Fat for scars: How does adipose tissue reduce skin stiffness?

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Skin scarring can occur as a result of disease, dysregulated wound healing or radiotherapy. At present there is no effective treatment for scarring (dermal fibrosis), which results in stiff tissues, pain, loss of function and disfigurement. Recent clinical observations and experience demonstrated that subcutaneous injection of adipose tissue was able to reverse radio-induced dermal fibrosis. To optimise this approach for scar treatment a mechanistic understanding of how it works is required. The overall aim of this project is to determine the mechanism through which lipoaspirate, and its constituent parts, are able to reduce and reverse the pathological characteristics of dermal fibrosis, to develop future treatments. A series of in vitro experiments will be performed to investigate the effect of adipose tissue on myofibroblasts, the key cell type responsible for contraction and scar formation in the dermis. Research question 1) How do paracrine signals from adipose tissue affect the gene expression and functional behaviour of dermal myofibroblasts?Human adipose tissue collected from surgery will be processed into three different clinical applicable formulations of adipose tissue (FAT): whole lipoaspirate, a mechanically disrupted formulation and an enzymatically extracted cell population called the stromal vascular fraction. Each FAT has different characteristics and while all have been used clinically there are no studies which have systematically compared them. Myofibroblast survival, persistence, differentiation and fibrotic gene expression will be measured following exposure to conditioned media from FAT and the paracrine factors secreted from each FAT will be measured. From this data we aim to determine which components of adipose tissue are responsible for observed myofibroblast changes and the mechanisms responsible. Research question 2) How do FAT affect extracellular matrix (ECM) production, contraction and tissue stiffness?Fibrotic tissue is associated with excess collagen and fibronectin deposition, ECM contraction and increased tissue stiffness. We will measure the expression of ECM components by myofibroblasts following the application of FAT and measure the degree of contraction in our previously developed three dimensional in vitro models of dermal contraction. Tissue stiffness of our models and of clinical scar tissue will be measured through Dynamic Shear Analysis, to gather quantitative data on how FAT affects tissue stiffness.Evidence from this research will allow evidence based decisions to be made on how adipose tissue should be engineered prior to administration and which components of adipose tissue are required for clinical benefit. This evidence is needed to inform new surgical interventions, in an area where there is an urgent unmet clinical need.The potential of stem cells is recognised by many to be a high priority research area however progress to the clinic is slow. This project takes clinical observations back to the lab to reverse engineer fat therapies to better understand how adipose tissue alters scar tissues in skin. This project aims to develop novel fat processing techniques, which can be rapidly applied in the clinic to engineer fat in such a way that it can be used in surgical interventions to optimise the treatment of scars and to ultimately improve patient outcomes.