Wound Healing Mechanisms in Mammalian Systems

Wound healing in mammals is a highly coordinated process encompassing four overlapping phases: haemostasis, inflammation, proliferation and remodelling. Immediate vascular constriction and clot formation limit blood loss, while activated platelets release cytokines that recruit neutrophils and macrophages to clear debris and orchestrate the inflammatory response. During the proliferative phase, keratinocytes migrate to re-epithelialize the wound surface, fibroblasts synthesise extracellular matrix components such as collagen and fibronectin, and endothelial cells drive angiogenesis to restore perfusion. Myofibroblasts generate contractile forces that reduce wound size, and dermal white adipose tissue contributes signalling factors and energy substrates. Over weeks to months, matrix remodelling mediated by matrix metalloproteinases and tissue inhibitors refines scar architecture. Transcription factors, growth factors (for example TGF-β, FGF and PDGF), bioactive lipids and metabolic sensors (notably AMP-activated protein kinase) integrate cellular behaviours. The balance between regeneration and fibrosis underpins scar formation, and insights into embryonic-like healing programmes inform novel therapies aimed at scar minimisation and functional tissue restoration.

Research from Nature Portfolio

Recent studies have shown that pharmacological activation of AMP-activated protein kinase in murine wounds promotes the assembly of actin cables at the epithelial margin, mimicking embryonic wound closure and reducing scar formation. Administration of salicylate immediately post-injury induced robust epithelial actin remodelling via AMPK-Rac1 signalling, enhanced panniculus carnosus contraction and achieved near-complete tissue regeneration in adult mice.

Investigations into fetal skin have identified critical developmental windows for scarless repair. Full-thickness incisions made before embryonic day 13 regenerate all skin layers and appendages; beyond this stage, loss of epidermis–dermis positional cues and actin cable formation leads to fibrosis. Manipulation of AMPK activity in utero demonstrated that modulation of actin cable dynamics can shift wounds between regenerative and reparative outcomes.

Proteomic analysis of cultured keratinocytes revealed that hypoxic conditions upregulate the transcription factor Foxn1, driving expression of matrix-remodelling enzymes such as Mmp-9. Hypoxia-induced Foxn1 amplifies pathways governing keratinocyte proliferation, differentiation and epithelial–mesenchymal transition, thus coordinating the re-epithelialization phase and influencing scar severity.

Wound Healing Mechanisms in Mammalian Systems publication trend

The graph below shows the total number of articles in wound healing mechanisms in mammalian systems across all publications each year (not limited to Nature Index journals).

Technical terms

Re-epithelialization: Restoration of a continuous epithelial layer through keratinocyte migration and proliferation over the wound bed.

Extracellular matrix (ECM): A complex network of proteins and glycosaminoglycans that provides structural support and biochemical cues to cells during repair.

Actin cable: Contractile bundles of filamentous actin assembled at the wound margin to drive epithelial sheet closure.

AMP-activated protein kinase (AMPK): A cellular energy sensor that regulates metabolic pathways and cytoskeletal dynamics in response to stress.

Epithelial–mesenchymal transition (EMT): A process by which epithelial cells acquire migratory properties, facilitating wound closure and remodelling.

Dermal white adipose tissue (dWAT): A local fat depot in the dermis that modulates inflammation, energy supply and paracrine signalling during skin repair.

References

1. Salicylate induces epithelial actin reorganization via activation of the AMP-activated protein kinase and promotes wound healing and contraction in mice. Scientific Reports (2024).
2. Actin cable formation and epidermis–dermis positional relationship during complete skin regeneration. Scientific Reports (2022).
3. Foxn1 expression in keratinocytes is stimulated by hypoxia: further evidence of its role in skin wound healing. Scientific Reports (2018).
4. Mesenchymal stem cells paracrine proteins from three‐dimensional dynamic culture system promoted wound healing in third‐degree burn models. Bioengineering & Translational Medicine (2023).
5. Gender Differences in Post-Operative Human Skin. Biomedicines (2023).
6. Dermal white adipose tissue development and metabolism: The role of transcription factor Foxn1. The FASEB Journal (2023).