Myocardial regeneration: Role of epicardium and implicated genes
Abstract
Lower invertebrates' hearts such as those of zebrafish have the capacity for scarless myocardial regeneration which is lost by mammalian hearts as they form a fibrotic scar tissue instead of regenerating the injured area. However, neonatal mammalian hearts have a remarkable capacity for regeneration highlighting conserved evolutionary mechanisms underlying such a process. Studies investigated the underlying mechanism of myocardial regeneration in species capable to do so, to see its applicability on mammals. The epicardium, the mesothelial outer layer of the vertebrate heart, has proven to play an important role in the process of repair and regeneration. It serves as an important source of smooth muscle cells, cardiac fibroblasts, endothelial cells, stem cells, and signaling molecules that are involved in this process. Here we review the role of the epicardium in myocardial regeneration focusing on the different involved; Activation, epithelial to mesenchymal transition, and differentiation. In addition, we will discuss its contributory role to different aspects that support myocardial regeneration. Of these we will discuss angiogenesis and the formation of a regenerate extracellular matrix. Moreover, we will discuss several factors that act on the epicardium to affect regeneration. Finally, we will highlight the utility of the epicardium as a mode of cell therapy in the treatment of myocardial injury.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Both inflammation and microvasculopathy promote cardiac fibrosis with the contribution of mesenchymal stem cells of the epicardium that can migrate into myocardium, where they can mature into fibroblasts.
“Both inflammation and microvasculopathy promote cardiac fibrosis with the contribution of mesenchymal stem cells of the epicardium that can migrate into myocardium, where they can mature into fibroblasts [101].”
From Dysregulated epicardial adipose tissue as a risk factor and potential therapeutic target of heart failure with preserved ejection fraction in diabetes (2022) · cites this paper as [101]
Cites
REST, M. V. D., & Garrone, R. (1991) · The FASEB Journal · doi:10.1096/fasebj.5.13.1916105 · Cited by 1,278 · see citing works
FAK integrates growth-factor and integrin signals to promote cell migration
Sieg, D. J., Hauck, C. R., Ilić, D., Klingbeil, C. K., SCHAEFER, E. M., Damsky, C. H., & Schlaepfer, D. D. (2000) · Nature Cell Biology · doi:10.1038/35010517 · Cited by 1,240 · see citing works
Neuregulin1/ErbB4 Signaling Induces Cardiomyocyte Proliferation and Repair of Heart Injury
Bersell, K. R., Arab, S., Haring, B., & Kühn, B. (2009) · Cell · doi:10.1016/j.cell.2009.04.060 · Cited by 1,023 · see citing works
Lepilina, A., Coon, A. N., Kikuchi, K., Holdway, J. E., Roberts, R. W., Burns, C. G., & Poss, K. D. (2006) · Cell · doi:10.1016/j.cell.2006.08.052 · Cited by 833 · see citing works
De novo cardiomyocytes from within the activated adult heart after injury
Smart, N., Bollini, S., Dubé, K. N., Vieira, J. M., Zhou, B., Davidson, S. M., Yellon, D. M., Riegler, J., Price, A. N., Lythgoe, M. F., et al. (2011) · Nature · doi:10.1038/nature10188 · Cited by 632 · see citing works
Bi, W., Huang, W., Whitworth, D. J., Deng, J. M., Zhang, Z., Behringer, R. R., & Crombrugghe, B. D. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.111092198 · Cited by 541 · see citing works
Coronary arteries form by developmental reprogramming of venous cells
Red‐Horse, K., Ueno, H., Weissman, I. L., & Krasnow, M. A. (2010) · Nature · doi:10.1038/nature08873 · Cited by 532 · see citing works
Epicardial FSTL1 reconstitution regenerates the adult mammalian heart
Wei, K., Serpooshan, V., Hurtado, C., Diez-Cuñado, M., Zhao, M., Maruyama, S., Zhu, W., Fajardo, G., Noseda, M., Nakamura, K., et al. (2015) · Nature · doi:10.1038/nature15372 · Cited by 490 · see citing works
The collagen superfamily: from the extracellular matrix to the cell membrane
Ricard‐Blum, S., & Ruggiero, F. (2005) · Pathologie Biologie · doi:10.1016/j.patbio.2004.12.024 · Cited by 428 · see citing works
Cheung, C., Bernardo, A. S., Trotter, M. W. B., Pedersen, R. A., & Sinha, S. (2012) · Nature Biotechnology · doi:10.1038/nbt.2107 · Cited by 397 · see citing works
Wu, B., Zhang, Z., Lui, W., Chen, X., Wang, Y., Chamberlain, A. A., Moreno‐Rodriguez, R. A., Markwald, R. R., O'Rourke, B. P., Sharp, D. J., et al. (2012) · Cell · doi:10.1016/j.cell.2012.10.023 · Cited by 394 · see citing works
Human and Mouse Gene Structure: Comparative Analysis and Application to Exon PredictionPreprint
Batzoglou, S., Pachter, L. S., Mesirov, J. P., Berger, B., & Lander, E. S. (2000) · Genome Research · doi:10.1101/gr.10.7.950 · Cited by 378 · see citing works
Distinct Compartments of the Proepicardial Organ Give Rise to Coronary Vascular Endothelial Cells
Katz, T. C., Singh, M. K., Degenhardt, K. R., Rivera‐Feliciano, J., Johnson, R. L., Epstein, J. A., & Tabin, C. J. (2012) · Developmental Cell · doi:10.1016/j.devcel.2012.01.012 · Cited by 352 · see citing works
Smith, C. L., Baek, S. T., Sung, C. Y., & Tallquist, M. D. (2011) · Circulation Research · doi:10.1161/circresaha.110.235531 · Cited by 339 · see citing works
Duan, J., Gherghe, C. M., Liu, D., Hamlett, E. D., Srikantha, L., Rodgers, L., Regan, J. N., Rojas, M., Willis, M. S., Leask, A., et al. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.418 · Cited by 315 · see citing works
Gemberling, M. P., Karra, R., Dickson, A. L., & Poss, K. D. (2015) · eLife · doi:10.7554/elife.05871 · Cited by 301 · see citing works
Mechanisms of Cardiac Regeneration
Uygur, A., & Lee, R. T. (2016) · Developmental Cell · doi:10.1016/j.devcel.2016.01.018 · Cited by 293 · see citing works
Essential role of Sox9 in the pathway that controls formation of cardiac valves and septa
Akiyama, H., Chaboissier, M.-C., Behringer, R. R., Rowitch, D. H., Schedl, A., Epstein, J. A., & de Crombrugghe, B. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401711101 · Cited by 265 · see citing works
Wang, J., Karra, R., Dickson, A. L., & Poss, K. D. (2013) · Developmental Biology · doi:10.1016/j.ydbio.2013.08.012 · Cited by 231 · see citing works
Cooperative action of Sox9, Snail2 and PKA signaling in early neural crest development
Sakai, D., SUZUKI, T. A., Osumi, N., & Wakamatsu, Y. (2006) · Development · doi:10.1242/dev.02297 · Cited by 201 · see citing works
Morabito, C. J., Dettman, R. W., Kattan, J., Collier, J. M., & Bristow, J. D. (2001) · Developmental Biology · doi:10.1006/dbio.2001.0254 · Cited by 193 · see citing works
Zebrafish heart regeneration: 15 years of discoveries
González‐Rosa, J. M., Burns, C. E., & Burns, C. G. (2017) · Regeneration · doi:10.1002/reg2.83 · Cited by 183 · see citing works
Re-employment of developmental transcription factors in adult heart disease
Oka, T., Xu, J., & Molkentin, J. D. (2006) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2006.11.012 · Cited by 179 · see citing works
Collagen XII: Protecting bone and muscle integrity by organizing collagen fibrils
Chiquet, M., Birk, D. E., Bönnemann, C. G., & Koch, M. (2014) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2014.04.020 · Cited by 169 · see citing works
Lu, J., Landerholm, T. E., Wei, J., Dong, X.-R., Wu, S., Liu, X., Nagata, K., Inagaki, M., & Majesky, M. W. (2001) · Developmental Biology · doi:10.1006/dbio.2001.0403 · Cited by 165 · see citing works
Iyer, D., Gambardella, L., Bernard, W. G., Serrano, F., Mascetti, V. L., Pedersen, R. A., Talasila, A., & Sinha, S. (2015) · Development · doi:10.1242/dev.119271 · Cited by 137 · see citing works
Hydrogen peroxide primes heart regeneration with a derepression mechanism
Han, P., Zhou, X., Chang, N., Xiao, C., Yan, S., Ren, H., Yang, X., Zhang, M., Wu, Q., Tang, B., et al. (2014) · Cell Research · doi:10.1038/cr.2014.108 · Cited by 137 · see citing works
Seong, J., Ouyang, M., Kim, T., Sun, J., Wen, P., Lu, S., Zhuo, Y., Llewellyn, N. M., Schlaepfer, D. D., Guan, J., et al. (2011) · Nature Communications · doi:10.1038/ncomms1414 · Cited by 133 · see citing works
Epicardium derived cells (EPDCs) in development, cardiac disease and repair of ischemia
Groot, A. C. G., Winter, E. M., & Poelmann, R. E. (2010) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2010.01077.x · Cited by 121 · see citing works
Myocardial NF-κB activation is essential for zebrafish heart regeneration
Karra, R., Knecht, A. K., Kikuchi, K., & Poss, K. D. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1511209112 · Cited by 113 · see citing works
Li, L., Qi, L., Liang, Z.-J., Song, W., Liu, Y., Wang, Y., Sun, B., Zhang, B., & Cao, W. (2015) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2015.2222 · Cited by 112 · see citing works
Compton, L. A., Potash, D. A., Mundell, N. A., & Barnett, J. V. (2006) · Developmental Dynamics · doi:10.1002/dvdy.20629 · Cited by 112 · see citing works
Cardiac endothelial cells express Wilms' tumor-1
Duim, S. N., Kurakula, K., Goumans, M., & Kruithof, B. P. T. (2015) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2015.02.007 · Cited by 100 · see citing works
A New Direction for Cardiac Regeneration Therapy
Winter, E. M., van Oorschot, A. A. M., Hogers, B., van der Graaf, L. M., Doevendans, P. A., Poelmann, R. E., Atsma, D. E., Groot, A. C. G., & Goumans, M. (2009) · Circulation Heart Failure · doi:10.1161/circheartfailure.108.843722 · Cited by 92 · see citing works
Vieira, J. M., Howard, S. M., del Campo, C. V., Bollini, S., Dubé, K. N., Masters, M., Barnette, D. N., Rohling, M., Sun, X., Hankins, L. E., et al. (2017) · Nature Communications · doi:10.1038/ncomms16034 · Cited by 90 · see citing works
Cheung, W.-F., Cruz, T. F., & Turley, E. A. (1999) · Biochemical Society Transactions · doi:10.1042/bst0270135 · Cited by 87 · see citing works
Primary and immortalized mouse epicardial cells undergo differentiation in response to TGFβ
Austin, A. F., Compton, L. A., Love, J. D., Brown, C. B., & Barnett, J. V. (2008) · Developmental Dynamics · doi:10.1002/dvdy.21421 · Cited by 86 · see citing works
Marro, J., Pfefferli, C., Charles, A.-S. D. P., Bise, T., & Jaźwińska, A. (2016) · PLoS ONE · doi:10.1371/journal.pone.0165497 · Cited by 81 · see citing works
Missinato, M. A., Tobita, K., Romano, N., Carroll, J. A., & Tsang, M. (2015) · Cardiovascular Research · doi:10.1093/cvr/cvv190 · Cited by 79 · see citing works
Bax, N. A. M., van Oorschot, A. A. M., Maas, S., Braun, J., van Tuyn, J., de Vries, A. A. F., Groot, A. C. G., & Goumans, M. (2011) · Basic Research in Cardiology · doi:10.1007/s00395-011-0181-0 · Cited by 76 · see citing works
Porsch, H., Mehić, M., Olofsson, B., Heldin, P., & Heldin, C. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.547273 · Cited by 71 · see citing works
Tano, N., Narita, T., Kaneko, M., Ikebe, C., Coppen, S. R., Campbell, N. G. S., Shiraishi, M., Shintani, Y., & Suzuki, K. (2014) · Molecular Therapy · doi:10.1038/mt.2014.110 · Cited by 60 · see citing works
The Epicardium As a Candidate for Heart Regeneration
Smart, N., & Riley, P. R. (2011) · Future Cardiology · doi:10.2217/fca.11.87 · Cited by 57 · see citing works
The Epicardium in the Embryonic and Adult Zebrafish
Peralta, M., González‐Rosa, J. M., Marques, I. J., & Mercader, N. (2014) · Journal of Developmental Biology · doi:10.3390/jdb2020101 · Cited by 56 · see citing works
Epicardial progenitor cells in cardiac regeneration and neovascularisation
Smart, N., Dubé, K. N., & Riley, P. R. (2012) · Vascular Pharmacology · doi:10.1016/j.vph.2012.08.001 · Cited by 55 · see citing works
Cardiac Regeneration in Model Organisms
Gamba, L., Harrison, M., & Lien, C. (2014) · Current Treatment Options in Cardiovascular Medicine · doi:10.1007/s11936-013-0288-8 · Cited by 44 · see citing works
Extending the time window of mammalian heart regeneration by thymosin beta 4
Rui, L., Nie, Y., Lian, H., He, F., Chunyong, H., Jian, M., Zheng, Z., & Hu, S. (2014) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.12421 · Cited by 37 · see citing works
Seeger, T., Xu, Q., Muhly-Reinholz, M., Fischer, A., Kremp, E.-M., Zeiher, A. M., & Dimmeler, S. (2016) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2016.04.002 · Cited by 36 · see citing works
Meglio, F. D., Castaldo, C., Nurzyńska, D., Romano, V., Miraglia, R., & Montagnani, S. (2009) · International Journal of Cardiology · doi:10.1016/j.ijcard.2008.12.137 · Cited by 28 · see citing works
DeLaughter, D. M., Clark, C. R., Christodoulou, D. C., Seidman, C. E., Baldwin, H. S., Seidman, J. G., & Barnett, J. V. (2016) · PLoS ONE · doi:10.1371/journal.pone.0159710 · Cited by 24 · see citing works
Xiang, F.-L., Yin, L., Lu, X., Jones, D. L., & Feng, Q. (2014) · Circulation Heart Failure · doi:10.1161/circheartfailure.114.001423 · Cited by 22 · see citing works
Clark, C. R., Robinson, J. Y., Sánchez, N., Townsend, T. A., Arrieta, J. A., Merryman, W. D., Trykall, D. Z., Olivey, H. E., Hong, C. C., & Barnett, J. V. (2016) · Cellular Signalling · doi:10.1016/j.cellsig.2016.03.004 · Cited by 20 · see citing works
Li, Y., Urban, A., Midura, D., Simon, H., & Wang, Q. T. (2017) · PLoS ONE · doi:10.1371/journal.pone.0174563 · Cited by 15 · see citing works
Wang, X., Liu, X., Zhang, H., Nie, L., Chen, M., & Ding, Z. (2015) · International Journal of Cardiology · doi:10.1016/j.ijcard.2015.09.002 · Cited by 10 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Salvatore, T., Galiero, R., Caturano, A., Vetrano, E., Rinaldi, L., Coviello, F., Di Martino, A., Albanese, G., Colantuoni, S., Medicamento, G., et al. (2022) · Biomolecules · doi:10.3390/biom12020176 · Cited by 62 · see citing works
Epicardial HDAC3 Promotes Myocardial Growth Through a Novel MicroRNA Pathway
Jang, J., Song, G., Pettit, S. M., Li, Q., Song, X., Cai, C., Kaushal, S., & Li, D. (2022) · Circulation Research · doi:10.1161/circresaha.122.320785 · Cited by 42 · see citing works
Single-cell and spatial heterogeneity landscapes of mature epicardial cells
Du, J., Yuan, X. H., Deng, H., Huang, R., Liu, B., Xiong, T., Long, X., Zhang, L., Li, Y., & She, Q. (2023) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2023.07.011 · Cited by 36 · see citing works
Qi, Z., Wu, D., Yan, Z., Wang, Q., Li, Y., Zhao, J., & Xu, F. (2025) · Obesity Reviews · doi:10.1111/obr.13912 · Cited by 13 · see citing works
Ge, Y., Smits, A. M., Liu, J., Zhang, J., van Brakel, T. J., Goumans, M., Jongbloed, M. R. M., & de Vries, A. A. F. (2021) · Cells · doi:10.3390/cells10082064 · Cited by 10 · see citing works
RACK1 contributes to the upregulation of embryonic genes in a model of cardiac hypertrophy
Ceci, M., Bonvissuto, D., Papetti, F., Silvestri, F., Sette, C., Catalani, E., Cervia, D., Gornati, R., & Romano, N. (2024) · Scientific Reports · doi:10.1038/s41598-024-76138-x · Cited by 3 · see citing works
Caño-Carrillo, S., García‐Padilla, C., Aránega, A. E., Lozano-Velasco, E., & Franco, D. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252312904 · Cited by 2 · see citing works
Kingma, J. G. (2020) · World Journal of Cardiovascular Diseases · doi:10.4236/wjcd.2020.104019 · Cited by 2 · see citing works
Dergilev, K. V., Tsokolaeva, Z. I., Beloglazova, I. B., Komova, A. V., Pavlova, S. V., Traktuev, D. O., & Parfyonova, Y. V. (2019) · General Reanimatology · doi:10.15360/1813-9779-2019-6-38-49 · Cited by 1 · see citing works
New Pathways for Regeneration and Repair after Myocardial Infarction: Epicardium
贾, 曰. (2024) · Advances in Clinical Medicine · doi:10.12677/acm.2024.1441121
- Authors
- Saifi, O., Ghandour, B., Jaalouk, D., Refaat, M., & Mahfouz, R.
- Affiliations
- American University of Beirut (LB)
- American University of Beirut Medical Center (LB)
- Corresponding author
- Mahfouz, Rami
- Venue
- Molecular Biology Reports
- Published
- 2019-09-23
- Volume
- 46
- Issue
- 6
- Pages
- 6661-6674
- ISSN
- 0301-4851 (ISSN-L)
- 1573-4978
- OpenAlex
- W2976782203
- Cited by
- 10
- References
- 54
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 1
- FWCI
- 0.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Biology Reports (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- cardiac regeneration, epicardium, zebrafish heart, epithelial-mesenchymal transition, angiogenesis, extracellular matrix, cardiac repair
- MeSH terms
- Animals, Extracellular Matrix, Humans, Mammals, Pericardium, Regeneration, Gene Regulatory Networks
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
