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

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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Discoidin Domain Receptor 1 on Bone Marrow–Derived Cells Promotes Macrophage Accumulation During Atherogenesis

Circulation Research ◽

10.1161/circresaha.109.207357 ◽

2009 ◽

Vol 105 (11) ◽

pp. 1141-1148 ◽

Cited By ~ 52

Author(s):

Christopher Franco ◽

Karen Britto ◽

Eric Wong ◽

Guangpei Hou ◽

Su-Ning Zhu ◽

...

Keyword(s):

Bone Marrow ◽

Discoidin Domain Receptor ◽

Bone Marrow Derived Cells ◽

Discoidin Domain Receptor 1 ◽

Macrophage Accumulation

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Abstract 366: Biglycan Deficiency Does Not Affect Angiotensin Ii-induced Atherosclerosis but Promotes Aortic Aneurysms Formation

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a366 ◽

2013 ◽

Vol 33 (suppl_1) ◽

Author(s):

Tao Tang ◽

Joel C Thompson ◽

Patriticia G Wilson ◽

Meghan H Yoder ◽

Lisa R Tannock

Keyword(s):

Aortic Rupture ◽

Critical Role ◽

Atherosclerotic Lesion ◽

Western Diet ◽

Aortic Aneurysms ◽

Lesion Area ◽

Abdominal Aneurysm ◽

Aortic Sinus ◽

Face Surface

Background Proteoglycans play a critical role in the development of atherosclerosis due to their ability to bind and retain atherogenic lipoproteins. Of all the vascular proteoglycans, biglycan has been shown to be the one most closely associated with apolipoprotein B. Our previous studies showed that angII increases vascular biglycan content and predisposes to diet-induced atherosclerosis in Ldlr null mice. The purpose of this study was to determine whether biglycan deficiency protected against angII induced atherosclerosis in vivo. Methods and Results Bgn KO or WT mice, crossed to Ldlr null (C57B/6 background), were infused with angII (1000 ng/kg/min) or saline for 28 days followed by 6-week western diet feeding. Bgn KO mice showed no difference in atherosclerotic lesion area at either aortic sinus or en face surface. Unexpectedly, Bgn KO mice exhibited a striking mortality (77% for males and 48% for females) due to aortic rupture upon angII infusion. Thus, a lower dose of angII was then infused to mice to study atherosclerosis. There was no difference in lesion area between Bgn KO or WT mice under angII (500 ng/kg/min) infusion followed by 6-week western diet feeding or under one-year normal chow feeding without angII infusion. However, angII (500 ng/kg/min) still induced greater aortic rupture in Bgn KO mice (30% for males and 13% for females) than in WT mice (0% for both gender). Besides rupture, 7 Bgn KO mice out of 35 also developed aneurysm at mid-thoracic aorta whereas only 1 Bgn WT mouse out of 25 developed abdominal aneurysm after angII (500 ng/kg/min) infusion. Therefore, our study demonstrated that biglycan deficiency did not affect atherosclerotic lesion development, but induced a striking aneurysm phenotype upon angII infusion.

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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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Eosinophilia in chimeric mice infected withToxocara canis

Journal of Helminthology ◽

10.1017/s0022149x00009925 ◽

1987 ◽

Vol 61 (2) ◽

pp. 157-162

Author(s):

Kazuo Sugane ◽

Tadashi Matsuura

Keyword(s):

Bone Marrow ◽

Time Course ◽

Toxocara Canis ◽

Oral Infection ◽

Chimeric Mice ◽

Strain Variation ◽

Radiation Chimeras ◽

Low Responder ◽

Bone Marrow Derived Cells

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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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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Receptor-interacting protein kinase 3 promotes platelet activation and thrombosis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1610963114 ◽

2017 ◽

Vol 114 (11) ◽

pp. 2964-2969 ◽

Cited By ~ 15

Author(s):

Yiwen Zhang ◽

Jian Zhang ◽

Rong Yan ◽

Jingluan Tian ◽

Yang Zhang ◽

...

Keyword(s):

Bone Marrow ◽

Protein Kinase ◽

Platelet Activation ◽

Thrombus Formation ◽

Critical Role ◽

In Vivo Model ◽

Clot Retraction ◽

Interacting Protein ◽

Bone Marrow Derived Cells

Previous studies have shown that receptor-interacting protein kinase 3 (RIP3) is involved in many important biological processes, including necroptosis, apoptosis, and inflammation. Here we show that RIP3 plays a critical role in regulating platelet functions and in vivo thrombosis and hemostasis. Tail bleeding times were significantly longer in RIP3-knockout (RIP3−/−) mice compared with their wild-type (WT) littermates. In an in vivo model of arteriole thrombosis, mice lacking RIP3 exhibited prolonged occlusion times. WT mice repopulated with RIP3−/− bone marrow-derived cells had longer occlusion times than RIP3−/− mice repopulated with WT bone marrow-derived cells, suggesting a role for RIP3-deficient platelets in arterial thrombosis. Consistent with these findings, we observed that RIP3 was expressed in both human and mice platelets. Deletion of RIP3 in mouse platelets caused a marked defect in aggregation and attenuated dense granule secretion in response to low doses of thrombin or a thromboxane A2 analog, U46619. Phosphorylation of Akt induced by U46619 or thrombin was diminished in RIP3−/− platelets. Moreover, RIP3 interacted with Gα13. Platelet spreading on fibrinogen and clot retraction were impaired in the absence of RIP3. RIP3 inhibitor dose-dependently inhibited platelet aggregation in vitro and prevented arterial thrombus formation in vivo. These data demonstrate a role for RIP3 in promoting in vivo thrombosis and hemostasis by amplifying platelet activation. RIP3 may represent a novel promising therapeutic target for thrombotic diseases.

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Increased Cell and Matrix Accumulation During Atherogenesis in Mice With Vessel Wall–Specific Deletion of Discoidin Domain Receptor 1

Circulation Research ◽

10.1161/circresaha.109.213637 ◽

2010 ◽

Vol 106 (11) ◽

pp. 1775-1783 ◽

Cited By ~ 44

Author(s):

Christopher Franco ◽

Pamela J. Ahmad ◽

Guangpei Hou ◽

Eric Wong ◽

Michelle P. Bendeck

Keyword(s):

Vessel Wall ◽

Discoidin Domain Receptor ◽

Matrix Accumulation ◽

Discoidin Domain Receptor 1 ◽

Specific Deletion

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Pre-metastatic Niche Formation in Different Organs Induced by Tumor Extracellular Vesicles

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.733627 ◽

2021 ◽

Vol 9 ◽

Author(s):

Qi Dong ◽

Xue Liu ◽

Ke Cheng ◽

Jiahao Sheng ◽

Jing Kong ◽

...

Keyword(s):

Bone Marrow ◽

Extracellular Vesicles ◽

Critical Role ◽

Matrix Remodeling ◽

Metastatic Niche ◽

Primary Tumors ◽

Target Organs ◽

Bone Marrow Derived Cells ◽

Metastatic Microenvironment ◽

Underlying Mechanisms

Primary tumors selectively modify the microenvironment of distant organs such as the lung, liver, brain, bone marrow, and lymph nodes to facilitate metastasis. This supportive metastatic microenvironment in distant organs was termed the pre-metastatic niche (PMN) that is characterized by increased vascular permeability, extracellular matrix remodeling, bone marrow-derived cells recruitment, angiogenesis, and immunosuppression. Extracellular vesicles (EVs) are a group of cell-derived membranous structures that carry various functional molecules. EVs play a critical role in PMN formation by delivering their cargos to recipient cells in target organs. We provide an overview of the characteristics of the PMN in different organs promoted by cancer EVs and the underlying mechanisms in this review.

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