LncRNAs in Cardiomyocyte Maturation: New Window for Cardiac Regenerative Medicine

Abstract

Cardiomyocyte (CM) maturation, which is characterized by structural, functional, and metabolic specializations, is the last phase of CM development that prepares the cells for efficient and forceful contraction throughout life. Over the past decades, CM maturation has gained increased attention due to the fact that pluripotent stem cell-derived CMs are structurally, transcriptionally, and functionally immature and embryonic-like, which causes a defect in cell replacement therapy. The current challenge is to discover and understand the molecular mechanisms, which control the CM maturation process. Currently, emerging shreds of evidence emphasize the role of long noncoding RNAs (lncRNAs) in regulating different aspects of CM maturation, including myofibril maturation, electrophysiology, and Ca²⁺ handling maturation, metabolic maturation and proliferation to hypertrophy transition. Here, we describe the structural and functional characteristics of mature CMs. Furthermore, this review highlights the lncRNAs as crucial regulators of different aspects in CM maturation, which have the potential to be used for mature CM production. With the current advances in oligonucleotide delivery; lncRNAs may serve as putative therapeutic targets to produce highly mature CMs for research and regenerative medicine.

Keywords: cardiomyocyte maturation; lncRNAs; myofibril maturation; regenerative medicine.

Figure 1

Cardiomyocyte maturation characteristics. (A) Cardiomyocytes undergo myofibril maturation, which is followed by increasing the sarcomere length, assembly and expansion; improvement of sarcomere alignment and M-line formation. (B) Calcium handling maturation is mediated by the development of T-tubules, expression of calcium handling proteins and increased volume of calcium stores of the sarcoplasmic reticulum. (C) Metabolic maturation causes the switch of glycolysis to fatty acid β-oxidation and increases in mitochondria number. The cristae structures in mitochondria are densely organized, and the mitochondria are localized close to the SR and myofibrillar structures to support efficient ATP transition. (D,E) Proliferation-to-hypertrophy transition occurs at the time of maturation. The postnatal heart size is increased through maturational hypertrophy followed by polyploidization (top) cardiomyocyte proliferation rate declines through downregulation of cell-cycle-associated genes (bottom).

Figure 2

Classification of LncRNA. (A) LncRNAs may be divided based on their position and orientation relative to protein-coding genes (genomic context) or by distinct chromatin marks around their transcription start-sites (chromatin context). (B) More details are described within the text.

Figure 3

Roles of Mhrt-LncRNA in cardiomyocyte maturation. Mhrt-lncRNA has a different regulatory function in myofibril formation and hypertrophy at the stage of cardiomyocyte maturation. Mhrt regulates the Myh6/Myh7 ratio and their expression during the development through Brg1 inhibition. Cardiomyocyte hypertrophy regulation is also occurred by Mhrt through myocardin expression and function regulation. More details are described within the text.

Figure 4

Regulatory effect of H19-LncRNA in cardiomyocyte maturation. (A) H19 regulates the cardiomyocyte maturation process at different steps, including apoptosis, proliferation, hypertrophy and contraction. A. H19 physically interacts with PRC2 to suppress pro-hypertrophic NFAT signaling. (B) H19 regulates the cardiac ca2+ flux and cardiac contraction function through the H19-miR-675-CamkIIδ axis. (C,D) The regulatory function of H19 lncRNA in mitochondrial apoptotic pathway and cardiomyocyte proliferation is mediated through either H19-miR-675-Vdac1 (C) or H19-miR-19b-Sox6 (D) axis. More details are described within the text.

Figure 5

The regulatory function of main lncRNAs related to cardiomyocyte maturation. (A) Zfas1 and Dach1 manipulate the cardiac function by regulating Ca2+ homeostasis, proliferation and apoptosis in mature cardiomyocytes. This happened through negative regulation of Serca2a through either its expression repression or functional restriction and regulating the Hippo signaling pathway. (B) Carl and Mdrl-lncRNAs regulate mitochondrial fission and apoptosis through regulating the combination of miRNAs and transcription factors in adult cardiomyocytes. Carl lncRNA sponges miR-539 in the cardiomyocytes, which in turn upregulates the expression of Phb2 as its target gene. Mdrl-lncRNA has direct interaction with miR-361 and downregulates its expression levels, which in turn promotes the processing of pri-miR-484 and represses the Fis1 expression. (C) Cpr lncRNA attenuates the cardiomyocyte proliferation in postnatal and adult hearts through direct interaction and recruitment of DNMT3A protein Mcm3 promoter to repress its expression. Sarrah lncRNA regulates cardiomyocyte survival and enhances the contractile capacity of adult cardiomyocytes through activating the NRF2 signaling pathway. Sarrah directly binds to the promoter region of the Nrf2 gene through RNA-DNA triple helix formation and recruits CRIP2 and p300 transcription factors to induce its expression. More details are described within the text.