Carbon Monoxide Improves Efficacy of Mesenchymal Stromal Cells During Sepsis by Production of Specialized Proresolving Lipid Mediators*

Tsoyi, Konstantin; Hall, Sean; Dalli, Jesmond; Colas, Romain A.; Ghanta, Sailaja; Ith, Bonna; Coronata, Anna; Fredenburgh, Laura E.; Baron, Rebecca M.; Choi, Augustine M.K.; Serhan, Charles N.; Liu, Xiaoli; Perrella, Mark A.

doi:10.1097/ccm.0000000000001999

Cited by 64 publications

(74 citation statements)

References 51 publications

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“…This study illustrates that low levels of CO can act as an inducer of autophagy. This concept is useful for the idea that MSCs can be preconditioned to have enhanced autophagy by a steady inducer, such as CO, before their injection (50).…”

Section: Original Researchmentioning

confidence: 99%

Mesenchymal Stromal Cells Deficient in Autophagy Proteins Are Susceptible to Oxidative Injury and Mitochondrial Dysfunction

Ghanta

Tsoyi

Liu

et al. 2017

Am J Respir Cell Mol Biol

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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 2/2 or Becn1 1/2 mice. MSCs from the LC3B 2/2 and Becn1 1/2 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 2/2 and Becn1 1/2 animals, further supporting the tenet that CO exerts its cytoprotective effects via the autophagy pathway.

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Section: Original Researchmentioning

confidence: 99%

Mesenchymal Stromal Cells Deficient in Autophagy Proteins Are Susceptible to Oxidative Injury and Mitochondrial Dysfunction

Ghanta

Tsoyi

Liu

et al. 2017

Am J Respir Cell Mol Biol

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“…These soluble factors include various cytokines such as transforming growth factor-β (46) and interleukin-10 (ref. 47), growth factors such as vascular endothelial growth factor (48), hepatocyte growth factor (49), keratinocyte growth factor (50) brain-derived neutrophic factor (13,51) (59) and resolvins in animal models of sepsis (60).…”

Section: Paracrine Protectionmentioning

confidence: 99%

Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders

et al. 2017

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Mesenchymal stem cell (MSC) transplantation represents the next breakthrough in the treatment of currently intractable and devastating neonatal disorders with complex multifactorial etiologies, including bronchopulmonary dysplasia, hypoxic ischemic encephalopathy, and intraventricular hemorrhage. Absent engraftment and direct differentiation of transplanted MSCs, and the "hit-and-run" therapeutic effects of these MSCs suggest that their pleiotropic protection might be attributable to paracrine activity via the secretion of various biologic factors rather than to regenerative activity. The transplanted MSCs, therefore, exert their therapeutic effects not by acting as "stem cells," but rather by acting as "paracrine factors factory." The MSCs sense the microenvironment of the injury site and secrete various paracrine factors that serve several reparative functions, including antiapoptotic, anti-inflammatory, antioxidative, antifibrotic, and/or antibacterial effects in response to environmental cues to enhance regeneration of the damaged tissue. Therefore, the therapeutic efficacy of MSCs might be dependent on their paracrine potency. In this review, we focus on recent investigations that elucidate the specifically regulated paracrine mechanisms of MSCs by injury type and discuss potential strategies to enhance paracrine potency, and thus therapeutic efficacy, of transplanted MSCs, including determining the appropriate source and preconditioning strategy for MSCs and the route and timing of their administration.

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“…Konstantin Tsoyi and his colleagues have published an exciting work on the beneficial effects of carbon monoxide (CO) that improved efficacy of mesenchymal stromal cells (MSCs) (1). MSCs preconditioned with CO attenuated organ injury, increased bacterial clearance, promoted resolution of inflammation, and improved survival in mice with polymicrobial sepsis (1).…”

mentioning

confidence: 99%

“…MSCs preconditioned with CO attenuated organ injury, increased bacterial clearance, promoted resolution of inflammation, and improved survival in mice with polymicrobial sepsis (1). Importantly, CO preconditioning preserved the efficacy of MSCs when they were administered at 6 hours post sepsis induction time.…”

mentioning

confidence: 99%

“…Although Tsoyi and his colleagues demonstrated that the beneficial effects CO-preconditioned MSCs were mediated by 5- and 12/15-lypoxigenase pathway, specific role of resolvins remain incompletely understood (1). This is especially the case when the resolvin alone did not affect phagocytic ability of neutrophils (1). It is quite possible that MSCs paracrine response is none specific to CO or other stimuli.…”

mentioning

confidence: 99%

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Cellular Therapy for Sepsis: A New Hope?*

Enkhbaatar

2016

Critical Care Medicine

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Carbon Monoxide Improves Efficacy of Mesenchymal Stromal Cells During Sepsis by Production of Specialized Proresolving Lipid Mediators*

Abstract: Supplemental Digital Content is available in the text.

Cited by 64 publications

References 51 publications

Mesenchymal Stromal Cells Deficient in Autophagy Proteins Are Susceptible to Oxidative Injury and Mitochondrial Dysfunction

Mesenchymal Stromal Cells Deficient in Autophagy Proteins Are Susceptible to Oxidative Injury and Mitochondrial Dysfunction

Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders

Cellular Therapy for Sepsis: A New Hope?*

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