Biomedical subjects

Eva Cukerman

Publications and source records attributed to Eva Cukerman.

4 recordsLinked to original sources

PubMed2006

Stem cell factor receptor induces progenitor and natural killer cell-mediated cardiac survival and repair after myocardial infarction.

Inappropriate cardiac remodeling and repair after myocardial infarction (MI) predisposes to heart failure. Studies have reported on the potential for lineage negative, steel factor positive (c-kit+) bone marrow-derived hematopoetic stem/progenitor cells (HSPCs) to repair damaged myocardium through neovascularization and myogenesis. However, the precise contribution of the c-kit signaling pathway to the cardiac repair process has yet to be determined. In this study, we sought to directly elucidate the mechanistic contributions of c-kit+ bone marrow-derived hematopoetic stem/progenitor cells in the maintenance and repair of damaged myocardium after MI. Using c-kit-deficient mice, we demonstrate the importance of c-kit signaling in preventing ventricular dilation and hypertrophy, and the maintenance of cardiac function after MI in c-kit-deficient mice. Furthermore, we show phenotypic rescue of cardiac repair after MI of c-kit-deficient mice by bone marrow transplantation of wild-type HSPCs. The transplanted group also had reduced apoptosis and collagen deposition, along with an increase in neovascularization. To better understand the mechanisms underlying this phenotypic rescue, we investigated the gene expression pattern within the infarcted region by using microarray analysis. This analysis suggested activation of inflammatory pathways, specifically natural killer (NK) cell-mediated mobilization after MI in rescued hearts. This finding was confirmed by immunohistology and by using an NK blocker. Thus, our investigation revealed a previously uncharacterized role for c-kit signaling after infarction by mediating bone marrow-derived NK and angiogenic cell mobilization, which contributes to improved remodeling and cardiac function after MI.

Animals↗

PubMed2005

The remote ischemic preconditioning stimulus modifies gene expression in mouse myocardium.

BACKGROUND: We have recently demonstrated that remote ischemic preconditioning reduces ischemia-reperfusion injury in animal models. The mechanisms by which the remote ischemic preconditioning stimulus exerts its effect remain to be fully defined, and its effect on myocardial gene expression is unknown. We tested the hypothesis that remote ischemic preconditioning modifies myocardial gene expression immediately after the remote ischemic preconditioning stimulus (early phase) and 24 hours later (late phase). METHODS: Twenty male (C57BL/6) 10- to 12-week-old mice were randomized into 4 groups: group 1 (control, early phase; n = 5), group 2 (remote ischemic preconditioning, early phase; n = 5), group 3 (control, late phase; n = 5), and group 4 (remote ischemic preconditioning, late phase; n = 5). Groups 2 and 4 underwent remote ischemic preconditioning induced by 6 cycles of 4 minutes of occlusion and 4 minutes of reperfusion of the femoral artery. Groups 1 and 2 were killed 15 minutes after completion of sham procedure or remote ischemic preconditioning, and the hearts were removed and frozen in liquid nitrogen. Groups 3 and 4 were killed 24 hours after remote ischemic preconditioning, and the hearts were harvested in the same fashion. Gene expression was assessed by using the Affymetrix MG-430A chip (Affymetrix, Santa Clara, Calif). RESULTS: Data filtering (P < .05, analysis of variance) and hierarchic 2-way clustering identified significant differences in gene expression among the 4 groups. Genes involved in protection against oxidative stress (eg, Hadhsc, Prdx4, and Fabp4) and cytoprotection (Hsp73) were upregulated, whereas many proinflammatory genes (eg, Egr-1 and Dusp 1 and 6) were suppressed. CONCLUSION: A simple remote ischemic preconditioning stimulus modifies myocardial gene expression by upregulating cardioprotective genes and suppressing genes potentially involved in the pathogenesis of ischemia-reperfusion injury.

Animals↗

PubMed2004

The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans.

Remote ischemic preconditioning (IPC) reduces tissue injury caused by ischemia-reperfusion (IR) in distant organs. We tested the hypothesis that remote IPC (rIPC) modifies inflammatory gene transcription in humans. Using a microarray method, we demonstrated that a simple model of brief forearm ischemia suppresses proinflammatory gene expression in circulating leukocytes. Genes encoding key proteins involved in cytokine synthesis, leukocyte chemotaxis, adhesion and migration, exocytosis, innate immunity signaling pathways, and apoptosis were all suppressed within 15 min (early phase IPC) and more so after 24 h (second window IPC). Changes in leukocyte CD11b expression measured by flow cytometry mirrored this pattern, with there being a significant (P = 0.01) reduction at 24 h. The results of this study show that the rIPC stimulus modifies leukocyte inflammatory gene expression. This effect may contribute to the protective effect of IPC against IR injury and may have broader implications in other inflammatory processes. This is the first study of human gene expression following rIPC stimulus. rIPC stimulus suppressed proinflammatory gene transcription in human leukocytes.

Adult↗

PubMed2002

A molecular compendium of genes expressed in multiple myeloma.

We have created a molecular resource of genes expressed in primary malignant plasma cells using a combination of cDNA library construction, 5' end single-pass sequencing, bioinformatics, and microarray analysis. In total, we identified 9732 nonredundant expressed genes. This dataset is available as the Myeloma Gene Index (www.uhnres.utoronto.ca/akstewart_lab).Predictably, the sequenced profile of myeloma cDNAs mirrored the known function of immunoglobulin-producing, high-respiratory rate, low-cycling, terminally differentiated plasma cells. Nevertheless, approximately 10% of myeloma-expressed sequences matched only entries in the database of Expressed Sequence Tags (dbEST) or the high-throughput genomic sequence (htgs) database. Numerous novel genes of potential biologic significance were identified. We therefore spotted 4300 sequenced cDNAs on glass slides creating a myeloma-enriched microarray. Several of the most highly expressed genes identified by sequencing, such as a novel putative disulfide isomerase (MGC3178), tumor rejection antigen TRA1, heat shock 70-kDa protein 5, and annexin A2, were also differentially expressed between myeloma and B lymphoma cell lines using this myeloma-enriched microarray. Furthermore, a defined subset of 34 up-regulated and 18 down-regulated genes on the array were able to differentiate myeloma from nonmyeloma cell lines. These not only include genes involved in B-cell biology such as syndecan, BCMA, PIM2, MUM1/IRF4, and XBP1, but also novel uncharacterized genes matching sequences only in the public databases. In summary, our expressed gene catalog and myeloma-enriched microarray contains numerous genes of unknown function and may complement other commercially available arrays in defining the molecular portrait of this hematopoietic malignancy. GenBank Accession numbers include BF169967-BF176369, BF185966-BF185969, and BF177280-BF177455.

Amino Acid Sequence↗