Lef ‐1 controls cell cycle progression in airway basal cells to regulate proliferation and differentiation

Airway basal stem cells utilize Lef ‐1 to regulate the expression of certain DNA damage response (DDR) genes, including Chek1, and facilitate proper G1/S checkpoint cell cycle progression required for self‐renewal and differentiation (left panel). Mouse tracheal epithelial cells conditionally deleted for Lef‐1 (Lef‐1cKO) have a selective disadvantage, compared with wild type Lef‐1 (Lef‐1WT) cells, to regenerate an injured epithelium. AbstractThe mammalian airways are lined by a continuous epithelial layer that is maintained by diverse populations of resident multipotent stem cells. These stem cells are responsible for replenishing the epithelium both at homeostasis and following injury, making them promising targets for stem cell and genetic ‐based therapies for a variety of respiratory diseases. However, the mechanisms that regulate when and how these stem cells proliferate, migrate, and differentiate remains incompletely understood. Here, we find that the high mobility group (HMG) domain transcription factor Lef‐1 regulates prolif eration and differentiation of mouse tracheal basal cells. We demonstrate that conditional deletion of Lef‐1 stalls basal cell proliferation at the G1/S transition of the cell cycle, and that Lef‐1 knockout cells are unable to maintain luminal tracheal cell types in long‐term air‐liquid inte rface culture. RNA sequencing analysis revealed that Lef‐1 knockout (Lef‐1KO) results in downregulation of key DNA damage response...
Source: Stem Cells - Category: Stem Cells Authors: Tags: Tissue ‐Specific Stem Cells Source Type: research