Unknown,Transcriptomics,Genomics,Proteomics

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Cardiac adiposity is regulated by Klf4 and c-Myc

ABSTRACT: In this study, we examined if KLF4 and c-MYC (KM)-transduced murine cardiac mesenchymal progenitors (CMPs) played a role in the differentiation into adipocytes in the absence of adipogenic stimulation cocktails. These progenitors exhibited increased expression of adipogenic-related genes, such as C/EBPα, PPARγ, and Fabp4, activation of the PPAR signaling pathway, and formation of cytoplasmic lipid droplets within 10 days. Moreover, these KM genes sharply increased following a reperfusion insult, resulting in increased ectopic fat formation. Thus, understanding CMP adipogenesis will clarify the pathophysiology of ischemic reperfusion injury and myocardial infarction and may pave the way for better treatment strategies. Adult mouse cardiac mesenchymal progenitor cells were treated with OSKM for 0, 4, 6, or 8 days.

ORGANISM(S): Mus musculus

SUBMITTER: Satoshi Gojo

PROVIDER: E-GEOD-70088 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:High levels of Hes1 expression are frequently found in BCR-ABL-positive chronic myelogenous leukemia in blast crisis (CML-BC). In mouse bone marrow transplantation (BMT) models, co-expression of BCR-ABL and Hes1 induces CML-BC–like disease; however the underlying mechanism remained elusive. Here, based on gene expression analysis, we show that MMP-9 is upregulated by Hes1 in common myeloid progenitors (CMPs). Analysis of promoter activity demonstrated that Hes1 upregulated MMP-9 by activating NF-kB. Analysis of 20 samples from CML-BC patients showed that MMP-9 was highly expressed in three, with two exhibiting high levels of Hes1 expression. Interestingly, MMP-9 deficiency impaired the cobblestone area-forming ability of CMPs expressing BCR-ABL and Hes1 that were in conjunction with a stromal cell layer. In addition, these CMPs secreted MMP-9, promoting the release of soluble Kit-ligand (sKitL) from stromal cells, thereby enhancing proliferation of the leukemic cells. In accordance, mice transplanted with CMPs expressing BCR-ABL and Hes1 exhibited high levels of sKitL as well as MMP-9 in the serum. Importantly, MMP-9 deficiency impaired the development of CML-BC–like disease induced by BCR-ABL and Hes1 in mouse BMT models. The present results suggest that Hes1 promotes the development of CML-BC, partly through MMP-9 upregulation in leukemic cells. Common myeloid progenitors (CMPs; Lineage negative, c-Kit positive, Sca-1 negative, Fc-gamma-receptor low, CD34 positive fraction) were sorted with a FACSAria cell sorter (Becton Dickinson). Retroviruses were generated by transfecting Plat-E packaging cells with retrovirus vector pMYs-Hes1-IRES-GFP or empty vector (pMYs-IRES-GFP) using FuGENE 6 (Roche Diagnostics). Infection of retrovirus harboring Hes1 (pMYs-Hes1-IRES-GFP) or empty vector (pMYs-IRES-GFP) into progenitors was performed using RetroNectin (Takara Bio). Hes1-transfected CMPs and Mock-transduced CMPs were isolated 36 hours after infection with a FACSAria cell sorter. One sample of Hes1-transfected CMPs and one sample of mock-transduced CMPs were analyzed with GeneChip Mouse Genome 430 2.0 Array.