The optimisation of neuromuscular assembloids by the integrating Schwann cells

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons (MNs). As a consequence, patients gradually lose muscle control and motor function, typically leading to death within 2–5 years after diagnosis. Current therapies are limited to symptomatic treatment, highlighting the urgent need for new disease-modifying strategies.

Increasing evidence suggests that disease processes begin at the neuromuscular junction (NMJ), the specialized synapse connecting motor neurons and muscle fibers. However, commonly used animal models only incompletely reflect human ALS pathology, partly due to structural and molecular differences between mouse and human NMJs.

To address this limitation, we develop human cell-based in vitro models of the neuromuscular junction. Our previous co-culture systems of motor neurons and muscle cells demonstrated functional connectivity but only partially reproduced the complex architecture and physiological properties of mature NMJs [1, 2]. An important missing component in most existing systems are terminal Schwann cells, which play a crucial role in NMJ formation, maturation, and maintenance and have been implicated in ALS-associated motor neuron degeneration.

Our goal is to generate human neuromuscular 3D assembloids composed of motor neurons, Schwann cells, and muscle cells derived from human induced pluripotent stem cells (hiPSCs). These advanced 3D models will allow us to study the formation and function of mature human NMJs and to identify ALS-specific alterations in a fully human system. Collectively, we aim to establish a physiologically relevant platform that complements and potentially reduces the need for animal models in ALS research.

Publications:

1.      Massih B, Veh A, Schenke M, Mungwa S, Seeger B, Selvaraj BT, Chandran S, Reinhardt P, Sterneckert J, Hermann A, Sendtner M, Lüningschrör P. „A 3D cell culture system for bioengineering human neuromuscular junctions to model ALS” Front Cell Dev Biol. 11:996952 (2023). htpps://doi: 10.3389/fcell.2023.996952

2.      Giridhar NJ, Hambrecht B, Schenke M, Seeger B, Bischler T, Briese M, Lüningschrör P. “Temporal transcriptomic profiling of human three-dimensional neuromuscular co-cultures” Biol Open. 14(9): bio062196 (2025). htpps://doi: 10.1242/bio.062196.