title: Conditioned media from mesenchymal stromal cells restore sodium transport and preserve epithelial permeability in an in vitro model of acute alveolar injury.
abstract: Mesenchymal stromal cells (MSCs) or their media (MSC-M) were reported to reverse acute lung injury (ALI)-induced decrease of alveolar fluid clearance. To determine the mechanisms by which MSC-M exert their beneficial effects, an in vitro model of alveolar epithelial injury was created by exposing primary rat alveolar epithelial cells (AECs) to hypoxia (3% O2) plus cytomix, a combination of IL-1β, TNF-α, and IFN-γ. MSC-M were collected from human MSCs exposed for 12 h to either normoxia (MSC-M) or to hypoxia plus cytomix (HCYT-MSC-M). This latter condition was used to model the effect of alveolar inflammation and hypoxia on paracrine secretion of MSCs in the injured lung. Comparison of paracrine soluble factors in MSC media showed that the IL-1 receptor antagonist and prostaglandin E2 were markedly increased while keratinocyte growth factor (KGF) was twofold lower in HCYT-MSC-M compared with MSC-M. In AECs, hypoxia plus cytomix increased protein permeability, reduced amiloride-sensitive short-circuit current (AS-Isc), and also decreased the number of α-epithelial sodium channel (α-ENaC) subunits in the apical membrane. To test the effects of MSC media, MSC-M and HCYT-MSC-M were added for an additional 12 h to AECs exposed to hypoxia plus cytomix. MSC-M and HCYT-MSC-M completely restored epithelial permeability to normal. MSC-M, but not HCYT-MSC-M, significantly prevented the hypoxia plus cytomix-induced decrease of ENaC activity and restored apical α-ENaC channels. Interestingly, KGF-deprived MSC-M were unable to restore amiloride-sensitive sodium transport, indicating a possible role for KGF in the beneficial effect of MSC-M. These results indicate that MSC-M may be a preferable therapeutic option for ALI.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U773, Paris, France;
authors.forename: Arnaud
authors.initials: A
authors.lastname: Goolaerts
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U773, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Unité Mixte de Recherche 773 and Unité Mixte de Recherche 940, Paris, France;
authors.forename: Nadia
authors.initials: N
authors.lastname: Pellan-Randrianarison
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Unité Mixte de Recherche 773 and Unité Mixte de Recherche 940, Paris, France; AP-HP, Hôpital Saint Louis, Unité de Thérapie Cellulaire et CIC de Biothérapies, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France;
authors.forename: Jérôme
authors.initials: J
authors.lastname: Larghero
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Unité Mixte de Recherche 773 and Unité Mixte de Recherche 940, Paris, France; AP-HP, Hôpital Saint Louis, Unité de Thérapie Cellulaire et CIC de Biothérapies, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France;
authors.forename: Valérie
authors.initials: V
authors.lastname: Vanneaux
authors.affiliation: Université Paris 13, Sorbonne Paris Cité, EA2363, Bobigny, France; AP-HP, Hôpital Avicenne, Bobigny, France; and.
authors.forename: Yurdagül
authors.initials: Y
authors.lastname: Uzunhan
authors.affiliation: Université Paris 13, Sorbonne Paris Cité, EA2363, Bobigny, France; AP-HP, Hôpital Avicenne, Bobigny, France; and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gille
authors.affiliation: Université Paris 13, Sorbonne Paris Cité, EA2363, Bobigny, France;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dard
authors.affiliation: Université Paris 13, Sorbonne Paris Cité, EA2363, Bobigny, France; AP-HP, Hôpital Avicenne, Bobigny, France; and.
authors.forename: Carole
authors.initials: C
authors.lastname: Planès
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U773, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Unité Mixte de Recherche 773 and Unité Mixte de Recherche 940, Paris, France;
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U773, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Unité Mixte de Recherche 773 and Unité Mixte de Recherche 940, Paris, France; AP-HP, Hôpital Bichat, Paris, France christine.clerici@bch.aphp.fr.
authors.forename: Christine
authors.initials: C
authors.lastname: Clerici
mesh_terms: D056809:Alveolar Epithelial Cells / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001692:Biological Transport; D015687:Cell Hypoxia; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D015232:Dinoprostone / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000378:metabolism; D051523:Fibroblast Growth Factor 7 / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D019899:Paracrine Communication; D011650:Pulmonary Alveoli / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D053503:Epithelial Sodium Channels; C496453:FGF7 protein, human; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D051523:Fibroblast Growth Factor 7; D012964:Sodium; D015232:Dinoprostone
keywords: growth factors; hypoxia; inflammation; membrane transport; mesenchymal stem cells; sodium channels