TY - JOUR
KW - amyotrophic lateral sclerosis
KW - Neural Stem Cells
AU - Benedetta Frizzi
AU - Adriana Margarida Barbosa Correia
AU - Irene Faravelli
AU - Ludo Van Den Bosch
AU - Stefania Corti
AB - Motor neuron diseases (MNDs) are caused by the progressive loss of motor neurons and eventually lead to paralysis and death. Once viewed as primarily neurocentric, MNDs are now recognized to be driven by intertwined cell-autonomous and non-cell-autonomous mechanisms. Dissecting these interactions is essential for developing effective therapies. Here, we describe induced pluripotent stem cell-derived 3D models that can be used to capture distinct aspects of MND pathology. We show that spinal cord organoids can be used to investigate cell-autonomous mechanisms and motor neuron–glia interactions (with axially elongated spinal cord organoids being particularly useful to study developmental vulnerability) as well as in 3D muscle and combined neuromuscular models to dissect muscle pathology and neuromuscular junction dismantling. In parallel, we discuss advances in bioengineering, machine learning and human trunk-like models, which together can begin to reproduce the coordinated co-development and spatial organization of the multiple tissues affected in MNDs. We discuss how these systems have advanced our understanding of disease mechanisms and highlight opportunities for drug repurposing. Finally, we propose a mechanism-informed and phenotype-informed framework to guide 3D model selection for future research and to prioritize promising avenues for therapeutic development.
BT - Nature Reviews Neuroscience
DA - 2026-07-06
DO - 10.1038/s41583-026-01057-x
LA - en
N2 - Motor neuron diseases (MNDs) are caused by the progressive loss of motor neurons and eventually lead to paralysis and death. Once viewed as primarily neurocentric, MNDs are now recognized to be driven by intertwined cell-autonomous and non-cell-autonomous mechanisms. Dissecting these interactions is essential for developing effective therapies. Here, we describe induced pluripotent stem cell-derived 3D models that can be used to capture distinct aspects of MND pathology. We show that spinal cord organoids can be used to investigate cell-autonomous mechanisms and motor neuron–glia interactions (with axially elongated spinal cord organoids being particularly useful to study developmental vulnerability) as well as in 3D muscle and combined neuromuscular models to dissect muscle pathology and neuromuscular junction dismantling. In parallel, we discuss advances in bioengineering, machine learning and human trunk-like models, which together can begin to reproduce the coordinated co-development and spatial organization of the multiple tissues affected in MNDs. We discuss how these systems have advanced our understanding of disease mechanisms and highlight opportunities for drug repurposing. Finally, we propose a mechanism-informed and phenotype-informed framework to guide 3D model selection for future research and to prioritize promising avenues for therapeutic development.
PY - 2026
SP - 1
EP - 21
T2 - Nature Reviews Neuroscience
TI - Using human 3D organoid models to gain mechanistic insight in motor neuron diseases
UR - https://www.nature.com/articles/s41583-026-01057-x
Y2 - 2026-07-23
SN - 1471-0048
ER -