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Cellular heterogeneity in hypertrophic burn scars in response to carbon dioxide laser therapy

ABSTRACT: Background: Ablative fractional carbon dioxide (AFCO2) laser therapy is used for treating pathological scarring. However, mechanisms underlying reduction in hypertrophic scarring are poorly understood. Methods: We investigated cellular mechanisms of AFCO2 laser therapy by performing single-cell RNA sequencing (scRNA-seq) on skin biopsies from burn survivors with hypertrophic scars before and after three sessions of AFCO2 therapy. Scar reduction was assessed subjectively and objectively. Results: Those with a good response (GR) to laser therapy have scars less than 6 years from injury, whereas poor responders (PR) have scars over 6 years since injury. ScRNA-seq analysis of skin biopsies reveals that genes enriched in GR are associated with extracellular matrix and structure organisation (COL14A1, POSTN, SPARC); whereas genes enriched in PR are related to enhanced immune inflammatory responses (CXCL14, JUN, TNC). Notably, expression of the pro-fibrotic gene Engrailed-1 (EN1) remains elevated in PR scars compared to GR. The ECM-regulatory gene TIMP-1 (Tissue Inhibitor of Metalloproteinases 1) is also significantly upregulated in PR scars following treatment relative to GR scars, although at the protein level TIMP1 levels decrease in PR but increase in GR after therapy. The regenerative-associated gene, TRPS1 (Transcriptional Repressor GATA Binding 1) expression demonstrates opposing regulation post treatment, with upregulation observed in GR scars but downregulation in PR scars, underscoring distinct transcriptional trajectories associated with differential therapeutic outcomes. Finally, distinct intercellular communication networks and differentiation trajectories are observed after AFCO2, with regenerative mesenchymal fibroblasts predominating in GR but inflammatory fibroblasts associated with PR. Conclusions: We conclude AFCO2 laser therapy is more effective if done early after injury and distinct fibroblast recruitment is associated with a good response, specifically regenerative fibroblasts. Plain English summary: Ablative fractional carbon dioxide (AFCO2) laser therapy is used for reducing scarring. However, results are varied and the factors associated with a good response are poorly understood. We assessed scar reduction after AFCO2 therapy in patients with excessive scarring, taking skin biopsies to determine the cell types present in the treated areas and which genes they expressed. We showed that the therapy was more effective in patients who were less than 6 years from injury, those with a good response had scars containing regenerative fibroblasts and gene expression that was distinct from those with a poor response. We conclude that AFCO2 therapy is most effective if used early after injury and that a more regenerative, less inflammatory cell infiltration is associated with scar reduction.

ORGANISM(S): Homo sapiens

PROVIDER: GSE320017 | GEO | 2026/02/25

REPOSITORIES: GEO

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Project description:While considerable progress has been made towards understanding the complex processes and pathways that regulate human wound healing, regenerative medicine has been unable to develop therapies that coax the natural wound environment to heal scar-free. The inability to induce perfect skin regeneration stems partly from our limited understanding of how scar-free healing occurs in a natural setting. Here we have investigated the wound repair process in adult axolotls and demonstrate that they are capable of perfectly repairing full thickness excisional wounds made on the flank. In the context of mammalian wound repair, our findings reveal a substantial reduction in hemostasis, reduced neutrophil infiltration and a relatively long delay in production of new extracellular matrix (ECM) during scar-free healing. Additionally, we test the hypothesis that metamorphosis leads to scarring and instead show that terrestrial axolotls also heal scar-free, albeit at a slower rate. Analysis of newly forming dermal ECM suggests that low levels of fibronectin and high levels of tenascin-C promote regeneration in lieu of scarring. Lastly, a genetic analysis during wound healing comparing epidermis between aquatic and terrestrial axolotls suggests that matrix metalloproteinases may regulate the fibrotic response. Our findings outline a blueprint to understand the cellular and molecular mechanisms coordinating scar-free healing that will be useful towards elucidating new regenerative therapies targeting fibrosis and wound repair. We used microarray analysis to determine the gene expression changes that take place during scar free wound healing in aquatic and terrestrial axolotl salamanders. Epidermal tissue was harvested using a 4mm biopsy punch. Two wounds were made along the flank and posterior to the forelimbs. Harvested epidermis was pooled for each animal. Four biological replicates were collected from uninjured epidermis (D0) and at 1, 3, and 7 days post injury.

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Cellular heterogeneity in hypertrophic burn scars in response to carbon dioxide laser therapy

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