Airway hillocks are injury-resistant reservoirs of unique plastic stem cells

Brian Lin (), Viral S. Shah, Chaim Chernoff, Jiawei Sun, Gergana G. Shipkovenska, Vladimir Vinarsky, Avinash Waghray, Jiajie Xu, Andrew D. Leduc, Constantin A. Hintschich, Manalee Vishnu Surve, Yanxin Xu, Diane E. Capen, Jorge Villoria, Zhixun Dou, Lida P. Hariri and Jayaraj Rajagopal ()
Additional contact information
Brian Lin: Massachusetts General Hospital
Viral S. Shah: Massachusetts General Hospital
Chaim Chernoff: Massachusetts General Hospital
Jiawei Sun: Massachusetts General Hospital
Gergana G. Shipkovenska: Massachusetts General Hospital
Vladimir Vinarsky: Massachusetts General Hospital
Avinash Waghray: Massachusetts General Hospital
Jiajie Xu: Massachusetts General Hospital
Andrew D. Leduc: Northeastern University
Constantin A. Hintschich: Tufts University
Manalee Vishnu Surve: Massachusetts General Hospital
Yanxin Xu: Massachusetts General Hospital
Diane E. Capen: Massachusetts General Hospital
Jorge Villoria: Massachusetts General Hospital
Zhixun Dou: Massachusetts General Hospital
Lida P. Hariri: Harvard Medical School
Jayaraj Rajagopal: Massachusetts General Hospital

Nature, 2024, vol. 629, issue 8013, 869-877

Abstract: Abstract Airway hillocks are stratified epithelial structures of unknown function1. Hillocks persist for months and have a unique population of basal stem cells that express genes associated with barrier function and cell adhesion. Hillock basal stem cells continually replenish overlying squamous barrier cells. They exhibit dramatically higher turnover than the abundant, largely quiescent classic pseudostratified airway epithelium. Hillocks resist a remarkably broad spectrum of injuries, including toxins, infection, acid and physical injury because hillock squamous cells shield underlying hillock basal stem cells from injury. Hillock basal stem cells are capable of massive clonal expansion that is sufficient to resurface denuded airway, and eventually regenerate normal airway epithelium with each of its six component cell types. Hillock basal stem cells preferentially stratify and keratinize in the setting of retinoic acid signalling inhibition, a known cause of squamous metaplasia2,3. Here we show that mouse hillock expansion is the cause of vitamin A deficiency-induced squamous metaplasia. Finally, we identify human hillocks whose basal stem cells generate functional squamous barrier structures in culture. The existence of hillocks reframes our understanding of airway epithelial regeneration. Furthermore, we show that hillocks are one origin of ‘squamous metaplasia’, which is long thought to be a precursor of lung cancer.

Date: 2024
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DOI: 10.1038/s41586-024-07377-1

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