Generation of induced alveolar assembloids with functional alveolar-like macrophages

Ji Su Kang, Youngsun Lee, Youngsun Lee, Dayeon Gil, Min Jung Kim, Connor Wood, Vincent Delorme, Jeong Mi Lee, Kyong-Cheol Ko, Jung-Hyun Kim () and Mi-Ok Lee ()
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Ji Su Kang: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Youngsun Lee: Korea National Institute of Health
Youngsun Lee: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Dayeon Gil: Korea National Institute of Health
Min Jung Kim: Korea National Institute of Health
Connor Wood: Institute Pasteur Korea
Vincent Delorme: Institute Pasteur Korea
Jeong Mi Lee: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Kyong-Cheol Ko: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Jung-Hyun Kim: Korea National Institute of Health
Mi-Ok Lee: Korea Research Institute of Bioscience and Biotechnology (KRIBB)

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

Abstract: Abstract Within the human lung, interactions between alveolar epithelial cells and resident macrophages shape lung development and function in both health and disease. To study these processes, we develop a co-culture system combining human pluripotent stem cell-derived alveolar epithelial organoids and induced macrophages to create a functional environment, termed induced alveolar assembloids. Using single-cell RNA sequencing and functional analyses, we identify alveolar type 2-like cells producing GM-CSF, which supports macrophage tissue adaptation, and macrophage-like cells that secrete interleukin-1β and interleukin-6, express surfactant metabolism genes, and demonstrate core immune functions. In response to alveolar epithelial injury, macrophage-like cells efficiently eliminate damaged cells and absorb oxidized lipids. Exposure to bacterial components or infection with Mycobacterium tuberculosis reveals that these assembloids replicate key aspects of human respiratory defense. These findings highlight the potential of induced alveolar assembloids as a platform to investigate human lung development, immunity, and disease.

Date: 2025
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DOI: 10.1038/s41467-025-58450-w

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