Functional Genomics Unique to Week 20 Post Wounding in the Deep Cone/Fat Dome of the Duroc/Yorkshire Porcine Model of Fibroproliferative Scarring

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.

Dermal Adipocytes: From Irrelevance to Metabolic Targets?

“…Each dermal cone consists of two parts, whereas its upper part is placed in the dermis and the lower part (referred to as the “fat dome”) transverses the dermis and penetrates into sWAT [18]. From this point of view, single dWAT units build the vertical fractional structures which are connected with each other through the inter-follicular dermis and which have a common reservoir of adipocytes in sWAT.…”

Cone of skin exists in rat: A “hypertrophic scarring free” animal

“…For a better understanding of cone of skin, it is nec-essary to increase our knowledge of the structure of cone of skin at different time points of hair follicle cycle. Based on these observations (Ishii et al, 1997;Matsumura et al, 2001;Zhu et al, 2003Zhu et al, , 2007Zhu et al, , 2008Ramos et al, 2008;Engrav et al, 2011;Wikramanayake et al, 2013), we designed this study. The merits of this study design can be summarized to this: First, the technique to induce a new hair follicle cycle in rat is convincing.…”

“…Since then, little followed from that observation in human. Zhu et al (2003Zhu et al ( , 2007Zhu et al ( , 2008; Ramos et al (2008);Engrav et al (2011) reported that cone of skin existed in porcine either, which was deemed to be an animal model of hypertrophic scarring.…”

Transcriptional Profiling of Rapamycin-Treated Fibroblasts From Hypertrophic and Keloid Scars

“…In a pig model of dermatome-induced scarring, several biologic pathways were implicated at wounds at 20 weeks after injury. 21 These included TGFβ signaling, ECM-receptor and focal adhesions, adipogenesis, inflammation, and angiogenesis; pathways implicated in human fibrotic diseases. In a mouse model of hypertrophic-like scarring, mechanical tension was shown to directly up-regulate the expression of inflammatory pathways, chemokine signaling, and cell-matrix interactions during early scar formation.…”