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Updated: Dec 19, 2025
Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Paired box 6 inhibits cardiac fibroblast differentiation
Yenan Feng1, Mingzhe Li1, Shuaixing Wang1
1Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.
Insights
Paired box 6 (Pax6) inhibits cardiac fibroblast differentiation and extracellular matrix production. Maintaining Pax6 expression in cardiac fibroblasts is crucial for preventing cardiac fibrosis and offers a potential therapeutic target.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Fibrosis Research
Background:
- Cardiac fibroblast (CF) differentiation is key to cardiac fibrosis, differentiating pathological from physiological hypertrophy.
- Paired box 6 (Pax6) DNA-binding activity is differentially regulated in hypertrophy, but its role in CF differentiation and fibrosis is unknown.
Purpose of the Study:
- To investigate the role of Pax6 in cardiac fibroblast differentiation and its involvement in cardiac fibrosis.
Main Methods:
- Assessed Pax6 expression in mouse hearts and isolated cardiac fibroblasts.
- Utilized angiotensin II (Ang II) to induce cardiac fibrosis in vitro and in vivo.
- Performed Pax6 knockdown in CFs to evaluate effects on myofibroblast markers and ECM synthesis.
- Validated Pax6 binding to promoter/intronic regions of target genes (Cxcl10, Il1r2, Tgfb1).
Main Results:
- Angiotensin II downregulated Pax6 expression in fibrotic hearts and cardiac myofibroblasts.
- Pax6 knockdown in CFs increased α-smooth muscle actin (α-SMA) and extracellular matrix (ECM) protein synthesis.
- Pax6 knockdown decreased CXCL10 and IL-1R2 expression while increasing TGFβ1 expression, mimicking Ang II effects.
Conclusions:
- Pax6 inhibits CF differentiation and ECM synthesis by activating anti-fibrotic factors (CXCL10, IL-1R2) and repressing pro-fibrotic factors (TGFβ1).
- Maintaining Pax6 expression in CFs is essential for preventing cardiac fibrosis, presenting Pax6 as a therapeutic target.
Abstract:
Cardiac fibroblast (CF) differentiation plays a crucial role in cardiac fibrosis, which is a specific manifestation distinguishing pathological cardiac hypertrophy from physiological hypertrophy. The DNA-binding activity of paired box 6 (Pax6) has been shown to be oppositely regulated in physiological and pathological hypertrophy; however, it remains unclear whether Pax6 is involved in CF differentiation during cardiac fibrosis. We found that Pax6 is expressed in the heart of and CFs isolated from adult mice. Moreover, angiotensin II (Ang II) induced the downregulation of Pax6 mRNA and protein expression in fibrotic heart tissue and cardiac myofibroblasts. Pax6 knockdown in CFs promoted the expression of the myofibroblast marker α-smooth muscle actin (α-SMA) and the synthesis of the extracellular matrix (ECM) proteins collagen I and fibronectin. Furthermore, we validated the ability of Pax6 to bind to the promoter regions of Cxcl10 and Il1r2 and the intronic region of Tgfb1. Pax6 knockdown in CFs decreased CXC chemokine 10 (CXCL10) and interleukin-1 receptor 2 (IL-1R2) expression and increased transforming growth factor β1 (TGFβ1) expression, mimicking the effects of Ang II. In conclusion, Pax6 exerts an inhibitory effect on CF differentiation and ECM synthesis by transcriptionally activating the expression of the anti-fibrotic factors CXCL10 and IL-1R2 and repressing the expression of the pro-fibrotic factor TGFβ1. Therefore, maintaining Pax6 expression in CFs is essential for preventing CF differentiation, and provides a new therapeutic target for cardiac fibrosis.
