Organ and tissue fibrosis: Molecular signals, cellular mechanisms and translational implications

Abstract

Fibrosis denotes excessive scarring, which exceeds the normal wound healing response to injury in many tissues. Although the extracellular matrix deposition appears unstructured disrupting the normal tissue architecture and subsequently impairing proper organ function, fibrogenesis is a highly orchestrated process determined by defined sequences of molecular signals and cellular response mechanisms. Persistent injury and parenchymal cell death provokes tissue inflammation, macrophage activation and immune cell infiltration. The release of biologically highly active soluble mediators (alarmins, cytokines, chemokines) lead to the local activation of collagen producing mesenchymal cells such as pericytes, myofibroblasts or Gli1 positive mesenchymal stem cell-like cells, to a transition of various cell types into myofibroblasts as well as to the recruitment of fibroblast precursors. Clinical observations and experimental models highlighted that fibrosis is not a one-way road. Specific mechanistic principles of fibrosis regression involve the resolution of chronic tissue injury, the shift of inflammatory processes towards recovery, deactivation of myofibroblasts and finally fibrolysis of excess matrix scaffold. The thorough understanding of common principles of fibrogenic molecular signals and cellular mechanisms in various organs - such as liver, kidney, lung, heart or skin - is the basis for developing improved diagnostics including biomarkers or imaging techniques and novel antifibrotic therapeutics.

Keywords: Biomarkers; Exosome; Fibroblasts; Imaging; Macrophage; Matrix; Organ fibrosis; Regression; Therapy.