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Updated: Oct 18, 2025
Refined CLARITY-Based Tissue Clearing for Three-Dimensional Fibroblast Organization in Healthy and Injured Mouse Hearts
Published on: May 16, 2021
Mechanisms of Fibroblast Activation and Myocardial Fibrosis: Lessons Learned from FB-Specific Conditional Mouse
Prachi Umbarkar1, Suma Ejantkar2, Sultan Tousif1
1Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Insights
Cardiac fibrosis, driven by fibroblasts, significantly impacts heart failure progression. Recent advancements in fibroblast-specific mouse models reveal key signaling pathways involved in cardiac remodeling and dysfunction.
Area of Science:
- Cardiovascular Biology
- Fibrosis Research
- Cardiac Pathophysiology
Background:
- Heart failure (HF) is a major global health burden.
- Cardiac fibrosis, excessive extracellular matrix accumulation, drives HF progression and cardiac dysfunction.
- Fibroblasts (FBs) are now recognized as key contributors to myocardial fibrosis.
Purpose of the Study:
- To review the evolving understanding of fibroblast biology in cardiac diseases.
- To highlight the critical role of fibroblasts in cardiac fibrosis pathogenesis.
- To update on FB-specific mouse models and validated fibrotic signaling pathways.
Main Methods:
- Review of existing literature on fibroblast biology and cardiac fibrosis.
- Focus on advancements in generating fibroblast-specific mouse models.
- Analysis of signaling pathways (e.g., TGF-β/SMAD3, Hippo) validated in vivo.
Main Results:
- Fibroblasts have shifted from a secondary to a primary role in understanding cardiac fibrosis.
- FB-specific mouse models have been crucial for validating fibrotic mechanisms.
- Key signaling pathways implicated in fibroblast activation and fibrosis have been identified.
Conclusions:
- Understanding fibroblast activation mechanisms is vital for managing cardiac fibrosis.
- Targeting fibroblast-driven fibrosis offers potential therapeutic strategies for heart failure.
- Continued research using advanced models will refine therapeutic approaches.
Abstract:
Heart failure (HF) is a leading cause of morbidity and mortality across the world. Cardiac fibrosis is associated with HF progression. Fibrosis is characterized by the excessive accumulation of extracellular matrix components. This is a physiological response to tissue injury. However, uncontrolled fibrosis leads to adverse cardiac remodeling and contributes significantly to cardiac dysfunction. Fibroblasts (FBs) are the primary drivers of myocardial fibrosis. However, until recently, FBs were thought to play a secondary role in cardiac pathophysiology. This review article will present the evolving story of fibroblast biology and fibrosis in cardiac diseases, emphasizing their recent shift from a supporting to a leading role in our understanding of the pathogenesis of cardiac diseases. Indeed, this story only became possible because of the emergence of FB-specific mouse models. This study includes an update on the advancements in the generation of FB-specific mouse models. Regarding the underlying mechanisms of myocardial fibrosis, we will focus on the pathways that have been validated using FB-specific, in vivo mouse models. These pathways include the TGF-β/SMAD3, p38 MAPK, Wnt/β-Catenin, G-protein-coupled receptor kinase (GRK), and Hippo signaling. A better understanding of the mechanisms underlying fibroblast activation and fibrosis may provide a novel therapeutic target for the management of adverse fibrotic remodeling in the diseased heart.
