Original ArticleMicroRNA-133a Engineered Mesenchymal Stem Cells Augment Cardiac Function and Cell Survival in the Infarct HeartDakhlallah, Duaa PhD*,†; Zhang, Jianying PhD‡; Yu, Lianbo PhD‡; Marsh, Clay B. MD*; Angelos, Mark G. MD§; Khan, Mahmood MPharm, PhD§Author Information *Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH; †Department of Engineering, American University of the Safat, Kuwait; ‡Department of Biomedical Informatics, Center for Biostatistics, The Ohio State University, Columbus, OH; and §Department of Emergency Medicine, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH. Reprints: Mahmood Khan, MPharm, PhD, Department of Emergency Medicine, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, 473 W, 12th Avenue, Columbus, OH 43210 (e-mail: [email protected]). A part of this project was supported by Award Number Grant UL1TR001070 from the National Center for Advancing Translational Sciences. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jcvp.org). Conceived and designed the experiments: D. Dakhlallah and M. Khan; Performed the experiments: D. Dakhlallah and M. Khan; Analyzed the data: D. Dakhlallah, J. Zhang, L. Yu, and M. Khan; Contributed reagents/materials/analysis tools: C. B. Marsh, M. G. Angelos, and M. Khan; Wrote the article: D. Dakhlallah, M. G. Angelos, and M. Khan. Received September 05, 2014 Accepted October 21, 2014 Journal of Cardiovascular Pharmacology: March 2015 - Volume 65 - Issue 3 - p 241-251 doi: 10.1097/FJC.0000000000000183 Buy SDC Metrics Abstract Abstract: Cardiovascular disease is the number 1 cause of morbidity and mortality in the United States. The most common manifestation of cardiovascular disease is myocardial infarction (MI), which can ultimately lead to congestive heart failure. Cell therapy (cardiomyoplasty) is a new potential therapeutic treatment alternative for the damaged heart. Recent preclinical and clinical studies have shown that mesenchymal stem cells (MSCs) are a promising cell type for cardiomyoplasty applications. However, a major limitation is the poor survival rate of transplanted stem cells in the infarcted heart. miR-133a is an abundantly expressed microRNA (miRNA) in the cardiac muscle and is downregulated in patients with MI. We hypothesized that reprogramming MSCs using miRNA mimics (double-stranded oligonucleotides) will improve survival of stem cells in the damaged heart. MSCs were transfected with miR-133a mimic and antagomirs, and the levels of miR-133a were measured by quantitative real-time polymerase chain reaction. Rat hearts were subjected to MI and MSCs transfected with miR-133a mimic or antagomir were implanted in the ischemic hearts. Four weeks after MI, cardiac function, cardiac fibrosis, miR-133a levels, and apoptosis-related genes (Apaf-1, Caspase-9, and Caspase-3) were measured in the heart. We found that transfecting MSCs with miR-133a mimic improves survival of MSCs as determined by the MTT assay. Similarly, transplantation of miR-133a mimic transfected MSCs in rat hearts subjected to MI led to a significant increase in cell engraftment, cardiac function, and decreased fibrosis when compared with MSCs only or MI groups. At the molecular level, quantitative real-time polymerase chain reaction data demonstrated a significant decrease in expression of the proapoptotic genes; Apaf-1, caspase-9, and caspase-3 in the miR-133a mimic transplanted group. Furthermore, luciferase reporter assay confirmed that miR-133a is a direct target for Apaf-1. Overall, bioengineering of stem cells through miRNAs manipulation could potentially improve the therapeutic outcome of patients undergoing stem cell transplantation for MI. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.