• Humans
• Hematopoietic Stem Cells/cytology
• Animals

• Animals
• Humans
• Mice
• Hematopoiesis
• Hematopoietic Stem Cells/cytology
• Hematopoietic Stem Cells/metabolism
• Homeostasis
• Single-Cell Analysis

• CCI
• bone marrow
• emergency myelopoiesis
• sepsis
• sepsis survivors

• Humans
• Critical Illness/therapy
• Myelopoiesis
• Neoplasm Recurrence, Local
• Sepsis/etiology
• Survivors
• Chronic Disease

• P30 AG028740 NIA NIH HHS
• R35 GM140806 NIGMS NIH HHS
• RM1 GM139690 NIGMS NIH HHS

Adult hematopoietic stem and progenitor cells (HSPCs) respond to bacterial infections by expansion to myeloid cells. Sepsis impairs this process by suppressing differentiation of stem cells subsequently contributing to an ineffective immune response. Whether the magnitude of HSPCs impairment in sepsis is severity-dependent remains unknown. This study investigated dynamics of the HSPC immune-inflammatory response in the bone marrow, splenic, and blood compartments in moribund and surviving septic mice. The 12-week-old outbred CD-1 female mice (n=65) were subjected to a cecal ligation and puncture (CLP) sepsis, treated with antibiotics and fluid resuscitation, and stratified into predicted-to-die (P-DIE) and predicted-to-survive (P-SUR) cohorts for analysis. CLP strongly reduced the common myeloid and multipotent progenitors, short- and long-term hematopoietic stem cell (HSC) counts in the bone marrow; lineage⁻ckit⁺Sca-1⁺ and short-term HSC suppression was greater in P-DIE versus P-SUR mice. A profound depletion of the common myeloid progenitors occurred in the blood (by 75%) and spleen (by 77%) of P-DIE. In P-SUR, most common circulating HSPCs subpopulations recovered to baseline by 72 h post-CLP. Analysis of activated caspase-1/-3/-7 revealed an increased apoptotic (by 30%) but not pyroptotic signaling in the bone marrow HSCs of P-DIE mice. The bone marrow from P-DIE mice revealed spikes of IL-6 (by 5-fold), CXCL1/KC (15-fold), CCL3/MIP-1α (1.7-fold), and CCL2/MCP-1 (2.8-fold) versus P-SUR and control (TNF, IFN-γ, IL-1β, -5, -10 remained unaltered). Summarizing, our findings demonstrate that an early sepsis-induced impairment of myelopoiesis is strongly outcome-dependent but varies among compartments. It is suggestive that the HSCPC loss is at least partly due to an increased apoptosis but not pyroptosis.

• caspases
• cecal ligation and puncture
• hematopoietic stem and progenitor cells
• immunity
• infection
• outcome prediction

• myeloid derived suppressor cells
• inflammation
• myelopoiesis
• erythropoiesis
• hepcidin

• Hematopoietic Stem Cells/physiology
• Hemorrhage/physiopathology
• Humans
• Sepsis/physiopathology
• Stem Cells/physiology
• Wounds and Injuries/physiopathology

• R01 GM113945 NIGMS NIH HHS
• T32 GM008721 NIGMS NIH HHS
• P30 AG028740 NIA NIH HHS
• P50 GM111152 NIGMS NIH HHS
• R01 GM105893 NIGMS NIH HHS

Background: Sepsis is life-threatening organ dysfunction associated with high risk of death. The immune response of sepsis is complex and varies over time. The immune cells are derived from hematopoietic stem and progenitor cells (HSPCs) which can respond to many infections. Our previous study found that sepsis causes HSPC dysregulation in mouse. But few studies have previously investigated the kinetics of HSPC and its contribution to immune system in sepsis patients.

Purpose: We aimed to identify the kinetics of HSPCs and their contribution to immune system in sepsis patients.

Methods: We enrolled eight sepsis patients and five healthy control subjects. Peripheral blood (PB) samples from each patient were collected three times: on the first, fourth, and seventh days, once from each healthy control subject. Peripheral blood mononuclear cells (PBMCs) were isolated by density centrifugation and stained with cocktails of antibodies. Populations of HSPCs and their subpopulation were analyzed by flow cytometry. Immune cells were characterized by flow cytometry and blood cell analysis. Correlations between HSPCs and immune cells were analyzed using the Pearson correlation test.

Results: We found that the frequency of HSPCs (CD34⁺ cells and CD34⁺CD38⁺ cells) in sepsis patients on day 4 was significantly higher than that in the healthy controls. The most pronounced change in subpopulation analysis is the frequency of common myeloid progenitors (CMPs; CD34⁺CD38⁺CD135⁺CD45RA⁻). But no difference in the immunophenotypically defined hematopoietic stem cells (HSCs; CD34⁺CD38⁻CD90⁺CD45RA⁻) in sepsis patients was observed due to rare HSC numbers in PB. The number of PBMCs and lymphocytes are decreased, whereas the white blood cell (WBC) and neutrophil counts were increased in sepsis patients. Importantly, we found a negative correlation between CD34⁺ on day 1 and WBC and lymphocytes on day 4 from correlation analysis in sepsis patients.

Conclusion: The present study demonstrated that the HSPC and its subpopulation in sepsis patients expanded. Importantly, the changes in HSPCs at early time points in sepsis patients have negative correlations with later immune cells. Our results may provide a novel diagnostic indicator and a new therapeutic approach.

• hematopoietic stem cells
• immune status
• phenotypical changes
• progenitor cells
• sepsis

The 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.

Postoperative 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.

Thirty-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).

Our 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.

ClinicalTrials.gov no. NCT02589535. Registered 28 October 2015.

• Endothelial progenitor cells
• Hematopoietic stem cells
• Hypoxia inducible factor-1α
• Postoperative abdominal laparoscopic patients
• Sepsis
• Stromal cell-derived factor-1α

• critical illness
• infection
• intensive care unit
• lymphocyte-to-monocyte ratio
• sepsis

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.

• circulatory CD34+ cells
• cytokines
• infection
• preterm infants

• Cardiovascular disease
• Circulating endothelial cells
• Circulating progenitor cells
• Exercise

• Bone Marrow Cells/cytology
• Bone Marrow Cells/physiology
• Cardiovascular Diseases/therapy
• Cell Differentiation
• Critical Care
• Endothelium, Vascular/cytology
• Humans
• Lung Injury
• Neovascularization, Physiologic
• Stem Cell Transplantation
• Stem Cells/cytology
• Stem Cells/physiology