Characterization of the Genomic Response to Tissue Expansion: Can It Help Us?
Joanna K. Ledwon, PhD1, Chiang C. Huang, PhD2, Elbert E. Vaca, MD1, Arun K. Gosain, MD1.
1Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Division of Plastic and Reconstructive Surgery, Stanley Manne Children's Research Institute, Chicago, IL, USA, 2University of Wisconsin, Joseph J Zilber School of Public Health, Milwaukee, IL, USA.
PURPOSE: Tissue expansion (TE) relies on the extraordinary ability of skin to grow in response to mechanical forces beyond the physiological limit. Although TE is widely used to recruit new skin for reconstructive surgery, there has been minimal investigation into genomic response to TE. The present study evaluates genomic response to TE to identify molecular pathways that could potentially be manipulated to improve the efficacy of TE for recruitment of new skin.
METHODS: Using a porcine TE model, the transcriptome was mapped from 1 hour to 7 days after inflation of expanders with 60 ml saline. The contralateral unexpanded sites served as a control. To identify differentially expressed genes, sequencing analysis (RNA-seq) was performed on RNA extracted from skin biopsies collected from the apex of expanded skin and corresponding controls. qRT-PCR analysis was performed to confirm altered genes expression level identified by RNA-seq.
RESULTS: Differential analysis revealed significant changes in the expression of 220 genes (P<0.005), representing a diverse response pattern. At 1 hour, 59 genes were upregulated and 121 were downregulated. Functional analysis demonstrated that differentially expressed genes are related to several pathways including inflammatory response (GO:0006954, p=0.001), lipid homeostasis (GO:0055088, p=0.007), and response to external stimulus (GO:0009605, p=0.00003). Based on the expression pattern, genes were classified into the following groups: early response genes, late response genes, late-transient response genes, and persistent response genes (Fig. 1).
Depending on the time point after expansion, different groups of genes were affected. After 1 hour, the most active was immune response pathway (NOS2, COX2, TLR7), but after 7 days, the major active pathways were lipid metabolism and tissue remodeling (STAR, LPL, TNC) (Fig. 2).
CONCLUSION: These results provide the most comprehensive characterization to date of the transcriptome's response to TE. Gene expression during TE involves an orchestrated response that engages multiple processes, including maintenance of homeostasis, keratinocyte proliferation, keratinocyte differentiation, and inflammation. Given that the structure of porcine skin is highly comparable to human skin, we believe that similar mechanisms are involved in tissue remodeling during TE in humans. Understanding the molecular response of TE may lead to potential mechanisms for skin pretreatment so as to increase recruitment of new skin and make expansion feasible even in compromised tissue beds.
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