Macrophage depletion using clodronate liposomes reveals latent dysfunction of the hematopoietic microenvironment associated with persistently imbalanced M1/M2 macrophage polarization in a mouse model of hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory syndrome, is caused by the incessant activation of lymphocytes and macrophages, resulting in damage to organs, including hematopoietic organs. Recently, we demonstrated that repeated lipopolysaccharide (LPS) treatment induces HLH-like features in senescence-accelerated (SAMP1/TA-1) mice but not in senescence-resistant control (SAMR1) mice. Hematopoietic failure in LPS-treated SAMP1/TA-1 mice was attributed to hematopoietic microenvironment dysfunction, concomitant with severely imbalanced M1 and M2 macrophage polarization.

Imbalanced M1 and M2 Macrophage Polarization in Bone Marrow Provokes Impairment of the Hematopoietic Microenvironment in a Mouse Model of Hemophagocytic Lymphohistiocytosis.

Lipopolysaccharide (LPS) treatment induced hemophagocytic lymphohistiocytosis in senescence-accelerated mice (SAMP1/TA-1), but not in senescence-resistant control mice (SAMR1). SAMP1/TA-1 treated with LPS exhibited functional impairment of the hematopoietic microenvironment, which disrupted the dynamics of hematopoiesis. Macrophages are a major component of the bone marrow (BM) hematopoietic microenvironment, which regulates hematopoiesis.

Age-related exacerbation of hematopoietic organ damage induced by systemic hyper-inflammation in senescence-accelerated mice.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyper-inflammatory disorder. The mortality of HLH is higher in the elderly than in young adults. Senescence-accelerated mice (SAMP1/TA-1) exhibit characteristic accelerated aging after 30 weeks of age, and HLH-like features, including hematopoietic organ damage, are seen after lipopolysaccharide (LPS) treatment.

Kinetics of leukemic cells in 3D culture with stromal cells and with arginine deprivation stress.

Previously, we established a three-dimensional (3D) bone marrow culture system that maintains normal hematopoiesis, including prolongation of hematopoietic stem cell proliferation and differentiation. To analyze the role of bone marrow stromal cells that compose the microenvironment, the growth of a leukemic cell line (K562) in the 3D condition and with arginine deprivation stress was compared with two-dimensional stromal cell monolayers (2D) and suspension cultures without stromal cells (stroma (-)). Arginine is essential for the proliferation and differentiation of erythrocytes.

Dynamics of hematopoiesis is disrupted by impaired hematopoietic microenvironment in a mouse model of hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyperinflammatory disorder. We found recently that repeated lipopolysaccharide (LPS) treatment induces HLH-like features in senescence-accelerated mice (SAMP1/TA-1) but not in senescence-resistant control mice (SAMR1). In this study, we analyzed the dynamics of hematopoiesis in this mouse model of HLH.

Senescence-accelerated mice (SAMP1/TA-1) treated repeatedly with lipopolysaccharide develop a condition that resembles hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis is a life-threatening systemic hyperinflammatory disorder with primary and secondary forms. Primary hemophagocytic lymphohistiocytosis is associated with inherited defects in various genes that affect the immunological cytolytic pathway. Secondary hemophagocytic lymphohistiocytosis is not inherited, but complicates various medical conditions including infections, autoinflammatory/autoimmune diseases, and malignancies.

Combined treatment with benzo[a]pyrene and 1α,25-dihydroxyvitamin D induces expression of plasminogen activator inhibitor 1 in monocyte/macrophage-derived cells.

Benzo[a]pyrene (BaP) is an environmental pollutant found in cigarette smoke and is implicated as a causative agent of tobacco-related diseases, such as arteriosclerosis. In contrast, vitamin D signaling, which is principally mediated by conversion of vitamin D to the active form, 1α,25-dihydroxyvitamin D [1,25(OH)D], decreases cardiovascular disease risk. However, combined treatment with BaP and 1,25(OH)D enhances BaP toxicity, including BaP-DNA adduct formation.

Long-Term Hypoxic Tolerance in Murine Cornea.

Unlabelled: Kosaku, Kazuhiro, Tomonori Harada, Toyoharu Jike, Isao Tsuboi, and Shin Aizawa. Long-term hypoxic tolerance in murine cornea. High Alt Med Biol 19:35-41, 2018.

Differential Regulation of Lympho-Myelopoiesis by Stromal Cells in the Early and Late Phases in BALB/c Mice Repeatedly Exposed to Lipopolysaccharide.

Chronic lipopolysaccharide (LPS) exposure to mice reduces the lymphoid compartment and skews the hematopoietic cell compartment toward myeloid-cells, which is considered to be a direct effect of LPS on hematopoietic stem cells. However, the effect of chronic LPS exposure on stromal-cells, which compose the hematopoietic microenvironment, has not been elucidated. Here, we investigated early- and late-phase effects of repeated LPS exposure on stromal-cells.

Cell cycle of primitive hematopoietic progenitors decelerated in senescent mice is reactively accelerated after 2-Gy whole-body irradiation.

Aging is considered to be a functional retardation of continuous xenobiotic responses over a lifetime after the developmental period; thus, the effects of ionizing radiation over a lifetime may be somewhat accounted for by a modifier of aging effects. This study was conducted to evaluate the possible/synergic effects of radiation during aging by determining cell-cycle parameters of hematopoietic stem cells/hematopoietic progenitor cells (HSCs/HPCs), such as the percent of cells in cycling, the generation doubling time, and the cumulative cycling-cell fraction, by bromodeoxyuridine-ultraviolet assay, which enables the determination of their cycling capacity in vivo. Colony-forming progenitor cells, such as colony-forming unit (CFU)-granulocyte/macrophage (GM), CFU in the spleen on day 9 (CFU-S9), and CFU-S on day 13 (CFU-S13) for mature, less mature, and immature HPCs, respectively, were evaluated in young and old mice (6 weeks and 21 months of age, respectively) with or without 2-Gy whole-body irradiation and a 4-week recovery period.

A case of a quadricuspid pulmonary valve in a Japanese female.

A supernumerary cusp of the pulmonary valve was incidentally found in an 88-year-old Japanese female during a gross anatomy course. The valve was composed of three equal-sized leaflets and one smaller leaflet. The supernumerary leaflet was located between the anterior and right semilunar leaflets.

Kinetics of hematopoietic stem cells and supportive activities of stromal cells in a three-dimensional bone marrow culture system.

In the bone marrow, hematopoietic cells proliferate and differentiate in close association with a three-dimensional (3D) hematopoietic microenvironment. Previously, we established a 3D bone marrow culture system. In this study, we analyzed the kinetics of hematopoietic cells, and more than 50% of hematopoietic progenitor cells, including CFU-Mix, CFU-GM and BFU-E in 3D culture were in a resting (non-S) phase.

Quantitative Analysis of Formaldehyde-induced Fluorescence in Paraffin-embedded Specimens of Malignant Melanomas and Other Melanocytic Lesions.

Inter-observer agreement is problematic in the histopathological diagnosis of melanoma and melanocytic naevi, even among expert pathologists. Formaldehyde-induced fluorescence (FIF) has been used for histochemical demonstration of catecholamines, 5-hydroxytryptamine and their immediate precursors. FIF can detect melanogenic activity and may be useful in differentiating malignant melanoma from other melanocytic lesions.

Lipopolysaccharide reciprocally alters the stromal cell-regulated positive and negative balance between myelopoiesis and B lymphopoiesis in C57BL/6 mice.

Hematopoiesis in the bone marrow (BM) and spleen is controlled by stromal cells. Inflammation promotes myelopoiesis and simultaneously suppresses B lymphopoiesis. However, the role of the reciprocal regulation of myelopoiesis and B lymphopoiesis by stromal cells during inflammation is not fully understood.

Experimentally induced, synergistic late effects of a single dose of radiation and aging: significance in LKS fraction as compared with mature blood cells.

The number of murine mature blood cells recovered within 6 weeks after 2-Gy whole-body irradiation at 6 weeks of age, whereas in the case of the undifferentiated hematopoietic stem/progenitor cell (HSC/HPC) compartment [cells in the lineage-negative, c-kit-positive and stem-cell-antigen-1-positive (LKS) fraction], the numerical differences between mice with and without irradiation remained more than a year, but conclusively the cells showed numerical recovery. When mice were exposed to radiation at 6 months of age, acute damages of mature blood cells were rather milder probably because of their maturation with age; but again, cells in the LKS fraction were specifically damaged, and their numerical recovery was significantly delayed probably as a result of LKS-specific cellular damages. Interestingly, in contrast to the recovery of the number of cells in the LKS fraction, their quality was not recovered, which was quantitatively assessed on the basis of oxidative-stress-related fluorescence intensity.

Decreased "ineffective erythropoiesis" preserves polycythemia in mice under long-term hypoxia.

Hypoxia induces innumerable changes in humans and other animals, including an increase in peripheral red blood cells (polycythemia) caused by the activation of erythropoiesis mediated by increased erythropoietin (EPO) production. However, the elevation of EPO is limited and levels return to normal ranges under normoxia within 5-7 days of exposure to hypoxia, whereas polycythemia continues for as long as hypoxia persists. We investigated erythropoiesis in bone marrow and spleens from mouse models of long-term normobaric hypoxia (10 % O2) to clarify the mechanism of prolonged polycythemia in chronic hypoxia.

Age-related decline of mast cell regeneration in senescence-accelerated mice (SAMP1) after chemical myeloablation due to senescent stromal cell impairment.

An age-related decline in immune functions is referred to as immunosenescence. Mast cells play an important role in the immune system. However, it has not yet been determined if aging may affect mast-cell development.

Neopterin, inflammation-associated product, prolongs erythropoiesis suppression in aged SAMP1 mice due to senescent stromal-cell impairment.

Anemia induced by inflammation is well known to be more serious in the elderly than in non-elderly adults; however, the reason why this is so remains unclear. Neopterin produced by monocytes during inflammation promotes myelopoiesis but suppresses B-lymphopoiesis and erythropoiesis, by activating stromal cells in mice. Here, age-related changes in the erythropoietic response to neopterin were determined using senescence accelerated mice (SAMP1) with senescence stromal-cell impairment.

Novel three-dimensional long-term bone marrow culture system using polymer particles with grafted epoxy-polymer-chains supports the proliferation and differentiation of hematopoietic stem cells.

Hematopoiesis occurs in the bone marrow, where primitive hematopoietic cells proliferate and differentiate in close association with a three-dimensional (3D) hematopoietic microenvironment composed of stromal cells. We examined the hematopoietic supportive ability of stromal cells in a 3D culture system using polymer particles with grafted epoxy polymer chains. Umbilical cord blood-derived CD34(+) cells were co-cultivated with MS-5 stromal cells.

Mast cell development and biostresses: different stromal responses in bone marrow and spleen after treatment of myeloablater, 5-fluorouracil, and inflammatory stressor, lipopolysaccharide.

Mast-cell-development in the bone-marrow (BM) and the spleen is restrictedly controlled by stromal-cells which produce positive-regulators such as stem cell factor (SCF), and negative-regulators such as transforming growth factor-β (TGF-β). How the balance between positive- and negative-regulation is achieved or maintained by stromal-cells is not well understood. We intravenously injected 5-fluorouracil (5-FU) and lipopolysaccharide (LPS) into C3H/HeN mice to disrupt mast-cell-development in order to reveal mechanisms of mast-cell-regulation.

Asymmetric uptake of sepiapterin and 7,8-dihydrobiopterin as a gateway of the salvage pathway of tetrahydrobiopterin biosynthesis from the lumenal surface of rat endothelial cells.

Rat aortic endothelial cells were cultured on a porous membrane to form a monolayer sheet. They efficiently accumulated tetrahydrobiopterin (BH(4)) by uptake of sepiapterin but did so only moderately by uptake of dihydrobiopterin. The endothelial cell sheet preferentially took up the pterins from the apical side.

Regeneration capability of Lin-/c-Kit+/Sca-1+ cells with or without radiation exposure for repopulation of peripheral blood in lethally irradiated mice monitored using Ly5.1 isotype on days 35, 90, and 270 after transplantation.

Objective: Hematopoietic stem cells are supposed to repopulate and maintain long-term regeneration of the recipient's bone marrow and peripheral blood. In this study, we evaluated the regeneration capability of Lin(-)/c-Kit(+)/Sca-1(+) (LKS) cells, the putative hematopoietic stem cells, after radiation exposure at graded doses, for long-term regeneration of peripheral blood in lethally irradiated recipients.

Materials And Methods: LKS primitive progenitor cells, collected from the bone marrow of Ly5.

Inflammatory biomarker, neopterin, predominantly enhances myelopoiesis, which suppresses erythropoiesis via activated stromal cells.

Neopterin is produced by monocytes and is a useful biomarker for inflammation. We found previously that neopterin enhanced myelopoiesis but suppressed B-lymphopoiesis triggered by the positive and negative regulations of cytokines produced by stromal cells in mice. The effects of neopterin on erythropoiesis during the enhancement of myelopoiesis were determined in the present study using C57BL/6J mice.

Comparison of murine gene expression profiles between spontaneous and radiation-induced myelogenous leukemias: stochastic and probabilistic expression variances in the former vs radiation-specific expression commonalities in the latter.

Objective: To elucidate the common characteristics of murine radiation-induced myelogenous leukemias, global gene-chip expression profiles were compared with age-matched steady-state bone marrow tissue profiles and spontaneous myelogenous leukemia profiles.

Materials And Methods: Six each of C3H/He mice-derived radiation-induced and spontaneously developed myelogenous leukemias were analyzed. Bone marrow cells from five each of 2- and 21-month-old mice were used to subtract nonleukemic information in the analysis.

Predominant regeneration of B-cell lineage, instead of myeloid lineage, of the bone marrow after 1 Gy whole-body irradiation in mice: role of differential cytokine expression between B-cell stimulation by IL10, Flt3 ligand and IL7 and myeloid suppression by GM-CSF and SCF.

Irradiation of mice at doses of 1-1.5 Gy induced a predominant regeneration of the B-cell lineage but suppressed the regeneration of the myeloid lineage. The mechanisms underlying such reciprocal regulation of regeneration and the relationship between the two lineages remain unclear.