Eosinophilia in chimeric mice infected withToxocara canis

ABSTRACTA marked strain variation in eosinophilia following oral infection withToxocara caniseggs was observed in mice. Mutual radiation chimeras between high and low responder mice in terms of eosinophilia were made and compared with the respective donor and recipient for eosinophilia after the infection. As a result, the degree and time course of eosinophilia in chimeric mice were similar to those in donors. The result suggested that genes which regulate inheritance of the trait, marked eosinophilia inT. canis-infected mice, might be expressed in bone marrow derived cells.

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Abstract 83: Bone Marrow Derived Cells Do Not Mediate Reductions in Cholesterol, Atherosclerosis and Adiposity in Microsomal Prostaglindin E Synthase 1 Deficient Mice Fed High Fat Diets Enriched in Cholesterol

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a83 ◽

2013 ◽

Vol 33 (suppl_1) ◽

Author(s):

Sarah Srodulski ◽

Victoria L King

Keyword(s):

Bone Marrow ◽

Weight Gain ◽

Marrow Cell ◽

Atherosclerotic Lesion ◽

Chimeric Mice ◽

High Fat ◽

Lesion Formation ◽

Bone Marrow Derived Cells ◽

Deficient Mice ◽

Atherosclerotic Lesion Formation

Microsomal prostaglandin E 2 synthase-1 (mPGES-1) catalyzes the conversion of COX-2 generated PGH 2 to PGE 2 and is the predominate source of PGE 2 during and inflammatory response. We and others have demonstrated that mPGES-1 deficiency attenuates atherosclerosis in mice on a mixed background. The present study investigated the effect of mPGES-1 deficiency on atherosclerosis in C57BL/6 low density lipoprotein receptor deficient (LDLr-/-) mice. mPGES-1 deficiency attenuated atherosclerosis in LDLr-/- mice fed either a low fat (LF) (P = 0.02) or high fat (HF) (P = 0.0026) diet enriched with cholesterol, or a western diet (P = 0.02) for 17 weeks. mPGES-1 deficiency attenuated weight gain and cholesterol concentrations in mice fed a western (P = 0.004 and P < 0.05; respectively) or HF diet (P = 0.01 and P = 0.012, respectively). However, body weight and cholesterol concentrations were not different in mice fed the LF diet. These data suggest that different mechanisms mediate the reduction in atherosclerosis in mPGES-1 deficient mice fed LF and HF diets. To determine if mPGES-1 deficiency in macrophages contributed to the reduction in atherosclerosis in mice fed HF diets, 4 groups of chimeric mice were generated. Four weeks post bone marrow cell transplant (BMT) mice were fed a western diet. BMT attenuated weight gain in all groups of chimeric mice; however, weight gain was not different between any of the groups. BMT decreased atherosclerotic lesion formation 10 fold in all groups of mice. Neither bone marrow cell specific deficiency of mPGES-1 (KO>WT) or mPGES-1 specific expression in bone marrow derived cells (WT>KO) had an effect on lesion formation compared to WT>WT or KO>KO mice. Cholesterol concentrations were decreased in KO>KO and WT>KO mice compared to WT>WT (P < 0.01) and KO>WT (P< 0.05) mice. These data suggest that mPGES-1 expression in bone marrow derived cells does not contribute to the development of atherosclerosis. Moreover, these data suggest that prostanoids may play a role in hepatic cholesterol homeostasis in mice fed HF diets enriched in cholesterol thereby contributing to atherosclerotic lesion formation. Moreover, these data provide further evidence that prostanoids play a role in regulating the accumulation of diet-induced adiposity.

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Granule cargo release from bone marrow-derived cells sustains cardiac hypertrophy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00951.2013 ◽

2014 ◽

Vol 307 (10) ◽

pp. H1529-H1538 ◽

Cited By ~ 1

Author(s):

Fanmuyi Yang ◽

Anping Dong ◽

Jasimuddin Ahamed ◽

Manjula Sunkara ◽

Susan S. Smyth

Keyword(s):

Bone Marrow ◽

Cardiac Hypertrophy ◽

Inflammatory Responses ◽

Pressure Overload ◽

Left Ventricular ◽

Enzyme Linked Immunosorbent Assay ◽

Late Time ◽

Chimeric Mice ◽

Bone Marrow Derived Cells ◽

Granule Secretion

Bone marrow-derived inflammatory cells, including platelets, may contribute to the progression of pressure overload-induced left ventricular hypertrophy (LVH). However, the underlying mechanisms for this are still unclear. One potential mechanism is through release of granule cargo. Unc13-d Jinx (Jinx) mice, which lack Munc13-4, a limiting factor in vesicular priming and fusion, have granule secretion defects in a variety of hematopoietic cells, including platelets. In the current study, we investigated the role of granule secretion in the development of LVH and cardiac remodeling using chimeric mice specifically lacking Munc13-4 in marrow-derived cells. Pressure overload was elicited by transverse aortic constriction (TAC). Chimeric mice were created by bone marrow transplantation. Echocardiography, histology staining, immunohistochemistry, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and mass spectrometry were used to study LVH progression and inflammatory responses. Wild-type (WT) mice that were transplanted with WT bone marrow (WT→WT) and WT mice that received Jinx bone marrow (Jinx→WT) developed LVH and a classic fetal reprogramming response early (7 days) after TAC. However, at late times (5 wk), mice lacking Munc13-4 in bone marrow-derived cells (Jinx→WT) failed to sustain the cardiac hypertrophy observed in WT chimeric mice. No difference in cardiac fibrosis was observed at early or late time points. Reinjection of WT platelets or platelet releasate partially restored cardiac hypertrophy in Jinx chimeric mice. These results suggest that sustained LVH in the setting of pressure overload depends on one or more factors secreted from bone marrow-derived cells, possibly from platelets. Inhibiting granule cargo release may represent a novel target for preventing sustained LVH.

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Impaired Virus Control and Severe CD8+ T-Cell-Mediated Immunopathology in Chimeric Mice Deficient in Gamma Interferon Receptor Expression on both Parenchymal and Hematopoietic Cells

Journal of Virology ◽

10.1128/jvi.79.15.10073-10076.2005 ◽

2005 ◽

Vol 79 (15) ◽

pp. 10073-10076 ◽

Cited By ~ 5

Author(s):

Pernille Henrichsen ◽

Christina Bartholdy ◽

Jan Pravsgaard Christensen ◽

Allan Randrup Thomsen

Keyword(s):

Bone Marrow ◽

T Cells ◽

Gamma Interferon ◽

Receptor Expression ◽

Chimeric Mice ◽

Virus Control ◽

Bone Marrow Derived Cells ◽

Ifn Γ ◽

Parenchymal Cells ◽

Bone Marrow Chimeras

ABSTRACT Bone marrow chimeras were used to determine the cellular target(s) for the antiviral activity of gamma interferon (IFN-γ). By transfusing such mice with high numbers of naive virus-specific CD8+ T cells, a system was created in which the majority of virus-specific CD8+ T cells would be capable of responding to IFN-γ, but expression of the relevant receptor on non-T cells could be experimentally controlled. Only when the IFN-γ receptor is absent on both radioresistant parenchymal and bone marrow-derived cells will chimeric mice challenged with a highly invasive, noncytolytic virus completely lack the ability to control the infection and develop severe wasting disease. Further, the study shows that IFN-γ receptor expression on parenchymal cells in the viscera is more important for virus control than IFN-γ receptor expression on bone marrow-derived cells.

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Adult hematopoietic stem cells require NKAP for maintenance and survival

Blood ◽

10.1182/blood-2010-02-268391 ◽

2010 ◽

Vol 116 (15) ◽

pp. 2684-2693 ◽

Cited By ~ 22

Author(s):

Anthony G. Pajerowski ◽

Michael J. Shapiro ◽

Kimberly Gwin ◽

Rhianna Sundsbak ◽

Molly Nelson-Holte ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Hematopoietic Stem Cells ◽

Time Course ◽

Kinase Inhibitors ◽

Conditional Knockout ◽

Similar Time ◽

Self Renewal ◽

Hematopoietic Stem ◽

Radiation Chimeras

Abstract Steady-state hematopoiesis is sustained through differentiation balanced with proliferation and self-renewal of hematopoietic stem cells (HSCs). Disruption of this balance can lead to hematopoietic failure, as hematopoietic differentiation without self-renewal leads to loss of the HSC pool. We find that conditional knockout mice that delete the transcriptional repressor NKAP in HSCs and all hematopoietic lineages during embryonic development exhibit perinatal lethality and abrogation of hematopoiesis as demonstrated by multilineage defects in lymphocyte, granulocyte, erythrocyte and megakaryocyte development. Inducible deletion of NKAP in adult mice leads to lethality within 2 weeks, at which point hematopoiesis in the bone marrow has halted and HSCs have disappeared. This hematopoietic failure and lethality is cell intrinsic, as radiation chimeras reconstituted with inducible Mx1-cre NKAP conditional knockout bone marrow also succumb with a similar time course. Even in the context of a completely normal bone marrow environment using mixed radiation chimeras, NKAP deletion results in HSC failure. NKAP deletion leads to decreased proliferation and increased apoptosis of HSCs, which is likely due to increased expression of the cyclin-dependent kinase inhibitors p21Cip1/Waf1 and p19Ink4d. These data establish NKAP as one of a very small number of transcriptional regulators that is absolutely required for adult HSC maintenance and survival.

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Allotype-specific analysis of anti-(TYR,GLU)-ALA-LYS antibodies produced by Ir-1A high and low responder chimeric mice

Journal of Experimental Medicine ◽

10.1084/jem.146.6.1815 ◽

1977 ◽

Vol 146 (6) ◽

pp. 1815-1820 ◽

Cited By ~ 19

Author(s):

JL Press ◽

HO McDevitt

Keyword(s):

Bone Marrow ◽

T Cells ◽

B Cells ◽

Lymphoid Cell ◽

Marrow Cell ◽

Cell Interaction ◽

Gene Control ◽

Chimeric Mice ◽

Low Responder ◽

Ig Allotype

Katz et al. (1) have demonstrated a restriction in lymphoid cell interaction when the antigen used is under immune response (Ir) gene control. T cells from (low responder x high responder) F(1) mice primed to the terpolymer L-glutamic acid, L-lysine, L-tyrosine (GLT) can collaborate with 2,4-dinitrophenyl (DNP)-primed B cells from the Ir-GLT high responder but not low responder strain in response to DNP-GLT (1). In contrast are the studies of Bechtol et al. and Bechtol and McDevitt (2,3), who examined the antibody responses of tetraparental mice immunized with the synthetic polypeptide poly-L(Tyr,Glu)-poly D,L-Ala- poly-L-Lys ((T,G)-A-L), an antigen under Ir-1A genetic control. Several tetraparental mice produced anti(T-,G)-A-L antibody of low responder strain immunoglobulin (Ig) allotype (2,3). These results indicated that he Ir-1A gene was not expressed in B cells and implied that interactions among genetically dissimilar cell populations could occur when tolerance existed to H-2 antigenic differences. Recent studies with bone marrow cell chimeric mice have shown that chimeric T cells can interact with H-2 histoincompatible B cells in response to antigens not under Ir gene control (4-6). To clarify whether lymphoid cell chimerism, with presumed tolerance to H-2 incompatibility, would permit effective cell interactions in response to antigens under Ir gene control, bone marrow cell chimeric mice were prepared by using strains differing both for Ig allotype and for high versus low responsiveness to (T,G)-A-L. An antigen-specific and allotype- specific antibody assay was used to discriminate the responses produced by high and low responder strain B cells in these chimeras. The results suggest that lymphoid cell chimerism per se is not sufficient to obviate Ir gene-mediated restriction in cell interaction.

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A method to generate enhanced GFP+ chimeric mice to study the role of bone marrow-derived cells in the eye

Experimental Eye Research ◽

10.1016/j.exer.2013.10.007 ◽

2013 ◽

Vol 116 ◽

pp. 366-370 ◽

Cited By ~ 13

Author(s):

Vivek Singh ◽

Ritika Jaini ◽

André A.M. Torricelli ◽

Vincent K. Tuohy ◽

Steven E. Wilson

Keyword(s):

Bone Marrow ◽

Chimeric Mice ◽

Bone Marrow Derived Cells

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DISTINCT ROLES FOR DISCOIDIN DOMAIN RECEPTOR 1 (DDR1) EXPRESSED ON BONE MARROW DERIVED CELLS AND VESSEL WALL CELLS DURINGATHEROGENESIS

Clinical & Investigative Medicine ◽

10.25011/cim.v31i4.4803 ◽

2008 ◽

Vol 31 (4) ◽

pp. 10

Author(s):

C Franco ◽

G Hou ◽

M P Bendeck

Keyword(s):

Bone Marrow ◽

Vessel Wall ◽

Critical Role ◽

Chimeric Mice ◽

Lesion Area ◽

Aortic Sinus ◽

Discoidin Domain Receptor ◽

Plaque Development ◽

Bone Marrow Derived Cells ◽

Discoidin Domain Receptor 1

We have recently described a critical role for the discoidin domain receptor 1 (DDR1) collagen receptor tyrosine kinase in the regulation of fibrosis and inflammation during atherosclerotic plaque development. DDR1 isexpressed on both SMCs and macrophages; however the role of DDR1 expressed in these distinct cells during atherogenesis remains unresolved. In the current study, female Ldlr^-/- mice that were either Ddr1^+/+ or Ddr1^-/-were lethally irradiated and reconstituted with bone marrow from male Ddr1^+/+ or Ddr1^-/- donors yielding three groups of chimeric mice: Ddr1^+/+^?^+/+ (control); Ddr1^+/+^?^-/-^ (vessel wall deletion); and Ddr1^-/-^?^+/+ (bone marrow deletion). Chimeric mice were placed on an atherogenic diet for 12 weeks and hadsimilar body weights, total leukocyte counts, levels of Sry chimerism, and fasting plasma triglycerides at sacrifice, although total cholesterol was increased by 42% in Ddr1^+/+^?^-/- mice. Deletion of DDR1 inbone marrow derived cells (Ddr1^-/-^?^+/+) resulted in a 66% reduction in atherosclerotic lesion area in thedescending aorta compared to Ddr1^+/+^?^+/+ mice. Aortic sinus plaquesfrom Ddr1^-/-^?^+/+ mice were 36% smaller than Ddr1^+/+^?^+/+ plaques but the proportion of plaque area occupied by cells and matrix was similar between groups. By contrast, deletion of DDR1 in vessel wall cells (Ddr1^+/+^?^-/-) resulted in a 57% increase in atherosclerosis in the descending aorta. Furthermore, aortic sinus plaques from Ddr1^+/+ ^?^-/- mice had markedly increased fibrillar collagen and elastin accumulation compared to Ddr1^+/+^?^+/+ plaques resulting in a 156% increase in lesion area and reduced SMC and macrophage content. In conclusion, while DDR1 on bone marrow derived cells is required for plaque development, DDR1 expressed on vessel wall cells negatively regulates plaque matrix accumulation and results in the formation of larger lesions with altered cellular composition. Our data suggest a dual role for DDR1 in the regulationof atherogenesis and plaque matrix content.

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