Work

Geometrically-engineered human motor assembloids-on-a-chip for neuromuscular interaction readout and hypoxia-driven disease modeling

Year: 2025

Type: article

Abstract: Precision medicine leverages stem cell-derived models to dissect complex interactions underlying disease-driven neuromuscular damage. However, such reductionist models form stochastic structures without external guidance, while available engineering solutions remain intricate. Here, simplified surface modification engineering is used to render spatially patterned human motor assembloids-on-a-chip by geometric confinement. The anisotropic architecture of skeletal muscle organoids (hSkM) can be conferred solely by localized mechanobiological cues within this predefined device without aligned scaffolds or adjuncts. The hSkM-orchestrated coupling of motor neuron spheroids (hMNS) promotes synergistic neuromuscular development. Furthermore, integration of optogenetic and microelectrode array mapping enables visualization of functional patterning in assembloids. Applied to oxygen deprivation model, hSkM exhibits structural anomalies, fatigable muscle remodeling and dysfunction, recapitulating muscle pathologies in intermittent hypoxia (IH)-associated respiratory disorders. Electrical activity mapping reveals the heterogeneity in neuromuscular responses to IH, indicating the neuroregulatory etiology of muscle dysfunction. Finally, we identify mitochondrial bioenergetic imbalance as a key IH target, proposing evaluation of NAD+ salvage pathway-targeting agents. Our findings provide an accessible platform with translational potential for neuromuscular physiopathology research. Challenges in simplicity and accessibility limit the current widespread applicability of neuromuscular models. Here, the authors present a readily fabricated, organised human motor assembloids-on-a-chip approach for neuromuscular research and hypoxia disease modelling.

Source: Nature Communications

DOI: 10.1038/s41467-025-63736-0