Unknown,Transcriptomics,Genomics,Proteomics

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Novel critical insights into the mechanism of cell-based therapy after myocardial infarction

ABSTRACT: Cell transplantation therapy is considered a novel and promising strategy in regenerative medicine. Recent studies point out that paracrine effects and inflammation induced by transplanted cells are key factors for the improvement of myocardial function. The present study aims at differentiating paracrine effects from inflammatory reactions after cell transplantation. Therefore, in vitro induced apoptotic bodies were transplanted after myocardial infarction in a rat model. Eight weeks after transplantation, the functional results showed no improvement in left ventricular function. Histological analysis revealed no significant differences in the amount of infiltrated cells and collagen content did not differ among the four groups, which sustains the functional data. Surprisingly, angiogenesis increased in groups with apoptotic bodies derived from HUVEC and endothelial progenitor cells, but not from fibroblasts. A complex genetic analysis of apoptotic bodies indicated that miRNAs could be responsible for these changes. In conclusion, our study demonstrates both that neoangiogenesis alone is not sufficient to improve function and that inflammation is critical for scar remodeling and improvement of the heart function after cell therapy. Given what we have learned about microRNAs, we hypthesized that the molecular mechanisms of angiogenesis induction could involve apoptotic bodies exerting paracrine angiogenic effects. Using GeneChip miRNA 3.0 Array, microRNAs were analysed in apoptotic bodies from endothelial progenitor cells (EPCs), human umbilical veno-endothelial cells (HUVECs), and fibroblasts. From human EPCs, human dermal fibroblasts, and HUVECs, apoptotic bodies were isolated after treatment with cycloheximide in hypoxia for 24 hours.

ORGANISM(S): Homo sapiens

SUBMITTER: Bernd Denecke

PROVIDER: E-GEOD-48218 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Apoptosis plays a pivotal role in embryogenesis and postnatal cell homeostasis, involving DNA or subcellular fragmentation, and shedding of small membranous microvesicles termed apoptotic bodies (AB). Following DNA damage, hypoxia, or vascular injury, the chemokine CXCL12 has been implicated in the recruitment of progenitor cells for tissue regeneration through its receptor CXCR4 and in mechanisms counteracting apoptosis. Whether AB deliver alarm signals for regenerative responses to neighbouring cells beyond recruitment or eat-me signals for phagocytes and relevance to diseases with abundant apoptosis, eg atherosclerosis, remains unknown. Here we show that endothelial cell-derived AB are generated during diet-induced atherosclerosis and can be transferred to recipient endothelial or smooth muscle cells to induce functional expression of CXCL12. This is mediated through miRNA-126 enriched in AB, which acts by silencing RGS16 translation and unlocking CXCR4 to unleash an auto-regulatory feedback loop inducing CXCL12. Injection of AB promoted mobilization and incorporation of progenitor cells, reducing diet-induced atherosclerosis in apolipoprotein E-deficient mice, and local transfer of microRNA-126 inhibited collar-induced arterial plaque formation. This was associated with increased smooth muscle content but decreased macrophage and apoptotic cell content, all features of plaque stability. Our data identify a new mechanism, by which AB confer microRNA-126 as a paracrine alarm messenger to enhance CXCR4 signals and CXCL12 expression, thereby limiting or repairing vascular damage. This adds to the important functions of microRNAs in health and disease and may extend to progenitor cell recruitment during other forms of tissue repair or homeostasis. AB were isolated from supernatants of apoptotic, serum-starved human umbilical vein endothelial cells (HUVECs) by sequential centrifugation steps. Total RNA was isolated from AB or HUVECs and microRNA was purified using the mirVanaTM miRNA Isolation Kit (Ambion). microRNA obtained from 10 µg of total RNA was labeled using the mirVanaTM miRNA Labeling Kit (Ambion) and fluorescent Cy3 (Molecular Probes), and hybridized to the Ambion mirVanaTM miRNA Bioarray (1566 v.1). Hybridized mirVana miRNA Bioarrays were scanned and quantified by using ImaGene 5.5.4 (Bio Discovery). Resulted signal intensities were background corrected and then normalized using variance stabilization normalization. (Huber, 2002).

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Novel critical insights into the mechanism of cell-based therapy after myocardial infarction

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