Elsevier

Drug Discovery Today

Volume 24, Issue 1, January 2019, Pages 233-240
Drug Discovery Today

Review
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microRNAs and cardiac stem cells in heart development and disease

https://doi.org/10.1016/j.drudis.2018.05.032Get rights and content

Highlights

  • CSCs dominate heart development and myocardial repair.

  • miRNAs are essential for CSC proliferation, differentiation and migration.

  • CSC based-miRNA therapeutics hold great promise for heart regeneration.

Cumulative evidence has proven that proliferation, differentiation and migration of cardiac stem cells (CSCs) dominate early heart development and contribute to the later occurrence of heart disease. Among other mechanisms, microRNAs work as the ‘fine-tuning’ to modulate the levels of target genes in a specific cell type. The distinct microRNA signatures in CSCs reveal the stages and functions of CSCs. The focus of this review is to summarize recent knowledge advances in CSC proliferation, differentiation and migration and to discuss how microRNAs regulate these processes during heart development and in heart disease. Better understanding of microRNA regulation on CSCs under different situations will enable the unveiling of the mechanisms of heart disease and open new avenues in the therapeutic potentials of microRNA modulation to treat heart disease.

Introduction

Heart disease is the leading cause of death in the USA. Over 1.2 million adults have a myocardial infarction (MI) each year [1]. New insights into how human hearts can be regenerated following injury suggest that endogenous cardiac stem cells (CSCs) in the adult mammalian heart can be rapidly activated and can differentiate into the major functional cell lineages, including cardiomyocytes (CMs), smooth muscle cells (SMCs) and endothelial cells (ECs) for myocardial regeneration 2, 3, 4. These findings agree that CSCs dominate early heart development and the later occurrence of heart disease, strengthening the substantial clinical interest in CSCs in myocardial regeneration 5, 6. Although resident CSCs only occupy 0.005–2% of all adult cardiac cells [7], the regenerative capacity of rare CSCs for cardiac homeostasis and myocardial repair has led to broader studies on them 7, 8. microRNAs (miRNAs) are small noncoding RNAs that modulate gene expression by binding to the targeted mRNAs, and play a crucial part in regulating cardiac development, proliferation, differentiation and migration of CSCs 9, 10, 11, 12, which have been linked to the initiation and development of heart disease. Here, we review the recent advances in our knowledge of proliferation, differentiation and migration of CSCs. In particular, we summarize how microRNAs regulate these processes during the development of the heart and in heart disease, as well as their therapeutic potentials.

Section snippets

Subsets of cardiac stem cells

Growing interest in the implementation of CSCs in heart development and disease has aroused superfine studies on CSC subsets. Markers, such as CD45 [2] and CD133 [13], can discriminate the subpopulations of c-kit+ cells for myocardial regeneration. Compared with CD45+/c-kit+ CSCs, CD45/c-kit+ CSCs are more committed to CMs in adult mouse or rat hearts [2]. In addition, CD133+/c-kit+ cells exhibit phenotypic properties of endothelial progenitor cells [13]. These studies have indicated that

miRNAs and cardiac stem cells in heart development

miRNAs are small (∼22 nucleotide) noncoding RNAs that most commonly regulate gene expression by binding to complementary sites found within the 3′ untranslated regions (3′UTRs) of the targeted mRNAs. miRNAs are commonly located in intergenic regions and introns of protein-coding genes and are transcribed either in clusters or individually. The majority of miRNAs are transcribed by RNA polymerase II which generates the primary transcript with a stem-loop structure – called pri-miRNA. pri-miRNAs

Therapeutic potential of miRNAs in heart disease

Dysregulation of miRNAs greatly impairs the function and repair efficacy of CSCs in heart disease. Identifying the miRNAs and the targeting gene pathways responsible for specific CSC-mediated cardiovascular effects raises the possibilities for developing novel CSC-based miRNA therapeutics. Indeed, emerging evidence supports that the therapeutic manipulation of miRNA-regulated processes improves CSC function and efficacy for the treatment of certain heart diseases. CSC transplants to the

Concluding remarks

A large body of evidence has suggested the fundamental role of miRNAs in regulating a variety of key cellular processes in CSCs during heart development, including CSC proliferation, differentiation and migration. Inappropriate expression of miRNAs in CSCs is involved in different pathophysiological conditions of the heart. Several miRNAs thus far have emerged as the attractive targets for enhancing stem cell therapy or endogenous repair processes. The overexpression or acute inhibition of

Conflicts of interest

The authors declare no conflicts of interest regarding the publication of this paper.

Acknowledgments

This work was supported in part by National Institutes of Health GrantsHL083966 (L.Z.), HL118861 (L.Z.) and NS103017 (L.Z.). We apologize to those authors whose excellent studies covered by the scope of this review were unable to be cited because of space limitations.

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