Protective effect of mesenchymal stem cells des (MSC) on hypoxia induced epithelial to mesenchymal transition (EMT) of alveolar epithelial cells (AEC)

The current paradigm suggests a central role of the epithelium in pulmonary fibrosis pathogenesis and progression. Hypoxia may promote myofibroblasts accumulation by facilating EMT. In animal models of lung fibrosis, administration of bone marrow derived MSC may reduce fibrosis and mortality. We hypothesized that MSC may favor alveolar wound healing by preventing hypoxia-induced EMT. We examined the role of hypoxia on AECs' phenotype in vitro and tested paracrine effects of MSC on these modifications. Involved mechanisms have been studied.

Rat AEC were exposed in vitro to hypoxia (3% and 1.5%) during short or long term (6 to 12d), with or without co-culture with MSC. Transepithelial electrical resistance (TER) was measured. Epithelial (E-cadherin, ZO-1, TTF-1) and mesenchymal (smooth muscle α-actine, vimentin) phenotype were assessed by immunofluorescence and Western blot.

Exposure of AEC to hypoxia resulted in dose-and time-dependent decrease of TER. Decreased epithelial markers concurrent with increased mesenchymal markers were observed. These effects were reproduced with Cobalt chlorure and were partially prevented by anti-oxydant drugs (Euk134 or N-acetyl-cystein). Co-culture with MSC (or conditionned media) prevented effects of hypoxia regarding TER and cells phenotype.

These results suggest that MSC may prevent hypoxia induced phenotype modifications of AEC resembling EMT. This protective effect may partly explain the anti-fibrotic effect of MSC on animal models.

Funded by: Collège des Enseignants de Pneumologie, la Chancellerie des Universités (Fondation du Legs Poix).