Mesenchymal stem cells reduce hypoxia-induced apoptosis in alveolar epithelial cells by modulating HIF and ROS hypoxic signaling

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 314; no. 3; pp. L360 - L371
• Main Authors: Bernard, Olivier, Jeny, Florence, Uzunhan, Yurdagül, Dondi, Elisabetta, Terfous, Rahma, Label, Rabab, Sutton, Angela, Larghero, Jérôme, Vanneaux, Valérie, Nunes, Hilario, Boncoeur, Emilie, Planès, Carole, Dard, Nicolas
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.03.2018
• Subjects: Accumulation; Alveolar Epithelial Cells - cytology; Alveolar Epithelial Cells - physiology; Alveoli; Animal models; Animals; Antioxidants; Apoptosis; Bcl-2 protein; BNIP3 protein; Cells, Cultured; Conditioning; Epithelial cells; Fibrosis; Hepatocyte growth factor; Humans; Hypoxia; Hypoxia - physiopathology; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factors; Keratinocyte growth factor; Life Sciences; Lung diseases; Male; Mesenchymal stem cells; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - physiology; Mesenchyme; Paracrine signalling; Pulmonary Alveoli - cytology; Pulmonary Alveoli - physiology; Pulmonary fibrosis; Rats; Rats, Sprague-Dawley; Reactive oxygen species; Reactive Oxygen Species - metabolism; Secretion; Signal Transduction; Stem cell transplantation; Stem cells; alveolar epithelial cells; hypoxia; keratinocyte growth factor; hypoxia-inducible factor-1α; mesenchymal stem cells; reactive oxygen species; apoptosis, hepatocyte growth factor
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00153.2017

Distal lung diseases, such as pulmonary fibrosis or acute lung injury, are commonly associated with local alveolar hypoxia that may be deleterious through the stimulation of alveolar epithelial cell (AEC) apoptosis. In various murine models of alveolar injury, administration of allogenic human mesenchymal stem cells (hMSCs) exerts an overall protective paracrine effect, limiting lung inflammation and fibrosis. However, the precise mechanisms on lung cells themselves remain poorly understood. Here, we investigated whether hMSC-conditioned medium (hMSC-CM) would protect AECs from hypoxia-induced apoptosis and explored the mechanisms involved in this cytoprotective effect. Exposure of rat primary AECs to hypoxia (1.5% O for 24 h) resulted in hypoxia-inducible factor (HIF)-1α protein stabilization, partly dependent on reactive oxygen species (ROS) accumulation, and in a twofold increase in AEC apoptosis that was prevented by the HIF inhibitor 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl-indazole and the antioxidant drug N-acetyl cysteine. Incubation of AECs with hMSC-CM significantly reduced hypoxia-induced apoptosis. hMSC-CM decreased HIF-1α protein expression, as well as ROS accumulation through an increase in antioxidant enzyme activities. Expression of Bnip3 and CHOP, two proapoptotic targets of HIF-1α and ROS pathways, respectively, was suppressed by hMSC-CM, while Bcl-2 expression was restored. The paracrine protective effect of hMSC was partly dependent on keratinocyte growth factor and hepatocyte growth factor secretion, preventing ROS and HIF-1α accumulation.