BMSCs-derived miR-223-containing exosomes contribute to liver protection in experimental autoimmune hepatitis

Chen, Lu; Lu, Feng‐Bin; Chen, Da-Zhi; Wu, Jer Horng; Hu, En-De; Xu, Lei; Zheng, Ming‐Hua; Li, Hui; Huang, Yu; Jin, Xiao-ya; Gong, Yuewen; Lin, Zhuo; Wang, Xiaodong; Chen, Yongping

doi:10.1016/j.molimm.2017.11.008

Cited by 187 publications

(154 citation statements)

References 48 publications

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“…The specificity of miR‐223 in exosome released from macrophage was demonstrated by miR‐223 antisense oligo treatment, which abolished the shuttling promoted invasiveness in breast cancer cells. Additional evidence points out the liver protective function of miR‐223 containing exosomes in murine liver injury . Indeed, exosomes containing miR‐223 were detected in BM‐derived mesenchymal stem cells (BMSCs) and overexpression of miR‐223 in BMSCs exosomes conferred protection in murine experimental autoimmune hepatitis.…”

Section: Functional Roles Of Myeloid Mir‐223 During Inflammatory Disementioning

confidence: 98%

MicroRNA miR-223 as regulator of innate immunity

Yuan

Berg

Lee

et al. 2018

Journal of Leukocyte Biology

134

105

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MicroRNAs were discovered more than 2 decades ago and have profound impact on diverse biological processes. Specific microRNAs have important roles in modulating the innate immune response and their dysregulation has been demonstrated to contribute to inflammatory diseases. MiR-223 in particular, is very highly expressed and tightly regulated in hematopoietic cells. It functions as key modulator for the differentiation and activation of myeloid cells. The central role of miR-223 in myeloid cells, especially neutrophil and macrophage differentiation and activation has been studied extensively. MiR-223 contributes to myeloid differentiation by enhancing granulopoiesis while inhibiting macrophage differentiation. Uncontrolled myeloid activation has detrimental consequences in inflammatory disease. MiR-223 serves as a negative feedback mechanism controlling excessive innate immune responses in the maintenance of myeloid cell homeostasis. This review summarizes several topics covering the function of miR-223 in myeloid differentiation, neutrophil and macrophage functions, as well as in inflammatory diseases including acute respiratory distress syndrome and inflammatory bowel disease. In addition, nonmyeloid functions of miR-223 are also discussed in this review. Therapeutic enhancement of miR-223 to dampen inflammatory targets is also highlighted as potential treatment to control excessive innate immune responses during mucosal inflammation.

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Section: Functional Roles Of Myeloid Mir‐223 During Inflammatory Disementioning

confidence: 98%

MicroRNA miR-223 as regulator of innate immunity

Yuan

Berg

Lee

et al. 2018

Journal of Leukocyte Biology

134

105

View full text Add to dashboard Cite

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“…In addition to immunosuppressive effects against NKT cells, MSC-sourced secretome may directly protect hepatocytes from cell death [38,39]. Injection of human menstrual blood-derived MSC-Exos significantly attenuated d-galactosamine/lipopolysaccharide (d-GalN/LPS)-induced acute liver injury and increased survival rate of experimental mice by suppressing caspase-3-driven apoptosis of hepatocytes [38].…”

Section: Molecular Mechanisms Responsible For Msc-evs-based Protectiomentioning

confidence: 99%

Mesenchymal Stem Cell-Derived Exosomes and Other Extracellular Vesicles as New Remedies in the Therapy of Inflammatory Diseases

Harrell¹,

Jovičić

Djonov

et al. 2019

Cells

558

379

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There is growing evidence that mesenchymal stem cell (MSC)-based immunosuppression was mainly attributed to the effects of MSC-derived extracellular vesicles (MSC-EVs). MSC-EVs are enriched with MSC-sourced bioactive molecules (messenger RNA (mRNA), microRNAs (miRNAs), cytokines, chemokines, immunomodulatory factors) that regulate phenotype, function and homing of immune cells. In this review article we emphasized current knowledge regarding molecular mechanisms responsible for the therapeutic effects of MSC-EVs in attenuation of autoimmune and inflammatory diseases. We described the disease-specific cellular targets of MSC-EVs and defined MSC-sourced molecules, which were responsible for MSC-EV-based immunosuppression. Results obtained in a large number of experimental studies revealed that both local and systemic administration of MSC-EVs efficiently suppressed detrimental immune response in inflamed tissues and promoted survival and regeneration of injured parenchymal cells. MSC-EVs-based anti-inflammatory effects were relied on the delivery of immunoregulatory miRNAs and immunomodulatory proteins in inflammatory immune cells (M1 macrophages, dendritic cells (DCs), CD4+Th1 and Th17 cells), enabling their phenotypic conversion into immunosuppressive M2 macrophages, tolerogenic DCs and T regulatory cells. Additionally, through the delivery of mRNAs and miRNAs, MSC-EVs activated autophagy and/or inhibited apoptosis, necrosis and oxidative stress in injured hepatocytes, neurons, retinal cells, lung, gut and renal epithelial cells, promoting their survival and regeneration.

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“…MSCEVs have also been shown to be a protective treatment when administered before ischemic‐reperfusion liver injury in mice . Additionally, MSCEVs that contained the miRNA miR‐223 have been shown to have a protective effect in an experimental hepatitis mouse model as well . LSCEVs have not been used in an in vivo model of liver injury before our study.…”

Section: Discussionmentioning

confidence: 98%

“…(25) Additionally, MSCEVs that contained the miRNA miR-223 have been shown to have a protective effect in an experimental hepatitis mouse model as well. (26) LSCEVs have not been used in an in vivo model of liver injury before our study. Recently, a mouse model of ex vivo normothermic machine perfusion (NMP) was used to test the ability of LSCEVs to protect against to ischemic-reperfusion liver injury, and it was shown that LSCEVs were able to reduce liver injury during hypoxic NMP.…”

Section: Discussionmentioning

confidence: 99%

Amelioration of Ductular Reaction by Stem Cell Derived Extracellular Vesicles in MDR2 Knockout Mice via Lethal‐7 microRNA

McDaniel

Wu²,

Zhou

et al. 2019

Hepatology

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Cholangiopathies are diseases that affect cholangiocytes, the cells lining the biliary tract. Liver stem cells (LSCs) are able to differentiate into all cells of the liver and possibly influence the surrounding liver tissue by secretion of signaling molecules. One way in which cells can interact is through secretion of extracellular vesicles (EVs), which are small membrane‐bound vesicles that contain proteins, microRNAs (miRNAs), and cytokines. We evaluated the contents of liver stem cell–derived EVs (LSCEVs), compared their miRNA contents to those of EVs isolated from hepatocytes, and evaluated the downstream targets of these miRNAs. We finally evaluated the crosstalk among LSCs, cholangiocytes, and human hepatic stellate cells (HSCs). We showed that LSCEVs were able to reduce ductular reaction and biliary fibrosis in multidrug resistance protein 2 (MDR2)‐/‐ mice. Additionally, we showed that cholangiocyte growth was reduced and HSCs were deactivated in LSCEV‐treated mice. Evaluation of LSCEV contents compared with EVs derived from hepatocytes showed a large increase in the miRNA, lethal‐7 (let‐7). Further evaluation of let‐7 in MDR2‐/‐ mice and human primary sclerosing cholangitis samples showed reduced levels of let‐7 compared with controls. In liver tissues and isolated cholangiocytes, downstream targets of let‐7 (identified by ingenuity pathway analysis), Lin28a (Lin28 homolog A), Lin28b (Lin28 homolog B), IL‐13 (interleukin 13), NR1H4 (nuclear receptor subfamily 1 group H member 4) and NF‐κB (nuclear factor kappa B), are elevated in MDR2‐/‐ mice, but treatment with LSCEVs reduced levels of these mediators of ductular reaction and biliary fibrosis through the inhibition of NF‐κB and IL‐13 signaling pathways. Evaluation of crosstalk using cholangiocyte supernatants from LSCEV‐treated cells on cultured HSCs showed that HSCs had reduced levels of fibrosis and increased senescence. Conclusion: Our studies indicate that LSCEVs could be a possible treatment for cholangiopathies or could be used for target validation for future therapies.

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BMSCs-derived miR-223-containing exosomes contribute to liver protection in experimental autoimmune hepatitis

Cited by 187 publications

References 48 publications

MicroRNA miR-223 as regulator of innate immunity

MicroRNA miR-223 as regulator of innate immunity

Mesenchymal Stem Cell-Derived Exosomes and Other Extracellular Vesicles as New Remedies in the Therapy of Inflammatory Diseases

Amelioration of Ductular Reaction by Stem Cell Derived Extracellular Vesicles in MDR2 Knockout Mice via Lethal‐7 microRNA

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