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Mobilization of Stem and Progenitor Cells in Septic Shock Patients.

ABSTRACT: Septic shock is associated with multiple injuries to organs and tissues. These events may induce the regenerative response of adult stem cells. However, little is known about how endogenous stem cells are modulated by sepsis. This study analyzed the circulation of hematopoietic stem cells (HSCs), endothelial progenitor cells (EPCs) and very small embryonic-like stem cells (VSELs) in the peripheral blood of patients with septic shock. Thirty-three patients with septic shock and twenty-two healthy control subjects were enrolled in this prospective observational study. Blood samples were collected on the first, third and seventh days of septic shock. Populations of stem cells were analyzed by flow cytometry. Chemotactic mediators were analyzed by HPLC and ELISA. Populations of early HSCs (Lin-CD133+CD45+ and CD34+CD38-) were mobilized to the peripheral blood after an initial decrease. Mobilized HSCs showed significantly increased expression of Ki-67, a marker of cell proliferation. Circulating EPCs and VSELs were mobilized to the blood circulation upon the first day of sepsis. Patients with a greater number of Lin-CD133+CD45+ HSCs and Lin-CD34+CD45- VSELs had a significantly lower probability of 60-day survival. The concentration of CXCL12 was elevated in the blood of septic patients, while the concentration of sphingosine-1-phosphate was significantly decreased. As an emergency early response to sepsis, VSELs and EPCs were mobilized to the peripheral blood, while the HSCs showed delayed mobilization. Differential mobilization of stem cell subsets reflected changes in the concentration of chemoattractants in the blood. The relationship between the probability of death and a large number of HSCs and VSELs in septic shock patients can be used as a novel prognostic marker and may provide new therapeutic approaches.

SUBMITTER: Skirecki T

PROVIDER: S-EPMC6397313 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Mobilization of Stem and Progenitor Cells in Septic Shock Patients.

Skirecki Tomasz T Mikaszewska-Sokolewicz Małgorzata M Godlewska Marlena M Dołęgowska Barbara B Czubak Jarosław J Hoser Grażyna G Kawiak Jerzy J Zielińska-Borkowska Urszula U

Scientific reports 20190301 1

Septic shock is associated with multiple injuries to organs and tissues. These events may induce the regenerative response of adult stem cells. However, little is known about how endogenous stem cells are modulated by sepsis. This study analyzed the circulation of hematopoietic stem cells (HSCs), endothelial progenitor cells (EPCs) and very small embryonic-like stem cells (VSELs) in the peripheral blood of patients with septic shock. Thirty-three patients with septic shock and twenty-two healthy ...[more]

PMID: 30824730

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Project description:BackgroundOur previous studies have proved the efficient exogenous repairing responses via bone marrow stem and progenitor cells (BMSPCs). However, the trafficking of endogenous bone marrow stem and progenitor cells to and from the bone marrow (BM) is a highly regulated process that remains to be elucidated. We aimed to study the relative importance of the hypothalamic-pituitary-adrenal (HPA) axis in the glucocorticoid-induced BMSPC mobilization.MethodsThe circulating mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) were examined in Crh (+/+, -/-) mice after running stress or glucocorticoid mini-infusion. The MSCs and EPCs were investigated ex vivo after treatment with glucocorticoid and glucocorticoid receptor (GR) antagonist, RU486. The expression of chemotaxis receptors, N-formyl peptide receptor (FPR), and Cys-X-Cys receptor 4 (CXCR4) of MSCs and EPCs as well as their colocalization were investigated after treatment with glucocorticoid, glucocorticoid receptor (GR) antagonist (RU486), and FPR antagonist (Cyclosporin H).ResultsForced running stress increased circulating MSCs and EPCs in mice, which was blunted when Crh was knocked out, and positively related to the levels of serum glucocorticoid. Prolonged glucocorticoid mini-infusion imitated the stress-induced increase in circulating MSCs and EPCs in Crh+/+ mice and rescued the impaired mobilization in circulating MSCs and EPCs in Crh-/- mice. Meanwhile, glucocorticoid promoted the chemotaxis of MSCs and EPCs ex vivo via GR, inhibited by RU486 (10 μM). Concurrently, glucocorticoid increased the expression of FPR of MSCs and EPCs, but inhibited their expression of CXCR4, followed by their changing colocalization in the cytoplasm. The GC-induced colocalization of FPR and CXCR4 was blunted by Cyclosporin H (1 μM).ConclusionGlucocorticoid-induced CXCR4-FPR responsiveness selectively guides the mobilization of BMSPCs, which is essential to functional tissue repair. Schematic view of the role of glucocorticoid on the mobilization of bone marrow-derived stem/progenitor cells subsets in the present study. The HPA axis activation promotes the release of glucocorticoid, which regulates the directional migration of MSCs and EPCs mainly via GR. The possible mechanisms refer to the signal coupling of FPR and CXCR4. Their two-sided changes regulated by glucocorticoid are involved in the egress of MSCs and EPCs from BM, which is helpful for wound healing. MSCs, mesenchymal stem cells; EPCs, endothelial progenitor cells.

Project description:BackgroundDespite the intensive efforts to improve the diagnosis and therapy of sepsis over the last decade, the mortality of septic shock remains high and causes substantial socioeconomical burden of disease. The function of immune cells is time-of-day-dependent and is regulated by several circadian clock genes. This study aims to investigate whether the rhythmicity of clock gene expression is altered in patients with septic shock.MethodsThis prospective pilot study was performed at the university hospital Charité-Universitätsmedizin Berlin, Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK). We included 20 patients with septic shock between May 2014 and January 2018, from whom blood was drawn every 4 h over a 24-h period to isolate CD14-positive monocytes and to measure the expression of 17 clock and clock-associated genes. Of these patients, 3 whose samples expressed fewer than 8 clock genes were excluded from the final analysis. A rhythmicity score SP was calculated, which comprises values between -1 (arrhythmic) and 1 (rhythmic), and expression data were compared to data of a healthy study population additionally.Results77% of the measured clock genes showed inconclusive rhythms, i.e., neither rhythmic nor arrhythmic. The clock genes NR1D1, NR1D2 and CRY2 were the most rhythmic, while CLOCK and ARNTL were the least rhythmic. Overall, the rhythmicity scores for septic shock patients were significantly (p < 0.0001) lower (0.23 ± 0.26) compared to the control group (12 healthy young men, 0.70 ± 0.18). In addition, the expression of clock genes CRY1, NR1D1, NR1D2, DBP, and PER2 was suppressed in septic shock patients and CRY2 was significantly upregulated compared to controls.ConclusionMolecular rhythms in immune cells of septic shock patients were substantially altered and decreased compared to healthy young men. The decrease in rhythmicity was clock gene-dependent. The loss of rhythmicity and down-regulation of clock gene expression might be caused by sepsis and might further deteriorate immune responses and organ injury, but further studies are necessary to understand underlying pathophysiological mechanisms. Trail registration Clinical trial registered with www.ClinicalTrials.gov (NCT02044575) on 24 January 2014.

Project description:BACKGROUND:Loss of vascular tone is a key pathophysiological feature of septic shock. Combination of gradual diastolic hypotension and tachycardia could reflect more serious vasodilatory conditions. We sought to evaluate the relationships between heart rate (HR) to diastolic arterial pressure (DAP) ratios and clinical outcomes during early phases of septic shock. METHODS:Diastolic shock index (DSI) was defined as the ratio between HR and DAP. DSI calculated just before starting vasopressors (Pre-VPs/DSI) in a preliminary cohort of 337 patients with septic shock (January 2015 to February 2017) and at vasopressor start (VPs/DSI) in 424 patients with septic shock included in a recent randomized controlled trial (ANDROMEDA-SHOCK; March 2017 to April 2018) was partitioned into five quantiles to estimate the relative risks (RR) of death with respect to the mean risk of each population (assumed to be 1). Matched HR and DAP subsamples were created to evaluate the effect of the individual components of the DSI on RRs. In addition, time-course of DSI and interaction between DSI and vasopressor dose (DSI*NE.dose) were compared between survivors and non-survivors from both populations, while ROC curves were used to identify variables predicting mortality. Finally, as exploratory observation, effect of early start of vasopressors was evaluated at each Pre-VPs/DSI quintile from the preliminary cohort. RESULTS:Risk of death progressively increased at gradual increments of Pre-VPs/DSI or VPs/DSI (One-way ANOVA, p < 0.001). Progressive DAP decrease or HR increase was associated with higher mortality risks only when DSI concomitantly increased. Areas under the ROC curve for Pre-VPs/DSI, SOFA and initial lactate were similar, while mean arterial pressure and systolic shock index showed poor performances to predict mortality. Time-course of DSI and DSI*NE.dose was significantly higher in non-survivors from both populations (repeated-measures ANOVA, p < 0.001). Very early start of vasopressors exhibited an apparent benefit at higher Pre-VPs/DSI quintile. CONCLUSIONS:DSI at pre-vasopressor and vasopressor start points might represent a very early identifier of patients at high risk of death. Isolated DAP or HR values do not clearly identify such risk. Usefulness of DSI to trigger or to direct therapeutic interventions in early resuscitation of septic shock need to be addressed in future studies.

Project description:BackgroundThe control of endothelial progenitor cells (CD133+/CD34+ EPCs) migrating from bone marrow to peripheral blood is not completely understood. Emerging evidence suggests that stromal cell-derived factor-1α (SDF-1α) mediates egression of EPCs from bone marrow, while the hypoxia inducible factor (HIF) transcriptional system regulates SDF-1α expression. Our study aimed to investigate the time course of circulating CD133+/CD34+ EPCs and its correlation with the expression of HIF-1α protein and SDF-1α in postoperative laparoscopic abdominal septic patients.MethodsPostoperative patients were divided in control (C group) and septic group (S group) operated immediately after the diagnosis of sepsis/septic shock. Blood samples were collected at baseline (0), 1, 3 and 7 postoperative days for CD133+/CD34+ EPCs count expressing or not the HIF-1α and SDF-1α analysis.ResultsThirty-two patients in S group and 39 in C group were analyzed. In C group CD133+/CD34+ EPCs count remained stable throughout the study period, increasing on day 7 (173 [0-421] /μl vs baseline: P = 0.04; vs day 1: P = 0.002). In S group CD133+/CD34+ EPCs count levels were higher on day 3 (vs day 1: P = 0.006 and day 7: P = 0.026). HIF-1α expressing CD133+/CD34+ EPCs count decreased on day 1 as compared with the other days in C group (day 0 vs 1: P = 0.003, days 3 and 7 vs 1: P = 0.008), while it was 321 [0-1418] /μl on day 3 (vs day 1; P = 0.004), and 400 [0-587] /μl on day 7 in S group. SDF-1α levels were higher not only on baseline but also on postoperative day 1 in S vs C group (219 [124-337] pg/ml vs 35 [27-325] pg/ml, respectively; P = 0.01).ConclusionOur results indicate that sepsis in abdominal laparoscopic patients might constitute an additional trigger of the EPCs mobilization as compared with non-septic surgical patients. A larger mobilization of CD133+/CD34+ EPCs, preceded by enhanced plasmatic SDF-1α, occurs in septic surgical patients regardless of HIF-1α expression therein.Trial registrationClinicalTrials.gov no. NCT02589535 . Registered 28 October 2015.

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Mobilization of Stem and Progenitor Cells in Septic Shock Patients.

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Mobilization of Stem and Progenitor Cells in Septic Shock Patients.

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