Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression profiles of bone marrow mesenchymal stem cells in pediatric patients with severe aplastic anemia

ABSTRACT: Pediatric severe aplastic anemia (PSAA) is a rare and life-threatening disease, which has been suggested to result from deficiency in essential cytokines or growth factors in bone marrow mesenchymal stem cells (MSCs). In this study, we examined expression profiles of the essential cytokines and growth factors, which were involved in proliferation and differentiation of MSC, in 5 PSAA patients using oligonucleotides microarrays. Following evaluation of gene expression patterns using cluster analysis and gene ontology classifications, fifteen potential genes that were cell proliferation- and cytokine-related and significantly down-regulated in PSAA were selected. The findings of the microarray analysis were validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Interestingly, silencing of chemokine ligand 12 (CXCL12, also named stromal cell-derived factor 1, SDF1) or hepatocyte growth factor (HGF) gene expression reduced cell growth and response to adipogenic factor-induced differentiation, but increased osteogenesis, which possibly derived from hematopoietic stem cells (HSCs). Re-introduction of the CXCL12 gene or exogenously added HGF, on the other hand, partially recovered cell function of PSAA MSC. These results suggest that gene expression in PSAA MSC is globally down-regulated by a yet-to-be-determined mechanism. Among these down-regulated genes, CXCL12 and HGF played vital roles in regulating cell growth and differentiation. Mesenchymal stem cells from five pediatric SAA patients vs. MSC from five healthy donors, which were pooled together.

ORGANISM(S): Homo sapiens

SUBMITTER: Kuan-Chih Chow

PROVIDER: E-GEOD-33812 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Purpose: We aimed to investigate the effect of several anti-leukemia drugs in combination with decitabine (DAC) on the proliferation of myeloid leukemia cells in vitro and in vivo, to select the most efficient combination group and explore associated mechanisms of these combination therapies. Experimental Design: After comparing with five anti-leukemia drugs in several different kinds of cell lines, the combination effect of idarubicin (IDA) with DAC was best. In vivo, by using microPET, TUNEL, and transmission electron microscopy, the inhibitory effects obtained by sequentially combining DAC with IDA, evidenced by evaluating tumor cell proliferation and cell apoptosis. Molecular studies were conducted using gene chip, which was used to explore associated pathways, and real-time quantitative reverse transcription-PCR, western blot and immunohistochemistry (IHC), used to assess regulation of Wnt/β-catenin pathway. Results: The sequential combination of DAC and IDA showed synergistic induction of cell death in U937, HEL, SKM-1 and cells isolated from AML patients. Importantly, the inhibition of tumor growth in the sequential combination group was found to be significantly higher than that of single drug group or control group in vivo. Moreover, sequential treatment with DAC and IDA induced apoptosis and depression of the Wnt/β-catenin pathway in both culture and animal studies. Conclusions: Our findings showed that sequentially combining decitabine with idarubicin had a synergistic anti-leukemia effect. These findings were attributed to demethylation of Wnt pathway inhibitors and downregulation of Wnt pathway nuclear targets observed in vitro and in vivo. After comparing with five anti-leukemia drugs in several different kinds of cell lines, the combination effect of idarubicin (IDA) with DAC was best. In vivo, by using microPET, TUNEL, and transmission electron microscopy, the inhibitory effects obtained by sequentially combining DAC with IDA, evidenced by evaluating tumor cell proliferation and cell apoptosis. Molecular studies were conducted using gene chip, which was used to explore associated pathways, and real-time quantitative reverse transcription-PCR, western blot and immunohistochemistry (IHC), used to assess regulation of Wnt/β-catenin pathway.

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Gene expression profiles of bone marrow mesenchymal stem cells in pediatric patients with severe aplastic anemia

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