Activated CD4+ T cells-derived exosomal miR-142-3p boosts post-ischemic ventricular remodeling by activating myofibroblast

Abstract

Cardiac fibrosis is a primary phenotype of cardiac remodeling that contributes to cardiac dysfunction and heart failure. The expansion and activation of CD4 + T cells in the heart has been identified to facilitate pathological cardiac remodeling and dysfunction; however, the underlying mechanisms remained not well clarified. Herein, we found that exosomes derived from activated CD4 + T cells (CD4-activated Exos) evoked pro-fibrotic effects of cardiac fibroblasts, and their delivery into the heart aggravated cardiac fibrosis and dysfunction post-infarction. Mechanistically, miR-142-3p that was enriched in CD4-activated Exos recapitulated the pro-fibrotic effects of CD4-activated Exos in cardiac fibroblasts, and vice versa. Furthermore, miR-142-3p directly targeted and inhibited the expression of Adenomatous Polyposis Coli (APC), a negative WNT signaling pathway regulator, contributing to the activation of WNT signaling pathway and cardiac fibroblast activation. Thus, CD4-activated Exos promote post-ischemic cardiac fibrosis through exosomal miR-142-3p-WNT signaling cascade-mediated activation of myofibroblasts. Targeting miR-142-3p in CD4-activated Exos may hold promise for treating cardiac remodeling post-MI.

The pivotal roles of exosomes derived from endogenous immune cells and exogenous stem cells in myocardial repair after acute myocardial infarction

“…But the experiments of Cai et al demonstrated that miR-142-3p enriched in exosomes derived from activated CD4 + T cells (CD4-activated Exos) targeted and inhibited the expression of Adenomatous Polyposis Coli, contributing to the activation of WNT signaling pathway and activation of cardiac fibroblast, thus evoking pro-fibrotic effects of cardiac fibroblasts. And the delivery of CD4-activated Exos into the heart aggravated cardiac fibrosis and caused post-MI dysfunction 52 . Therefore, the cardioprotective effects of exosomes secreted from DCs deserve further research.…”

Extracellular Vesicles in Organ Fibrosis: Mechanisms, Therapies, and Diagnostics

“…Infiltrating CD4+ T cells are important drivers of inflammation and fibrosis after MI [ 178 ] and exosomes from activated CD4+ T cells promoted cardiac fibroblast activation in vitro and exacerbated fibrosis and heart dysfunction in mouse MI [ 179 ]. This effect was attributed to exosomal 142-3p, which promoted Wnt signaling and cardiac fibroblast activation by attenuating expression of the Wnt suppressor molecule, adenomatous polyposis coli [ 179 ].…”

The effect of immune cell‐derived exosomes in the cardiac tissue repair after myocardial infarction: Molecular mechanisms and pre‐clinical evidence

“…To sum up, T-activated EXs are the critical signal carriers in cardiac fibrosis following MI, and exosomal miR-142-3p serves as the signal conductor, providing a potential therapeutic target for treating MI-related cardiac fibrosis. 116 In conclusion, systemic deliveries of helpful exosomes or specific targeting of detrimental exosomes can provide an effective therapeutic window for treating MI-injured myocardium. However, further experimental studies are necessary to understand the exact effects of these exosomes as well as other immune cells, like neutrophils, mast cells and B lymphocytes, in the infracted myocardium after MI.…”