Abstract 18790: Identification of a Novel Regulator of the Mesenchymal Stem Cell Secretome and Myocardial Repair
| Autor: | Feng Dong, Matthew Kiedrowski, Marc Penn, Mary E Mayorga |
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| Rok vydání: | 2015 |
| Předmět: | |
| Zdroj: | Circulation. 132 |
| ISSN: | 1524-4539 0009-7322 |
| Popis: | The delivery of mesenchymal stem cells (MSC) in acute myocardial infarction (AMI) leads to significant preservation of myocardium and improved cardiac function. We have previously shown that the down-regulation of the tumor suppressor protein disabled-2 (Dab2) leads to increased MSC function in AMI. We sought to define the molecular mechanisms associated with down-regulation of disabled-2 and improved MSC function. We observed that the improvement in cardiac function following engraftment of Dab2-/- MSC was associated with modulation of the MSC secretome, in that of conditioned media conferred the same benefits as cell transplantation. To begin to define the down-stream targets of disabled-2 we completed a detailed Illumina array comparing Dab2 down-regulation by three methods (MSC treated with TGFß1 or MSC transfected with miR-145 or dab2:siRNA). Comparing gene expression in these three treatment groups to control MSC we identified 23 genes whose expression were similarly significantly modulated by dab2 down-regulation. Of this group we have focused to date on CAMKK1 as a possible regulator of the MSC secretome. CAMKK1, is a kinase with multiple down-stream targets including CAMK1, CAMKIV and Akt. Inhibition of CAMKK1 leads to an increase in pro-inflammatory cytokines and chemokines in the conditioned media of MSC. To determine if CAMKK1 over-expression was sufficient to induce an MSC like benefit in AMI we generated a plasmid vector in which CAMKK1 expression is regulated by the CMV promoter and the 5’-UTR RU5 enhancer element. We performed randomized blinded study in an AMI model in Sprague Dawley rats in which 500 ug of plasmid encoding CAMKK1 in 5 divided doses was injected into the infarct borderzone immediately after LAD ligation. CAMKK1 over-expression led to a significant improvement in cardiac function at 1, 2 and 8 weeks after AMI (Ejection Fraction at 8 weeks: CAMKK1: 83.2%±5.4% vs. Placebo: 51.7%±5.8%, p |
| Databáze: | OpenAIRE |
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