GSK-3β Inhibitor CHIR-99021 Promotes Proliferation Through Upregulating β-Catenin in Neonatal Atrial Human Cardiomyocytes

Wang, Shoubao; Ye, Lincai; Li, Minghui; Liu, Jinfen; Jiang, Chuan; Hong, Haifa; Zhu, Huajian; Sun, Yanjun

doi:10.1097/fjc.0000000000000429

Cited by 33 publications

(24 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our study, we demonstrated that CHIR99021 treatment exhibited the best potential for cardiac regeneration as it is not only more efficient in inducing cardioproliferation, it also does not interfere with the function of N-cadherin required for cell adhesion and cardiac electrophysiological activity [ 42 ]. Consistent with this, recent studies have demonstrated that CHIR99021 alone can promote cardiomyocyte proliferation in neonatal atrial human cardiomyocytes [ 43 ], emphasizing again the feasibility of using CHIR99021 as a potential drug that can endogenously repair injured cardiac tissue and promote cardiac regeneration. We found that CHIR99021 exhibits cytotoxic effects at a concentration of more than 1 μM, plausibly due to several reasons which were not uncovered in this study.…”

Section: Discussionmentioning

confidence: 59%

Wnt/β-catenin-mediated signaling re-activates proliferation of matured cardiomyocytes

Fan

Pang

et al. 2018

Stem Cell Res Ther

View full text Add to dashboard Cite

BackgroundThe Wnt/β-catenin signaling pathway plays an important role in the development of second heart field (SHF Isl1+) that gives rise to the anterior heart field (AHF) cardiac progenitor cells (CPCs) for the formation of the right ventricle, outflow tract (OFT), and a portion of the inflow tract (IFT). During early cardiogenesis, these AHF CPCs reside within the pharyngeal mesoderm (PM) that provides a microenvironment for them to receive signals that direct their cell fates. Here, N-cadherin, which is weakly expressed by CPCs, plays a significant role by promoting the adhesion of CPCs within the AHF, regulating β-catenin levels in the cytoplasm to maintain high Wnt signaling and cardioproliferation while also preventing the premature differentiation of CPCs. On the contrary, strong expression of N-cadherin observed throughout matured myocardium is associated with downregulation of Wnt signaling due to β-catenin sequestration at the cell membrane, inhibiting cardioproliferation. As such, upregulation of Wnt signaling pathway to enhance cardiac tissue proliferation in mature cardiomyocytes can be explored as an interesting avenue for regenerative treatment to patients who have suffered from myocardial infarction.MethodsTo investigate if Wnt signaling is able to enhance cellular proliferation of matured cardiomyocytes, we treated cardiomyocytes isolated from adult mouse heart and both murine and human ES cell-derived matured cardiomyocytes with N-cadherin antibody or CHIR99021 GSK inhibitor in an attempt to increase levels of cytoplasmic β-catenin. Immunostaining, western blot, and quantitative PCR for cell proliferation markers, cell cycling markers, and Wnt signaling pathway markers were used to quantitate re-activation of cardioproliferation and Wnt signaling.ResultsN-cadherin antibody treatment releases sequestered β-catenin at N-cadherin-based adherens junction, resulting in an increased pool of cytoplasmic β-catenin, similar in effect to CHIR99021 GSK inhibitor treatment. Both treatments therefore upregulate Wnt signaling successfully and result in significant increases in matured cardiomyocyte proliferation.ConclusionAlthough both N-cadherin antibody and CHIR99021 treatment resulted in increased Wnt signaling and cardioproliferation, CHIR99021 was found to be the more effective treatment method for human ES cell-derived cardiomyocytes. Therefore, we propose that CHIR99021 could be a potential therapeutic option for myocardial infarction patients in need of regeneration of cardiac tissue.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-1086-8) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 59%

Wnt/β-catenin-mediated signaling re-activates proliferation of matured cardiomyocytes

Fan

Pang

et al. 2018

Stem Cell Res Ther

View full text Add to dashboard Cite

show abstract

“…Addition of CHIR99021 results in robust proliferation of mouse and human PSC-derived cardiomyocytes ( Figure 2 ), consistent with the essential roles of the Wnt/β-catenin pathway for ventricular cardiomyocyte proliferation during embryonic development ( Klaus et al, 2012 ; Buikema et al, 2013 , 2020 ). In addition, Wnt signaling-induced cardiomyocyte proliferation is also observed in human neonatal cardiomyocytes and mouse adult cardiomyocytes ( Wang et al, 2016 ; Fan et al, 2018 ). As NOTCH and Hippo pathways control cardiomyocyte proliferation through regulating Wnt/β-catenin pathway, manipulation of these pathway activities could boost the proliferation of early human iPSC-CMs to generate clinical-level magnitude for repairing the damaged myocardium.…”

Section: Harness Human Ipsc-derived Cardiomyocytes For Heart Regeneramentioning

confidence: 97%

Cardiomyocyte Proliferation and Maturation: Two Sides of the Same Coin for Heart Regeneration

Zhao

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

In the past few decades, cardiac regeneration has been the central target for restoring the injured heart. In mammals, cardiomyocytes are terminally differentiated and rarely divide during adulthood. Embryonic and fetal cardiomyocytes undergo robust proliferation to form mature heart chambers in order to accommodate the increased workload of a systemic circulation. In contrast, postnatal cardiomyocytes stop dividing and initiate hypertrophic growth by increasing the size of the cardiomyocyte when exposed to increased workload. Extracellular and intracellular signaling pathways control embryonic cardiomyocyte proliferation and postnatal cardiac hypertrophy. Harnessing these pathways could be the future focus for stimulating endogenous cardiac regeneration in response to various pathological stressors. Meanwhile, patient-specific cardiomyocytes derived from autologous induced pluripotent stem cells (iPSCs) could become the major exogenous sources for replenishing the damaged myocardium. Human iPSC-derived cardiomyocytes (iPSC-CMs) are relatively immature and have the potential to increase the population of cells that advance to physiological hypertrophy in the presence of extracellular stimuli. In this review, we discuss how cardiac proliferation and maturation are regulated during embryonic development and postnatal growth, and explore how patient iPSC-CMs could serve as the future seed cells for cardiac cell replacement therapy.

show abstract

“…These results were confirmed by Kim et al (2016), who showed that BIO not only induced BrdU incorporation in cultured neonatal rat CMs but also reduced BrdU incorporation in rat neonatal cardiac fibroblasts. Increased proliferation was also observed in cultured human atrial CMs treated with the GSK3-b inhibitor CHIR99021, albeit that the increase in proliferating CMs was modest (control: 1.83% 6 0.01%; CHIR: 2.67% 6 0.08%); in this study, inhibition of WNT/b-catenin signaling with 4-(1,3,3a,4,7,7a-hexahydro-1,3-dioxo-4,7-methano-2H-isoindol-2-yl)-N-8-quinolinyl-benzamide (IWR-1) resulted in a ∼35% reduction in CM proliferation (Wang et al, 2016). Adenoviral-mediated overexpression of b-catenin in neonatal rat CM, however, showed an initiation of the cell cycle; this did not result in an increased number of CMs but augmented CM hypertrophy and the number of binucleated cells (Hahn et al, 2006).…”

Section: Wnt Signalingmentioning

confidence: 56%

Interventions in WNT Signaling to Induce Cardiomyocyte Proliferation: Crosstalk with Other Pathways

Blankesteijn

2019

Mol Pharmacol

View full text Add to dashboard Cite

Myocardial infarction is a frequent cardiovascular event and a major cause for cardiomyocyte loss. In adult mammals, cardiomyocytes are traditionally considered to be terminally differentiated cells, unable to proliferate. Therefore, the woundhealing response in the infarct area typically yields scar tissue rather than newly formed cardiomyocytes. In the last decade, several lines of evidence have challenged the lack of proliferative capacity of the differentiated cardiomyocyte: studies in zebrafish and neonatal mammals have convincingly demonstrated the regenerative capacity of cardiomyocytes. Moreover, multiple signaling pathways have been identified in these models that-when activated in adult mammalian cardiomyocytes-can reactivate the cell cycle in these cells. However, cardiomyocytes frequently exit the cell cycle before symmetric division into daughter cells, leading to polyploidy and multinucleation. Now that there is more insight into the reactivation of the cell cycle machinery, other prerequisites for successful symmetric division of cardiomyocytes, such as the control of sarcomere disassembly to allow cytokinesis, require more investigation. This review aims to discuss the signaling pathways involved in cardiomyocyte proliferation, with a specific focus on wingless/int-1 protein signaling. Comparing the conflicting results from in vitro and in vivo studies on this pathway illustrates that the interaction with other cells and structures around the infarct is likely to be essential to determine the outcome of these interventions. The extensive crosstalk with other pathways implicated in cardiomyocyte proliferation calls for the identification of nodal points in the cell signaling before cardiomyocyte proliferation can be moved forward toward clinical application as a cure of cardiac disease. SIGNIFICANCE STATEMENT Evidence is mounting that proliferation of pre-existing cardiomyocytes can be stimulated to repair injury of the heart. In this review article, an overview is provided of the different signaling pathways implicated in cardiomyocyte proliferation with emphasis on wingless/int-1 protein signaling, crosstalk between the pathways, and controversial results obtained in vitro and in vivo.

show abstract

GSK-3β Inhibitor CHIR-99021 Promotes Proliferation Through Upregulating β-Catenin in Neonatal Atrial Human Cardiomyocytes

Cited by 33 publications

References 30 publications

Wnt/β-catenin-mediated signaling re-activates proliferation of matured cardiomyocytes

Wnt/β-catenin-mediated signaling re-activates proliferation of matured cardiomyocytes

Cardiomyocyte Proliferation and Maturation: Two Sides of the Same Coin for Heart Regeneration

Interventions in WNT Signaling to Induce Cardiomyocyte Proliferation: Crosstalk with Other Pathways

Contact Info

Product

Resources

About