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  • 1
    Abstract: Mesenchymal stem cells (MSC) comprise a promising tool for cellular therapy. These cells are usually culture expanded prior to their application. However, a precise molecular definition of MSC and the sequel of long-term in vitro culture are yet unknown. In this study, we have addressed the impact of replicative senescence on human MSC preparations. Within 43 to 77 days of cultivation (7 to 12 passages), MSC demonstrated morphological abnormalities, enlargement, attenuated expression of specific surface markers, and ultimately proliferation arrest. Adipogenic differentiation potential decreased whereas the propensity for osteogenic differentiation increased. mRNA expression profiling revealed a consistent pattern of alterations in the global gene expression signature of MSC at different passages. These changes are not restricted to later passages, but are continuously acquired with increasing passages. Genes involved in cell cycle, DNA replication and DNA repair are significantly down-regulated in late passages. Genes from chromosome 4q21 were over-represented among differentially regulated transcripts. Differential expression of 10 genes has been verified in independent donor samples as well as in MSC that were isolated under different culture conditions. Furthermore, miRNA expression profiling revealed an up-regulation of hsa-mir-371, hsa-mir-369-5P, hsa-mir-29c, hsa-mir-499 and hsa-let-7f upon in vitro propagation. Our studies indicate that replicative senescence of MSC preparations is a continuous process starting from the first passage onwards. This process includes far reaching alterations in phenotype, differentiation potential, global gene expression patterns, and miRNA profiles that need to be considered for therapeutic application of MSC preparations.
    Type of Publication: Journal article published
    PubMed ID: 18493317
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  • 2
    Keywords: ANGIOGENESIS ; CANCER ; CANCER CELLS ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; INHIBITOR ; BLOOD ; carcinoma ; CELL ; ENDOTHELIAL GROWTH-FACTOR ; Germany ; human ; IN-VIVO ; MICROSCOPY ; VITRO ; VIVO ; DENSITY ; DIFFERENTIATION ; MICE ; fibroblasts ; BONE-MARROW ; NUDE-MICE ; CANCER-CELLS ; ADHESION ; MIGRATION ; STEM-CELLS ; RECRUITMENT ; VESSELS ; pancreatic cancer ; pancreatic carcinoma ; VEGF ; INHIBITORS ; ELISA ; ONCOLOGY ; pancreas ; PANCREATIC-CANCER ; fibroblast ; BLOOD-VESSELS ; stem cells ; analysis ; BONE ; ENGLAND ; tumor stroma ; VESSEL MATURATION ; STEM ; SMOOTH-MUSCLE-CELLS ; mesenchymal stem cells ; MARROW ; MARROW STROMAL CELLS ; EGF ; lentivirus ; MSC
    Abstract: Little is known about the factors that enable the mobilisation of human mesenchymal stem cells (MSC) from the bone marrow into the blood stream and their recruitment to and retention in the tumour. We found specific migration of MSC towards growth factors present in pancreatic tumours, such as PDGF, EGF, VEGF and specific inhibitors Glivec, Erbitux and Avastin interfered with migration. Within a few hours, MSC migrated into spheroids consisting of pancreatic cancer cells, fibroblasts and endothelial cells as measured by time-lapse microscopy. Supernatant from subconfluent MSC increased sprouting of HUVEC due to VEGF production by MSC itself as demonstrated by RT-PCR and ELISA. Only few MSCs were differentiated into endothelial cells in vitro, whereas in vivo differentiation was not observed. Lentiviral GFP-marked MSCs, injected in nude mice xenografted with orthotopic pancreatic tumours, preferentially migrated into the tumours as observed by FACS analysis of green fluorescent cells. By immunofluorescence and intravital microscopic studies, we found the interaction of MSC with the endothelium of blood vessels. Mesenchymal stem cells supported tumour angiogenesis in vivo, that is CD31(+) vessel density was increased after the transfer of MSC compared with siVEGF-MSC. Our data demonstrate the migration of MSC toward tumour vessels and suggest a supportive role in angiogenesis
    Type of Publication: Journal article published
    PubMed ID: 18665180
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  • 3
    Keywords: CANCER ; CELLS ; GROWTH ; IN-VITRO ; tumor ; CELL ; Germany ; human ; LUNG ; THERAPY ; TOOL ; liver ; POPULATION ; GENE ; GENES ; PROTEIN ; DIFFERENTIATION ; gene therapy ; MICE ; TRANSDUCTION ; gene transfer ; GENE-TRANSFER ; kidney ; BONE-MARROW ; MOUSE ; NUMBER ; genetics ; NUDE-MICE ; FUSION ; MIGRATION ; STEM-CELLS ; PROGENITOR CELLS ; SELECTION ; GENE-THERAPY ; RETROVIRAL VECTORS ; pancreatic cancer ; heredity ; VELOCITY ; ONCOLOGY ; homing ; XENOGRAFTS ; THERAPIES ; EX-VIVO ; HUMAN BONE-MARROW ; stem cells ; BONE ; EXTENT ; microbiology ; ENGLAND ; STEM ; UMBILICAL-CORD BLOOD ; MEDICINE ; biotechnology ; modification ; mesenchymal stem cells ; DELIVERY VEHICLES ; INDUCIBLE RNA INTERFERENCE ; lentiviral transduction ; TARGETED-DELIVERY
    Abstract: Genetic modification of human bone marrow mesenchymal stem cells ( MSC) is highly valuable for their exploitation in basic science and therapeutic applications, for example in cancer. We present here a new, fast and easy-to-use method to enrich a functional population of lentiviral (LV)-transduced MSC expressing enhanced green fluorescent protein (eGFP). We replaced the eGFP gene by a fusion gene of puromycin acetyltransferase and eGFP. Upon LV gene transfer and puromycin selection, we quickly obtained a pure transduced MSC population, in which growth, differentiation capacity and migration preferences were not compromised. Furthermore, we are the first to report the migration velocity of MSC among which 30% were moving and velocity of about 15 mu mh(-1) was not altered by LV transduction. Manipulated MSC underwent senescence one passage earlier than non-transduced cells, suggesting the use for therapeutic intervention in early passage numbers. Upon tail vein application in nude mice, the majority of LV-transduced MSC could be detected in human orthotopic pancreatic tumor xenografts and to a minor extent in mouse liver, kidney and lung. Together, LV transduction of genes to MSC followed by puromycin selection is a powerful tool for basic research and improves the therapeutic prospects of MSC as vehicles in gene therapy
    Type of Publication: Journal article published
    PubMed ID: 18202717
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  • 4
  • 5
    ISSN: 1618-2650
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: Zusammenfassung Die Verbindung Dünnschicht-Chromatographie/Röntgenfluorescenzspektrometrie gestattet eine schnelle Wirkstoffbestimmung in Pflanzenschutz- und Schädlingsbekämpfungsmitteln. Die Bedingungen zur Bestimmung von HCH und DDT werden am Beispiel eines Kombinationspräparates angegeben; die Methode wird anhand der erzielten Reproduzierbarkeit diskutiert. Es ergaben sich mittlere relative Fehler von ±4% (HCH) bzw. ±2% (DDT).
    Notes: Summary The combination of thin-layer chromatography and X-ray fluorescence spectrometry permits a rapid determination of the active substance in pesticides. The conditions for determining BHC and DDT are shown by the example of a combined preparation. The method is discussed on the basis of the reproducibility. The relative mean errors amounted to ±4% (BHC) and ±2% (DDT), respectively.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 0044-2313
    Keywords: Chemistry ; Inorganic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: β-Methylmercapto-ethyl amine (MÄA) behaves as a chelate ligand in 1,1, 1,2 and 1,3 complexes of Cu(II) and Ni(II). In 1,4 complexes of Cu(II), however, two of the MÄA ligands are only bound to the cation by the amino group, and the same is true for both MÄA molecules in [Co(MÄA)2Cl2] and [Zn(MÄA)2Cl2]. β-Ethoxy-ethylamine (ÄÄA)reacts with Cu(II)and Ni(II) salts forming 1,2 and 1,4 complexes in which the ether group probably has no ligand properties. The blue [Co(ÄÄA)2Cl2] having a tetrahedral configuration takes up two addtional ÄÄA molecules into its lattice at room temperature.
    Notes: β-Methylmercapto-äthylmin (MÄA) fungiert in 1,1-, 1,2- und 1,3-Komplexen mit Kupfer(II)- bzw. Nickel(II)-Ionen als Chelatligand. Dagegen sind in den 1,4-Komplexen, die bei der Umsetzung mit Kupfer(II)-Salzen erhalten werden konnten, 2 der MÄA-Liganden nur über den Aminstickstoff an das Zentralatom gebunden. Auch in den Verbindungen [Co(MÄA)2Cl2] und [Zn(MÄA)2Cl2] besetzt MÄA nur eine Koordinationsstelle. β-Äthoxy-äthylamin (ÄÄA) bildet mit Kupfer(II)-und Nickel(II)-Salzen 1,2- und 1,4-Komplexe, in denen die Äthergruppe sehr wahrscheinlich keine Haftgruppenfunktion besetzt. Der blaue Komplex [Co(ÄÄA)2Cl2], der eine tetraedrische Struktur aufweist, lagert bei normaler Temperatur 2 Mol ÄÄA in das Kristallgitter ein.
    Additional Material: 2 Tab.
    Type of Medium: Electronic Resource
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