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

Weihua Zhang, Liming Yu, Jie Pan, Jiajia Deng, Xianqin Tong, Bingjiao Zhao, Wen Liu, Liangyan Sun, Menghan Zhang, Xinxin Han, Tingjiao Liu, Yun Lu (), Jiao Li () and Yuehua Liu ()
Additional contact information
Weihua Zhang: Fudan University
Liming Yu: Fudan University
Jie Pan: Fudan University
Jiajia Deng: Fudan University
Xianqin Tong: Fudan University
Bingjiao Zhao: Fudan University
Wen Liu: Fudan University
Liangyan Sun: Fudan University
Menghan Zhang: Zhejiang Key Laboratory of Oral Biomedical
Xinxin Han: Fudan University
Tingjiao Liu: Fudan University
Yun Lu: Fudan University
Jiao Li: Fudan University
Yuehua Liu: Fudan University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-63736-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63736-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-63736-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().