Distinct roles of tip progenitor subpopulation in shaping the murine lung

A gradient SOX9+ distal progenitor cell differentiation impacts the patterning of the lung during branching morphogenesis. Although the heterogeneity of this population has been suggested, the specific roles of these subgroups still largely obscure. Here, we explore at least two distinct functional subgroups: the tip progenitors residing at the tips are critical for bud extension and cell allocation, while the transition progenitors sitting immediately to them are indispensable for cell transition. It’s suggested Hippo pathway could regulate the gradient cell differentiation during lung branching. We observed the Cre recombinase driving by Sftpc promoter couldn’t delete Lats1/2 floxed alleles in majority of the tip of SOX9+ distal region, even though the Cre was activated in all the conducting airway. Genetic evidence implied the distal tip progenitors alone is sufficient to help construct the comparable lung structures, while cells at transition stage contributed to the conducting airways. At the expense of themselves, the distal tip progenitors would quickly switch to the transition state when activate YAP via LATS1/2 perturbation. The increasing of cells at transition state results in aggregation of AT1 cells and missing of AT2 cells. Lacking Lats1/2 in SOX9+ distal progenitors in 3D culture could also promote the cell differentiation toward the transition state. Thus, a lower YAP activity is benefit for tip progenitor cell reservation.