Redirecting cardiac growth mechanisms for therapeutic regeneration

Karra, Ravi; Poss, Kenneth D.

doi:10.1172/jci89786

Cited by 56 publications

(42 citation statements)

References 155 publications

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“…Isolation and culture of adult CMs. Isolation of adult CMs from mice was performed using the Langendorff perfusion method as previously described (1). After isolation, dissociated CMs were plated on laminin 2 (10 µg/ml)-coated culture dishes.…”

Section: Supplementary Methodsmentioning

confidence: 99%

“…Real-time PCR was performed in 96-well plates using an ABI 7900 Fast (Applied Biosystems). Geometric mean values of GAPDH and HPRT housekeeping genes were used for normalization, as previously described (1). Melting curve analysis was performed to ensure a single PCR product and a specific amplification.…”

Section: Analysis Of Cardiomyocyte Cell Cyclementioning

confidence: 99%

“…In the recent years, reinitiating the proliferative activity of differentiated resident cardiomyocytes (CMs) has emerged as an exciting avenue for cardiac regenerative medicine 1 . Theoretically, this challenging concept could provide the opportunity to yield sufficient CMs to replace their profuse loss after myocardial damage.…”

Section: Introductionmentioning

confidence: 99%

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Ephrin-B1 blocks adult cardiomyocyte proliferation and heart regeneration

Cauquil

Mias

Guilbeau‐Frugier

et al. 2019

Preprint

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Aims.Deciphering the innate mechanisms governing the blockade of proliferation in adult cardiomyocytes (CMs) is challenging for mammalian heart regeneration. Despite the exit of CMs from the cell cycle during the postnatal maturation period coincides with their morphological switch to a typical adult rod-shape, whether these two processes are connected is unknown. Here, we examined the role of ephrin-B1, a CM rod-shape stabilizer, in adult CM proliferation and cardiac regeneration. Methods and results:Transgenic-or AAV9-based ephrin-B1 repression in adult mouse heart led to substantial proliferation of resident CMs and tissue regeneration to compensate for apex resection, myocardial infarction (MI) and senescence. Interestingly, in the resting state, CMs lacking ephrin-B1 did not constitutively proliferate, indicative of no major cardiac defects. However, they exhibited proliferation-competent signature, as indicated by higher mononucleated state and a dramatic decrease of miR-195 mitotic blocker, which can be mobilized under neuregulin-1 stimulation in vitro and in vivo. Mechanistically, the postmitotic state of the adult CM relies on ephrin-B1 sequestering of inactive phospho-Yap1, the effector of the Hippo-pathway, at the lateral membrane. Hence, ephrin-B1 repression leads to phospho-Yap1 release in the cytosol but CM quiescence at resting state. Upon cardiac stresses (apectomy, MI, senescence), Yap1 could be activated and translocated to the nucleus to induce proliferation-gene expression and consequent CM proliferation Conclusions:Our results identified ephrin-B1 as a new natural locker of adult CM proliferation and emphasize that targeting ephrin-B1 may prove a future promising approach in cardiac regenerative medicine for HF treatment. SignificanceThe mammalian adult heart is unable to regenerate due to the inability of cardiomyocytes (CMs) to proliferate and replace cardiac tissue lost. Exploiting CM-specific transgenic mice or AAV9-based gene therapy, this works identifies ephrin-B1, a specific rod-shape stabilizer of the adult CM, as a natural padlock of adult CM proliferation for compensatory adaptation to different cardiac stresses (apectomy, MI, senescence), thus emphasizing a new link between the adult CM morphology and their proliferation potential. Moreover, the study demonstrates proof-of-concept that targeting ephrin-B1 may be an innovative therapeutic approach for ischemic heart failure. MethodsDetailed materials and methods are provided in the Supplementary material online.Animal models. Global (KO) and CM-specific (cKO) efnb1 KO mice have already been described 23 . Efnb1 WT and KO mice were kept in a mixed S129/S4 × C57BL/6 background. All studies were performed on male and age-matched mice. Experimental animal protocols were carried out in accordance with the French regulation guidelines for animal experimentation and were approved by the French CEEA-122 ethical committee.Data analysis. The n number for each experiment and analysis are stated in each figure legend. All bar graphs, except fo...

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Section: Supplementary Methodsmentioning

confidence: 99%

Section: Analysis Of Cardiomyocyte Cell Cyclementioning

confidence: 99%

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Ephrin-B1 blocks adult cardiomyocyte proliferation and heart regeneration

Cauquil

Mias

Guilbeau‐Frugier

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Another intriguing analogy can be found with vertebrate cardiac muscle cells that represent an important target of regeneration medicine (Taylor et al, 2014; Kochegarov and Lemanski, 2016; Karra and Poss, 2017; Sommese et al, 2017). In these cells, Ca 2+ currents are also at the base of spike generation, while in skeletal muscle cells spikes rely upon occurrence and propagation of Na + spikes (see Figures 1C,D).…”

Section: Cephalopods Neuro-muscular Systemmentioning

confidence: 98%

Molecular Determinants of Cephalopod Muscles and Their Implication in Muscle Regeneration

Zullo

Fossati

Imperadore³

et al. 2017

Front. Cell Dev. Biol.

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The ability to regenerate whole-body structures has been studied for many decades and is of particular interest for stem cell research due to its therapeutic potential. Several vertebrate and invertebrate species have been used as model systems to study pathways involved in regeneration in the past. Among invertebrates, cephalopods are considered as highly evolved organisms, which exhibit elaborate behavioral characteristics when compared to other mollusks including active predation, extraordinary manipulation, and learning abilities. These are enabled by a complex nervous system and a number of adaptations of their body plan, which were acquired over evolutionary time. Some of these novel features show similarities to structures present in vertebrates and seem to have evolved through a convergent evolutionary process. Octopus vulgaris (the common octopus) is a representative of modern cephalopods and is characterized by a sophisticated motor and sensory system as well as highly developed cognitive capabilities. Due to its phylogenetic position and its high regenerative power the octopus has become of increasing interest for studies on regenerative processes. In this paper we provide an overview over the current knowledge of cephalopod muscle types and structures and present a possible link between these characteristics and their high regenerative potential. This may help identify conserved molecular pathways underlying regeneration in invertebrate and vertebrate animal species as well as discover new leads for targeted tissue treatments in humans.

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“…The Crispr-Cas9 system applied to aquatic model organisms will offer an unprecedented opportunity to characterize the key genes and pathways that are active following injury or degeneration. They promote regeneration responses in animals with regenerative capacities and could be useful in regenerative medicine, if (re)activated in humans (Karra and Poss 2017).…”

Section: In Biomedical Research Why and How Should We Use Aquatic Momentioning

confidence: 99%

Aquatic Model Organisms in Neurosciences: The Genome-Editing Revolution

Joly¹

2017

Research and Perspectives in Neurosciences

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The use of aquatic model organisms has been greatly diversified in laboratories. Zebrafish is the most advanced aquatic species for the use of Crispr-Cas9 in laboratories. Because of the simplicity and broad applicability of this later system, knock-out is now efficiently performed at medium scale. Forward genetics in zebrafish can now be performed by CRISPR-based F0 screening using high speed and high content phenotyping for example by confocal imaging. As zebrafish, marine model organisms have the prominent advantage to be transparent, all the more at young stages (embryos and larvae) or when fixed samples are cleared by novel methods. The Cripsr-Cas9 system is routinely used in the ascidian Ciona intestinalis. It also starts to be used in many other marine models, such as the medusa Clythia hemispherica. We provide at the end of this review a list of aquatic model species and some examples of questions on the origin of our nervous system that can be coped with these models, where the possibility to perform genome editing would constitute a major advance.

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Redirecting cardiac growth mechanisms for therapeutic regeneration

Cited by 56 publications

References 155 publications

Ephrin-B1 blocks adult cardiomyocyte proliferation and heart regeneration

Ephrin-B1 blocks adult cardiomyocyte proliferation and heart regeneration

Molecular Determinants of Cephalopod Muscles and Their Implication in Muscle Regeneration

Aquatic Model Organisms in Neurosciences: The Genome-Editing Revolution

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