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

脂肪去除疤痕：脂肪组织如何减少皮肤僵硬？

基本信息

批准号：
2126554
负责人：
金额：
--
依托单位：
University of Sheffield
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2126554
关键词：
Fat scars How does adipose

项目摘要

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.

皮肤疤痕可能是由疾病、伤口愈合失调或放射治疗引起的。目前尚无有效治疗疤痕（真皮纤维化）的方法，疤痕会导致组织僵硬、疼痛、功能丧失和毁容。最近的临床观察和经验表明，皮下注射脂肪组织能够逆转放射引起的真皮纤维化。为了优化这种疤痕治疗方法，需要对其工作原理有一个机械性的了解。该项目的总体目标是确定吸脂及其组成部分能够减少和逆转真皮纤维化病理特征的机制，以开发未来的治疗方法。将进行一系列体外实验来研究脂肪组织对肌成纤维细胞的影响，肌成纤维细胞是负责真皮收缩和疤痕形成的关键细胞类型。研究问题 1) 来自脂肪组织的旁分泌信号如何影响真皮肌成纤维细胞的基因表达和功能行为？从手术中收集的人体脂肪组织将被加工成三种不同的临床适用的脂肪组织制剂（FAT）：全脂抽吸物、机械破坏的制剂和称为基质血管部分的酶法提取的细胞群。每种 FAT 都有不同的特性，虽然所有 FAT 都已用于临床，但还没有研究对它们进行系统比较。暴露于 FAT 的条件培养基后，将测量肌成纤维细胞的存活、持久性、分化和纤维化基因表达，并测量每个 FAT 分泌的旁分泌因子。根据这些数据，我们的目的是确定脂肪组织的哪些成分导致观察到的肌成纤维细胞变化以及相关机制。研究问题 2) FAT 如何影响细胞外基质 (ECM) 的产生、收缩和组织硬度？纤维化组织与过量的胶原蛋白和纤连蛋白沉积、ECM 收缩和组织硬度增加有关。我们将测量应用 FAT 后肌成纤维细胞 ECM 成分的表达，并测量我们之前开发的三维体外真皮收缩模型的收缩程度。我们的模型和临床疤痕组织的组织硬度将通过动态剪切分析进行测量，以收集有关 FAT 如何影响组织硬度的定量数据。这项研究的证据将允许就给药前应如何设计脂肪组织以及临床益处需要脂肪组织的哪些成分做出基于证据的决策。在临床急需未得到满足的领域，需要这一证据来为新的外科手术干预提供信息。许多人认为干细胞的潜力是一个高度优先的研究领域，但临床进展缓慢。该项目将临床观察带回实验室，对脂肪疗法进行逆向工程，以更好地了解脂肪组织如何改变皮肤中的疤痕组织。该项目旨在开发新型脂肪加工技术，该技术可以快速应用于临床，以工程化脂肪，使其可用于外科手术，以优化疤痕的治疗并最终改善患者的治疗效果。