Persistent scarring and dilated cardiomyopathy suggest incomplete regeneration of the apex resected neonatal mouse myocardium — A 180 days follow up study

Andersen, Ditte Caroline; Jensen, Charlotte Harken; Baun, Christina; Hvidsten, Svend; Zebrowski, David C.; Engel, Felix B.; Sheikh, Søren Paludan

doi:10.1016/j.yjmcc.2015.11.031

Cited by 27 publications

(28 citation statements)

References 18 publications

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“…Quantification of the heart axes using FDG-PET showed a 10% shortening of the long axis in AR hearts (Fig. 5g ), which is in agreement with our previous results in mouse 13 , reflecting minimal apex outgrowth. Collectively, these observations indicate that AR exposing the left ventricular chamber does not result in complete regeneration in terms of scar removal or restoring wall motion.…”

Section: Resultssupporting

confidence: 91%

Cardiac injury of the newborn mammalian heart accelerates cardiomyocyte terminal differentiation

Zebrowski

Jensen

Becker

et al. 2017

Sci Rep

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After birth cardiomyocytes undergo terminal differentiation, characterized by binucleation and centrosome disassembly, rendering the heart unable to regenerate. Yet, it has been suggested that newborn mammals regenerate their hearts after apical resection by cardiomyocyte proliferation. Thus, we tested the hypothesis that apical resection either inhibits, delays, or reverses cardiomyocyte centrosome disassembly and binucleation. Our data show that apical resection rather transiently accelerates centrosome disassembly as well as the rate of binucleation. Consistent with the nearly 2-fold increased rate of binucleation there was a nearly 2-fold increase in the number of cardiomyocytes in mitosis indicating that the majority of injury-induced cardiomyocyte cell cycle activity results in binucleation, not proliferation. Concurrently, cardiomyocytes undergoing cytokinesis from embryonic hearts exhibited midbody formation consistent with successful abscission, whereas those from 3 day-old cardiomyocytes after apical resection exhibited midbody formation consistent with abscission failure. Lastly, injured hearts failed to fully regenerate as evidenced by persistent scarring and reduced wall motion. Collectively, these data suggest that should a regenerative program exist in the newborn mammalian heart, it is quickly curtailed by developmental mechanisms that render cardiomyocytes post-mitotic.

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Section: Resultssupporting

confidence: 91%

Cardiac injury of the newborn mammalian heart accelerates cardiomyocyte terminal differentiation

Zebrowski

Jensen

Becker

et al. 2017

Sci Rep

Self Cite

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“…Currently, our knowledge of cardiac regeneration and scarring processes is dominated by data obtained from zebrafish and mouse models [4–9,30,31,46]. Vertebrate cardiac regenerative capacity has recently been discussed in an evolutionary and comparative context [26].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the amount of tissue collected is standardised by biopsy forceps size, increasing the reproducibility of the extent of inflicted damage; we estimated that 4% of ventricle volume was amputated in our experiments. Standardisation has the benefit of eliminating potential variation in the results arising from technical difficulties like different injury sizes, an issue that was proposed to explain different cardiac regeneration results observed in mice [9,30,31,46]. If amphibian endoscopy is performed correctly, complications are rare, although iatrogenic trauma can occur, as can buoyancy issues if CO 2 remains from insufflation after suture [33].…”

Section: Discussionmentioning

confidence: 99%

Persistent fibrosis, hypertrophy and sarcomere disorganisation after endoscopy-guided heart resection in adult Xenopus

et al. 2017

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Models of cardiac repair are needed to understand mechanisms underlying failure to regenerate in human cardiac tissue. Such studies are currently dominated by the use of zebrafish and mice. Remarkably, it is between these two evolutionary separated species that the adult cardiac regenerative capacity is thought to be lost, but causes of this difference remain largely unknown. Amphibians, evolutionary positioned between these two models, are of particular interest to help fill this lack of knowledge. We thus developed an endoscopy-based resection method to explore the consequences of cardiac injury in adult Xenopus laevis. This method allowed in situ live heart observation, standardised tissue amputation size and reproducibility. During the first week following amputation, gene expression of cell proliferation markers remained unchanged, whereas those relating to sarcomere organisation decreased and markers of inflammation, fibrosis and hypertrophy increased. One-month post-amputation, fibrosis and hypertrophy were evident at the injury site, persisting through 11 months. Moreover, cardiomyocyte sarcomere organisation deteriorated early following amputation, and was not completely recovered as far as 11 months later. We conclude that the adult Xenopus heart is unable to regenerate, displaying cellular and molecular marks of scarring. Our work suggests that, contrary to urodeles and teleosts, with the exception of medaka, adult anurans share a cardiac injury outcome similar to adult mammals. This observation is at odds with current hypotheses that link loss of cardiac regenerative capacity with acquisition of homeothermy.

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“…The understanding of regenerative processes is expected to help designing regenerative medicine strategies to address a variety of diseases. Even though neonatal mice have been shown to regenerate their hearts after an injury (8)(9)(10)(11)(12)(13), the par excellence regenerative organisms are nonmammalian vertebrates such as urodele amphibians and zebrafish (14)(15)(16)(17). Zebrafish can regenerate their heart after a 20% amputation (18,19), cryoinjury (20)(21)(22)(23) or genetic ablation (24).…”

Section: Introductionmentioning

confidence: 99%

Proteomics analysis of extracellular matrix remodeling during zebrafish heart regeneration

Garcia-Puig

Mosquera

Jiménez‐Delgado

et al. 2019

Preprint

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Adult zebrafish, in contrast to mammals, are able to regenerate their hearts in response to injury or experimental amputation. Our understanding of the cellular and molecular bases that underlie this process, although fragmentary, has increased significantly over the last years. However, the role of the extracellular matrix (ECM) during zebrafish heart regeneration has been comparatively rarely explored. Here, we set out to characterize the ECM protein composition in adult zebrafish hearts, and whether it changed during the regenerative response. For this purpose, we first established a decellularization protocol of adult zebrafish ventricles that significantly enriched the yield of ECM proteins. We then performed proteomic analyses of decellularized control hearts and at different times of regeneration. Our results show a dynamic change in ECM protein composition, most evident at the earliest (7 days post-amputation) time-point analyzed. Regeneration associated with sharp increases in specific ECM proteins, and with an overall decrease in collagens and cytoskeletal proteins. We finally tested by atomic force microscopy that the changes in ECM composition translated to decreased ECM stiffness. Our cumulative results identify changes in the protein composition and mechanical properties of the zebrafish heart ECM during regeneration.

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Persistent scarring and dilated cardiomyopathy suggest incomplete regeneration of the apex resected neonatal mouse myocardium — A 180 days follow up study

Cited by 27 publications

References 18 publications

Cardiac injury of the newborn mammalian heart accelerates cardiomyocyte terminal differentiation

Cardiac injury of the newborn mammalian heart accelerates cardiomyocyte terminal differentiation

Persistent fibrosis, hypertrophy and sarcomere disorganisation after endoscopy-guided heart resection in adult Xenopus

Proteomics analysis of extracellular matrix remodeling during zebrafish heart regeneration

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