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Review
. 2017 Mar;74(6):1019-1034.
doi: 10.1007/s00018-016-2375-y. Epub 2016 Sep 30.

Understanding cardiomyocyte proliferation: an insight into cell cycle activity

Murugavel Ponnusamy  1 , Pei-Feng Li  2 , Kun Wang  3
Affiliations
Review

Understanding cardiomyocyte proliferation: an insight into cell cycle activity

Murugavel Ponnusamy et al. Cell Mol Life Sci. 2017 Mar.

Abstract

Cardiomyocyte proliferation and regeneration are key to the functional recovery of myocardial tissue from injury. In the recent years, studies on cardiomyocyte proliferation overturned the traditional belief that adult cardiomyocytes permanently withdraw from the cell cycle activity. Hence, targeting cardiomyocyte proliferation is one of the potential therapeutic strategies for myocardial regeneration and repair. To achieve this, a deep understanding of the fundamental mechanisms involved in cardiomyocyte cell cycle as well as differences between neonatal and adult cardiomyocytes' cell cycle activity is required. This review focuses on the recent progress in understanding of cardiomyocyte cell cycle activity at different life stages viz., gestation, birth, and adulthood. The temporal expression/activities of major cell cycle activators (cyclins and CDKs), inhibitors (p21, p27, p57, p16, and p18), and cell-cycle-associated proteins (Rb, p107, and p130) in cardiomyocytes during gestation and postnatal life are described in this review. The influence of different transcription factors and microRNAs on the expression of cell cycle proteins is demonstrated. This review also deals major pathways (PI3K/AKT, Wnt/β-catenin, and Hippo-YAP) associated with cardiomyocyte cell cycle progression. Furthermore, the postnatal alterations in structure and cellular events responsible for the loss of cell cycle activity are also illustrated.

Keywords: Cardiomyocytes; Cell cycle; Cyclins; MicroRNAs; Signaling pathways; Transcription factors.

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Figures

Fig. 1
Fig. 1
Diagrammatic representation of temporal expression/activity of cell cycle proteins in cardiomyocytes at different stages of heart development. The circles with different shades indicate the expression and activity of different cell cycle proteins. Dark shade formula image indicates higher expression and activity. Lighter shades formula image indicate comparatively decreased/lower activity. Empty circles formula image indicate barely detectable or undetectable. CDK cyclin-dependent kinase, CDC cell division cycle protein, Rb retinoblastoma
Fig. 2
Fig. 2
Transcription factors involved in regulation of cardiomyocyte cell cycle activity. The transcription factors, such as E2F1, E2F2, E2F4, CASZ1, GATAT4, Tbx20, and FoxM1, positively regulate cell cycle by the increasing expression of cyclins. E2F transcription factors promote the cell cycle progression by increasing expression of cyclin D, E, A, and B. Tbx20 promotes cell cycle by increasing the expression of both G1/S and G2/M cyclins (cyclins D, E and A). GATA4 upregulates cyclin D and cyclin A expression and it contributes to G1/S-phase transition. FoxM1 acts as a mitosis inducing factor by increasing expression of cyclin B. The transcription factors, such as Meis1, MEF2D, FoxO1, and FoxO3, inhibit cell cycle progression by increasing the expression of p21, p27, p15, and p16
Fig. 3
Fig. 3
Major pathways involved in cardiomyocyte proliferation. The proliferation stimuli activates mitogenic receptors (ErbB2, ErbB4, IGF1R, fibroblast growth factor inducible molecule 14 receptor (FN14R), etc.) and its cytoplasmic signaling, such as PI3K-AKT, Wnt/β-catenin, and YAP. Wnt and PI3K-AKT pathways directly promote β-catenin nuclear translocation by inhibiting GsK3β, which blocks β-catenin activity by increasing its phosphorylation and degradation. Wnt and Frizzled receptors classically activate disheveled (Dvl) protein to block β-catenin destructive complex. The nuclear β-catenin binds with LEF/TCF transcription factors and this complex upregulates expression of various cell cycle genes. YAP is a positive regulator of many cell cycle genes expression. Non-phosphorylated form of YAP (active) translocates to the nucleus and binds with TEAD to activate cell cycle gene expression. YAP and PI3K-AKT pathway are interconnected. YAP directly upregulates PI3K-AKT pathway by increasing the expression of catalytic submit of PI3K (Pi3kcb), and thereby it indirectly promotes β-catenin activity. In addition, YAP interacts with β-catenin in the nucleus and enhances its transcriptional activity. In contrast, p38MAPK activation inhibits PI3K-AKT pathway to turn off cell cycle progression. GPCR-activated Hippo kinases (Mst1/2, Sav1, and LATS1/2) regulate (switch off) YAP activity by phosphorylation. The growth-factor-dependent activation of PI3K stimulates the dissociation of PDK1 from hippokinase complex (Mst1/2-Sav1-LATS1/2), which leads to the dispersing of YAP inactivation complex and turns on YAP signaling
Fig. 4
Fig. 4
MicroRNAs in cardiomyocyte cell cycle proteins expression. MicroRNAs (miRNAs) are differentially expressed by cardiomyocytes during fetal and postnatal heart development. Among the cell-cycle-associated miRNAs, miR499, miR302-367, miR590, miR199a, miR204, and miR17-29 positively regulate cardiomyocyte cell cycle, while miR1, miR15, miR16, miR26a, miR29a, miR30a, 34a, miR133a, and miR141 negatively regulate cell cycle by modulating the expression of different cyclins (cyclins D, E, A, and B) and cyclin-dependent kinases (CDK1, 2, and 6). In contrast to all these miRNAs, miR195 blocks G2/M transition by inhibiting the expression of chek1
Fig. 5
Fig. 5
Cell cycle variation yields cardiomyocytes with hypertrophic growth, multiple nuclei, and polyploidy. The solid green arrow indicates normal flow of cell cycle, and dotted line indicates obstruction/impairment of cell cycle phases. The solid red arrow indicates cells bypassing failed/impaired cell cycle phase and proceeding to other phases of cell cycle. In typical cell cycle, the cell enters G1 phase and gain sufficient growth prior to the onset of DNA replication in S phase. Another gap phase (G2) prepares the cell for the nuclear division (ND) and cytokinesis (CK) in M phase. In hypertrophic growth, cells enter G1 phase and exit before or after the entry into S phase. The polyploidazation and multinucleation result from oscillation of cell cycle activity between gap phase (G) and DNA synthesis phase (S) when there is a defect in mitotic phase. During multinucleation process, the cell normally completes all the events of cell cycle, including telophase (nuclear division; ND) of M phase, but it fails at cytokinesis (CK) part of M phase. The polyploidazation is distinct from multinucleation, which is due to the failure of entry into mitotic phase (M phase). In this event, the cell completes G1, S, and G2 phases of cell cycle and it exits from cell cycle or continues another round without entering into M phase
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