Mechanisms & Challenges

Fibrosis is primarily driven by fibroblasts embedded in a complex extracellular matrix (ECM). Normally quiescent, these fibroblasts activate into myofibroblasts in response to tissue injury. Myofibroblasts are characterized by a contractile phenotype (due to increased expression of smooth muscle actin ), a secretory phenotype (synthesizing collagen I and III), and stabilized focal adhesions. While transient fibroblast activation is crucial for wound healing, the prolonged presence of myofibroblasts leads to excessive ECM production and tissue stiffening, progressively and irreversibly impairing tissue function. 

In many cases, organ transplantation remains the only hope for patients affected by fibrosis.
The lack of understanding of the molecular mechanisms controlling healthy healing versus pathological fibrosis, combined with the limitations of existing in vitro and in vivo models, remain the key obstacles to developing effective treatments.

Signaling pathways and therapeutic strategies

Phenoconversion is cooperatively regulated by multiple pro-fibrotic molecules and mechanical signals. The TGFβ signaling pathway is recognized as a key driver of fibroblast phenoconversion. Briefly, once released, TGFβ binds to TGFβR2 and TGFβR1 receptors. Constitutively active TGFβR2 phosphorylates TGFβR1, ensuring both canonical and non-canonical ligand-induced signaling. Canonical signaling is mediated by SMAD2/SMAD3 phosphorylation, which then binds to SMAD4. The complex translocates to the nucleus, binding to specific promoters and inducing the transcription of pro-fibrotic genes. In the non-canonical pathway, TGFβRs phosphorylate TAK1 kinase, which in turn activates c-Jun and p38, both of which induce pro-fibrotic gene transcription. Other biochemical signals such as angiotensin II, endothelin I, CTGF, and PDGF, along with components of the provisional extracellular matrix like fibronectin ED-A, hyaluronan (HA), and versican, can also promote fibroblast phenoconversion. Mechanical forces and proteins involved in mechanotransduction further contribute to the differentiation of fibroblasts into myofibroblasts and a few therapeutic strategies aimed at modulating mechanical phenoconversion in fibroblasts have been explored in clinical settings, including targeting integrins, collagen fiber cross-linking (via HSP27 and LOXL2), CTGF, or FAK.