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Extracellular Vesicles as Therapeutic Agents for Cardiac Fibrosis.

ABSTRACT: Heart disease remains an increasing major public health challenge in the United States and worldwide. A common end-organ feature in diseased hearts is myocardial fibrosis, which stiffens the heart and interferes with normal pump function, leading to pump failure. The development of cells for regenerative therapy has been met with many pitfalls on its path to clinical translation. Recognizing that regenerative cells secrete therapeutically bioactive vesicles has paved the way to circumvent many failures of cell therapy. In this review, we provide an overview of extracellular vesicles (EVs), with a focus on their utility as therapeutic agents for cardiac regeneration. We also highlight the engineering potential of EVs to enhance their therapeutic application.

SUBMITTER: Rogers RG

PROVIDER: S-EPMC7255103 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Extracellular Vesicles as Therapeutic Agents for Cardiac Fibrosis.

Rogers Russell G RG Ciullo Alessandra A Marbán Eduardo E Ibrahim Ahmed G AG

Frontiers in physiology 20200521

Heart disease remains an increasing major public health challenge in the United States and worldwide. A common end-organ feature in diseased hearts is myocardial fibrosis, which stiffens the heart and interferes with normal pump function, leading to pump failure. The development of cells for regenerative therapy has been met with many pitfalls on its path to clinical translation. Recognizing that regenerative cells secrete therapeutically bioactive vesicles has paved the way to circumvent many f ...[more]

PMID: 32528309

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Project description:The lack of approved therapies for hepatic fibrosis seriously limits medical management of patients with chronic liver disease. Since extracellular vesicles (EVs) function as conduits for intercellular molecular transfer, we investigated if EVs from healthy individuals have anti-fibrotic properties. Hepatic fibrogenesis or fibrosis in carbon tetrachloride (CCl4)- or thioacetic acid-induced liver injury models in male or female mice were suppressed by serum EVs from normal mice (EVN) but not from fibrotic mice (EVF). CCl4-treated mice undergoing EVN therapy also exhibited reduced levels of hepatocyte death, inflammatory infiltration, circulating AST/ALT levels and hepatic or circulating pro-inflammatory cytokines. Hepatic histology, liver function tests or circulating proinflammatory cytokine levels were unaltered in control mice receiving EVN. As determined using PKH26-labelled EVN, principal target cells included hepatic stellate cells (HSC; a normally quiescent fibroblastic cell that undergoes injury-induced activation and produces fibrosis during chronic injury) or hepatocytes which showed increased EVN binding after, respectively, activation or exposure to CCl4. In vitro, EVN decreased proliferation and fibrosis-associated molecule expression in activated HSC, while reversing the inhibitory effects of CCl4 or ethanol on hepatocyte proliferation. In mice, microRNA-34c, -151-3p, -483-5p, -532-5p and -687 were more highly expressed in EVN than EVF and mimics of these microRNAs (miRs) individually suppressed fibrogenic gene expression in activated HSC. A role for these miRs in contributing to EVN actions was shown by the ability of their corresponding antagomirs to individually and/or collectively block the therapeutic effects of EVN on activated HSC or injured hepatocytes. Similarly, the activated phenotype of human LX-2 HSC was attenuated by serum EVs from healthy human subjects and contained higher miR-34c, -151-3p, -483-5p or -532-5p than EVs from hepatic fibrosis patients. In conclusion, serum EVs from normal healthy individuals are inherently anti-fibrogenic and anti-fibrotic, and contain microRNAs that have therapeutic actions in activated HSC or injured hepatocytes. Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; CCl4: carbon tetrachloride; CCN2: connective tissue growth factor; E: eosin; EGFP: enhanced green fluorescent protein; EVs: extracellular vesicles; EVF: serum EVs from mice with experimental hepatic fibrosis; EVN: serum EVs from normal mice; H: hematoxylin; HSC: hepatic stellate cell; IHC: immunohistochemistry; IL: interleukin; MCP-1: monocyte chemotactic protein-1; miR: microRNA; mRNA: messenger RNA; NTA: nanoparticle tracking analysis; PCNA: proliferating cell nuclear antigen; qRT-PCR: quantitative real-time polymerase chain reaction; SDS-PAGE: sodium dodecyl sulphate - polyacrylamide gel electrophoresis; ?SMA: alpha smooth muscle actin; TAA: thioacetic acid; TG: transgenic; TGF-?: transforming growth factor beta; TEM: transmission electron microscopy; TNF?: tumour necrosis factor alpha.

Project description:Extracellular vesicles (EVs) are nano-sized membrane-limited organelles that are liberated from their producer cells, traverse the intercellular space, and may interact with other cells resulting in the uptake of the EV molecular payload by the recipient cells which may become functionally reprogramed as a result. Previous in vitro studies showed that EVs purified from normal mouse AML12 hepatocytes ("EVNorm") attenuate the pro-fibrogenic activities of activated hepatic stellate cells (HSCs), a principal fibrosis-producing cell type in the liver. In a 10-day CCl4 injury model, liver fibrogenesis, expression of hepatic cellular communication network factor 2 [CCN2, also known as connective tissue growth factor (CTGF)] or alpha smooth muscle actin (αSMA) was dose-dependently blocked during concurrent administration of EVNorm. Hepatic inflammation and expression of inflammatory cytokines were also reduced by EVNorm. In a 5-week CCl4 fibrosis model in mice, interstitial collagen deposition and mRNA and/or protein for collagen 1a1, αSMA or CCN2 were suppressed following administration of EVNorm over the last 2 weeks. RNA sequencing (RNA-seq) revealed that EVNorm therapy of mice receiving CCl4 for 5 weeks resulted in significant differences [false discovery rate (FDR) <0.05] in expression of 233 CCl4-regulated hepatic genes and these were principally associated with fibrosis, cell cycle, cell division, signal transduction, extracellular matrix (ECM), heat shock, cytochromes, drug detoxification, adaptive immunity, and membrane trafficking. Selected gene candidates from these groups were verified by qRT-PCR as targets of EVNorm in CCl4-injured livers. Additionally, EVNorm administration resulted in reduced activation of p53, a predicted upstream regulator of 40% of the genes for which expression was altered by EVNorm following CCl4 liver injury. In vitro, EVs from human HepG2 hepatocytes suppressed fibrogenic gene expression in activated mouse HSC and reversed the reduced viability or proliferation of HepG2 cells or AML12 cells exposed to CCl4. Similarly, EVs produced by primary human hepatocytes (PHH) protected PHH or human LX2 HSC from CCl4-mediated changes in cell number or gene expression in vitro. These findings show that EVs from human or mouse hepatocytes regulate toxin-associated gene expression leading to therapeutic outcomes including suppression of fibrogenesis, hepatocyte damage, and/or inflammation.

Dataset Information

Extracellular Vesicles as Therapeutic Agents for Cardiac Fibrosis.

Publications

Extracellular Vesicles as Therapeutic Agents for Cardiac Fibrosis.

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