Lipogenic switch of fibroblast to lipofibroblast induce lung regeneration in a model of bronchopulmonary dysplasia

Introduction: Lung regeneration is essential for damage recovering after lung injury at different age of life. Whether lipofibroblasts (LIF) are able to enhance endogenous alveolar regeneration once alveoli are damaged remains to be determined. Aim: To determine in a mouse model of bronchopulmonary dysplasia if a lipid switch of fibroblasts to LIF induce a curative lung regeneration. Methods: Wt C57BL/6J mice were exposed to hyperoxia (85% O2) or room air from days 3 to 14 of post-natal life. Rosiglitazone (RGZ), a PPARγ agonist which activates fibroblasts differentiation into LIF, was administered intraperitoneally at a dose of 5µg/g of mice daily, 5 days a week, starting after hyperoxia exposure, until adulthood (D60). Tissues were immunostained with anti-ADRP and anti-proSpC antibodies for LIF and AT2 detection respectively. Number of alveoli were estimated by the mean linear intercept and secondary septation by septal crest number (Weigert). Results: Compared to mice exposed to room air, mice exposed to hyperoxia presented a significant decreased number of LIF in lung associated with an arrested alveolar development revealed by a reduced number of alveoli and a concomitant disruption of secondary septation. Compared to hyperoxic, non-treated mice, RGZ administration increased the number of LIF and AT2 cells in the lung, associated with an increase in the number of alveoli and septal crests at adulthood. Conclusion: Switching fibroblasts towards LIF through PPARγ agonist administration induces lung regeneration after hypoalveolization due to post-natal hyperoxia. Administration of PPARγ agonists can be a new pharmacologic strategy to promote lung recovery after injury.