Human embryonic stem cells recover in vivo acute lung inflammation bleomycin-induced.

Idiopathic pulmonary fibrosis (IPF) is characterized by alveolar epithelial cell injury, type II cell activation, apoptosis and bronchiolar epithelial cell proliferation, accumulation of extracellular matrix and fibroblasts. No current animal model recapitulates all of these cardinal manifestation of the human disease. However, bleomycin instillation in mice lung by intranasal way (ITN) represents the best experimental model of pulmonary fibrosis in which alveolar pneumocytes type II (ATII) are usually depleted. The aim of this study was to test the possibility to recover acute lung fibrosis after transplantation of human embryonic type II derived-pneumocytes in a murine model of bleomycin-induced damage. Our results indicate the striking "clinical" beneficial effect of differentiated HUES-3 cells into ATII in terms of lung function, weight loss and mortality in injured mice, suggesting this stem cell therapy as a promising, systemic and specific treatment of human pulmonary fibrosis.

Rescue of murine silica-induced lung injury and fibrosis by human embryonic stem cells.

Alveolar type II pneumocytes (ATII cells) are considered putative alveolar stem cells. Since no treatment is available to repair damaged epithelium and prevent lung fibrosis, novel approaches to induce regeneration of injured alveolar epithelium are desired. The objective of this study was to assess both the capacity of human embryonic stem cells (HUES-3) to differentiate in vitro into ATII cells and the ability of committed HUES-3 cells (HUES-3-ATII cells) to recover in vivo a pulmonary fibrosis model obtained by silica-induced damage. In vitro differentiated HUES-3-ATII cells displayed an alveolar phenotype characterised by multi-lamellar body and tight junction formation, by the expression of specific markers such as surfactant protein (SP)-B, SP-C and zonula occludens (ZO)-1 and the activity of cystic fibrosis transmembrane conductance regulator-mediated chloride ion transport. After transplantation of HUES-3-ATII cells into silica-damaged mice, histological and biomolecular analyses revealed a significant reduction of inflammation and fibrosis markers along with lung function improvement, weight recovery and increased survival. The persistence of human SP-C, human nuclear antigen and human DNA in the engrafted lungs indicates that differentiated cells remained engrafted up to 10 weeks. In conclusion, cell therapy using HUES-3 cells may be considered a promising approach to lung injury repair.