Abstract
BackgroundHypertrophic scar was first described over 100 years ago; PubMed has more than 1,000 references on the topic. Nevertheless prevention and treatment remains poor, because 1) there has been no validated animal model; 2) human scar tissue, which is impossible to obtain in a controlled manner, has been the only source for study; 3) tissues typically have been homogenized, mixing cell populations; and 4) gene-by-gene studies are incomplete.Methodology/Principal FindingsWe have assembled a system that overcomes these barriers and permits the study of genome-wide gene expression in microanatomical locations, in shallow and deep partial-thickness wounds, and pigmented and non-pigmented skin, using the Duroc(pigmented fibroproliferative)/Yorkshire(non-pigmented non-fibroproliferative) porcine model. We used this system to obtain the differential transcriptome at 1, 2, 3, 12 and 20 weeks post wounding. It is not clear when fibroproliferation begins, but it is fully developed in humans and the Duroc breed at 20 weeks. Therefore we obtained the derivative functional genomics unique to 20 weeks post wounding. We also obtained long-term, forty-six week follow-up with the model.Conclusions/Significance1) The scars are still thick at forty-six weeks post wounding further validating the model. 2) The differential transcriptome provides new insights into the fibroproliferative process as several genes thought fundamental to fibroproliferation are absent and others differentially expressed are newly implicated. 3) The findings in the derivative functional genomics support old concepts, which further validates the model, and suggests new avenues for reductionist exploration. In the future, these findings will be searched for directed networks likely involved in cutaneous fibroproliferation. These clues may lead to a better understanding of the systems biology of cutaneous fibroproliferation, and ultimately prevention and treatment of hypertrophic scarring.
Highlights
IntroductionAfter deep partial-thickness injury to the skin, it is common for patients to heal with fibroproliferative (hypertrophic) scarring
After deep partial-thickness injury to the skin, it is common for patients to heal with fibroproliferative scarring
Mixed effects linear regression on the factor breed(pigment) was accomplished. Selection of those genes for which q,0.2 and for which p,0.1 at one or more time points, returned a differential transcriptome of 162 genes. This differential transcriptome is the core result of this project and includes genes for which the difference between shallow and deep partial-thickness wounds is different between breeds over time
Summary
After deep partial-thickness injury to the skin, it is common for patients to heal with fibroproliferative (hypertrophic) scarring. The family of fibroproliferative disorders includes cirrhosis, idiopathic pulmonary fibrosis, myelofibrosis, atherosclerosis, rheumatoid arthritis, postsurgical adhesions, corneal fibrosis, Dupuytren’s disease and the three dermal variants, fibroproliferative scarring, keloid formation and scleroderma. Tredget reviewed these dermal conditions in 1994 [2] and in 2009 [3], making it clear that in the 15 years between reviews no real advances in prevention or treatment occurred. Scarring is a topic of interest to burn researchers; Broerse has reported that burn survivors rank it among the most undesirable outcomes to be solved [4]. Hypertrophic scar was first described over 100 years ago; PubMed has more than 1,000 references on the topic. Prevention and treatment remains poor, because 1) there has been no validated animal model; 2) human scar tissue, which is impossible to obtain in a controlled manner, has been the only source for study; 3) tissues typically have been homogenized, mixing cell populations; and 4) gene-by-gene studies are incomplete
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