administration (1.75%, 2%, and 2.5% DSS), followed by 14 d of water drinking. UC/PL-scrtm was intraperitoneally administered in the late phase (from day 50, 10 times) or early phase (from day 29, 10 times) of DSS cycles. HIMFs were treated with TGF-β1 and co-treated with UC/PL-scrtm (10% of culture media) in the cellular model. Results: In the animal study, UC/PL-scrtm reduced submucosa/muscularis propria thickness and collagen deposition, which improved intestinal fibrosis in chronic DSS colitis. The UC/PL-scrtm significantly reduced the expressions of procollagen1A1 and α-smooth muscle actin, which DSS significantly elevated. The anti-fibrogenic effect was more apparent in the UC-scrtm or early-phase treatment model. The UC/PL-scrtm reduced procollagen1A1, fibronectin, and α-smooth muscle actin expression in HIMFs in cellular model. The UC/PL-scrtm downregulated fibrogenesis by suppressing RhoA, MRTF-A, and SRF expression. Conclusions: Human UC/PL-scrtm inhibits TGF-β1-induced fibrogenic activation in HIMFs by blocking the Rho/MRTF/SRF pathway and chronic DSS colitis-induced intestinal fibrosis. Thus, it may be regarded as a novel candidate for stem cell-based therapy of intestinal fibrosis.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Human umbilical cord/placenta-derived mesenchymal stem cell secretome attenuates intestinal fibrosis

Choi

Kim

et al. 2023

Preprint

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“…The resulting cell debris and various inflammatory factors recognize pathogen‐associated molecular patterns (PAMPs) or danger‐associated molecular patterns (DAMPs), recruiting adaptor proteins such as ASC containing a caspase‐recruitment domain (ASC) and effector Caspase 1 to assemble the NLRP3 inflammasome (Xia et al, 2023; Zhan et al, 2022; Zhang et al, 2023). Caspase 1 undergoes self‐cleavage into the enzymatically active cleaved Caspase 1, activating intracellular inflammatory responses (Hou et al, 2023). Through in vivo I/R and in vitro H/R experiments, we found that overexpression of cFLIP L inhibits the expression of NLRP3 and ASC, while Caspase 1 cleavage is also targeted and suppressed.…”

Section: Discussionmentioning

confidence: 99%

cFLIP_L alleviates myocardial ischemia‐reperfusion injury by regulating pyroptosis

Zhang,

Wu,

Liu

et al. 2023

Cell Biology International

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Alleviating myocardial ischemia‐reperfusion injury (MIRI) plays a critical role in the prognosis and improvement of cardiac function following acute myocardial infarction. Pyroptosis is a newly identified form of cell death that has been implicated in the regulation of MIRI. In our study, H9c2 cells and SD rats were transfected using a recombinant adenovirus vector carrying cFLIPL, and the transfection was conducted for 3 days. Subsequently, H9c2 cells were subjected to 4 h of hypoxia followed by 12 h of reoxygenation to simulate an in vitro ischemia‐reperfusion model. SD rats underwent 30 min of ischemia followed by 2 h of reperfusion to establish an MIRI model. Our findings revealed a notable decrease in cFLIPL expression in response to ischemia/reperfusion (I/R) and hypoxia/reoxygenation (H/R) injuries. Overexpression of cFLIPL can inhibit pyroptosis, reducing myocardial infarction area in vivo, and enhancing H9c2 cell viability in vitro. I/R and H/R injuries induced the upregulation of ASC, cleaved Caspase 1, NLRP3, GSDMD‐N, IL‐1β, and IL‐18 proteins, promoting cell apoptosis. Our research indicates that cFLIPL may suppress pyroptosis by strategically binding with Caspase 1, inhibiting the release of inflammatory cytokines and preventing cell membrane rupture. Therefore, cFLIPL could potentially serve as a promising target for alleviating MIRI by suppressing the pyroptotic pathway.

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“…Several EV-miRNAs (e.g., miR-124a, miR-146a, miR-21, miR-29b, miR-873a-5p) have been reported to show potential effects to reduce oxidative stress and neuroinflammation in Alzheimer’s disease or traumatic brain injury models (Bang and Kim, 2022). Another study has also demonstrated the protective function of these microvesicles by transferring the miR-223-3p to suppress the circular RNA PWWP2A, thereby alleviating pulmonary fibrosis through the NLRP3 signaling pathway (Hou et al, 2023). Conversely, our results show that MSC-EVs are able to diminish the levels of the inflammatory miRNAs (miR-21a-5p, miR-146a-5p and miR-141-5p) induced by binge-like ethanol treatment in adolescent mice.…”

Section: Discussionmentioning

confidence: 99%

Emerging role of mesenchymal stem cell-derived extracellular vesicles to ameliorate hippocampal NLRP3 inflammation induced by binge-like ethanol treatment in adolescence

Mellado,

Morillo-Bargues,

Perpiñá-Clérigues

et al. 2023

Preprint

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NOD-like receptors are innate immunity sensors that provide an early and effective response to pathogenic or injury conditions. However, abnormalities in these receptors may cause excessive inflammation. Our studies have reported that an activation of the NLRP3-inflammasome complex in ethanol-treated astrocytes and in chronic alcohol-fed mice could be associated with neuroinflammation and brain damage. Considering the therapeutic role of the molecules contained in the extracellular vesicles (EVs) derived by mesenchymal stem cells (MSC-EVs), the present study aims to evaluate whether the intravenous administration of MSC-EVs from adipose tissue, through inhibiting the NLRP3 inflammasome activation, is capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking. We demonstrate that MSC-EVs ameliorate the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes (e.g., NLRP1, NLRC4 and AIM2), as well as the alterations of inflammatory genes (IL-1β, IL-18, iNOS, NF-κB, MCP-1 and CX3CL1) and miRNAs (miR-21a-5p, miR-146a-5p and miR-141-5p) induced by binge-like ethanol treatment in adolescent mice. Bioinformatic analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling pathways. Taken together, these findings provide, for the first time, evidence of the therapeutic potential of MSC-derived EVs to restore the hippocampal neuroinflammatory response through the NLRP3 inflammasome activation induced by binge drinking in adolescence.

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Human umbilical cord mesenchymal stem cell-derived extracellular vesicles alleviated silica induced lung inflammation and fibrosis in mice via circPWWP2A/miR-223–3p/NLRP3 axis

Cited by 26 publications

References 47 publications

Human umbilical cord/placenta-derived mesenchymal stem cell secretome attenuates intestinal fibrosis

Human umbilical cord/placenta-derived mesenchymal stem cell secretome attenuates intestinal fibrosis

cFLIP_L alleviates myocardial ischemia‐reperfusion injury by regulating pyroptosis

Emerging role of mesenchymal stem cell-derived extracellular vesicles to ameliorate hippocampal NLRP3 inflammation induced by binge-like ethanol treatment in adolescence

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Human umbilical cord mesenchymal stem cell-derived extracellular vesicles alleviated silica induced lung inflammation and fibrosis in mice via circPWWP2A/miR-223–3p/NLRP3 axis

Cited by 26 publications

References 47 publications

Human umbilical cord/placenta-derived mesenchymal stem cell secretome attenuates intestinal fibrosis

Human umbilical cord/placenta-derived mesenchymal stem cell secretome attenuates intestinal fibrosis

cFLIPL alleviates myocardial ischemia‐reperfusion injury by regulating pyroptosis

Emerging role of mesenchymal stem cell-derived extracellular vesicles to ameliorate hippocampal NLRP3 inflammation induced by binge-like ethanol treatment in adolescence

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cFLIP_L alleviates myocardial ischemia‐reperfusion injury by regulating pyroptosis