Signaling Pathways Associated with Chronic Wound Progression: A Systems Biology Approach.

Previously we have shown that several oxidative stress-driven pathways in cutaneous chronic wounds are dysregulated in the first 48 h post-wounding. Here, we performed an RNASeq analysis of tissues collected up to day 20 after wounding, when we have determined full chronicity is established. Weighted Gene Correlation Network Analysis was performed in R segregating the genes into 14 modules. Genes in the modules significantly correlated (p < 0.05) to early and full chronicity were used for pathway analysis using pathfindR. In early chronicity, we observed enrichment of several pathways. Dysregulation of Ephrin/Eph signaling leads to growth cone collapse and impairs neuronal regeneration. Adra2b and Adra2a overexpression in early and full chronicity, respectively, decreased cAMP production and impaired re-epithelialization and granulation tissue formation. Several pathways involving a Smooth-muscle-actin (Acta1) were also enriched with Acta1 overexpression contributing to impaired angiogenesis. During full chronicity, the ‘JAK-STAT’ pathway was suppressed undermining host defenses against infection. Wnt signaling was also suppressed, impairing re-epithelialization and granulation tissue formation. Biomarkers of cancer such as overexpression of SDC1 and constitutive activation of ErbB2/HER2 were also identified. In conclusion, we show that during progression to full chronicity, numerous signaling pathways are dysregulated, including some related to carcinogenesis, suggesting that chronic wounds behave much like cancer. Experimental verification in vivo could identify candidates for treatment of chronic wounds.