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

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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-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 as a whole. We previously identified miR-1343 as a potent repressor of TGF-β signaling and fibrosis through the direct attenuation of both canonical TGF-β 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-β 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-β 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-β signaling and markers of fibrosis. These results highlight a role for miR-1343 in fine-tuning the TGF-β pathway and suggest its use as a therapeutic in fibrotic disease.

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Acknowledgments

We thank Dr. Scott Randell, Dr. Wanda O’Neal and Lisa Jones (University of North Carolina Marsico Lung Institute) for the primary lung fibroblast cultures and A549 RNA-seq.

Funding

This work was supported by the National Institutes of Health (R01HL117843 to AH; F31HL126458 to LRS) and the Children’s Research Fund.

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Authors and Affiliations

  1. Human Molecular Genetics Program, Lurie Children’s Research Center, Chicago, IL, 60614, USA

    Lindsay R. Stolzenburg & Ann Harris

  2. Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA

    Lindsay R. Stolzenburg & Ann Harris

  3. Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44016, USA

    Ann Harris

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  1. Lindsay R. Stolzenburg
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  2. Ann Harris
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Correspondence to Ann Harris.

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Stolzenburg, L.R., Harris, A. Microvesicle-mediated delivery of miR-1343: impact on markers of fibrosis. Cell Tissue Res 371, 325–338 (2018). https://doi.org/10.1007/s00441-017-2697-6

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