The role of Wnt regulation in heart development, cardiac repair and disease: A tissue engineering perspective

Pahnke, Aric; Conant, Genna; Huyer, Locke Davenport; Zhao, Yong; Feric, Nicole

doi:10.1016/j.bbrc.2015.11.060

Cited by 55 publications

(40 citation statements)

References 71 publications

(71 reference statements)

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“…As a result, the further activation of JNK signaling under 25% with inhibited Piezo1 indicates that the cardiomyocytes might be under mechanical overloading ( Figure 3 C). Consistent with Pahnke A. et al review in which the Wnt activation is reported to be involved in cardiac development, repair, and disease [ 26 ]. Mechanistically, the Wnt binds to receptor Frizzled (Frz), as well as low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6) to stabilize cytosolic β-catenin through glycogen synthase kinase 3 (GSK-3) inhibition.…”

Section: Discussionsupporting

confidence: 78%

Mechanical Stretching Simulates Cardiac Physiology and Pathology through Mechanosensor Piezo1

Wong

Juang

Tsai

et al. 2018

JCM

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The dynamics of a living body enables organs to experience mechanical stimulation at cellular level. The human cardiomyocytes cell line provides a source for simulating heart dynamics; however, a limited understanding of the mechanical stimulation effect on them has restricted potential applications. Here, we investigated the effect of mechanical stimulation on the cardiac function-associated protein expressions in human cardiomyocytes. Human cardiomyocyte cell line AC16 was subjected to different stresses: 5% mild and 25% aggressive, at 1 Hz for 24 h. The stretched cardiomyocytes showed down-regulated Piezo1, phosphorylated-Ak transforming serine473 (P-AKTS473), and phosphorylated-glycogen synthase kinase-3 beta serine9 P-GSK3βS9 compared to no stretch. In addition, the stretched cardiomyocytes showed increased low-density lipoprotein receptor-related protein 6 (LRP6), and phosphorylated-c-Jun N-terminal kinase threonine183/tyrosine185 (P-JNKT183/Y185). When Piezo inhibitor was added to the cells, the LRP6, and P-JNKT183/Y185 were further increased under 25%, but not 5%, suggesting that higher mechanical stress further activated the wingless integrated-(Wnt)-related signaling pathway when Piezo1 was inhibited. Supporting this idea, when Piezo1 was inhibited, the expression of phosphorylated-endothelial nitric oxide synthase serine1177 (P-eNOSS1177) and release of calcium ions were reduced under 25% compared to 5%. These studies demonstrate that cyclic mechanical stimulation affects cardiac function-associated protein expressions, and Piezo1 plays a role in the protein regulation.

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Section: Discussionsupporting

confidence: 78%

Mechanical Stretching Simulates Cardiac Physiology and Pathology through Mechanosensor Piezo1

Wong

Juang

Tsai

et al. 2018

JCM

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“…These highly proliferative cells form the second heart field and are tightly regulated by Wnt2 via the β -catenin pathway ( Tian et al, 2010 ; Norden and Kispert, 2012 ; Ruiz-Villalba et al, 2016 ). Removal of the β -catenin resulted in a reduction of cells within SHF with subsequent aberrant development of the right ventricle and outflow tract ( Klaus et al, 2007 ; Pahnke et al, 2016 ).…”

Section: Wnt Signaling In Cardiac and Vascular Developmentmentioning

confidence: 99%

WNT Signaling in Cardiac and Vascular Disease

et al. 2017

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WNT signaling is an elaborate and complex collection of signal transduction pathways mediated by multiple signaling molecules. WNT signaling is critically important for developmental processes, including cell proliferation, differentiation and tissue patterning. Little WNT signaling activity is present in the cardiovascular system of healthy adults, but reactivation of the pathway is observed in many pathologies of heart and blood vessels. The high prevalence of these pathologies and their significant contribution to human disease burden has raised interest in WNT signaling as a potential target for therapeutic intervention. In this review, we first will focus on the constituents of the pathway and their regulation and the different signaling routes. Subsequently, the role of WNT signaling in cardiovascular development is addressed, followed by a detailed discussion of its involvement in vascular and cardiac disease. After highlighting the crosstalk between WNT, transforming growth factor-β and angiotensin II signaling, and the emerging role of WNT signaling in the regulation of stem cells, we provide an overview of drugs targeting the pathway at different levels. From the combined studies we conclude that, despite the sometimes conflicting experimental data, a general picture is emerging that excessive stimulation of WNT signaling adversely affects cardiovascular pathology. The rapidly increasing collection of drugs interfering at different levels of WNT signaling will allow the evaluation of therapeutic interventions in the pathway in relevant animal models of cardiovascular diseases and eventually in patients in the near future, translating the outcomes of the many preclinical studies into a clinically relevant context.

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“…Many of the molecular mechanisms involved in the regulation of EndMT and angiogenesis remain unknown. Nevertheless, we know that the activity of several molecules, including NRP1 (Oh et al, 2002;Matkar et al, 2016), SNAI1 (Sun et al, 2018), SNAI2 (Welch-Reardon et al, 2015),n WNT5b (Wang et al, 2017a), and WNT7a (Howe et al, 2003;Pahnke et al, 2016) induce both EC activation and EndMT. Furthermore, TWIST1 (Mammoto et al, 2018), ZEB1 (Sanchez-Tillo et al, 2010), and ZEB2 (DaSilva-Arnold et al, 2018) induce EndMT and are not known to be involved in EC activation during angiogenesis.…”

Section: The Model As Theoretical Frameworkmentioning

confidence: 99%

A Computational Model of the Endothelial to Mesenchymal Transition

2020

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Endothelial cells (ECs) form the lining of lymph and blood vessels. Changes in tissue requirements or wounds may cause ECs to behave as tip or stalk cells. Alternatively, they may differentiate into mesenchymal cells (MCs). These processes are known as EC activation and endothelial-to-mesenchymal transition (EndMT), respectively. EndMT, Tip, and Stalk EC behaviors all require SNAI1, SNAI2, and Matrix metallopeptidase (MMP) function. However, only EndMT inhibits the expression of VE-cadherin, PECAM1, and VEGFR2, and also leads to EC detachment. Physiologically, EndMT is involved in heart valve development, while a defective EndMT regulation is involved in the physiopathology of cardiovascular malformations, congenital heart disease, systemic and organ fibrosis, pulmonary arterial hypertension, and atherosclerosis. Therefore, the control of EndMT has many promising potential applications in regenerative medicine. Despite the fact that many molecular components involved in EC activation and EndMT have been characterized, the system-level molecular mechanisms involved in this process have not been elucidated. Toward this end, hereby we present Boolean network model of the molecular involved in the regulation of EC activation and EndMT. The simulated dynamic behavior of our model reaches fixed and cyclic patterns of activation that correspond to the expected EC and MC cell types and behaviors, recovering most of the specific effects of simple gain and loss-of-function mutations as well as the conditions associated with the progression of several diseases. Therefore, our model constitutes a theoretical framework that can be used to generate hypotheses and guide experimental inquiry to comprehend the regulatory mechanisms behind EndMT. Our main findings include that both the extracellular microevironment and the pattern of molecular activity within the cell regulate EndMT. EndMT requires a lack of VEGFA and sufficient oxygen in the extracellular microenvironment as well as no FLI1 and GATA2 activity within the cell. Additionally Tip cells cannot undergo EndMT directly. Furthermore, the specific conditions that are sufficient to trigger EndMT depend on the specific pattern of molecular activation within the cell.

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The role of Wnt regulation in heart development, cardiac repair and disease: A tissue engineering perspective

Cited by 55 publications

References 71 publications

Mechanical Stretching Simulates Cardiac Physiology and Pathology through Mechanosensor Piezo1

Mechanical Stretching Simulates Cardiac Physiology and Pathology through Mechanosensor Piezo1

WNT Signaling in Cardiac and Vascular Disease

A Computational Model of the Endothelial to Mesenchymal Transition

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