Dysfunction of Airway Basal Progenitors Can Be Rescued by a Healthy Microenvironment. Implications in Regenerative Therapy.

RATIONALE: Airway basal progenitor cells are critical for maintenance and repair of the epithelium after injury, because they can renew themselves and differentiate into all cell types that make up a normal airway. We have shown that these functions of progenitors are significantly impaired in smoking-induced lung diseases, such as chronic obstructive pulmonary disease and airway premalignancy. Interestingly, progenitors isolated from the diseased airways mimic the in vivo histology after differentiation in vitro at the air-liquid interface (ALI). However, in a subset of patients, progenitor function can be rescued by treating with iloprost, a potent antiinflammatory drug, suggesting that the factors provided by the microenvironment can influence progenitor function.

OBJECTIVES: On the basis of these results, we hypothesize that a healthy microenvironment is necessary to reverse functional perturbation of progenitor cells.

METHODS: To test this hypothesis, we ran parallel studies in which differentiation fates of dysplastic basal progenitors from the same subjects were examined both in the ALI culture that lacks a microenvironment and by transplantation in the mouse lung. Clonal human basal progenitor cells were grown from bronchial biopsies and either plated on Transwell membranes for differentiation or labeled with green-fluorescent protein using lentivirus and transplanted intratracheally in BL6 mice. The mice were preconditioned with naphthalene for 48 hours to produce airway injury and evade cell removal by mucociliary clearance. Phosphate-buffered saline instillation was used as control for cell transplantation. Lung tissues were harvested 14 days after transplantation and embedded, and sections were stained.

RESULTS: In contrast to ALI culture, where dysplastic progenitors generated a dysplastic epithelium, after transplantation in mice, the same cells differentiated into all cell types of a normal airway, including basal, mucus-secreting, and ciliated cells. Thus, our preliminary studies demonstrated that a healthy microenvironment is necessary to rescue differentiation of dysplastic basal progenitor cells to a normal mucociliary epithelium.

CONCLUSIONS: These results have broad implications in regenerative therapy for chronic lung disease conditions. Our data showed that a bad "seed" (sick progenitor cells) can give rise to a healthy plant if put into good "soil" (healthy microenvironment). Thus, regenerative therapy needs to include both the cells and their microenvironment for optimal results.