The alarmin HMGB-1 influences healing outcomes in fetal skin wounds
In mice, cutaneous wounds generated early in development (embryonic day 15, E15) heal scarlessly, while wounds generated late in gestation (embryonic day 18, E18) heal with scar formation. Even though both types of wounds are generated in the same sterile uterine environment, scarless fetal wounds h...
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| Published in | Wound repair and regeneration Vol. 21; no. 2; pp. 282 - 291 |
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| Main Authors | , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Blackwell Publishing Ltd
01.03.2013
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| Subjects | |
| Online Access | Get full text |
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| Summary: | In mice, cutaneous wounds generated early in development (embryonic day 15, E15) heal scarlessly, while wounds generated late in gestation (embryonic day 18, E18) heal with scar formation. Even though both types of wounds are generated in the same sterile uterine environment, scarless fetal wounds heal without inflammation, but a strong inflammatory response is observed in scar‐forming fetal wounds. We hypothesized that altered release of alarmins, endogenous molecules that trigger inflammation in response to damage, may be responsible for the age‐related changes in inflammation and healing outcomes in fetal skin. The purpose of this study was to determine whether the alarmin high‐mobility group box‐1 (HMGB‐1) is involved in fetal wound repair. Immunohistochemical analysis showed that in unwounded skin, E18 keratinocytes expressed higher levels of HMGB‐1 compared with E15 keratinocytes. After injury, HMGB‐1 was released to a greater extent from keratinocytes at the margin of scar‐forming E18 wounds, compared with scarless E15 wounds. Furthermore, instead of healing scarlessly, E15 wounds healed with scars when treated with HMGB‐1. HMGB‐1‐injected wounds also had more fibroblasts, blood vessels, and macrophages compared with control wounds. Together, these data suggest that extracellular HMGB‐1 levels influence the quality of healing in cutaneous wounds. |
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| Bibliography: | ArticleID:WRR12028 NIH - No. R01-CA127109 istex:A96DCA10748A4825D1C6355B871575F1BF94F146 ark:/67375/WNG-T5318J5W-1 Ohio State University Department of Pathology Figure S1. Wound closure and cellular apoptosis are unaffected by HMGB-1 in E15 fetal wounds. Wound closure was determined by examining histologic sections (A). Serial sections of the entire length of the wound were taken to ensure accuracy. All wounds, whether treated with PBS or HMGB-1, were unhealed at 12 hours post-wounding (not shown). Similar percentages of wounds contained an intact epithelial layer at 24 hours (25% or 2/8 wounds for PBS; 28% or 2/7 wounds for HMGB-1). All wounds, regardless of treatment, were completely reepithelialized by 48 hours (n = 4-8 per group at each time point). Immunohistochemical staining for cleaved caspase-3 was used to identify apoptotic cells (B-E). The number of cleaved caspase-3-positive cells was counted in the skin adjacent to the wound at 1 day (B) or in the wound bed at 3 and 7 days post-wounding (C). Bars represent average number of positive cells per high-power field (HPF) ± SEM (n = 3-5 per group at each time point). The data are presented as positive cells per HPF rather than positive cell density because of the low number of positive cells (0-2 cells per HPF). Similar results were obtained with TUNEL staining, except that the overall number of positive cells was slightly higher for all wounds (0-12 cells per HPF; data not shown). Representative sections stained for cleaved caspase-3 are shown for E15 wounds injected with PBS (D) or 400 ng HMGB-1 (E) at 7 days post-wounding. Arrows are used to highlight positive cells; scale bar = 50 μm.Figure S2. Mast cell density in fetal wounds treated with HMGB-1. Toluidine blue staining was used to evaluate mast cell density at the wound margin 12 and 24 hours postwounding (A). Bars represent average mast cell density (mast cell number per mm2) ± SEM (n = 3-5 per group). Representative toluidine blue-stained sections of E15 wounds injected with PBS (B) or 400 ng HMGB-1 (C) at 24 hours post-wounding are shown. Wound margins are marked with large arrows, and small arrows are used to highlight mast cells; scale bars = 100 μm. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ISSN: | 1067-1927 1524-475X |
| DOI: | 10.1111/wrr.12028 |