Autologous human iPSC-derived alveolus-on-chip reveals early pathological events of Mycobacterium tuberculosis infection
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Jakson Luk Gabriel Conway Kim Goh Tony Fearns Irene Rodriguez Hernandez Nathan Day Natalia Athanasiadi Rocco D'Antuono Enrica Pellegrino Janick D Stucki Nina Hobi Maximiliano GutierrezAbstract
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.
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Journal
Science advances
Volume
12
Issue number
1
Pages
eaea9874
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10.1126/sciadv.aea9874
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Europe PubMed Central
41477823
Pubmed
41477823
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