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

Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305-5454, USA.
Circulation (Impact Factor: 14.95). 09/2011; 124(11 Suppl):S27-34. DOI: 10.1161/CIRCULATIONAHA.111.017954
Source: PubMed

ABSTRACT 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 prosurvival strategies to boost stem cell survival will be of significant benefit to this field.
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 microRNA precursors, or green fluorescent protein as a control. After challenge in serum free medium, CPCs treated with the 3 microRNA cocktail showed significantly higher viability compared with untreated CPCs. After intramuscular and intramyocardial injections, in vivo bioluminescence imaging showed that microRNA cocktail-treated CPCs survived significantly longer after transplantation. After left anterior descending artery ligation, microRNA cocktail-treated CPCs boost the therapeutic efficacy in terms of functional recovery. Histological analysis confirmed increased myocardial wall thickness and CPC engraftment in the myocardium with the microRNA 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 microRNA cocktail, which collectively can bind to the 3'UTR region of Bim and suppress its expression.
We have demonstrated that a microRNA prosurvival 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.

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Available from: Zongjin Li, Aug 26, 2015
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    • "Recently, it was demonstrated that in mouse and human hematopoietic stem and progenitor cells, low expression of Bim or Bmf provokes a similar effect to overexpression of Bcl-2 and that their downregulation inhibits apoptosis, favoring HSC long-term engraftment (Labi et al., 2013). Furthermore , Bim is an important target for a miRNA cocktail (miR-21, miR-24, and miR-221) that significantly improves survival of untreated Sca1 + CPCs (Hu et al., 2011). In agreement with these data, our results suggest that miR-133 protects CPCs from oxidative stress-induced apoptosis, at least in part, through targeting of Bmf and Bim. "
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    ABSTRACT: miR-133a and miR-1 are known as muscle-specific microRNAs that are involved in cardiac development and pathophysiology. We have shown that both miR-1 and miR-133a are early and progressively upregulated during in vitro cardiac differentiation of adult cardiac progenitor cells (CPCs), but only miR-133a expression was enhanced under in vitro oxidative stress. miR-1 was demonstrated to favor differentiation of CPCs, whereas miR-133a overexpression protected CPCs against cell death, targeting, among others, the proapoptotic genes Bim and Bmf. miR-133a-CPCs clearly improved cardiac function in a rat myocardial infarction model by reducing fibrosis and hypertrophy and increasing vascularization and cardiomyocyte proliferation. The beneficial effects of miR-133a-CPCs seem to correlate with the upregulated expression of several relevant paracrine factors and the plausible cooperative secretion of miR-133a via exosomal transport. Finally, an in vitro heart muscle model confirmed the antiapoptotic effects of miR-133a-CPCs, favoring the structuration and contractile functionality of the artificial tissue. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Stem Cell Reports 11/2014; 3(6). DOI:10.1016/j.stemcr.2014.10.010 · 5.64 Impact Factor
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    • "loci. Previous works demonstrated that miR-24 is a key player in the regulation of important cell-cycle regulatory genes (Cheng et al., 2005; Lal et al., 2009; Liu et al., 2010; Takagi et al., 2010; Hu et al., 2011; Guo et al., 2012). Moreover, this miR result upregulated in different types of human cancers, as demonstrated by studies performed on hepatic, breast, lung, prostate, and oral tumors (Lin et al., 2010; Hatziapostolou et al., 2011; Nymark et al., 2011; Wu et al., 2012), supporting the importance of this factor for tumor cell proliferation. "
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    Journal of Cellular Physiology 10/2013; 228(10). DOI:10.1002/jcp.24368 · 3.87 Impact Factor
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    • "It was reported that during cardiac stem cell therapy, paracrine effect causing inhibition of cardiac fibrosis, apoptosis and enhanced contractility [4], could be a possible factor mediated by matrix modulation. Another report using a cocktail of prosurvival miRNA-21, -24 and -221 was shown to enhance the engraftment and viability of transplanted cardiac progenitor cells [5] corroborating the fact that synergism of miRNA and stem cell could be a better therapeutic approach in heart failure [6]. We have demonstrated that targeted deletion of MMP-9 induces miRNAs that are downregulated in failing hearts and improves contractility and calcium handling by up regulating SERCA2 in cardiomyocytes [7]. "
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