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Genome Editing and Induced Pluripotent Stem Cell Technologies for Personalized Study of Cardiovascular Diseases

  • Regenerative Medicine (SM Wu, Section Editor)
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Abstract

Purpose of Review

The goal of this review is to highlight the potential of induced pluripotent stem cell (iPSC)-based modeling as a tool for studying human cardiovascular diseases. We present some of the current cardiovascular disease models utilizing genome editing and patient-derived iPSCs.

Recent Findings

The incorporation of genome-editing and iPSC technologies provides an innovative research platform, providing novel insight into human cardiovascular disease at molecular, cellular, and functional level. In addition, genome editing in diseased iPSC lines holds potential for personalized regenerative therapies.

Summary

The study of human cardiovascular disease has been revolutionized by cellular reprogramming and genome editing discoveries. These exceptional technologies provide an opportunity to generate human cell cardiovascular disease models and enable therapeutic strategy development in a dish. We anticipate these technologies to improve our understanding of cardiovascular disease pathophysiology leading to optimal treatment for heart diseases in the future.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Gharib WH, Robinson-Rechavi M. When orthologs diverge between human and mouse. Brief Bioinform. 2011;12(5):436–41.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Dixon JA, Spinale FG. Large animal models of heart failure a critical link in the translation of basic science to clinical practice. Circ Heart Fail. 2009;2(3):262–71.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Moon A. Mouse models of congenital cardiovascular disease. Curr Top Dev Biol. 2008;84:171–248.

    Article  PubMed  CAS  Google Scholar 

  4. Ostergaard GH, Hansen HN, Ottesen JL. Physiological, hematological, and clinical chemistry parameters, including conversion factors. In: Hau J, Schapiro SJ, editors. Handbook of laboratory animal science, vol. 1. 3rd ed. Boca Raton: CRC press; 2010. p. 40.

    Google Scholar 

  5. Szentadrassy N, Banyasz T, Biro T, Szabo G, Toth BI, Magyar J, et al. Apico-basal inhomogeneity in distribution of ion channels in canine and human ventricular myocardium. Cardiovasc Res. 2005;65(4):851–60.

    Article  PubMed  CAS  Google Scholar 

  6. Zicha S, Ling X, Stafford S, Cha TJ, Wei H, Varro A, et al. Transmural expression of transient outward potassium current subunits in normal and failing canine and human hearts. J Physiol London. 2004;561(3):735–48.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Milani-Nejad N, Janssen PM. Small and large animal models in cardiac contraction research: advantages and disadvantages. Pharmacol Ther. 2014;141(3):235–49.

    Article  PubMed  CAS  Google Scholar 

  8. Camacho PF, Liu H, He Z. J. Large mammalian animal models of heart disease. J Cardiovasc Dev Dis. 2016;3(30):11.

    Google Scholar 

  9. Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292(5819):154–6.

    Article  PubMed  CAS  Google Scholar 

  10. Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci U S A. 1981;78(12):7634–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145–7.

    Article  PubMed  CAS  Google Scholar 

  12. Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature. 2007;448(7151):313–U1.

    Article  PubMed  CAS  Google Scholar 

  13. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.

    Article  PubMed  CAS  Google Scholar 

  14. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.

    Article  PubMed  CAS  Google Scholar 

  15. Plath K, Lowry WE. Progress in understanding reprogramming to the induced pluripotent state. Nat Rev Genet. 2011;12(4):253–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Burnett LC, LeDuc CA, Sulsona CR, Paull D, Eddiry S, Levy B, et al. Induced pluripotent stem cells (iPSC) created from skin fibroblasts of patients with Prader-Willi syndrome (PWS) retain the molecular signature of PWS. Stem Cell Res. 2016;17(3):526–30.

    Article  PubMed  CAS  Google Scholar 

  17. Lee HK, Morin P, Xia W. Peripheral blood mononuclear cell-converted induced pluripotent stem cells (iPSCs) from an early onset Alzheimer’s patient. Stem Cell Res. 2016;16(2):213–5.

    Article  PubMed  CAS  Google Scholar 

  18. Shi L, Cui Y, Luan J, Zhou X, Han J. Urine-derived induced pluripotent stem cells as a modeling tool to study rare human diseases. Intractable Rare Dis Res. 2016;5(3):192–201.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Jia FJ, Wilson KD, Sun N, Gupta DM, Huang M, Li ZJ, et al. A nonviral minicircle vector for deriving human iPS cells. Nat Methods. 2010;7(3):197–U46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Yu J. Human induced pluripotent stem cells free of vector and transgene sequences (vol 324, pg 797, 2009). Science. 2009;324(5932):1266.

    Article  CAS  Google Scholar 

  21. Itzhaki I, Maizels L, Huber I, Zwi-Dantsis L, Caspi O, Winterstern A, et al. Modelling the long QT syndrome with induced pluripotent stem cells. Nature. 2011;471(7337):225–9.

    Article  PubMed  CAS  Google Scholar 

  22. Moretti A, Bellin M, Welling A, Jung CB, Lam JT, Bott-Flugel L, et al. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N Engl J Med. 2010;363(15):1397–409.

    Article  PubMed  CAS  Google Scholar 

  23. Lu JT, Kass RS. Recent progress in congenital long QT syndrome. Curr Opin Cardiol. 2010;25(3):216–21.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Moss AJ. The QT interval and torsade de pointes. Drug Saf. 1999;21(Suppl 1):5–10. discussion 81-7

    Article  PubMed  CAS  Google Scholar 

  25. Schulze-Bahr E, Wedekind H, Haverkamp W, Borggrefe M, Assmann G, Breithardt G, et al. The LQT syndromes--current status of molecular mechanisms. Z Kardiol. 1999;88(4):245–54.

    Article  PubMed  CAS  Google Scholar 

  26. Yang T, Chun YW, Stroud DM, Mosley JD, Knollmann BC, Hong C, et al. Screening for acute IKr block is insufficient to detect torsades de pointes liability: role of late sodium current. Circulation. 2014;130(3):224–34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Del Rosario ME, Weachter R, Flaker GC. Drug-induced QT prolongation and sudden death. Mo Med. 2010;107(1):53–8.

    PubMed  Google Scholar 

  28. Jouni M, Si-Tayeb K, Es-Salah-Lamoureux Z, Latypova X, Champon B, Caillaud A, et al. Toward personalized medicine: using cardiomyocytes differentiated from urine-derived pluripotent stem cells to recapitulate electrophysiological characteristics of type 2 long QT syndrome. J Am Heart Assoc. 2015;4(9):e002159.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Rocchetti M, Sala L, Dreizehnter L, Crotti L, Sinnecker D, Mura M, et al. Elucidating arrhythmogenic mechanisms of long-QT syndrome CALM1-F142L mutation in patient-specific induced pluripotent stem cell-derived cardiomyocytes. Cardiovasc Res. 2017;113(5):531–41.

    Article  PubMed  CAS  Google Scholar 

  30. Sun N, Yazawa M, Liu J, Han L, Sanchez-Freire V, Abilez OJ, et al. Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy. Sci Transl Med. 2012;4(130):130ra47.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kodo K, Ong SG, Jahanbani F, Termglinchan V, Hirono K, InanlooRahatloo K, et al. iPSC-derived cardiomyocytes reveal abnormal TGF-beta signalling in left ventricular non-compaction cardiomyopathy. Nat Cell Biol. 2016;18(10):1031–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Seidman JG, Seidman C. The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms. Cell. 2001;104(4):557–67.

    Article  PubMed  CAS  Google Scholar 

  33. Lan F, Lee AS, Liang P, Sanchez-Freire V, Nguyen PK, Wang L, et al. Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells. Cell Stem Cell. 2013;12(1):101–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339(6121):819–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Ishibashi S, Love NR, Amaya E. A simple method of transgenesis using I-SceI meganuclease in Xenopus. Methods Mol Biol. 2012;917:205–18.

    Article  PubMed  CAS  Google Scholar 

  36. Urnov FD, Rebar EJ, Holmes MC, Zhang HS, Gregory PD. Genome editing with engineered zinc finger nucleases. Nat Rev Genet. 2010;11(9):636–46.

    Article  PubMed  CAS  Google Scholar 

  37. Hentze MW, Kulozik AE. A perfect message: RNA surveillance and nonsense-mediated decay. Cell. 1999;96(3):307–10.

    Article  PubMed  CAS  Google Scholar 

  38. Boissel S, Jarjour J, Astrakhan A, Adey A, Gouble A, Duchateau P, et al. megaTALs: a rare-cleaving nuclease architecture for therapeutic genome engineering. Nucleic Acids Res. 2014;42(4):2591–601.

    Article  PubMed  CAS  Google Scholar 

  39. Smith J, Grizot S, Arnould S, Duclert A, Epinat JC, Chames P, et al. A combinatorial approach to create artificial homing endonucleases cleaving chosen sequences. Nucleic Acids Res. 2006;34(22):e149.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Miller JC, Holmes MC, Wang J, Guschin DY, Lee YL, Rupniewski I, et al. An improved zinc-finger nuclease architecture for highly specific genome editing. Nature Biotechnol. 2007;25(7):778–85.

    Article  CAS  Google Scholar 

  41. Urnov FD, Miller JC, Lee YL, Beausejour CM, Rock JM, Augustus S, et al. Highly efficient endogenous human gene correction using designed zinc-finger nucleases. Nature. 2005;435(7042):646–51.

    Article  PubMed  CAS  Google Scholar 

  42. Boch J, Scholze H, Schornack S, Landgraf A, Hahn S, Kay S, et al. Breaking the code of DNA binding specificity of TAL-type III effectors. Science. 2009;326(5959):1509–12.

    Article  PubMed  CAS  Google Scholar 

  43. Mahfouz MM, Li L, Shamimuzzaman M, Wibowo A, Fang X, Zhu JK. De novo-engineered transcription activator-like effector (TALE) hybrid nuclease with novel DNA binding specificity creates double-strand breaks. Proc Natl Acad Sci U S A. 2011;108(6):2623–8.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, et al. RNA-guided human genome engineering via Cas9. Science. 2013;339(6121):823–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Sapranauskas R, Gasiunas G, Fremaux C, Barrangou R, Horvath P, Siksnys V. The Streptococcus thermophilus CRISPR/Cas system provides immunity in Escherichia coli. Nucleic Acids Res. 2011;39(21):9275–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. Genome engineering using the CRISPR-Cas9 system. Nat Protoc. 2013;8(11):2281–308.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Richardson CD, Ray GJ, Bray NL, Corn JE. Non-homologous DNA increases gene disruption efficiency by altering DNA repair outcomes. Nat Commun. 2016;7:12463.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Hess GT, Tycko J, Yao D, Bassik MC. Methods and applications of CRISPR-mediated base editing in eukaryotic genomes. Mol Cell. 2017;68(1):26–43.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  49. •• Kim YB, Komor AC, Levy JM, Packer MS, Zhao KT, Liu DR. Increasing the genome-targeting scope and precision of base editing with engineered Cas9-cytidine deaminase fusions. Nature Biotechnol. 2017;35(4):371–6. This study reported an important technical advance that substantially increased the efficiency and precision of genome editing.

    Article  CAS  Google Scholar 

  50. Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature. 2016;533(7603):420–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Blair E, Redwood C, Ashrafian H, Oliveira M, Broxholme J, Kerr B, et al. Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis. Hum Mol Genet. 2001;10(11):1215–20.

    Article  PubMed  CAS  Google Scholar 

  52. Arad M, Seidman CE, Seidman JG. AMP-activated protein kinase in the heart: role during health and disease. Circ Res. 2007;100(4):474–88.

    Article  PubMed  CAS  Google Scholar 

  53. Ben Jehuda R, Eisen B, Shemer Y, Mekies LN, Szantai A, Reiter I, et al. CRISPR correction of the PRKAG2 gene mutation in a patient’s induced pluripotent stem cell-derived cardiomyocytes eliminates electrophysiological and structural abnormalities. Heart Rhythm. 2017;15(2):267–76.

    Article  PubMed  Google Scholar 

  54. • Granata A, Serrano F, Bernard WG, McNamara M, Low L, Sastry P, et al. An iPSC-derived vascular model of Marfan syndrome identifies key mediators of smooth muscle cell death. Nat Genet. 2017;49(1):97–109. Using iPSC-based cell models and genome editing, this study identified key mediators of Marfan syndrome pathophysiology as well as potential therapeutic strategy.

    Article  PubMed  CAS  Google Scholar 

  55. Hinson JT, Nakamura K, Wu SM. Induced pluripotent stem cell modeling of complex genetic diseases. Drug Discov Today Dis Models. 2012;9(4):e147–e52.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Strauss DG, Vicente J, Johannesen L, Blinova K, Mason JW, Weeke P, et al. Common genetic variant risk score is associated with drug-induced qt prolongation and torsade de pointes risk: a pilot study. Circulation. 2017;135(14):1300–10.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Chun YW, Voyles DE, Rath R, Hofmeister LH, Boire TC, Wilcox H, et al. Differential responses of induced pluripotent stem cell-derived cardiomyocytes to anisotropic strain depends on disease status. J Biomechan. 2015;48(14):3890–6.

    Article  Google Scholar 

  58. • Feaster TK, Cadar AG, Wang L, Williams CH, Chun YW, Hempel JE, et al. Matrigel mattress: a method for the generation of single contracting human-induced pluripotent stem cell-derived cardiomyocytes. Circulation Res. 2015;117(12):995–1000. This study describes a relatively simple method to rapidly promote human iPSC-CM maturation for functional evaluation of patient-specific cardiomyocytes.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Chun YW, Balikov DA, Feaster TK, Williams CH, Sheng CC, Lee JB, et al. Combinatorial polymer matrices enhance in vitro maturation of human induced pluripotent stem cell-derived cardiomyocytes. Biomaterials. 2015;67:52–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

This work was supported by the National Institutes of Health grants 5R01HL104040, 5R01HL095813, and P50GM115305 to C.C.H. and by UL1TR000445 from the National Center for Advancing Translational Sciences.

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Correspondence to Charles C. Hong.

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Young Wook Chun, Matthew D. Durbin, and Charles C. Hong declare that they have no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Chun, Y.W., Durbin, M.D. & Hong, C.C. Genome Editing and Induced Pluripotent Stem Cell Technologies for Personalized Study of Cardiovascular Diseases. Curr Cardiol Rep 20, 38 (2018). https://doi.org/10.1007/s11886-018-0984-9

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