L. C. Dewberry1, M. M. Hodges1, C. Zgheib1, J. Xu1, S. A. Hilton1, J. Hu1, K. W. Liechty1,2 1University Of Colorado Denver,Department Of Surgery,Aurora, CO, USA 2Children’s Hospital Colorado,Pediatric Surgery,Aurora, CO, USA
Introduction:
We have previously shown fetal skin wounds heal without scar formation, however, if fetal wound size increases there is a transition from scarless regeneration to scar formation, similar to scar formation seen in the adult. This transition from scarless regeneration to scar formation was also associated with an increased inflammatory response. Inflammation is regulated, in part, through gene expression of proinflammatory cytokines. Previous work from our laboratory has demonstrated increased gene expression of these proinflammatory cytokines (IL-6, IL-8). An additional layer of regulation is provided by micrRNAs. Specifically, miRNA-146a has been shown to act as a “molecular brake” on inflammation by inhibiting proinflammatory gene expression (specifically IL-6 and IL-8). We hypothesized that the transition from scarless regeneration to scar formation is associated with increased inflammation, increased proinflammatory signaling, and decreased miRNA-146a expression.
Methods:
To test this hypothesis 2-mm and 8-mm dermal wounds were created in mid-gestation fetal sheep (70-75 days gestation). Wounds were harvested at 3 and 7 days post-wounding, total RNA extracted, and gene expression of miR-146a analyzed with real-time PCR.
Results:
Large wounds were associated with increased inflammation and increased expression of proinflammatory cytokine expression. In addition, miRNA-146a expression was significantly upregulated in day three small wounds compared to day three large wounds (Figure 1; p=0.03). There was no difference in gene expression between small and large wounds at day 7.
Conclusion:
We conclude that inflammation and inflammatory signaling plays a role in scarless wound healing. In particular, upregulation of miRNA-146a in the smaller wounds may create an environment conducive to regeneration by decreasing the inflammatory response. More studies are needed to further elucidate the mechanisms of inflammatory regulation in fetal regeneration.
