A hub for Engineering and exploiting the stem cell niche

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 hub of scientists and clinicians working to understand what controls the behaviour of stem cells in their normal tissue environment.

The niche ("the soil") that surrounds stem/progenitor cells ("the seed") in developing or damaged organs has a profound effect upon the behaviour of stem/progenitor cells. The niche has received less attention than the stem cells themselves in research programs around the world. This program of work aims to fill that gap and focus work on this area. By understand how the niche influences stem cells in tissues we aim to use this knowledge to develop future treatments for serious untreatable diseases. We will do this by extending the knowledge of the niche in three main programs of work.

(1) We will extend our understanding of niches by creating artificial niches and looking at how they influence stem cells growing in them. By manipulating signals and attachments between the niches and the stem cells we can develop a clear understanding of how the niches "talk" to stem cells. When we understand clearly the signals between the niches and the stem cells we can try to influence the stem cells in the artificial niches by adding drugs or other synthetic molecules onto the stem cells to influence their behaviour.

(2) To promote "healthy regeneration" in tissues and organs we will use the information from aim 1 to test whether we can improve the growth of stem cells in the organs and tissues of experimental models of organ injury and regeneration using drugs and small synthetic molecules that will act on the stem cells and their niches.

(3) One way of treating damaged tissues and organs is to transplant stem cells or cells from stem cells into the damaged organ (such as bone marrow transplantation). Whilst this is successful in some situations, in many cases this treatment doesn't work as the cells don't grow well in the tissues. We need too understand why the tissue ("soil") does not allow the cells ("seeds") to grow well. By using information from part 1 and 2 we will seek to add the factors that we have found to keep cells "happy" and allow them to grow well in the damaged tissue.

By creating a network of scientist and doctors with different but complementary skills we aim to make these advances as quickly as possible.

Our objectives and overall strategy is: (1) Through an understanding of normal tissue stem cell niches we will reconstruct the normal niche microenvironment to enable expansion and accurate differentiation of stem cells, and optimize small molecule and drug development strategies using adult stem cell, MSC, ES or iPS cell-based screening platforms. (2) To promote "healthy regeneration" we will identify the niche signals that control proliferation and differentiation of endogenous stem/progenitor cells within a diseased organ so as to facilitate the direct targeting of these cells using biological agents, drugs/small molecules or synthetic materials. This will utilise in vivo models or organ regeneration using zebrafish and then mouse models of organ injury and regeneration (3) To improve repair by transplanted cells we will understand and manipulate the abnormal niche created by the inflammation and damage of disease, as the milieu surrounding the transplanted cell has a profound effect upon both its longevity and function. We will utilise information from section (1) to facilitate this aim by providing the optimal defined niche around transplanted cells to make this successful.

1. Regenerating damaged tissues and restoring their function is one of the major goals of biomedicine. Diseases that cause tissue degeneration and injury present a huge and ever-increasing clinical burden, in the UK costing the NHS well over £1 bn/year, with musculoskeletal disease alone accounting for 8.8 million UK working days lost/annum. The 'niche' hub will expedite stem/progenitor cell discoveries, focusing on developing new skeletal, liver and brain repair/regeneration strategies for patient benefit. We will achieve this by determining how local tissue niche composition, notably extracellular matrix, cytokines and growth factors, direct stem/progenitor cell phenotype, growth and differentiation, by building niche-based biomaterial platforms for tissue-specific engraftment and regulation of cell phenotype in vitro and in vivo, and by the discovery of novel targets for promoting endogenous repair. We will utilise high throughput, high content and phenotype screens (including small molecules) to fast track achievement of these key goals. Our distinctive research has the potential to transform regenerative medicine worldwide because it draws on internationally recognised strengths into how extracellular signals in the niche direct cell behaviour and phenotype and their ability to repair tissues, allowing us to address directly the well-recognised need to understand and exploit the cellular microenvironment to drive effective tissue regeneration. To engagement with UK and international biomedical communities, we will: hold joint workshops with other UK RMP hubs/annual Symposium, all open to hub members, national (UK RMP hub) and international colleagues, thus strengthening UK standing in international stem cell networks; participate at a high level in major national and international conferences where we will report our scientific discoveries and translational advances; disseminate our data in high-impact scientific journals. Thus contributing prominently to the development of a world-leading UK 'brand' in tissue regeneration and repair. 2. Biopharma and Translation: Stem cells offer great hope but have so far delivered only relatively modest benefits worldwide, with few cell-based and no drug-based regenerative strategies in the clinic to meet the huge demand. Our philosophy is that major clinical advances in tissue regeneration will only be possible once address the "soil" - the environment within which we wish to "seed" stem cells to promote repair. We will exploit new understanding of how the niche environment directs stem/progenitor cell phenotype, function and fate, and drives tissue formation in health and in disease. Thus our research will be of interest to industry, e.g. in the development of niche-based products and tools such as stem cell selection systems, marker arrays, lineage pathway inducers, natural epitope-derived biomaterials and extracellular matrix products. Hub members are already directly involved in marketing new products such as EpranEx microtitre plates to analyse protein-glycan interactions (UoMan) and novel polymer substrates to promote hepatocyte differentiation (FibromEd, UoE), and we are developing a range of novel biomaterials based on these and other bioengineering technologies. All our Universities have strong records of exploiting innovative research findings through commercialisation of intellectual property (e.g. UoM Intellectual Property (UMIP) and Edinburgh BioQuarter). Outputs for exploitation will be selected by the Management Committee, with a decision made on the appropriate host University to lead commercialisation activity of research products (based on balance of IP): these may include licensing of cellular and extracellular matrix reagents/biologics and protocols, provision of research expertise such as iPS cells or or glycomic technologies, novel lineage-inducing small molecules, in-house assays/technologies, co-development of technologies licensing of IP, consultancies.