Wnt signalling and stem cell mobilisation in tissue injury repair

When tissues are injured (damaged) the body has to respond very rapidly to prevent blood loss and possible infection. Injury to many tiissues stimulates a process of natural repair that involves stem cells. Stem cells, resident in the tissue receive signals release 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. Little is currently known about how the different parts of the overall process are activated and co-ordinated to achieve efficient repair of tissue damage. This is however an important area in modern medicine since wounds above crtiical sizes often fail to repair and the effectiveness of repair processes decreases with age. A detailed knowledge of the natural repair processes can thus provide improtant information that can be used to improve tissue repair.

We have identified a particular molecular (signalling) process that is activated immediately following tissue injury, in all tissues of all species. This identifies this signalling pathway as of fundamental importance in the initiation of the repair process. We have further shown that a source of stem cells that are mobilised following tissue damage are located on the outside of blood vessels (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 realease that initiate a chain of events whereby stem cells, including pericytes, proliferate (increase in number), are attracted to the site of damge whereupon they differentiate in specilaised cells to mediate repair.

The aim of this research project is to learn more about this chain of events and the molecules and cells that take part in the repair process. We will used a highly clinically-relevant tissue as our experimental system, namely teeth, which in common with other tisues and organs, have a natural repair process following damage. When the damage is too great or repair fails, teeth become infected and require extenisve and painful treatment such as root canals. We will use a particualr tooth type that has three different areas where stem cells are located, including pericytes on blood vessels. This will allow us to look at different responses in the same tissue. We are able to injury teeth in animals (mice) and also in culture systems where there is no blood supply, thus enabling us to distinguish the relative contributions of blood vessel cells and other cells to the repair process. Mice also have the advantage of being a well-studied model where many different genetically manipulated strains are available to allow is to mark cells to follow their progress during repair.

The overall aim of this project is to learn more about the mechanisms that control a crucially important biological process, tissue repair and in doing so provide the basis for the development of novel clinical approaches to improve tissue repair.

Canonical Wnt signalling is involved in multiple developmental and postnatal biological processes and when disregulated is a direct cause of cancers such as colorectal cancer. Recently a new role has been identified in tissue damage repair where Wnt activity is upregulated immediately following damage in all tissues and species (both vertebrate and invertebrate) examined. Experimental abrogation of this increase in signalling activity severely impairs natural repair of tissue damage. A key response to tissue damage is the mobilisation of mesenchymal stem cells and a generic source of these cells are perivascular cells (pericytes).This proposal aims to investigate the mechanisms by which canonical Wnt activity initiates a cascade of cellular processes required for tissue damage repair. These include stem cell proliferation, cell homing (chemotaxis) and differentiation. We will use a novel, extremely tractable model system of experimemtally creating tissue damage to mouse incisor teeth. The damage responses observed in teeth are the same as those described in other tissues but incisors have a number of signficant advatages as a model system. Mouse incisors have three separate and clearly recognisable mesenchymal stem cell niches and can be easily manipulated in vivo and in vitro. We will use this system to identify the molecular pathways downstream of damage-induced Wnt activiation and by manipulating the Wnt activity follwoing damage, determine the effects on stem cell mobilisation from the different niches.

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. 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 is the 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 treatments.
-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 latest example was an appearance on The One Show (BBC1) in March 2012. 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 an organ that costs 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 process 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 increased understanding of the cell and molecular biology of natural tissue repair processes. Identification of downstream targets of Wnt activity (disseminated via the Roel Nusse Wnt web site) and the pathways that lead to stem cell mobilisation.
- 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; Effects of Wnt signalling modulation on stem cell mobilisation and repair. 2. Year 2/3; Microarray analysis and validation of gene expression 3.Year 3;Direct roles of Wnt and other ligands.