What is cardiac fibrosis, and what is the role of the extracellular matrix?

Cardiac fibrosis refers to the excessive accumulation of extracellular matrix (ECM) proteins, such as collagen, in the heart. This process is part of the body’s natural response to injury, but when it becomes chronic or uncontrolled, it can impair heart function³.

There are two main types of fibrosis in the heart. Reactive interstitial fibrosis expands the space between muscle fibers and around blood vessels without significantly losing heart muscle cells or altering muscle bundle structure⁴. This fibrosis reflects a stress or injury response while preserving heart tissue architecture. Replacement fibrosis occurs when damaged or dead cardiomyocytes are replaced by extracellular matrix and fibroblasts, disrupting muscle bundle continuity but maintaining tissue integrity. It is commonly associated with ischaemia, ischaemia/reperfusion injury, inflammation, or toxic exposure agents.

Common triggers of cardiac fibrosis include hypertension, myocardial infarction, aging, and genetic cardiomyopathies. In each case, the fibrotic response is driven by a complex interplay of mechanical stress, inflammation, and molecular signaling⁵. Inflammatory cells infiltrate the heart tissue and contribute to the development and progression of fibrosis by releasing cytokines and growth factors, while immune responses regulate the activation and behavior of these cells during the fibrotic process.

Overview of the TGF-β signaling axis

TGF-β is a cytokine family that regulates cell growth, differentiation, and ECM production. The TGF-β family is part of the larger TGF-β superfamily, which includes multiple subfamilies and isoforms that regulate diverse cellular processes such as development, immune response, and cancer progression. Among the three TGF-β isoforms (TGF-β1, TGF-β2, and TGF-β3), TGF-β1 is the most studied in the context of fibrosis, while the other isoforms have distinct but overlapping roles in tissue development and immune regulation⁶.

Once active, TGF-β binds to the TGF-β receptor, a type of cell receptor, on the cell surface. This interaction is a critical step in the TGF-β pathway and β signaling pathway, initiating two main signaling routes:

• Canonical pathway: This involves SMAD proteins. TGF-β binding leads to phosphorylation of SMAD2 and SMAD3, which then form a complex with SMAD4 and move into the nucleus to regulate gene expression⁷.
• Non-canonical pathways: These include MAPK, PI3K/AKT, and Rho-like GTPase signaling. These routes can modulate cell behavior independently or in conjunction with SMAD signaling.

TGF-β signaling increases the expression of collagen I and III, fibronectin, and alpha-smooth muscle actin (α-SMA). These proteins are key components of the fibrotic ECM and markers of activated fibroblasts⁸.

TGF-β signaling in cardiac fibroblast activation

Cardiac fibroblasts are the main producers of ECM in the heart. Under normal conditions, they help maintain tissue structure. However, in response to TGF-β, these cells can transform into myofibroblasts – a more active form that secretes large amounts of ECM and expresses contractile proteins like α-SMA⁹.

This fibroblast-to-myofibroblast transition is a hallmark of fibrosis. Myofibroblasts not only deposit ECM but also generate mechanical tension, which further activates TGF-β signaling in a positive feedback loop¹⁰.

TGF-β can act in both autocrine (affecting the same cell that produces it) and paracrine (affecting nearby cells) manners. This amplifies the fibrotic response and helps sustain it even after the initial trigger has subsided.

Experimental models and research insights

Animal models have been instrumental in studying cardiac fibrosis. In pressure overload models, such as transverse aortic constriction in mice, TGF-β signaling is upregulated and correlates with increased fibrosis. Similarly, myocardial infarction models show elevated TGF-β activity in the infarct and border zones¹¹.

Mechanisms of TGF-β activation in these experimental models include integrin expression on various cell types and the generation of reactive oxygen species, both of which can activate latent TGF-β and influence cellular mechanisms underlying fibrosis¹².

More recently, researchers have turned to human induced pluripotent stem cell (iPSC)-derived cardiac fibroblasts and 3D cardiac organoids. These models offer a more human-relevant system for studying fibrosis and testing therapies. The use of retinoic acid in these systems has enabled the study of immune cell differentiation, including regulatory T cells, within the cardiac microenvironment¹³.

Studies have also revealed crosstalk between TGF-β and other pathways, such as Wnt, Hippo, and Notch. These interactions can fine-tune the fibrotic response and may offer additional therapeutic targets¹⁴.

Therapeutic implications

Given its central role in fibrosis, TGF-β signaling is an attractive target for therapy¹⁵. Several strategies are being explored:

• Small molecule inhibitors that block TGF-β receptors or downstream kinases
• Neutralizing antibodies that bind to TGF-β ligands
• Gene therapy approaches that modulate TGF-β expression or signaling components

TGF-β's regulatory function in immune regulation is critical, as it helps maintain immune homeostasis and balance between pro-inflammatory and anti-inflammatory responses. However, targeting TGF-β is not without challenges. This pathway involves many physiological processes, including immune regulation and tissue repair. Broad inhibition can lead to unwanted side effects¹⁶.

Timing is also important. Inhibiting TGF-β too early may impair healing, while late intervention may be less effective. Identifying biomarkers that indicate when and where to intervene is a key area of research.

Future directions

Several questions remain. Can we develop therapies that selectively modulate TGF-β in the heart without affecting other tissues? What are the best biomarkers to guide treatment? How can we predict which patients will benefit from anti-fibrotic therapies?

Emerging tools like multi-omics profiling and AI-driven drug discovery are helping to answer these questions. By integrating data from genomics, proteomics, and imaging, researchers can build more detailed maps of fibrotic signaling networks¹⁷.

There is also growing interest in precision medicine approaches. By stratifying patients based on genetic, molecular, or imaging data, we may be able to tailor therapies more effectively¹⁸.

As our understanding of the TGF-β signaling axis deepens, new opportunities are emerging to manage cardiac fibrosis in a more targeted and personalized way.

References

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11. Ding, Y.  et al.  Morphological and functional characteristics of animal models of myocardial fibrosis induced by pressure overload.  Int. J. Hypertens.  2020, 3014693 (2020).

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14. Bakalenko, N.  et al.  The complex interplay of TGF-β and Notch signaling in the pathogenesis of fibrosis.  Int. J. Mol. Sci.  25, 10803 (2024).

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