Canadian Blood Services R and D

Edmonton, Canada

Canadian Blood Services R and D

Edmonton, Canada

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Xu P.,University of Alberta | Xu P.,Canadian National Institute For Nanotechnology | Gul-Uludag H.,University of Alberta | Gul-Uludag H.,IntelligentNano Inc. | And 12 more authors.
Biotechnology Letters | Year: 2012

Low-intensity pulsed ultrasound (LIPUS) stimulated the viability, proliferation and differentiation of hematopoietic stem/progenitor cells (HSPC) from fresh and cryopreserved peripheral blood leukapheresis product, as well as cord blood when applied for 10 min each day for 4 days. Cell viability, proliferation and differentiation were assessed on day 5 by viable cell counting, MTS proliferation assay, flow cytometry, and colony-forming unit assay. LIPUS stimulation: (i) enhanced the proliferation of fresh HSPC and maintained the viability of cryopreserved HSPC in vitro; (ii) did not affect the percentage of CD34 + and CD14 + cells; and (iii) enhanced burst-forming unit-erythroid colony formation. Hence, we suggest that this novel LIPUS stimulation approach might enhance the efficacy of clinical transplantation and cellular therapies using HSPC. © 2012 Springer Science+Business Media B.V.

Marquez-Curtis L.A.,Canadian Blood Services R and D | Shirvaikar N.,Canadian Blood Services R and D | Robert Turner A.,University of Alberta | Mirza I.,University of Alberta | And 4 more authors.
Cancers | Year: 2012

Membrane type-1 matrix metalloproteinase (MT1-MMP) has been implicated in tumor invasion, as well as trafficking of normal hematopoietic cells, and acts as a physiologic activator of proMMP-2. In this study we examined MT1-MMP expression in primary acute myeloid leukemia (AML) cells. Because tumor necrosis factor (TNF)-α is known to be elevated in AML, we also investigated the effect of TNF-α on MT1-MMP expression. We found (i) MT1-MMP mRNA expression in 41 out of 43 primary AML samples tested; (ii) activation of proMMP-2 in co-cultures of AML cells with normal bone marrow stromal cells; and (iii) inhibition of proMMP-2 activation and trans-Matrigel migration of AML cells by gene silencing using MT1-MMP siRNA. Moreover, recombinant human TNF-α upregulated MT1-MMP expression in AML cells resulting in enhanced proMMP-2 activation and trans-Matrigel migration. Thus, AML cells express MT1-MMP and TNF-α enhances it leading to increased MMP-2 activation and most likely contributing to the invasive phenotype. We suggest that MT1-MMP, together with TNF-α, should be investigated as potential therapeutic targets in AML. © 2012 by the authors; licensee MDPI, Basel, Switzerland.

Gul H.,Canadian Blood Services R and D | Gul H.,University of Alberta | Marquez-Curtis L.A.,Canadian Blood Services R and D | Jahroudi N.,University of Alberta | And 3 more authors.
Leukemia Research | Year: 2010

We recently reported that the histone deacetylase inhibitor, valproic acid (VPA), increases CXCR4 receptor expression and function in cord blood hematopoietic stem/progenitor cells (HSPC) and the immature, highly CD34-positive AML cell lines KG-1a and KG-1. In this study, we investigated whether VPA influences CXCR4 in CD34-negative AML cell lines (promyelocytic HL-60 and monocytic THP-1), as well as both CD34-positive and CD34-negative primary AML cells. We found that VPA (i) diminishes CXCR4 expression and chemotaxis in HL-60 cells and in the CD34-negative subtypes of primary AML cells and (ii) increases CXCR4 expression and function in the highly CD34-positive subtypes of primary AML cells. Hence, we suggest that VPA exerts different effects on CXCR4 depending on cell maturation status, and this novel finding may have important implications for AML therapy. © 2009 Elsevier Ltd. All rights reserved.

Shirvaikar N.,Canadian Blood Services R and D | Shirvaikar N.,University of Alberta | Marquez-Curtis L.A.,Canadian Blood Services R and D | Ratajczak M.Z.,University of Louisville | And 2 more authors.
Stem Cells and Development | Year: 2011

One of the hurdles of cord blood (CB) transplantation is delayed hematopoietic engraftment. Previously, we demonstrated that supernatants isolated from leukapheresis products of granulocyte-colony stimulating factor (G-CSF)-mobilized patients primed the homing of hematopoietic stem/progenitor cells (HSPC) by enhancing their chemotactic responses to stromal cell-derived factor (SDF)-1 and stimulating matrix metalloproteinases (MMPs) MMP-2 and MMP-9. Since membrane type 1 (MT1)-MMP activates proMMP-2 and localizes proteolytic activity at the leading edge of migrating cells, in this study we investigated whether MT1-MMP contributes to the priming of the homing-related responses of CB HSPC. We found that components of supernatants of leukapheresis products such as hyaluronic acid and thrombin (i) increase the secretion of proMMP-9 and transcription and protein synthesis of MT1-MMP in CB CD34 + cells; (ii) increase the levels of active MMP-2 in co-cultures of CD34 + cells with endothelial cells; (iii) increase the chemoinvasion across reconstituted basement membrane Matrigel of CD34 + cells toward a low SDF-1 gradient (20 ng/mL); and (iv) activate mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and Rac-1 signaling pathways. Inhibition of phosphatidylinositol 3-kinase and Rac-1 by their respective inhibitors LY290042 and NSC23766 attenuated MT1-MMP expression in CB CD34 + cells, leading to reduced proMMP-2 activation and HSPC trans-Matrigel chemoinvasion toward SDF-1. Thus, our data suggest that MT1-MMP plays an important role in the homing-related responses of HSPC, and we propose that pretreatment of CB HSPC with hyaluronic acid or thrombin before transplantation could improve their homing and engraftment. © 2011 Mary Ann Liebert, Inc.

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