Targeted Preconditioning and Cell Transplantation in the Murine Lower Respiratory Tract

Transplantation of airway basal stem cells could achieve a durable cure for genetic diseases of the airway, such as cystic fibrosis and primary ciliary dyskinesia. Recent work demonstrated the potential of primary and pluripotent stem cell-derived basal cells to efficiently engraft into the mouse trachea after injury. However, there are many hurdles to overcome in translating these approaches to humans, including developing safe and efficient methods for delivery in larger animal models. We propose a model that targets preconditioning and cell delivery to intrapulmonary airways using a microbronchoscope for delivery. The detergent polidocanol was adapted for distal lung preconditioning, inducing intrapulmonary airway epithelial denudation by 5 and 24 hours after delivery. Although initial reepithelialization of airways occurred later than that of tracheas, complete repair was observed within 7 days. Both pluripotent stem cell-derived and primary basal cells delivered via microbronchoscope after polidocanol injury engrafted in tracheas and intrapulmonary airways, respectively. Transplanted cells differentiated into ciliated and secretory lineages while maintaining a population of basal cells. These findings demonstrate the utility of bronchoscopically targeted preconditioning and cell delivery to the conducting intrapulmonary airways, thus providing an important framework for preclinical translation of approaches for engineered airway epithelial regeneration.