title: Mesenchymal stem cells protect from hypoxia-induced alveolar epithelial-mesenchymal transition.
abstract: Administration of bone marrow-derived human mesenchymal stem cells (hMSC) reduces lung inflammation, fibrosis, and mortality in animal models of lung injury, by a mechanism not completely understood. We investigated whether hMSC would prevent epithelial-mesenchymal transition (EMT) induced by hypoxia in primary rat alveolar epithelial cell (AEC). In AEC cultured on semipermeable filters, prolonged hypoxic exposure (1.5% O2 for up to 12 days) induced phenotypic changes consistent with EMT, i.e., a change in cell morphology, a decrease in transepithelial resistance (Rte) and in the expression of epithelial markers [zonula occludens-1 (ZO-1), E-cadherin, AQP-5, TTF-1], together with an increase in mesenchymal markers [vimentin, α-smooth muscle actin (α-SMA)]. Expression of transcription factors driving EMT such as SNAIL1, ZEB1, and TWIST1 increased after 2, 24, and 48 h of hypoxia, respectively. Hypoxia also induced TGF-β1 mRNA expression and the secretion of active TGF-β1 in apical medium, and the expression of connective tissue growth factor (CTGF), two inducers of EMT. Coculture of AEC with hMSC partially prevented the decrease in Rte and in ZO-1, E-cadherin, and TTF-1 expression, and the increase in vimentin expression induced by hypoxia. It also abolished the increase in TGF-β1 expression and in TGF-β1-induced genes ZEB1, TWIST1, and CTGF. Finally, incubation with human recombinant KGF at a concentration similar to what was measured in hMSC-conditioned media restored the expression of TTF-1 and prevented the increase in TWIST1, TGF-β1, and CTGF in hypoxic AEC. Our results indicate that hMSC prevent hypoxia-induced alveolar EMT through the paracrine modulation of EMT signaling pathways and suggest that this effect is partly mediated by KGF.
authors.affiliation: Université Paris 13, Sorbonne Paris Cité, Laboratoire Hypoxie & Poumon, Bobigny, France; AP-HP, Hôpital Avicenne, Bobigny, France;
authors.forename: Yurdagül
authors.initials: Y
authors.lastname: Uzunhan
authors.affiliation: Université Paris 13, Sorbonne Paris Cité, Laboratoire Hypoxie & Poumon, Bobigny, France;
authors.forename: Olivier
authors.initials: O
authors.lastname: Bernard
authors.affiliation: Université Paris 13, Sorbonne Paris Cité, Laboratoire Hypoxie & Poumon, Bobigny, France;
authors.forename: Dominique
authors.initials: D
authors.lastname: Marchant
authors.affiliation: Université Paris 13, Sorbonne Paris Cité, Laboratoire Hypoxie & Poumon, Bobigny, France;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dard
authors.affiliation: AP-HP, Hôpital Saint Louis, Unité de Thérapie Cellulaire et CIC de Biothérapies, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France;
authors.forename: Valérie
authors.initials: V
authors.lastname: Vanneaux
authors.affiliation: AP-HP, Hôpital Saint Louis, Unité de Thérapie Cellulaire et CIC de Biothérapies, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France;
authors.forename: Jérôme
authors.initials: J
authors.lastname: Larghero
authors.affiliation: Université Paris 13, Sorbonne Paris Cité, Laboratoire Hypoxie & Poumon, Bobigny, France; AP-HP, Hôpital Avicenne, Bobigny, France;
authors.forename: Thomas
authors.initials: T
authors.lastname: Gille
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Inserm U1152, Paris, France; and AP-HP, Hôpital Bichat, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Clerici
authors.affiliation: Université Paris 13, Sorbonne Paris Cité, Laboratoire Hypoxie & Poumon, Bobigny, France; AP-HP, Hôpital Avicenne, Bobigny, France;
authors.forename: Dominique
authors.initials: D
authors.lastname: Valeyre
authors.affiliation: Université Paris 13, Sorbonne Paris Cité, Laboratoire Hypoxie & Poumon, Bobigny, France; AP-HP, Hôpital Avicenne, Bobigny, France;
authors.forename: Hilario
authors.initials: H
authors.lastname: Nunes
authors.affiliation: Université Paris 13, Sorbonne Paris Cité, Laboratoire Hypoxie & Poumon, Bobigny, France;
authors.forename: Emilie
authors.initials: E
authors.lastname: Boncoeur
authors.affiliation: Université Paris 13, Sorbonne Paris Cité, Laboratoire Hypoxie & Poumon, Bobigny, France; AP-HP, Hôpital Avicenne, Bobigny, France; carole.planes@avc.aphp.fr.
authors.forename: Carole
authors.initials: C
authors.lastname: Planès
mesh_terms: D056809:Alveolar Epithelial Cells / Q000378:metabolism*; D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D008168:Lung / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology
chemical_list: D055513:Connective Tissue Growth Factor
keywords: alveolar epithelial cells; epithelial-mesenchymal transition; hypoxia; keratinocyte growth factor; transforming growth factor-β1