Login Register Cart 0
Generic placeholder image

Current Molecular Medicine

Editor-in-Chief

ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Transcription Factors – the Essence of Heart Regeneration: A Potential Novel Therapeutic Strategy

Author(s): Basheer Abdullah Marzoog*

Volume 23, Issue 3, 2023

Published on: 01 April, 2022

Page: [232 - 238] Pages: 7

DOI: 10.2174/1566524022666220216123650

Price: $65

Abstract

Myocardial cell injury and following sequelae are the primary reasons for death globally. Unfortunately, myocardiocytes in adults have limited regeneration capacity. Therefore, the generation of neo myocardiocytes from non-myocardial cells is a surrogate strategy. Transcription factors (TFs) can be recruited to achieve this tremendous goal. Transcriptomic analyses have suggested that GATA, Mef2c, and Tbx5 (GMT cocktail) are master TFs to transdifferentiate/reprogram cell linage of fibroblasts, somatic cells, mesodermal cells into myocardiocytes. However, adding MESP1, MYOCD, ESRRG, and ZFPM2 TFs induces the generation of more efficient and physiomorphological features for induced myocardiocytes. Moreover, the same cocktail of transcription factors can induce the proliferation and differentiation of induced/pluripotent stem cells into myocardial cells. Amelioration of impaired myocardial cells involves the activation of healing transcription factors, which are induced by inflammation mediators; IL6, tumor growth factor β, and IL22. Transcription factors regulate the cellular and subcellular physiology of myocardiocytes to include mitotic cell cycling regulation, karyokinesis and cytokinesis, hypertrophic growth, adult sarcomeric contractile protein gene expression, fatty acid metabolism, and mitochondrial biogenesis and maturation. Cell therapy by transcription factors can be applied to cardiogenesis and ameliorating impaired cardiocytes. Transcription factors are the cornerstone in cell differentiation.

Keywords: Myocardial infarction, regeneration, myocardiocytes, transcription factor, transdifferentiation, reprogramming, angiogenesis, cell lineage, cell plasticity, somatic cell, stem cell.

« Previous Next »
[1]
Virani SS, Alonso A, Aparicio HJ, et al. American heart association council on epidemiology and prevention statistics committee and stroke statistics subcommittee. Heart disease and stroke statistics-2021 update: A report from the American heart association. Circulation 2021; 143(8): e254-743.
[http://dx.doi.org/10.1161/CIR.0000000000000950] [PMID: 33501848]
[2]
Mazzola M, Di Pasquale E. Toward cardiac regeneration: Combination of pluripotent stem cell-based therapies and bioengineering strategies. Front Bioeng Biotechnol 2020; 8: 455.
[http://dx.doi.org/10.3389/fbioe.2020.00455] [PMID: 32528940]
[3]
Waddingham MT, Sonobe T, Tsuchimochi H, et al. Diastolic dysfunction is initiated by cardiomyocyte impairment ahead of endothelial dysfunction due to increased oxidative stress and inflammation in an experimental prediabetes model. J Mol Cell Cardiol 2019; 137: 119-31.
[http://dx.doi.org/10.1016/j.yjmcc.2019.10.005] [PMID: 31669609]
[4]
Paige SL, Plonowska K, Xu A, Wu SM. Molecular regulation of cardiomyocyte differentiation. Circ Res 2015; 116(2): 341-53.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.302752] [PMID: 25593278]
[5]
Vagnozzi RJ, Molkentin JD, Houser SR. New myocyte formation in the adult heart: Endogenous sources and therapeutic implications. Circ Res 2018; 123(2): 159-76.
[http://dx.doi.org/10.1161/CIRCRESAHA.118.311208] [PMID: 29976685]
[6]
Galdos F, Guo Y, Paige S, et al. NV-C, 2017 undefined Cardiac regeneration: lessons from development. Am Hear Assoc. 2017; pp. 391-404.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.309040]
[7]
Denning C, Borgdorff V, Crutchley J, et al. Cardiomyocytes from human pluripotent stem cells: From laboratory curiosity to industrial biomedical platform. Biochim Biophys Acta 2016; 1863 (7 Pt B): 1728-48.
[http://dx.doi.org/10.1016/j.bbamcr.2015.10.014] [PMID: 26524115]
[8]
Begeman IJ, Kang J. Transcriptional programs and regeneration enhancers underlying heart regeneration. J Cardiovasc Dev Dis 2018; 6(1): 1-12.
[http://dx.doi.org/10.3390/jcdd6010002] [PMID: 30583498]
[9]
Maliken BD, Kanisicak O, Karch J, et al. Gata4-dependent differentiation of c-Kit+-Derived endothelial cells underlies artefactual cardiomyocyte regeneration in the heart. Circulation 2018; 138(10): 1012-24.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.118.033703] [PMID: 29666070]
[10]
Tian J, Wang R, Hou Q, et al. Optimization and enrichment of induced cardiomyocytes derived from mouse fibroblasts by reprogramming with cardiac transcription factors. Mol Med Rep 2018; 17(3): 3912-20.
[PMID: 29257325]
[11]
Duddu S, Chakrabarti R, Ghosh A, Shukla PC. Hematopoietic stem cell transcription factors in cardiovascular pathology. Front Genet 2020; 11: 588602.
[http://dx.doi.org/10.3389/fgene.2020.588602] [PMID: 33193725]
[12]
Inagawa K, Miyamoto K, Yamakawa H, et al. Induction of cardiomyocyte-like cells in infarct hearts by gene transfer of Gata4, Mef2c, and Tbx5. Circ Res 2012; 111(9): 1147-56.
[http://dx.doi.org/10.1161/CIRCRESAHA.112.271148] [PMID: 22931955]
[13]
Takashima S, Usui S, Inoue O, et al. Myocyte-specific enhancer factor 2c triggers transdifferentiation of adipose tissue-derived stromal cells into spontaneously beating cardiomyocyte-like cells. Sci Rep 2021; 11(1): 1520.
[http://dx.doi.org/10.1038/s41598-020-80848-3] [PMID: 33452355]
[14]
Zwi-Dantsis L, Huber I, Habib M, et al. Derivation and cardiomyocyte differentiation of induced pluripotent stem cells from heart failure patients. Eur Heart J 2013; 34(21): 1575-86.
[http://dx.doi.org/10.1093/eurheartj/ehs096] [PMID: 22621821]
[15]
Barad L, Schick R, Zeevi-Levin N, Itskovitz-Eldor J, Binah O. Human embryonic stem cells vs human induced pluripotent stem cells for cardiac repair. Can J Cardiol 2014; 30(11): 1279-87.
[http://dx.doi.org/10.1016/j.cjca.2014.06.023] [PMID: 25442431]
[16]
Takeuchi JK, Bruneau BG. Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors. Nature 2009; 459(7247): 708-11.
[http://dx.doi.org/10.1038/nature08039] [PMID: 19396158]
[17]
Inagawa K, Ieda M. Direct reprogramming of mouse fibroblasts into cardiac myocytes. J Cardiovasc Transl Res 2013; 6(1): 37-45.
[http://dx.doi.org/10.1007/s12265-012-9412-5] [PMID: 23054660]
[18]
Song K, Nam YJ, Luo X, et al. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature 2012; 485(7400): 599-604.
[http://dx.doi.org/10.1038/nature11139] [PMID: 22660318]
[19]
Muraoka N, Yamakawa H, Miyamoto K, et al. MiR-133 promotes cardiac reprogramming by directly repressing Snai1 and silencing fibroblast signatures. EMBO J 2014; 33(14): 1565-81.
[http://dx.doi.org/10.15252/embj.201387605] [PMID: 24920580]
[20]
Qian L, Huang Y, Spencer CI, et al. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature 2012; 485(7400): 593-8.
[http://dx.doi.org/10.1038/nature11044] [PMID: 22522929]
[21]
Jiang C, Gong F. MiR-148a promotes myocardial differentiation of human bone mesenchymal stromal cells via DNA methyltransferase 1 (DNMT1). Cell Biol Int 2018; 42(8): 913-22.
[http://dx.doi.org/10.1002/cbin.10813] [PMID: 28656724]
[22]
Li TS, Hayashi M, Ito H, et al. Regeneration of infarcted myocardium by intramyocardial implantation of ex vivo transforming growth factor-beta-preprogrammed bone marrow stem cells. Circulation 2005; 111(19): 2438-45.
[http://dx.doi.org/10.1161/01.CIR.0000167553.49133.81] [PMID: 15883211]
[23]
Hwang GH, Park SM, Han HJ, et al. Purification of small molecule-induced cardiomyocytes from human induced pluripotent stem cells using a reporter system. J Cell Physiol 2017; 232(12): 3384-95.
[http://dx.doi.org/10.1002/jcp.25783] [PMID: 28063225]
[24]
Chow A, Stuckey DJ, Kidher E, et al. Human induced pluripotent stem cell-derived cardiomyocyte encapsulating bioactive hydrogels improve rat heart function post myocardial infarction. Stem Cell Reports 2017; 9(5): 1415-22.
[http://dx.doi.org/10.1016/j.stemcr.2017.09.003] [PMID: 28988988]
[25]
Shiba Y, Gomibuchi T, Seto T, et al. Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts. Nature 2016; 538(7625): 388-91.
[http://dx.doi.org/10.1038/nature19815] [PMID: 27723741]
[26]
Mauritz C, Schwanke K, Reppel M, et al. Generation of functional murine cardiac myocytes from induced pluripotent stem cells. Circulation 2008; 118(5): 507-17.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.108.778795] [PMID: 18625890]
[27]
Chong JJHJ, Yang X, Don CW, et al. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature 2014; 510(7504): 273-7.
[http://dx.doi.org/10.1038/nature13233] [PMID: 24776797]
[28]
Wang J, Jiang X, Zhao L, et al. Lineage reprogramming of fibroblasts into induced cardiac progenitor cells by CRISPR/Cas9-based transcriptional activators. Acta Pharm Sin B 2020; 10(2): 313-26.
[http://dx.doi.org/10.1016/j.apsb.2019.09.003] [PMID: 32082976]
[29]
McGinley LM, McMahon J, Stocca A, et al. Mesenchymal stem cell survival in the infarcted heart is enhanced by lentivirus vector-mediated heat shock protein 27 expression. Hum Gene Ther 2013; 24(10): 840-51.
[http://dx.doi.org/10.1089/hum.2011.009] [PMID: 23987185]
[30]
Chavez A, Scheiman J, Vora S, et al. Highly efficient Cas9-mediated transcriptional programming. Nat Methods 2015; 12(4): 326-8.
[http://dx.doi.org/10.1038/nmeth.3312] [PMID: 25730490]
[31]
Chang Y, Lee E, Kim J, Kwon YW, Kwon Y, Kim J. Efficient in vivo direct conversion of fibroblasts into cardiomyocytes using a nanoparticle-based gene carrier. Biomaterials 2019; 192: 500-9.
[http://dx.doi.org/10.1016/j.biomaterials.2018.11.034] [PMID: 30513475]
[32]
Tao G, Kahr PC, Morikawa Y, et al. Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury. Nature 2016; 534(7605): 119-23.
[http://dx.doi.org/10.1038/nature17959] [PMID: 27251288]
[33]
Dal-Pra S, Hodgkinson CP, Mirotsou M, Kirste I, Dzau VJ. Demethylation of H3K27 is essential for the induction of direct cardiac reprogramming by miR combo. Circ Res 2017; 120(9): 1403-13.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.308741] [PMID: 28209718]
[34]
Zhao Y, Londono P, Cao Y, et al. High-efficiency reprogramming of fibroblasts into cardiomyocytes requires suppression of pro-fibrotic signalling. Nat Commun 2015; 6: 8243.
[http://dx.doi.org/10.1038/ncomms9243] [PMID: 26354680]
[35]
Ouyang Z, Wei K. miRNA in cardiac development and regeneration. Cell Regen (Lond) 2021; 10(1): 14.
[http://dx.doi.org/10.1186/s13619-021-00077-5] [PMID: 34060005]
[36]
Marzoog BA, Vlasova TI. Transcription factors in deriving β cell regeneration; a potential novel therapeutic target. Curr Mol Med 2021; 21.
[http://dx.doi.org/10.2174/1566524021666210712144638]
[37]
Liu J, Sluijter JP, Goumans M-J, et al. Cell therapy for myocardial regeneration. Curr Mol Med 2009; 9(3): 287-98.
[http://dx.doi.org/10.2174/156652409787847218] [PMID: 19355911]
[38]
Sahara M, Santoro F, Chien KR. Programming and reprogramming a human heart cell. EMBO J 2015; 34(6): 710-38.
[http://dx.doi.org/10.15252/embj.201490563] [PMID: 25712211]
[39]
Wu P, Deng G, Sai X, Guo H, Huang H, Zhu P. Maturation strategies and limitations of induced pluripotent stem cell-derived cardiomyocytes. Biosci Rep 2021; 41(6): BSR20200833.
[http://dx.doi.org/10.1042/BSR20200833] [PMID: 33057659]
[40]
Yang G, Xiao Z, Ren X, et al. Obtaining spontaneously beating cardiomyocyte-like cells from adipose-derived stromal vascular fractions cultured on enzyme-crosslinked gelatin hydrogels. Sci Rep 2017; 7: 41781.
[http://dx.doi.org/10.1038/srep41781] [PMID: 28155919]
[41]
Churko JM, Garg P, Treutlein B, et al. Defining human cardiac transcription factor hierarchies using integrated single-cell heterogeneity analysis. Nat Commun 2018; 9: 1-14.
[http://dx.doi.org/10.1038/s41467-018-07333-4]
[42]
Mathiasen AB, Qayyum AA, Jørgensen E, et al. Bone marrow-derived mesenchymal stromal cell treatment in patients with ischaemic heart failure: final 4-year follow-up of the MSC-HF trial. Eur J Heart Fail 2020; 22(5): 884-92.
[http://dx.doi.org/10.1002/ejhf.1700] [PMID: 31863561]
[43]
Miyagawa S, Sawa Y. Building a new strategy for treating heart failure using induced pluripotent stem cells. J Cardiol 2018; 72(6): 445-8.
[http://dx.doi.org/10.1016/j.jjcc.2018.05.002] [PMID: 30172684]
[44]
Schwach V, Passier R. Generation and purification of human stem cell-derived cardiomyocytes. Differentiation 2016; 91(4-5): 126-38.
[http://dx.doi.org/10.1016/j.diff.2016.01.001] [PMID: 26915912]
[45]
Ramos-Mejía V, Montes R, Bueno C, et al. Residual expression of the reprogramming factors prevents differentiation of iPSC generated from human fibroblasts and cord blood CD34+ progenitors. PLoS One 2012; 7(4): e35824.
[http://dx.doi.org/10.1371/journal.pone.0035824] [PMID: 22545141]
[46]
Jansen JA, van Veen TAB, de Bakker JMT, van Rijen HVM. Cardiac connexins and impulse propagation. J Mol Cell Cardiol 2010; 48(1): 76-82.
[http://dx.doi.org/10.1016/j.yjmcc.2009.08.018] [PMID: 19729017]
[47]
Zwi L, Caspi O, Arbel G, et al. Cardiomyocyte differentiation of human induced pluripotent stem cells. Circulation 2009; 120(15): 1513-23.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.109.868885] [PMID: 19786631]
[48]
Veerman CC, Mengarelli I, Lodder EM, et al. Switch from fetal to adult SCN5A isoform in human induced pluripotent stem cell-derived cardiomyocytes unmasks the cellular phenotype of a conduction disease-causing mutation. J Am Heart Assoc 2017; 6(7): e005135.
[http://dx.doi.org/10.1161/JAHA.116.005135] [PMID: 28739862]
[49]
Pesl M, Pribyl J, Caluori G, et al. Phenotypic assays for analyses of pluripotent stem cell-derived cardiomyocytes. J Mol Recognit 2017; 30(6)
[http://dx.doi.org/10.1002/jmr.2602] [PMID: 27995655]
[50]
Zhou Y, Wang L, Liu Z, et al. Comparative gene expression analyses reveal distinct molecular signatures between differentially reprogrammed cardiomyocytes. Cell Rep 2017; 20(13): 3014-24.
[http://dx.doi.org/10.1016/j.celrep.2017.09.005] [PMID: 28954220]
[51]
Tiburcy M, Hudson JE, Balfanz P, et al. Defined engineered human myocardium with advanced maturation for applications in heart failure modeling and repair. Circulation 2017; 135(19): 1832-47.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.116.024145] [PMID: 28167635]
[52]
Galdos FX, Guo Y, Paige SL, VanDusen NJ, Wu SM, Pu WT. Cardiac regeneration. Circ Res 2017; 120(6): 941-59.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.309040] [PMID: 28302741]
[53]
Desjardins CA, Naya FJ. The function of the MEF2 family of transcription factors in cardiac development, cardiogenomics, and direct reprogramming. J Cardiovasc Dev Dis 2016; 3(3): 26.
[http://dx.doi.org/10.3390/jcdd3030026] [PMID: 27630998]
[54]
Wei J, Joshi S, Speransky S, et al. Reversal of pathological cardiac hypertrophy via the MEF2-coregulator interface. JCI Insight 2017; 2(17): 91068.
[http://dx.doi.org/10.1172/jci.insight.91068] [PMID: 28878124]
[55]
Murry CE, Soonpaa MH, Reinecke H, et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 2004; 428(6983): 664-8.
[http://dx.doi.org/10.1038/nature02446] [PMID: 15034593]
[56]
Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature 2001; 410(6829): 701-5.
[http://dx.doi.org/10.1038/35070587] [PMID: 11287958]
[57]
Nygren JM, Jovinge S, Breitbach M, et al. Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat Med 2004; 10(5): 494-501.
[http://dx.doi.org/10.1038/nm1040] [PMID: 15107841]
[58]
Wei K, Serpooshan V, Hurtado C, et al. Epicardial FSTL1 reconstitution regenerates the adult mammalian heart. Nature 2015; 525(7570): 479-85.
[http://dx.doi.org/10.1038/nature15372] [PMID: 26375005]
[59]
Polizzotti BD, Ganapathy B, Walsh S, et al. Neuregulin stimulation of cardiomyocyte regeneration in mice and human myocardium reveals a therapeutic window. Sci Transl Med 2015; 7(281): 281ra45.
[http://dx.doi.org/10.1126/scitranslmed.aaa5171] [PMID: 25834111]
[60]
Korf-Klingebiel M, Reboll MR, Klede S, et al. Myeloid-derived growth factor (C19orf10) mediates cardiac repair following myocardial infarction. Nat Med 2015; 21(2): 140-9.
[http://dx.doi.org/10.1038/nm.3778] [PMID: 25581518]
[61]
Zhou Y, Wang L, Vaseghi HR, et al. Bmi1 is a key epigenetic barrier to direct cardiac reprogramming. Cell Stem Cell 2016; 18(3): 382-95.
[http://dx.doi.org/10.1016/j.stem.2016.02.003] [PMID: 26942853]
[62]
Beauchemin M, Smith A, Yin VP. Dynamic microRNA-101a and Fosab expression controls zebrafish heart regeneration. Development 2015; 142(23): 4026-37.
[http://dx.doi.org/10.1242/dev.126649] [PMID: 26628091]
[63]
Yin VP, Lepilina A, Smith A, Poss KD. Regulation of zebrafish heart regeneration by miR-133. Dev Biol 2012; 365(2): 319-27.
[http://dx.doi.org/10.1016/j.ydbio.2012.02.018] [PMID: 22374218]
[64]
Porrello ER, Mahmoud AI, Simpson E, et al. Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family. Proc Natl Acad Sci USA 2013; 110(1): 187-92.
[http://dx.doi.org/10.1073/pnas.1208863110] [PMID: 23248315]
[65]
Huang W, Feng Y, Liang J, et al. Loss of microRNA-128 promotes cardiomyocyte proliferation and heart regeneration. Nat Commun 2018; 9(1): 700.
[http://dx.doi.org/10.1038/s41467-018-03019-z] [PMID: 29453456]
[66]
Gemberling M, Karra R, Dickson AL, Poss KD. Nrg1 is an injury-induced cardiomyocyte mitogen for the endogenous heart regeneration program in zebrafish. eLife 2015; 4.
[http://dx.doi.org/10.7554/eLife.05871] [PMID: 25830562]
[67]
D’Uva G, Aharonov A, Lauriola M, et al. ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nat Cell Biol 2015; 17(5): 627-38.
[http://dx.doi.org/10.1038/ncb3149] [PMID: 25848746]
[68]
Bersell K, Arab S, Haring B, Kühn B. Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell 2009; 138(2): 257-70.
[http://dx.doi.org/10.1016/j.cell.2009.04.060] [PMID: 19632177]
[69]
Ganapathy B, Nandhagopal N, Polizzotti BD, et al. Neuregulin-1 administration protocols sufficient for stimulating cardiac regeneration in young mice do not induce somatic, organ, or neoplastic growth. PLoS One 2016; 11(5): e0155456.
[http://dx.doi.org/10.1371/journal.pone.0155456] [PMID: 27175488]
[70]
Xiang FL, Guo M, Yutzey KE. Overexpression of Tbx20 in adult cardiomyocytes promotes proliferation and improves cardiac function after myocardial infarction. Circulation 2016; 133(11): 1081-92.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.115.019357] [PMID: 26841808]
[71]
Shen T, Aneas I, Sakabe N, et al. Tbx20 regulates a genetic program essential to adult mouse cardiomyocyte function. J Clin Invest 2011; 121(12): 4640-54.
[http://dx.doi.org/10.1172/JCI59472] [PMID: 22080862]
[72]
González-Rosa JM, Sharpe M, Field D, et al. Myocardial polyploidization creates a barrier to heart regeneration in Zebrafish. Dev Cell 2018; 44(4): 433-446.e7.
[http://dx.doi.org/10.1016/j.devcel.2018.01.021] [PMID: 29486195]
[73]
Patterson M, Barske L, Van Handel B, et al. Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration. Nat Genet 2017; 49(9): 1346-53.
[http://dx.doi.org/10.1038/ng.3929] [PMID: 28783163]
[74]
Nakada Y, Canseco DC, Thet S, et al. Hypoxia induces heart regeneration in adult mice. Nature 2017; 541(7636): 222-7.
[http://dx.doi.org/10.1038/nature20173] [PMID: 27798600]
[75]
Puente BNB, Kimura W, Muralidhar SA, et al. The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. Cell 2014; 157(3): 565-79.
[http://dx.doi.org/10.1016/j.cell.2014.03.032] [PMID: 24766806]

Rights & Permissions Print Cite
Article Metrics
7
© 2024 Bentham Science Publishers | Privacy Policy