Maternal High-Fat Diet Persistently Alters Bone Marrow Immune Cell Proportions and Function in a Nonhuman Primate Model

Background: Atherosclerosis and its complications (myocardial infarction, stroke, peripheral vascular disease) are the major cause of morbidity and mortality in developed countries. Despite considerable efforts, the underlying pathomechanisms remain incompletely understood. In this study, we examined the role of a matricellular protein termed CCN3 in the pathogenesis of atherosclerosis. Methods and Results: To investigate whether CCN3 deficiency affects the development of atherosclerosis, control (ApoE-/-) and CCN3/ApoE double knockout mice were subjected to high fat diet feeding. In response to 16-week high fat diet feeding, the aortas of CCN3/ApoE double knockout (DKO) mice demonstrated exquisite susceptibility to atherosclerosis formation as evidenced by significantly increased size of aortic lipid-rich plaques in aortic roots, arch, thoracic and abdominal aorta. Concomitant with this, the atherosclerosis phenotype of DKO mice was manifested as follows: (1) a profoundly enhanced immune cell infiltration; (2) significantly increased expression of inflammatory markers; (3) heightened reactive oxygen species generation. Next, to address the cellular contributor(s) within or outside of the vessel wall responsible for the atherosclerosis phenotype, we performed reciprocal bone marrow transplantation (BMT) experiments. Transplantation of DKO bone marrow to ApoE-/- mice resulted in an increase of atherosclerosis formation, while transplantation of ApoE-/- marrow to DKO mice caused a reduction of atherosclerosis. These results indicate CCN3 deficiency in the bone marrow plays a major role in the development of atherosclerosis. Mechanistically, our cell-based studies in isolated macrophages demonstrated that CCN3 deficiency leads to an increase of lipid uptake and foam cell formation, an effect attributed to the modulation of key factors (e.g., increase of CD36, decrease of ABCG1) involved in lipoprotein transport. Conclusion: These results demonstrate bone marrow-derived CCN3 as an essential regulator of atherosclerosis and suggest the potential for future therapeutic strategies by manipulating CCN3 levels.

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Use of Allogeneic Bone Marrow Labeled with Neomycin Resistance Gene to Examine Bone Marrow-Derived Chimerism in Experimental Organ Transplantation

Cell Transplantation ◽

10.1177/096368979700600403 ◽

1997 ◽

Vol 6 (4) ◽

pp. 369-376 ◽

Cited By ~ 1

Author(s):

J. P. Smith ◽

J. Kasten-Jolly ◽

L. Rebellato ◽

Carl E. Haisch ◽

Judith M. Thomas

Keyword(s):

Bone Marrow ◽

Resistance Gene ◽

Nonhuman Primate ◽

Antithymocyte Globulin ◽

Molecular Techniques ◽

Allogeneic Bone ◽

Nonhuman Primate Model ◽

Primate Model ◽

Neomycin Resistance Gene ◽

Neomycin Resistance

Posttransplant infusion of viable donor bone marrow cells (DBMC) has been shown in our previous studies to promote acceptance of incompatible kidney allografts in rhesus monkeys after treatment with polyclonal antithymocyte globulin to deplete peripheral T-lymphocytes. In this nonhuman primate model, the infusion of the DBMC is requisite for the induction of functional graft tolerance and specific MLR and CTLp unresponsiveness, although the relevant role and fate of bone marrow-derived chimeric cells is uncertain. Standard immunological and molecular techniques applied to this monkey model are unable to differentiate between chimeric cells derived from the infused DBMC and those derived from allograft-borne passenger leukocyte emigrants. To distinguish chimerism due to infused DBMC, we transduced DBMC with a functional neomycin resistance gene (Neor) using the retroviral vector pHSG-Neo. Neor-Mransduced BMC were infused into recipients approximately 2 wk after kidney transplantation and treatment with rabbit antithymocyte globulin. No maintenance immunosuppressive drugs were given. Genomic DNA isolated from peripheral blood leukocytes was used to monitor the presence of Neor-positive cells. Tissue samples obtained at necropsy also were assessed for Neor-positive chimeric cells. The presence of DBMC-derived chimerism was assessed by polymerase chain reaction using Neor sequence-specific primers (PCR-SSP). Chimerism was detectable in recipient tissues at various times for up to 6 mo after DBMC infusion. These studies using gene transduction methodology indicate that a stable genetic marker can provide capability to examine DBMC-derived chimerism for prolonged periods in a nonhuman primate model. This approach should facilitate future studies in preclinical models to study the role and type of chimeric cell lineages in relation to functional allograft tolerance.

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Histopathological Features of the Development of Intestine and Mesenteric Lymph Node Injury in a Nonhuman Primate Model of Partial-body Irradiation with Minimal Bone Marrow Sparing

Health Physics ◽

10.1097/hp.0000000000000932 ◽

2019 ◽

Vol 116 (3) ◽

pp. 426-446 ◽

Cited By ~ 9

Author(s):

George A. Parker ◽

Na Li ◽

Kyle Takayama ◽

Catherine Booth ◽

Gregory L. Tudor ◽

...

Keyword(s):

Bone Marrow ◽

Lymph Node ◽

Nonhuman Primate ◽

Mesenteric Lymph Node ◽

Nonhuman Primate Model ◽

Primate Model ◽

Histopathological Features ◽

Mesenteric Lymph ◽

Partial Body ◽

Bone Marrow Sparing

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Endometrial Stromal Cells and Immune Cell Populations Within Lymph Nodes in a Nonhuman Primate Model of Endometriosis

Reproductive Sciences ◽

10.1177/1933719110397210 ◽

2011 ◽

Vol 18 (8) ◽

pp. 747-754 ◽

Cited By ~ 17

Author(s):

A. J. Hey-Cunningham ◽

A. T. Fazleabas ◽

A. G. Braundmeier ◽

R. Markham ◽

I. S. Fraser ◽

...

Keyword(s):

Lymph Nodes ◽

Nonhuman Primate ◽

Stromal Cells ◽

Immune Cell ◽

Cell Populations ◽

Nonhuman Primate Model ◽

Primate Model ◽

Endometrial Stromal Cells

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Exploring the Innate Immunological Response of an Alternative Nonhuman Primate Model of Infectious Disease; the Common Marmoset

Journal of Immunology Research ◽

10.1155/2014/913632 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

M. Nelson ◽

M. Loveday

Keyword(s):

Infectious Disease ◽

Immune Response ◽

Nonhuman Primate ◽

Immune Cell ◽

Common Marmoset ◽

Cell Types ◽

Nonhuman Primate Model ◽

Primate Model ◽

The Common ◽

Activation Status

The common marmoset (Callithrix jacchus) is increasingly being utilised as a nonhuman primate model for human disease, ranging from autoimmune to infectious disease. In order to fully exploit these models, meaningful comparison to the human host response is necessary. Commercially available reagents, primarily targeted to human cells, were utilised to assess the phenotype and activation status of key immune cell types and cytokines in naive and infected animals. Single cell suspensions of blood, spleen, and lung were examined. Generally, the phenotype of cells was comparable between humans and marmosets, with approximately 63% of all lymphocytes in the blood of marmosets being T cells, 25% B-cells, and 12% NK cells. The percentage of neutrophils in marmoset blood were more similar to human values than mouse values. Comparison of the activation status of cells following experimental systemic or inhalational infection exhibited different trends in different tissues, most obvious in cell types active in the innate immune response. This work significantly enhances the ability to understand the immune response in these animals and fortifies their use as models of infectious disease.

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