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Exosomes of Antler Mesenchymal Stem Cells Improve Postoperative Cognitive Dysfunction in Cardiopulmonary Bypass Rats through Inhibiting the TLR2/TLR4 Signaling Pathway.

ABSTRACT: Postoperative cognitive dysfunction (POCD) is a severe complication of cardiopulmonary bypass (CPB) and has common characteristics such as acute cognitive dysfunction, impaired memory, and inattention. Mesenchymal stem cells (MSCs) are multipotent cells that have therapeutic potentials mainly through paracrine action via secreting growth factors and cytokines. Exosomes are one of the important paracrine factors and have been reported as potential cell-free therapy for the treatment of autoimmune and central nervous system disorders. In this study, we examined exosomes derived from antler MSCs (AMSCs) of POCD rats after CPB and evaluated their potential regulatory mechanisms. AMSC-derived exosomes reduced neurological damage and brain damage and prevent apoptosis in CPB rats. Furthermore, AMSC-derived exosomes were found to reduce hippocampal neuronal apoptosis and the expression of TLR2, TLR4, MyD88, and NF-?B in CPB rats. However, the above effects of AMSC-derived exosomes on CPB rats were abolished partially by toll-like receptor 2/4 (TLR2/TLR4) agonist (LPS-EB). In conclusion, AMSC-derived exosomes can improve cognitive function in CPB rats through inhibiting the TLR2/TLR4 signaling pathway.

SUBMITTER: Yang C

PROVIDER: S-EPMC7136781 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Exosomes of Antler Mesenchymal Stem Cells Improve Postoperative Cognitive Dysfunction in Cardiopulmonary Bypass Rats through Inhibiting the TLR2/TLR4 Signaling Pathway.

Yang Chun C Sun Shengnan S Zhang Qi Q Guo Jia J Wu Tengfei T Liu Ying Y Yang Min M Zhang Yan Y Peng Yinghua Y

Stem cells international 20200326

Postoperative cognitive dysfunction (POCD) is a severe complication of cardiopulmonary bypass (CPB) and has common characteristics such as acute cognitive dysfunction, impaired memory, and inattention. Mesenchymal stem cells (MSCs) are multipotent cells that have therapeutic potentials mainly through paracrine action via secreting growth factors and cytokines. Exosomes are one of the important paracrine factors and have been reported as potential cell-free therapy for the treatment of autoimmune ...[more]

PMID: 32300366

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Project description:ObjectivesCardiopulmonary bypass-induced endothelial dysfunction has been inferred by changes in pulmonary vascular resistance, alterations in circulating biomarkers, and postoperative capillary leak. Endothelial-dependent vasomotor dysfunction of the systemic vasculature has never been quantified in this setting. The objective of the present study was to quantify acute effects of cardiopulmonary bypass on endothelial vasomotor control and attempt to correlate these effects with postoperative cytokines, tissue edema, and clinical outcomes in infants.DesignSingle-center prospective observational cohort pilot study.SettingPediatric cardiac ICU at a tertiary children's hospital.PatientsChildren less than 1 year old requiring cardiopulmonary bypass for repair of a congenital heart lesion.InterventionNone.Measurements and main resultsLaser Doppler perfusion monitoring was coupled with local iontophoresis of acetylcholine (endothelium-dependent vasodilator) or sodium nitroprusside (endothelium-independent vasodilator) to quantify endothelial-dependent vasomotor function in the cutaneous microcirculation. Measurements were obtained preoperatively, 2-4 hours, and 24 hours after separation from cardiopulmonary bypass. Fifteen patients completed all laser Doppler perfusion monitor (Perimed, Järfälla, Sweden) measurements. Comparing prebypass with 2-4 hours postbypass responses, there was a decrease in both peak perfusion (p = 0.0006) and area under the dose-response curve (p = 0.005) following acetylcholine, but no change in responses to sodium nitroprusside. Twenty-four hours after bypass responsiveness to acetylcholine improved, but typically remained depressed from baseline. Conserved endothelial function was associated with higher urine output during the first 48 postoperative hours (R = 0.43; p = 0.008).ConclusionsCutaneous endothelial dysfunction is present in infants immediately following cardiopulmonary bypass and recovers significantly in some patients within 24 hours postoperatively. Confirmation of an association between persistent endothelial-dependent vasomotor dysfunction and decreased urine output could have important clinical implications. Ongoing research will explore the pattern of endothelial-dependent vasomotor dysfunction after cardiopulmonary bypass and its relationship with biochemical markers of inflammation and clinical outcomes.

Project description:BackgroundIntraoperative burst-suppression is associated with postoperative delirium. Whether this association is causal remains unclear. Therefore, the authors investigated whether burst-suppression during cardiopulmonary bypass (CPB) mediates the effects of known delirium risk factors on postoperative delirium.MethodsThis was a retrospective cohort observational substudy of the Minimizing ICU [intensive care unit] Neurological Dysfunction with Dexmedetomidine-induced Sleep (MINDDS) trial. The authors analyzed data from patients more than 60 yr old undergoing cardiac surgery (n = 159). Univariate and multivariable regression analyses were performed to assess for associations and enable causal inference. Delirium risk factors were evaluated using the abbreviated Montreal Cognitive Assessment and Patient-Reported Outcomes Measurement Information System questionnaires for applied cognition, physical function, global health, sleep, and pain. The authors also analyzed electroencephalogram data (n = 141).ResultsThe incidence of delirium in patients with CPB burst-suppression was 25% (15 of 60) compared with 6% (5 of 81) in patients without CPB burst-suppression. In univariate analyses, age (odds ratio, 1.08 [95% CI, 1.03 to 1.14]; P = 0.002), lowest CPB temperature (odds ratio, 0.79 [0.66 to 0.94]; P = 0.010), alpha power (odds ratio, 0.65 [0.54 to 0.80]; P < 0.001), and physical function (odds ratio, 0.95 [0.91 to 0.98]; P = 0.007) were associated with CPB burst-suppression. In separate univariate analyses, age (odds ratio, 1.09 [1.02 to 1.16]; P = 0.009), abbreviated Montreal Cognitive Assessment (odds ratio, 0.80 [0.66 to 0.97]; P = 0.024), alpha power (odds ratio, 0.75 [0.59 to 0.96]; P = 0.025), and CPB burst-suppression (odds ratio, 3.79 [1.5 to 9.6]; P = 0.005) were associated with delirium. However, only physical function (odds ratio, 0.96 [0.91 to 0.99]; P = 0.044), lowest CPB temperature (odds ratio, 0.73 [0.58 to 0.88]; P = 0.003), and electroencephalogram alpha power (odds ratio, 0.61 [0.47 to 0.76]; P < 0.001) were retained as predictors in the burst-suppression multivariable model. Burst-suppression (odds ratio, 4.1 [1.5 to 13.7]; P = 0.012) and age (odds ratio, 1.07 [0.99 to 1.15]; P = 0.090) were retained as predictors in the delirium multivariable model. Delirium was associated with decreased electroencephalogram power from 6.8 to 24.4 Hertz.ConclusionsThe inference from the present study is that CPB burst-suppression mediates the effects of physical function, lowest CPB temperature, and electroencephalogram alpha power on delirium.

Project description:Endothelial activation leading to vascular barrier dysfunction and organ failure is a well-recognized complication of cardiovascular surgery with cardiopulmonary bypass (CPB). The endothelial-specific angiopoietin-Tie2 ligand-receptor system has been identified as a non-redundant regulator of endothelial activation. Binding of angiopoietin-2 (Ang-2) to the Tie2 receptor antagonizes Tie2 signaling and renders the endothelial barrier responsive to pro-inflammatory cytokines. We aimed to study the time course and potential triggering factors of Ang-2 release after CPB, as well as the association of Ang-2 changes with surrogates of increased vascular permeability, organ dysfunction, and outcome.Serum levels of Ang-2 from 25 adult patients (140 screened) were measured before and at 0, 12, and 24h following CPB procedure by in-house immuno-luminometric assay (ILMA), and compared with indices of organ dysfunction, duration of mechanical ventilation (MV), length of stay (LOS) in the intensive care unit (ICU), and hospital mortality. The effect of Ang-2 was studied in vitro by incubating high Ang-2 patient serum with endothelial cells (EC).Ang-2 levels steadily increased from 2.6 ± 2.4 ng/mL at 0 h up to 7.3 ± 4.6 ng/mL at 24h following CPB (P<0.001). The release of Ang-2 correlated with the duration of CPB, aortic cross-clamp time, and post-CPB lactate levels. Changes in Ang-2 during follow-up correlated with partial pressure of oxygen in arterial blood (PaO(2))/fraction of inspired oxygen (FiO(2)) ratio, alveolar-arterial oxygen tension difference (AaDO(2)), hemodynamics, fluid balance, and disease severity measures. Ang-2 levels at 12h predicted the duration of MV, ICU-LOS, and hospital mortality. High Ang-2 patient sera disrupted EC architecture in vitro, an effect reversed by treatment with the competitive Tie2 ligand angiopoietin-1 (Ang-1).Collectively, our results suggest that Ang-2 is a putative mediator of endothelial barrier dysfunction after CPB. These findings suggest that targeting the Ang/Tie2 pathway may mitigate organ dysfunction and improve outcome in patients undergoing CPB.

Dataset Information

Exosomes of Antler Mesenchymal Stem Cells Improve Postoperative Cognitive Dysfunction in Cardiopulmonary Bypass Rats through Inhibiting the TLR2/TLR4 Signaling Pathway.

Publications

Exosomes of Antler Mesenchymal Stem Cells Improve Postoperative Cognitive Dysfunction in Cardiopulmonary Bypass Rats through Inhibiting the TLR2/TLR4 Signaling Pathway.

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