The roles of the secretome, cell aging and the wound microenvironment in the paracrine activity of canine mesenchymal cells

背景：干细胞治疗已经成为科学兴趣和活动的一个主要领域。过去20年的研究取得了突破性的发现，以确定干细胞是如何工作的，以及它们如何用于治疗疾病或损伤。这项研究的大部分集中在干细胞改变其特性的能力，以提供成熟细胞具有特殊功能，例如为神经损伤患者形成神经，或为心脏病发作后的患者形成心肌细胞。然而，最近的证据表明，这种工作方式可能不适用于被称为间充质基质细胞(MSCs)的特定干细胞群体，这种干细胞存在于终生存在于骨髓或脂肪储存中。相反，这些细胞被认为向存在于患病或受损组织中的其他细胞提供重要信号，以触发受体细胞修复组织。MSCs可以从组织的活检组织中获得，在细胞培养中分离和生长，通过这种方式，它们已被用于治疗身体的其他部位，例如通过移植到受伤部位。来自阿斯顿的主要申请者(尤斯塔斯·约翰逊博士)在这一研究领域拥有长期的专业知识。科学问题：当骨髓间充质干细胞移植到患病/受伤的组织中时，临床结果好坏参半--骨髓间充质干细胞移植并不总是像预期的那样有效。这阻碍了基于MSC的疗法的更广泛使用。MSC疗法不能显示出可重复的强大益处的各种原因已被提出。然而，归根结底，我们在分子水平上还不清楚MSCs如何刺激其他类型的细胞修复组织，或者其他关键因素如何影响结果，包括移植的MSCs的质量和正在治疗的疾病/受损部位的可变性。目的：我们假设MSCs分泌因子与组织损伤部位已经存在的细胞进行沟通，以防止进一步的损伤并帮助修复组织，例如通过停止有害的炎症反应或刺激血管生长。有大量数据支持这一假设，但其作用机制尚不清楚。我们将使用分析方法的组合来研究这个问题。此外，该项目还将评估MSCs的质量和创伤/疾病环境的关键特征如何影响MSCs在组织中产生最佳修复反应的能力。合作伙伴关系：兽医组织银行有限公司是一家中小型公司，核心业务是提供犬只细胞和组织，用于治疗狗的损伤和疾病。2013年开始使用骨髓间充质干细胞治疗患有骨关节炎(OA)的狗，方法是将细胞注射到受影响的关节中。临床结果是有希望的和迅速的，表明骨髓间充质干细胞通过抗炎作用影响骨关节炎关节。出于这个原因，VTB已经瞄准了与阿斯顿大学(Johnson，安德鲁·德维特博士补充了专业知识)的合作伙伴关系，以探索MSCs在狗身上工作的潜在机制。该公司的优势包括利用MSC保密产品开发他们的产品组合和客户基础，以及能够帮助培训一名高技能的研究人员来推进这些活动。在学术上，博士学位将使我们能够解决与我们了解细胞如何传递到治疗效果相关的关键科学问题。BBSRC的职责：该项目符合BBSRC战略研究优先事项，通过增加知识和减轻疾病和疼痛来改善动物的福利，以及通过产生新知识来研究健康老龄化，以促进再生生物学，包括干细胞和组织工程的研究，以提高老龄人口的生活质量。

BACKGROUND: Stem cell therapies have become a major area of scientific interest and activity. Research over the last 20 years has made ground breaking discoveries to identify how stem cells work and how they can be used to treat disease orinjury. Much of this research has centred on the ability of stem cells to change their characteristic to provide mature cells with specialist function, e.g. to form nerves for people suffering from nerve injury or heart muscle cells for those following heart attack. However recent evidence suggests that this way of working may not be true for a particular population of stem cells, called mesenchymal stromal cells (MSCs) which are present in bone marrow or fat stores through life. Instead thesecells are thought to provide important signals to other cells present in diseased or damaged tissue to trigger the recipient cells to repair the tissue. MSCs can be obtained from biopsies of tissue, isolated and grown in cell culture, and in this waythey have been used to treat other areas of the body e.g. by transplantation into the injured site. The lead applicant from Aston (Dr Eustace Johnson) has a long standing expertise in this area of research.THE SCIENTIFIC PROBLEM: When MSCs are transplanted into diseased/injured tissue, the clinical results have been mixed - the MSC transplants do not always work as well as expected. This has prevented the wider use of MSC-based therapies. Various reasons for an inability of MSC therapies to show reproducibly strong benefits have been suggested. However, the bottom line is that we do not know enough at the molecular level about how MSCs stimulate other cell types to repair tissues, or about how other key factors can affect the outcome, including the quality of MSCs being transplanted and variability in the disease/damaged sites being treated.THE PROJECT AIM: We hypothesise that MSCs secrete factors to communicate with cells that are already present at sites of tissue damage, which prevents further damage and helps repair the tissue e.g. by stopping harmful inflammatory reactions or stimulating blood vessel growth. There is substantial data to support this hypothesis but the mechanism of action is unknown. We will investigate this problem using a combination of analytical approaches. In addition, the projectwill evaluate how MSC quality and key features of the wound/disease environment affects the ability of the MSCs to bring about the best repair response in the tissue.THE PARTNERSHIP: The Veterinary Tissue Bank Ltd is a small to medium sized company with a core business in the provision of canine cells and tissues for the treatment of injury and disease in dogs. The use of MSCs to treat dogs with osteoarthritis (OA) commenced in 2013 by injection of cells into the affected joint. The clinical results are promising and rapid, suggesting that the MSCs are affecting the OA joint through an anti-inflammatory action. For this reason, VTB have targeted a partnership with Aston University (Johnson with the added expertise of Dr Andrew Devitt) to explore the underlying mechanisms of how MSCs work in dogs. The advantages to the company include the development of their product portfolio and customer base utilising MSC secreted products, as well as being able to help train a highly skilled researcher to advance these activities. Academically the PhD studentship will enable us to address key scientific problems associated with our understanding of how cells communicate to therapeutic effect.THE BBSRC REMIT: The project fits within the BBSRC strategic research priorities to improve the welfare of animals through increasing knowledge and alleviating disease and pain, as well as research into healthy ageing by generating newknowledge to advance regenerative biology including research in stem cells and tissue engineering to improve the quality of life for the ageing population.