Seminar: João Pereira
Date: September 11, 2018. 12:00
Location: CCU Seminar Room
Title: An organoid spinal cord model in the context of ALS.
Affiliation: Brian Wainger Lab, Harvard Medical School/Massachusetts General Hospital.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that leads to the progressive death of motor neurons. Familial ALS (fALS), with known genetic causes, comprises 5-10% of the total number of reported ALS cases. The remainder 90-95% of cases are of sporadic (sALS), with no identifiable underlying mutation. While animal models exist for fALS, no models exist for sALS. To address this issue, we have developed a patient specific, iPSC-based, organoid model of the human spinal cord.
Spinal cord organoids contain cells belonging to either the mesodermal or ectodermal lineages, possess internal organization into a neural tube-like structure, and differentiate into multiple components of the spinal cord derived from ectodermal lineages. Immunocytochemistry confirmed the presence of motor neurons, sensory neurons and astrocytes, as well as of skeletal muscle. The skeletal muscle is innervated by the motor neurons, with the formation of neuromuscular junctions and neuronal dependent contractions lasting up to 7 weeks. These contractions are dependent on neuronal activity and are inhibited by curare and Botulinum toxin. At later stages the contractions diminish in frequency, but can be restored with the application of Bicuculline, indicating the presence of inhibitory networks. The sensory neurons form clusters and respond to capsaicin stimulation. We have used this model to identify a phenotype of reduction of the number of NMJs in a TDP43G298S model when compared to isogenic controls, and in the future to potentially model the onset and progression of sALS.