Single cell profiling of human airway identifies tuft-ionocyte progenitor cells displaying cytokine-dependent differentiation bias in vitro

Viral S. Shah, Avinash Waghray, Brian Lin, Atharva Bhagwat, Isha Monga, Michal Slyper, Bruno Giotti, Sunghyun Kim, Dawei Sun, Ke Xu, Eric Park, Mohamad Bairakdar, Jiajie Xu, Julia Waldman, Danielle Dionne, Lan T. Nguyen, Wendy Lou, Peiwen Cai, Christoph Muus, Jiawei Sun, Manalee V. Surve, Lujia Cha Cha Yang, Orit Rozenblatt-Rosen, Toni M. Delorey, Srinivas Vinod Saladi, Aviv Regev (), Jayaraj Rajagopal () and Alexander M. Tsankov ()
Additional contact information
Viral S. Shah: Massachusetts General Hospital
Avinash Waghray: Massachusetts General Hospital
Brian Lin: Massachusetts General Hospital
Atharva Bhagwat: Icahn School of Medicine at Mount Sinai (ISMMS)
Isha Monga: Icahn School of Medicine at Mount Sinai (ISMMS)
Michal Slyper: Broad Institute of MIT and Harvard
Bruno Giotti: Icahn School of Medicine at Mount Sinai (ISMMS)
Sunghyun Kim: Massachusetts General Hospital
Dawei Sun: Massachusetts General Hospital
Ke Xu: Icahn School of Medicine at Mount Sinai (ISMMS)
Eric Park: Icahn School of Medicine at Mount Sinai (ISMMS)
Mohamad Bairakdar: Icahn School of Medicine at Mount Sinai (ISMMS)
Jiajie Xu: Massachusetts General Hospital
Julia Waldman: Broad Institute of MIT and Harvard
Danielle Dionne: Broad Institute of MIT and Harvard
Lan T. Nguyen: Broad Institute of MIT and Harvard
Wendy Lou: Broad Institute of MIT and Harvard
Peiwen Cai: Icahn School of Medicine at Mount Sinai (ISMMS)
Christoph Muus: Broad Institute of MIT and Harvard
Jiawei Sun: Massachusetts General Hospital
Manalee V. Surve: Massachusetts General Hospital
Lujia Cha Cha Yang: Harvard College
Orit Rozenblatt-Rosen: Broad Institute of MIT and Harvard
Toni M. Delorey: Broad Institute of MIT and Harvard
Srinivas Vinod Saladi: Broad Institute of MIT and Harvard
Aviv Regev: Broad Institute of MIT and Harvard
Jayaraj Rajagopal: Massachusetts General Hospital
Alexander M. Tsankov: Icahn School of Medicine at Mount Sinai (ISMMS)

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Human airways contain specialized rare epithelial cells including CFTR-rich ionocytes that regulate airway surface physiology and chemosensory tuft cells that produce asthma-associated inflammatory mediators. Here, using a lung cell atlas of 311,748 single cell RNA-Seq profiles, we identify 687 ionocytes (0.45%). In contrast to prior reports claiming a lack of ionocytes in the small airways, we demonstrate that ionocytes are present in small and large airways in similar proportions. Surprisingly, we find only 3 mature tuft cells (0.002%), and demonstrate that previously annotated tuft-like cells are instead highly replicative progenitor cells. These tuft-ionocyte progenitor (TIP) cells produce ionocytes as a default lineage. However, Type 2 and Type 17 cytokines divert TIP cell lineage in vitro, resulting in the production of mature tuft cells at the expense of ionocyte differentiation. Our dataset thus provides an updated understanding of airway rare cell composition, and further suggests that clinically relevant cytokines may skew the composition of disease-relevant rare cells.

Date: 2025
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DOI: 10.1038/s41467-025-60441-w

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