Bone marrow-fibroblast progenitor cell-derived small extracellular vesicles promote cardiac fibrosis via miR-21-5p and integrin subunit αV signalling
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Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Prabhat Ranjan1, Roshan Kumar Dutta1, Karen Colin1,2
1Department of Medicine, Division of Cardiovascular Disease The University of Alabama at Birmingham Birmingham Alabama USA.
Insights
Interleukin-10 (IL10) knockout fibroblast progenitor cell-derived small extracellular vesicles (sEVs) worsen cardiac fibrosis. Inhibiting miR-21a-5p in these sEVs reduces fibrosis and improves heart function, revealing a therapeutic target for heart failure.
Area of Science:
- Cardiovascular Biology
- Extracellular Vesicles
- Molecular Cardiology
Background:
- Cardiac fibrosis is a key feature of cardiovascular disease (CVD), a leading global cause of death.
- Interleukin-10 (IL10) mitigates pressure overload-induced cardiac fibrosis by limiting fibroblast progenitor cell (FPC) recruitment.
- The exact role of FPCs in cardiac fibrosis and the involvement of extracellular vesicles (EVs) remain incompletely understood.
Purpose of the Study:
- To investigate the role of small extracellular vesicles (sEVs) derived from IL10-deficient FPCs in promoting cardiac fibrosis.
- To identify specific microRNAs (miRNAs) within these sEVs that contribute to fibrosis.
- To elucidate the molecular mechanism by which these sEVs exacerbate cardiac fibrosis and to explore therapeutic potential.
Main Methods:
- Isolation and characterization of sEVs from FPCs according to MISEV-2018 guidelines.
- miRNA profiling of sEVs using a fibrosis-associated miRNA kit.
- In vivo functional analysis involving sEV injection in a mouse model of pressure overload (transverse aortic constriction - TAC).
- Assessment of gene expression, miRNA-mRNA interactions, and cardiac function.
Main Results:
- sEVs from IL10-knockout (KO) FPCs, particularly those treated with TGFβ, enhanced profibrotic gene expression in cardiac fibroblasts.
- miRNA profiling identified miR-21a-5p as a key pro-fibrotic miRNA enriched in these sEVs.
- Inhibition of miR-21a-5p in sEVs attenuated profibrotic signaling and reduced pressure overload-induced cardiac fibrosis.
- Mechanistically, miR-21a-5p was found to bind and stabilize ITGAV mRNA, impacting the ITGAV/Col1α pathway.
- Silencing miR-21a-5p in sEVs improved cardiac function following TAC surgery.
Conclusions:
- Inflammatory FPC-derived sEVs exacerbate cardiac fibrosis via the miR-21a-5p/ITGAV/Col1α signaling axis.
- miR-21a-5p within these sEVs plays a critical role in promoting cardiac remodeling and dysfunction.
- Targeting miR-21a-5p presents a potential therapeutic strategy for hypertrophic cardiac remodeling and heart failure.
Abstract:
Cardiac fibrosis is the hallmark of cardiovascular disease (CVD), which is leading cause of death worldwide. Previously, we have shown that interleukin-10 (IL10) reduces pressure overload (PO)-induced cardiac fibrosis by inhibiting the recruitment of bone marrow fibroblast progenitor cells (FPCs) to the heart. However, the precise mechanism of FPC involvement in cardiac fibrosis remains unclear. Recently, exosomes and small extracellular vesicles (sEVs) have been linked to CVD progression. Thus, we hypothesized that pro-fibrotic miRNAs enriched in sEV-derived from IL10 KO FPCs promote cardiac fibrosis in pressure-overloaded myocardium. Small EVs were isolated from FPCs cultured media and characterized as per MISEV-2018 guidelines. Small EV's miRNA profiling was performed using Qiagen fibrosis-associated miRNA profiler kit. For functional analysis, sEVs were injected in the heart following TAC surgery. Interestingly, TGFβ-treated IL10-KO-FPCs sEV increased profibrotic genes expression in cardiac fibroblasts. The exosomal miRNA profiling identified miR-21a-5p as the key player, and its inhibition with antagomir prevented profibrotic signalling and fibrosis. At mechanistic level, miR-21a-5p binds and stabilizes ITGAV (integrin av) mRNA. Finally, miR-21a-5p-silenced in sEV reduced PO-induced cardiac fibrosis and improved cardiac function. Our study elucidates the mechanism by which inflammatory FPC-derived sEV exacerbate cardiac fibrosis through the miR-21a-5p/ITGAV/Col1α signalling pathway, suggesting miR-21a-5p as a potential therapeutic target for treating hypertrophic cardiac remodelling and heart failure.
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