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

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 or
injury. 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 these
cells 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 way
they 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 project
will 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 new
knowledge to advance regenerative biology including research in stem cells and tissue engineering to improve the quality of life for the ageing population.