A Human iPS Cell-Derived Artificial Skeletal Muscle for Regenerative Medicine, Disease Modelling and Drug Screening

Skeletal muscle is the most abundant human tissue and contains mainly post-mitotic nuclei. It also expresses the largest gene known in nature – dystrophin – whose mutations cause Duchenne muscular dystrophy, the most frequent and incurable childhood muscle disorder. These characteristics create hurdles that negatively impact on the development of therapies for muscle diseases, ranging from acute tissue loss to chronic neuromuscular disorders. Moreover, a lack of humanised models of muscle regeneration delays the understanding of its regenerative dynamics.My work has pioneered the use of human induced pluripotent stem (iPS) cells to generate genetically corrected myogenic cells for the autologous cell therapy of muscular dystrophies. Here I propose to exploit this technology together with biocompatible materials to develop three dimensional, iPS cell-derived, patient-specific artificial muscles. These bioengineered skeletal muscles will provide a model to study human muscle regeneration and a platform for tissue engineering and therapy development for severe muscle diseases.The project will be developed in two phases. First we will develop the iPS cell-derived muscle in vitro, introducing cell types and stimuli necessary to obtain a functional tissue. In the second phase we will exploit the muscle “organoids” for regenerative medicine and drug development. Specifically, we will investigate the artificial muscle potential for tissue replacement in vivo and then model different muscular dystrophies in vitro to screen drugs with therapeutic relevance. Finally, we will combine the tools and knowledge developed in the two aforementioned areas into a novel platform to optimise skeletal muscle gene and cell therapies. This project will bring together tissue engineering, drug development and cell therapy under the same translational technology, advancing the understanding of pathogenesis and the development of therapies for muscle diseases.