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Biomedical subjects

Arjun Deb

Publications and source records attributed to Arjun Deb.

14 recordsLinked to original sources
PubMed2006

Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation.

We previously reported that intramyocardial injection of bone marrow-derived mesenchymal stem cells overexpressing Akt (MSC-Akt) efficiently repaired infarcted rat myocardium and improved cardiac function. Controversy still exists over the mechanisms by which MSC contribute to tissue repair. Herein, we tested if cellular fusion of MSC plays a determinant role in cardiac repair. We injected MSC expressing Cre recombinase, with or without Akt, into Cre reporter mice. In these mice, LacZ is expressed only after Cre-mediated excision of a loxP-flanked stop signal and is indicative of fusion. MSC engraftment within infarcted myocardium was transient but significantly enhanced by Akt. MSC fusion with cardiomyocytes was observed as early as 3 days, but was infrequent, and we found a low rate of differentiation of MSC into cardiomyocytes. MSC-Akt decreased infarct size at 3 days and restored early cardiac function. In conclusion, MSC-Akt improved early repair despite transient engraftment, low levels of cellular fusion, and differentiation. These new observations further confirm our recently reported data that early paracrine mechanisms mediated by MSC are responsible for enhancing the survival of existing myocytes and that Akt could alter the secretion of various cytokines and growth factors.

Animals↗
PubMed2005

Proapoptotic, antimigratory, antiproliferative, and antiangiogenic effects of commercial C-reactive protein on various human endothelial cell types in vitro: implications of contaminating presence of sodium azide in commercial preparation.

Recent experimental studies suggest C-reactive protein (CRP) may be a potential mediator of atherosclerosis and its complications. However, there is growing criticism of in vitro CRP studies that use commercial CRP preparations containing biologically active contaminants. The effects of commercial CRP, dialyzed commercial CRP (dCRP) to remove azide, and sodium azide (NaN3) alone at equivalent concentrations to the undialyzed preparation were tested at varying concentrations on human umbilical vein endothelial cells (HUVEC), circulating endothelial outgrowth cells (EOC), and endothelial progenitor cells (EPC) in vitro. CRP and NaN3 alone exhibited equivalent concentration-dependent, proapoptotic effects on HUVEC, EOC, and EPC (P<0.01 versus control), whereas dCRP had no such effect. Similarly, CRP and NaN3 alone caused equivalent concentration-dependent decreases in migration, proliferation, and matrigel tube formation (P<0.01 versus control) in EOC and HUVEC, whereas dCRP had absolutely no effect on these biological functions at any of the concentrations used. We conclude that proapoptotic, antiproliferative, antimigratory, and antiangiogenic effects of this commercial CRP preparation on a number of endothelial cell phenotypes in culture may be explained by the presence of sodium azide in this preparation. This study has implications for interpretation of in vitro studies using CRP preparations containing azide at equivalent or higher concentrations.

Angiogenesis Inhibitors↗
PubMed2005

Leptin receptor and functional effects of leptin in human endothelial progenitor cells.

Circulating endothelial progenitor cells (EPCs) may be involved in the maintenance of vascular homeostasis and their impairment may be conducive to vascular disease. We studied the role of an adipocyte-derived hormone, leptin, in the regulation of human EPC function. EPCs were grown from human circulating mononuclear cells. The presence of the leptin receptor and the functional effects of leptin in EPCs were investigated. EPCs stained positive for endothelial cell markers (Flk-1 and Tie-2 receptors) and the hematopoietic CD34 marker. The presence of the long form of the leptin receptor in EPCs was confirmed by Western blotting and with immunofluorescence. Leptin, at a physiological concentration of 10 ng/ml, significantly increased tube formation from 2.1+/-2.2 to 12.4+/-4.9 tubes/25 mm2. At a higher concentration of 100 ng/ml of leptin, tube formation was reduced compared to the lower concentration. This higher concentration of leptin also inhibited EPC migration, decreasing it from 0.45+/-0.14 to 0.28+/-0.12 mm/48 h. Leptin did not have any effect on EPC proliferation. In summary, the leptin receptor is present in human EPCs and leptin may affect EPC function, both in physiological and in hyperleptinemic conditions. These findings are relevant to leptin-mediated regulation of vasculogenesis in humans, and the association between hyperleptinemia and obesity with cardiovascular disease.

Adult↗
PubMed2005

Bone marrow-derived myofibroblasts are present in adult human heart valves.

BACKGROUND AND AIM OF THE STUDY: Endothelial, smooth muscle and cardiomyocyte chimerism has been shown to occur in the human heart. It is currently unknown whether the bone marrow contributes to cellular components of adult human heart valves. Here, it was determined whether bone marrow-derived smooth muscle-like cells (SMLC) are present in the heart valves of adult subjects. METHODS: By combining immunofluorescence staining and fluorescence in-situ hybridization (FISH) for X and Y chromosomes, the heart valves of gender-mismatched bone marrow transplant patients were examined for the presence of chimeric cells expressing calponin, a smooth muscle-specific protein. Concomitant staining for CD68 antigen was carried out to exclude cells of a monocytic lineage. RESULTS: The mean percentage of bone marrow-derived SMLC in valves was 0.28 +/- 0.03%, with the total proportion of chimeric cells estimated at 0.71 +/- 0.05%. The mean proportion of CD68+ cells was 0.33 +/- 0.05%. Not a single cell stained doubly for calponin and CD68 antigen. CONCLUSION: These data establish, for the first time, human bone marrow as a source of progenitor cells contributing to SMLC in adult human heart valves.

Adult↗
PubMed2004

Integrin profile and in vivo homing of human smooth muscle progenitor cells.

BACKGROUND: Recently, we identified circulating smooth muscle progenitor cells (SPCs) in human peripheral blood. The integrin profile of such progenitors is currently unknown and may affect their in vivo homing characteristics. In this study, we determined the integrin profile of vascular progenitors and SPC adhesion to extracellular matrix (ECM) proteins in vitro and in vivo. METHODS AND RESULTS: SPCs and endothelial progenitor cells (EPCs) were isolated from peripheral blood of healthy human subjects, and expression of surface integrins and adhesion to several vascular ECM proteins were determined. Homing of SPCs in vivo to specific ECM protein was determined by intracoronary infusion of fluorescent SPCs into porcine coronary arteries containing a fibronectin-coated mesh stent. SPCs had high expression of beta1 integrin, moderate expression of alpha1, low levels of alpha(v)beta3, and did not express alpha(v)beta5, beta2, alpha2beta1, or alpha4beta1 integrins. In contrast, EPCs had high expression of alpha2beta1, alpha(v)beta3, alpha(v)beta5, beta1, and alpha1 and minimal expression of alpha4beta1. Moreover, SPCs showed increased adherence to fibronectin and collagen type I compared with vitronectin, consistent with their integrin profile, and demonstrated a similar degree of in vivo attachment to fibronectin-coated mesh. CONCLUSIONS: These data for the first time show a spectrum of integrin expression on vascular progenitors and suggest the potential importance of integrins in mediating adherence of SPCs to specific ECM both in vitro and in vivo.

Animals↗
PubMed2004

Lipoprotein(a): new insights into mechanisms of atherogenesis and thrombosis.

Lipoprotein(a) (Lp[a]) continues to be a controversial molecule regarding its role in human vascular disease. Although the physiologic role of this molecule is still unclear, novel discoveries within the last few years have suggested numerous mechanisms whereby Lp(a) may contribute to atherosclerosis and its complications in human subjects. These effects may differentially occur in vascular tissue and circulating blood compartments. A complex interplay between tissue-specific effects is probably more relevant to the pathogenicity of this molecule than one single effect alone. This review briefly describes the structure of Lp(a) in relation to its biochemical function, summarizing the current literature on various pathophysiologic mechanisms of Lp(a)-induced vascular disease and the role of cell and tissue-specific effects in promoting atherogenesis and thrombosis.

Arteriosclerosis↗
PubMed2004

Myocardial-cell replacement: the science, the clinic and the future.

The traditional view of the heart is of an organ incapable of self-renewal. Hypotheses on the genesis of pump dysfunction in heart failure include emerging concepts of myocyte deficiency due to attritional ischemia and chronic apoptotic cell loss. In the adult heart, inadequate regenerative capacity was presumed to exist to counterbalance such extensive myocyte depletion. Preliminary animal and human studies now challenge the paradigm of myocardial regenerative inadequacy, with findings suggesting that noncardiac cells implanted in the dysfunctional heart augment myocyte deficiency and contractile mass. Data from these studies remain inconclusive and have generated much debate in the basic science and clinical communities. Controversial issues center on the scientific basis for regeneration in the heart, the mechanism of cell-therapy benefit and the safety and appropriateness of clinical trials based on these concepts. This review will evaluate the scientific basis for myocardial-cell replacement, with emphasis on current experimental and human data. We will explore unresolved questions of experimental design, mechanism of action, therapeutic strategies and safety concerns in an era of rising numbers of human cell-therapy trials. Prospects for more widespread clinical application of myocardial-cell replacement and future hurdles to be overcome in this field will also be addressed.

Animals↗
PubMed2003

Endothelial progenitor cells are decreased in blood of cardiac allograft patients with vasculopathy and endothelial cells of noncardiac origin are enriched in transplant atherosclerosis.

BACKGROUND: Recent studies in animals suggest that circulating recipient endothelial precursors may participate in the biology of transplant vasculopathy. It is currently unknown whether a similar interaction between recipient endothelial cells and the vessel wall occurs in human subjects undergoing allogeneic cardiac transplantation. METHODS AND RESULTS: Circulating endothelial cells and endothelial progenitor cells (EPCs) were quantified in 15 cardiac transplantation subjects with and without angiographic evidence of vasculopathy. In a separate series of experiments, the origin (donor or recipient) of transplant plaque endothelial cells was assessed in subjects who had undergone a gender-mismatched cardiac transplantation and had histological evidence of severe vasculopathy at the time of heart explantation. Circulating EPC outgrowth colonies in peripheral blood were significantly reduced in subjects with transplant vasculopathy compared with those without angiographic evidence of disease (EPC colony-forming units [CFUEPC]: 4.5+/-1.9 versus 15.1+/-3.7, P<0.05). There was no significant difference in circulating endothelial cell numbers as defined by day 4 culture acetylated LDL/lectin assay in either of these patient groups. In a separate group of 5 subjects who underwent gender-mismatched cardiac transplantation, there was a significant seeding of recipient endothelial cells (range: 1% to 24% of all luminal endothelial cells) in large-vessel lumen and adventitial microvessel lumen of arteriopathic vessels. No opposite-sex chimeric cells were observed in control gender-matched transplantation scenarios. CONCLUSIONS: These data suggest that the human cardiac transplant arteriopathy is associated with reduction in circulating endothelial precursors and with seeding of recipient-derived endothelial cells at the site of plaque development.

Adult↗
PubMed2003

Bone marrow-derived cardiomyocytes are present in adult human heart: A study of gender-mismatched bone marrow transplantation patients.

BACKGROUND: Recent studies have identified cardiomyocytes of extracardiac origin in transplanted human hearts, but the exact origin of these myocyte progenitors is currently unknown. METHODS AND RESULTS: Hearts of female subjects (n=4) who had undergone sex-mismatched bone marrow transplantation (BMT) were recovered at autopsy and analyzed for the presence of Y chromosome-positive cardiomyocytes. Four female gender-matched BMT subjects served as controls. Fluorescence in situ hybridization (FISH) for the Y chromosome was performed on paraffin-embedded sections to identify cells of bone marrow origin with concomitant immunofluorescent labeling for alpha-sarcomeric actin to identify cardiomyocytes. A total of 160 000 cardiomyocyte nuclei were analyzed approximating 20 000 nuclei per patient. The mean percentage of Y chromosome-positive cardiomyocytes in patients with sex-mismatched BMT was 0.23+/-0.06%. Not a single Y chromosome-positive cardiomyocyte was identified in any of the control patients. Immunofluorescent costaining for laminin and chromosomal ploidy analysis with FISH showed no evidence of either pseudonuclei or cell fusion in any of the chimeric cardiac myocytes identified. CONCLUSIONS: These data establish for the first time human bone marrow as a source of extracardiac progenitor cells capable of de novo cardiomyocyte formation.

Actins↗
PubMed2002

Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene.

Approximately 10% of catecholamine-secreting tumors are malignant, and 10% are familial. These tumors have been associated with several hereditary syndromes, including multiple endocrine neoplasia type 2, von Hippel-Lindau syndrome, neurofibromatosis type 1, and familial paraganglioma. Mutations in succinate dehydrogenase (SDH) subunit genes have been identified in some kindreds with catecholamine-secreting tumors. In 1972 at the Mayo Clinic, a metastatic catecholamine-secreting paraganglioma was diagnosed in a 32-yr-old man. In 1979, 7 yr after the initial surgical treatment, a lytic metastasis to the left femur was found and was treated with local external radiotherapy. Locally metastatic abdominal catecholamine-secreting paragangliomas were diagnosed in the patient's 27-yr-old son. Analyses of the VHL, RET, SDHD, and SDHC genes revealed no mutations. However, a missense point mutation was detected in the SDHB gene: c.725G-->A in exon 7, which alters a conserved arginine at amino acid position 242 to a histidine (R242H). Sequencing of the SDHB gene in the tumors did not reveal any somatic mutations or loss of heterozygosity of the remaining allele. Thirty years after the initial diagnosis, the father is one of the longest living survivors of malignant catecholamine-secreting paraganglioma. Our findings indicate that mutations in SDHB may be associated with metastatic, yet clinically indolent, abdominal paraganglioma in some families.

Adult↗
PubMedDate not supplied

Primary synovial sarcoma of the mitral valve.

Primary cardiac synovial sarcoma is a rare malignancy, comprising approximately 5% of cardiac sarcomas and less than 0.1% of all primary cardiac tumors. Herein, we describe a synovial sarcoma arising on the anterior mitral leaflet in a 66-year-old man. The histopathologic diagnosis was supported by the immunohistochemical profile and the presence of the SYT-SSX1 fusion transcript identified by molecular genetic studies.

Aged↗