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However, it remains unclear how diverse basal cells are and how distinct subpopulations respond to airway challenges. Using single cell RNA-sequencing and functional approaches, we report a significant and previously underappreciated degree of heterogeneity in the basal cell pool, leading to identification of six subpopulations in the adult murine trachea. Among these, we found two major subpopulations, collectively comprising the most uncommitted of all the pools, but with distinct gene expression signatures. Notably, these occupy distinct ventral and dorsal tracheal niches and differ in their ability to self-renew and initiate a program of differentiation in response to environmental perturbations in primary cultures and in mouse injury models in vivo. We found that such heterogeneity is acquired prenatally, when the basal cell pool and local niches are still being established, and depends on the integrity of these niches, as supported by the altered basal cell phenotype of tracheal cartilage-deficient mouse mutants. Finally, we show that features that distinguish these progenitor subpopulations in murine airways are conserved in humans. Together, the data provide novel insights into the origin and impact of basal cell heterogeneity on the establishment of regionally distinct responses of the airway epithelium during injury-repair and in disease conditions.<\/jats:p>","DOI":"10.7554\/elife.80083","type":"journal-article","created":{"date-parts":[[2022,9,30]],"date-time":"2022-09-30T06:15:14Z","timestamp":1664518514000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.80083","source":"Crossref","is-referenced-by-count":55,"title":["Airway basal cells show regionally distinct potential to undergo metaplastic differentiation"],"prefix":"10.7554","volume":"11","author":[{"given":"Yizhuo","family":"Zhou","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01esghr10","id-type":"ROR","asserted-by":"publisher"}],"name":"Columbia Center for Human Development, Columbia University Irving Medical Center","place":["New York, United States"]},{"id":[{"id":"https:\/\/ror.org\/01esghr10","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicine, Pulmonary Allergy Critical Care, Columbia University Irving Medical Center","place":["New York, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4197-6216","authenticated-orcid":true,"given":"Ying","family":"Yang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01esghr10","id-type":"ROR","asserted-by":"publisher"}],"name":"Columbia Center for Human Development, Columbia University Irving Medical Center","place":["New York, United States"]},{"id":[{"id":"https:\/\/ror.org\/01esghr10","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Genetics and Development, Columbia University Irving Medical Center","place":["New York, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihao","family":"Guo","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03m2x1q45","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona","place":["Tucson, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Qian","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01esghr10","id-type":"ROR","asserted-by":"publisher"}],"name":"Columbia Center for Human Development, Columbia University Irving Medical Center","place":["New York, United States"]},{"id":[{"id":"https:\/\/ror.org\/01esghr10","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicine, Pulmonary Allergy Critical Care, Columbia University Irving Medical Center","place":["New York, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Ge","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01esghr10","id-type":"ROR","asserted-by":"publisher"}],"name":"Columbia Center for Human Development, Columbia University Irving Medical Center","place":["New York, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0704-5223","authenticated-orcid":true,"given":"Debora","family":"Sinner","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02p72h367","id-type":"ROR","asserted-by":"publisher"}],"name":"Neonatology and Pulmonary Biology Perinatal Institute, Cincinnati Children\u2019s Hospital Medical Center and University of Cincinnati, College of Medicine","place":["Cincinnati, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7846-9744","authenticated-orcid":true,"given":"Hongxu","family":"Ding","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03m2x1q45","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona","place":["Tucson, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4742-3679","authenticated-orcid":true,"given":"Andrea","family":"Califano","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01esghr10","id-type":"ROR","asserted-by":"publisher"}],"name":"Departments of Systems Biology, Biochemistry & Molecular Biophysics, Biomedical Informatics, Medicine; 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