FibrosisLab
Article
2025-11-24

Myofibroblast Origins and Activation: Why They 'Won't Die'—and How to Find Drug Targets

Myofibroblasts—the executors of fibrosis—should disappear after wound healing. Why do they persist and worsen fibrosis? We explore their origins (resident, pericyte, EMT) and survival signals to identify drug targets.

Fibroblasts and Myofibroblasts: The "Architects" of Fibrosis

"Why won't myofibroblasts die?"—this question holds the key to drug discovery.

In normal wound healing, myofibroblasts disappear via apoptosis after doing their job. But in fibrotic tissue, they persist, churning out collagen indefinitely. "Kill them" or "silence them"—this strategic choice is the focus of anti-fibrotic drug discovery. This article dives deep into the diverse origins and activation maintenance mechanisms of myofibroblasts.

1. What are Myofibroblasts?

Definition and Characteristics

Myofibroblasts are cells with intermediate properties between Fibroblasts and Smooth Muscle Cells.

  • Contractility: Contract like smooth muscle to physically shrink wounds (Wound Contraction).
  • Vigorous ECM Production: Produce far greater amounts of collagen and fibronectin than normal fibroblasts.
  • Marker: Expression of α-SMA (Alpha-Smooth Muscle Actin) is the most common indicator.

Role: A Double-Edged Sword

  • Normal Healing: Close wounds, create a scaffold (ECM), and disappear via apoptosis when healing is complete.
  • Fibrotic Disease: Remain after healing (apoptosis resistance), continue to produce excessive ECM, making organs stiff and dysfunctional.

2. Where Do They Come From? (Diversity of Origins)

The origin of myofibroblasts is not single. Recent lineage tracing studies have revealed diverse roots.

1. Resident Fibroblasts

  • The major source. Fibroblasts originally present in the tissue activate and transform.

2. Pericytes

  • Cells surrounding blood vessels. Detaching from vessels and differentiating into myofibroblasts is considered important, especially in kidney and lung fibrosis.

3. Epithelial-Mesenchymal Transition (EMT)

  • A phenomenon where epithelial cells lose their properties and change into mesenchymal cells (fibroblast-like).
  • Once thought to be a major source, recent studies have re-evaluated its role as creating an environment (promoting fibrosis) via paracrine factors rather than direct differentiation into myofibroblasts.

4. Bone Marrow-Derived Cells (Fibrocytes)

  • Progenitor cells that migrate to the injury site via the bloodstream.

3. Activation Mechanisms: Why Do They Go Out of Control?

TGF-β Signaling: The Strongest Driver

  • TGF-β1 is the most potent cytokine that differentiates fibroblasts into myofibroblasts.
  • Directly turns on gene expression of α-SMA and collagen via the Smad pathway.

Mechanotransduction (Sensing Stiffness)

  • Vicious Cycle of "Stiffness Begets Stiffness": Fibroblasts have the ability to sense the stiffness of the scaffold (ECM).
  • When tissue becomes stiff, mechanosensors like YAP/TAZ translocate into the nucleus, causing further activation. It is known that a stiff environment alone can promote myofibroblast differentiation even without TGF-β.

FAP (Fibroblast Activation Protein)

  • A surface enzyme specifically expressed in activated fibroblasts (especially Cancer-Associated Fibroblasts CAFs and fibrosis sites).
  • May label a different subset than α-SMA, attracting attention as a new therapeutic target.

4. Therapeutic Application: How to Stop Them?

Deactivation / Reversion

  • Attempts to return myofibroblasts to their original quiet fibroblast state.
  • Rho kinase inhibitors and YAP/TAZ inhibitors are being researched.

Induction of Apoptosis

  • Ordering "death" to the lingering myofibroblasts.
  • Bcl-2 inhibitors and others are being researched in the context of senolysis (removal of senescent cells).

Conclusion

Fibroblasts and myofibroblasts are the execution unit of fibrosis. Their origins and activation mechanisms are complex, but understanding markers like α-SMA and FAP, and control pathways like TGF-β and Mechanotransduction, is essential for selecting drug discovery targets. Our models have established efficacy evaluation systems using these marker expressions as indicators, and we can propose the optimal test system tailored to the mechanism of action (MOA) of the compound.

References

  1. Hinz B, et al. The myofibroblast: one function, multiple origins. Am J Pathol. 2007;170(6):1807-1816.
  2. Klingberg F, et al. The myofibroblast matrix: implications for tissue repair and fibrosis. J Pathol. 2013;229(2):298-309.
  3. Pakshir P, et al. The myofibroblast at a glance. J Cell Sci. 2020;133(13):jcs227900.