The combination of four cell-cycle regulators: a new direction for inducing adult cardiomyocyte proliferation

Abstract

Cardiomyocytes, also known as myocardial fibers, are the muscle cells which form the heart tissue. Previous studies have indicated that fetal mammalian cardiomyocytes maintain the regeneration capacity, which promotes the fetal heart growth. Regardless of environment insults including nutrient deprivation, changes of blood flow, along with mechanical and volume loading [1], embryonic mammalian cardiac muscle cells are also related to robust proliferation response. Similarly, the hearts of 1-day-old neonatal mice could also be fully regenerated after surgical resection of the left ventricular apex or myocardial infarction (MI) [2]. Intriguingly, studies have also shown that certain fish, such as adult zebrafish, or urodele amphibians retain an observable capacity for regeneration [3]. In response to cardiac damage, zebrafish exhibits complete regeneration primarily due to the proliferation of cardiomyocytes. Nevertheless, the mouse heart loses this potential in the first week after birth. Tragically, it has been demonstrated that the adult mammalian cardiomyocyte unable to proliferate (Fig. 1A). Adult heart is considered as a terminally differentiated organ [4] that has limited capacity for cardiomyogenesis. Therefore, patients suffering from cardiovascular failure are unable to repair the heart and survive after MI or other heart diseases. Therefore, finding a feasible approach to stimulate adult mammalian cardiomyocyte proliferation is beneficial for the treatment of MI and other heart diseases. As we all know, cell cycle is the complete cell process from the completion of one mitosis to the end of the next split, which is regulated by a series of cell-cycle regulators. Cyclins and their catalytic partners, the cyclin-dependent kinases (CDKs) play central roles in this process. At a specific stage of cell cycle, the heterodimeric cyclin–CDK complexes phosphorylate a set of cellular proteins and further promote these phosphorylated proteins to enter the progression through the G1 phase and drive DNA synthesis. Most importantly, cyclin–CDK complexes also trigger the segregation of the newlyformed double-stranded chromosomes to the daughter cells in mitosis, thereby ensuring the cell-cycle progress [5]. Nevertheless, it has been found that only a few cyclin–CDK complexes directly participate in the cell division cycle. For example, the combination of CDK2 and cyclin D (CCND) plays an important role in G1-S phase. CDK1–cyclin A (CCNA) complexes are involved in the S-G2 phase, while CDK1–cyclin B (CCNB) complexes are responsible for promoting the G2-M phase and inducing cardiomyocyte karyokinesis. CDK4–CCND complexes promote the G1-S phase and cardiomyocyte DNA synthesis. At the same time, CCND–CDK4 and CCND– CDK6 complexes phosphorylate and inactivate pocket proteins, thereby enabling the transcription of genes that participate in cellcycle progression (Fig. 1B). Although it has been well established that cyclin–CDK complexes drive cell-cycle progression, mammalian cyclins and CDKs may also play important roles in other cellular events [6], such as gene transcription, DNA damage repair, cell death, cell differentiation, immune response, and metabolism. A previous report also showed that overexpression of cyclins and CDKs are implicated in human tumors [7]. Recently, Mohamed et al. [6]. reported that overexpression of CDK1, CDK4, CCNB, CCND, and a combination of cell-cycle regulators, efficiently induce adult cardiomyocyte proliferation and subsequent cell survival in vitro and in vivo. CDK1, CCNB, CDK4, and CCND play an important role in the post-mitotic cell proliferation. They further revealed that CDK1, CCNB, and aurora kinase B induce the most of the cardiac cells that undergo complete cell division [6]. By comprehensively testing the cell-cycle regulators, they observed that the combination of CDK1–CCNB complexes and CDK4–CCND complexes most efficiently contribute to the onset of the adult cardiomyocyte proliferation. Furthermore, they explored whether the combination of CDK1–CCNB–CDK4–CCND notably induce the adult cardiomyocyte division in vivo through lineage tracing method to track cellular proliferation, differentiation,