Exposure of the immature lung to oxygen concentrations higher that the ones in utero – relative (room air) or absolute hyperoxia - represents a major risk factor for the development of bronchopulmonary dysplasia (BPD) in preterm infants. Here, we isolated resident CD146pos./GD-2neg. mesenchymal stem- or stromal cells (MSCs) from human fetal lungs at the canalicular stage of development (16th–18th week of gestation) to obtain new insights into their behaviour in conditions reflecting normal (5% O2) and oxygen disrupted (21% and 60% O2) lung development. We compared them to potentially therapeutic MSCs isolated from the umbilical cord stroma.
First, we were able to show that the mesenchyme of the fetal lung is abundant in MSCs, suggesting an important role of these cells in lung development. Single-cell plating of lung MSCs in physiological hypoxic and ambient oxygen atmospheres revealed profound reductions of colony-forming ability and colony size in normoxic conditions. Furthermore, when exposed to absolute hyperoxic (60% O2) atmospheres, MSCs lost ability to form colonies, reduced expression of stem cell-restricted proteins like Oct-4 and Sox2, proliferated and switched cytokine secretion profiles towards a pro-fibrotic, pro-inflammatory phenotype. Alterations in the composition of the extracellular matrix were observed. Conversely, MSCs from the umbilical cord secreted high amounts of anti-fibrotic and lung-protecting proteins like PGE2 and stanniocalcin-1.
We conclude that the physiological function of resident lung MSCs is affected by relative and absolute hyperoxia, suggesting a key role of these cells in the immature lung responding to extrauterine oxygen conditions.
Support (Bengt-Robertson-Award): Charles-Christopher Roehr.