Myofibroblast Differentiation: Main Features, Biomedical Relevance, and the Role of Reactive Oxygen Species

SIGNIFICANCE: Myofibroblasts are prototypical fibrotic cells, which are involved in a number of more or less pathological conditions, from foreign body reactions to scarring, from liver, kidney, or lung fibrosis to neoplastic phenomena. The differentiation of precursor cells (not only of fibroblastic nature) is characterized by a complex interplay between soluble factors (growth factors such as transforming growth factor β1, reactive oxygen species [ROS]) and material properties (matrix stiffness). RECENT ADVANCES: The last 15 years have seen very significant advances in the identification of appropriate differentiation markers, in the understanding of the differentiation mechanism, and above all, the involvement of ROS as causative and persistence factors. CRITICAL ISSUES: The specific mechanisms of action of ROS remain largely unknown, although evidence suggests that both intracellular and extracellular phenomena play a role. FUTURE DIRECTIONS: Approaches based on antioxidant (ROS-scavenging) principles and on the potentiation of nitric oxide signaling hold much promise in view of a pharmacological therapy of fibrotic phenomena. However, how to make the active principles available at the target sites is yet a largely neglected issue.