Skin fibrosis is disfiguring and debilitating, and causes a large economic burden to society (De Roche et al., 1994). We have carried out multiple studies to examine characteristics of fibrosis at a molecular level to find targets for treatment of fibrosis.
Two studies were carried out examining the methylome and transcriptome of skin fibroblasts, one in normotrophic scar and one in keloid scar, looking for genes of interest that were both differentially methylated and expressed. The normotrophic scar study compared normotrophic scar and normal skin, and found 13 genes of interest. Modulation of two of these in vitro caused a decrease in collagen production. The keloid study compared keloid scar to normotrophic scar and normal skin, and using more stringent cut offs found 26 genes of interest. To identify common pathways in fibrosis, more methylation datasets from were obtained for from neck keloid fibroblasts, idiopathic lung fibrosis (IPF) and scleroderma fibroblasts. These were compared against the normal skin and lung fibroblasts to identify genes common in multiple fibrosis phenotypes.
A genome-wide association study and pathway analysis was also carried out on 665 adults and children (953 recruited) who sustained a burn injury. Scar height (SH) and scar pliability (SP) sub-scores were the outcome measures, and using this approach we found that biological processes related to the nervous system and cell adhesion were the predominant pathways associated with both SH and SP.
Finally, preliminary data has been generated using single cell RNA-sequencing technology on keloid scar tissue, identifying 6 distinct fibroblast lineages. These lineages have been validated in vitro, and will be interrogated further to determine the effect of each fibroblast subtype in driving keloid fibrosis.
These data sets have been interrogated for overlapping genes and pathways, looking for common pathways and mediators of fibrosis for targeting by anti-fibrotic therapies.