Mesenchymal stromal cells deficient in autophagy proteins are susceptible to oxidative injury and mitochondrial dysfunction

Sailaja Ghanta, Konstantin Tsoyi, Xiaoli Liu, Kiichi Nakahira, Bonna Ith, Anna A. Coronata, Laura E. Fredenburgh, Joshua A. Englert, Claude A. Piantadosi, Augustine M.K. Choi, Mark A. Perrella

Research output: Contribution to journalArticle

25 Scopus citations

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 Becn-/- mice. MSCs from the LC3B-/- and Becn-/- 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 Becn-/- animals, further supporting the tenet that CO exerts its cytoprotective effects via the autophagy pathway.

Original languageEnglish (US)
Pages (from-to)300-309
Number of pages10
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume56
Issue number3
DOIs
StatePublished - Mar 2017

Keywords

  • Autophagy
  • Carbon monoxide
  • Mesenchymal stromal cells
  • Mitochondria
  • Oxidative stress

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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