Laboratory Research
Introduction: A well-conserved program for cutaneous wound healing is completely deregulated in diabetic foot ulcers (DFUs) and venous leg ulcers (VLUs). Despite differences in etiologies, both DFUs and VLUs share common features, including a hyperproliferative and non-migratory epidermis, fibrosis, decreased angiogenesis, deregulated inflammatory response, and recurrent infection. This suggests that key cellular functions of healing are failing in a similar manner between the two ulcer types. Although genomic studies have been reported on these individual ulcer types by our team and others, a comprehensive bioinformatic analysis of shared pathways common for both types of chronic wounds has not been evaluated.
Methods:
Methods: We collected tissue samples from DFUs (N=12) and VLUs (N=11) patients treated with standard care. Tissue sample quality was assessed by histology followed by RNA sequencing and genomic data was analyzed using Partek Flow and Ingenuity Pathway Analysis. RNAseq findings were validated using integrative, patient-relevant models including human skin ex vivo wounds, quantitative PCR, and immunostaining of prospectively collected patients’ tissue samples.
Results:
Results: Comparative analysis of the DFU and VLU transcriptome revealed 2350 differentially expressed genes (DEGs) that are shared between the two ulcer types (p< 0.05, FDR< 0.05, |FC| >1.5), identifying a novel core chronic wound transcriptome. A dominant feature of the chronic wound core transcriptome was transcriptional repression, as 72.8% of the common DEGs were found suppressed in chronic wounds. Top biological pathways include WNT/ß-catenin signaling, cellular migration and proliferation to name a few. Interestingly, a well-known regulator of skin barrier function and response to commensal bacteria, Aryl Hydrocarbon Receptor (AHR) signaling, was also found dysregulated in both types of chronic wounds, all of which was confirmed on the mRNA level by qPCR and the protein level by immunostaining
Discussion:
Discussion: The innovative bioinformatics approach discovered many shared mechanisms that contribute to non-healing of two major chronic wound types of different etiology, DFUs and VLUs. This study identified multiple potential therapeutic targets common for DFUs and VLUs that can be utilized to re-activate a physiological healing response and successfully promote wound closure.