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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
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Cardiac Myofibroblast-Derived Small Extracellular Vesicles Moderate Fibrotic Responses via
Shichao Li1,2, Shuwen Su1,2, Gaopeng Xian1,2
1State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Journal of Extracellular Vesicles
|November 28, 2025
Summary
Researchers discovered a new feedback loop in heart cells that uses small RNAs within vesicles to reduce fibrosis. This Angiotensin II pathway involving piRNA-62788 offers potential new treatments for heart failure.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Fibrosis Research
Background:
- Fibrosis involves negative feedback loops to control excessive fibrotic responses.
- Activated fibroblasts can develop anti-fibrotic properties, but the mechanisms are unclear.
- Understanding fibroblast autoregulation is key to developing anti-fibrotic therapies.
Purpose of the Study:
- To investigate intrinsic autoregulatory mechanisms in fibroblasts.
- To identify specific inhibitory modulators of fibrotic responses.
- To explore the role of small extracellular vesicles (sEVs) and piRNAs in cardiac fibrosis.
Main Methods:
- Angiotensin II (AngII) priming of cardiac myofibroblasts.
- Small extracellular vesicle (sEV) isolation and characterization.
- Small RNA sequencing to identify piRNAs.
- In vitro studies with primary cardiac fibroblasts (overexpression/knockdown of piRNA-62788).
- In vivo studies using a mouse model of transverse aortic constriction.
- Analysis of plasma sEVs from heart failure (HF) patients.
Main Results:
- AngII-primed cardiac myofibroblasts showed suppressed profibrotic activation, mediated by sEVs.
- sEVs were found to be rich in Piwi-interacting RNAs (piRNAs).
- piRNA-62788, induced by Angiotensin II receptor type 2 (AT2R) stimulation, was encapsulated in sEVs.
- piRNA-62788 overexpression attenuated fibrogenic responses, while knockdown aggravated them.
- In vivo, piRNA-62788 or HF patient sEVs mitigated cardiac remodeling; inhibitors worsened fibrosis.
- piRNA-62788 complexes with PIWIL2, inhibiting SRF signaling via Srf mRNA 3' UTR binding.
- Plasma sEV-derived piRNA-62788 was elevated in HF patients and correlated inversely with ejection fraction.
Conclusions:
- A novel AngII/AT2R/sEVs axis acts as a protective negative feedback circuit against cardiac fibrosis.
- piRNA-62788 is a key mediator within this pathway, suppressing SRF signaling.
- This endogenous anti-fibrotic pathway presents a potential therapeutic target for heart failure.
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