Cellular and Molecular Mechanisms of Scarless vs. Fibrotic Wound Healing: A Comprehensive Review
DOI:
https://doi.org/10.22034/JATE.2026.229Keywords:
Wound healing, Fibrosis, Myofibroblasts, Macrophage Activation, Extracellular matrixAbstract
Wound healing restores tissue integrity through overlapping phases of hemostasis, inflammation, proliferation, and remodeling. While adult wounds typically heal via fibrotic repair with excessive extracellular matrix deposition and scarring, early gestation fetal skin demonstrates scarless regenerative healing with complete architectural restoration. Understanding mechanisms distinguishing these outcomes is critical given the clinical burden of pathological fibrosis and chronic wounds.
This review synthesizes recent advances from single-cell and spatial transcriptomics to present a comprehensive framework comparing fibrotic and regenerative healing. We evaluate cellular heterogeneity, molecular signaling networks, and environmental drivers determining healing phenotype.
Healing outcome emerges from three interconnected regulatory axes: fibroblast lineage specification, where distinct developmental subpopulations (POSTN+, CD26+) carry predispositions toward fibrotic or regenerative responses; mechanical signaling, wherein YAP/TAZ mechanotransduction integrates matrix stiffness and tension to amplify fibroblast programs; and immune modulation, with prolonged neutrophil persistence and macrophage activation driving fibrosis through NET release and pro-fibrotic crosstalk. Critical molecular determinants include the TGF-β3/TGF-β1 ratio with isoform-specific Smad activation, inflammatory dynamics, and extracellular matrix composition, particularly high molecular weight hyaluronic acid and collagen organization. Cell-cell communication networks, notably POSTN-SPP1 positive feedback loops between profibrotic fibroblasts and macrophages, establish self-reinforcing fibrotic cycles.
Therapeutic strategies targeting multiple axes sequentially or simultaneously hold greater promise than isolated pathway inhibition. However, significant challenges remain in achieving spatiotemporal delivery control, addressing patient heterogeneity, and translating rodent findings to humans. Future progress requires biomarker-stratified approaches, validated predictive markers, and clinical trials with scar quality endpoints to redirect adult wound healing toward regeneration.
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