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Ephrin-B1 blocks adult cardiomyocyte proliferation and heart regeneration

Marie Cauquil, Céline Mias, Céline Guilbeau-Frugier, Clément Karsenty, Marie-Hélène Seguelas, Gaël Genet, Edith Renaud-Gabardos, Anne-Catherine Prats, Véronique Pons, Maxime Branchereau, Christophe Heymes, Denis Calise, Olivier Lairez, Danièle Daviaud, Benjamin Honton, Céline Frongia, Bernard Ducommun, Marie-Bernadette Delisle, Dina N. Arvanitis, Atul Pathak, Jean-Michel Sénard, Céline Galés

Preprint posted on 15 August 2019 https://www.biorxiv.org/content/10.1101/735571v1

A new link between CM rod shape and proliferation - Ephrin B1 sequestration of Yap1 at the lateral membrane

Selected by Suraj Kannan

Background

During the perinatal time period, cardiomyocytes (CMs), the primary contractile cells of the heart, undergo a range of structural, functional, and metabolic changes [1]. These cells transition from small, round, disorganized cells to large, rod-shaped cells with significant subcellular organization. During this perinatal window (P1 to P7 in mice), CMs also lose their proliferative capacity. This change is of significant biomedical and clinical relevance, as later in life, loss of CMs during disease cannot be compensated due to the lack of a CM regenerative response. Thus, there is significant interest in trying to understand pathways enabling perinatal CM proliferation, and how these pathways are arrested early in postnatal life.

In this preprint, Cauquil and colleagues study a novel link between stabilization of the rod-shape phenotype of mature CMs and cell cycle arrest through ephrin-B1. The authors previously found that ephrin-B1 helps maintain the rod shape of CMs by stretching the lateral membrane independent of the contractile apparatus of the cell [2]. Correspondingly, CMs with ephrin-B1 knockout have a spindle-like shape with disrupted subcellular structure. Given the temporal overlap between transition to rod shaped CMs and cell cycle cessation, Cauquil and colleagues investigated the link between ephrin-B1 loss and CM proliferation.

Working model of Ephrin B1 lateral membrane stabilization in CMs. Taken from [2].

 

Key Findings

Ephrin-B1 Knockout CMs display increased proliferation following stimulation or cardiac injury

The authors used their previously established CM-specific efbn1 KO (cKO) to investigate the link between ephrin-B1 and proliferation. While adult CMs did not display increased proliferation under homeostatic conditions, the authors found that adult cKO CMs could be induced to undergo proliferation under a variety of stimuli. For example, in an in vitro CM culture system, the authors found that neuregulin-1 treatment (previously shown to induce CM proliferation) led to increased BrdU, Aurora B Kinase, and pHH3 staining in efbn1 cKO CMs compared to control. Similarly, the authors used a ventricular apical resection model in adult mice. In controls, this leads to failed regeneration and extensive scar tissue. However, in cKO mice, the resected area was at least partially replaced by myocardial tissue with decreased fibrosis, increased numbers of CMs, and increase in proliferative CMs (assessed by BrdU and Aurora B Kinase). Interestingly, aged cKO mice also demonstrate increased CM proliferation compared to control as a result of aging stress. Taken together, these results support a re-established proliferative capacity in efbn1 cKO CMs.

2. Ephrin-B1 directly interacts with Yap1 and sequesters it at the lateral membrane to inhibit proliferation

The authors next aimed to identify a mechanism by which ephrin-B1 regulates cell cycle capacity. Because Yap1 is a known effector of CM proliferation, the authors investigated the link between ephrin-B1 and Yap1. The authors found that efbn1 cKO CMs did not display increased Yap1 activation. However, in control CMs, inactivated Yap1 was found localized with ephrin-B1 at the lateral membrane; in the knockout, inactivated Yap1 was instead found throughout the cytosol and absent from the lateral membrane. The connection between ephrin-B1 and Yap1 was found to be direct based on coimmunoprecipitation and BRET assays. Moreover, the authors found that using their previously tested stimuli (neuregulin-1, apical resection, aging) led to Yap1 activation and nuclear localization only in the efbn1 cKO. These results suggest that ephrin-B1 sequesters Yap1 at the lateral membrane; knockout increases cytosolic availability and enables CM proliferation following an appropriate stimulus.

Working model of Ephrin B1 regulation of CM proliferation through Yap sequestration.

 

Why I Like This Preprint

One of the biggest ongoing areas of investigation in cardiac biology is that of CM proliferation and maturation. The perinatal window is a particularly fascinating time period, when CMs simultaneously undergo a number of important phenotypic changes (including structural, metabolic, cell cycle, electrophysiological etc.). Given that these changes coincide, it seems logical to think that they may be connected – and indeed, there is evidence that this might be the case [1], particularly in terms of metabolic and cell cycle changes. I enjoyed this preprint for not only highlighting a direct linkage between structural stabilization and cell cycle cessation, but for identifying a novel mechanism by which this occurs. The authors have highlighted an interesting new niche in CM subcellular structure (ephrin-B1 complex at the lateral membrane), and I am interested to see what further research uncovers about this complex.

Questions/Thoughts for Future Studies

The authors have already highlighted several tasty questions for future research. For one, there are several non-mammalian species that maintain proliferative CMs throughout their lives (such as zebrafish) – these species tend to have spindle-shaped CMs. Do these species lack an ephrin-B1 equivalent or is it structurally different? Secondly, how does the ephrin-B1 complex at the lateral membrane interact with other ECM-driven mechanisms for regulating CM cell cycle (for example, the agrin-dystrophin-glycoprotein complex [3])? I would also be interested in seeing the link between ephrin-B1 localization and hypoxia, given that hypoxic niches in the heart may contribute proliferative CMs [4]. Lastly, I am also curious to know a bit more about what happens to ephrin-B1 localization when CM structure is experimentally modulated. For example, ECM micropatterning has been used to pattern the structure of CMs in vitro, in turn leading to changes in myofibril alignment [5]. How would ephrin-B1 localization look in these cases?

[1] Kannan S, Kwon C. Regulation of cardiomyocyte proliferation during critical perinatal window. J Physiol (2019).

[2] Genet G et al. Ephrin-B1 is a novel specific component of the lateral membrane of the cardiomyocyte and is essential for the stability of cardiac tissue architecture cohesion. Circ Res (2012), 110(5):688-700.

[3] Bassat E et al. The extracellular matrix protein agrin promotes heart regeneration in mice. Nature 2017, 547(7662):179-184.

[4] Nakada Y et al. Hypoxia induces heart regeneration in adult mice. Nature (2017), 12;541(7636):222-227.

[5] McCain ML, Parker KK. Mechanotransduction: the role of mechanical stress, myocyte shape, and cytoskeletal architecture on cardiac function. Eur J Physiol (2011), 462:89–104.

Tags: cardiomyocyte, heart regeneration, proliferation, regenerative medicine

Posted on: 17 October 2019

doi: https://doi.org/10.1242/prelights.14629

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