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3. Hydrogel-Based Delivery of antimiR-195 Improves Cardiac Efficacy after Ischemic Injury

Author

Onderzoek Molecular Cardiology, Regenerative Medicine and Stem Cells, Circulatory Health, Eding, Joep E.C., Vigil-Garcia, Marta, Vink, Marit, Demkes, Charlotte J., Versteeg, Danielle, Kooijman, Lieneke, Bakker, Maarten H., Schotman, Maaike J.G., Dankers, Patricia Y.W., van Rooij, Eva, Onderzoek Molecular Cardiology, Regenerative Medicine and Stem Cells, Circulatory Health, Eding, Joep E.C., Vigil-Garcia, Marta, Vink, Marit, Demkes, Charlotte J., Versteeg, Danielle, Kooijman, Lieneke, Bakker, Maarten H., Schotman, Maaike J.G., Dankers, Patricia Y.W., and van Rooij, Eva

Published
2024

4. Hydrogel-Based Delivery of antimiR-195 Improves Cardiac Efficacy after Ischemic Injury

Author

Eding, Joep E.C., Vigil-Garcia, Marta, Vink, Marit, Demkes, Charlotte J., Versteeg, Danielle, Kooijman, Lieneke, Bakker, Maarten H., Schotman, Maaike J.G., Dankers, Patricia Y.W., van Rooij, Eva, Eding, Joep E.C., Vigil-Garcia, Marta, Vink, Marit, Demkes, Charlotte J., Versteeg, Danielle, Kooijman, Lieneke, Bakker, Maarten H., Schotman, Maaike J.G., Dankers, Patricia Y.W., and van Rooij, Eva

Abstract

MicroRNAs (miRs) are potent regulators of biology and disease. The miR-15 family is shown to regulate cardiomyocyte proliferation and antimiR-based inhibition induces a cardioprotective effect after myocardial infarction in mice. However, systemic delivery of antimiRs leads to accumulation in kidneys and liver, with relatively poor cardiac exposure. Injectable hydrogels are proposed to serve as sustained-release drug delivery depots and can potentially be used to improve cardiac efficacy of antimiR therapeutics. Here, the effect of a hydrogel-formulated antimiR-195 after myocardial infarction in mice is studied. For this, an injectable, pH-switchable supramolecular hydrogel based on poly(ethylene glycol) (PEG) functionalized with hydrogen bonding ureido-pyrimidinone (UPy) units is used. Intracardiac injections under baseline conditions of this UPy–PEG hydrogelator induce a transient inflammatory response that is no longer present 7 days postinjection. In vitro experiments show that antimiR-195 is released from the gel, and induces microRNA inhibition leading to downstream cardiomyocyte proliferation. In vivo, intramyocardial delivery of antimiR-195 in UPy–PEG enhances cardiac target derepression compared to phosphate-buffered-saline-dissolved antimiR-195, despite a low cardiac retention. After ischemic injury, this translates into a greater therapeutic effect by increasing both target derepression and cardiomyocyte proliferation. Intramyocardial injection of UPy–PEG-formulated antimiR-195 is sufficient to improve cardiac efficacy of antimiR-195.

Published
2024

9. Profiling proliferative cells and their progeny in damaged murine hearts

Author

Kretzschmar, Kai, Post, Yorick, Bannier-Hélaouët, Marie, Mattiotti, Andrea, Drost, Jarno, Basak, Onur, Li, Vivian S. W., van den Born, Maaike, Gunst, Quinn D., Versteeg, Danielle, Kooijman, Lieneke, van der Elst, Stefan, van Es, Johan H., van Rooij, Eva, van den Hoff, Maurice J. B., and Clevers, Hans

Published
2018

11. Desmosomal protein degradation as an underlying cause of arrhythmogenic cardiomyopathy

Author

Tsui, Hoyee, van Kampen, Sebastiaan Johannes, Han, Su Ji, Meraviglia, Viviana, van Ham, Willem B, Casini, Simona, van der Kraak, Petra, Vink, Aryan, Yin, Xiaoke, Mayr, Manuel, Bossu, Alexandre, Marchal, Gerard A, Monshouwer-Kloots, Jantine, Eding, Joep, Versteeg, Danielle, de Ruiter, Hesther, Bezstarosti, Karel, Groeneweg, Judith, Klaasen, Sjoerd J, van Laake, Linda W, Demmers, Jeroen A A, Kops, Geert J P L, Mummery, Christine L, van Veen, Toon A B, Remme, Carol Ann, Bellin, Milena, van Rooij, Eva, Tsui, Hoyee, van Kampen, Sebastiaan Johannes, Han, Su Ji, Meraviglia, Viviana, van Ham, Willem B, Casini, Simona, van der Kraak, Petra, Vink, Aryan, Yin, Xiaoke, Mayr, Manuel, Bossu, Alexandre, Marchal, Gerard A, Monshouwer-Kloots, Jantine, Eding, Joep, Versteeg, Danielle, de Ruiter, Hesther, Bezstarosti, Karel, Groeneweg, Judith, Klaasen, Sjoerd J, van Laake, Linda W, Demmers, Jeroen A A, Kops, Geert J P L, Mummery, Christine L, van Veen, Toon A B, Remme, Carol Ann, Bellin, Milena, and van Rooij, Eva

Abstract

Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive cardiac disease. Many patients with ACM harbor mutations in desmosomal genes, predominantly in plakophilin-2 (PKP2). Although the genetic basis of ACM is well characterized, the underlying disease-driving mechanisms remain unresolved. Explanted hearts from patients with ACM had less PKP2 compared with healthy hearts, which correlated with reduced expression of desmosomal and adherens junction (AJ) proteins. These proteins were also disorganized in areas of fibrotic remodeling. In vitro data from human-induced pluripotent stem cell-derived cardiomyocytes and microtissues carrying the heterozygous PKP2 c.2013delC pathogenic mutation also displayed impaired contractility. Knockin mice carrying the equivalent heterozygous Pkp2 c.1755delA mutation recapitulated changes in desmosomal and AJ proteins and displayed cardiac dysfunction and fibrosis with age. Global proteomics analysis of 4-month-old heterozygous Pkp2 c.1755delA hearts indicated involvement of the ubiquitin-proteasome system (UPS) in ACM pathogenesis. Inhibition of the UPS in mutant mice increased area composita proteins and improved calcium dynamics in isolated cardiomyocytes. Additional proteomics analyses identified lysine ubiquitination sites on the desmosomal proteins, which were more ubiquitinated in mutant mice. In summary, we show that a plakophilin-2 mutation can lead to decreased desmosomal and AJ protein expression through a UPS-dependent mechanism, which preceded cardiac remodeling. These findings suggest that targeting protein degradation and improving desmosomal protein stability may be a potential therapeutic strategy for the treatment of ACM.

Published
2023

12. Spatial transcriptomics unveils ZBTB11 as a regulator of cardiomyocyte degeneration in arrhythmogenic cardiomyopathy

Author

Boogerd, Cornelis J, Lacraz, Grégory P A, Vértesy, Ábel, van Kampen, Sebastiaan J, Perini, Ilaria, de Ruiter, Hesther, Versteeg, Danielle, Brodehl, Andreas, van der Kraak, Petra, Giacca, Mauro, de Jonge, Nicolaas, Junker, Jan Philipp, van Oudenaarden, Alexander, Vink, Aryan, van Rooij, Eva, Boogerd, Cornelis J, Lacraz, Grégory P A, Vértesy, Ábel, van Kampen, Sebastiaan J, Perini, Ilaria, de Ruiter, Hesther, Versteeg, Danielle, Brodehl, Andreas, van der Kraak, Petra, Giacca, Mauro, de Jonge, Nicolaas, Junker, Jan Philipp, van Oudenaarden, Alexander, Vink, Aryan, and van Rooij, Eva

Abstract

AIMS: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder that is characterized by progressive loss of myocardium that is replaced by fibro-fatty cells, arrhythmias, and sudden cardiac death. While myocardial degeneration and fibro-fatty replacement occur in specific locations, the underlying molecular changes remain poorly characterized. Here, we aim to delineate local changes in gene expression to identify new genes and pathways that are relevant for specific remodelling processes occurring during ACM.METHODS AND RESULTS: Using Tomo-Seq, genome-wide transcriptional profiling with high spatial resolution, we created transmural epicardial-to-endocardial gene expression atlases of explanted ACM hearts to gain molecular insights into disease-driving processes. This enabled us to link gene expression profiles to the different regional remodelling responses and allowed us to identify genes that are potentially relevant for disease progression. In doing so, we identified distinct gene expression profiles marking regions of cardiomyocyte degeneration and fibro-fatty remodelling and revealed Zinc finger and BTB domain-containing protein 11 (ZBTB11) to be specifically enriched at sites of active fibro-fatty replacement of myocardium. Immunohistochemistry indicated ZBTB11 to be induced in cardiomyocytes flanking fibro-fatty areas, which could be confirmed in multiple cardiomyopathy patients. Forced overexpression of ZBTB11 induced autophagy and cell death-related gene programmes in human cardiomyocytes, leading to increased apoptosis.CONCLUSION: Our study shows the power of Tomo-Seq to unveil new molecular mechanisms in human cardiomyopathy and uncovers ZBTB11 as a novel driver of cardiomyocyte loss.

Published
2023

13. Cardiomyocyte proliferation is suppressed by ARID1A-mediated YAP inhibition during cardiac maturation

Author

Boogerd, Cornelis J, Perini, Ilaria, Kyriakopoulou, Eirini, Han, Su Ji, La, Phit, van der Swaan, Britt, Berkhout, Jari B, Versteeg, Danielle, Monshouwer-Kloots, Jantine, van Rooij, Eva, Boogerd, Cornelis J, Perini, Ilaria, Kyriakopoulou, Eirini, Han, Su Ji, La, Phit, van der Swaan, Britt, Berkhout, Jari B, Versteeg, Danielle, Monshouwer-Kloots, Jantine, and van Rooij, Eva

Abstract

The inability of adult human cardiomyocytes to proliferate is an obstacle to efficient cardiac regeneration after injury. Understanding the mechanisms that drive postnatal cardiomyocytes to switch to a non-regenerative state is therefore of great significance. Here we show that Arid1a, a subunit of the switching defective/sucrose non-fermenting (SWI/SNF) chromatin remodeling complex, suppresses postnatal cardiomyocyte proliferation while enhancing maturation. Genome-wide transcriptome and epigenome analyses revealed that Arid1a is required for the activation of a cardiomyocyte maturation gene program by promoting DNA access to transcription factors that drive cardiomyocyte maturation. Furthermore, we show that ARID1A directly binds and inhibits the proliferation-promoting transcriptional coactivators YAP and TAZ, indicating ARID1A sequesters YAP/TAZ from their DNA-binding partner TEAD. In ischemic heart disease, Arid1a expression is enhanced in cardiomyocytes of the border zone region. Inactivation of Arid1a after ischemic injury enhanced proliferation of border zone cardiomyocytes. Our study illuminates the pivotal role of Arid1a in cardiomyocyte maturation, and uncovers Arid1a as a crucial suppressor of cardiomyocyte proliferation.

Published
2023

14. Therapeutic efficacy of AAV-mediated restoration of PKP2 in arrhythmogenic cardiomyopathy

Author

Child Health, Circulatory Health, Cancer, Genetica Groep Van Tintelen, Onderzoek Molecular Cardiology, Regenerative Medicine and Stem Cells, Kyriakopoulou, Eirini, Versteeg, Danielle, de Ruiter, Hesther, Perini, Ilaria, Seibertz, Fitzwilliam, Döring, Yannic, Zentilin, Lorena, Tsui, Hoyee, van Kampen, Sebastiaan J., Tiburcy, Malte, Meyer, Tim, Voigt, Niels, Tintelen, van J.Peter, Zimmermann, Wolfram H., Giacca, Mauro, van Rooij, Eva, Child Health, Circulatory Health, Cancer, Genetica Groep Van Tintelen, Onderzoek Molecular Cardiology, Regenerative Medicine and Stem Cells, Kyriakopoulou, Eirini, Versteeg, Danielle, de Ruiter, Hesther, Perini, Ilaria, Seibertz, Fitzwilliam, Döring, Yannic, Zentilin, Lorena, Tsui, Hoyee, van Kampen, Sebastiaan J., Tiburcy, Malte, Meyer, Tim, Voigt, Niels, Tintelen, van J.Peter, Zimmermann, Wolfram H., Giacca, Mauro, and van Rooij, Eva

Published
2023

15. Cardiomyocyte proliferation is suppressed by ARID1A-mediated YAP inhibition during cardiac maturation

Author

Onderzoek Molecular Cardiology, Circulatory Health, Regenerative Medicine and Stem Cells, Boogerd, Cornelis J., Perini, Ilaria, Kyriakopoulou, Eirini, Han, Su Ji, La, Phit, van der Swaan, Britt, Berkhout, Jari B., Versteeg, Danielle, Monshouwer-Kloots, Jantine, van Rooij, Eva, Onderzoek Molecular Cardiology, Circulatory Health, Regenerative Medicine and Stem Cells, Boogerd, Cornelis J., Perini, Ilaria, Kyriakopoulou, Eirini, Han, Su Ji, La, Phit, van der Swaan, Britt, Berkhout, Jari B., Versteeg, Danielle, Monshouwer-Kloots, Jantine, and van Rooij, Eva

Published
2023

16. Spatial transcriptomics unveils ZBTB11 as a regulator of cardiomyocyte degeneration in arrhythmogenic cardiomyopathy

Author

Team Medisch, Circulatory Health, CMM Sectie Molecular Cancer Research, Cancer, Hubrecht Institute with UMC, Pathologie Pathologen staf, Onderzoek Molecular Cardiology, Regenerative Medicine and Stem Cells, Boogerd, Cornelis J, Lacraz, Grégory P A, Vértesy, Ábel, van Kampen, Sebastiaan J, Perini, Ilaria, de Ruiter, Hesther, Versteeg, Danielle, Brodehl, Andreas, van der Kraak, Petra, Giacca, Mauro, de Jonge, Nicolaas, Junker, Jan Philipp, van Oudenaarden, Alexander, Vink, Aryan, van Rooij, Eva, Team Medisch, Circulatory Health, CMM Sectie Molecular Cancer Research, Cancer, Hubrecht Institute with UMC, Pathologie Pathologen staf, Onderzoek Molecular Cardiology, Regenerative Medicine and Stem Cells, Boogerd, Cornelis J, Lacraz, Grégory P A, Vértesy, Ábel, van Kampen, Sebastiaan J, Perini, Ilaria, de Ruiter, Hesther, Versteeg, Danielle, Brodehl, Andreas, van der Kraak, Petra, Giacca, Mauro, de Jonge, Nicolaas, Junker, Jan Philipp, van Oudenaarden, Alexander, Vink, Aryan, and van Rooij, Eva

Published
2023

17. Desmosomal protein degradation as an underlying cause of arrhythmogenic cardiomyopathy

Author

Pathologie Pathologen staf, Circulatory Health, Medische Fysiologie, Team Medisch, Regenerative Medicine and Stem Cells, CMM, Cancer, Hubrecht Institute with UMC, Conductiegroep, Onderzoek Molecular Cardiology, Tsui, Hoyee, van Kampen, Sebastiaan Johannes, Han, Su Ji, Meraviglia, Viviana, van Ham, Willem B, Casini, Simona, van der Kraak, Petra, Vink, Aryan, Yin, Xiaoke, Mayr, Manuel, Bossu, Alexandre, Marchal, Gerard A, Monshouwer-Kloots, Jantine, Eding, Joep, Versteeg, Danielle, de Ruiter, Hesther, Bezstarosti, Karel, Groeneweg, Judith, Klaasen, Sjoerd J, van Laake, Linda W, Demmers, Jeroen A A, Kops, Geert J P L, Mummery, Christine L, van Veen, Toon A B, Remme, Carol Ann, Bellin, Milena, van Rooij, Eva, Pathologie Pathologen staf, Circulatory Health, Medische Fysiologie, Team Medisch, Regenerative Medicine and Stem Cells, CMM, Cancer, Hubrecht Institute with UMC, Conductiegroep, Onderzoek Molecular Cardiology, Tsui, Hoyee, van Kampen, Sebastiaan Johannes, Han, Su Ji, Meraviglia, Viviana, van Ham, Willem B, Casini, Simona, van der Kraak, Petra, Vink, Aryan, Yin, Xiaoke, Mayr, Manuel, Bossu, Alexandre, Marchal, Gerard A, Monshouwer-Kloots, Jantine, Eding, Joep, Versteeg, Danielle, de Ruiter, Hesther, Bezstarosti, Karel, Groeneweg, Judith, Klaasen, Sjoerd J, van Laake, Linda W, Demmers, Jeroen A A, Kops, Geert J P L, Mummery, Christine L, van Veen, Toon A B, Remme, Carol Ann, Bellin, Milena, and van Rooij, Eva

Published
2023

19. Desmosomal protein degradation as an underlying cause of arrhythmogenic cardiomyopathy

Author

Tsui, Hoyee, primary, van Kampen, Sebastiaan Johannes, additional, Han, Su Ji, additional, Meraviglia, Viviana, additional, van Ham, Willem B., additional, Casini, Simona, additional, van der Kraak, Petra, additional, Vink, Aryan, additional, Yin, Xiaoke, additional, Mayr, Manuel, additional, Bossu, Alexandre, additional, Marchal, Gerard A., additional, Monshouwer-Kloots, Jantine, additional, Eding, Joep, additional, Versteeg, Danielle, additional, de Ruiter, Hesther, additional, Bezstarosti, Karel, additional, Groeneweg, Judith, additional, Klaasen, Sjoerd J., additional, van Laake, Linda W., additional, Demmers, Jeroen A.A., additional, Kops, Geert J.P.L., additional, Mummery, Christine L., additional, van Veen, Toon A.B., additional, Remme, Carol Ann, additional, Bellin, Milena, additional, and van Rooij, Eva, additional

Published
2023
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22. Spatial transcriptomics unveils ZBTB11 as a regulator of cardiomyocyte degeneration in arrhythmogenic cardiomyopathy

Author

Boogerd, Cornelis J, Lacraz, Grégory P A, Vértesy, Ábel, van Kampen, Sebastiaan J, Perini, Ilaria, de Ruiter, Hesther, Versteeg, Danielle, Brodehl, Andreas, van der Kraak, Petra, Giacca, Mauro, de Jonge, Nicolaas, Junker, Jan Philipp, van Oudenaarden, Alexander, Vink, Aryan, van Rooij, Eva, Boogerd, Cornelis J, Lacraz, Grégory P A, Vértesy, Ábel, van Kampen, Sebastiaan J, Perini, Ilaria, de Ruiter, Hesther, Versteeg, Danielle, Brodehl, Andreas, van der Kraak, Petra, Giacca, Mauro, de Jonge, Nicolaas, Junker, Jan Philipp, van Oudenaarden, Alexander, Vink, Aryan, and van Rooij, Eva

Abstract

AIMS: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder that is characterized by progressive loss of myocardium that is replaced by fibro-fatty cells, arrhythmias, and sudden cardiac death. While myocardial degeneration and fibro-fatty replacement occur in specific locations, the underlying molecular changes remain poorly characterized. Here we aim to delineate local changes in gene expression to identify new genes and pathways that are relevant for specific remodelling processes occurring during ACM.METHODS AND RESULTS: Using Tomo-Seq, genome-wide transcriptional profiling with high spatial resolution, we created transmural epicardial to endocardial gene expression atlases of explanted ACM hearts to gain molecular insights into disease-driving processes. This enabled us to link gene expression profiles to the different regional remodelling responses and allowed us to identify genes that are potentially relevant for disease progression. In doing so, we identified distinct gene expression profiles marking regions of cardiomyocyte degeneration and fibro-fatty remodelling and revealed Zinc finger and BTB domain-containing protein 11 (ZBTB11) to be specifically enriched at sites of active fibro-fatty replacement of myocardium. Immunohistochemistry indicated ZBTB11 to be induced in cardiomyocytes flanking fibro-fatty areas, which could be confirmed in multiple cardiomyopathy patients. Forced overexpression of ZBTB11 induced autophagy and cell death-related gene programs in human cardiomyocytes, leading to increased apoptosis.CONCLUSIONS: Our study shows the power of Tomo-Seq to unveil new molecular mechanisms in human cardiomyopathy and uncovers ZBTB11 as a novel driver of cardiomyocyte loss.

Published
2022

25. Spatial transcriptomics unveils ZBTB11 as a regulator of cardiomyocyte degeneration in arrhythmogenic cardiomyopathy

Author

Boogerd, Cornelis J., primary, Lacraz, Grégory P.A., additional, Vértesy, Ábel, additional, van Kampen, Sebastiaan J., additional, Perini, Ilaria, additional, de Ruiter, Hesther, additional, Versteeg, Danielle, additional, Brodehl, Andreas, additional, van der Kraak, Petra, additional, Giacca, Mauro, additional, de Jonge, Nicolaas, additional, Junker, Jan Philipp, additional, van Oudenaarden, Alexander, additional, Vink, Aryan, additional, and van Rooij, Eva, additional

Published
2022
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26. Thymosin β4 and prothymosin α promote cardiac regeneration post-ischaemic injury in mice.

Author

Gladka, Monika M, Johansen, Anne Katrine Z, Kampen, Sebastiaan J van, Peters, Marijn M C, Molenaar, Bas, Versteeg, Danielle, Kooijman, Lieneke, Zentilin, Lorena, Giacca, Mauro, and Rooij, Eva van

Subjects
CARDIAC regeneration, THYMOSIN, GENE expression profiling, MYOCARDIAL ischemia, HEART diseases
Abstract

Aims The adult mammalian heart is a post-mitotic organ. Even in response to necrotic injuries, where regeneration would be essential to reinstate cardiac structure and function, only a minor percentage of cardiomyocytes undergo cytokinesis. The gene programme that promotes cell division within this population of cardiomyocytes is not fully understood. In this study, we aimed to determine the gene expression profile of proliferating adult cardiomyocytes in the mammalian heart after myocardial ischaemia, to identify factors to can promote cardiac regeneration. Methods and results Here, we demonstrate increased 5-ethynyl-2'deoxyuridine incorporation in cardiomyocytes 3 days post-myocardial infarction in mice. By applying multi-colour lineage tracing, we show that this is paralleled by clonal expansion of cardiomyocytes in the borderzone of the infarcted tissue. Bioinformatic analysis of single-cell RNA sequencing data from cardiomyocytes at 3 days post ischaemic injury revealed a distinct transcriptional profile in cardiomyocytes expressing cell cycle markers. Combinatorial overexpression of the enriched genes within this population in neonatal rat cardiomyocytes and mice at postnatal day 12 (P12) unveiled key genes that promoted increased cardiomyocyte proliferation. Therapeutic delivery of these gene cocktails into the myocardial wall after ischaemic injury demonstrated that a combination of thymosin beta 4 (TMSB4) and prothymosin alpha (PTMA) provide a permissive environment for cardiomyocyte proliferation and thereby attenuated cardiac dysfunction. Conclusion This study reveals the transcriptional profile of proliferating cardiomyocytes in the ischaemic heart and shows that overexpression of the two identified factors, TMSB4 and PTMA, can promote cardiac regeneration. This work indicates that in addition to activating cardiomyocyte proliferation, a supportive environment is a key for regeneration to occur. [ABSTRACT FROM AUTHOR]

Published
2023
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27. Ischemic tolerance and cardiac repair in the spiny mouse (Acomys)

Author

Onderzoek Molecular Cardiology, Regenerative Medicine and Stem Cells, Circulatory Health, Koopmans, Tim, van Beijnum, Henriette, Roovers, Elke F., Tomasso, Antonio, Malhotra, Divyanshu, Boeter, Jochem, Psathaki, Olympia E., Versteeg, Danielle, van Rooij, Eva, Bartscherer, Kerstin, Onderzoek Molecular Cardiology, Regenerative Medicine and Stem Cells, Circulatory Health, Koopmans, Tim, van Beijnum, Henriette, Roovers, Elke F., Tomasso, Antonio, Malhotra, Divyanshu, Boeter, Jochem, Psathaki, Olympia E., Versteeg, Danielle, van Rooij, Eva, and Bartscherer, Kerstin

Published
2021

28. Cardiomyocytes stimulate angiogenesis after ischemic injury in a ZEB2-dependent manner

Author

CMM Groep Burgering, Cancer, Genetica Sectie Genoomdiagnostiek, Onderzoek Molecular Cardiology, Circulatory Health, Regenerative Medicine and Stem Cells, Gladka, Monika M, Kohela, Arwa, Molenaar, Bas, Versteeg, Danielle, Kooijman, Lieneke, Monshouwer-Kloots, Jantine, Kremer, Veerle, Vos, Harmjan R, Huibers, Manon M H, Haigh, Jody J, Huylebroeck, Danny, Boon, Reinier A, Giacca, Mauro, van Rooij, Eva, CMM Groep Burgering, Cancer, Genetica Sectie Genoomdiagnostiek, Onderzoek Molecular Cardiology, Circulatory Health, Regenerative Medicine and Stem Cells, Gladka, Monika M, Kohela, Arwa, Molenaar, Bas, Versteeg, Danielle, Kooijman, Lieneke, Monshouwer-Kloots, Jantine, Kremer, Veerle, Vos, Harmjan R, Huibers, Manon M H, Haigh, Jody J, Huylebroeck, Danny, Boon, Reinier A, Giacca, Mauro, and van Rooij, Eva

Published
2021

29. Single-cell transcriptomics following ischemic injury identifies a role for B2M in cardiac repair

Author

Onderzoek Vrouw Hart & Vaatziekten, Onderzoek Molecular Cardiology, Circulatory Health, Regenerative Medicine and Stem Cells, Molenaar, Bas, Timmer, Louk T., Droog, Marjolein, Perini, Ilaria, Versteeg, Danielle, Kooijman, Lieneke, Monshouwer-Kloots, Jantine, de Ruiter, Hesther, Gladka, Monika M., van Rooij, Eva, Onderzoek Vrouw Hart & Vaatziekten, Onderzoek Molecular Cardiology, Circulatory Health, Regenerative Medicine and Stem Cells, Molenaar, Bas, Timmer, Louk T., Droog, Marjolein, Perini, Ilaria, Versteeg, Danielle, Kooijman, Lieneke, Monshouwer-Kloots, Jantine, de Ruiter, Hesther, Gladka, Monika M., and van Rooij, Eva

Published
2021

30. Gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodelling

Author

Other research (not in main researchprogram), Onderzoek Molecular Cardiology, Team Medisch, Circulatory Health, Pathologie Pathologen staf, Onderzoek Precision medicine, Medische Fysiologie, Conductiegroep, Regenerative Medicine and Stem Cells, Vigil-Garcia, Marta, Demkes, Charlotte J, Eding, Joep E C, Versteeg, Danielle, de Ruiter, Hesther, Perini, Ilaria, Kooijman, Lieneke, Gladka, Monika M, Asselbergs, Folkert W, Vink, Aryan, Harakalova, Magdalena, Bossu, Alexander, van Veen, Toon A B, Boogerd, Cornelis J, van Rooij, Eva, Other research (not in main researchprogram), Onderzoek Molecular Cardiology, Team Medisch, Circulatory Health, Pathologie Pathologen staf, Onderzoek Precision medicine, Medische Fysiologie, Conductiegroep, Regenerative Medicine and Stem Cells, Vigil-Garcia, Marta, Demkes, Charlotte J, Eding, Joep E C, Versteeg, Danielle, de Ruiter, Hesther, Perini, Ilaria, Kooijman, Lieneke, Gladka, Monika M, Asselbergs, Folkert W, Vink, Aryan, Harakalova, Magdalena, Bossu, Alexander, van Veen, Toon A B, Boogerd, Cornelis J, and van Rooij, Eva

Published
2021

31. Gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodeling

Author

Vigil-Garcia, Marta, Demkes, Charlotte J, Eding, Joep E C, Versteeg, Danielle, de Ruiter, Hesther, Perini, Ilaria, Kooijman, Lieneke, Gladka, Monika M, Asselbergs, Folkert W, Vink, Aryan, Harakalova, Magdalena, Bossu, Alexander, van Veen, Toon A B, Boogerd, Cornelis J, van Rooij, Eva, Vigil-Garcia, Marta, Demkes, Charlotte J, Eding, Joep E C, Versteeg, Danielle, de Ruiter, Hesther, Perini, Ilaria, Kooijman, Lieneke, Gladka, Monika M, Asselbergs, Folkert W, Vink, Aryan, Harakalova, Magdalena, Bossu, Alexander, van Veen, Toon A B, Boogerd, Cornelis J, and van Rooij, Eva

Abstract

AIMS: Pathological cardiac remodeling is characterized by cardiomyocyte hypertrophy and fibroblast activation, which can ultimately lead to maladaptive hypertrophy and heart failure (HF). Genome-wide expression analysis on heart tissue has been instrumental for the identification of molecular mechanisms at play. However, these data were based on signals derived from all cardiac cell types. Here we aimed for a more detailed view on molecular changes driving maladaptive cardiomyocyte hypertrophy to aid in the development of therapies to reverse pathological remodeling.METHODS AND RESULTS: Utilizing cardiomyocyte-specific reporter mice exposed to pressure overload by transverse aortic banding and cardiomyocyte isolation by flow cytometry, we obtained gene expression profiles of hypertrophic cardiomyocytes in the more immediate phase after stress, and cardiomyocytes showing pathological hypertrophy. We identified subsets of genes differentially regulated and specific for either stage. Among the genes specifically upregulated in the cardiomyocytes during the maladaptive phase we found known stress markers, such as Nppb and Myh7, but additionally identified a set of genes with unknown roles in pathological hypertrophy, including the platelet isoform of phosphofructokinase (PFKP). Norepinephrine-angiotensin II treatment of cultured human cardiomyocytes induced secretion of NT pro-BNP and recapitulated the upregulation of these genes, indicating conservation of the upregulation in failing cardiomyocytes. Moreover, several genes induced during pathological hypertrophy were also found to be increased in human heart failure, with their expression positively correlating to the known stress markers NPPB and MYH7. Mechanistically, suppression of Pfkp in primary cardiomyocytes attenuated stress-induced gene expression and hypertrophy, indicating that Pfkp is an important novel player in pathological remodeling of cardiomyocytes.CONCLUSIONS: Using cardiomyocyte-spe

Published
2020

33. Gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodelling

Author

Vigil-Garcia, Marta, primary, Demkes, Charlotte J, additional, Eding, Joep E C, additional, Versteeg, Danielle, additional, de Ruiter, Hesther, additional, Perini, Ilaria, additional, Kooijman, Lieneke, additional, Gladka, Monika M, additional, Asselbergs, Folkert W, additional, Vink, Aryan, additional, Harakalova, Magdalena, additional, Bossu, Alexander, additional, van Veen, Toon A B, additional, Boogerd, Cornelis J, additional, and van Rooij, Eva, additional

Published
2020
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36. Abstract 262: Gene Expression Profiling of Hypertrophic and Failing Cardiomyocytes Identifies New Players Involved in Heart Failure

Author

Vigil-Garcia, Marta, primary, Demkes, Charlotte J, additional, Eding, Joep E, additional, Versteeg, Danielle, additional, de Ruiter, Hesther, additional, Gladka, Monika M, additional, Harakalova, Magdalena, additional, Bossu, Alex, additional, Vink, Aryan, additional, Asselbergs, Folkert W, additional, van Veen, Toon, additional, and van Rooij, Eva, additional

Published
2019
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37. Gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodelling.

Author

Vigil-Garcia, Marta, Demkes, Charlotte J, Eding, Joep E C, Versteeg, Danielle, Ruiter, Hesther de, Perini, Ilaria, Kooijman, Lieneke, Gladka, Monika M, Asselbergs, Folkert W, Vink, Aryan, Harakalova, Magdalena, Bossu, Alexander, Veen, Toon A B van, Boogerd, Cornelis J, and Rooij, Eva van

Subjects
GENE expression profiling, CARDIAC hypertrophy, HEART failure, HEART cells, GENE expression
Abstract

Aims Pathological cardiac remodelling is characterized by cardiomyocyte (CM) hypertrophy and fibroblast activation, which can ultimately lead to maladaptive hypertrophy and heart failure (HF). Genome-wide expression analysis on heart tissue has been instrumental for the identification of molecular mechanisms at play. However, these data were based on signals derived from all cardiac cell types. Here, we aimed for a more detailed view on molecular changes driving maladaptive CM hypertrophy to aid in the development of therapies to reverse pathological remodelling. Methods and results Utilizing CM-specific reporter mice exposed to pressure overload by transverse aortic banding and CM isolation by flow cytometry, we obtained gene expression profiles of hypertrophic CMs in the more immediate phase after stress, and CMs showing pathological hypertrophy. We identified subsets of genes differentially regulated and specific for either stage. Among the genes specifically up-regulated in the CMs during the maladaptive phase we found known stress markers, such as Nppb and Myh7 , but additionally identified a set of genes with unknown roles in pathological hypertrophy, including the platelet isoform of phosphofructokinase (PFKP). Norepinephrine-angiotensin II treatment of cultured human CMs induced the secretion of N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP) and recapitulated the up-regulation of these genes, indicating conservation of the up-regulation in failing CMs. Moreover, several genes induced during pathological hypertrophy were also found to be increased in human HF, with their expression positively correlating to the known stress markers NPPB and MYH7. Mechanistically, suppression of Pfkp in primary CMs attenuated stress-induced gene expression and hypertrophy, indicating that Pfkp is an important novel player in pathological remodelling of CMs. Conclusion Using CM-specific transcriptomic analysis, we identified novel genes induced during pathological hypertrophy that are relevant for human HF, and we show that PFKP is a conserved failure-induced gene that can modulate the CM stress response. [ABSTRACT FROM AUTHOR]

Published
2021
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38. Profiling proliferative cells and their progeny in damaged murine hearts

Author

TN Onderwijs, Hubrecht Institute with UMC, Onderzoek Molecular Cardiology, Circulatory Health, Regenerative Medicine and Stem Cells, CMM Sectie Molecular Cancer Research, Cancer, Child Health, Brain, Kretzschmar, Kai, Post, Yorick, Bannier-Hélaouët, Marie, Mattiotti, Andrea, Drost, Jarno, Basak, Onur, Li, Vivian S.W., van den Born, Maaike, Gunst, Quinn D., Versteeg, Danielle, Kooijman, Lieneke, van der Elst, Stefan, van Es, Johan H., van Rooij, Eva, van den Hoff, Maurice J.B., Clevers, Hans, TN Onderwijs, Hubrecht Institute with UMC, Onderzoek Molecular Cardiology, Circulatory Health, Regenerative Medicine and Stem Cells, CMM Sectie Molecular Cancer Research, Cancer, Child Health, Brain, Kretzschmar, Kai, Post, Yorick, Bannier-Hélaouët, Marie, Mattiotti, Andrea, Drost, Jarno, Basak, Onur, Li, Vivian S.W., van den Born, Maaike, Gunst, Quinn D., Versteeg, Danielle, Kooijman, Lieneke, van der Elst, Stefan, van Es, Johan H., van Rooij, Eva, van den Hoff, Maurice J.B., and Clevers, Hans

Published
2018

39. Single-Cell Sequencing of the Healthy and Diseased Heart Reveals Cytoskeleton-Associated Protein 4 as a New Modulator of Fibroblasts Activation

Author

Pathologie Laboratorium diagnostiek, Cancer, Hubrecht Institute with UMC, Circulatory Health, Regenerative Medicine and Stem Cells, Gladka, Monika M., Molenaar, Bas, De Ruiter, Hesther, Van Der Elst, Stefan, Tsui, Hoyee, Versteeg, Danielle, Lacraz, Grègory P.A., Huibers, Manon M.H., Van Oudenaarden, Alexander, Van Rooij, Eva, Pathologie Laboratorium diagnostiek, Cancer, Hubrecht Institute with UMC, Circulatory Health, Regenerative Medicine and Stem Cells, Gladka, Monika M., Molenaar, Bas, De Ruiter, Hesther, Van Der Elst, Stefan, Tsui, Hoyee, Versteeg, Danielle, Lacraz, Grègory P.A., Huibers, Manon M.H., Van Oudenaarden, Alexander, and Van Rooij, Eva

Published
2018

40. Tomo-Seq Identifies SOX9 as a Key Regulator of Cardiac Fibrosis During Ischemic Injury

Author

Lacraz, Grégory P A, Junker, Jan Philipp, Gladka, Monika M, Molenaar, Bas, Scholman, Koen T, Vigil-Garcia, Marta, Versteeg, Danielle, de Ruiter, Hesther, Vermunt, Marit W, Creyghton, Menno P, Huibers, Manon M H, de Jonge, Nicolaas, van Oudenaarden, Alexander, van Rooij, Eva, Lacraz, Grégory P A, Junker, Jan Philipp, Gladka, Monika M, Molenaar, Bas, Scholman, Koen T, Vigil-Garcia, Marta, Versteeg, Danielle, de Ruiter, Hesther, Vermunt, Marit W, Creyghton, Menno P, Huibers, Manon M H, de Jonge, Nicolaas, van Oudenaarden, Alexander, and van Rooij, Eva

Abstract

BACKGROUND: Cardiac ischemic injury induces a pathological remodeling response, which can ultimately lead to heart failure. Detailed mechanistic insights into molecular signaling pathways relevant for different aspects of cardiac remodeling will support the identification of novel therapeutic targets.METHODS: Although genome-wide transcriptome analysis on diseased tissues has greatly advanced our understanding of the regulatory networks that drive pathological changes in the heart, this approach has been disadvantaged by the fact that the signals are derived from tissue homogenates. Here we used tomo-seq to obtain a genome-wide gene expression signature with high spatial resolution spanning from the infarcted area to the remote to identify new regulators of cardiac remodeling. Cardiac tissue samples from patients suffering from ischemic heart disease were used to validate our findings.RESULTS: Tracing transcriptional differences with a high spatial resolution across the infarcted heart enabled us to identify gene clusters that share a comparable expression profile. The spatial distribution patterns indicated a separation of expressional changes for genes involved in specific aspects of cardiac remodeling, such as fibrosis, cardiomyocyte hypertrophy, and calcium handling (Col1a2, Nppa, and Serca2). Subsequent correlation analysis allowed for the identification of novel factors that share a comparable transcriptional regulation pattern across the infarcted tissue. The strong correlation between the expression levels of these known marker genes and the expression of the coregulated genes could be confirmed in human ischemic cardiac tissue samples. Follow-up analysis identified SOX9 as common transcriptional regulator of a large portion of the fibrosis-related genes that become activated under conditions of ischemic injury. Lineage-tracing experiments indicated that the majority of COL1-positive fibroblasts stem from a pool of SOX9-expressing cells, and

Published
2017

44. Postnatal Cardiac Gene Editing Using CRISPR/Cas9 With AAV9-Mediated Delivery of Short Guide RNAs Results in Mosaic Gene Disruption

Author

Charlotte Demkes, Mauro Giacca, Bastiaan Spanjaard, Farhad Akbari Moqadam, Lieneke Kooijman, Hesther de Ruiter, Lorena Zentilin, D Versteeg, Bas Molenaar, Anne Katrine Johansen, Eva van Rooij, Ana Rita Leitoguinho, Johansen, Anne Katrine, Molenaar, Ba, Versteeg, Danielle, Leitoguinho, Ana Rita, Demkes, Charlotte, Spanjaard, Bastiaan, de Ruiter, Hesther, Akbari Moqadam, Farhad, Kooijman, Lieneke, Zentilin, Lorena, Giacca, Mauro, van Rooij, Eva, and Hubrecht Institute for Developmental Biology and Stem Cell Research

Subjects
0301 basic medicine, sequence analysis, Physiology, Inbred C57BL, Genome, Transgenic, chemistry.chemical_compound, Mice, Genome editing, molecular biology, RNA, Guide, CRISPR, CRISPR-Cas System, Myocytes, Cardiac, Guide RNA, NIH 3T3 Cell, Cells, Cultured, Mice, Knockout, Gene Editing, Cultured, Palindrome, Gene Transfer Techniques, Dependovirus, Dependoviru, clustered regularly interspaced short palindromic repeats, gene editing, myocytes, cardiac, sequence analysis, DNA, Animals, Animals, Newborn, Base Sequence, CRISPR-Cas Systems, Mice, Inbred C57BL, Mice, Transgenic, NIH 3T3 Cells, Cardiology and Cardiovascular Medicine, Cardiac, RNA, Guide, Kinetoplastida, Cells, Knockout, Computational biology, Biology, Article, 03 medical and health sciences, Journal Article, Gene, Myocytes, Animal, Cas9, DNA, Gene Transfer Technique, Newborn, 030104 developmental biology, chemistry, RNA, clustered regularly interspaced short palindromic repeat, Guide
Abstract

Rationale: CRISPR/Cas9 (clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9)–based DNA editing has rapidly evolved as an attractive tool to modify the genome. Although CRISPR/Cas9 has been extensively used to manipulate the germline in zygotes, its application in postnatal gene editing remains incompletely characterized. Objective: To evaluate the feasibility of CRISPR/Cas9-based cardiac genome editing in vivo in postnatal mice. Methods and Results: We generated cardiomyocyte-specific Cas9 mice and demonstrated that Cas9 expression does not affect cardiac function or gene expression. As a proof-of-concept, we delivered short guide RNAs targeting 3 genes critical for cardiac physiology, Myh6 , Sav1 , and Tbx20 , using a cardiotropic adeno-associated viral vector 9. Despite a similar degree of DNA disruption and subsequent mRNA downregulation, only disruption of Myh6 was sufficient to induce a cardiac phenotype, irrespective of short guide RNA exposure or the level of Cas9 expression. DNA sequencing analysis revealed target-dependent mutations that were highly reproducible across mice resulting in differential rates of in- and out-of-frame mutations. Finally, we applied a dual short guide RNA approach to effectively delete an important coding region of Sav1 , which increased the editing efficiency. Conclusions: Our results indicate that the effect of postnatal CRISPR/Cas9-based cardiac gene editing using adeno-associated virus serotype 9 to deliver a single short guide RNA is target dependent. We demonstrate a mosaic pattern of gene disruption, which hinders the application of the technology to study gene function. Further studies are required to expand the versatility of CRISPR/Cas9 as a robust tool to study novel cardiac gene functions in vivo.

Published
2017
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45. Hypoxia-responsive zinc finger E-box-binding homeobox 2 (ZEB2) regulates a network of calcium-handling genes in the injured heart.

Author

Gladka MM, Kohela A, de Leeuw AE, Molenaar B, Versteeg D, Kooijman L, van Geldorp M, van Ham WB, Caliandro R, Haigh JJ, van Veen TAB, and van Rooij E

Abstract

Aims: Intracellular calcium (Ca2+) overload is known to play a critical role in the development of cardiac dysfunction. Despite the remarkable improvement in managing the progression of heart disease, developing effective therapies for heart failure (HF) remains a challenge. A better understanding of molecular mechanisms that maintain proper Ca2+ levels and contractility in the injured heart could be of therapeutic value., Methods and Results: Here, we report that transcription factor zinc finger E-box-binding homeobox 2 (ZEB2) is induced by hypoxia-inducible factor 1-alpha (HIF1α) in hypoxic cardiomyocytes and regulates a network of genes involved in Ca2+ handling and contractility during ischaemic heart disease. Gain- and loss-of-function studies in genetic mouse models revealed that ZEB2 expression in cardiomyocytes is necessary and sufficient to protect the heart against ischaemia-induced diastolic dysfunction and structural remodelling. Moreover, RNA sequencing of ZEB2-overexpressing (Zeb2 cTg) hearts post-injury implicated ZEB2 in regulating numerous Ca2+-handling and contractility-related genes. Mechanistically, ZEB2 overexpression increased the phosphorylation of phospholamban at both serine-16 and threonine-17, implying enhanced activity of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a), thereby augmenting SR Ca2+ uptake and contractility. Furthermore, we observed a decrease in the activity of Ca2+-dependent calcineurin/NFAT signalling in Zeb2 cTg hearts, which is the main driver of pathological cardiac remodelling. On a post-transcriptional level, we showed that ZEB2 expression can be regulated by the cardiomyocyte-specific microRNA-208a (miR-208a). Blocking the function of miR-208a with anti-miR-208a increased ZEB2 expression in the heart and effectively protected from the development of pathological cardiac hypertrophy., Conclusion: Together, we present ZEB2 as a central regulator of contractility and Ca2+-handling components in the mammalian heart. Further mechanistic understanding of the role of ZEB2 in regulating Ca2+ homeostasis in cardiomyocytes is an essential step towards the development of improved therapies for HF., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Published
2024
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46. Spatial transcriptomics unveils ZBTB11 as a regulator of cardiomyocyte degeneration in arrhythmogenic cardiomyopathy.

Author

Boogerd CJ, Lacraz GPA, Vértesy Á, van Kampen SJ, Perini I, de Ruiter H, Versteeg D, Brodehl A, van der Kraak P, Giacca M, de Jonge N, Junker JP, van Oudenaarden A, Vink A, and van Rooij E

Subjects
Humans, Arrhythmias, Cardiac metabolism, Myocardium metabolism, Myocytes, Cardiac metabolism, Transcriptome, Arrhythmogenic Right Ventricular Dysplasia genetics, Arrhythmogenic Right Ventricular Dysplasia metabolism, Cardiomyopathies genetics, Cardiomyopathies metabolism
Abstract

Aims: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder that is characterized by progressive loss of myocardium that is replaced by fibro-fatty cells, arrhythmias, and sudden cardiac death. While myocardial degeneration and fibro-fatty replacement occur in specific locations, the underlying molecular changes remain poorly characterized. Here, we aim to delineate local changes in gene expression to identify new genes and pathways that are relevant for specific remodelling processes occurring during ACM., Methods and Results: Using Tomo-Seq, genome-wide transcriptional profiling with high spatial resolution, we created transmural epicardial-to-endocardial gene expression atlases of explanted ACM hearts to gain molecular insights into disease-driving processes. This enabled us to link gene expression profiles to the different regional remodelling responses and allowed us to identify genes that are potentially relevant for disease progression. In doing so, we identified distinct gene expression profiles marking regions of cardiomyocyte degeneration and fibro-fatty remodelling and revealed Zinc finger and BTB domain-containing protein 11 (ZBTB11) to be specifically enriched at sites of active fibro-fatty replacement of myocardium. Immunohistochemistry indicated ZBTB11 to be induced in cardiomyocytes flanking fibro-fatty areas, which could be confirmed in multiple cardiomyopathy patients. Forced overexpression of ZBTB11 induced autophagy and cell death-related gene programmes in human cardiomyocytes, leading to increased apoptosis., Conclusion: Our study shows the power of Tomo-Seq to unveil new molecular mechanisms in human cardiomyopathy and uncovers ZBTB11 as a novel driver of cardiomyocyte loss., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Published
2023
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