- 作者：Quanfu Xu ; MD?/sup> ; &dagger ; ; Florian H. Seeger ; MD&Dagger ; ; Jessica Castillo ; MD?/sup> ; &Dagger ; ; Kazuma Iekushi ; MD ; PhD?/sup> ; Reinier A. Boon ; PhD?/sup> ; Ruxandra Farcas ; PhD?/sup> ; Yosif Manavski ; MSc?/sup> ; Yi-Gang Li ; MD&dagger ; ; Birgit Assmus ; MD&Dagger ; ; Andreas M. Zeiher ; MD&Dagger ; ; Stefanie Dimmeler ; PhD?/sup> ; dimmeler@em.uni-frankfurt.de
- 关键词：acute myocardial infarction ; bone marrow mononuclear cells ; cell therapy ; locked nucleic acid ; microRNA ; miR-34a
- 刊名：Journal of the American College of Cardiology
- 出版年：2012
- 出版时间：5 June, 2012
- 年：2012
- 卷：59
- 期：23
- 页码：2107-2117
- 全文大小：1156 K
Objectives
This study evaluated the regulation and function of micro-RNAs (miRs) in bone marrow-mononuclear cells (BMCs).Background
Although cell therapy with BMCs may represent a therapeutic option to treat patients with heart disease, the impaired functionality of patient-derived cells remains a major challenge. Small noncoding miRs post-transcriptionally control gene expression patterns and play crucial roles in modulating cell survival and function.
Methods
Micro-RNAs were detected by miR profiling in BMCs isolated from healthy volunteers (n = 6) or from patients with myocardial infarction (n = 6), and the results were confirmed by polymerase chain reaction (PCR) in a larger cohort (n = 37). The function of selected miRs was determined by gain-of-function studies in vitro and by locked nuclear acid (LNA) modified inhibitors in vitro and in vivo.
Results
We identified several miRs that are up-regulated in BMCs from patients with myocardial infarction compared with BMCs from healthy controls, including the pro-apoptotic and antiproliferative miR-34a and the hypoxia-controlled miR-210. Inhibition of miR-34 by LNA-34a significantly reduced miR-34a expression and blocked hydrogen peroxide-induced cell death of BMC in vitro, whereas overexpression of miR-34a reduced the survival of BMCs in vitro. Pre-treatment of BMCs with LNA-34a ex vivo significantly increased the therapeutic benefit of transplanted BMCs in mice after acute myocardial infarction (AMI).
Conclusions
These results demonstrate that cardiovascular disease modulates the miR expression of BMCs in humans. Reducing the expression of the pro-apoptotic miR-34a improves the survival of BMCs in vitro and enhances the therapeutic benefit of cell therapy in mice after AMI. (BMC Registry, ; Progenitor Cell Therapy in Dilative Cardiomyopathy, )