缺血性心臟病是全球頭號死因之首。由於人類心臟再生的能力退化至極弱，因血管阻塞而造成心肌梗塞時的受傷部位，會形成疤痕組織而造成心臟結構的重塑和心搏出功能的下降，嚴重時會導致心臟衰竭，甚至死亡。然而和哺乳類動物不同，斑馬魚具有再生受損心臟的能力，但是其再生機制仍未被充分了解。因此，研究斑馬魚在受傷後的再生過程，對於我們了解心臟受損和發展治療方式是重要的課題。許多的研究指出，參與斑馬魚心臟發育過程的訊息傳遞路徑，會於再生時再度啟動來修復受損的組識。因此，我們以發育時和心肌組成相關的人類先天性遺傳疾病(肥厚型心肌病)的相關基因做為線索，結合斑馬魚心臟受損後的時間序列微陣列基因表現資訊，來探討斑馬魚心臟再生過程中心肌重塑的分子機制。藉由分析肥厚型心肌病的基因在心臟受損後的動態表現差異，我們辨認出和心肌重塑和再生相關的基因。利用生物資訊的工具和資料庫，我們進一步建構了訊息途徑網路並找出其上游進行調控的關鍵受體。分析指出β-2-microglobulin可能會在心肌重塑過程中扮演重要的角色。我們的研究結合生物資訊工具，呈現了一個以人類發育遺傳疾病為線索，辨認心臟再生時的分子和訊息途的方法，有助我們理解斑馬魚相對於人類心臟受損異變後的修復機制與過程。

Unlike mammals, adult zebrafish hearts retain a remarkable capacity to regenerate after injury. Since regeneration shares many common molecular pathways with embryonic development, we investigated myocardial remodeling genes and pathways by performing a comparative transcriptomic analysis of zebrafish heart regeneration using a set of known human hereditary heart disease genes related to myocardial hypertrophy during development. We cross-matched human hypertrophic cardiomyopathy-associated genes with a time-course microarray dataset of adult zebrafish heart regeneration. Genes in the expression profiles that were highly elevated in the early phases of myocardial repair and remodeling after injury in zebrafish were identified. These genes were further analyzed with web-based bioinformatics tools to construct a regulatory network revealing potential transcription factors and their upstream receptors. In silico functional analysis of these genes showed that they are involved in cardiomyocyte proliferation and differentiation, angiogenesis, and inflammation-related pathways. The regulatory network indicated that β-2-microglobulin-mediated signaling may play an important role in myocardial remodeling after injury. This novel cross-species bioinformatics approach to uncover key modulators of zebrafish heart regeneration through human hereditary disease genomic analysis could greatly facilitate the understanding of the evolutionarily conserved cardiac remodeling process.

1. Writing Group, M., D. Mozaffarian, E.J. Benjamin, A.S. Go, D.K. Arnett, M.J. Blaha, M. Cushman, S.R. Das, S. de Ferranti, J.P. Despres, H.J. Fullerton, V.J. Howard, M.D. Huffman, C.R. Isasi, M.C. Jimenez, S.E. Judd, B.M. Kissela, J.H. Lichtman, L.D. Lisabeth, S. Liu, R.H. Mackey, D.J. Magid, D.K. McGuire, E.R. Mohler, 3rd, C.S. Moy, P. Muntner, M.E. Mussolino, K. Nasir, R.W. Neumar, G. Nichol, L. Palaniappan, D.K. Pandey, M.J. Reeves, C.J. Rodriguez, W. Rosamond, P.D. Sorlie, J. Stein, A. Towfighi, T.N. Turan, S.S. Virani, D. Woo, R.W. Yeh, M.B. Turner, C. American Heart Association Statistics, and S. Stroke Statistics, Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation, 2016. 133(4): p. e38-360.
2. Pfeffer, M.A. and E. Braunwald, Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation, 1990. 81(4): p. 1161-72.
3. Tzahor, E. and K.D. Poss, Cardiac regeneration strategies: Staying young at heart. Science, 2017. 356(6342): p. 1035-1039.
4. Ponikowski, P., A.A. Voors, S.D. Anker, H. Bueno, J.G.F. Cleland, A.J.S. Coats, V. Falk, J.R. Gonzalez-Juanatey, V.P. Harjola, E.A. Jankowska, M. Jessup, C. Linde, P. Nihoyannopoulos, J.T. Parissis, B. Pieske, J.P. Riley, G.M.C. Rosano, L.M. Ruilope, F. Ruschitzka, F.H. Rutten, P. van der Meer, and E.S.C.S.D. Group, 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J, 2016. 37(27): p. 2129-2200.
5. Chen, J., A.F. Hsieh, K. Dharmarajan, F.A. Masoudi, and H.M. Krumholz, National trends in heart failure hospitalization after acute myocardial infarction for Medicare beneficiaries: 1998-2010. Circulation, 2013. 128(24): p. 2577-84.
6. Desta, L., T. Jernberg, I. Lofman, C. Hofman-Bang, I. Hagerman, J. Spaak, and H. Persson, Incidence, temporal trends, and prognostic impact of heart failure complicating acute myocardial infarction. The SWEDEHEART Registry (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies): a study of 199,851 patients admitted with index acute myocardial infarctions, 1996 to 2008. JACC Heart Fail, 2015. 3(3): p. 234-42.
7. Le, T.Y., S. Thavapalachandran, E. Kizana, and J.J. Chong, New Developments in Cardiac Regeneration. Heart Lung Circ, 2017. 26(4): p. 316-322.
8. Bergmann, O., S. Zdunek, J. Frisen, S. Bernard, H. Druid, and S. Jovinge, Cardiomyocyte renewal in humans. Circ Res, 2012. 110(1): p. e17-8; author reply e19-21.
9. Bergmann, O., S. Zdunek, A. Felker, M. Salehpour, K. Alkass, S. Bernard, S.L. Sjostrom, M. Szewczykowska, T. Jackowska, C. Dos Remedios, T. Malm, M. Andra, R. Jashari, J.R. Nyengaard, G. Possnert, S. Jovinge, H. Druid, and J. Frisen, Dynamics of Cell Generation and Turnover in the Human Heart. Cell, 2015. 161(7): p. 1566-75.
10. Poss, K.D., L.G. Wilson, and M.T. Keating, Heart regeneration in zebrafish. Science, 2002. 298(5601): p. 2188-90.
11. Becker, J.R., R.C. Deo, A.A. Werdich, D. Panakova, S. Coy, and C.A. MacRae, Human cardiomyopathy mutations induce myocyte hyperplasia and activate hypertrophic pathways during cardiogenesis in zebrafish. Dis Model Mech, 2011. 4(3): p. 400-10.
12. Lepilina, A., A.N. Coon, K. Kikuchi, J.E. Holdway, R.W. Roberts, C.G. Burns, and K.D. Poss, A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Cell, 2006. 127(3): p. 607-19.
13. Tomanek, R.J., H.K. Hansen, and L.P. Christensen, Temporally expressed PDGF and FGF-2 regulate embryonic coronary artery formation and growth. Arterioscler Thromb Vasc Biol, 2008. 28(7): p. 1237-43.
14. Jopling, C., E. Sleep, M. Raya, M. Marti, A. Raya, and J.C. Izpisua Belmonte, Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature, 2010. 464(7288): p. 606-9.
15. Chablais, F. and A. Jazwinska, The regenerative capacity of the zebrafish heart is dependent on TGFbeta signaling. Development, 2012. 139(11): p. 1921-30.
16. Sanchez-Iranzo, H., M. Galardi-Castilla, A. Sanz-Morejon, J.M. Gonzalez-Rosa, R. Costa, A. Ernst, J. Sainz de Aja, X. Langa, and N. Mercader, Transient fibrosis resolves via fibroblast inactivation in the regenerating zebrafish heart. Proc Natl Acad Sci U S A, 2018. 115(16): p. 4188-4193.
17. Porrello, E.R., A.I. Mahmoud, E. Simpson, J.A. Hill, J.A. Richardson, E.N. Olson, and H.A. Sadek, Transient regenerative potential of the neonatal mouse heart. Science, 2011. 331(6020): p. 1078-80.
18. Zhu, W., E. Zhang, M. Zhao, Z. Chong, C. Fan, Y. Tang, J.D. Hunter, A.V. Borovjagin, G.P. Walcott, J.Y. Chen, G. Qin, and J. Zhang, Regenerative Potential of Neonatal Porcine Hearts. Circulation, 2018.
19. Kikuchi, K., J.E. Holdway, R.J. Major, N. Blum, R.D. Dahn, G. Begemann, and K.D. Poss, Retinoic acid production by endocardium and epicardium is an injury response essential for zebrafish heart regeneration. Dev Cell, 2011. 20(3): p. 397-404.
20. Furtado, M.B., M.W. Costa, and N.A. Rosenthal, The cardiac fibroblast: Origin, identity and role in homeostasis and disease. Differentiation, 2016. 92(3): p. 93-101.
21. Cao, J. and K.D. Poss, The epicardium as a hub for heart regeneration. Nat Rev Cardiol, 2018.
22. Kim, J., Q. Wu, Y. Zhang, K.M. Wiens, Y. Huang, N. Rubin, H. Shimada, R.I. Handin, M.Y. Chao, T.L. Tuan, V.A. Starnes, and C.L. Lien, PDGF signaling is required for epicardial function and blood vessel formation in regenerating zebrafish hearts. Proc Natl Acad Sci U S A, 2010. 107(40): p. 17206-10.
23. Itou, J., I. Oishi, H. Kawakami, T.J. Glass, J. Richter, A. Johnson, T.C. Lund, and Y. Kawakami, Migration of cardiomyocytes is essential for heart regeneration in zebrafish. Development, 2012. 139(22): p. 4133-42.
24. Lien, C.L., M. Schebesta, S. Makino, G.J. Weber, and M.T. Keating, Gene expression analysis of zebrafish heart regeneration. PLoS Biol, 2006. 4(8): p. e260.
25. Sleep, E., S. Boue, C. Jopling, M. Raya, A. Raya, and J.C. Izpisua Belmonte, Transcriptomics approach to investigate zebrafish heart regeneration. J Cardiovasc Med (Hagerstown), 2010. 11(5): p. 369-80.
26. Fishman, M.C. and K.R. Chien, Fashioning the vertebrate heart: earliest embryonic decisions. Development, 1997. 124(11): p. 2099-117.
27. Birket, M.J., M.C. Ribeiro, A.O. Verkerk, D. Ward, A.R. Leitoguinho, S.C. den Hartogh, V.V. Orlova, H.D. Devalla, V. Schwach, M. Bellin, R. Passier, and C.L. Mummery, Expansion and patterning of cardiovascular progenitors derived from human pluripotent stem cells. Nat Biotechnol, 2015. 33(9): p. 970-9.
28. Weeke-Klimp, A., N.A. Bax, A.R. Bellu, E.M. Winter, J. Vrolijk, J. Plantinga, S. Maas, M. Brinker, E.A. Mahtab, A.C. Gittenberger-de Groot, M.J. van Luyn, M.C. Harmsen, and H. Lie-Venema, Epicardium-derived cells enhance proliferation, cellular maturation and alignment of cardiomyocytes. J Mol Cell Cardiol, 2010. 49(4): p. 606-16.
29. Zhou, B., L.B. Honor, H. He, Q. Ma, J.H. Oh, C. Butterfield, R.Z. Lin, J.M. Melero-Martin, E. Dolmatova, H.S. Duffy, A. Gise, P. Zhou, Y.W. Hu, G. Wang, B. Zhang, L. Wang, J.L. Hall, M.A. Moses, F.X. McGowan, and W.T. Pu, Adult mouse epicardium modulates myocardial injury by secreting paracrine factors. J Clin Invest, 2011. 121(5): p. 1894-904.
30. Mohl, W., D. Milasinovic, T. Aschacher, A. Jusic, A. Maimaitiaili, and F. Rattay, The Hypothesis of “Embryonic Recall”: Mechanotransduction as Common Denominator Linking Normal Cardiogenesis to Recovery in Adult Failing Hearts. Journal of Cardiovascular Development and Disease, 2014. 1(1): p. 73-82.
31. Ahuja, P., P. Sdek, and W.R. MacLellan, Cardiac myocyte cell cycle control in development, disease, and regeneration. Physiol Rev, 2007. 87(2): p. 521-44.
32. Seeley, M., W. Huang, Z. Chen, W.O. Wolff, X. Lin, and X. Xu, Depletion of zebrafish titin reduces cardiac contractility by disrupting the assembly of Z-discs and A-bands. Circ Res, 2007. 100(2): p. 238-45.
33. Huttner, I.G., L.W. Wang, C.F. Santiago, C. Horvat, R. Johnson, D. Cheng, M. von Frieling-Salewsky, K. Hillcoat, T.J. Bemand, G. Trivedi, F. Braet, D. Hesselson, K. Alford, C.S. Hayward, J.G. Seidman, C.E. Seidman, M.P. Feneley, W.A. Linke, and D. Fatkin, A-Band Titin Truncation in Zebrafish Causes Dilated Cardiomyopathy and Hemodynamic Stress Intolerance. Circ Genom Precis Med, 2018. 11(8): p. e002135.
34. Sehnert, A.J., A. Huq, B.M. Weinstein, C. Walker, M. Fishman, and D.Y. Stainier, Cardiac troponin T is essential in sarcomere assembly and cardiac contractility. Nat Genet, 2002. 31(1): p. 106-10.
35. Rottbauer, W., G. Wessels, T. Dahme, S. Just, N. Trano, D. Hassel, C.G. Burns, H.A. Katus, and M.C. Fishman, Cardiac myosin light chain-2: a novel essential component of thick-myofilament assembly and contractility of the heart. Circ Res, 2006. 99(3): p. 323-31.
36. Chen, Z., W. Huang, T. Dahme, W. Rottbauer, M.J. Ackerman, and X. Xu, Depletion of zebrafish essential and regulatory myosin light chains reduces cardiac function through distinct mechanisms. Cardiovasc Res, 2008. 79(1): p. 97-108.
37. Berdougo, E., H. Coleman, D.H. Lee, D.Y. Stainier, and D. Yelon, Mutation of weak atrium/atrial myosin heavy chain disrupts atrial function and influences ventricular morphogenesis in zebrafish. Development, 2003. 130(24): p. 6121-9.
38. Wang, L., J.G. Seidman, and C.E. Seidman, Narrative review: harnessing molecular genetics for the diagnosis and management of hypertrophic cardiomyopathy. Ann Intern Med, 2010. 152(8): p. 513-20, W181.
39. Hodatsu, A., T. Konno, K. Hayashi, A. Funada, T. Fujita, Y. Nagata, N. Fujino, M.A. Kawashiri, and M. Yamagishi, Compound heterozygosity deteriorates phenotypes of hypertrophic cardiomyopathy with founder MYBPC3 mutation: evidence from patients and zebrafish models. Am J Physiol Heart Circ Physiol, 2014. 307(11): p. H1594-604.
40. Sisakian, H., Cardiomyopathies: Evolution of pathogenesis concepts and potential for new therapies. World J Cardiol, 2014. 6(6): p. 478-94.
41. Chung, M.W., T. Tsoutsman, and C. Semsarian, Hypertrophic cardiomyopathy: from gene defect to clinical disease. Cell Res, 2003. 13(1): p. 9-20.
42. Westerfield, M., The zebrafish book : a guide for the laboratory use of zebrafish (Brachydanio rerio). 1993, Eugene, OR: M. Westerfield.
43. Huang, W.C., Y.S. Hsieh, I.H. Chen, C.H. Wang, H.W. Chang, C.C. Yang, T.H. Ku, S.R. Yeh, and Y.J. Chuang, Combined use of MS-222 (tricaine) and isoflurane extends anesthesia time and minimizes cardiac rhythm side effects in adult zebrafish. Zebrafish, 2010. 7(3): p. 297-304.
44. Becker, K.G., K.C. Barnes, T.J. Bright, and S.A. Wang, The genetic association database. Nat Genet, 2004. 36(5): p. 431-2.
45. Ernst, J. and Z. Bar-Joseph, STEM: a tool for the analysis of short time series gene expression data. BMC Bioinformatics, 2006. 7: p. 191.
46. Kwon, A.T., D.J. Arenillas, R. Worsley Hunt, and W.W. Wasserman, oPOSSUM-3: advanced analysis of regulatory motif over-representation across genes or ChIP-Seq datasets. G3 (Bethesda), 2012. 2(9): p. 987-1002.
47. Choi, W.Y., M. Gemberling, J. Wang, J.E. Holdway, M.C. Shen, R.O. Karlstrom, and K.D. Poss, In vivo monitoring of cardiomyocyte proliferation to identify chemical modifiers of heart regeneration. Development, 2013. 140(3): p. 660-6.
48. Gupta, V., M. Gemberling, R. Karra, G.E. Rosenfeld, T. Evans, and K.D. Poss, An injury-responsive gata4 program shapes the zebrafish cardiac ventricle. Curr Biol, 2013. 23(13): p. 1221-7.
49. Bradford, Y., T. Conlin, N. Dunn, D. Fashena, K. Frazer, D.G. Howe, J. Knight, P. Mani, R. Martin, S.A. Moxon, H. Paddock, C. Pich, S. Ramachandran, B.J. Ruef, L. Ruzicka, H. Bauer Schaper, K. Schaper, X. Shao, A. Singer, J. Sprague, B. Sprunger, C. Van Slyke, and M. Westerfield, ZFIN: enhancements and updates to the Zebrafish Model Organism Database. Nucleic Acids Res, 2011. 39(Database issue): p. D822-9.
50. Lien, C.L., M.R. Harrison, T.L. Tuan, and V.A. Starnes, Heart repair and regeneration: recent insights from zebrafish studies. Wound Repair Regen, 2012. 20(5): p. 638-46.
51. Gonzalez-Rosa, J.M., C.E. Burns, and C.G. Burns, Zebrafish heart regeneration: 15 years of discoveries. Regeneration (Oxf), 2017. 4(3): p. 105-123.
52. Häggström, M., Medical gallery of Mikael Häggström. WikiJournal of Medicine, 2014. 1(2).
53. Dogra, D., S. Ahuja, H.T. Kim, S.J. Rasouli, D.Y.R. Stainier, and S. Reischauer, Opposite effects of Activin type 2 receptor ligands on cardiomyocyte proliferation during development and repair. Nat Commun, 2017. 8(1): p. 1902.
54. Huang, W.C., C.C. Yang, I.H. Chen, Y.M. Liu, S.J. Chang, and Y.J. Chuang, Treatment of Glucocorticoids Inhibited Early Immune Responses and Impaired Cardiac Repair in Adult Zebrafish. PLoS One, 2013. 8(6): p. e66613.
55. Marin-Juez, R., M. Marass, S. Gauvrit, A. Rossi, S.L. Lai, S.C. Materna, B.L. Black, and D.Y. Stainier, Fast revascularization of the injured area is essential to support zebrafish heart regeneration. Proc Natl Acad Sci U S A, 2016. 113(40): p. 11237-11242.
56. Vincentz, J.W., R.M. Barnes, B.A. Firulli, S.J. Conway, and A.B. Firulli, Cooperative interaction of Nkx2.5 and Mef2c transcription factors during heart development. Dev Dyn, 2008. 237(12): p. 3809-19.
57. Yang, J., X. Zhang, J. Wang, J. Qian, L. Zhang, M. Wang, L.W. Kwak, and Q. Yi, Anti beta2-microglobulin monoclonal antibodies induce apoptosis in myeloma cells by recruiting MHC class I to and excluding growth and survival cytokine receptors from lipid rafts. Blood, 2007. 110(8): p. 3028-35.
58. Yang, X., L. Pabon, and C.E. Murry, Engineering adolescence: maturation of human pluripotent stem cell-derived cardiomyocytes. Circ Res, 2014. 114(3): p. 511-23.
59. Pugh, T.J., M.A. Kelly, S. Gowrisankar, E. Hynes, M.A. Seidman, S.M. Baxter, M. Bowser, B. Harrison, D. Aaron, L.M. Mahanta, N.K. Lakdawala, G. McDermott, E.T. White, H.L. Rehm, M. Lebo, and B.H. Funke, The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. Genet Med, 2014. 16(8): p. 601-8.
60. Grunig, E., J.A. Tasman, H. Kucherer, W. Franz, W. Kubler, and H.A. Katus, Frequency and phenotypes of familial dilated cardiomyopathy. J Am Coll Cardiol, 1998. 31(1): p. 186-94.
61. Ganesh, S.K., D.K. Arnett, T.L. Assimes, C.T. Basson, A. Chakravarti, P.T. Ellinor, M.B. Engler, E. Goldmuntz, D.M. Herrington, R.E. Hershberger, Y. Hong, J.A. Johnson, S.J. Kittner, D.A. McDermott, J.F. Meschia, L. Mestroni, C.J. O'Donnell, B.M. Psaty, R.S. Vasan, M. Ruel, W.K. Shen, A. Terzic, S.A. Waldman, G. American Heart Association Council on Functional, B. Translational, E. American Heart Association Council on, Prevention, S. American Heart Association Council on Basic Cardiovascular, Y. American Heart Association Council on Cardiovascular Disease in the, C. American Heart Association Council on, N. Stroke, and C. American Heart Association Stroke, Genetics and genomics for the prevention and treatment of cardiovascular disease: update: a scientific statement from the American Heart Association. Circulation, 2013. 128(25): p. 2813-51.
62. Shih, Y.H., Y. Zhang, Y. Ding, C.A. Ross, H. Li, T.M. Olson, and X. Xu, Cardiac transcriptome and dilated cardiomyopathy genes in zebrafish. Circ Cardiovasc Genet, 2015. 8(2): p. 261-9.
63. Knoll, R., R. Postel, J. Wang, R. Kratzner, G. Hennecke, A.M. Vacaru, P. Vakeel, C. Schubert, K. Murthy, B.K. Rana, D. Kube, G. Knoll, K. Schafer, T. Hayashi, T. Holm, A. Kimura, N. Schork, M.R. Toliat, P. Nurnberg, H.P. Schultheiss, W. Schaper, J. Schaper, E. Bos, J. Den Hertog, F.J. van Eeden, P.J. Peters, G. Hasenfuss, K.R. Chien, and J. Bakkers, Laminin-alpha4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells. Circulation, 2007. 116(5): p. 515-25.
64. Maron, B.J., M.S. Maron, and C. Semsarian, Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J Am Coll Cardiol, 2012. 60(8): p. 705-15.
65. Marques, M.A. and G.A. de Oliveira, Cardiac Troponin and Tropomyosin: Structural and Cellular Perspectives to Unveil the Hypertrophic Cardiomyopathy Phenotype. Front Physiol, 2016. 7: p. 429.
66. Abdul-Wajid, S., B.L. Demarest, and H.J. Yost, Loss of embryonic neural crest derived cardiomyocytes causes adult onset hypertrophic cardiomyopathy in zebrafish. Nat Commun, 2018. 9(1): p. 4603.
67. Gemberling, M., T.J. Bailey, D.R. Hyde, and K.D. Poss, The zebrafish as a model for complex tissue regeneration. Trends Genet, 2013. 29(11): p. 611-20.
68. Liu, F.Y., T.C. Hsu, P. Choong, M.H. Lin, Y.J. Chuang, B.S. Chen, and C. Lin, Uncovering the regeneration strategies of zebrafish organs: a comprehensive systems biology study on heart, cerebellum, fin, and retina regeneration. BMC Syst Biol, 2018. 12(Suppl 2): p. 29.
69. Teekakirikul, P., S. Eminaga, O. Toka, R. Alcalai, L. Wang, H. Wakimoto, M. Nayor, T. Konno, J.M. Gorham, C.M. Wolf, J.B. Kim, J.P. Schmitt, J.D. Molkentin, R.A. Norris, A.M. Tager, S.R. Hoffman, R.R. Markwald, C.E. Seidman, and J.G. Seidman, Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-beta. J Clin Invest, 2010. 120(10): p. 3520-9.
70. Schultz Jel, J., S.A. Witt, B.J. Glascock, M.L. Nieman, P.J. Reiser, S.L. Nix, T.R. Kimball, and T. Doetschman, TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II. J Clin Invest, 2002. 109(6): p. 787-96.
71. Zijlstra, M., M. Bix, N.E. Simister, J.M. Loring, D.H. Raulet, and R. Jaenisch, Beta 2-microglobulin deficient mice lack CD4-8+ cytolytic T cells. Nature, 1990. 344(6268): p. 742-6.
72. Hao, H.F., T.Y. Yang, R.Q. Yan, F.S. Gao, and C. Xia, cDNA cloning and genomic structure of grass carp (Ctenophayngodon idellus) beta2-microglobulin gene. Fish Shellfish Immunol, 2006. 20(1): p. 118-23.
73. Li, L., M. Dong, and X.G. Wang, The Implication and Significance of Beta 2 Microglobulin: A Conservative Multifunctional Regulator. Chin Med J (Engl), 2016. 129(4): p. 448-55.
74. Elmer, B.M., M.L. Estes, S.L. Barrow, and A.K. McAllister, MHCI requires MEF2 transcription factors to negatively regulate synapse density during development and in disease. J Neurosci, 2013. 33(34): p. 13791-804.
75. Ieda, M., J.D. Fu, P. Delgado-Olguin, V. Vedantham, Y. Hayashi, B.G. Bruneau, and D. Srivastava, Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell, 2010. 142(3): p. 375-86.
76. Qian, L., Y. Huang, C.I. Spencer, A. Foley, V. Vedantham, L. Liu, S.J. Conway, J.D. Fu, and D. Srivastava, In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature, 2012. 485(7400): p. 593-8.
77. Hinits, Y., L. Pan, C. Walker, J. Dowd, C.B. Moens, and S.M. Hughes, Zebrafish Mef2ca and Mef2cb are essential for both first and second heart field cardiomyocyte differentiation. Dev Biol, 2012. 369(2): p. 199-210.
78. Josson, S., T. Nomura, J.T. Lin, W.C. Huang, D. Wu, H.E. Zhau, M. Zayzafoon, M.N. Weizmann, M. Gururajan, and L.W. Chung, beta2-microglobulin induces epithelial to mesenchymal transition and confers cancer lethality and bone metastasis in human cancer cells. Cancer Res, 2011. 71(7): p. 2600-10.
79. Shi, C., Y. Zhu, Y. Su, L.W. Chung, and T. Cheng, Beta2-microglobulin: emerging as a promising cancer therapeutic target. Drug Discov Today, 2009. 14(1-2): p. 25-30.
80. Mockel, M., R. Muller, J. Searle, A. Slagman, B. De Bruyne, P. Serruys, G. Weisz, K. Xu, F. Holert, C. Muller, A. Maehara, and G.W. Stone, Usefulness of Beta2-Microglobulin as a Predictor of All-Cause and Nonculprit Lesion-Related Cardiovascular Events in Acute Coronary Syndromes (from the PROSPECT Study). Am J Cardiol, 2015. 116(7): p. 1034-40.
81. Zafiriou, M.P., C. Noack, B. Unsold, M. Didie, E. Pavlova, H.J. Fischer, H.M. Reichardt, M.W. Bergmann, A. El-Armouche, W.H. Zimmermann, and L.C. Zelarayan, Erythropoietin responsive cardiomyogenic cells contribute to heart repair post myocardial infarction. Stem Cells, 2014. 32(9): p. 2480-91.
82. Ellison, G.M., C. Vicinanza, A.J. Smith, I. Aquila, A. Leone, C.D. Waring, B.J. Henning, G.G. Stirparo, R. Papait, M. Scarfo, V. Agosti, G. Viglietto, G. Condorelli, C. Indolfi, S. Ottolenghi, D. Torella, and B. Nadal-Ginard, Adult c-kit(pos) cardiac stem cells are necessary and sufficient for functional cardiac regeneration and repair. Cell, 2013. 154(4): p. 827-42.
83. Cao, J., A. Navis, B.D. Cox, A.L. Dickson, M. Gemberling, R. Karra, M. Bagnat, and K.D. Poss, Single epicardial cell transcriptome sequencing identifies Caveolin 1 as an essential factor in zebrafish heart regeneration. Development, 2016. 143(2): p. 232-43.
84. Kang, J., J. Hu, R. Karra, A.L. Dickson, V.A. Tornini, G. Nachtrab, M. Gemberling, J.A. Goldman, B.L. Black, and K.D. Poss, Modulation of tissue repair by regeneration enhancer elements. Nature, 2016. 532(7598): p. 201-6.
85. Doppler, S.A., M.A. Deutsch, R. Lange, and M. Krane, Cardiac regeneration: current therapies-future concepts. J Thorac Dis, 2013. 5(5): p. 683-97.