Apoptotic adipose-derived mesenchymal stem cell therapy protects against lung and kidney injury in sepsis syndrome caused by cecal ligation puncture in rats

Abstract

IntroductionWe tested the hypothesis that apoptotic adipose-derived mesenchymal stem cells (A-ADMSC) are superior to healthy (H)-ADMSC in attenuating cecal ligation puncture (CLP)-induced sepsis-mediated lung and kidney injuries.MethodsAdult male rats divided into group 1 (sham controls), group 2 (CLP), group 3 [CLP + H-ADMSC administered at 0.5, 6, and 18 hours after CLP], and group 4 [CLP + A-ADMSC administered as in group 3] were sacrificed 72 hours after CLP with blood, lung, and kidney collected for studies.ResultsWhite blood cell (WBC) count, circulating TNF-α and creatinine levels were higher in groups 2 and 3 than in groups 1 and 4 (all P < 0.001). Kidney and lung damage scores were highest in group 2, lowest in group 1, significantly higher in group 3 than in group 4 (all P < 0.0001). Protein expressions of inflammatory (ICAM-1, MMP-9, TNF-α, NF-κB), oxidative, and apoptotic (Bax, caspase-3, PARP) biomarkers were higher in groups 2 and 3 than groups 1 and 4, whereas anti-apoptotic (Bcl-2) and mitochondrial integrity (cytochrome-C) biomarkers were lower in groups 2 and 3 than in groups 1 and 4 (all P < 0.001). Expressions of anti-oxidant biomarkers at protein (GR, GPx, NQO-1, HO-1) and cellular (GR, GPx) levels were highest in group 4 (all P < 0.001). The number of inflammatory cells (CD3+) in lungs and levels of DNA damage marker (γ-H2AX) in kidneys were higher in groups 2 and 3 than in groups 1 and 4 (all P < 0.001).ConclusionsA-ADMSC therapy was superior to H-ADMSC therapy in protecting major organs from damage in rats with CLP-induced sepsis syndrome.

Intravenous Infusion of Human Adipose Mesenchymal Stem Cells Modifies the Host Response to Lipopolysaccharide in Humans: A Randomized, Single-Blind, Parallel Group, Placebo Controlled Trial

“…Possibly, the increased early proinflammatory response as detected by the blood transcriptome played a role herein. Although these data contrast with the effect of MSCs in animal models of sepsis and endotoxemia, where MSCs diminished apoptosis of cells in various organs , they are not necessarily contradictive. Indeed, intravenous injection of low‐dose LPS into healthy subjects induces only a mild and transient response, whereas experimental sepsis in animals or clinical sepsis on the intensive care unit are associated with sustained hyperinflammation with injury to multiple cell types in multiple organs .…”

“…MSCs can exert many different immunomodulatory effects that theoretically could be beneficial in sepsis, including inhibition of microbial growth, reduction of pro‐inflammatory cytokine release with concurrent enhancement of anti‐inflammatory cytokine production, attenuation of inflammatory cell adhesion to endothelium, stimulation of endothelial regeneration, and inhibition of apoptosis . In accordance, treatment with MSCs improved a variety of outcome parameters in animal models of sepsis .…”

Human Adipose-Derived Mesenchymal Stem Cells Modify Lung Immunity and Improve Antibacterial Defense in Pneumosepsis Caused by Klebsiella pneumoniae

“…The therapeutic potential of MSCs has been demonstrated in animal models of sepsis and other infections . Notably, the vast majority of these investigations studied the effect of bone marrow‐derived MSC .…”

Mesenchymal stromal cells and their derivatives – putative therapeutics in the management of autoimmune pancreatitis

“…Mesenchymal stromal cells that have undergone apoptosis have been shown to reduce inflammatory endpoints in mouse models of allergic airway inflammation induced by ovalbumin (OVA) causing noncytotoxic T helper‐type cell inflammation [34]. Apoptotic rat adipose‐derived MSCs have also been proven superior in ameliorating the condition of cecal ligation and puncture‐induced sepsis in rat models in comparison with living MSCs [35–37]. Autophagic mesenchymal stromal cells have also been proven to have therapeutic benefits.…”