Mechanisms of Fibrosis: Pathology at the End of Healing

Introduction: What is Fibrosis?

"Fibrosis" is a pathological condition where tissue becomes hard and scarred due to the excessive accumulation of extracellular matrix (ECM). Originally, in wound healing after tissue injury, ECM such as collagen temporarily increases but is usually degraded and removed after repair is complete. However, if this repair process runs out of control due to chronic inflammation or persistent tissue injury, irreversible fibrosis progresses, leading to organ failure. Based on findings from top journals like Nature and Cell, this article explains the molecular mechanisms of fibrosis.

1. The Central Player of Fibrosis: The Myofibroblast

The essence of fibrosis is the abnormal activation and persistent presence of specialized cells called "Myofibroblasts."

Origins of Myofibroblasts

Myofibroblasts differentiate from diverse cell sources (Nature Reviews Molecular Cell Biology):

Resident fibroblasts: The most primary source.
Pericytes: Existing around blood vessel walls.
Epithelial/Endothelial cells: Via EMT (Epithelial-Mesenchymal Transition) or EndMT (Endothelial-Mesenchymal Transition).
Bone marrow-derived circulating cells (Fibrocytes): Recruited from circulation.
Hepatic stellate cells: Specific to the liver.

α-SMA Expression and Contractility

The most defining feature of myofibroblasts is the expression of α-SMA (α-smooth muscle actin), a marker of smooth muscle, and their strong contractile force. This contraction promotes wound closure, but when excessive, it physically deforms the tissue and impairs organ function.

2. TGF-β Signaling: The "Master Regulator" of Fibrosis

The most important cytokine in fibrosis is TGF-β (Transforming Growth Factor-beta).

Actions of TGF-β

Induces differentiation from fibroblasts to myofibroblasts.
Powerfully promotes ECM production (collagen, fibronectin, etc.).
Increases inhibitors of ECM-degrading enzymes (TIMPs), suppressing degradation.

TGF-β is continuously released from macrophages activated by chronic inflammation or damaged epithelial cells, accelerating fibrosis (Cell 2017).

3. Mechanical Feedback: Stiffness Begets Stiffness

Recent research highlights Mechanotransduction, a mechanism where the physical stiffness of tissue alters cell behavior.

ECM Stiffening Accelerates Fibrosis

As fibrosis progresses, tissue becomes stiffer due to excessive collagen deposition.
Fibroblasts sensing this stiffness activate transcription factors called YAP/TAZ, further increasing ECM production.
A positive feedback loop is established: Stiffness → Fibroblast Activation → More Stiffness.

This mechanism is considered one reason why fibrosis may not stop even if TGF-β is suppressed by drugs (Nature 2018).

4. Irreversibility of Fibrosis: Why Doesn't It Heal?

As fibrosis progresses, spontaneous healing becomes difficult due to:

Myofibroblast "Memory": Once activated, myofibroblasts maintain activity via epigenetic changes even after the stimulus is removed.
ECM Cross-linking: Collagen fibers bind tightly together, becoming resistant to enzymatic degradation.
Impaired Angiogenesis: Excessive ECM compresses blood vessels, reducing nutrient supply.

Conclusion

Fibrosis is described as "wound healing that never stops." Strategies to not only treat acute inflammation but also to "regress" already formed fibrotic tissue are at the forefront of current drug discovery research. Our fibrosis models serve as a powerful platform to evaluate this complex process in stages and determine the true efficacy of anti-fibrotic drugs.

References

Distler JHW, et al. Shared and distinct mechanisms of fibrosis. Nat Rev Rheumatol. 2019;15(12):705-730.
Henderson NC, et al. Fibrosis: from mechanisms to medicines. Nature. 2020;587(7835):555-566.
Hinz B. Myofibroblasts. Exp Eye Res. 2016;142:56-70.

Molecular Mechanisms of Fibrosis: Myofibroblasts, TGF-β, and Mechanotransduction