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  • 1
    Keywords: IN-VIVO ; BONE-MARROW ; PROGENITOR CELLS ; VASCULATURE ; FLOW-CYTOMETRY ; PERIPHERAL-BLOOD ; GENE-THERAPY ; PRECURSORS ; PROTOCOL ; MESENCHYMAL STEM-CELLS
    Abstract: BACKGROUND AIMS: Endothelial progenitor cells (EPCs) specifically home to sites of malignant growth, rendering them attractive for anti-cancer therapies. Data are conflicting on the phenotype and quantitative contribution toward tumor angiogenesis based on differing culture assays to outgrow EPCs. To evaluate the origin and early phenotype of EPCs and to define a population with enhanced tumor-targeting capacity, we evaluated a hierarchy of cord blood-derived EPCs modeling the multi-step nature of tumor homing. METHODS: CD34(+) mononuclear cells were isolated from fresh cord blood and cultured to derive endothelial colony-forming cells (ECFCs). Human umbilical vein endothelial cells (HUVECs) served as control. Using intra-vital microscopy, the recruitment was analyzed in mice bearing C6 xenografts. Adhesion, migration, transmigration and differentiation were further addressed. RESULTS: Within the primary passage, ECFCs underwent a rapid maturation from a CD45(+) and CD31(+) phenotype to a CD45(-) and endothelial marker positive phenotype. Assessing in vivo tumor recruitment, ECFCs had the highest activity in all steps analyzed. In vitro, ECFCs demonstrated significantly higher adhesion under static and flow conditions. Similarly, ECFCs exhibited highest migratory and trans-migratory activity toward tumor-conditioned medium. On subcutaneous implantation, only ECFCs formed blood vessels covered with perivascular cells, similar to HUVECs. CONCLUSIONS: Our study indicates that ECFCs emerge from a CD45(+) and CD31(+) progenitor and rapidly mature in culture. ECFCs have a significantly higher potential for tumor targeting than non-cultured CD34(+) cells and HUVECs. They are ideal candidates for future cell-based anti-cancer therapies.
    Type of Publication: Journal article published
    PubMed ID: 23491253
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  • 2
    Keywords: CELLS ; EXPRESSION ; tumor ; BLOOD ; CELL ; Germany ; human ; IN-VIVO ; THERAPY ; VIVO ; FOLLOW-UP ; POPULATION ; GENE ; DRUG ; gene therapy ; MICE ; TRANSDUCTION ; gene transfer ; GENE-TRANSFER ; MARKER ; FLOW ; BIOLOGY ; MATURATION ; TARGET ; HUMANS ; resistance ; VECTOR ; MARKERS ; STEM-CELLS ; FLOW-CYTOMETRY ; HEMATOPOIETIC PROGENITOR CELLS ; HEMATOPOIETIC-CELLS ; PERIPHERAL-BLOOD ; MULTIDRUG-RESISTANCE ; MULTIDRUG-RESISTANCE-1 GENE ; P-GLYCOPROTEIN ; EX-VIVO ; LINEAGE ; RESISTANCE 1 GENE ; SEVERE COMBINED IMMUNODEFICIENCY ; DRUGS ; REPOPULATING CELLS ; in vivo ; progenitor cell ; VARIETIES ; MDR1 gene therapy ; myeloid differentiation ; P-GLYCOPROTEIN EXPRESSION ; peripheral blood ; TRANSDUCED CELLS
    Abstract: Background The objective of multidrug resistance-1 (MDR1) gene therapy is protection of the myeloid cell lineage. It is therefore important to examine the effect of retroviral transduction on myeloid maturation. Transfer of the human MDR1 gene can confer resistance to a variety of cytostatic drugs. For a safe application in humans it is paramount to follow-up the development of transduced cells. Methods We transduced human mobilized peripheral blood progenitor cells (PBPC) with a viral vector containing the human MDR1 cDNA and transplanted the transduced cells into non-obese diabetic severe combined immunodeficient (NOD/SCID) mice. The progeny of the transduced cells was analyzed in detail by flow cytometry. Results A detailed analysis by four-color flow cytometry showed that MDR1 transgene-expressing CD33(+) myeloid cells were preferentially negative for the maturation-associated myeloid markers CD11b and CD10, while the untransduced CD33(+) myeloid cells expressed significantly higher proportions of these Ag (PB 〈 0.01 each). There was no difference in the expression of B- or T-lymphoid Ag among the MDR1-transduced and untransduced lymphoid cells. Discussion These data indicate that retroviral MDR1 gene transfer results in preferential P-glycoprotein expression in myeloid progenitor cells, which is the target cell population for myelotoxicity of cytostatic drugs
    Type of Publication: Journal article published
    PubMed ID: 17148033
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  • 3
    Keywords: CELLS ; EXPRESSION ; IN-VITRO ; proliferation ; tumor ; IN-VIVO ; MODEL ; THERAPY ; DISEASE ; DISEASES ; GENE ; MICE ; TRANSPLANTATION ; BONE-MARROW ; NOD/Scid mice ; MOUSE ; MOUSE MODEL ; cord blood ; ONCOLOGY ; interaction ; BLOOD PROGENITOR CELLS ; SDF-1 ; FATE ; REPOPULATION ; mesenchymal stromal cells ; ENGRAFTMENT ; NOD/SCID/B2M(NULL) MICE
    Abstract: Abstract Background aims. Transplantation of allogeneic hematopoietic stem cells (HSC) within the framework of hematologic oncology or inherited diseases may be associated with complications such as engraftment failure and long-term pancytopenia. HSC engraftment can be improved, for example by co-transplantation with mesenchymal stem cells (MSC). Recently, a new multipotent MSC line from umbilical cord blood, unrestricted somatic stem cells (USSC), has been described. It was demonstrated that USSC significantly support proliferation of HSC in an in vitro feeder layer assay. Methods. A NOD/SCID mouse model was used to assess the effect of USSC on co-transplanted CD34(+) cells and look for the fate of transplanted USSC. The migration potential of USSC was studied in a Boyden chamber migration assay and in vivo. Quantitative real-time polymerase chain reaction (qRT-PCR) for CXCR4, CD44, LFA1, CD62L, VLA4, RAC2, VLA5A and RAC1 were performed. NMR1 nu/nu mice were used for a tumorigenicity test. Results. After 4 weeks, homing of human cells (CD45(+)) to the bone marrow of NOD/SCID mice was significantly increased in mice co-transplanted with CD34(+) cells and USSC (median 30.9%, range 7-50%) compared with the CD34(+) cell-only control group (median 5.9%, range 3-10%; P = 0.004). Homing of USSC could not be shown in the bone marrow. A cell-cell contact was not required for the graft enhancing effect of USSC. An in vivo tumorigenicity assay showed no tumorigenic potential of USSC. Conclusions. This pre-clinical study clearly shows that USSC have an enhancing effect on engraftment of human CD34(+) cells. USSC are a safe graft adjunct.
    Type of Publication: Journal article published
    PubMed ID: 20950214
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