Pathological Interplay of ROS With Myofibroblasts: An Impediment to Corneal Restitution

Myofibroblasts are morphologically similar cells with diverse origins that exhibit characteristics of both fibroblasts and smooth muscle cells. Following insults, myofibroblasts play critical roles in tissue reintegration and restitution. However, their prolonged presence and activity impede physiological recovery, leading to persistent or progressive tissue complications, as evidenced in corneal fibrosis and opacification. Reactive oxygen species (ROS) are key signaling intermediates in various cellular events, playing critical roles in the physiology of myofibroblasts. However, when dysregulated, these molecules can engage in misinstructive manners with myofibroblasts, directing these cells toward pathogenic states and behaviors. In brief, dysregulated ROS pathologically modulate myofibroblast differentiation, extracellular matrix (ECM) remodeling, and immune evasion, maintaining self-perpetuating cycles of myofibroblast survival. The mediation of ROS promotes maladaptive intra and extracellular responses that contribute to myofibroblast persistence by enhancing ECM stiffness, increasing resistance to apoptosis, inducing senescence, and impairing immune clearance. ROS-mediated alterations in ECM components, most notably in proteoglycans (PGs) and glycosaminoglycans (GAGs), further dysregulate the ECM and make it more conducive to myofibroblast persistence. Additionally, ROS-induced immune privilege mechanisms prevent the proper clearance of myofibroblasts. Therefore, targeting ROS collectively offers promising therapeutic potential for mitigating their pathological presence and behavior, thereby enhancing overall corneal recovery following insults.