Combining stem cell science and Tissue engineering to study the development and repair of Human skeletal tissues

With an ever increasing ageing population, strategies that allow the simple repair and enhancement of bone tissue, lost due to diseases such as osteoporosis and osteoarthritis or with ageing or after an accident, are urgently needed. Whilst there are a number of surgical techniques that can be used to repair bone and to aid fracture healing, there is a great need for the development of alternative bone and cartilage repair and regeneration strategies. To try and solve the lack of bone a patient may have at one site, the surgeon can try and harvest and use existing bone from another site (known as autogenous bone) in the patient although, naturally, the amounts available to use are limited. Other options include the use of donor bone from a different individual (known as allogeneic bone). However donor bone carries risks of rejection and infection. Tissue engineering aims to make tissues and organs - including bone tissue - using stem and precursor cells, scaffolds upon which the cells can grow and be guided, and necessary mechanical cues to create bone tissue in the laboratory for transplantation to replace damaged or diseased tissues. Within all our bone marrow are stem cells (called skeletal or mesenchymal stem cells), which can be isolated using selective markers and which can be grown up to give lots of cells, while retaining their ability to form a variety of tissues like bone and fat. Similarly we have expertise in the ability to create structures (scaffolds) for the cells to grow on and these scaffolds can be tailored to release select growth factors and proteins needed to guide and tell the stem cells to make bone and cartilage. In addition, we know that mechanical cues are very important in stimulating new bone growth (for example we know excessive bed rest or weightlessness leads to loss of bone). Thus the application of stem cells, select scaffolds and the use of signalling cues to generate new bone tissue is currently one of the most exciting and promising areas for disease treatment and bone repair. We propose as well as combining these key ingredients, that, critically, a new way of thinking as to how scientists currently try to create skeletal tissue is urgently needed if we are to meet the challenges of new skeletal formation for an increasing ageing population. We propose that it is vital to understand bone development and formation and that if we can harness the information of how bone develops and if we can understand bone biology, this will set the foundation and inform us how to repair and make new skeletal tissue. Thus, we propose an ambitious programme of research to significantly advance the state-of-the-art in developmental biology, stem cells, materials chemistry, mechanical signalling and loading and translational medicine to generate new models of skeletal development that can be used to inform skeletal repair strategies for clinical use in bone repair and regeneration. To achieve our goal we will use a multidisciplinary strategy that brings together stem cell biologists, developmental biologists, materials scientists, mechanobiologists and clinicians with an ability to draw lessons from skeletal developmental biology to inform our tissue engineering strategy for skeletal formation and repair.

The application of stem cells, select scaffolds and the incorporation of appropriate signalling cascades in the generation of new tissue is currently one of the most exciting and promising areas for disease treatment and reparative medicine. This has gained prominence given the demographic challenges of an advancing ageing population and the need for innovative approaches to augment and repair skeletal tissue. We propose that a paradigm shift in current research strategy is required if we are to meet the goal of skeletal tissue formation. We propose to enhance our understanding of skeletal developmental biology and apply this to underpin and inform the skeletal regenerative process. Currently, our progress in the isolation and culture of skeletal stem cells and in the application of scaffolds that control 3D architecture, soluble factor gradients and surface adhesion motifs has reached a point where we can mimic specific pathways used by the human body in skeletal tissue development and regeneration. Critically, mechanobiology has emerged as an important component in the regeneration of skeletal tissue. However, there remain significant challenges for the reconstruction of complex tissues, such as bone, that can only be informed by a thorough understanding of the developing tissue environment. Through Lola funding we propose that elucidation of the skeletal niche is critical in the identification of the key growth factors, matrix constituents and physiological conditions that will enhance and inform tissue regeneration. The approach advocated necessitates a truly inter- and multidisciplinary approach which could not be addressed through standard project routes of funding. The outcomes of this LOLA will be new in vitro and ex vivo models of human development translating to improved scaffolds and skeletal stem cell treatments for regenerative medicine. Joint with BB/G010587/1, BB/010579/1, BB/G010617/1. This joint project was co-funded by EPSRC under BBSRC Responsive Mode.