The long non-coding road to endogenous cardiac regeneration

Abstract

The human heart has a markedly low regenerative capacity, leaving patients who suffered from cardiac insults vulnerable to heart failure. The inability to regenerate lost myocardium is accompanied by extensive remodeling that leads to further deterioration in cardiac functions and structure. Although adult mammals seem to lack the ability to regenerate, some lower vertebrates have a cardio-regenerative potential. Emerging studies revealed that mammals do have the ability to undergo endogenous cardiac regeneration during development and shortly after birth. Later, it was proven that the source of the new cardiomyocytes is the proliferation of the pre-existing cardiomyocyte pool. Research is currently focused on finding suitable methods to restore this lost potential in adulthood and enhancing the proliferative capacity of cardiomyocytes. Long non-coding RNAs (lncRNAs) are critical functionally diverse epigenetic regulators capable of either activating or repressing gene expression. LncRNAs have been previously implicated in cardiac development, lineage commitment, and aging. Recent reports suggest that lncRNAs are capable of inducing endogenous cardiac regeneration through manipulating gene expression in cardiomyocytes. This review gives a concise overview of endogenous cardiac regeneration. It further summarizes and critically appraises the current literature on the roles of lncRNAs in endogenous cardiac regeneration and the challenges that face the field.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Anderson JL, Morrow DA (2017) Acute myocardial infarction. N Engl J Med 376(21):2053–2064. https://doi.org/10.1056/NEJMra1606915

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Inamdar AA, Inamdar AC (2016) Heart failure: diagnosis, management and utilization. J Clin Med 5(7). https://doi.org/10.3390/jcm5070062

  3. 3.

    Banerjee MN, Bolli R, Hare JM (2018) Clinical studies of cell therapy in cardiovascular medicine: recent developments and future directions. Circ Res 123(2):266–287. https://doi.org/10.1161/CIRCRESAHA.118.311217

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Eschenhagen T, Bolli R, Braun T, Field LJ, Fleischmann BK, Frisen J, Giacca M, Hare JM, Houser S, Lee RT, Marban E, Martin JF, Molkentin JD, Murry CE, Riley PR, Ruiz-Lozano P, Sadek HA, Sussman MA, Hill JA (2017) Cardiomyocyte regeneration: a consensus statement. Circulation 136(7):680–686. https://doi.org/10.1161/CIRCULATIONAHA.117.029343

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    The Lancet E (2014) Expression of concern: the SCIPIO trial. Lancet 383(9925):1279. https://doi.org/10.1016/S0140-6736(14)60608-5

    Article  Google Scholar 

  6. 6.

    Li Y, He L, Huang X, Bhaloo SI, Zhao H, Zhang S, Pu W, Tian X, Li Y, Liu Q, Yu W, Zhang L, Liu X, Liu K, Tang J, Zhang H, Cai D, Ralf AH, Xu Q, Lui KO, Zhou B (2018) Genetic lineage tracing of nonmyocyte population by dual recombinases. Circulation 138(8):793–805. https://doi.org/10.1161/CIRCULATIONAHA.118.034250

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Menasche P (2018) Cell therapy trials for heart regeneration—lessons learned and future directions. Nat Rev Cardiol 15(11):659–671. https://doi.org/10.1038/s41569-018-0013-0

    Article  PubMed  Google Scholar 

  8. 8.

    Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabe-Heider F, Walsh S, Zupicich J, Alkass K, Buchholz BA, Druid H, Jovinge S, Frisen J (2009) Evidence for cardiomyocyte renewal in humans. Science 324(5923):98–102. https://doi.org/10.1126/science.1164680

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Soonpaa MH, Field LJ (1997) Assessment of cardiomyocyte DNA synthesis in normal and injured adult mouse hearts. Am J Phys 272(1 Pt 2):H220–H226. https://doi.org/10.1152/ajpheart.1997.272.1.H220

  10. 10.

    Soonpaa MH, Field LJ (1998) Survey of studies examining mammalian cardiomyocyte DNA synthesis. Circ Res 83(1):15–26

    CAS  Article  Google Scholar 

  11. 11.

    Porrello ER, Mahmoud AI, Simpson E, Hill JA, Richardson JA, Olson EN, Sadek HA (2011) Transient regenerative potential of the neonatal mouse heart. Science 331(6020):1078–1080. https://doi.org/10.1126/science.1200708

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Lam N, Sadek H (2018) Neonatal heart regeneration: comprehensive literature review, vol 138. doi:https://doi.org/10.1161/CIRCULATIONAHA.118.033648

  13. 13.

    Puente BN, Kimura W, Muralidhar SA, Moon J, Amatruda JF, Phelps KL, Grinsfelder D, Rothermel BA, Chen R, Garcia JA, Santos CX, Thet S, Mori E, Kinter MT, Rindler PM, Zacchigna S, Mukherjee S, Chen DJ, Mahmoud AI, Giacca M, Rabinovitch PS, Aroumougame A, Shah AM, Szweda LI, Sadek HA (2014) The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. Cell 157(3):565–579. https://doi.org/10.1016/j.cell.2014.03.032

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Nakada Y, Canseco DC, Thet S, Abdisalaam S, Asaithamby A, Santos CX, Shah AM, Zhang H, Faber JE, Kinter MT, Szweda LI, Xing C, Hu Z, Deberardinis RJ, Schiattarella G, Hill JA, Oz O, Lu Z, Zhang CC, Kimura W, Sadek HA (2017) Hypoxia induces heart regeneration in adult mice. Nature 541(7636):222–227. https://doi.org/10.1038/nature20173

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Kimura W, Sadek HA (2012) The cardiac hypoxic niche: emerging role of hypoxic microenvironment in cardiac progenitors. Cardiovasc Diagn Ther 2(4):278–289. https://doi.org/10.3978/j.issn.2223-3652.2012.12.02

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Heallen T, Morikawa Y, Leach J, Tao G, Willerson JT, Johnson RL, Martin JF (2013) Hippo signaling impedes adult heart regeneration. Development 140(23):4683–4690. https://doi.org/10.1242/dev.102798

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Lin Z, von Gise A, Zhou P, Gu F, Ma Q, Jiang J, Yau AL, Buck JN, Gouin KA, van Gorp PR, Zhou B, Chen J, Seidman JG, Wang DZ, Pu WT (2014) Cardiac-specific YAP activation improves cardiac function and survival in an experimental murine MI model. Circ Res 115(3):354–363. https://doi.org/10.1161/CIRCRESAHA.115.303632

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Bersell K, Arab S, Haring B, Kuhn B (2009) Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell 138(2):257–270. https://doi.org/10.1016/j.cell.2009.04.060

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    D'Uva G, Aharonov A, Lauriola M, Kain D, Yahalom-Ronen Y, Carvalho S, Weisinger K, Bassat E, Rajchman D, Yifa O, Lysenko M, Konfino T, Hegesh J, Brenner O, Neeman M, Yarden Y, Leor J, Sarig R, Harvey RP, Tzahor E (2015) ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nat Cell Biol 17(5):627–638. https://doi.org/10.1038/ncb3149

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Porrello ER, Olson EN (2014) A neonatal blueprint for cardiac regeneration. Stem Cell Res 13(3 Pt B):556–570. https://doi.org/10.1016/j.scr.2014.06.003

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Uygur A, Lee RT (2016) Mechanisms of cardiac regeneration. Dev Cell 36(4):362–374. https://doi.org/10.1016/j.devcel.2016.01.018

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Fratz S, Hager A, Schreiber C, Schwaiger M, Hess J, Stern HC (2011) Long-term myocardial scarring after operation for anomalous left coronary artery from the pulmonary artery. Ann Thorac Surg 92(5):1761–1765. https://doi.org/10.1016/j.athoracsur.2011.06.021

    Article  PubMed  Google Scholar 

  23. 23.

    Haubner BJ, Schneider J, Schweigmann U, Schuetz T, Dichtl W, Velik-Salchner C, Stein JI, Penninger JM (2016) Functional recovery of a human neonatal heart after severe myocardial infarction. Circ Res 118(2):216–221. https://doi.org/10.1161/CIRCRESAHA.115.307017

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Boulton J, Henry R, Roddick LG, Rogers D, Thompson L, Warner G (1991) Survival after neonatal myocardial infarction. Pediatrics 88(1):145–150

    CAS  PubMed  Google Scholar 

  25. 25.

    Cesna S, Eicken A, Juenger H, Hess J (2013) Successful treatment of a newborn with acute myocardial infarction on the first day of life. Pediatr Cardiol 34(8):1868–1870. https://doi.org/10.1007/s00246-012-0417-2

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Deutsch MA, Cleuziou J, Noebauer C, Eicken A, Vogt M, Hoerer J, Lange R, Schreiber C (2014) Successful management of neonatal myocardial infarction with ECMO and intracoronary r-tPA lysis. Congenit Heart Dis 9(5):E169–E174. https://doi.org/10.1111/chd.12117

    Article  PubMed  Google Scholar 

  27. 27.

    Farooqi KM, Sutton N, Weinstein S, Menegus M, Spindola-Franco H, Pass RH (2012) Neonatal myocardial infarction: case report and review of the literature. Congenit Heart Dis 7(6):E97–E102. https://doi.org/10.1111/j.1747-0803.2012.00660.x

  28. 28.

    Saker DM, Walsh-Sukys M, Spector M, Zahka KG (1997) Cardiac recovery and survival after neonatal myocardial infarction. Pediatr Cardiol 18(2):139–142. https://doi.org/10.1007/s002469900133

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Mollova M, Bersell K, Walsh S, Savla J, Das LT, Park SY, Silberstein LE, Dos Remedios CG, Graham D, Colan S, Kuhn B (2013) Cardiomyocyte proliferation contributes to heart growth in young humans. Proc Natl Acad Sci U S A 110(4):1446–1451. https://doi.org/10.1073/pnas.1214608110

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Ohno S (1972) So much "junk" DNA in our genome. Brookhaven Symp Biol 23:366–370

    CAS  PubMed  Google Scholar 

  31. 31.

    Davis CA, Hitz BC, Sloan CA, Chan ET, Davidson JM, Gabdank I, Hilton JA, Jain K, Baymuradov UK, Narayanan AK, Onate KC, Graham K, Miyasato SR, Dreszer TR, Strattan JS, Jolanki O, Tanaka FY, Cherry JM (2018) The encyclopedia of DNA elements (ENCODE): data portal update. Nucleic Acids Res 46(D1):D794–D801. https://doi.org/10.1093/nar/gkx1081

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    O'Brien J, Hayder H, Zayed Y, Peng C (2018) Overview of microRNA biogenesis, mechanisms of actions, and circulation. Front Endocrinol (Lausanne) 9:402. https://doi.org/10.3389/fendo.2018.00402

    CAS  Article  Google Scholar 

  33. 33.

    Gnecchi M, Pisano F, Bariani R (2015) microRNA and cardiac regeneration. Adv Exp Med Biol 887:119–141. https://doi.org/10.1007/978-3-319-22380-3_7

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Sahakyan A, Yang Y, Plath K (2018) The role of Xist in X-chromosome dosage compensation. Trends Cell Biol 28(12):999–1013. https://doi.org/10.1016/j.tcb.2018.05.005

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Devaux Y, Zangrando J, Schroen B, Creemers EE, Pedrazzini T, Chang CP, Dorn GW, 2nd, Thum T, Heymans S, Cardiolinc n (2015) Long noncoding RNAs in cardiac development and ageing. Nat Rev Cardiol 12 (7):415–425. doi:https://doi.org/10.1038/nrcardio.2015.55

  36. 36.

    Quinn JJ, Chang HY (2016) Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet 17(1):47–62. https://doi.org/10.1038/nrg.2015.10

    CAS  Article  Google Scholar 

  37. 37.

    Pang KC, Frith MC, Mattick JS (2006) Rapid evolution of noncoding RNAs: lack of conservation does not mean lack of function. Trends Genet 22(1):1–5. https://doi.org/10.1016/j.tig.2005.10.003

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Kapranov P, Cheng J, Dike S, Nix DA, Duttagupta R, Willingham AT, Stadler PF, Hertel J, Hackermuller J, Hofacker IL, Bell I, Cheung E, Drenkow J, Dumais E, Patel S, Helt G, Ganesh M, Ghosh S, Piccolboni A, Sementchenko V, Tammana H, Gingeras TR (2007) RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 316(5830):1484–1488. https://doi.org/10.1126/science.1138341

    CAS  Article  Google Scholar 

  39. 39.

    Han P, Li W, Lin CH, Yang J, Shang C, Nuernberg ST, Jin KK, Xu W, Lin CY, Lin CJ, Xiong Y, Chien H, Zhou B, Ashley E, Bernstein D, Chen PS, Chen HV, Quertermous T, Chang CP (2014) A long noncoding RNA protects the heart from pathological hypertrophy. Nature 514(7520):102–106. https://doi.org/10.1038/nature13596

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Klattenhoff CA, Scheuermann JC, Surface LE, Bradley RK, Fields PA, Steinhauser ML, Ding H, Butty VL, Torrey L, Haas S, Abo R, Tabebordbar M, Lee RT, Burge CB, Boyer LA (2013) Braveheart, a long noncoding RNA required for cardiovascular lineage commitment. Cell 152(3):570–583. https://doi.org/10.1016/j.cell.2013.01.003

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Ounzain S, Micheletti R, Beckmann T, Schroen B, Alexanian M, Pezzuto I, Crippa S, Nemir M, Sarre A, Johnson R, Dauvillier J, Burdet F, Ibberson M, Guigo R, Xenarios I, Heymans S, Pedrazzini T (2015) Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs. Eur Heart J 36(6):353–368a. https://doi.org/10.1093/eurheartj/ehu180

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Tragante V, Barnes MR, Ganesh SK, Lanktree MB, Guo W, Franceschini N, Smith EN, Johnson T, Holmes MV, Padmanabhan S, Karczewski KJ, Almoguera B, Barnard J, Baumert J, Chang YP, Elbers CC, Farrall M, Fischer ME, Gaunt TR, Gho JM, Gieger C, Goel A, Gong Y, Isaacs A, Kleber ME, Mateo Leach I, McDonough CW, Meijs MF, Melander O, Nelson CP, Nolte IM, Pankratz N, Price TS, Shaffer J, Shah S, Tomaszewski M, van der Most PJ, Van Iperen EP, Vonk JM, Witkowska K, Wong CO, Zhang L, Beitelshees AL, Berenson GS, Bhatt DL, Brown M, Burt A, Cooper-DeHoff RM, Connell JM, Cruickshanks KJ, Curtis SP, Davey-Smith G, Delles C, Gansevoort RT, Guo X, Haiqing S, Hastie CE, Hofker MH, Hovingh GK, Kim DS, Kirkland SA, Klein BE, Klein R, Li YR, Maiwald S, Newton-Cheh C, O'Brien ET, Onland-Moret NC, Palmas W, Parsa A, Penninx BW, Pettinger M, Vasan RS, Ranchalis JE, MR P, Rose LM, Sever P, Shimbo D, Steele L, Stolk RP, Thorand B, Trip MD, van Duijn CM, Verschuren WM, Wijmenga C, Wyatt S, Young JH, Zwinderman AH, Bezzina CR, Boerwinkle E, Casas JP, Caulfield MJ, Chakravarti A, Chasman DI, Davidson KW, Doevendans PA, Dominiczak AF, FitzGerald GA, Gums JG, Fornage M, Hakonarson H, Halder I, Hillege HL, Illig T, Jarvik GP, Johnson JA, Kastelein JJ, Koenig W, Kumari M, Marz W, Murray SS, O'Connell JR, Oldehinkel AJ, Pankow JS, Rader DJ, Redline S, Reilly MP, Schadt EE, Kottke-Marchant K, Snieder H, Snyder M, Stanton AV, Tobin MD, Uitterlinden AG, van der Harst P, van der Schouw YT, Samani NJ, Watkins H, Johnson AD, Reiner AP, Zhu X, de Bakker PI, Levy D, Asselbergs FW, Munroe PB, Keating BJ (2014) Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci. Am J Hum Genet 94(3):349–360. https://doi.org/10.1016/j.ajhg.2013.12.016

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Helgadottir A, Thorleifsson G, Manolescu A, Gretarsdottir S, Blondal T, Jonasdottir A, Jonasdottir A, Sigurdsson A, Baker A, Palsson A, Masson G, Gudbjartsson DF, Magnusson KP, Andersen K, Levey AI, Backman VM, Matthiasdottir S, Jonsdottir T, Palsson S, Einarsdottir H, Gunnarsdottir S, Gylfason A, Vaccarino V, Hooper WC, Reilly MP, Granger CB, Austin H, Rader DJ, Shah SH, Quyyumi AA, Gulcher JR, Thorgeirsson G, Thorsteinsdottir U, Kong A, Stefansson K (2007) A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316(5830):1491–1493. https://doi.org/10.1126/science.1142842

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Ishii N, Ozaki K, Sato H, Mizuno H, Saito S, Takahashi A, Miyamoto Y, Ikegawa S, Kamatani N, Hori M, Saito S, Nakamura Y, Tanaka T (2006) Identification of a novel non-coding RNA, MIAT, that confers risk of myocardial infarction. J Hum Genet 51(12):1087–1099. https://doi.org/10.1007/s10038-006-0070-9

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Frank S, Aguirre A, Hescheler J, Kurian L (2016) A lncRNA perspective into (re)building the heart. Front Cell Dev Biol 4:128. https://doi.org/10.3389/fcell.2016.00128

    Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Ounzain S, Crippa S, Pedrazzini T (2013) Small and long non-coding RNAs in cardiac homeostasis and regeneration. Biochim Biophys Acta 1833(4):923–933. https://doi.org/10.1016/j.bbamcr.2012.08.010

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Uchida S, Dimmeler S (2015) Long noncoding RNAs in cardiovascular diseases. Circ Res 116(4):737–750. https://doi.org/10.1161/CIRCRESAHA.116.302521

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Chen YM, Li H, Fan Y, Zhang QJ, Li X, Wu LJ, Chen ZJ, Zhu C, Qian LM (2017) Identification of differentially expressed lncRNAs involved in transient regeneration of the neonatal C57BL/6J mouse heart by next-generation high-throughput RNA sequencing. Oncotarget 8(17):28052–28062. https://doi.org/10.18632/oncotarget.15887

    Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Wang J, Geng Z, Weng J, Shen L, Li M, Cai X, Sun C, Chu M (2016) Microarray analysis reveals a potential role of lncRNAs expression in cardiac cell proliferation. BMC Dev Biol 16(1):41. https://doi.org/10.1186/s12861-016-0139-4

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Li B, Hu Y, Li X, Jin G, Chen X, Chen G, Yanmei C, Huang S, Liao W, Liao Y, Teng Z, Bin J (2018) Sirt1 antisense long noncoding RNA promotes cardiomyocyte proliferation by enhancing the stability of Sirt1, vol 7. doi:https://doi.org/10.1161/JAHA.118.009700

  51. 51.

    Li X, He X, Wang H, Li M, Huang S, Chen G, Jing Y, Wang S, Chen Y, Liao W, Liao Y, Bin J (2018) Loss of AZIN2 splice variant facilitates endogenous cardiac regeneration. Cardiovasc Res 114(12):1642–1655. https://doi.org/10.1093/cvr/cvy075

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Chen G, Li H, Li X, Li B, Zhong L, Huang S, Zheng H, Li M, Jin G, Liao W, Liao Y, Chen Y, Bin J (2018) 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 122:152–164. https://doi.org/10.1016/j.yjmcc.2018.08.013

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Yanmei C, Li X, Li B, Wang H, Li M, Huang S, Sun Y, Chen G, Si X, Huang C, Liao W, Liao Y, Bin J (2018) Long non-coding RNA ECRAR triggers postnatal myocardial regeneration by activating ERK1/2 signaling. https://doi.org/10.1016/j.ymthe.2018.10.021

    Google Scholar 

  54. 54.

    Wang J, Chen X, Shen D, Ge D, Chen J, Pei J, Li Y, Yue Z, Feng J, Chu M, Nie Y (2018) A long noncoding RNA NR_045363 controls cardiomyocyte proliferation and cardiac repair. J Mol Cell Cardiol 127:105–114. https://doi.org/10.1016/j.yjmcc.2018.12.005

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Cai B, Ma W, Ding F, Zhang L, Huang Q, Wang X, Hua B, Xu J, Li J, Bi C, Guo S, Yang F, Han Z, Li Y, Yan G, Yu Y, Bao Z, Yu M, Li F, Tian Y, Pan Z, Yang B (2018) The long noncoding RNA CAREL controls cardiac regeneration. J Am Coll Cardiol 72(5):534–550. https://doi.org/10.1016/j.jacc.2018.04.085

    Article  PubMed  Google Scholar 

  56. 56.

    Thum T (2018) Translational opportunities and challenges of long noncoding RNAs in cardiac regeneration. J Am Coll Cardiol 72(5):551–552. https://doi.org/10.1016/j.jacc.2018.05.039

    Article  PubMed  Google Scholar 

  57. 57.

    Ounzain S, Pezzuto I, Micheletti R, Burdet F, Sheta R, Nemir M, Gonzales C, Sarre A, Alexanian M, Blow MJ, May D, Johnson R, Dauvillier J, Pennacchio LA, Pedrazzini T (2014) Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease. J Mol Cell Cardiol 76:55–70. https://doi.org/10.1016/j.yjmcc.2014.08.009

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Ounzain S, Micheletti R, Arnan C, Plaisance I, Cecchi D, Schroen B, Reverter F, Alexanian M, Gonzales C, Ng SY, Bussotti G, Pezzuto I, Notredame C, Heymans S, Guigo R, Johnson R, Pedrazzini T (2015) CARMEN, a human super enhancer-associated long noncoding RNA controlling cardiac specification, differentiation and homeostasis. J Mol Cell Cardiol 89 (Pt A:98–112. https://doi.org/10.1016/j.yjmcc.2015.09.016

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Grote P, Wittler L, Hendrix D, Koch F, Wahrisch S, Beisaw A, Macura K, Blass G, Kellis M, Werber M, Herrmann BG (2013) The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse. Dev Cell 24(2):206–214. https://doi.org/10.1016/j.devcel.2012.12.012

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Plaisance I, Perruchoud S, Fernandez-Tenorio M, Gonzales C, Ounzain S, Ruchat P, Nemir M, Niggli E, Pedrazzini T (2016) Cardiomyocyte lineage specification in adult human cardiac precursor cells via modulation of enhancer-associated long noncoding RNA expression. JACC Basic Transl Sci 1(6):472–493. https://doi.org/10.1016/j.jacbts.2016.06.008

    Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Kurian L, Aguirre A, Sancho-Martinez I, Benner C, Hishida T, Nguyen TB, Reddy P, Nivet E, Krause MN, Nelles DA, Esteban CR, Campistol JM, Yeo GW, Belmonte JCI (2015) Identification of novel long noncoding RNAs underlying vertebrate cardiovascular development. Circulation 131(14):1278–1290. https://doi.org/10.1161/CIRCULATIONAHA.114.013303

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Yin A, Feng M, Cheng Z, Zhang Q, Li H, Xu J, Zhang H, Li Y, Qian L (2018) Altered DNA methylation of long noncoding RNA uc.167 inhibits cell differentiation in heart development. Biomed Res Int 2018:4658024. https://doi.org/10.1155/2018/4658024

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Gore-Panter SR, Hsu J, Barnard J, Moravec CS, Van Wagoner DR, Chung MK, Smith JD (2016) PANCR, the PITX2 adjacent noncoding RNA, is expressed in human left atria and regulates PITX2c expression. Circ Arrhythm Electrophysiol 9(1):e003197. https://doi.org/10.1161/CIRCEP.115.003197

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Matkovich SJ, Edwards JR, Grossenheider TC, de Guzman Strong C, Dorn GW 2nd (2014) Epigenetic coordination of embryonic heart transcription by dynamically regulated long noncoding RNAs. Proc Natl Acad Sci U S A 111(33):12264–12269. https://doi.org/10.1073/pnas.1410622111

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Korostowski L, Sedlak N, Engel N (2012) The Kcnq1ot1 long non-coding RNA affects chromatin conformation and expression of Kcnq1, but does not regulate its imprinting in the developing heart. PLoS Genet 8(9):e1002956. https://doi.org/10.1371/journal.pgen.1002956

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Han Y, Xu H, Cheng J, Zhang Y, Gao C, Fan T, Peng B, Li B, Liu L, Cheng Z (2016) Downregulation of long non-coding RNA H19 promotes P19CL6 cells proliferation and inhibits apoptosis during late-stage cardiac differentiation via miR-19b-modulated Sox6. Cell Biosci 6:58. https://doi.org/10.1186/s13578-016-0123-5

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Zhu JG, Shen YH, Liu HL, Liu M, Shen YQ, Kong XQ, Song GX, Qian LM (2014) Long noncoding RNAs expression profile of the developing mouse heart. J Cell Biochem 115(5):910–918. https://doi.org/10.1002/jcb.24733

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    Li H, Jiang L, Yu Z, Han S, Liu X, Li M, Zhu C, Qiao L, Huang L (2017) The role of a novel long noncoding RNA TUC40- in cardiomyocyte induction and maturation in P19 cells. Am J Med Sci 354(6):608–616. https://doi.org/10.1016/j.amjms.2017.08.019

    Article  PubMed  Google Scholar 

  69. 69.

    Wu R, Xue P, Wan Y, Wang S, Gu M (2018) LncRNA-uc.40 silence promotes P19 embryonic cells differentiation to cardiomyocyte via the PBX1 gene. In Vitro Cell Dev Biol Anim 54(8):600–609. https://doi.org/10.1007/s11626-018-0284-0

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Zhang Q, Feng M, Zhang H, Xu J, Zhang L, Wang X, Cheng Z, Qian L (2018) Long noncoding RNA uc.4 inhibits cell differentiation in heart development by altering DNA methylation. J Cell Biochem. https://doi.org/10.1002/jcb.28084

  71. 71.

    Cheng Z, Zhang Q, Yin A, Feng M, Li H, Liu H, Li Y, Qian L (2018) The long non-coding RNA uc.4 influences cell differentiation through the TGF-beta signaling pathway. Exp Mol Med 50(2):e447. https://doi.org/10.1038/emm.2017.278

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Ulitsky I, Shkumatava A, Jan CH, Sive H, Bartel DP (2011) Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution. Cell 147(7):1537–1550. https://doi.org/10.1016/j.cell.2011.11.055

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Guo X, Gao L, Wang Y, Chiu DK, Wang T, Deng Y (2016) Advances in long noncoding RNAs: identification, structure prediction and function annotation. Brief Funct Genomics 15(1):38–46. https://doi.org/10.1093/bfgp/elv022

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Amaral PP, Leonardi T, Han N, Vire E, Gascoigne DK, Arias-Carrasco R, Buscher M, Pandolfini L, Zhang A, Pluchino S, Maracaja-Coutinho V, Nakaya HI, Hemberg M, Shiekhattar R, Enright AJ, Kouzarides T (2018) Genomic positional conservation identifies topological anchor point RNAs linked to developmental loci. Genome Biol 19(1):32. https://doi.org/10.1186/s13059-018-1405-5

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Kirk JM, Kim SO, Inoue K, Smola MJ, Lee DM, Schertzer MD, Wooten JS, Baker AR, Sprague D, Collins DW, Horning CR, Wang S, Chen Q, Weeks KM, Mucha PJ, Calabrese JM (2018) Functional classification of long non-coding RNAs by k-mer content. Nat Genet 50(10):1474–1482. https://doi.org/10.1038/s41588-018-0207-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP (2011) A ceRNA hypothesis: the Rosetta stone of a hidden RNA language? Cell 146(3):353–358. https://doi.org/10.1016/j.cell.2011.07.014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Thomson DW, Dinger ME (2016) Endogenous microRNA sponges: evidence and controversy. Nat Rev Genet 17(5):272–283. https://doi.org/10.1038/nrg.2016.20

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Denzler R, McGeary SE, Title AC, Agarwal V, Bartel DP, Stoffel M (2016) Impact of microRNA levels, target-site complementarity, and cooperativity on competing endogenous RNA-regulated gene expression. Mol Cell 64(3):565–579. https://doi.org/10.1016/j.molcel.2016.09.027

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Cai X, Cullen BR (2007) The imprinted H19 noncoding RNA is a primary microRNA precursor. RNA 13(3):313–316. https://doi.org/10.1261/rna.351707

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Wang Y, Hu Y, Wu G, Yang Y, Tang Y, Zhang W, Wang K, Liu Y, Wang X, Li T (2017) Long noncoding RNA PCAT-14 induces proliferation and invasion by hepatocellular carcinoma cells by inducing methylation of miR-372. Oncotarget 8(21):34429–34441. https://doi.org/10.18632/oncotarget.16260

    Article  PubMed  PubMed Central  Google Scholar 

  81. 81.

    DeLaughter DM, Bick AG, Wakimoto H, McKean D, Gorham JM, Kathiriya IS, Hinson JT, Homsy J, Gray J, Pu W, Bruneau BG, Seidman JG, Seidman CE (2016) Single-cell resolution of temporal gene expression during heart development. Dev Cell 39(4):480–490. https://doi.org/10.1016/j.devcel.2016.10.001

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82.

    See K, Tan WLW, Lim EH, Tiang Z, Lee LT, Li PYQ, Luu TDA, Ackers-Johnson M, Foo RS (2017) Single cardiomyocyte nuclear transcriptomes reveal a lincRNA-regulated de-differentiation and cell cycle stress-response in vivo. Nat Commun 8(1):225. https://doi.org/10.1038/s41467-017-00319-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Paradis AN, Gay MS, Zhang L (2014) Binucleation of cardiomyocytes: the transition from a proliferative to a terminally differentiated state. Drug Discov Today 19(5):602–609. https://doi.org/10.1016/j.drudis.2013.10.019

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    Hesse M, Doengi M, Becker A, Kimura K, Voeltz N, Stein V, Fleischmann BK (2018) Midbody positioning and distance between daughter nuclei enable unequivocal identification of cardiomyocyte cell division in mice. Circ Res 123(9):1039–1052. https://doi.org/10.1161/CIRCRESAHA.118.312792

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Mohamed TMA, Ang YS, Radzinsky E, Zhou P, Huang Y, Elfenbein A, Foley A, Magnitsky S, Srivastava D (2018) Regulation of cell cycle to stimulate adult cardiomyocyte proliferation and cardiac regeneration. Cell 173(1):104–116 e112. https://doi.org/10.1016/j.cell.2018.02.014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Ye L, D'Agostino G, Loo SJ, Wang CX, Su LP, Tan SH, Tee GZ, Pua CJ, Pena EM, Cheng RB, Chen WC, Abdurrachim D, Lalic J, Tan RS, Lee TH, Zhang J, Cook SA (2018) Early regenerative capacity in the porcine heart. Circulation 138(24):2798–2808. https://doi.org/10.1161/CIRCULATIONAHA.117.031542

    Article  PubMed  Google Scholar 

  87. 87.

    Zhu W, Zhang E, Zhao M, Chong Z, Fan C, Tang Y, Hunter JD, Borovjagin AV, Walcott GP, Chen JY, Qin G, Zhang J (2018) Regenerative potential of neonatal porcine hearts. Circulation 138(24):2809–2816. https://doi.org/10.1161/CIRCULATIONAHA.118.034886

    Article  PubMed  Google Scholar 

  88. 88.

    Voges HK, Mills RJ, Elliott DA, Parton RG, Porrello ER, Hudson JE (2017) Development of a human cardiac organoid injury model reveals innate regenerative potential. Development 144(6):1118–1127. https://doi.org/10.1242/dev.143966

    CAS  Article  PubMed  Google Scholar 

  89. 89.

    Lennox KA, Behlke MA (2016) Cellular localization of long non-coding RNAs affects silencing by RNAi more than by antisense oligonucleotides. Nucleic Acids Res 44(2):863–877. https://doi.org/10.1093/nar/gkv1206

    CAS  Article  PubMed  Google Scholar 

  90. 90.

    Stein CA, Castanotto D (2017) FDA-approved oligonucleotide therapies in 2017. Mol Ther 25(5):1069–1075. https://doi.org/10.1016/j.ymthe.2017.03.023

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Collins M, Thrasher A (2015) Gene therapy: progress and predictions. Proc Biol Sci 282(1821):20143003. https://doi.org/10.1098/rspb.2014.3003

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, McIntosh J, Della Peruta M, Lheriteau E, Patel N, Raj D, Riddell A, Pie J, Rangarajan S, Bevan D, Recht M, Shen YM, Halka KG, Basner-Tschakarjan E, Mingozzi F, High KA, Allay J, Kay MA, Ng CY, Zhou J, Cancio M, Morton CL, Gray JT, Srivastava D, Nienhuis AW, Davidoff AM (2014) Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med 371(21):1994–2004. https://doi.org/10.1056/NEJMoa1407309

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, Chowdary P, Riddell A, Pie AJ, Harrington C, O'Beirne J, Smith K, Pasi J, Glader B, Rustagi P, Ng CY, Kay MA, Zhou J, Spence Y, Morton CL, Allay J, Coleman J, Sleep S, Cunningham JM, Srivastava D, Basner-Tschakarjan E, Mingozzi F, High KA, Gray JT, Reiss UM, Nienhuis AW, Davidoff AM (2011) Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 365(25):2357–2365. https://doi.org/10.1056/NEJMoa1108046

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Haemmig S, Feinberg MW (2017) Targeting LncRNAs in cardiovascular disease: options and expeditions. Circ Res 120(4):620–623. https://doi.org/10.1161/CIRCRESAHA.116.310152

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Ha D, Yang N, Nadithe V (2016) Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges. Acta Pharm Sin B 6(4):287–296. https://doi.org/10.1016/j.apsb.2016.02.001

    Article  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Zangi L, Lui KO, von Gise A, Ma Q, Ebina W, Ptaszek LM, Spater D, Xu H, Tabebordbar M, Gorbatov R, Sena B, Nahrendorf M, Briscoe DM, Li RA, Wagers AJ, Rossi DJ, Pu WT, Chien KR (2013) Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nat Biotechnol 31(10):898–907. https://doi.org/10.1038/nbt.2682

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Mahmoud AI, O'Meara CC, Gemberling M, Zhao L, Bryant DM, Zheng R, Gannon JB, Cai L, Choi WY, Egnaczyk GF, Burns CE, Burns CG, MacRae CA, Poss KD, Lee RT (2015) Nerves regulate cardiomyocyte proliferation and heart regeneration. Dev Cell 34(4):387–399. https://doi.org/10.1016/j.devcel.2015.06.017

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Aurora AB, Porrello ER, Tan W, Mahmoud AI, Hill JA, Bassel-Duby R, Sadek HA, Olson EN (2014) Macrophages are required for neonatal heart regeneration. J Clin Invest 124(3):1382–1392. https://doi.org/10.1172/JCI72181

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Boeckel JN, Perret MF, Glaser SF, Seeger T, Heumuller AW, Chen W, John D, Kokot KE, Katus HA, Haas J, Lackner MK, Kayvanpour E, Grabe N, Dieterich C, von Haehling S, Ebner N, Hunecke S, Leuschner F, Fichtlscherer S, Meder B, Zeiher AM, Dimmeler S, Keller T (2018) Identification and regulation of the long non-coding RNA Heat2 in heart failure. J Mol Cell Cardiol 126:13–22. https://doi.org/10.1016/j.yjmcc.2018.11.004

    CAS  Article  PubMed  Google Scholar 

  100. 100.

    Weirick T, Militello G, Uchida S (2018) Long non-coding RNAs in endothelial biology. Front Physiol 9:522. https://doi.org/10.3389/fphys.2018.00522

    Article  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Hou J, Wang L, Wu Q, Zheng G, Long H, Wu H, Zhou C, Guo T, Zhong T, Wang L, Chen X, Wang T (2018) Long noncoding RNA H19 upregulates vascular endothelial growth factor a to enhance mesenchymal stem cells survival and angiogenic capacity by inhibiting miR-199a-5p. Stem Cell Res Ther 9(1):109. https://doi.org/10.1186/s13287-018-0861-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Ounzain S, Pedrazzini T (2015) The promise of enhancer-associated long noncoding RNAs in cardiac regeneration. Trends Cardiovasc Med 25(7):592–602. https://doi.org/10.1016/j.tcm.2015.01.014

    CAS  Article  PubMed  Google Scholar 

  103. 103.

    Gomes CPC, Salgado-Somoza A, Creemers EE, Dieterich C, Lustrek M, Devaux Y, Cardiolinc n (2018) Circular RNAs in the cardiovascular system. Noncoding RNA Res 3 (1):1–11. doi:https://doi.org/10.1016/j.ncrna.2018.02.002

Download references

Acknowledgments

I would like to express my deepest appreciation to Abdelaziz AI for his guidance and continuous support.

Funding

None.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Abdel Rahman Yousry Afify.

Ethics declarations

Conflict of interest

None to declare.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Afify, A.R.Y. The long non-coding road to endogenous cardiac regeneration. Heart Fail Rev 24, 587–600 (2019). https://doi.org/10.1007/s10741-019-09782-5

Download citation

Keywords

  • Long non-coding RNAs
  • Epigenetics
  • Cardiac regeneration
  • Heart failure
  • Cardiomyocyte proliferation