Discovering small molecules as Wnt inhibitors that promote heart regeneration and injury repair

Xie, Shuying; Fu, Wei; Yu, Guangju; Hu, Xueli; Lai, Kaa Seng; Peng, Xiangwen; Zhou, Yating; Zhu, Xuejiao; Christov, Plamen P.; Sawyer, Leah; Ni, Terri T.; Sulikowski, Gary A.; Yang, Zhongzhou; Lee, Ethan; Zeng, Chunyu; Wang, Wei E; Zhong, Tao

doi:10.1093/jmcb/mjz023

Cited by 24 publications

(25 citation statements)

References 39 publications

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“…A similar observation of cells expressing CM markers at the epicardial side was reported by treating female rats with ICG-001, a compound blocking the binding of b-catenin to the transcription complex (Sasaki et al, 2013). Recently, targeting WNT/b-catenin at the level of the transcription complex was also demonstrated to increase the newly formed CMs and reduce scarring in the zebrafish model of apical amputation (Xie et al, 2019). Taken together, the majority of studies now shows that targeting WNT/b-catenin at the level of the transcription complex by either a genetic or a pharmacological intervention induces a proliferative response in cells showing expression of CM markers located at the epicardial and endocardial borders of the infarct.…”

Section: Wnt Signalingsupporting

confidence: 69%

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

Blankesteijn

2019

Mol Pharmacol

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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.

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Section: Wnt Signalingsupporting

confidence: 69%

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

Blankesteijn

2019

Mol Pharmacol

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“…The compound Cardiomogen 1 (CDMG1) was suggested by preliminary work to inhibit β-catenin and to negatively affect TCF/LEF-mediated transcription. Thus, CDMG1 was tested in a mouse permanent LAD ligation model and it exhibited a strong inhibitory effect on the scar length, indicating a smaller infarct [ 63 ]. In the same direction, Matteucci et al applied the small molecule WNT inhibitor SEN195 in rats overexpressing a β-catenin responsive TCF/LEF reporter via AAV9 gene therapy.…”

Section: Effect Of Interventions In Wnt Signaling On Infarct Sizementioning

confidence: 99%

“…Administration of the small molecule β-catenin/TCF inhibitor SEN195 exhibited a strong ~1.5-fold increase in EF and important reductions in LV volumes in both systole and diastole, in a mouse MI model [ 15 ]. Notably, similar beneficial effects in EF and FS and LVIDD were conferred by CDMG1 i/p injections when administered for 27 days in mice following MI [ 63 ]. It is clear that the conclusions from the above studies point to an attenuating effect of WNT/β-catenin signaling inhibition on cardiac dysfunction and thus, a beneficial effect in attenuating LV remodeling.…”

Section: Effects Of Interventions In Wnt Signaling On Cardiac Funcmentioning

confidence: 99%

Effect of Interventions in WNT Signaling on Healing of Cardiac Injury: A Systematic Review

Daskalopoulos

Blankesteijn

2021

Cells

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The wound healing that follows myocardial infarction is a complex process involving multiple mechanisms, such as inflammation, angiogenesis and fibrosis. In the last two decades, the involvement of WNT signaling has been extensively studied and effects on virtually all aspects of this wound healing have been reported. However, as often is the case in a newly emerging field, inconsistent and sometimes even contradictory findings have been reported. The aim of this systematic review is to provide a comprehensive overview of studies in which the effect of interventions in WNT signaling were investigated in in vivo models of cardiac injury. To this end, we used different search engines to perform a systematic search of the literature using the key words “WNT and myocardial and infarction”. We categorized the interventions according to their place in the WNT signaling pathway (ligand, receptor, destruction complex or nuclear level). The most consistent improvements of the wound healing response were observed in studies in which the acylation of WNT proteins was inhibited by administering porcupine inhibitors, by inhibiting of the downstream glycogen synthase kinase-3β (GSK3β) and by intervening in the β-catenin-mediated gene transcription. Interestingly, in several of these studies, evidence was presented for activation of cardiomyocyte proliferation around the infarct area. These findings indicate that inhibition of WNT signaling can play a valuable role in the repair of cardiac injury, thereby improving cardiac function and preventing the development of heart failure.

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“…For instances, proliferative CMs in zebrafish are mononuclear and diploid, whereas most adult human CMs become polyploidy that restrains CM proliferation (Xin et al, 2013;Tzahor and Poss, 2017). Although CM renewal is extremely low in uninjured mammalian hearts, a small number of proliferative CMs can be detectable in the injury border zone of murine hearts after myocardial infarction (Malliaras et al, 2013;Xiang et al, 2016;Xie et al, 2020). We believe that specific factors and mechanisms obtained from zebrafish regeneration study should be confirmed in mammal system such as mouse before exploring potential therapeutics in humans.…”

Section: Discussionmentioning

confidence: 99%

Tbx20 Induction Promotes Zebrafish Heart Regeneration by Inducing Cardiomyocyte Dedifferentiation and Endocardial Expansion

Fang

Lai

She

et al. 2020

Front. Cell Dev. Biol.

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Heart regeneration requires replenishment of lost cardiomyocytes (CMs) and cells of the endocardial lining. However, the signaling regulation and transcriptional control of myocardial dedifferentiation and endocardial activation are incompletely understood during cardiac regeneration. Here, we report that T-Box Transcription Factor 20 (Tbx20) is induced rapidly in the myocardial wound edge in response to various sources of cardiac damages in zebrafish. Inducing Tbx20 specifically in the adult myocardium promotes injury-induced CM proliferation through CM dedifferentiation, leading to loss of CM cellular contacts and re-expression of cardiac embryonic or fetal gene programs. Unexpectedly, we identify that myocardial Tbx20 induction activates the endocardium at the injury site with enhanced endocardial cell extension and proliferation, where it induces the endocardial Bone morphogenetic protein 6 (Bmp6) signaling. Pharmacologically inactivating endocardial Bmp6 signaling reduces expression of its targets, Id1 and Id2b, attenuating the increased endocardial regeneration in tbx20overexpressing hearts. Altogether, our study demonstrates that Tbx20 induction promotes adult heart regeneration by inducing cardiomyocyte dedifferentiation as well as non-cell-autonomously enhancing endocardial cell regeneration.

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Discovering small molecules as Wnt inhibitors that promote heart regeneration and injury repair

Cited by 24 publications

References 39 publications

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

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

Effect of Interventions in WNT Signaling on Healing of Cardiac Injury: A Systematic Review

Tbx20 Induction Promotes Zebrafish Heart Regeneration by Inducing Cardiomyocyte Dedifferentiation and Endocardial Expansion

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