{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T02:04:07Z","timestamp":1789610647148,"version":"build-2803163510"},"reference-count":112,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2019,7,4]],"date-time":"2019-07-04T00:00:00Z","timestamp":1562198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["13SDG14580035"],"award-info":[{"award-number":["13SDG14580035"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NIH-1R01HL139006"],"award-info":[{"award-number":["NIH-1R01HL139006"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Coronary artery disease is the most common form of cardiovascular diseases, resulting in the loss of cardiomyocytes (CM) at the site of ischemic injury. To compensate for the loss of CMs, cardiac fibroblasts quickly respond to injury and initiate cardiac remodeling in an injured heart. In the remodeling process, cardiac fibroblasts proliferate and differentiate into myofibroblasts, which secrete extracellular matrix to support the intact structure of the heart, and eventually differentiate into matrifibrocytes to form chronic scar tissue. Discovery of direct cardiac reprogramming offers a promising therapeutic strategy to prevent\/attenuate this pathologic remodeling and replace the cardiac fibrotic scar with myocardium in situ. Since the first discovery in 2010, many progresses have been made to improve the efficiency and efficacy of reprogramming by understanding the mechanisms and signaling pathways that are activated during direct cardiac reprogramming. Here, we overview the development and recent progresses of direct cardiac reprogramming and discuss future directions in order to translate this promising technology into an effective therapeutic paradigm to reverse cardiac pathological remodeling in an injured heart.<\/jats:p>","DOI":"10.3390\/cells8070679","type":"journal-article","created":{"date-parts":[[2019,7,5]],"date-time":"2019-07-05T11:44:16Z","timestamp":1562327056000},"page":"679","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Ameliorating the Fibrotic Remodeling of the Heart through Direct Cardiac Reprogramming"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3558-2886","authenticated-orcid":false,"given":"Emre","family":"Bektik","sequence":"first","affiliation":[{"name":"Department of Medicine, Heart and Vascular Research Center, The MetroHealth System, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-dong","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Heart and Vascular Research Center, The MetroHealth System, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e146","DOI":"10.1161\/CIR.0000000000000485","article-title":"Heart Disease and Stroke Statistics-2017 Update: A Report from the American Heart Association","volume":"135","author":"Benjamin","year":"2017","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3012","DOI":"10.1002\/jbm.a.35442","article-title":"Enhanced engraftment and repairing ability of human adipose-derived stem cells, conveyed by pharmacologically active microcarriers continuously releasing HGF and IGF-1, in healing myocardial infarction in rats","volume":"103","author":"Savi","year":"2015","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1161\/CIRCRESAHA.111.245969","article-title":"Autologous mesenchymal stem cells mobilize cKit+ and CD133+ bone marrow progenitor cells and improve regional function in hibernating myocardium","volume":"109","author":"Suzuki","year":"2011","journal-title":"Circ. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"15007","DOI":"10.1038\/cddiscovery.2015.7","article-title":"Rap1-mediated nuclear factor-kappaB (NF-kappaB) activity regulates the paracrine capacity of mesenchymal stem cells in heart repair following infarction","volume":"1","author":"Zhang","year":"2015","journal-title":"Cell Death Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.yexcr.2016.03.024","article-title":"Enhanced cell survival and paracrine effects of mesenchymal stem cells overexpressing hepatocyte growth factor promote cardioprotection in myocardial infarction","volume":"344","author":"Zhao","year":"2016","journal-title":"Exp. Cell Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3711","DOI":"10.1007\/s00018-017-2546-5","article-title":"Human heart disease: Lessons from human pluripotent stem cell-derived cardiomyocytes","volume":"74","author":"Giacomelli","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1161\/CIRCULATIONAHA.111.045146","article-title":"Human embryonic and induced pluripotent stem cell-derived cardiomyocytes exhibit beat rate variability and power-law behavior","volume":"125","author":"Mandel","year":"2012","journal-title":"Circulation"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1139\/cjpp-2016-0726","article-title":"Induced pluripotent stem-cell-derived cardiomyocytes: Cardiac applications, opportunities, and challenges","volume":"95","author":"Moreau","year":"2017","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1038\/nature10188","article-title":"De novo cardiomyocytes from within the activated adult heart after injury","volume":"474","author":"Smart","year":"2011","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1016\/j.jacc.2011.05.013","article-title":"Endogenous cardiac stem cell activation by insulin-like growth factor-1\/hepatocyte growth factor intracoronary injection fosters survival and regeneration of the infarcted pig heart","volume":"58","author":"Ellison","year":"2011","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1161\/01.RES.0000183733.53101.11","article-title":"Cardiac stem cells possess growth factor-receptor systems that after activation regenerate the infarcted myocardium, improving ventricular function and long-term survival","volume":"97","author":"Urbanek","year":"2005","journal-title":"Circ. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8966","DOI":"10.1073\/pnas.0502678102","article-title":"Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function","volume":"102","author":"Linke","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1083\/jcb.200806104","article-title":"Notch activates cell cycle reentry and progression in quiescent cardiomyocytes","volume":"183","author":"Campa","year":"2008","journal-title":"J. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1161\/01.RES.85.3.294","article-title":"A mammalian myocardial cell-free system to study cell cycle reentry in terminally differentiated cardiomyocytes","volume":"85","author":"Engel","year":"1999","journal-title":"Circ. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1038\/s41598-017-01426-8","article-title":"Adult murine cardiomyocytes exhibit regenerative activity with cell cycle reentry through STAT3 in the healing process of myocarditis","volume":"7","author":"Miyawaki","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.cell.2018.02.014","article-title":"Regulation of Cell Cycle to Stimulate Adult Cardiomyocyte Proliferation and Cardiac Regeneration","volume":"173","author":"Mohamed","year":"2018","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.cell.2010.07.002","article-title":"Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors","volume":"142","author":"Ieda","year":"2010","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1161\/CIRCRESAHA.112.271148","article-title":"Induction of cardiomyocyte-like cells in infarct hearts by gene transfer of Gata4, Mef2c, and Tbx5","volume":"111","author":"Inagawa","year":"2012","journal-title":"Circ. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1161\/CIRCRESAHA.112.269035","article-title":"MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes","volume":"110","author":"Jayawardena","year":"2012","journal-title":"Circ. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1038\/nature11044","article-title":"In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes","volume":"485","author":"Qian","year":"2012","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/nature11139","article-title":"Heart repair by reprogramming non-myocytes with cardiac transcription factors","volume":"485","author":"Song","year":"2012","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1126\/science.aam5894","article-title":"Cardiac regeneration strategies: Staying young at heart","volume":"356","author":"Tzahor","year":"2017","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"239rv1","DOI":"10.1126\/scitranslmed.3006681","article-title":"Strategies for cardiac regeneration and repair","volume":"6","author":"Lin","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Tani, H., Sadahiro, T., and Ieda, M. (2018). Direct Cardiac Reprogramming: A Novel Approach for Heart Regeneration. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092629"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Vaseghi, H., Liu, J., and Qian, L. (2017). Molecular barriers to direct cardiac reprogramming. Protein Cell.","DOI":"10.1007\/s13238-017-0402-x"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1186\/s13287-017-0569-3","article-title":"Direct reprogramming of fibroblasts into cardiomyocytes","volume":"8","author":"Chen","year":"2017","journal-title":"Stem Cell Res. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1002\/cphy.c150006","article-title":"Pathophysiology of Myocardial Infarction","volume":"5","author":"Frangogiannis","year":"2015","journal-title":"Compr. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1016\/j.cell.2015.05.026","article-title":"Dynamics of Cell Generation and Turnover in the Human Heart","volume":"161","author":"Bergmann","year":"2015","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"H1883","DOI":"10.1152\/ajpheart.00514.2007","article-title":"Determination of cell types and numbers during cardiac development in the neonatal and adult rat and mouse","volume":"293","author":"Banerjee","year":"2007","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1161\/CIRCRESAHA.115.307778","article-title":"Revisiting Cardiac Cellular Composition","volume":"118","author":"Pinto","year":"2016","journal-title":"Circ. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1161\/CIRCRESAHA.109.209809","article-title":"Cardiac fibroblast: The renaissance cell","volume":"105","author":"Souders","year":"2009","journal-title":"Circ. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1161\/CIRCRESAHA.110.231910","article-title":"Origins of cardiac fibroblasts","volume":"107","author":"Zeisberg","year":"2010","journal-title":"Circ. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1161\/01.RES.0000163017.13772.3a","article-title":"CCL2\/Monocyte Chemoattractant Protein-1 regulates inflammatory responses critical to healing myocardial infarcts","volume":"96","author":"Dewald","year":"2005","journal-title":"Circ. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0008-6363(00)00158-9","article-title":"Myofibroblasts in reperfused myocardial infarcts express the embryonic form of smooth muscle myosin heavy chain (SMemb)","volume":"48","author":"Frangogiannis","year":"2000","journal-title":"Cardiovasc. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.yjmcc.2017.11.012","article-title":"Resident fibroblast expansion during cardiac growth and remodeling","volume":"114","author":"Ivey","year":"2018","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1161\/hy0202.103268","article-title":"Stimulation of collagen production by transforming growth factor-beta1 during differentiation of cardiac fibroblasts to myofibroblasts","volume":"39","author":"Petrov","year":"2002","journal-title":"Hypertension"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1093\/cvr\/cvu138","article-title":"CXCR3-independent actions of the CXC chemokine CXCL10 in the infarcted myocardium and in isolated cardiac fibroblasts are mediated through proteoglycans","volume":"103","author":"Saxena","year":"2014","journal-title":"Cardiovasc. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1161\/CIRCRESAHA.109.199471","article-title":"Induction of the CXC chemokine interferon-gamma-inducible protein 10 regulates the reparative response following myocardial infarction","volume":"105","author":"Bujak","year":"2009","journal-title":"Circ. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/1755-1536-5-19","article-title":"Common threads in cardiac fibrosis, infarct scar formation, and wound healing","volume":"5","author":"Czubryt","year":"2012","journal-title":"Fibrogenes. Tissue Repair"},{"key":"ref_40","first-page":"56","article-title":"Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar","volume":"146","author":"Desmouliere","year":"1995","journal-title":"Am. J. Pathol."},{"key":"ref_41","first-page":"868","article-title":"The alpha-smooth muscle actin-positive cells in healing human myocardial scars","volume":"145","author":"Willems","year":"1994","journal-title":"Am. J. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2127","DOI":"10.1172\/JCI98215","article-title":"Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart","volume":"128","author":"Fu","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7988","DOI":"10.1073\/pnas.87.20.7988","article-title":"MyoD converts primary dermal fibroblasts, chondroblasts, smooth muscle, and retinal pigmented epithelial cells into striated mononucleated myoblasts and multinucleated myotubes","volume":"87","author":"Choi","year":"1990","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.cell.2006.07.024","article-title":"Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors","volume":"126","author":"Takahashi","year":"2006","journal-title":"Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of pluripotent stem cells from adult human fibroblasts by defined factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.yjmcc.2013.04.004","article-title":"Optimization of direct fibroblast reprogramming to cardiomyocytes using calcium activity as a functional measure of success","volume":"60","author":"Addis","year":"2013","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.yjmcc.2012.04.010","article-title":"A new approach to transcription factor screening for reprogramming of fibroblasts to cardiomyocyte-like cells","volume":"53","author":"Protze","year":"2012","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1093\/cvr\/cvt167","article-title":"Accelerated direct reprogramming of fibroblasts into cardiomyocyte-like cells with the MyoD transactivation domain","volume":"100","author":"Hirai","year":"2013","journal-title":"Cardiovasc. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.15252\/embj.201387605","article-title":"MiR-133 promotes cardiac reprogramming by directly repressing Snai1 and silencing fibroblast signatures","volume":"33","author":"Muraoka","year":"2014","journal-title":"EMBO J."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Stone, N.R., Gifford, C.A., Thomas, R., Pratt, K.J.B., Samse-Knapp, K., Mohamed, T.M.A., Radzinsky, E.M., Schricker, A., Yu, P., and Ivey, K.N. (2019). Unique Transcription Factor Functions Regulate Epigenetic and Transcriptional Dynamics During Cardiac Reprogramming. bioRxiv.","DOI":"10.1101\/642900"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"6362","DOI":"10.1038\/s41598-019-42945-w","article-title":"Ensuring expression of four core cardiogenic transcription factors enhances cardiac reprogramming","volume":"9","author":"Zhang","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/j.1749-6632.2012.06696.x","article-title":"Cardiac repair with thymosin \u03b24 and cardiac reprogramming factors","volume":"1270","author":"Srivastava","year":"2012","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1161\/CIRCRESAHA.116.304510","article-title":"MicroRNA induced cardiac reprogramming in vivo: Evidence for mature cardiac myocytes and improved cardiac function","volume":"116","author":"Jayawardena","year":"2015","journal-title":"Circ. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1161\/CIRCRESAHA.116.305547","article-title":"Stoichiometry of Gata4, Mef2c, and Tbx5 Influences the Efficiency and Quality of Induced Cardiac Myocyte Reprogramming","volume":"116","author":"Wang","year":"2015","journal-title":"Circ. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1093\/cvr\/cvv223","article-title":"In vivo cardiac reprogramming using an optimal single polycistronic construct","volume":"108","author":"Ma","year":"2015","journal-title":"Cardiovasc. Res."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Liu, Z., Wang, L., Welch, J.D., Ma, H., Zhou, Y., Vaseghi, H.R., Yu, S., Wall, J.B., Alimohamadi, S., and Zheng, M. (2017). Single-cell transcriptomics reconstructs fate conversion from fibroblast to cardiomyocyte. Nature.","DOI":"10.1038\/nature24454"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"12667","DOI":"10.1073\/pnas.1304053110","article-title":"Induction of human cardiomyocyte-like cells from fibroblasts by defined factors","volume":"110","author":"Wada","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.stemcr.2013.07.005","article-title":"Direct reprogramming of human fibroblasts toward a cardiomyocyte-like state","volume":"1","author":"Fu","year":"2013","journal-title":"Stem Cell Rep."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Bektik, E., Dennis, A., Prasanna, P., Madabhushi, A., and Fu, J.-D.D. (2017). Single cell qPCR reveals that additional HAND2 and microRNA-1 facilitate the early reprogramming progress of seven-factor-induced human myocytes. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0183000"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1161\/CIRCULATIONAHA.116.024692","article-title":"Chemical Enhancement of In Vitro and In Vivo Direct Cardiac Reprogramming Clinical Perspective","volume":"135","author":"Mohamed","year":"2016","journal-title":"Circulation"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"5588","DOI":"10.1073\/pnas.1301019110","article-title":"Reprogramming of human fibroblasts toward a cardiac fate","volume":"110","author":"Nam","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/j.stem.2015.12.001","article-title":"Lineage Reprogramming of Fibroblasts into Proliferative Induced Cardiac Progenitor Cells by Defined Factors","volume":"18","author":"Lalit","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.stem.2016.02.001","article-title":"Expandable Cardiovascular Progenitor Cells Reprogrammed from Fibroblasts","volume":"18","author":"Zhang","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Ifkovits, J.L., Addis, R.C., Epstein, J.A., and Gearhart, J.D. (2014). Inhibition of TGFbeta signaling increases direct conversion of fibroblasts to induced cardiomyocytes. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0089678"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"8243","DOI":"10.1038\/ncomms9243","article-title":"High-efficiency reprogramming of fibroblasts into cardiomyocytes requires suppression of pro-fibrotic signalling","volume":"6","author":"Zhao","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Bektik, E., Dennis, A., Pawlowski, G., Zhou, C., Maleski, D., Takahashi, S., Laurita, K.R., Desch\u00eanes, I., and Fu, J.-D.D. (2018). S-phase Synchronization Facilitates the Early Progression of Induced-Cardiomyocyte Reprogramming through Enhanced Cell-Cycle Exit. Int. J. Mol. Sci., 19.","DOI":"10.20944\/preprints201803.0185.v1"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.stemcr.2017.01.025","article-title":"Notch Inhibition Enhances Cardiac Reprogramming by Increasing MEF2C Transcriptional Activity","volume":"8","author":"Abad","year":"2017","journal-title":"Stem Cell Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"11864","DOI":"10.1073\/pnas.1516237112","article-title":"Akt1\/protein kinase B enhances transcriptional reprogramming of fibroblasts to functional cardiomyocytes","volume":"112","author":"Zhou","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1016\/j.stemcr.2015.10.019","article-title":"Fibroblast Growth Factors and Vascular Endothelial Growth Factor Promote Cardiac Reprogramming under Defined Conditions","volume":"5","author":"Yamakawa","year":"2015","journal-title":"Stem Cell Rep."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1101\/gad.305482.117","article-title":"ZNF281 enhances cardiac reprogramming by modulating cardiac and inflammatory gene expression","volume":"31","author":"Zhou","year":"2017","journal-title":"Genes Dev."},{"key":"ref_71","unstructured":"Yijing, G., Ienglam, L., Shuo, T., Wenbin, G., Karatas, H., Yangbing, L., Shaomeng, W., Liu, L., and Zhong, W. (2019). Enhancing Cardiac Reprogramming by Suppressing Specific C-C Chemokine Signaling Pathways. bioRxiv."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/s41467-019-08626-y","article-title":"Role of cyclooxygenase-2-mediated prostaglandin E2-prostaglandin E receptor 4 signaling in cardiac reprogramming","volume":"10","author":"Muraoka","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1016\/j.cell.2012.09.045","article-title":"Facilitators and impediments of the pluripotency reprogramming factors\u2019 initial engagement with the genome","volume":"151","author":"Soufi","year":"2012","journal-title":"Cell"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.cell.2016.12.016","article-title":"Cooperative Binding of Transcription Factors Orchestrates Reprogramming","volume":"168","author":"Chronis","year":"2017","journal-title":"Cell"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.cell.2013.09.028","article-title":"Hierarchical mechanisms for direct reprogramming of fibroblasts to neurons","volume":"155","author":"Wapinski","year":"2013","journal-title":"Cell"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.stemcr.2014.05.020","article-title":"Generation of induced neuronal cells by the single reprogramming factor ASCL1","volume":"3","author":"Chanda","year":"2014","journal-title":"Stem Cell Rep."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.scr.2016.02.037","article-title":"Re-patterning of H3K27me3, H3K4me3 and DNA methylation during fibroblast conversion into induced cardiomyocytes","volume":"16","author":"Liu","year":"2016","journal-title":"Stem Cell Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1093\/cvr\/cvu023","article-title":"Inhibitors of suppressive histone modification promote direct reprogramming of fibroblasts to cardiomyocyte-like cells","volume":"102","author":"Hirai","year":"2014","journal-title":"Cardiovasc. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1161\/CIRCRESAHA.116.308741","article-title":"Demethylation of H3K27 Is Essential for the Induction of Direct Cardiac Reprogramming by miR Combo","volume":"120","author":"Hodgkinson","year":"2017","journal-title":"Circ. Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/j.stem.2016.02.003","article-title":"Bmi1 Is a Key Epigenetic Barrier to Direct Cardiac Reprogramming","volume":"18","author":"Zhou","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Hashimoto, H., Wang, Z., Garry, G.A., Malladi, V.S., Botten, G.A., Ye, W., Zhou, H., Osterwalder, M., Dickel, D.E., and Visel, A. (2019). Cardiac Reprogramming Factors Synergistically Activate Genome-wide Cardiogenic Stage-Specific Enhancers. Cell Stem Cell.","DOI":"10.1016\/j.stem.2019.03.022"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1038\/s41588-017-0034-3","article-title":"Genetic determinants and epigenetic effects of pioneer-factor occupancy","volume":"50","author":"Donaghey","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"54","DOI":"10.4161\/epi.2.1.3880","article-title":"Variations in DNA methylation patterns during the cell cycle of HeLa cells","volume":"2","author":"Brown","year":"2007","journal-title":"Epigenetics"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1042\/bse0480107","article-title":"Epigenetic dynamics across the cell cycle","volume":"48","author":"Lund","year":"2010","journal-title":"Essays Biochem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"3014","DOI":"10.1016\/j.celrep.2017.09.005","article-title":"Comparative Gene Expression Analyses Reveal Distinct Molecular Signatures between Differentially Reprogrammed Cardiomyocytes","volume":"20","author":"Zhou","year":"2017","journal-title":"Cell Rep."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Zhou, Y., Liu, Z., Welch, J.D., Gao, X., Wang, L., Garbutt, T., Keepers, B., Ma, H., Prins, J.F., and Shen, W. (2019). Single-Cell Transcriptomic Analyses of Cell Fate Transitions during Human Cardiac Reprogramming. Cell Stem Cell.","DOI":"10.1016\/j.stem.2019.05.020"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1111\/dgd.12134","article-title":"Regulation of cardiomyocyte proliferation during development and regeneration","volume":"56","author":"Takeuchi","year":"2014","journal-title":"Dev. Growth Differ."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1016\/j.jbiomech.2011.11.023","article-title":"Reprogramming cardiomyocyte mechanosensing by crosstalk between integrins and hyaluronic acid receptors","volume":"45","author":"Chopra","year":"2012","journal-title":"J. Biomech."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3794","DOI":"10.1242\/jcs.029678","article-title":"Embryonic cardiomyocytes beat best on a matrix with heart-like elasticity: Scar-like rigidity inhibits beating","volume":"121","author":"Engler","year":"2008","journal-title":"J. Cell Sci."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"12705","DOI":"10.1073\/pnas.1508073112","article-title":"Contractility of single cardiomyocytes differentiated from pluripotent stem cells depends on physiological shape and substrate stiffness","volume":"112","author":"Ribeiro","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.biomaterials.2016.06.034","article-title":"Effect of biophysical cues on reprogramming to cardiomyocytes","volume":"103","author":"Sia","year":"2016","journal-title":"Biomaterials"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Li, Y.Z., Dal-Pra, S., Mirotsou, M., Jayawardena, T.M., Hodgkinson, C.P., Bursac, N., and Dzau, V.J. (2016). Tissue-engineered 3-dimensional (3D) microenvironment enhances the direct reprogramming of fibroblasts into cardiomyocytes by microRNAs. Sci. Rep., 6.","DOI":"10.1038\/srep38815"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1111\/j.1582-4934.2010.01217.x","article-title":"Infarcted myocardium-like stiffness contributes to endothelial progenitor lineage commitment of bone marrow mononuclear cells","volume":"15","author":"Zhang","year":"2011","journal-title":"J. Cell. Mol. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.yjmcc.2015.06.006","article-title":"Building a better infarct: Modulation of collagen cross-linking to increase infarct stiffness and reduce left ventricular dilation post-myocardial infarction","volume":"85","author":"Voorhees","year":"2015","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"27","DOI":"10.2222\/jsv.65.27","article-title":"Gene therapy using retrovirus vectors: Vector development and biosafety at clinical trials","volume":"65","author":"Doi","year":"2015","journal-title":"Uirusu"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1534\/g3.115.026849","article-title":"Genome-Wide Analysis of Transposon and Retroviral Insertions Reveals Preferential Integrations in Regions of DNA Flexibility","volume":"6","author":"Vrljicak","year":"2016","journal-title":"G3"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Mathison, M., Gersch, R.P., Nasser, A., Lilo, S., Korman, M., Fourman, M., Hackett, N., Shroyer, K., Yang, J., and Ma, Y. (2012). In vivo cardiac cellular reprogramming efficacy is enhanced by angiogenic preconditioning of the infarcted myocardium with vascular endothelial growth factor. J. Am. Heart Assoc., 1.","DOI":"10.1161\/JAHA.112.005652"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.jtcvs.2016.09.041","article-title":"In situ reprogramming to transdifferentiate fibroblasts into cardiomyocytes using adenoviral vectors: Implications for clinical myocardial regeneration","volume":"153","author":"Mathison","year":"2017","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"4267","DOI":"10.1242\/dev.114025","article-title":"Induction of diverse cardiac cell types by reprogramming fibroblasts with cardiac transcription factors","volume":"141","author":"Nam","year":"2014","journal-title":"Development"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"5918","DOI":"10.1021\/acsomega.8b00904","article-title":"Chimeric Adeno-Associated Virus-Mediated Cardiovascular Reprogramming for Ischemic Heart Disease","volume":"3","author":"Yoo","year":"2018","journal-title":"ACS Omega"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.stem.2017.11.010","article-title":"Direct In Vivo Reprogramming with Sendai Virus Vectors Improves Cardiac Function after Myocardial Infarction","volume":"22","author":"Miyamoto","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Chang, Y., Lee, E., Kim, J., Kwon, Y.-W., Kwon, Y., and Kim, J. (2018). Efficient in vivo direct conversion of fibroblasts into cardiomyocytes using a nanoparticle-based gene carrier. Biomaterials.","DOI":"10.1016\/j.biomaterials.2018.11.034"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1038\/cr.2015.99","article-title":"Direct reprogramming of mouse fibroblasts into cardiomyocytes with chemical cocktails","volume":"25","author":"Fu","year":"2015","journal-title":"Cell Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/s41422-018-0036-4","article-title":"Chemical-induced cardiac reprogramming in vivo","volume":"28","author":"Huang","year":"2018","journal-title":"Cell Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1126\/science.aaf1502","article-title":"Conversion of human fibroblasts into functional cardiomyocytes by small molecules","volume":"352","author":"Cao","year":"2016","journal-title":"Science"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"E4661","DOI":"10.1073\/pnas.1720065115","article-title":"Distinct roles of resident and nonresident macrophages in nonischemic cardiomyopathy","volume":"115","author":"Liao","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1152\/physrev.00019.2015","article-title":"Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue","volume":"96","author":"Golpanian","year":"2016","journal-title":"Physiol. Rev."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1038\/nprot.2013.067","article-title":"Reprogramming of mouse fibroblasts into cardiomyocyte-like cells in vitro","volume":"8","author":"Qian","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1161\/CIRCRESAHA.112.271452","article-title":"Critical factors for cardiac reprogramming","volume":"111","author":"Srivastava","year":"2012","journal-title":"Circ. Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1161\/CIRCRESAHA.112.270264","article-title":"Inefficient reprogramming of fibroblasts into cardiomyocytes using Gata4, Mef2c, and Tbx5","volume":"111","author":"Chen","year":"2012","journal-title":"Circ. Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.cels.2018.07.006","article-title":"Aligning Single-Cell Developmental and Reprogramming Trajectories Identifies Molecular Determinants of Myogenic Reprogramming Outcome","volume":"7","author":"Cacchiarelli","year":"2018","journal-title":"Cell Syst."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1253\/circj.CJ-14-1372","article-title":"Direct reprogramming of fibroblasts into cardiomyocytes for cardiac regenerative medicine","volume":"79","author":"Fu","year":"2015","journal-title":"Circ. J."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/7\/679\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:02:46Z","timestamp":1760187766000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/7\/679"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,4]]},"references-count":112,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2019,7]]}},"alternative-id":["cells8070679"],"URL":"https:\/\/doi.org\/10.3390\/cells8070679","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,4]]}}}