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TGF-β1–induced endothelial-mesenchymal transition: a potential contributor to fibrotic remodeling in atrial fibrillation?
Arnela Saljic, … , Eleonora Grandi, Dobromir Dobrev
Arnela Saljic, … , Eleonora Grandi, Dobromir Dobrev
Published July 1, 2022
Citation Information: J Clin Invest. 2022;132(13):e161070. https://doi.org/10.1172/JCI161070.
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Commentary Article has an altmetric score of 6

TGF-β1–induced endothelial-mesenchymal transition: a potential contributor to fibrotic remodeling in atrial fibrillation?

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Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide, with an unmet therapeutic need. Fibrotic remodeling, in which collagen-producing atrial fibroblasts play a crucial role, substantially contributes to arrhythmia promotion and progression. In this issue of the JCI, Lai, Tsai, and co-authors reveal that TGF-β1 promoted endothelial-mesenchymal transition during AF and put forward the notion that, in the adult heart, atrial fibroblasts can originate from different cellular sources. These important findings extend our understanding of the origin, biology, and function of fibroblasts and offer possibilities for therapeutic targeting of fibrosis in AF.

Authors

Arnela Saljic, Eleonora Grandi, Dobromir Dobrev

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Figure 1

Origin and consequences of fibroblast activation for atrial arrhythmogenesis.

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Origin and consequences of fibroblast activation for atrial arrhythmogen...
Cardiac fibroblasts originate from multiple cellular sources including endothelial and epithelial cells. During development, the primary pool of resident, quiescent cardiac fibroblasts arises from the mesenchyme via EMT and EndMT. Resident fibroblasts are the primary cells responsible for ECM homeostasis. In disease, a secondary pool of fibroblast-like cells arises from various cellular sources including epithelial and endothelial cells via EMT and EndMT. The exact contribution of the secondary pool to fibroblast generation is unknown. Profibrotic stimuli cause the proliferation and differentiation of fibroblasts into myofibroblasts, increasing collagen production. Ca2+ influx importantly regulates fibroblast function, and increases in intracellular Ca2+ promote the differentiation of fibroblasts into collagen-secreting myofibroblasts. Collagen production steadily increases throughout the fibroblast activation loop and peaks when the fibroblasts have fully differentiated into activated myofibroblasts. Whether the collagen-secreting myofibroblasts differentiate into quiescent matrifibrocytes in the atria is unknown. Pro-collagen is synthesized in the ER and secreted into the extracellular space, where it matures and assembles into collagen fibers. Enhanced collagen deposits result in fibrotic remodeling and conduction abnormalities that promote AF-maintaining reentrant activity. Activated fibroblasts and myofibroblasts secrete signaling molecules and can electrotonically couple with cardiomyocytes to potentially promote delayed afterdepolarization (DAD), DAD-triggered action potentials (AP), and ectopic (triggered) activity that may cause AF.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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