UKRMP Hub: The Engineered Cell Environment.

Stem cells have great potential in medicine as they can grow into many different cell types in the body. Our aim is to create a research network of scientists and clinicians working towards understanding how stem cells behave within their normal tissue environment. The environment or "Niche" within the body that surrounds stem cells has a profound effect on the behaviour of stem cells and whether they can repair damaged organs. By understanding how the Niche influences stem cells in tissues we aim to use this knowledge to develop future treatments for serious untreatable diseases.

To promote "healthy regeneration" in tissues and organs, we will use 2 main strategies: (1) test drugs and small synthetic molecules in experimental models of organ injury. We hope to influence the behaviour of the stem cells within their Niche environment by adding drugs. (2) Another way of treating damaged tissue and organs is to transplant stem cells or cells from stem cells into the damaged organ - this kind of treatment is known as a cell therapy and an example of this used today to treat patients is bone marrow transplantation. Whilst this treatment is successful for many diseases, in some cases this treatment does not work and the cells do not grow well. Our network wants to understand why the Niche environment does not always allow cells to grow well. We hope to develop novel treatments using cell transplantation to promote healthy regeneration of tissue and organs.

We aim to develop treatments for patients who are currently suffering from untreatable diseases affecting the (a) liver, (b) joints and the (c) lungs.

(a) Liver disease is the 5th most common cause of death in the UK. The current treatment for patients with end-stage cirrhosis and acute liver failure is a liver transplant, however organ availability cannot meet demand and many patients die waiting for an organ. Those who do undergo transplantation require lifelong immunosuppression with concomitant risks of infection, cancer, renal and cardiovascular disease. Thus, there is a clear imperative to identify alternatives treatments. One of our research themes will investigate healthy regeneration of the liver using drugs or cell therapies.

(b) Another research theme from our Hub investigates new treatments for Osteoarthritis (OA) which is one of the fastest most rapidly increasing major health conditions, with over 8 million people affected in the UK alone. Whilst end-stage disease is suited to joint replacement, there is an urgent need to address earlier disease stages with repair and regenerative strategies.

(c) We are also investigating regeneration of the lung; chronic lung disease is responsible for 6 million inpatient bed days a year in the UK. There is a clear unmet need for this research to be carried out.

We will bring together scientists with the different kinds of expertise that we think are required to tackle these scientific and medical challenges. By linking these experts with doctors working in these clinical areas and helping them to collaborate together we hope to make more rapid progress in the development of new treatments for these chronic diseases.

The UKRMP Engineered Cell Environment Hub (ECEH) aims create a platform, linking excellence in the regenerative biology of the stem cell niche with experimental medicine to translate regenerative therapies to the clinic. We will bring together leading scientists in regenerative biology, stem cells, niche biology, phenotypic screening, safety and transplant immunity with clinician scientists working in regenerative medicine in a highly collaborative network.

We will develop two linked translational regenerative strategies:
(1) Developing Cell Therapies for Damaged Organs: We will use our knowledge of niche biology to optimise cells for therapy. Artificial niches will be constructed that mimic healthy tissue and facilitate effective cell therapy. Pluripotent and adult human stem cell sources will be optimised in vitro and tested in our pre-clinical models of liver, joint and lung repair. Immune responses to the transplanted cells will be assayed in relevant humanized mouse models.
(2) Promoting endogenous repair of damaged organs:Using stem cells in vitro, we will create high content 2D and 3D phenotypic screens for liver, cartilage and lung repair. We will study the behaviour of stem cells in their niche aiming towards optimising endogenous repair and use FDA approved compound libraries to identify potential drugs and biological agents for translation.

The Hub is structured with 3 basic underpinning scientific areas and technologies: (a) Understanding and improving the physical properties of Aged and Injured Tissue Niches; (b) Developing Artificial Wnt Niches to act as regenerative signals for tissue formation and repair; (C) High content phenotypic screening for the discovery of novel targets for endogenous repair.

We have 3 clinical translational exemplars: liver (WP1), joint (WP2), lung (WP3) repair. Each theme is led by a pair of investigators with complimentary expertise, common underpinning biology and enabling technologies that span the WPs.

The disease exemplars that will be investigated during the course of this project are liver regeneration, lung regeneration and joint regeneration.

Liver disease is the 5th commonest cause of death in the UK and the deaths from cirrhosis are rapidly rising (British Liver Trust, www.britishlivertrust.org.uk). 16,087 people in the UK died from liver disease in 2008, a 4.5% increase since 2007. Most liver deaths were in people under 70, while one in 10 deaths of all people in their 40s were from liver conditions. The only curative option for end-stage liver disease is liver transplantation but donor organ availability cannot meet current demand and many patients die whilst waiting for a suitable organ; may patients with severe liver disease are not eligible for transplantation.

Chronic lung disease is responsible for 6 million inpatient bed days a year in the UK. Chronic Obstructive Pulmonary Disease (including emphysema) and idiopathic pulmonary fibrosis are both now thought to be diseases of epithelial damage and failed repair, with no treatments that reverse lung function decline.

Osteoarthritis (OA) is a rapidly increasing health burden, affecting over 8 million people in the UK. Whilst end-stage disease is suited to joint replacement, repair and regenerative strategies could address earlier disease stages.

It is foreseen that the results generated from the proposed cell therapy research would allow further funding to be leveraged (this would be the subject of a future funding application) in order to head towards a Phase 1 study. It is likely that this next stage of the research would involve input from the Cell and Gene Therapy Catapult.

If any pertinent results are generated from the endogenous repair screening work packages, the investigators would look to partner with an appropriate Pharma/biotech partner in order to advance towards making a clinical impact. It is proposed to screen FDA approved libraries in the first instance which would mean that there is the potential to move towards clinical studies in an efficient manner.

The MRC Centre for Regenerative Medicine has a strong outreach program which will help to disseminate results to appropriate patient groups and stakeholders. To maximise the scientific and clinical impact from the regenerative medicine the investigators will closely involve the UKRMP network. The investigators involved have a record of publishing in high impact journals with wide readership in the relevant scientific and clinical communities. Any intellectual property generated during the course of the project will be appropriately protected by the relevant partner University/Universities and exploited by the relevant technology transfer organisation.