Gene expression profiling of cutaneous wound healing
Kavita Deonarine1, Monica C Panelli, Mitchell E Stashower
1Immunogenetics Section, Department of Transfusion Medicine, Clinical Center National Institutes of Health, Bethesda, MD 20892, USA. kavitasoleil@yahoo.com
Background:
Although the sequence of events leading to wound repair has been described at the cellular and, to a limited extent, at the protein level this process has yet to be fully elucidated. Genome wide transcriptional analysis tools promise to further define the global picture of this complex progression of events.
Study Design:
This study was part of a placebo-controlled double-blind clinical trial in which basal cell carcinomas were treated topically with an immunomodifier--toll-like receptor 7 agonist: imiquimod. The fourteen patients with basal cell carcinoma in the placebo arm of the trial received placebo treatment consisting solely of vehicle cream. A skin punch biopsy was obtained immediately before treatment and at the end of the placebo treatment (after 2, 4 or 8 days). 17.5K cDNA microarrays were utilized to profile the biopsy material.
Results:
Four gene signatures whose expression changed relative to baseline (before wound induction by the pre-treatment biopsy) were identified. The largest group was comprised predominantly of inflammatory genes whose expression was increased throughout the study. Two additional signatures were observed which included preferentially pro-inflammatory genes in the early post-treatment biopsies (2 days after pre-treatment biopsies) and repair and angiogenesis genes in the later (4 to 8 days) biopsies. The fourth and smallest set of genes was down-regulated throughout the study. Early in wound healing the expression of markers of both M1 and M2 macrophages were increased, but later M2 markers predominated.
Conclusion:
The initial response to a cutaneous wound induces powerful transcriptional activation of pro-inflammatory stimuli which may alert the host defense. Subsequently and in the absence of infection, inflammation subsides and it is replaced by angiogenesis and remodeling. Understanding this transition which may be driven by a change from a mixed macrophage population to predominantly M2 macrophages, may help the interpretation of the cellular and molecular events occurring in the microenvironment of serially biopsied tissues.
Insights
This study reveals that wound healing involves an initial inflammatory gene response followed by genes promoting repair and angiogenesis. Macrophage populations shift from mixed M1/M2 to predominantly M2, driving this transition.
Area of Science:
- Dermatology
- Molecular Biology
- Immunology
Background:
- Wound repair is a complex biological process not fully understood at the molecular level.
- Genome-wide transcriptional analysis offers a powerful tool to investigate this process comprehensively.
Purpose of the Study:
- To elucidate the transcriptional changes during the early stages of wound healing.
- To identify gene signatures associated with inflammation, repair, and angiogenesis in response to topical treatment.
Main Methods:
- A placebo-controlled, double-blind clinical trial involving patients with basal cell carcinoma.
- Topical application of imiquimod (toll-like receptor 7 agonist) or vehicle cream.
- Skin punch biopsies analyzed using 17.5K cDNA microarrays at multiple time points (0, 2, 4, 8 days).
Main Results:
- Four distinct gene expression signatures were identified.
- An increase in inflammatory genes was observed throughout the study.
- Early biopsies showed pro-inflammatory genes and M1/M2 macrophage markers, while later biopsies revealed repair, angiogenesis genes, and predominantly M2 markers.
Conclusions:
- Cutaneous wound healing initiates with strong pro-inflammatory transcriptional activation.
- This is followed by a transition to angiogenesis and remodeling, potentially mediated by a shift to M2 macrophages.
- Understanding this inflammatory-to-repair transition is crucial for interpreting molecular events in wound healing.
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