miR-25 Promotes Cardiomyocyte Proliferation by Targeting FBXW7

Abstract

Induction of endogenous cardiomyocyte (CM) proliferation is one of the key strategies for heart regeneration. Increasing evidence points to the potential role of microRNAs (miRNAs) in the regulation of CM proliferation. Here, we used human embryonic stem cell (hESC)-derived CMs (hESC-CMs) as a tool to identify miRNAs that promote CM proliferation. We profiled miRNA expression at an early stage of CM differentiation and identified a list of highly expressed miRNAs. Among these miRNAs, miR-25 was enriched in early-stage hESC-CMs, but its expression decreased over time. Overexpression of miR-25 promoted CM proliferation. RNA sequencing (RNA-seq) analysis revealed that genes related to cell-cycle signal were strongly influenced by miR-25 overexpression. We further showed that miR-25 promoted CM proliferation by targeting FBXW7. Finally, the function of miR-25 in the regulation of CM proliferation was demonstrated in zebrafish. Our study suggested that miR-25 is a promising molecule for heart regeneration.

A microRNA program controls the transition of cardiomyocyte hyperplasia to hypertrophy and stimulates mammalian cardiac regeneration

“…Some reports indicate that inhibition of miR-25 expression can lead to derepression of the target gene Serca2a and improve cardiac function, 44 and others report protection against oxidative stress or apoptosis induced by sepsis. 45,46 In contrast, others report that overexpression of miR-25 is innocuous and induces proliferation by altering cell cycle genes in zebrafish, 37 while here we report cardiac enlargement secondary to enhanced cardiomyocyte proliferation, which at first sight could be misinterpreted as a pathological phenotype. From a therapeutic perspective, miR-25 loss-of-function approaches have also shown disparate results from improving contractility on the one side, 44 or inducing high blood pressure, 47 atrial fibrillation, 48 eccentric remodeling and dysfunction, 20,47 on the other.…”

“…35 That members of the miR-106b~25 cluster can evoke cardiomyocyte proliferation is confirmed by an unbiased, high-content screen to identify proliferative microRNAs, 36 while more recently, miR-25 was demonstrated to provoke cardiomyocyte proliferation in zebrafish by repressing the cell cycle inhibitor Cdknc1 and tumor suppressor Lats2. 37 Our results also revealed components of the Hippo/Yap pathway as miR-106b~25 targetome members. Hippo signaling has been widely studied in the context of cardiac regeneration.…”

MicroRNA Profiling of HL-1 Cardiac Cells-Derived Extracellular Vesicles

“…TIAM1-Rac1 is also involved in the hypertrophy of neonatal rat cardiomyocytes [ 62 ]. Alongside this, miR-25 can regulate the proliferation of cardiomyocytes derived from human embryonic stem cells, modulating the F-Box and WD repeat domain containing 7 (FBXW7) gene, which is involved in the proteasome-mediated degradation of proteins such as cyclin E [ 63 ]. In an experimental model involving rats with ischemia/reperfusion injuries, Qin X.F.…”

Non-coding RNAs in Cardiac Regeneration

“…miR-25, which has the same seed sequences as miR-92a, is also able to stimulate cardiomyocyte proliferation in neonatal rat cardiomyocytes (NRCs) by targeting the Bcl-like protein BCL2 like 11 (Bim) ( Qin et al, 2019 ). Another study has also shown that miR-25 overexpression promotes cardiomyocyte proliferation in hPSC-CMs by targeting F-Box And WD Repeat Domain Containing 7 (FBXW7) ( Wang et al, 2020 ). Overexpressing miR-204 improves cardiomyocyte proliferation via targeting Jarid2, resulted in the upregulation of cell cycle regulator Cyclin A, Cyclin B, cyclin D2, Cyclin E, CDC2 and PCNA in vitro and in vivo ( Liang et al, 2015 ).…”