Generation of position specific organoids to study human neuromuscular system development and disease

Title Generation of position specific organoids to study human neuromuscular system development and disease
Acronym GPSorganoids
Start date 2021-07-01
End date 2026-06-30
Sponsor European Research Council - Consolidator Grant (ERC-CoG)
Institution Max Delbrück Center Berlin Buch
Principal investigator Mina Gouti

Associated cell lines

Project Description

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). These diseases often show regional selectivity but the underlying reasons remain obscure due to the lack of a suitable model system. In previous work of my laboratory, we established a 3D neuromuscular organoid (NMO) model that allows the simultaneous generation of spinal cord neurons and skeletal muscle cells from human pluripotent stem cells (hPSCs) through a bipotent neuromesodermal progenitor (NMP). NMPs, located in the posterior part of the embryo, are driving axial elongation and coordinated growth of the trunk neuromuscular system. We coaxed hPSC derived NMPs to develop into neuromuscular organoids that form functional neuromuscular junctions supported by the presence of terminal Schwann cells and central pattern generator-like circuits. Thus, we are in the unique position to study in an organoid model the regulatory mechanisms involved in the formation and maintenance of the human neuromuscular system, and the disruption of these mechanisms in diseases. We will (i) identify the molecular requirements for the Generation of Position Specific (GPS) organoids representing distinct spinal cord segments, (ii) use NMOs to model and study ALS and SMA including the establishment of a drug screening platform and (iii) assemble hPSC-derived cerebral organoids and NMOs to include in the model human corticospinal tracts. In the long term, the information gained will have important implications for understanding and eventually treating neuromuscular diseases.