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Identification of Novel and Potent Modulators Involved in Neonatal Cardiac Regeneration

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A Correction to this article was published on 02 February 2022

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Abstract

Neonatal mammalian heart has been shown to possess the capacity to regenerate substantially after an injury. This remarkable regenerative capacity is lost in a week. This transition has been marked with cardiomyocyte cell cycle arrest and induction of fibrotic response similar to what occurs after myocardial infarction in adult hearts. Recent studies outlined the function of several cardiogenic factors that play a pivotal role in neonatal cardiac regeneration. However, underlying molecular mechanisms of neonatal cardiac regeneration and other cardiogenic factors remained elusive. Here, we investigated the involvement of novel putative cardiogenic factors in neonatal cardiac regeneration and cardiomyocyte cell cycle withdrawal. We have shown that Cbl, Dnmt3a, and Itch are significantly downregulated during neonatal cardiac regeneration process after cardiac injury in vivo. Intriguingly, several of studied factors are upregulated in non-regenerative period of 7-day-old mice after cardiac injury. Knockdown of Cbl, Dnmt3a and Itch in rat neonatal cardiomyocytes lead to the induction of cardiomyocyte proliferation. Cardiomyocyte proliferation accompanies upregulation of positive regulators of cardiomyocyte division and downregulation of CDKIs. Taken together, our findings suggest that Cbl, Dnmt3a, and Itch may be involved in the regulation of cardiomyocyte cell cycle withdrawal and may represent new targets for the induction of cardiac regeneration.

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Acknowledgements

We like to thank to the support by The Scientific and Technological Research Council of Turkey (TÜBİTAK) ARDEB 1001 [#115S185] program. FK is supported by funds provided by EU, BAGEP-2015, ICGEB, Gilead Sciences, and ERA-CVD program. DY has been supported by TÜBİTAK-BİDEB 2209A program. We like to thank Prof. Dr. Bayram Yuksel and Unal Uslu from Yeditepe University for their help in the establishment of tissue sectioning and immunostaining. We would like to thank Dr. Emrah Nikerel from Yeditepe University for their help in bioinformatical and statistical analysis.

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Authors and Affiliations

  1. Institute for Cardiovascular Regeneration, Goethe University, Frankfurt, Germany

    Galip Servet Aslan

  2. Regenerative Biology Research Laboratory, Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, Istanbul, Turkey

    Galip Servet Aslan, Feyza Polat, Seyma Nur Eren & Fatih Kocabas

  3. Faculty of Medicine, University of Minnesota, Minnesota, USA

    Dogacan Yucel

  4. Koc University, Istanbul, Turkey

    Semih Arbatli

  5. Department of Histology and Embryology, Faculty of Medicine, Yeditepe University, Istanbul, Turkey

    Alev Cumbul

  6. Faculty of Biological Science, Goethe University, Frankfurt, Germany

    Galip Servet Aslan

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  1. Galip Servet Aslan
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Contributions

G.S.A performed neonatal cardiac injuries and performed RT-qPCR, contributed to manuscript. S.N.E performed IHC and cardiac injuries, and contributed to manuscript. S.Y and S.A. contributed to RT-qPCR and neonatal cardiomyocyte culture. A.C. contributed to IHC studies. F.P. performed and contributed to Western blot studies, and manuscript. F.K designed the all experiments and wrote the article. All authors contributed to data analysis and reviewed the manuscript.

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Correspondence to Fatih Kocabas.

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Aslan, G.S., Polat, F., Eren, S.N. et al. Identification of Novel and Potent Modulators Involved in Neonatal Cardiac Regeneration. Pediatr Cardiol 42, 1554–1566 (2021). https://doi.org/10.1007/s00246-021-02640-y

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