Building advanced neuromuscular organoids to study human disease

Locomotion results from the interaction between muscles and the nervous system. Dysfunction of such cells results in deadly diseases such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). Neuromuscular diseases often show regional selectivity but the underlying reasons remain obscure due to the lack of a suitable human model system. The Gouti lab at Max Delbrück Center, has pioneered the generation of complex human neuromuscular organoids from pluripotent stem cells. Neuromuscular organoids (NMOs) simultaneously generate spinal cord neurons and skeletal muscle cells that self-organize in 3D (Martins et al, Cell Stem Cell, 2020) to form functional neuromuscular junctions supported by terminal Schwann cells. NMOs contract and develop central pattern generator-like neuronal circuits. We are currently applying NMOs to model human neuromuscular diseases. To elucidate the mechanisms of disease, we utilize patient-specific NMOs in combination with gain and loss of gene function approaches (Crispr/Cas9 system), single-cell genomics (scRNA-seq), spatial transcriptomics as well as advanced live cell imaging techniques. By integrating these approaches, we aim to uncover the sequence of events and provide greater insight into the mechanisms that lead to specific diseases. In the long term, our research holds the promise of revolutionizing treatment strategies for debilitating neuromuscular and neurodegenerative diseases.