title: Mesenchymal Stromal Cells Deficient in Autophagy Proteins Are Susceptible to Oxidative Injury and Mitochondrial Dysfunction.
abstract: Oxidative stress resulting from inflammatory responses that occur during acute lung injury and sepsis can initiate changes in mitochondrial function. Autophagy regulates cellular processes in the setting of acute lung injury, sepsis, and oxidative stress by modulating the immune response and facilitating turnover of damaged cellular components. We have shown that mesenchymal stromal cells (MSCs) improve survival in murine models of sepsis by also regulating the immune response. However, the effect of autophagy on MSCs and MSC mitochondrial function during oxidative stress is unknown. This study investigated the effect of depletion of autophagic protein microtubule-associated protein 1 light chain 3B (LC3B) and beclin 1 (BECN1) on the response of MSCs to oxidative stress. MSCs were isolated from wild-type (WT) and LC3B-/-or Becn1+/-mice. MSCs from the LC3B-/-and Becn1+/-animals had increased susceptibility to oxidative stress-induced cell death as compared with WT MSCs. The MSCs depleted of autophagic proteins also had impaired mitochondrial function (decreased intracellular ATP, reduced mitochondrial membrane potential, and increased mitochondrial reactive oxygen species production) under oxidative stress as compared with WT MSCs. In WT MSCs, carbon monoxide (CO) preconditioning enhanced autophagy and mitophagy, and rescued the cells from oxidative stress-induced death. CO preconditioning was not able to rescue the decreased survival of MSCs from the LC3B-/-and Becn1+/-animals, further supporting the tenet that CO exerts its cytoprotective effects via the autophagy pathway.
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.|2 Department of Pediatric Newborn Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Sailaja
authors.initials: S
authors.lastname: Ghanta
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Tsoyi
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.|2 Department of Pediatric Newborn Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Liu
authors.affiliation: 3 Department of Medicine, New York-Presbyterian Hospital and Weill Cornell Medical College, New York, New York.
authors.forename: Kiichi
authors.initials: K
authors.lastname: Nakahira
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.
authors.forename: Bonna
authors.initials: B
authors.lastname: Ith
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Coronata
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Fredenburgh
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Englert
authors.affiliation: 4 Department of Medicine, Duke University School of Medicine, Durham, North Carolina; and.
authors.forename: Claude A
authors.initials: CA
authors.lastname: Piantadosi
authors.affiliation: 3 Department of Medicine, New York-Presbyterian Hospital and Weill Cornell Medical College, New York, New York.
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.|2 Department of Pediatric Newborn Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Perrella
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D000071183:Autophagy-Related Proteins / Q000378:metabolism*; D002248:Carbon Monoxide / Q000494:pharmacology; D002478:Cells, Cultured; D042541:Intracellular Space / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D063306:Mitophagy / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype
chemical_list: D000975:Antioxidants; D000071183:Autophagy-Related Proteins; D002248:Carbon Monoxide; D000255:Adenosine Triphosphate
keywords: autophagy; carbon monoxide; mesenchymal stromal cells; mitochondria; oxidative stress