Autologous human iPSC–derived alveolus-on-chip reveals early pathological events of Mycobacterium tuberculosis infection

Luk, C. H. ORCID: https://orcid.org/0000-0002-5155-2257, Conway, G. L. ORCID: https://orcid.org/0009-0001-6702-8994, Goh, K. J. ORCID: https://orcid.org/0000-0001-8051-7867, Fearns, A. ORCID: https://orcid.org/0000-0001-9937-8545, Hernandez, I. R. ORCID: https://orcid.org/0000-0002-6487-452X, Day, N. J. ORCID: https://orcid.org/0000-0002-9141-3833, Athanasiadi, N., D’Antuono, R. ORCID: https://orcid.org/0000-0003-0180-6500, Pellegrino, E., Stucki, J. D., Hobi, N. and Gutierrez, M. G. ORCID: https://orcid.org/0000-0003-3199-0337 (2026) Autologous human iPSC–derived alveolus-on-chip reveals early pathological events of Mycobacterium tuberculosis infection. Science Advances, 12 (1). eaea9874. ISSN 2375-2548 doi: 10.1126/sciadv.aea9874

Abstract/Summary

Immunocompetent and experimentally accessible alveolar systems to study human respiratory diseases are lacking. Here, we developed a single-donor human induced pluripotent stem cell-derived lung-on-chip (iLoC) containing type II and I alveolar epithelial cells, vascular endothelial cells, and macrophages in a microfluidic device that mimic lung three-dimensional mechanical stretching and air-liquid interface. Imaging and single-cell RNA sequencing analysis revealed that the iLoC recapitulated cellular profiles present in the human distal lung. Infection of the iLoC with the human pathogen Mycobacterium tuberculosis (Mtb) showed that both macrophages and epithelial cells were infected but not permissive to bacterial replication. Stochastically, large macrophage clusters containing necrotic macrophages supporting Mtb replication were observed. A genetically engineered autophagy-deficient iLoC revealed that after Mtb infection, macrophage necrosis was higher upon ATG14 deficiency without bacterial replication. Together, we report an autologous, genetically tractable human alveolar model to study lung diseases and therapies.

Item Type	Article
URI	https://centaur.reading.ac.uk/id/eprint/127849
Identification Number/DOI	10.1126/sciadv.aea9874
Refereed	Yes
Divisions	Life Sciences > School of Biological Sciences > Biomedical Sciences
Publisher	American Association for the Advancement of Science
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