Metabolic reprogramming in skin wound healing

Abstract

Metabolic reprogramming refers to the ability of a cell to alter its metabolism in response to different stimuli and forms of pressure. It helps cells resist external stress and provides them with new functions. Skin wound healing involves the metabolic reprogramming of nutrients, such as glucose, lipids, and amino acids, which play vital roles in the proliferation, differentiation, and migration of multiple cell types. During the glucose metabolic process in wounds, glucose transporters and key enzymes cause elevated metabolite levels. Glucose-mediated oxidative stress drives the proinflammatory response and promotes wound healing. Reprogramming lipid metabolism increases the number of fibroblasts and decreases the number of macrophages. It enhances local neovascularization and improves fibrin stability to promote extracellular matrix remodelling, accelerates wound healing, and reduces scar formation. Reprogramming amino acid metabolism affects wound re-epithelialization, collagen deposition, and angiogenesis. However, comprehensive reviews on the role of metabolic reprogramming in skin wound healing are lacking. Therefore, we have systematically reviewed the metabolic reprogramming of glucose, lipids, and amino acids during skin wound healing. Notably, we identified their targets with potential therapeutic value and elucidated their mechanisms of action.

Keywords: Metabolic reprogramming; Molecular mechanism; Skin; Therapeutic potential; Wound healing.

Figure 1

Three processes of wound healing (1) In the inflammatory stage, neutrophils migrate to the wound surface, and macrophages kill bacteria and ingest foreign debris through phagocytosis and hydrolase release. (2) In the proliferation stage, endothelial cells promote angiogenesis, fibroblasts produce a large amount of ECM to form granulation tissue to encapsulate damaged tissue, and keratinocytes mediate epithelialization. (3) At the stage of tissue remodeling, fibroblasts differentiate into muscle fibroblasts, and the ECM increases. ECM extracellular matrix

Figure 2

Reprogramming of glucose metabolism in wound healing. Glycolysis and the relative metabolic pathways are shown. Broad arrows (in red) indicate increased expression/activity of enzymes and the relative metabolic pathways. GLUT promotes glucose intake, supporting the glycolytic pathway. High expression of HK, PKM2, and LDHA activate glycolysis, promoting wound healing. α-KG α-ketoglutarate, GLUT glucose transporter, G6P glucose-6-phosphate, HK hexokinase, LDHA lactate dehydrogenase A, PKM2 pyruvate kinase 2, TCA tricarboxylic acid

Figure 3

Reprogramming of lipids metabolism in wound healing. Lipid synthesis, β-oxidation, and the relative metabolic pathways are shown. Broad arrows (in red) indicate increased expression/activity of enzymes and the relative metabolic pathways. The consequent raise of exogenous fatty acids up-take sustains increased lipid synthesis and β-oxidation. Fatty aceyl-CoA stimulates citrate, which acts as positive feedback, driving the progression of wound healing. α-KG α-ketoglutarate, FA fatty acid, HMGCR 3-hydroxy-3-methyl glutaryl coenzyme A reductase, SCD1 stearoyl-CoA desaturase-1, TCA tricarboxylic acid

Figure 4

Reprogramming of amino acids metabolism in wound healing. Metabolism of amino acids in wound healing are shown. Broad arrows (in red) indicate activity of the relative metabolic pathways. Amino acids are crucial for collagen synthesis, ECM production, wound healing, and tissue remodeling, all of which are achieved through the metabolism of amino acids. α-KG α-ketoglutarate, TCA tricarboxylic acid

Figure 5

Landscape of metabolic reprogramming and related pathways in wound healing. The metabolism of glucose, lipids, and amino acids is reprogrammed owing to changes in key enzymes and transporters. These altered metabolic pathways provide opportunities for therapy. Long solid and dotted arrows represent direct and indirect shifts or bioconversions, respectively. Square symbols (in blue) represent metabolic materials and products in metabolic reprogramming in wound healing, whereas yellow oval symbols represent enzymes and transporters. α-KG α-ketoglutarate, FA fatty acid, GLUT glucose transporter, G6P glucose-6-phosphate, HK hexokinase, HMGCR 3-hydroxy-3-methyl glutaryl coenzyme A reductase, LDHA lactate dehydrogenase A, PKM2 pyruvate kinase 2, SCD1 stearoyl-CoA desaturase-1, SREBPs sterol-regulatory element binding proteins, TCA tricarboxylic acid