Signalling Underlying Wound Healing

Abstract

Wound healing is critical for normal tissue function and the survival of most multicellular organisms. Understanding the biochemical and cellular mechanisms underlying constructive physiological wound healing is crucial for developing therapies to aid in repair and regeneration. Wound healing involves multiple systems including blood, vasculature, somatosensory, immune system and the skin. Following vascular damage, coagulation system activation occurs resulting in clot formation and cell signalling events in both cells of the vasculature (e.g. endothelial cells) as well as circulating cells (e.g. platelets, leukocytes) in order to drive cessation of blood loss. Pain signalling is initiated in part by surrounding inflammatory cues and is used to prevent further damage to the wound. Following these initial responses to the wound, healing/regeneration returns the damaged tissue to a functional state. This occurs by engaging the fibrin network to create a new microenvironment architecture. A broad overview is presented of how the different organ systems are integrated to repair tissue after a wound. Key Concepts Blood coagulation is driven by exposure of the subendothelial receptor tissue factor that drives activation of downstream clotting factors, including activation of the central protease thrombin. Platelet activation is mediated by thrombin cleavage of cell surface protease‐activated receptors, tight receptor‐mediated binding to collagen or activation of the purinergic receptors (i.e. P2Y1, P2Y12). In addition to platelet activation, thrombin catalyses the conversion of fibrinogen into fibrin, the primary structural component of the blood clot. Immune cells like mast cells and macrophages are recruited and activated once a wound occurs, releasing cytokines and histamine. This inflammatory response aids in promoting pain signalling and eventually aids in the wound healing process. In response to the wound and release of inflammatory factors (e.g. cytokines, histamine, bradykinin, NGF and PGE2) sensory neurons become hypersensitive. This hypersensitisation (hyperalgesia) leads to innocuous tactile information to be interpreted as painful by both the peripheral nervous system (PNS) and central nervous system (CNS). Numerous stem cell populations derived from the dermis and hair follicle contribute to wound remodelling. These stem cells differentiate into cell types like myofibroblasts, which either repopulate the site of the wound and/or deposit new extracellular matrix proteins to form a fibrotic scar. A balance between Wnt and TGF‐β signalling guides regenerative and healing processes, respectively. Wnt signalling leads to cell proliferation and the reappearance of hair follicles inducing wounds to heal without a scar. TGF‐β signalling induces reticular dermis stem cells to differentiate into myofibroblasts, which leads to scar tissue.