Stem cells for tissue repair
Transplantation of cells, tissues and organs has been identified by the World Health Organisation as an important global therapeutic approach. It has improved patients’ lives and extended the lifespan of many hundreds of thousands of individuals worldwide. The use of stem cells and their products may therefore lead to novel cell and molecular therapies for a wide variety of medical conditions, including haematological malignancies, wound repair and cardiovascular disease. The Stem Cell Research Laboratory research programme aims to understand the biology of stem cell development, stem cell decision making and the homing/engraftment of stem cells into tissues, with the objective of translating this research into the clinic. As stem cells and their progeny play a pivotal role in regulating blood and blood vessel formation, our particular studies concentrate on the role of haemopoietic and vascular stem cells and their progeny in blood and blood vessel regeneration. We use the bone marrow, cardiovascular system and skin as tissue exemplars.
Haemopoietic stem cells
Haemopoietic stem cell transplantation is now an established regenerative medicine for treating a range of haematological diseases, some metabolic disorders and some solid cancers. Despite therapeutic advantages, the probability of 5 year survival following haemopoietic stem cell transplantation is variable. In healthy human adults, the bone marrow produces over 1011 to 1012 new blood cells from stem/progenitor cells each day. This is associated with three anatomical regions, the sinusoids (the vascular niche), the endosteum (the osteoblastic niche) and the haemopoietic tissue proper, in the bone marrow. Our research is based on three observations. First, blood sourced from the umbilical cord at birth is increasingly used as a source of haemopoietic stem cells for transplantation and blood regeneration, although its disadvantages include limited cell content and delayed haemopoietic reconstitution. Secondly, oxygen tensions can influence stem/progenitor cell self-renewal and differentiation within the bone marrow niche and hypoxia is associated with rapid cell growth and aberrant blood vessel formation in certain haematological malignancies. Thirdly, the repair of the bone marrow vascular niche is essential for normal post-natal haemopoiesis and for haemopoietic recovery after bone marrow damage, as exemplified by the response to preconditioning regimes during the treatment of malignancies and prior to transplants and following radiation damage.
Our research objectives here focus on improving the treatment and outcomes for severely ill patients suffering from both malignant and non-malignant diseases of the blood and our particular aims are:
i) To understand the role of hypoxia in the stem cell self-renewal and differentiation;
ii) To improve the quality of the cord blood graft for haemopoietic stem cell transplants by developing cost-effective graft engineering technologies to improve engraftment and to prevent graft failure, infections or relapse post-transplant and to ensure full and efficacious haemopoietic reconstitution over the longer term;
iii) To define components of and to repair the vascular niche following conditioning or radiation damage to promote normal haemopoietic reconstitution and prevent relapse.
Stem cell therapies for wound and cardiovascular repair
Cardiovascular disease is a leading cause of morbidity and mortality worldwide, but less known is the fact that in the UK and USA alone chronic wounds currently affect over 6.7 million patients. This burden is growing rapidly with an aging population and a sharp rise in diabetes and obesity worldwide.
Generating a blood supply is fundamental to most tissue repair, while its dysregulation can contribute to serious disease. Future therapies in regenerative medicine will use better defined products and more personalised and tissue specific approaches. Our objectives are therefore to use our knowledge of and research on stem cells found in blood and blood vessels
i) To understand the mechanisms of blood vessel formation in such tissues as the heart and skin;
ii) To develop clinical grade products (stem or progenitor cells/biologics) to support blood vessel formation in the heart and skin.
Does osteogenic potential of clonal human bone marrow mesenchymal stem/stromal cells correlate with their vascular supportive ability?
Merryweather-Clarke AT. et al, (2018), Stem Cell Res Ther, 9
Junctional Adhesion Molecule-A Is Highly Expressed on Human Hematopoietic Repopulating Cells and Associates with the Key Hematopoietic Chemokine Receptor CXCR4.
Chang C-H. et al, (2016), Stem Cells, 34, 1664 - 1678
Cord and cord blood-derived endothelial cells
Watt SM. et al, (2014), Cord Blood Stem Cells Medicine, 49 - 61
A novel application for a 3-dimensional timelapse assay that distinguishes chemotactic from chemokinetic responses of hematopoietic CD133(+) stem/progenitor cells.
Pepperell EE. and Watt SM., (2013), Stem Cell Res, 11, 707 - 720