Novel MicroRNA Prosurvival Cocktail for Improving Engraftment and Function of Cardiac Progenitor Cell Transplantation

Abstract

Background Although stem cell therapy has provided a promising treatment for myocardial infarction, the low survival of the transplanted cells in the infarcted myocardium is possibly a primary reason for failure of long-term improvement. Therefore, the development of novel pro-survival strategies to boost stem cell survival will be of significant benefit to this field. Method and Results Cardiac progenitor cells (CPCs) were isolated from transgenic mice which constitutively express firefly luciferase and green fluorescent protein. The CPCs were transduced with individual lentivirus carrying the precursor of miR-21, miR-24, and miR-221, a cocktail of these 3 miRNA precursors, or GFP as control. After challenge in serum free medium, CPCs treated with the 3 miRNA cocktail showed significantly higher viability compared to untreated CPCs. Following intramuscular and intramyocardial injections, in vivo bioluminescence imaging (BLI) showed that miRNA cocktail-treated CPCs survived significantly longer after transplantation. Following left anterior descending artery ligation, miRNA cocktail-treated CPCs boosts the therapeutic efficacy in terms of functional recovery. Histological analysis confirmed increased myocardial wall thickness and CPC engraftment in the myocardium with miRNA cocktail. Finally, we used bioinformatics analysis and experimental validation assays to show that Bim, a critical apoptotic activator, is an important target gene of the miRNA cocktail, which collectively can bind to the 3’UTR region of Bim and suppress its expression. Conclusion We have demonstrated that a miRNA pro-survival cocktail (miR-21, miR-24, and miR-221) can improve the engraftment of transplanted cardiac progenitor cells and therapeutic efficacy for treatment of ischemic heart disease.

Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs

“…Furthermore, several studies have shown that these cardiac progenitor cells are capable of differentiating into cardiac tissue and improving cardiac function after a myocardial injury. Exponential advances in stem cell and regenerative biology are beginning to foster a transition toward therapeutic goals for cardiac regenerative medicine (8,14,15,33). However, poor cell viability, proliferation, and inefficient differentiation following transplantation have limited the reparative capacity of these cells in vivo (26,29,39).…”

Strategies to deliver microRNAs as potential therapeutics in the treatment of cardiovascular pathology

“…One of these fields may concern using miRNAs to improve growth, differentiation, and regenerative properties of progenitor and stem cells before transplantation to the infarcted heart. This new approach has been recently launched, and mesenchymal stem cells or cardiac progenitor cells genetically modified with miRNAs such as miR-1, miR-21, miR-24, miR-126, miR-155, and miR-221 showed advanced prosurvival properties and regenerative capacity in animal models of cardiovascular disease (Chen & Zhou, 2011;Glass & Singla, 2011;Hu et al, 2011;Liu et al, 2011).…”

MicroRNA and Cardiac Stem Cell Therapy

“…In this way, it would be possible to start reprogramming in vitro, and to continue in vivo obtaining the best efficiency in cell commitment and myocardial differentiation. [71]. Moreover, the overexpression of miR-155 in CPCs improves cell survival inhibiting the necrotic process and blocking cell migration [72].…”

“…A pro-survival cocktail of miR-21, miR-24 and miR-221 was employed to improve cell viability and survival of Sca-1 positive CPCs both in vitro and in vivo ( Figure 3) [71].…”