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Microvesicle-mediated delivery of miR-1343: impact on markers of fibrosis.

ABSTRACT: Tissue fibrosis, the development of fibrous connective tissue as a result of injury or damage, is associated with many common diseases and cannot be treated effectively. The complex biological processes accompanying fibrosis often involve aberrant signaling through the transforming growth factor beta (TGF-?) pathway. In the search for mechanisms to repress this signaling, microRNAs have emerged as a novel class of molecules capable of targeting single members of the TGF-? pathway, or the pathway as a whole. We previously identified miR-1343 as a potent repressor of TGF-? signaling and fibrosis through the direct attenuation of both canonical TGF-? receptors. Here, we build upon our previous findings to better characterize the function of endogenous miR-1343 in normal biology and examine the potential role of exogenous miR-1343 as a repressor of TGF-? signaling. CRISPR/Cas9-mediated deletion of miR-1343 from A549 lung epithelial cells impacts several processes and genes implicated in fibrosis and known to be TGF-? pathway effectors. Moreover, the responses are opposite to those we observed previously when miR-1343 was overexpressed in the same cell type. We also show that miR-1343 can be shuttled into exosomes, a type of extracellular vesicle that are exported by cells into the surrounding medium and can be absorbed by distant target cells. miR-1343 delivered into primary lung fibroblasts by exosomes has a measurable function in reducing TGF-? signaling and markers of fibrosis. These results highlight a role for miR-1343 in fine-tuning the TGF-? pathway and suggest its use as a therapeutic in fibrotic disease.

SUBMITTER: Stolzenburg LR

PROVIDER: S-EPMC5809304 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Microvesicle-mediated delivery of miR-1343: impact on markers of fibrosis.

Stolzenburg Lindsay R LR Harris Ann A

Cell and tissue research 20171011 2

Tissue fibrosis, the development of fibrous connective tissue as a result of injury or damage, is associated with many common diseases and cannot be treated effectively. The complex biological processes accompanying fibrosis often involve aberrant signaling through the transforming growth factor beta (TGF-β) pathway. In the search for mechanisms to repress this signaling, microRNAs have emerged as a novel class of molecules capable of targeting single members of the TGF-β pathway, or the pathway ...[more]

PMID: 29022142

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Project description:Although glucocorticoids are the mainstays in the treatment of renal diseases for decades, the dose dependent side effects have largely restricted their clinical use. Microvesicles (MVs) are small lipid-based membrane-bound particles generated by virtually all cells. Here we show that RAW 264.7 macrophage cell-derived MVs can be used as vectors to deliver dexamethasone (named as MV-DEX) targeting the inflamed kidney efficiently. Methods: RAW macrophages were incubated with dexamethasone and then MV-DEX was isolated from the supernatants by centrifugation method. Nanoparticle tracking analysis, transmission electron microscopy, western blot and high-performance liquid chromatography were used to analyze the properties of MV-DEX. The LC-MS/MS was applied to investigate the protein compositions of MV-DEX. Based on the murine models of LPS- or Adriamycin (ADR)-induced nephropathy or in-vitro culture of glomerular endothelial cells, the inflammation-targeting characteristics and the therapeutic efficacy of MV-DEX was examined. Finally, we assessed the side effects of chronic glucocorticoid therapy in MV-DEX-treated mice. Results: Proteomic analysis revealed distinct integrin expression patterns on the MV-DEX surface, in which the integrin ?L?2 (LFA-1) and ?4?1 (VAL-4) enabled them to adhere to the inflamed kidney. Compared to free DEX treatment, equimolar doses of MV-DEX significantly attenuated renal injury with an enhanced therapeutic efficacy against renal inflammation and fibrosis in murine models of LPS- or ADR-induced nephropathy. In vitro, MV-DEX with about one-fifth of the doses of free DEX achieved significant anti-inflammatory efficacy by inhibiting NF-?B activity. Mechanistically, MV-DEX could package and deliver glucocorticoid receptors to renal cells, thereby, increasing cellular levels of the receptor and improving cell sensitivity to glucocorticoids. Notably, delivering DEX in MVs significantly reduced the side effects of chronic glucocorticoid therapy (e.g., hyperglycemia, suppression of HPA axis). Conclusion: In summary, macrophage-derived MVs efficiently deliver DEX into the inflamed kidney and exhibit a superior capacity to suppress renal inflammation and fibrosis without apparent glucocorticoid adverse effects. Our findings demonstrate the effectiveness and security of a novel drug delivery strategy with promising clinical applications.

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Microvesicle-mediated delivery of miR-1343: impact on markers of fibrosis.

Publications

Microvesicle-mediated delivery of miR-1343: impact on markers of fibrosis.

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