Rewiring autophagy to target cutaneous wound healing: investigation of molecular mechanisms to therapeutic interventions

Rewiring of pathways regulating inflammation, metabolism, and regeneration must occur in a coordinated fashion during wound healing; however, this orchestration gets disrupted in chronic and diabetic wounds. Autophagy is a conserved lysosome-dependent pathway that controls the integration of nutrient homeostasis, adaptation to stresses, immune regulation, and cell remodelling during wound repair. Here we summarize the pivotal role of autophagy in the different crucial steps of wound healing. An open wound often attracts pathogens, leading to infection and inflammation. During this inflammation stage, autophagy mediates signalling from the pattern recognition receptors, generates cytokines, manoeuvres the defence against infection, and polarizes macrophage. During proliferation stage, autophagy promotes keratinocyte migration, fibroblast function, endothelial cell survival, angiogenesis, while minimizing oxidative injury and apoptosis. During the remodelling stage, autophagy participates in the remodelling of the extracellular matrix, collagen maturation, and scar formation. However, these processes are context-dependent; while insufficient autophagy prevents adaptation and regeneration, we see excessive autophagy may contribute to pathological conditions associated with chronic wounds. The analysis also considers new therapeutic approaches including mTOR and AMPK inhibitors, phytochemicals, exosomes from mesenchymal stem cells, and the use of biomaterials for the delivery of drugs. Although they improve re-epithelization, vascularization, and matrix organization in preclinical models, the clinical application of these approaches is hampered by the lack of specificity of the pathway, poor stability and penetrability of drugs, off-target effects, and a lack of clinical trials in humans.