Tissue-specific programming of pericyte-derived mesenchymal stem cells

When tissues are injured (damaged) the body has to respond very rapidly to prevent blood loss and possible infection. Injury to many tissues stimulates a process of natural repair that involves mesenchymal stem cells (MSCs). MSCs resident in the tissue receive signals released from damaged cells that stimulates them to divide, migrate towards the damage and then differentiate in specific types of cells needed to repair the damage. We have shown that a source of stem cells that are mobilised following tissue damage are located on the outside of blood capillaries (pericytes) and these cells are able to differentiate into different types of specialised cells needed to repair damage. This suggests that upon tissue damage, signalling molecues are released that initiate a chain of events whereby pericytes are stimulated to leave the blood vessels, proliferate (increase in number), are attracted to the site of damage whereupon they differentiate in specialised cells to mediate repair. The attraction of pericytes as a source of MSCs is their ubiquitous location on blood vessels that means they are present in almost all tissues of the body, ready to be stimulated.
MSCs are an important source of adult stem cells for use in many different clinical applications. There are currently over 150 clinical trails underway to evaluate these cells for a wide range of therapeutic uses. The main defining characteristic of MSCs is their ability to differentiate into multiple different types of mesenchymal cells when stimulated to do so in laboratory cultures. These include, bone cells. cartilage cells and fat cells among others. Recently, evidence has started to emerge that suggests that although MSCs isolated from different tissues are all derived from pericytes, they exhibit fundamental differences in their differentiation capacities. Thus when grown in non-stimulatory conditions, MSCs from muscle will only form muscle cells and MSCs from bone will only form bone cells. Moreover, tantilising results from tissue transplantation experiments suggest that MSCs from different anatomical sites within one tissue, eg. bone, are inaffective at repairing the tissue when transplantated to the other location. These results suggest that MSCs (pericytes) retain a knowledge of their origin that in turn affects their behaviour (pregramme). This makes biological sense since it may be a way of the body ensuring that MSCs dont differentiate into the wrong type of cell. However it has important implications for using these cells in tissue repair.
The aim of our research is to understand the biological nature of this MSC "programming" so that ways can be devised to reprogramme the cells to enable cells isolated from one tissue can be used to efficiently and safely repair another tissue.

Adult mesenchymal stem cells (MSCs) promise great potential for use in tissue engineering and other cell-based clinical therapies. The fact that these cells can be isolated from individual patients makes them amenable to use as an autologous cell source. Research is emerging from both the MSC and iPS field suggesting that adult cells retain a functional epigenetic memory of their developmental histology. The clinical importance of MSCs makes it of great importance to understand the basis of this memory (programme) and how it affects their differentiation and response to tissue injury. In this study we aim to investigate the molecular basis of epigenetic programming of cells (pericytes) that are now generally accepted as a source of MSC in most tissues. The general concept we have formulated is that pericytes are programmed, as a result of their developmental origins, in order to restrict their differentiation potential in vivo. If this is true it has important consequences for their clinical use. We will use the latest approaches in epigenetic analysis and gene expression profiling to identify differences between pericytes of different origins. We will use heterotypic transplantation of pericytes following tissue damage to correlate repair efficiency with epigenetic (gene expression) status and finally carry out reprogramming experiments to determine the extent to which this improves repair efficiency.

Who benefits?: - Academics (PI's postdocs and students): The PA regularly presents plenary lectures at international meetings that cover a wide range of disciplines including developmental biology, tissue engineering and regenerative medicine. In June 2011 for example the principle applicant was a plenary speaker at the TERMIS (Tissue Engineering Regenerative Medicine International Society) conference and will present an invited lecture at the 2012 AAA conference in San Diego and at the Craniofacial Development GRC in Los Angeles.
- Academic clinicians and clinical students: The PA is a regular plenary and invited speaker at the International Association for Dental Research (society for dental researchers) and the FDI World Dental Federation (society for clinical dentists), AAAS conferences and UK Dental Student Association annual conferences. In 2012 for example he is an invited speaker at the IADR Congress in Rio and the FDI Congress in Hong Kong. He presents at numerous major conferences of dental specialities including periodontal disease, implantology and dental hygiene and has several such invited presentations scheduled for 2012 and 2013. In September he was special guest overseas speaker invited by dental undergraduate students to present at the Brazilian Dental Congress in Sao Paulo. In 2012 he is planning to launch the worlds first MSc course in Regenerative Dentistry, aimed at providing training for young dentists in the latest scientific advances in the application of stem cell and biologically-based treatments to dental diseases.
-National bodies: In the UK the PA is a regular guest speaker at dental meetings organised by the British Dental Association, UK and International dental speciality societies and the Academy of Medical Sciences.
-High street dentists and the NHS: The PA gives invited presentations to local groups of high street dentists throughout the UK and delivers courses to NHS dental nurses on regenerative dentistry.
-The general public: The PA has generated considerable international press coverage from discoveries relating to tooth regeneration and appeared in numerous TV news items both here and abroad and maintains regular contact with TV, radio and newspaper journalists. The PA has given lectures at Kings to visiting groups of local school children and has presented at several local schools.
How do they benefit?: -High street dentists and the NHS: Just considering dentistry alone, teeth are organs that cost the NHS £1Billion per year to treat and almost all treatments are non-biologically based. Considerable emphasis is now being placed on prevention of dental diseases to reduce the costs of treatment and enhancement of natural dental repair processes such as those proposed to be studied in this project are thus of major significance.
-Academic clinicians and clinical students: Dental clinical academics will be in a position to deliver clinical trials in the dental hospital setting and at the same time educate and train dental undergraduates. Medical clinicians will have a better understanding of injury repair processes and how they might be improved.
- Academics (PI's postdocs and students): An understanding of the tissue-specific properties of mesenchymal stem cells (pericytes) and their impact on function in tissue repair. Identification of the genes involved in this tissue specificity.
- National bodies: Will be able to make their memberships aware of the research findings and their impact on future clinical therapies.
-The general public: An awareness of the existence of natural repair and acknowledgement of how this research leads to improved treatment.
Project Milestones:1. Year 1; Completion of epigenetic studies and gene profiling. Initial results of transplantation experiments. Year 2; In vitro culture of pericytes and analaysis of gene expression and epigenetic changes. Completion of analysis of transplantation experiments. Year 3; Reprogramming experiments.