miRNA in cardiac development and regeneration

Zhaohui Ouyang1, Ke Wei1
1Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, P.R. China

Tóm tắt

AbstractIschemic heart disease is one of the main causes of morbidity and mortality in the world. In adult mammalian hearts, most cardiomyocytes are terminally differentiated and have extremely limited capacity of proliferation, making it impossible to regenerate the heart after injuries such as myocardial infarction. MicroRNAs (miRNAs), a class of non-coding single-stranded RNA, which are involved in mRNA silencing and the regulation of post-transcriptional gene expression, have been shown to play a crucial role in cardiac development and cardiomyocyte proliferation. Muscle specific miRNAs such as miR-1 are key regulators of cardiomyocyte maturation and growth, while miR-199-3p and other miRNAs display potent activity to induce proliferation of cardiomyocytes. Given their small size and relative pleiotropic effects, miRNAs have gained significant attraction as promising therapeutic targets or tools in cardiac regeneration. Increasing number of studies demonstrated that overexpression or inhibition of specific miRNAs could induce cardiomyocyte proliferation and cardiac regeneration. Some common targets of pro-proliferation miRNAs, such as the Hippo-Yap signaling pathway, were identified in multiple species, highlighting the power of miRNAs as probes to dissect core regulators of biological processes. A number of miRNAs have been shown to improve heart function after myocardial infarction in mice, and one trial in swine also demonstrated promising outcomes. However, technical difficulties, especially in delivery methods, and adverse effects, such as uncontrolled proliferation, remain. In this review, we summarize the recent progress in miRNA research in cardiac development and regeneration, examine the mechanisms of miRNA regulating cardiomyocyte proliferation, and discuss its potential as a new strategy for cardiac regeneration therapy.

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Tài liệu tham khảo

Adams D, Gonzalez-Duarte A, O'Riordan WD, Yang CC, Ueda M, Kristen AV, Tournev I, Schmidt HH, Coelho T, Berk JL, et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018;379:11–21.

Aguirre A, Montserrat N, Zacchigna S, Nivet E, Hishida T, Krause MN, Kurian L, Ocampo A, Vazquez-Ferrer E, Rodriguez-Esteban C, et al. In vivo activation of a conserved microRNA program induces mammalian heart regeneration. Cell Stem Cell. 2014;15:589–604.

Alles J, Fehlmann T, Fischer U, Backes C, Galata V, Minet M, Hart M, Abu-Halima M, Grässer FA, Lenhof H-P, et al. An estimate of the total number of true human miRNAs. Nucleic acids research. 2019;47:3353–64.

Ambros V. The functions of animal microRNAs. Nature. 2004;431:350–5.

Ambros V. MicroRNAs and developmental timing. Current opinion in genetics & development. 2011;21:511–7.

Arif M, Pandey R, Alam P, Jiang S, Sadayappan S, Paul A, Ahmed RPH. MicroRNA-210-mediated proliferation, survival, and angiogenesis promote cardiac repair post myocardial infarction in rodents. J Mole Med. 2017;95:1369–85.

Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.

Bartel DP. Metazoan MicroRNAs. Cell. 2018;173:20–51.

Barwari T, Joshi A, Mayr M. MicroRNAs in Cardiovascular Disease. J Am Coll Cardiol. 2016;68:2577–84.

Bassat E, Mutlak YE, Genzelinakh A, Shadrin IY, Baruch Umansky K, Yifa O, Kain D, Rajchman D, Leach J, Riabov Bassat D, et al. The extracellular matrix protein agrin promotes heart regeneration in mice. Nature. 2017;547:179–84.

Beauchemin M, Smith A, Yin VP. Dynamic microRNA-101a and Fosab expression controls zebrafish heart regeneration. Development. 2015;142:4026–37.

Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabé-Heider F, Walsh S, Zupicich J, Alkass K, Buchholz BA, Druid H, et al. Evidence for cardiomyocyte renewal in humans. Science. 2009;324:98-102.

Bernstein E, Kim SY, Carmell MA, Murchison EP, Alcorn H, Li MZ, Mills AA, Elledge SJ, Anderson KV, Hannon GJ. Dicer is essential for mouse development. Nat Genet. 2003;35:215–7.

Bersell K, Arab S, Haring B, Kühn B. Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell. 2009;138:257–70.

Borden A, Kurian J, Nickoloff E, Yang Y, Troupes CD, Ibetti J, Lucchese AM, Gao E, Mohsin S, Koch WJ, et al. Transient Introduction of miR-294 in the Heart Promotes Cardiomyocyte Cell Cycle Reentry After Injury. Circulation research. 2019;125:14–25.

Braga L, Ali H, Secco I, Giacca M. Non-coding RNA therapeutics for cardiac regeneration. Cardiovasc Res. 2021;117:674-93.

Cai B, Ma W, Ding F, Zhang L, Huang Q, Wang X, Hua B, Xu J, Li J, Bi C, et al. The Long Noncoding RNA CAREL Controls Cardiac Regeneration. J Am Coll Cardiol. 2018;72:534–50.

Cai X, Hagedorn CH, Cullen BR. Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA (New York, NY). 2004;10:1957–66.

Callis TE, Pandya K, Seok HY, Tang RH, Tatsuguchi M, Huang ZP, Chen JF, Deng Z, Gunn B, Shumate J, et al. MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice. J Clin Invest. 2009;119:2772–86.

Campa VM, Gutierrez-Lanza R, Cerignoli F, Diaz-Trelles R, Nelson B, Tsuji T, Barcova M, Jiang W, Mercola M. Notch activates cell cycle reentry and progression in quiescent cardiomyocytes. J Cell Biol. 2008;183:129–41.

Cao X, Wang J, Wang Z, Du J, Yuan X, Huang W, Meng J, Gu H, Nie Y, Ji B, et al. MicroRNA profiling during rat ventricular maturation: A role for miR-29a in regulating cardiomyocyte cell cycle re-entry. FEBS Lett. 2013;587:1548–55.

Chen G, Li H, Li X, Li B, Zhong L, Huang S, Zheng H, Li M, Jin G, Liao W, et al. Loss of long non-coding RNA CRRL promotes cardiomyocyte regeneration and improves cardiac repair by functioning as a competing endogenous RNA. J Mol Cell Cardiol. 2018;122:152–64.

Chen J, Huang ZP, Seok HY, Ding J, Kataoka M, Zhang Z, Hu X, Wang G, Lin Z, Wang S, et al. mir-17-92 cluster is required for and sufficient to induce cardiomyocyte proliferation in postnatal and adult hearts. Circ Res. 2013;112:1557–66.

Chen JF, Mandel EM, Thomson JM, Wu Q, Callis TE, Hammond SM, Conlon FL, Wang DZ. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet. 2006;38:228–33.

Chen J-F, Murchison EP, Tang R, Callis TE, Tatsuguchi M, Deng Z, Rojas M, Hammond SM, Schneider MD, Selzman CH, et al. Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure. Proceedings of the National Academy of Sciences of the United States of America. 2008;105:2111–6.

Chiavacci E, Dolfi L, Verduci L, Meghini F, Gestri G, Evangelista AM, Wilson SW, Cremisi F, Pitto L. MicroRNA 218 mediates the effects of Tbx5a over-expression on zebrafish heart development. PLoS One. 2012;7:e50536.

Chistiakov DA, Orekhov AN, Bobryshev YV. Cardiac-specific miRNA in cardiogenesis, heart function, and cardiac pathology (with focus on myocardial infarction). J Mol Cell Cardiol. 2016;94:107–21.

Chong JJ, Yang X, Don CW, Minami E, Liu YW, Weyers JJ, Mahoney WM, Van Biber B, Cook SM, Palpant NJ, et al. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature. 2014;510:273–7.

Collaborators, G.C.o.D. (2018). Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study . Lancet (London, England) 2017;392;1736-88.

Cordes KR, Sheehy NT, White MP, Berry EC, Morton SU, Muth AN, Lee TH, Miano JM, Ivey KN, Srivastava D. miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature. 2009;460:705–10.

da Costa Martins PA, Bourajjaj M, Gladka M, Kortland M, van Oort RJ, Pinto YM, Molkentin JD, De Windt LJ. Conditional dicer gene deletion in the postnatal myocardium provokes spontaneous cardiac remodeling. Circulation. 2008;118:1567–76.

Deacon DC, Nevis KR, Cashman TJ, Zhou Y, Zhao L, Washko D, Guner-Ataman B, Burns CG, Burns CE. The miR-143-adducin3 pathway is essential for cardiac chamber morphogenesis. Development. 2010;137:1887–96.

Deng S, Zhao Q, Zhen L, Zhang C, Liu C, Wang G, Zhang L, Bao L, Lu Y, Meng L, et al. Neonatal Heart-Enriched miR-708 Promotes Proliferation and Stress Resistance of Cardiomyocytes in Rodents. Theranostics. 2017;7:1953–65.

Diez-Cuñado M, Wei K, Bushway PJ, Maurya MR, Perera R, Subramaniam S, Ruiz-Lozano P, Mercola M. miRNAs that Induce Human Cardiomyocyte Proliferation Converge on the Hippo Pathway. Cell Reports. 2018;23:2168–74.

el Azzouzi H, Leptidis S, Dirkx E, Hoeks J, van Bree B, Brand K, McClellan EA, Poels E, Sluimer JC, van den Hoogenhof MMG, et al. The hypoxia-inducible microRNA cluster miR-199a∼214 targets myocardial PPARδ and impairs mitochondrial fatty acid oxidation. Cell Metabolism. 2013;18:341–54.

Engel FB, Schebesta M, Duong MT, Lu G, Ren S, Madwed JB, Jiang H, Wang Y, Keating MT. p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes. Genes Development. 2005;19:1175–87.

Eschenhagen T, Bolli R, Braun T, Field LJ, Fleischmann BK, Frisen J, Giacca M, Hare JM, Houser S, Lee RT, et al. Cardiomyocyte Regeneration: A Consensus Statement. Circulation. 2017;136:680–6.

Eulalio A, Mano M, Dal Ferro M, Zentilin L, Sinagra G, Zacchigna S, Giacca M. Functional screening identifies miRNAs inducing cardiac regeneration. Nature. 2012;492:376–81.

Fish JE, Wythe JD, Xiao T, Bruneau BG, Stainier DY, Srivastava D, Woo S. A Slit/miR-218/Robo regulatory loop is required during heart tube formation in zebrafish. Development. 2011;138:1409–19.

Fu J-D, Rushing SN, Lieu DK, Chan CW, Kong C-W, Geng L, Wilson KD, Chiamvimonvat N, Boheler KR, Wu JC, et al. Distinct roles of microRNA-1 and -499 in ventricular specification and functional maturation of human embryonic stem cell-derived cardiomyocytes. PloS one. 2011;6:e27417.

Gabisonia K, Prosdocimo G, Aquaro GD, Carlucci L, Zentilin L, Secco I, Ali H, Braga L, Gorgodze N, Bernini F, et al. MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs. Nature. 2019;569:418–22.

Gan J, Tang FMK, Su X, Lu G, Xu J, Lee HSS, Lee KKH. microRNA-1 inhibits cardiomyocyte proliferation in mouse neonatal hearts by repressing CCND1 expression. Ann Transl Med. 2019;7:455.

Gao F, Kataoka M, Liu N, Liang T, Huang ZP, Gu F, Ding J, Liu J, Zhang F, Ma Q, et al. Therapeutic role of miR-19a/19b in cardiac regeneration and protection from myocardial infarction. Nat Commun. 2019;10:1802.

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:e05871.

Giraldez AJ, Cinalli RM, Glasner ME, Enright AJ, Thomson JM, Baskerville S, Hammond SM, Bartel DP, Schier AF. MicroRNAs regulate brain morphogenesis in zebrafish. Science. 2005;308:833–8.

Glass C, Singla DK. MicroRNA-1 transfected embryonic stem cells enhance cardiac myocyte differentiation and inhibit apoptosis by modulating the PTEN/Akt pathway in the infarcted heart. Am J Physiol Heart Circulatory Physiol. 2011;301:H2038–49.

Guo Y, Pu WT. Cardiomyocyte Maturation: New Phase in Development. Circ Res. 2020;126:1086–106.

Gupta MP. Factors controlling cardiac myosin-isoform shift during hypertrophy and heart failure. J Mol Cell Cardiol. 2007;43:388–403.

Ha M, Kim VN. Regulation of microRNA biogenesis. Nature Reviews Molecular Cell Biol. 2014;15:509–24.

He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y, Xue W, Zender L, Magnus J, Ridzon D, et al. A microRNA component of the p53 tumour suppressor network. Nature. 2007;447:1130–4.

He L, Nguyen NB, Ardehali R, Zhou B. Heart Regeneration by Endogenous Stem Cells and Cardiomyocyte Proliferation: Controversy, Fallacy, and Progress. Circulation. 2020;142:275–91.

He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C, Lowe SW, Hannon GJ, et al. A microRNA polycistron as a potential human oncogene. Nature. 2005;435:828–33.

Heallen, T., Morikawa, Y., Leach, J., Tao, G., Willerson, J.T., Johnson, R.L., and Martin, J.F.. Hippo signaling impedes adult heart regeneration. Development (Cambridge, England). 2013;140:4683-90.

Heallen T, Zhang M, Wang J, Bonilla-Claudio M, Klysik E, Johnson RL, Martin JF. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science (New York, NY). 2011;332:458–61.

Heidersbach A, Saxby C, Carver-Moore K, Huang Y, Ang YS, de Jong PJ, Ivey KN, Srivastava D. microRNA-1 regulates sarcomere formation and suppresses smooth muscle gene expression in the mammalian heart. Elife. 2013;2:e01323.

Hirose K, Payumo AY, Cutie S, Hoang A, Zhang H, Guyot R, Lunn D, Bigley RB, Yu H, Wang J, et al. Evidence for hormonal control of heart regenerative capacity during endothermy acquisition. Science. 2019;364:184–8.

Hu S, Huang M, Li Z, Jia F, Ghosh Z, Lijkwan MA, Fasanaro P, Sun N, Wang X, Martelli F, et al. MicroRNA-210 as a novel therapy for treatment of ischemic heart disease. Circulation. 2010;122:S124–31.

Hu Y, Jin G, Li B, Chen Y, Zhong L, Chen G, Chen X, Zhong J, Liao W, Liao Y, et al. Suppression of miRNA let-7i-5p promotes cardiomyocyte proliferation and repairs heart function post injury by targetting CCND2 and E2F2. Clin Sci (London, England : 1979). 2019;133:425–41.

Huang W, Feng Y, Liang J, Yu H, Wang C, Wang B, Wang M, Jiang L, Meng W, Cai W, et al. Loss of microRNA-128 promotes cardiomyocyte proliferation and heart regeneration. Nature Communications. 2018;9:700.

Hullinger TG, Montgomery RL, Seto AG, Dickinson BA, Semus HM, Lynch JM, Dalby CM, Robinson K, Stack C, Latimer PA, et al. Inhibition of miR-15 protects against cardiac ischemic injury. Circ Res. 2012;110:71–81.

Hutvágner G, McLachlan J, Pasquinelli AE, Bálint E, Tuschl T, Zamore PD. A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science (New York, NY). 2001;293:834–8.

Ivey KN, Muth A, Arnold J, King FW, Yeh R-F, Fish JE, Hsiao EC, Schwartz RJ, Conklin BR, Bernstein HS, et al. MicroRNA regulation of cell lineages in mouse and human embryonic stem cells. Cell Stem Cell. 2008;2:219–29.

Iwasaki S, Kobayashi M, Yoda M, Sakaguchi Y, Katsuma S, Suzuki T, Tomari Y. Hsc70/Hsp90 chaperone machinery mediates ATP-dependent RISC loading of small RNA duplexes. Molecular Cell. 2010;39:292–9.

Jayawardena TM, Egemnazarov B, Finch EA, Zhang L, Payne JA, Pandya K, Zhang Z, Rosenberg P, Mirotsou M, Dzau VJ. MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res. 2012;110:1465–73.

Jiang L, Vader P, Schiffelers RM. Extracellular vesicles for nucleic acid delivery: progress and prospects for safe RNA-based gene therapy. Gene Ther. 2017;24:157–66.

Kaiser J. Suspect science leads to pause in stem cell trial. Science. 2018;362:513.

Kawamata T, Tomari Y. Making RISC. Trends Biochem Sci. 2010;35:368–76.

Kimura W, Xiao F, Canseco DC, Muralidhar S, Thet S, Zhang HM, Abderrahman Y, Chen R, Garcia JA, Shelton JM, et al. Hypoxia fate mapping identifies cycling cardiomyocytes in the adult heart. Nature. 2015;523:226–30.

Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, Stoffel M. Silencing of microRNAs in vivo with 'antagomirs'. Nature. 2005;438:685–9.

Kulkarni JA, Cullis PR, van der Meel R. Lipid Nanoparticles Enabling Gene Therapies: From Concepts to Clinical Utility. Nucleic Acid Ther. 2018;28:146–57.

Kwon C, Han Z, Olson EN, Srivastava D. MicroRNA1 influences cardiac differentiation in Drosophila and regulates Notch signaling. Proceed National Acad Sci USA. 2005;102:18986–91.

Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T. Identification of tissue-specific microRNAs from mouse. Current Biol. 2002;12:735–9.

LaRocca TJ, Seeger T, Prado M, Perea-Gil I, Neofytou E, Mecham BH, Ameen M, Chang ACY, Pandey G, Wu JC, et al. Pharmacological Silencing of MicroRNA-152 Prevents Pressure Overload-Induced Heart Failure. Circ Heart Fail. 2020;13:e006298.

Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75:843–54.

Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Rådmark O, Kim S, et al. The nuclear RNase III Drosha initiates microRNA processing. Nature. 2003;425:415–9.

Lee Y, Kim M, Han J, Yeom K-H, Lee S, Baek SH, Kim VN. MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 2004;23:4051–60.

Lee Y, Song AJ, Baker R, Micales B, Conway SJ, Lyons GE. Jumonji, a nuclear protein that is necessary for normal heart development. Circ Res. 2000;86:932–8.

Lesizza P, Prosdocimo G, Martinelli V, Sinagra G, Zacchigna S, Giacca M. Single-Dose Intracardiac Injection of Pro-Regenerative MicroRNAs Improves Cardiac Function After Myocardial Infarction. Circ Res. 2017;120:1298–304.

Li X, He X, Wang H, Li M, Huang S, Chen G, Jing Y, Wang S, Chen Y, Liao W, et al. Loss of AZIN2 splice variant facilitates endogenous cardiac regeneration. Cardiovasc Res. 2018a;114:1642–55.

Li Y, He L, Huang X, Bhaloo SI, Zhao H, Zhang S, Pu W, Tian X, Li Y, Liu Q, et al. Genetic Lineage Tracing of Nonmyocyte Population by Dual Recombinases. Circulation. 2018b;138:793–805.

Li Z, Song Y, Liu L, Hou N, An X, Zhan D, Li Y, Zhou L, Li P, Yu L, et al. miR-199a impairs autophagy and induces cardiac hypertrophy through mTOR activation. Cell Death Differentiation. 2017;24:1205–13.

Liang D, Li J, Wu Y, Zhen L, Li C, Qi M, Wang L, Deng F, Huang J, Lv F, et al. miRNA-204 drives cardiomyocyte proliferation via targeting Jarid2. Int J Cardiol. 2015;201:38–48.

Liu N, Bezprozvannaya S, Williams AH, Qi X, Richardson JA, Bassel-Duby R, Olson EN. microRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart. Genes Dev. 2008;22:3242–54.

Liu N, Williams AH, Kim Y, McAnally J, Bezprozvannaya S, Sutherland LB, Richardson JA, Bassel-Duby R, Olson EN. An intragenic MEF2-dependent enhancer directs muscle-specific expression of microRNAs 1 and 133. Proceed National Acad Sci USA. 2007;104:20844–9.

Lompré AM, Nadal-Ginard B, Mahdavi V. Expression of the cardiac ventricular alpha- and beta-myosin heavy chain genes is developmentally and hormonally regulated. J Biol Chem. 1984;259:6437–46.

Lu T-Y, Lin B, Li Y, Arora A, Han L, Cui C, Coronnello C, Sheng Y, Benos PV, Yang L. Overexpression of microRNA-1 promotes cardiomyocyte commitment from human cardiovascular progenitors via suppressing WNT and FGF signaling pathways. J Molecular Cell Cardiol. 2013;63:146–54.

Lund, E., Güttinger, S., Calado, A., Dahlberg, J.E., and Kutay, U. Nuclear export of microRNA precursors. Science. 2004;303:95-98.

MacDiarmid JA, Brahmbhatt H. Minicells: versatile vectors for targeted drug or si/shRNA cancer therapy. Curr Opin Biotechnol. 2011;22:909–16.

Mahmoud AI, Kocabas F, Muralidhar SA, Kimura W, Koura AS, Thet S, Porrello ER, Sadek HA. Meis1 regulates postnatal cardiomyocyte cell cycle arrest. Nature. 2013;497:249–53.

Mahmoudi S, Mancini E, Xu L, Moore A, Jahanbani F, Hebestreit K, Srinivasan R, Li X, Devarajan K, Prelot L, et al. Heterogeneity in old fibroblasts is linked to variability in reprogramming and wound healing. Nature. 2019;574:553–8.

McCarthy JJ. MicroRNA-206: the skeletal muscle-specific myomiR. Biochim Biophys Acta. 2008;1779:682–91.

Mishima Y, Abreu-Goodger C, Staton AA, Stahlhut C, Shou C, Cheng C, Gerstein M, Enright AJ, Giraldez AJ. Zebrafish miR-1 and miR-133 shape muscle gene expression and regulate sarcomeric actin organization. Genes Dev. 2009;23:619–32.

Mohamed TMA, Ang YS, Radzinsky E, Zhou P, Huang Y, Elfenbein A, Foley A, Magnitsky S, Srivastava D. Regulation of Cell Cycle to Stimulate Adult Cardiomyocyte Proliferation and Cardiac Regeneration. Cell. 2018;173(104-116):e112.

Morton SU, Scherz PJ, Cordes KR, Ivey KN, Stainier DY, Srivastava D. microRNA-138 modulates cardiac patterning during embryonic development. Proc Natl Acad Sci U S A. 2008;105:17830–5.

Nasevicius A, Ekker SC. Effective targeted gene 'knockdown' in zebrafish. Nat Genet. 2000;26:216–20.

Nguyen TA, Jo MH, Choi Y-G, Park J, Kwon SC, Hohng S, Kim VN, Woo J-S. Functional Anatomy of the Human Microprocessor. Cell. 2015;161:1374–87.

Pan Z, Sun X, Shan H, Wang N, Wang J, Ren J, Feng S, Xie L, Lu C, Yuan Y, et al. MicroRNA-101 inhibited postinfarct cardiac fibrosis and improved left ventricular compliance via the FBJ osteosarcoma oncogene/transforming growth factor-beta1 pathway. Circulation. 2012;126:840–50.

Pandey R, Velasquez S, Durrani S, Jiang M, Neiman M, Crocker JS, Benoit JB, Rubinstein J, Paul A, Ahmed RP. MicroRNA-1825 induces proliferation of adult cardiomyocytes and promotes cardiac regeneration post ischemic injury. Am J Transl Res. 2017;9:3120–37.

Paoletti C, Divieto C, Tarricone G, Di Meglio F, Nurzynska D, Chiono V. MicroRNA-Mediated Direct Reprogramming of Human Adult Fibroblasts Toward Cardiac Phenotype. Front Bioeng Biotechnol. 2020;8:529.

Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B, Hayward DC, Ball EE, Degnan B, Müller P, et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature. 2000;408:86–9.

Pasumarthi KB, Nakajima H, Nakajima HO, Soonpaa MH, Field LJ. Targeted expression of cyclin D2 results in cardiomyocyte DNA synthesis and infarct regression in transgenic mice. Circ Res. 2005;96:110–8.

Poller W, Dimmeler S, Heymans S, Zeller T, Haas J, Karakas M, Leistner DM, Jakob P, Nakagawa S, Blankenberg S, et al. Non-coding RNAs in cardiovascular diseases: diagnostic and therapeutic perspectives. Eur Heart J. 2018;39:2704–16.

Ponnusamy M, Liu F, Zhang YH, Li RB, Zhai M, Liu F, Zhou LY, Liu CY, Yan KW, Dong YH, et al. Long Noncoding RNA CPR (Cardiomyocyte Proliferation Regulator) Regulates Cardiomyocyte Proliferation and Cardiac Repair. Circulation. 2019;139:2668–84.

Porrello ER, Johnson BA, Aurora AB, Simpson E, Nam YJ, Matkovich SJ, Dorn GW 2nd, van Rooij E, Olson EN. MiR-15 family regulates postnatal mitotic arrest of cardiomyocytes. Circ Res. 2011a;109:670–9.

Porrello ER, Mahmoud AI, Simpson E, Hill JA, Richardson JA, Olson EN, Sadek HA. Transient regenerative potential of the neonatal mouse heart. Science (New York, NY). 2011b;331:1078–80.

Porrello ER, Mahmoud AI, Simpson E, Johnson BA, Grinsfelder D, Canseco D, Mammen PP, Rothermel BA, Olson EN, Sadek HA. Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family. Proc Natl Acad Sci U S A. 2013;110:187–92.

Porrello ER, Olson EN. A neonatal blueprint for cardiac regeneration. Stem cell research. 2014;13:556–70.

Poss KD, Wilson LG, Keating MT. Heart regeneration in zebrafish. Science (New York, NY). 2002;298:2188–90.

Qian L, Huang Y, Spencer CI, Foley A, Vedantham V, Liu L, Conway SJ, Fu JD, Srivastava D. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature. 2012;485:593–8.

Qian L, Srivastava D. Direct cardiac reprogramming: from developmental biology to cardiac regeneration. Circ Res. 2013;113:915–21.

Qin X, Gao S, Yang Y, Wu L, Wang L. microRNA-25 promotes cardiomyocytes proliferation and migration via targeting Bim. J Cellular Physiol. 2019;234:22103–15.

Rojas A, Kong SW, Agarwal P, Gilliss B, Pu WT, Black BL. GATA4 is a direct transcriptional activator of cyclin D2 and Cdk4 and is required for cardiomyocyte proliferation in anterior heart field-derived myocardium. Mol Cell Biol. 2008;28:5420–31.

Roth GA, Johnson C, Abajobir A, Abd-Allah F, Abera SF, Abyu G, Ahmed M, Aksut B, Alam T, Alam K, et al. Global, Regional, and National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015. J Am Coll Cardiol. 2017;70:1–25.

Sadahiro T, Ieda M. Direct Cardiac Reprogramming for Cardiovascular Regeneration and Differentiation. Keio J Med. 2020;69:49–58.

Sadek H, Olson EN. Toward the Goal of Human Heart Regeneration. Cell Stem Cell. 2020;26:7–16.

Saxena A, Tabin CJ. miRNA-processing enzyme Dicer is necessary for cardiac outflow tract alignment and chamber septation. Proc Natl Acad Sci U S A. 2010;107:87–91.

Schindler YL, Garske KM, Wang J, Firulli BA, Firulli AB, Poss KD, Yelon D. Hand2 elevates cardiomyocyte production during zebrafish heart development and regeneration. Development. 2014;141:3112–22.

Sempere LF, Freemantle S, Pitha-Rowe I, Moss E, Dmitrovsky E, Ambros V. Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome biology. 2004;5:R13.

Shi J, Bei Y, Kong X, Liu X, Lei Z, Xu T, Wang H, Xuan Q, Chen P, Xu J, et al. miR-17-3p Contributes to Exercise-Induced Cardiac Growth and Protects against Myocardial Ischemia-Reperfusion Injury. Theranostics. 2017;7:664–76.

Shiba Y, Gomibuchi T, Seto T, Wada Y, Ichimura H, Tanaka Y, Ogasawara T, Okada K, Shiba N, Sakamoto K, et al. Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts. Nature. 2016;538:388–91.

Song X-W, Li Q, Lin L, Wang X-C, Li D-F, Wang G-K, Ren A-J, Wang Y-R, Qin Y-W, Yuan W-J, et al. MicroRNAs are dynamically regulated in hypertrophic hearts, and miR-199a is essential for the maintenance of cell size in cardiomyocytes. J Cellular Physiol. 2010;225:437–43.

Takahashi K, Yamanaka S. Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell. 2006;126:663–76.

Tao Y, Zhang H, Huang S, Pei L, Feng M, Zhao X, Ouyang Z, Yao S, Jiang R, Wei K. miR-199a-3p promotes cardiomyocyte proliferation by inhibiting Cd151 expression. Biochemical Biophysical Research Communications. 2019;516:28–36.

Thompson BJ, Cohen SM. The Hippo pathway regulates the bantam microRNA to control cell proliferation and apoptosis in Drosophila. Cell. 2006;126:767–74.

Tian Y, Liu Y, Wang T, Zhou N, Kong J, Chen L, Snitow M, Morley M, Li D, Petrenko N, et al. A microRNA-Hippo pathway that promotes cardiomyocyte proliferation and cardiac regeneration in mice. Sci Transl Med. 2015;7:279ra238.

Torrini C, Cubero RJ, Dirkx E, Braga L, Ali H, Prosdocimo G, Gutierrez MI, Collesi C, Licastro D, Zentilin L, Mano M, Zacchigna S, Vendruscolo M, Marsili M, Samal A, Giacca M. Common Regulatory Pathways Mediate Activity of MicroRNAs Inducing Cardiomyocyte Proliferation. Cell Rep. 2019;27:2759-71.

Toyoda M, Shirato H, Nakajima K, Kojima M, Takahashi M, Kubota M, Suzuki-Migishima R, Motegi Y, Yokoyama M, Takeuchi T. jumonji downregulates cardiac cell proliferation by repressing cyclin D1 expression. Dev Cell. 2003;5:85–97.

Vacante F, Denby L, Sluimer JC, Baker AH. The function of miR-143, miR-145 and the MiR-143 host gene in cardiovascular development and disease. Vascul Pharmacol. 2019;112:24–30.

van Rooij E, Quiat D, Johnson BA, Sutherland LB, Qi X, Richardson JA, Kelm RJ Jr, Olson EN. A family of microRNAs encoded by myosin genes governs myosin expression and muscle performance. Dev Cell. 2009;17:662–73.

van Rooij E, Sutherland LB, Qi X, Richardson JA, Hill J, Olson EN. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science. 2007;316:575–9.

Ventura A, Young AG, Winslow MM, Lintault L, Meissner A, Erkeland SJ, Newman J, Bronson RT, Crowley D, Stone JR, et al. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell. 2008;132:875–86.

Wahlquist C, Jeong D, Rojas-Munoz A, Kho C, Lee A, Mitsuyama S, van Mil A, Park WJ, Sluijter JP, Doevendans PA, et al. Inhibition of miR-25 improves cardiac contractility in the failing heart. Nature. 2014;508:531–5.

Wang B, Xu M, Li M, Wu F, Hu S, Chen X, Zhao L, Huang Z, Lan F, Liu D, et al. miR-25 Promotes Cardiomyocyte Proliferation by Targeting FBXW7. Mol Ther Nucleic Acids. 2020;19:1299–308.

Wang J, Chen X, Shen D, Ge D, Chen J, Pei J, Li Y, Yue Z, Feng J, Chu M, et al. A long noncoding RNA NR_045363 controls cardiomyocyte proliferation and cardiac repair. J Mol Cell Cardiol. 2019;127:105–14.

Wang J, Greene SB, Bonilla-Claudio M, Tao Y, Zhang J, Bai Y, Huang Z, Black BL, Wang F, Martin JF. Bmp signaling regulates myocardial differentiation from cardiac progenitors through a MicroRNA-mediated mechanism. Dev Cell. 2010;19:903–12.

Wang L, Zhang H, Rodriguez S, Cao L, Parish J, Mumaw C, Zollman A, Kamoka MM, Mu J, Chen DZ, et al. Notch-dependent repression of miR-155 in the bone marrow niche regulates hematopoiesis in an NF-κB-dependent manner. Cell stem cell. 2014;15:51–65.

Wang LL, Liu Y, Chung JJ, Wang T, Gaffey AC, Lu M, Cavanaugh CA, Zhou S, Kanade R, Atluri P, et al. Local and sustained miRNA delivery from an injectable hydrogel promotes cardiomyocyte proliferation and functional regeneration after ischemic injury. Nat Biomed Eng. 2017;1:983–92.

Wang X, Ha T, Liu L, Hu Y, Kao R, Kalbfleisch J, Williams D, Li C. TLR3 Mediates Repair and Regeneration of Damaged Neonatal Heart through Glycolysis Dependent YAP1 Regulated miR-152 Expression. Cell Death Differentiation. 2018;25:966–82.

Wei K, Serpooshan V, Hurtado C, Diez-Cunado M, Zhao M, Maruyama S, Zhu W, Fajardo G, Noseda M, Nakamura K, et al. Epicardial FSTL1 reconstitution regenerates the adult mammalian heart. Nature. 2015;525:479–85.

Wei Y, Peng S, Wu M, Sachidanandam R, Tu Z, Zhang S, Falce C, Sobie EA, Lebeche D, Zhao Y. Multifaceted roles of miR-1s in repressing the fetal gene program in the heart. Cell Res. 2014;24:278–92.

Welcker M, Clurman BE. FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer. 2008;8:83–93.

Wienholds E, Koudijs MJ, van Eeden FJ, Cuppen E, Plasterk RH. The microRNA-producing enzyme Dicer1 is essential for zebrafish development. Nat Genet. 2003;35:217–8.

Wilson KD, Hu S, Venkatasubrahmanyam S, Fu JD, Sun N, Abilez OJ, Baugh JJ, Jia F, Ghosh Z, Li RA, et al. Dynamic microRNA expression programs during cardiac differentiation of human embryonic stem cells: role for miR-499. Circ Cardiovasc Genet. 2010;3:426–35.

Witman N, Murtuza B, Davis B, Arner A, Morrison JI. Recapitulation of developmental cardiogenesis governs the morphological and functional regeneration of adult newt hearts following injury. Developmental Biol. 2011;354:67–76.

Wystub K, Besser J, Bachmann A, Boettger T, Braun T. miR-1/133a clusters cooperatively specify the cardiomyogenic lineage by adjustment of myocardin levels during embryonic heart development. PLoS Genet. 2013;9:e1003793.

Xiao J, Liu H, Cretoiu D, Toader DO, Suciu N, Shi J, Shen S, Bei Y, Sluijter JP, Das S, et al. miR-31a-5p promotes postnatal cardiomyocyte proliferation by targeting RhoBTB1. Experimental Molecular Med. 2017;49:e386.

Xin M, Kim Y, Sutherland LB, Murakami M, Qi X, McAnally J, Porrello ER, Mahmoud AI, Tan W, Shelton JM, et al. Hippo pathway effector Yap promotes cardiac regeneration. Proc Natl Acad Sci U S A. 2013;110:13839–44.

Xin M, Small EM, Sutherland LB, Qi X, McAnally J, Plato CF, Richardson JA, Bassel-Duby R, Olson EN. MicroRNAs miR-143 and miR-145 modulate cytoskeletal dynamics and responsiveness of smooth muscle cells to injury. Genes Dev. 2009;23:2166–78.

Xu T, Liu N, Shao Y, Huang Y, Zhu D. MiR-218 regulated cardiomyocyte differentiation and migration in mouse embryonic stem cells by targeting PDGFRalpha. J Cell Biochem. 2019;120:4355–65.

Yang H, Qin X, Wang H, Zhao X, Liu Y, Wo HT, Liu C, Nishiga M, Chen H, Ge J, et al. An in Vivo miRNA Delivery System for Restoring Infarcted Myocardium. ACS Nano. 2019;13:9880–94.

Yang Y, Cheng H-W, Qiu Y, Dupee D, Noonan M, Lin Y-D, Fisch S, Unno K, Sereti K-I, Liao R. MicroRNA-34a Plays a Key Role in Cardiac Repair and Regeneration Following Myocardial Infarction. Circulation Research. 2015;117:450–9.

Ye L, D'Agostino G, Loo SJ, Wang CX, Su LP, Tan SH, Tee GZ, Pua CJ, Pena EM, Cheng RB, et al. Early Regenerative Capacity in the Porcine Heart. Circulation. 2018;138:2798–808.

Yu F-X, Guan K-L. The Hippo pathway: regulators and regulations. Genes Development. 2013;27:355–71.

Zhang H, Li S, Zhou Q, Sun Q, Shen S, Zhou Y, Bei Y, Li X. Qiliqiangxin Attenuates Phenylephrine-Induced Cardiac Hypertrophy through Downregulation of MiR-199a-5p. Cellular Physiol Biochemistry. 2016;38:1743–51.

Zhao Y, Ransom JF, Li A, Vedantham V, von Drehle M, Muth AN, Tsuchihashi T, McManus MT, Schwartz RJ, Srivastava D. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell. 2007;129:303–17.

Zhao Y, Samal E, Srivastava D. Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature. 2005;436:214–20.

Zheng Y, Pan D. The Hippo Signaling Pathway in Development and Disease. Dev Cell. 2019;50:264–82.