Understanding the activities of connective tissue fibroblasts during muscle formation towards understanding disease and engineering muscle tissue

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Diseases that effect proper functioning of the musculoskeletal (MSK) system are common and can arise from birth defects, sports injuries, trauma, disease, normal wear-and-tear and age-related diseases. Together, MSK diseases contribute a significant burden on health care systems, carers and lead to lost productivity. The expanding ageing population means the number of cases of MSK disease, and the burden this imposes, will expand dramatically in the future. We aim to address the challenges of MSK disease and contribute to health benefits that will enhance quality of life, health and productivity.The proposed work packages are unified in tackling the fundamental question of how are muscle tissues built and how this can become disrupted in disease. Understanding how tissues are built is essential to develop tissue engineering strategies and regenerative therapies that can replace tissue lost through trauma, wear-and-tear or disease. Disruption of tissue formation produces limb birth defects and understanding what and when events have gone wrong is critical for diagnosis, management and treatment regimes. Our aim is by studying and understanding the molecular and cellular mechanisms that underpin how tissues are built, we can develop ways to replicate and harness these processes for tissue engineering and regenerative therapies.We have chosen to focus on limb muscles as an experimentally tractable system and one that has clear clinical applicability. Tools are already available to make muscle fibres in a dish and we have a good understanding and control over how the progression of terminal differentiation of muscle precursors to myofibres is regulated. We have very poor understanding, however, of how myofibres are organised into blocks of tissue and as a result we are still a long way from being able to engineer functional muscle tissue.Muscle tissue is not simply a collection of muscle fibres. A muscle bundle is a composite of muscle fibres and irregular connective tissue (ICT) fibroblasts, which are critical constituents of the highly organised architecture of a functional muscle bundle. Although the importance of ICT is well established, very little is known about what these cells do and how they act during muscle formation and repair. ICT and its derivatives, e.g. muscle fascia) is an essential component of muscle tissue. Learning and how to replicate or mimic the activities of ICT is an essential in any strategy to engineer muscle. We are focussing on filling the current gap in understanding of the functions of ICT, in developing novel approaches to study ICT function and in developing novel approaches to engineer muscle tissue.We are taking novel, mullti-disciplinary approaches to identify the mechanisms controlling muscle formation and repair and in developing tools to study these process and translate our findings into new treatments for MSK diseases.We will also produce a freely accessible, reference database of human embryonic limb development that will create a permanent resource for educators, researchers and clinicians. This resource will help explain the precise origins of congenital limb abnormalities and reveal the sensitivity window when nascent tissues have been disrupted during human embryonic development.