Single cell profiling of human airway identifies tuft-ionocyte progenitor cells displaying cytokine-dependent differentiation bias in vitro
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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-06-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60441-w |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849725087193759744 |
|---|---|
| author | 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 Alexander M. Tsankov |
| author_facet | 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 Alexander M. Tsankov |
| author_sort | Viral S. Shah |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d817a5ae4d2d46a9b1faf83f599f5711 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d817a5ae4d2d46a9b1faf83f599f57112025-08-20T03:10:34ZengNature PortfolioNature Communications2041-17232025-06-0116111510.1038/s41467-025-60441-wSingle cell profiling of human airway identifies tuft-ionocyte progenitor cells displaying cytokine-dependent differentiation bias in vitroViral S. Shah0Avinash Waghray1Brian Lin2Atharva Bhagwat3Isha Monga4Michal Slyper5Bruno Giotti6Sunghyun Kim7Dawei Sun8Ke Xu9Eric Park10Mohamad Bairakdar11Jiajie Xu12Julia Waldman13Danielle Dionne14Lan T. Nguyen15Wendy Lou16Peiwen Cai17Christoph Muus18Jiawei Sun19Manalee V. Surve20Lujia Cha Cha Yang21Orit Rozenblatt-Rosen22Toni M. Delorey23Srinivas Vinod Saladi24Aviv Regev25Jayaraj Rajagopal26Alexander M. Tsankov27Simches 4, Northeast Corridor, Massachusetts General HospitalSimches 4, Northeast Corridor, Massachusetts General HospitalSimches 4, Northeast Corridor, Massachusetts General HospitalDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai (ISMMS)Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai (ISMMS)Klarman Cell Observatory, Broad Institute of MIT and HarvardDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai (ISMMS)Simches 4, Northeast Corridor, Massachusetts General HospitalSimches 4, Northeast Corridor, Massachusetts General HospitalDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai (ISMMS)Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai (ISMMS)Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai (ISMMS)Simches 4, Northeast Corridor, Massachusetts General HospitalKlarman Cell Observatory, Broad Institute of MIT and HarvardKlarman Cell Observatory, Broad Institute of MIT and HarvardKlarman Cell Observatory, Broad Institute of MIT and HarvardKlarman Cell Observatory, Broad Institute of MIT and HarvardDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai (ISMMS)Klarman Cell Observatory, Broad Institute of MIT and HarvardSimches 4, Northeast Corridor, Massachusetts General HospitalSimches 4, Northeast Corridor, Massachusetts General HospitalHarvard CollegeKlarman Cell Observatory, Broad Institute of MIT and HarvardKlarman Cell Observatory, Broad Institute of MIT and HarvardBroad Institute of MIT and HarvardKlarman Cell Observatory, Broad Institute of MIT and HarvardSimches 4, Northeast Corridor, Massachusetts General HospitalDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai (ISMMS)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.https://doi.org/10.1038/s41467-025-60441-w |
| spellingShingle | 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 Alexander M. Tsankov Single cell profiling of human airway identifies tuft-ionocyte progenitor cells displaying cytokine-dependent differentiation bias in vitro Nature Communications |
| title | Single cell profiling of human airway identifies tuft-ionocyte progenitor cells displaying cytokine-dependent differentiation bias in vitro |
| title_full | Single cell profiling of human airway identifies tuft-ionocyte progenitor cells displaying cytokine-dependent differentiation bias in vitro |
| title_fullStr | Single cell profiling of human airway identifies tuft-ionocyte progenitor cells displaying cytokine-dependent differentiation bias in vitro |
| title_full_unstemmed | Single cell profiling of human airway identifies tuft-ionocyte progenitor cells displaying cytokine-dependent differentiation bias in vitro |
| title_short | Single cell profiling of human airway identifies tuft-ionocyte progenitor cells displaying cytokine-dependent differentiation bias in vitro |
| title_sort | single cell profiling of human airway identifies tuft ionocyte progenitor cells displaying cytokine dependent differentiation bias in vitro |
| url | https://doi.org/10.1038/s41467-025-60441-w |
| work_keys_str_mv | AT viralsshah singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT avinashwaghray singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT brianlin singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT atharvabhagwat singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT ishamonga singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT michalslyper singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT brunogiotti singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT sunghyunkim singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT daweisun singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT kexu singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT ericpark singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT mohamadbairakdar singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT jiajiexu singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT juliawaldman singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT danielledionne singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT lantnguyen singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT wendylou singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT peiwencai singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT christophmuus singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT jiaweisun singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT manaleevsurve singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT lujiachachayang singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT oritrozenblattrosen singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT tonimdelorey singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT srinivasvinodsaladi singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT avivregev singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT jayarajrajagopal singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro AT alexandermtsankov singlecellprofilingofhumanairwayidentifiestuftionocyteprogenitorcellsdisplayingcytokinedependentdifferentiationbiasinvitro |