Knockdown of miR-23, miR-27, and miR-24 Alters Fetal Liver Development and Blocks Fibrosis in Mice

Rogler, Charles E.; Matarlo, Joe S.; Kosmyna, Brian; Fulop, Daniel; Rogler, Leslie E.

doi:10.3727/105221616x693891

Cited by 20 publications

(13 citation statements)

References 46 publications

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“…MiR-24 is also a member of miR-23b cluster that could be used as non-invasive biomarkers in fibrogenic liver diseases (Oksuzet al, 2015). Although some other studies on miR-23b cluster regulating HSC activation are inconsistent with our study (Yuan et al, 2011;Zeng et al, 2016;Hall et al, 2017;Rogler et al, 2017), a quite recent study showed that knockdown of miR-23, miR-27, and miR-24 had a distinctly blocking effect on mouse liver fibrosis (Rogler et al, 2017), which is consistent with our findings.…”

Section: Discussionsupporting

confidence: 90%

LncRNA Gm5091 alleviates alcoholic hepatic fibrosis by sponging miR‐27b/23b/24 in mice

Zhou

Yuan

2018

Cell Biology International

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The regulatory roles of lncRNAs in the development of alcoholic hepatic fibrosis (AHF) have not been revealed. Here, we found lncRNA Gm5091 was being downregulated in mouse hepatic stellate cells (HSCs) during AHF. Then, Gm5091 was, respectively, overexpressed and knocked down in alcohol-treated primary HSCs. Our results showed that Gm5091 negatively regulated cell migration, ROS content, IL-1β secretion, and expression of Collagen I and markers of HSC activation including α-SMA and Desmin. Furthermore, bioinformatics analysis showed that Gm5091 sequence contained binding sites of miR-27b, miR-23b, and miR-24, and we proved that miR-27b/23b/24 all bound to Gm5091 by using RNA pull-down assay. Full-length Gm5091 could decrease the miR-27b/23b/24 levels, but the truncated Gm5091 deleting the binding sites could not. Finally, we confirmed that full-length Gm5091 could alleviate AHF in vivo, but the truncated Gm5091 could not. In conclusion, lncRNA Gm5091 alleviates mouse AHF by sponging miR-27b/23b/24.

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Section: Discussionsupporting

confidence: 90%

LncRNA Gm5091 alleviates alcoholic hepatic fibrosis by sponging miR‐27b/23b/24 in mice

Zhou

Yuan

2018

Cell Biology International

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“…We identified several highly abundant and specific miRNAs derived from hAFSC-exo, including let-7-5p, miR-22-3p, miR-27a-3p, miR-21-5p, and miR-23a-3p, all of which directly target TGF-βRs. Let-7-5p ( Elliot et al, 2019 ), miR-22-3p ( Hong et al, 2016 ), miR-27a-3p ( Zhang et al, 2019 ), and miR-23a-3p ( Rogler et al, 2017 ) have been previously shown to inhibit fibrotic diseases. Many studies have shown that these four miRNAs directly target the TGF-βR, and consistent with our results.…”

Section: Discussionmentioning

confidence: 99%

Human Amniotic Fluid Stem Cell-Derived Exosomes as a Novel Cell-Free Therapy for Cutaneous Regeneration

Zhang

Yan

Liu

et al. 2021

Front. Cell Dev. Biol.

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Adult wound healing often results in fibrotic scarring that is caused by myofibroblast aggregation. Human amniotic fluid stem cells (hAFSCs) exhibit significantly anti-fibrotic scarring properties during wound healing. However, it is little known whether hAFSCs directly or indirectly (paracrine) contribute to this process. Using the full-thickness skin-wounded rats, we investigated the therapeutic potential of hAFSC-derived exosomes (hAFSC-exo). Our results showed that hAFSC-exo accelerated the wound healing rate and improved the regeneration of hair follicles, nerves, and vessels, as well as increased proliferation of cutaneous cells and the natural distribution of collagen during wound healing. Additionally, hAFSC-exo suppressed the excessive aggregation of myofibroblasts and the extracellular matrix. We identified several miRNAs, including let-7-5p, miR-22-3p, miR-27a-3p, miR-21-5p, and miR-23a-3p, that were presented in hAFSC-exo. The functional analysis demonstrated that these hAFSC-exo-miRNAs contribute to the inhibition of the transforming growth factor-β (TGF-β) signaling pathway by targeting the TGF-β receptor type I (TGF-βR1) and TGF-β receptor type II (TGF-βR2). The reduction of TGF-βR1 and TGF-βR2 expression induced by hAFSC-exo was also confirmed in the healing tissue. Finally, using mimics of miRNAs, we found that hAFSC-exo-miRNAs were essential for myofibroblast suppression during the TGF-β1-induced human dermal fibroblast-to-myofibroblast transition in vitro. In summary, this study is the first to show that exosomal miRNAs used in hAFSC-based therapy inhibit myofibroblast differentiation. Our study suggests that hAFSC-exo may represent a strategic tool for suppressing fibrotic scarring during wound healing.

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“…Activation of NADPH oxidases (NOXs) induces HSCs activation ( Jiang et al, 2010 ), and inhibition of NOX1/NOX4 has been shown to suppress fibrogenesis in the bile duct ligation (BDL) and CCl 4 models ( Aoyama et al, 2012 ; Crosas-Molist and Fabregat, 2015 ). The immune response, that has multiple interactions with the fibrogenic process, may be also a candidate for therapy ( Pellicoro et al, 2014 ); thus, several strategies to block the TGF-β activity have shown efficacy ( Vogt et al, 2011 ; Rogler et al, 2017 ), and inhibition of chemokines and their receptors demonstrated antifibrotic effects in rodent models of liver fibrosis ( Zaldivar et al, 2010 ; Seifert et al, 2015 ; Zubiete-Franco et al, 2017 ).…”

Section: Mechanisms Involved In the Pathogenesis Of Liver Fibrosismentioning

confidence: 99%

Sphingosine 1-Phosphate Signaling as a Target in Hepatic Fibrosis Therapy

et al. 2017

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Liver fibrosis is an excess production of extracellular matrix proteins as a result of chronic liver disease which leads to cell death and organ dysfunction. The key cells involved in fibrogenesis are resident hepatic stellate cells (HSCs) which are termed myofibroblasts after activation, acquiring contractile, proliferative, migratory and secretory capability. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid with well-established effects on angiogenesis, carcinogenesis and immunity. Accumulating evidence demonstrates that this metabolite is involved in the profibrotic inflammatory process through the regulation of pleiotropic cell responses, such as vascular permeability, leukocyte infiltration, cell survival, migration, proliferation and HSCs differentiation to myofibroblasts. S1P is synthesized by sphingosine kinases (SphKs) and many of its actions are mediated by S1P specific cell surface receptors (S1P1-5), although different intracellular targets of S1P have been identified. Modulation of SphKs/S1P/S1P receptors signaling is known to result in beneficial effects on various in vivo and in vitro models of liver fibrosis. Thus, a better knowledge of the molecular mechanisms involved in the modulation of the S1P pathway could help to improve liver fibrosis therapy. In this review, we analyze the effects of the S1P axis on the fibrogenic process, and the involvement of a range of inhibitors or approaches targeting enzymes related to S1P in the abrogation of pathological fibrogenesis. All in all, targeting this pathway offers therapeutic potential in the treatment of hepatic fibrosis.

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Knockdown of miR-23, miR-27, and miR-24 Alters Fetal Liver Development and Blocks Fibrosis in Mice

Cited by 20 publications

References 46 publications

LncRNA Gm5091 alleviates alcoholic hepatic fibrosis by sponging miR‐27b/23b/24 in mice

LncRNA Gm5091 alleviates alcoholic hepatic fibrosis by sponging miR‐27b/23b/24 in mice

Human Amniotic Fluid Stem Cell-Derived Exosomes as a Novel Cell-Free Therapy for Cutaneous Regeneration

Sphingosine 1-Phosphate Signaling as a Target in Hepatic Fibrosis Therapy

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