Neuroepithelial bodies and terminal bronchioles are niches for distinctive club cells that repair the airways following acute notch inhibition
Sai Manoz Lingamallu,
Aditya Deshpande,
Neenu Joy,
Kirthana Ganeshan,
Neelanjana Ray,
Rajesh Kumar Ladher,
Makoto Mark Taketo,
Daniel Lafkas,
Arjun Guha
Affiliations
Sai Manoz Lingamallu
Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore 560065, India; Manipal Academy of Higher Education (MAHE), Madhav Nagar, Manipal 576104, India
Aditya Deshpande
Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore 560065, India; The University of Trans-Disciplinary Health Sciences and Technology (TDU), Yelahanka 560064, Bangalore, India
Neenu Joy
Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore 560065, India; SASTRA Deemed University, Tirumalaisamudram, Thanjavur 613401, India
Kirthana Ganeshan
Immunology Discovery, Genentech Inc., South San Francisco, CA 94080, USA
Neelanjana Ray
National Centre for Biological Sciences, Tata Institute for Fundamental Research, Bangalore 560065, India
Rajesh Kumar Ladher
National Centre for Biological Sciences, Tata Institute for Fundamental Research, Bangalore 560065, India
Makoto Mark Taketo
Colon Cancer Project, Kyoto University Hospital-iACT, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
Daniel Lafkas
Immunology, Infectious Diseases, and Ophthalmology (I2O) Discovery and Translational Area, Roche Innovation Center, Basel, Switzerland
Arjun Guha
Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore 560065, India; Corresponding author
Summary: Lower airway club cells (CCs) serve the dual roles of a secretory cell and a stem cell. Here, we probe how the CC fate is regulated. We find that, in response to acute perturbation of Notch signaling, CCs adopt distinct fates. Although the vast majority transdifferentiate into multiciliated cells, a “variant” subpopulation (v-CCs), juxtaposed to neuroepithelial bodies (NEBs; 5%–10%) and located at bronchioalveolar duct junctions (>80%), does not. Instead, v-CCs transition into lineage-ambiguous states but can revert to a CC fate upon restoration of Notch signaling and repopulate the airways with CCs and multiciliated cells. The v-CC response to Notch inhibition is dependent on localized activation of β-catenin in v-CCs. We propose that the CC fate is stabilized by canonical Notch signaling, that airways are susceptible to perturbations to this pathway, and that NEBs/terminal bronchioles comprise niches that modulate CC plasticity via β-catenin activation to facilitate airway repair post Notch inhibition.
