microRNAs and cardiac stem cells in heart development and disease

Abstract

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.

Figure 1

CSCs) in cardiac regeneration after myocardial injury. Resting endogenous CSCs are rapidly activated after myocardial injury. These activated CSCs proliferate speedily and migrate to the injured field to directly differentiate into functional cell lineages, including CMs, ECs and SMCs. Meanwhile, exogenous factors could further enhance the regenerative capacity of endogenous CSCs. For example, engrafted CSCs that are injected into the injured border zone promote differentiation of activated CSCs into trilineage cells via paracrine effects. All these processes contribute to the improvement of the heart function. Abbreviations: CSCs, cardiac stem cells; CMs, cardiomyocytes; SMCs, smooth muscle cells; ECs, endothelial cells.

Figure 2

Role of miRNAs in regulating CSC proliferation, differentiation and migration. (a) Various miRNAs regulate proliferation-related signaling pathways in CSCs. Several miRNAs, such as miR-21, miR-218, miR-548c, miR-509 and miR-23b, induce CSC proliferation by targeting negative regulators of cell proliferation, whereas miR-1, miR-200b and miR-204 inhibit CSC proliferation by modulating proliferation-related transcription factors. (b) Several miRNAs regulate CSC differentiation into CMs. miRNAs from the miR-322/-503 cluster (miR-499 as well as miR-708) promote CM commitment by suppressing the factors that inhibit cardiac differentiation. By contrast, miR-133 targets NELF-A, a nuclear factor promoting cardiogenesis. miR-218 and miR-142 inhibit CSC differentiation by modulating sFRP2, a negative regulator of proliferation, and cardiac transcription factor MEF2C, respectively. (c) miR-22 and miR-29 promote SMC commitment. Their targets, EVI1 and YY1, suppress the SMC marker gene expression and negatively regulate SMC transcription factors, respectively. (d) miR-206 and miR-21 have been shown to directly control migration of CSCs. Induction of CSC migration to injured heart could enhance cardiac regeneration. Abbreviations: ATF2, activating transcription factor 2; miRNAs, microRNAs; CSCs, cardiac stem cells; CMs, cardiomyocytes; SMC, smooth muscle cell; Celf1, CUG-binding protein Elav-like family member 1; EVI1, ecotropic virus integration site 1 protein homolog; GATA-4, GATA-binding protein 4; Hand 2, hand transcription factor 2; HDAC, histone deacetylase 4; MEF2C, myocyte enhancer factor 2C; NELF-A, negative elongation factor-A; PDCD4, programmed cell death 4; PTEN, phosphatase and tensin homolog; Rod1, regulator of differentiation 1; sFRP2, secreted frizzled-related protein 2; TIMP-3, tissue inhibitor of metalloproteinases-3; YY1, transcription factor Yin Yang 1.

Figure 2

Role of miRNAs in regulating CSC proliferation, differentiation and migration. (a) Various miRNAs regulate proliferation-related signaling pathways in CSCs. Several miRNAs, such as miR-21, miR-218, miR-548c, miR-509 and miR-23b, induce CSC proliferation by targeting negative regulators of cell proliferation, whereas miR-1, miR-200b and miR-204 inhibit CSC proliferation by modulating proliferation-related transcription factors. (b) Several miRNAs regulate CSC differentiation into CMs. miRNAs from the miR-322/-503 cluster (miR-499 as well as miR-708) promote CM commitment by suppressing the factors that inhibit cardiac differentiation. By contrast, miR-133 targets NELF-A, a nuclear factor promoting cardiogenesis. miR-218 and miR-142 inhibit CSC differentiation by modulating sFRP2, a negative regulator of proliferation, and cardiac transcription factor MEF2C, respectively. (c) miR-22 and miR-29 promote SMC commitment. Their targets, EVI1 and YY1, suppress the SMC marker gene expression and negatively regulate SMC transcription factors, respectively. (d) miR-206 and miR-21 have been shown to directly control migration of CSCs. Induction of CSC migration to injured heart could enhance cardiac regeneration. Abbreviations: ATF2, activating transcription factor 2; miRNAs, microRNAs; CSCs, cardiac stem cells; CMs, cardiomyocytes; SMC, smooth muscle cell; Celf1, CUG-binding protein Elav-like family member 1; EVI1, ecotropic virus integration site 1 protein homolog; GATA-4, GATA-binding protein 4; Hand 2, hand transcription factor 2; HDAC, histone deacetylase 4; MEF2C, myocyte enhancer factor 2C; NELF-A, negative elongation factor-A; PDCD4, programmed cell death 4; PTEN, phosphatase and tensin homolog; Rod1, regulator of differentiation 1; sFRP2, secreted frizzled-related protein 2; TIMP-3, tissue inhibitor of metalloproteinases-3; YY1, transcription factor Yin Yang 1.