A Novel Type of Stem Cells Double-Positive for SSEA-3 and CD45 in Human Peripheral Blood.

Peripheral blood (PB) contains several types of stem/progenitor cells, including hematopoietic stem and endothelial progenitor cells. We identified a population positive for both the pluripotent surface marker SSEA-3 and leukocyte common antigen CD45 that comprises 0.04% ± 0.003% of the mononuclear cells in human PB. The average size of the SSEA-3(+)/CD45(+) cells was 10.1 ± 0.3 µm and ∼22% were positive for CD105, a mesenchymal marker; ∼85% were positive for CD19, a B cell marker; and ∼94% were positive for HLA-DR, a major histocompatibility complex class II molecule relevant to antigen presentation. These SSEA-3(+)/CD45(+) cells expressed the pluripotency markers Nanog, Oct3/4, and Sox2, as well as sphingosine-1-phosphate (S1P) receptor 2, and migrated toward S1P, although their adherence and proliferative activities in vitro were low. They expressed NeuN at 7 d, Pax7 and desmin at 7 d, and alpha-fetoprotein and cytokeratin-19 at 3 d when supplied to mouse damaged tissues of the brain, skeletal muscle and liver, respectively, suggesting the ability to spontaneously differentiate into triploblastic lineages compatible to the tissue microenvironment. Multilineage-differentiating stress enduring (Muse) cells, identified as SSEA-3(+) in tissues such as the bone marrow and organ connective tissues, express pluripotency markers, migrate to sites of damage via the S1P-S1P receptor 2 system, and differentiate spontaneously into tissue-compatible cells after homing to the damaged tissue where they participate in tissue repair. After the onset of acute myocardial infarction and stroke, patients are reported to have an increase in the number of SSEA-3(+) cells in the PB. The SSEA-3(+)/CD45(+) cells in the PB showed similarity to tissue-Muse cells, although with difference in surface marker expression and cellular properties. Thus, these findings suggest that human PB contains a subset of cells that are distinct from known stem/progenitor cells, and that CD45(+)-mononuclear cells in the PB comprise a novel subpopulation of cells that express pluripotency markers.

Mobilization of Pluripotent Multilineage-Differentiating Stress-Enduring Cells in Ischemic Stroke.

GOAL: This prospective study was aimed to prove the hypothesis that multilineage-differentiating stress-enduring (Muse) cells are mobilized from bone marrow into peripheral blood in patients with ischemic stroke. MATERIALS AND METHODS: This study included 29 patients with ischemic stroke. To quantify the circulating Muse cells, peripheral blood was obtained from all patients on admission and at days 7 and 30. Using fluorescence-activated cell sorting, Muse cells were identified as stage-specific embryonic antigen-3-positive cells. The control values were obtained from 5 healthy volunteers. Separately, immunohistochemistry was performed to evaluate the distribution of Muse cells in the bone marrow of 8 autopsy cases. FINDINGS: The number of Muse cells robustly increased within 24 hours after the onset, compared with the controls, but their baseline number and temporal profile widely varied among patients. No clinical data predicted the baseline number of Muse cells at the onset. Multivariate analysis revealed that smoking and alcohol intake significantly affect the increase in circulating Muse cells. The odds ratio was .0027 (P = .0336) and 1688 (P = .0220) for smoking and alcohol intake, respectively. The percentage of Muse cells in the bone marrow was .20% ± .17%. CONCLUSION: This study shows that pluripotent Muse cells are mobilized from the bone marrow into peripheral blood in the acute stage of ischemic stroke. Smoking and alcohol intake significantly affect their temporal profile. Therapeutic interventions that increase endogenous Muse cells or exogenous administration of Muse cells may improve functional outcome after ischemic stroke.

Stage-specific embryonic antigen-4 is expressed in basaloid lung cancer and associated with poor prognosis.

Basaloid carcinoma represents a rare variant of nonsmall cell lung cancer (NSCLC), which has shown a poor prognosis in a number of studies. Although it is considered to derive from a pluri- or multipotent pulmonary stem cells, little is known about the expression and clinical significance of stem cell antigens in this variant. Stage-specific embryonic antigen-4 (SSEA-4) was analysed by immunohistochemistry in 38 patients with resected early-stage basaloid NSCLC who had a median follow-up of 72.9 months. The expression of SSEA-4 was related to clinico-pathological characteristics, to the expression of the adult stem cell antigens CD117, CD133 and breast cancer resistance protein 1 (BCRP1), and to prognosis. SSEA-4 was positive in 37% of the specimens and showed no association with clinico-pathological characteristics or the expression of adult stem cell antigens. Cox proportional hazards regression analysis revealed a 6.0-fold increased risk of relapse (p = 0.001) and a 4.2-fold increased risk of disease-related mortality (p = 0.017) in SSEA-4-positive patients, while SSEA-4-negative patients showed a prognosis comparable with that of other early-stage NSCLC. SSEA-4 is expressed in a fraction of basaloid NSCLC and is associated with poor prognosis.