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

• 成果类型: Article
• 署名作者: Lin, Brian; Shah, Viral S.; Chernoff, Chaim; Sun, Jiawei; Shipkovenska, Gergana G.; Vinarsky, Vladimir; Waghray, Avinash; Xu, Jiajie; Leduc, Andrew D.; Hintschich, Constantin A.; Surve, Manalee Vishnu; Xu, Yanxin; Capen, Diane E.; Villoria, Jorge; Dou, Zhixun; Hariri, Lida P.; Rajagopal, Jayaraj
• 署名单位: Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Tufts University; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital; Northeastern University; University of Regensburg; Harvard University; Harvard University Medical Affiliates; Massachusetts Eye & Ear Infirmary; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6498
• DOI: 10.1038/s41586-024-07377-1
• 发表日期: 2024-05-23
• 关键词: squamous metaplasia; basal-cells; in-vitro; lung; alveolar; regeneration; expression; niches; gene; differentiation

摘要

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. In the lungs, recently identified epithelial structures known as hillocks can act as injury-resistant reservoirs of stem cells.