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12. Histone deacetylase 1 controls cardiomyocyte proliferation during embryonic heart development and cardiac regeneration in zebrafish

Author

Bühler, Anja, primary, Gahr, Bernd M., additional, Park, Deung-Dae, additional, Bertozzi, Alberto, additional, Boos, Alena, additional, Dalvoy, Mohankrishna, additional, Pott, Alexander, additional, Oswald, Franz, additional, Kovall, Rhett A., additional, Kühn, Bernhard, additional, Weidinger, Gilbert, additional, Rottbauer, Wolfgang, additional, and Just, Steffen, additional

Published
2021
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13. Is zebrafish heart regeneration 'complete'?: Lineage-restricted cardiomyocytes proliferate to pre-injury numbers but some fail to differentiate in fibrotic hearts

Author

Medische Fysiologie, Circulatory Health, Cardiologie onderzoek 2, Onderzoek, Bertozzi, Alberto, Wu, Chi-Chung, Nguyen, Phong D, Vasudevarao, Mohankrishna Dalvoy, Mulaw, Medhanie A, Koopman, Charlotte D, de Boer, Teun P, Bakkers, Jeroen, Weidinger, Gilbert, Medische Fysiologie, Circulatory Health, Cardiologie onderzoek 2, Onderzoek, Bertozzi, Alberto, Wu, Chi-Chung, Nguyen, Phong D, Vasudevarao, Mohankrishna Dalvoy, Mulaw, Medhanie A, Koopman, Charlotte D, de Boer, Teun P, Bakkers, Jeroen, and Weidinger, Gilbert

Published
2021

15. Investigation of the extent of cardiomyocyte regeneration in the injured zebrafish heart and the role of Wnt signaling during cardiac repair

Author

Bertozzi, Alberto, Weidinger, Gilbert, and Just, Steffen

Subjects
Myocardium, Heart, Heart injuries, Cardiomyocyte, Wnt proteins, Zebrabärbling, DDC 570 / Life sciences, ddc:570, Regeneration, Myocytes, Cardiac, Herzmuskelzelle, ddc:610, Herz, DDC 610 / Medicine & health, Herzmuskel, Repair, Zebrafish, Wnt-Proteine
Abstract

Unlike mammals, zebrafish can achieve scar-free healing of heart injuries, which is associated with dedifferentiation and cell cycle re-entry of cardiomyocytes. However, it is unknown to which extent cardiomyocytes lost to injury are restored, since only indirect evidences of myocardial regeneration exist thus far. In addition, while Wnt signaling has been shown to induce fibrosis and prevent production of new cardiomyocytes in the infarcted murine heart, involvement of this pathway in zebrafish cardiac regeneration has not been yet investigated. Hence, we set out to provide the first absolute quantification of cardiomyocyte numbers before and after injury in zebrafish, as well as to address whether Wnt signaling impinges on cardiomyocyte proliferation and wound healing. Firstly, we used stereological methods to quantify the number of cardiomyocytes on heart sections at 3, 14, 30 and 90 days post cryoinjury. Based on histological markers, we investigated the morphology of the regenerated myocardium. Secondly, we performed quantitative PCR and in situ hybridization to check whether Wnt signaling is active, and which Wnt ligands are expressed in the injured heart. Finally, we employed genetic tools for Wnt/β-catenin manipulation and measured proliferation and dedifferentiation in cardiomyocytes, as well as wound resorption, upon inhibition of the pathway. We found that injured zebrafish hearts did regenerate to the pre-injury number of cardiomyocytes already within four weeks. Mathematical modeling indicated that all cardiomyocytes that enter the cell cycle at the wound border actually proliferate. The regenerated myocardium does not display signs of altered morphology compared to uninjured hearts. Thus, we establish that zebrafish can indeed completely and faithfully regenerate the ventricular myocardium. Surprisingly, full cardiomyocyte regeneration also occurred in hearts that retained scars, indicating that cardiomyocyte regeneration is more efficient than scar-free healing. In addition, we found that Wnt/β-catenin signaling is active in regenerating hearts both in cardiomyocytes and in endothelial cells. Blockade of the pathway impairs cardiomyocyte dedifferentiation and proliferation, likely in a cell autonomous manner. However, Wnt signaling has no significant effect on scar removal. Finally, we found significant upregulation of the Wnt9a ligand in endothelial cells after injury. Our results show that zebrafish cardiomyocyte regeneration is efficient and complete, and it does not require complete scar removal. Wnt/β-catenin is an important player in this process, since it is required to promote cell cycle re-entry and dedifferentiation of pre-existing cardiomyocytes.

Published
2020

16. Thoughts in potentiality: provisional reflections on Agamben's understanding of potentiality and its relevance for theology and politics

Author

Bertozzi, Alberto

Subjects
Philosophers -- Beliefs, opinions and attitudes, Incarnation -- Analysis, Liberty -- Analysis, Philosophy and religion
Abstract

Giorgio Agamben's understanding of potentiality and its relevance on subjects pertaining to theological discourse and contemporary reflection on politics is discussed along with the issues of incarnation and freedom.

Published
2007

17. Is zebrafish heart regeneration 'complete'?: Lineage-restricted cardiomyocytes proliferate to pre-injury numbers but some fail to differentiate in fibrotic hearts

Author

Bertozzi, Alberto, Wu, Chi-Chung, Nguyen, Phong D, Vasudevarao, Mohankrishna Dalvoy, Mulaw, Medhanie A, Koopman, Charlotte D, de Boer, Teun P, Bakkers, Jeroen, Weidinger, Gilbert, Bertozzi, Alberto, Wu, Chi-Chung, Nguyen, Phong D, Vasudevarao, Mohankrishna Dalvoy, Mulaw, Medhanie A, Koopman, Charlotte D, de Boer, Teun P, Bakkers, Jeroen, and Weidinger, Gilbert

Abstract

Adult zebrafish are frequently described to be able to "completely" regenerate the heart. Yet, the extent to which cardiomyocytes lost to injury are replaced is unknown, since only indirect evidence for cardiomyocyte proliferation exists. We established stereological methods to quantify the number of cardiomyocytes at several time-points post cryoinjury. Intriguingly, after cryoinjuries that killed about 1/3 of the ventricular cardiomyocytes, pre-injury cardiomyocyte numbers were restored already within 30 days. Yet, many hearts retained small residual scars, and a subset of cardiomyocytes bordering these fibrotic areas remained smaller, lacked differentiated sarcomeric structures, and displayed defective calcium signaling. Thus, a subset of regenerated cardiomyocytes failed to fully mature. While lineage-tracing experiments have shown that regenerating cardiomyocytes are derived from differentiated cardiomyocytes, technical limitations have previously made it impossible to test whether cardiomyocyte trans-differentiation contributes to regeneration of non-myocyte cell lineages. Using Cre responder lines that are expressed in all major cell types of the heart, we found no evidence for cardiomyocyte transdifferentiation into endothelial, epicardial, fibroblast or immune cell lineages. Overall, our results imply a refined answer to the question whether zebrafish can completely regenerate the heart: in response to cryoinjury, preinjury cardiomyocyte numbers are indeed completely regenerated, while restoration of cardiomyocyte differentiation and function, as well as resorption of scar tissue, is less robustly achieved.

Published
2020

19. Is zebrafish heart regeneration “complete”? Lineage-restricted cardiomyocytes proliferate to pre-injury numbers but some fail to differentiate in fibrotic hearts

Author

Bertozzi, Alberto, primary, Wu, Chi-Chung, additional, Nguyen, Phong D., additional, Vasudevarao, Mohankrishna Dalvoy, additional, Mulaw, Medhanie A., additional, Koopman, Charlotte D., additional, de Boer, Teun P., additional, Bakkers, Jeroen, additional, and Weidinger, Gilbert, additional

Published
2020
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20. Single-cell analysis uncovers that metabolic reprogramming by ErbB2 signaling is essential for cardiomyocyte proliferation in the regenerating heart

Author

Honkoop, Hessel, de Bakker, Dennis Em, Aharonov, Alla, Kruse, Fabian, Shakked, Avraham, Nguyen, Phong D, de Heus, Cecilia, Garric, Laurence, Muraro, Mauro J, Shoffner, Adam, Tessadori, Federico, Peterson, Joshua Craiger, Noort, Wendy, Bertozzi, Alberto, Weidinger, Gilbert, Posthuma, George, Grun, Dominic, van der Laarse, Willem J, Klumperman, Judith, Jaspers, Richard T, Poss, Kenneth D, van Oudenaarden, Alexander, Tzahor, Eldad, Bakkers, Jeroen, Honkoop, Hessel, de Bakker, Dennis Em, Aharonov, Alla, Kruse, Fabian, Shakked, Avraham, Nguyen, Phong D, de Heus, Cecilia, Garric, Laurence, Muraro, Mauro J, Shoffner, Adam, Tessadori, Federico, Peterson, Joshua Craiger, Noort, Wendy, Bertozzi, Alberto, Weidinger, Gilbert, Posthuma, George, Grun, Dominic, van der Laarse, Willem J, Klumperman, Judith, Jaspers, Richard T, Poss, Kenneth D, van Oudenaarden, Alexander, Tzahor, Eldad, and Bakkers, Jeroen

Abstract

While the heart regenerates poorly in mammals, efficient heart regeneration occurs in zebrafish. Studies in zebrafish have resulted in a model in which preexisting cardiomyocytes dedifferentiate and reinitiate proliferation to replace the lost myocardium. To identify which processes occur in proliferating cardiomyocytes we have used a single-cell RNA-sequencing approach. We uncovered that proliferating border zone cardiomyocytes have very distinct transcriptomes compared to the nonproliferating remote cardiomyocytes and that they resemble embryonic cardiomyocytes. Moreover, these cells have reduced expression of mitochondrial genes and reduced mitochondrial activity, while glycolysis gene expression and glucose uptake are increased, indicative for metabolic reprogramming. Furthermore, we find that the metabolic reprogramming of border zone cardiomyocytes is induced by Nrg1/ErbB2 signaling and is important for their proliferation. This mechanism is conserved in murine hearts in which cardiomyocyte proliferation is induced by activating ErbB2 signaling. Together these results demonstrate that glycolysis regulates cardiomyocyte proliferation during heart regeneration.

Published
2019

21. Single-cell analysis uncovers that metabolic reprogramming by ErbB2 signaling is essential for cardiomyocyte proliferation in the regenerating heart

Author

Medische Fysiologie, Cancer, CMM Groep Klumperman, Child Health, Genetica Groep Van Haaften, CMM Sectie Celbiologie, Regenerative Medicine and Stem Cells, Brain, CMM Sectie Molecular Cancer Research, Hubrecht Institute with UMC, Circulatory Health, Honkoop, Hessel, de Bakker, Dennis Em, Aharonov, Alla, Kruse, Fabian, Shakked, Avraham, Nguyen, Phong D, de Heus, Cecilia, Garric, Laurence, Muraro, Mauro J, Shoffner, Adam, Tessadori, Federico, Peterson, Joshua Craiger, Noort, Wendy, Bertozzi, Alberto, Weidinger, Gilbert, Posthuma, George, Grun, Dominic, van der Laarse, Willem J, Klumperman, Judith, Jaspers, Richard T, Poss, Kenneth D, van Oudenaarden, Alexander, Tzahor, Eldad, Bakkers, Jeroen, Medische Fysiologie, Cancer, CMM Groep Klumperman, Child Health, Genetica Groep Van Haaften, CMM Sectie Celbiologie, Regenerative Medicine and Stem Cells, Brain, CMM Sectie Molecular Cancer Research, Hubrecht Institute with UMC, Circulatory Health, Honkoop, Hessel, de Bakker, Dennis Em, Aharonov, Alla, Kruse, Fabian, Shakked, Avraham, Nguyen, Phong D, de Heus, Cecilia, Garric, Laurence, Muraro, Mauro J, Shoffner, Adam, Tessadori, Federico, Peterson, Joshua Craiger, Noort, Wendy, Bertozzi, Alberto, Weidinger, Gilbert, Posthuma, George, Grun, Dominic, van der Laarse, Willem J, Klumperman, Judith, Jaspers, Richard T, Poss, Kenneth D, van Oudenaarden, Alexander, Tzahor, Eldad, and Bakkers, Jeroen

Published
2019

22. Single-cell analysis uncovers that metabolic reprogramming by ErbB2 signaling is essential for cardiomyocyte proliferation in the regenerating heart

Author

Honkoop, Hessel, primary, de Bakker, Dennis EM, additional, Aharonov, Alla, additional, Kruse, Fabian, additional, Shakked, Avraham, additional, Nguyen, Phong D, additional, de Heus, Cecilia, additional, Garric, Laurence, additional, Muraro, Mauro J, additional, Shoffner, Adam, additional, Tessadori, Federico, additional, Peterson, Joshua Craiger, additional, Noort, Wendy, additional, Bertozzi, Alberto, additional, Weidinger, Gilbert, additional, Posthuma, George, additional, Grün, Dominic, additional, van der Laarse, Willem J, additional, Klumperman, Judith, additional, Jaspers, Richard T, additional, Poss, Kenneth D, additional, van Oudenaarden, Alexander, additional, Tzahor, Eldad, additional, and Bakkers, Jeroen, additional

Published
2019
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23. Author response: Single-cell analysis uncovers that metabolic reprogramming by ErbB2 signaling is essential for cardiomyocyte proliferation in the regenerating heart

Author

Honkoop, Hessel, primary, de Bakker, Dennis EM, additional, Aharonov, Alla, additional, Kruse, Fabian, additional, Shakked, Avraham, additional, Nguyen, Phong D, additional, de Heus, Cecilia, additional, Garric, Laurence, additional, Muraro, Mauro J, additional, Shoffner, Adam, additional, Tessadori, Federico, additional, Peterson, Joshua Craiger, additional, Noort, Wendy, additional, Bertozzi, Alberto, additional, Weidinger, Gilbert, additional, Posthuma, George, additional, Grün, Dominic, additional, van der Laarse, Willem J, additional, Klumperman, Judith, additional, Jaspers, Richard T, additional, Poss, Kenneth D, additional, van Oudenaarden, Alexander, additional, Tzahor, Eldad, additional, and Bakkers, Jeroen, additional

Published
2019
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26. The Language of Subjectivity: Postmodernity, Lacan, Levinas, Theology.

Author

BERTOZZI, Alberto

Subjects
*THEOLOGY, *CHRISTIANITY, *SUBJECTIVITY, *THEORY of knowledge, *ACADEMIC dissertations
Abstract

The article offers information regarding a thesis that aims to give a certain order and coherence to the few readings and author's reflections, relative to a linguistic approach within post modern theory, to such notion for Christian theology. It is also emphasized that the author seeks to explain the import of postmodern linguistic critique to the concept of subjectivity for Christian theology.

Published
2002

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