MicroRNA-1 and -499 Regulate Differentiation and Proliferation in Human-Derived Cardiomyocyte Progenitor Cells

Abstract

Objective-To improve regeneration of the injured myocardium, it is necessary to enhance the intrinsic capacity of the heart to regenerate itself and/or replace the damaged tissue by cell transplantation. Cardiomyocyte progenitor cells (CMPCs) are a promising cell population, easily expanded and efficiently differentiated into beating cardiomyocytes.Recently, several studies have demonstrated that microRNAs (miRNAs) are important for stem cell maintenance and differentiation via translational repression. We hypothesize that miRNAs are also involved in proliferation/differentiation of the human CMPCs in vitro. Methods and Results-Human fetal CMPCs were isolated, cultured, and efficiently differentiated into beating cardiomyocytes. miRNA expression profiling demonstrated that muscle-specific miR-1 and miR-499 were highly upregulated in differentiated cells.

MicroRNAs as novel regulators of stem cell fate

“…In human ESC-derived embryoid bodies, miR-1 also increased the expression of myosin heavy chain (MHC) genes [78] . Additionally, miR-1 increased the expression of cardiomyocyte-specific genes and enhanced cardiomyocyte differentiation from human-derived cardiomyocyte progenitor cells by targeting HDAC4 [79] . Interestingly, the transplantation of murine ESCs overexpressing miR-1 into the border zone of infarcted mouse hearts prevented ischemia-induced apoptosis [80] .…”

“…Concurrently, our group also discovered that miR-133a expression increased during differentiation and that the overexpression of miR-133a promoted cardiac differentiation in human MSCs by targeting EGFR [87] . Increased miR-499 expression was discovered in adult cardiac progenitor cells and human ESCs [78,79] . This miRNA is encoded by an intron of MHC [88] and shares many predicted targets with miR-208, which plays a crucial role in the stress-adaptation of the adult heart.…”

“…This miRNA is encoded by an intron of MHC [88] and shares many predicted targets with miR-208, which plays a crucial role in the stress-adaptation of the adult heart. The overexpression of miR-499 reduced the proliferation and enhanced the differentiation of human cardiomyocyte progenitor cells and ESCs through targeting Sox6, which is expressed in heart and skeletal muscle [79] . The miRNA miR-499 has also been shown to play a role in myocyte lineage differentiation and the generation of mature working cardiomyocytes in vitro and after infarction in vivo [89] .…”

Microarray Analysis of Undifferentiated and Differentiated Human Pluripotent Stem Cells

“…Moreover, we identified miR-208a/b and miR-499 as significantly induced in all cardiac-like samples. Interestingly, these miRNAs are also reported as enriched in cardiac tissue by others (Adachi et al, 2010, Ji et al, 2009, Sluijter et al, 2010. Both miRNA-499 and miRNA-1 are suggested to regulate the proliferation of human CM progenitors and their further differentiation into CMs (Sluijter et al, 2010).…”

“…Interestingly, these miRNAs are also reported as enriched in cardiac tissue by others (Adachi et al, 2010, Ji et al, 2009, Sluijter et al, 2010. Both miRNA-499 and miRNA-1 are suggested to regulate the proliferation of human CM progenitors and their further differentiation into CMs (Sluijter et al, 2010). In addition, miR-499 is also proposed as a marker for acute myocardial infarction in humans (Adachi et al, 2010).…”