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 metaplasia^2,3. 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.

气道小丘是功能未知的分层上皮结构¹。小丘持续数月，并具有独特的基底干细胞群，表达与屏障功能和细胞粘附相关的基因。小丘基底干细胞不断补充覆盖的鳞状屏障细胞。它们表现出比丰富的、基本上静止的经典假复层气道上皮显着更高的周转率。小丘能够抵抗非常广泛的伤害，包括毒素、感染、酸和身体损伤，因为小丘鳞状细胞可以保护下面的小丘基底干细胞免受伤害。 Hillock 基底干细胞能够进行大规模克隆扩增，足以重塑裸露的气道，并最终用其六种组成细胞类型中的每一种再生正常气道上皮。 Hillock 基底干细胞在视黄酸信号传导抑制的情况下优先分层和角化，这是鳞状上皮化生的已知原因^2,3。在这里，我们发现小鼠小丘扩张是维生素 A 缺乏引起的鳞状化生的原因。最后，我们确定了人类小丘的基底干细胞在培养物中产生功能性鳞状屏障结构。小丘的存在重塑了我们对气道上皮再生的理解。此外，我们发现小丘是“鳞状化生”的起源之一，长期以来，“鳞状化生”被认为是肺癌的先兆。