Regulation of human lung alveolar multipotent cells by a novel p38α MAPK/miR‐17‐92 axis

The cellular and molecular mechanisms that control lung homeostasis and regeneration are still poorly understood. It has been proposed that a population of cells exists in the mouse lung with the potential to differentiate into all major lung bronchioalveolar epithelium cell types in homeostasis or in response to virus infection. A new population of E‐Cad/Lgr6+ putative stem cells has been isolated, and indefinitely expanded from human lungs, harbouring both, self‐renewal capacity and the potency to differentiate in vitro and in vivo. Recently, a putative population of human lung stem cells has been proposed as being c‐Kit+. Unlike Integrin‐α6+ or c‐Kit+ cells, E‐Cad/Lgr6+ single‐cell injections in the kidney capsule produce differentiated bronchioalveolar tissue, while retaining self‐renewal, as they can undergo serial transplantations under the kidney capsule or in the lung. In addition, a signalling network involving the p38α pathway, the activation of p53 and the regulation of the miR‐17‐92 cluster has been identified. Disruption of the proper cross‐regulation of this signalling axis might be involved in the promotion of human lung diseases. This study characterizes putative human lung stem cells based on E‐cadherin/Lgr6 expression. Long‐term clonal expansion, the ability to form bronchioalveolar‐like epithelia and the discovery of the miR‐17‐92 cluster as regulator of their proliferative capacity are features of this unique stem cell population.