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Disease Modeling and Drug Development with DM1 Patient-Derived iPS Cells

  • Toshiyuki ArakiEmail author
  • Masayoshi Kamon
  • Hidetoshi Sakurai
Chapter
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Abstract

Since generation of induced pluripotent stem cells (iPSCs) was first reported in human in 2007, application of the technology to generate iPSCs has been applied to basic research on pathogenic mechanism of human diseases as well as development of regeneration therapy. For the former application, iPSCs generated from cell/tissue samples obtained from patients, particularly of inherited disorders, have been used for modeling diseases in cellular levels and drug screening by using the disease model developed with iPSCs generated from patient samples. Among a number of genetically inherited disorders, type 1 myotonic dystrophy (DM1) is well suitable for disease modeling studies using iPSCs derived from patients’ cells/tissues. In this chapter, previous research applications of iPSCs generated from DM1 patients’ cells/tissues are reviewed, and potentials of DM1 patient-derived iPSCs as a powerful tool for DM1 pathogenesis research and drug development against DM1 are discussed.

Keywords

Induced pluripotent stem cells (iPSCs) Trinucleotide repeat RNA toxicity Repeat instability Dystrophia myotonica protein kinase (DMPK) Mismatch repair Muscleblind-like 1 (MBNL1) 

References

  1. 1.
    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.CrossRefGoogle Scholar
  2. 2.
    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.CrossRefGoogle Scholar
  3. 3.
    Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, et al. Disease-specific induced pluripotent stem cells. Cell. 2008;134(5):877–86.CrossRefGoogle Scholar
  4. 4.
    Tiscornia G, Vivas EL, Izpisua Belmonte JC. Diseases in a dish: modeling human genetic disorders using induced pluripotent cells. Nat Med. 2011;17(12):1570–6.CrossRefGoogle Scholar
  5. 5.
    Han SS, Williams LA, Eggan KC. Constructing and deconstructing stem cell models of neurological disease. Neuron. 2011;70(4):626–44.CrossRefGoogle Scholar
  6. 6.
    Campbell KA, Terzic A, Nelson TJ. Induced pluripotent stem cells for cardiovascular disease: from product-focused disease modeling to process-focused disease discovery. Regen Med. 2015;10(6):773–83.CrossRefGoogle Scholar
  7. 7.
    Lam AQ, Freedman BS, Bonventre JV. Directed differentiation of pluripotent stem cells to kidney cells. Semin Nephrol. 2014;34(4):445–61.CrossRefGoogle Scholar
  8. 8.
    Arai S, Miyauchi M, Kurokawa M. Modeling of hematologic malignancies by iPS technology. Exp Hematol. 2015;43(8):654–60.CrossRefGoogle Scholar
  9. 9.
    Barruet E, Hsiao EC. Using human induced pluripotent stem cells to model skeletal diseases. Methods Mol Biol. 2016;1353:101–18.CrossRefGoogle Scholar
  10. 10.
    Hotta A, Yamanaka S. From genomics to gene therapy: induced pluripotent stem cells meet genome editing. Annu Rev Genet. 2015;49:47–70.CrossRefGoogle Scholar
  11. 11.
    Huard J, Cao B, Qu-Petersen Z. Muscle-derived stem cells: potential for muscle regeneration. Birth Defects Res C Embryo Today. 2003;69(3):230–7.CrossRefGoogle Scholar
  12. 12.
    Bird T. Myotonic dystrophy type 1. Seattle, WA: University of Washington, Seattle; 1993–2017.Google Scholar
  13. 13.
    Dalton JC, Ranum RPW, Day JW. Myotonic dystrophy type 2. GeneReviews. 1993–2017.Google Scholar
  14. 14.
    Thornton CA. Myotonic dystrophy. Neurol Clin. 2014;32(3):705–19. viiiCrossRefGoogle Scholar
  15. 15.
    Turner C, Hilton-Jones D. Myotonic dystrophy: diagnosis, management and new therapies. Curr Opin Neurol. 2014;27(5):599–606.CrossRefGoogle Scholar
  16. 16.
    de Die-Smulders CE, Howeler CJ, Thijs C, Mirandolle JF, Anten HB, Smeets HJ, et al. Age and causes of death in adult-onset myotonic dystrophy. Brain. 1998;121(Pt 8):1557–63.CrossRefGoogle Scholar
  17. 17.
    Mathieu J, Allard P, Potvin L, Prevost C, Begin P. A 10-year study of mortality in a cohort of patients with myotonic dystrophy. Neurology. 1999;52(8):1658–62.CrossRefGoogle Scholar
  18. 18.
    Barberi T, Bradbury M, Dincer Z, Panagiotakos G, Socci ND, Studer L. Derivation of engraftable skeletal myoblasts from human embryonic stem cells. Nat Med. 2007;13(5):642–8.CrossRefGoogle Scholar
  19. 19.
    Mahmood A, Harkness L, Schroder HD, Abdallah BM, Kassem M. Enhanced differentiation of human embryonic stem cells to mesenchymal progenitors by inhibition of TGF-beta/activin/nodal signaling using SB-431542. J Bone Miner Res. 2010;25(6):1216–33.CrossRefGoogle Scholar
  20. 20.
    Darabi R, Arpke RW, Irion S, Dimos JT, Grskovic M, Kyba M, et al. Human ES- and iPS-derived myogenic progenitors restore DYSTROPHIN and improve contractility upon transplantation in dystrophic mice. Cell Stem Cell. 2012;10(5):610–9.CrossRefGoogle Scholar
  21. 21.
    Davis RL, Weintraub H, Lassar AB. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell. 1987;51(6):987–1000.CrossRefGoogle Scholar
  22. 22.
    Mizuno H, Zuk PA, Zhu M, Lorenz HP, Benhaim P, Hedrick MH. Myogenic differentiation by human processed lipoaspirate cells. Plast Reconstr Surg. 2002;109(1):199–209; discussion 210–1CrossRefGoogle Scholar
  23. 23.
    Tapscott SJ, Davis RL, Thayer MJ, Cheng PF, Weintraub H, Lassar AB. MyoD1: a nuclear phosphoprotein requiring a Myc homology region to convert fibroblasts to myoblasts. Science. 1988;242(4877):405–11.CrossRefGoogle Scholar
  24. 24.
    Gianakopoulos PJ, Mehta V, Voronova A, Cao Y, Yao Z, Coutu J, et al. MyoD directly up-regulates premyogenic mesoderm factors during induction of skeletal myogenesis in stem cells. J Biol Chem. 2011;286(4):2517–25.CrossRefGoogle Scholar
  25. 25.
    Warren L, Manos PD, Ahfeldt T, Loh YH, Li H, Lau F, et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell. 2010;7(5):618–30.CrossRefGoogle Scholar
  26. 26.
    Goudenege S, Lebel C, Huot NB, Dufour C, Fujii I, Gekas J, et al. Myoblasts derived from normal hESCs and dystrophic hiPSCs efficiently fuse with existing muscle fibers following transplantation. Mol Ther. 2012;20(11):2153–67.CrossRefGoogle Scholar
  27. 27.
    Ozasa S, Kimura S, Ito K, Ueno H, Ikezawa M, Matsukura M, et al. Efficient conversion of ES cells into myogenic lineage using the gene-inducible system. Biochem Biophys Res Commun. 2007;357(4):957–63.CrossRefGoogle Scholar
  28. 28.
    Tanaka A, Woltjen K, Miyake K, Hotta A, Ikeya M, Yamamoto T, et al. Efficient and reproducible myogenic differentiation from human iPS cells: prospects for modeling Miyoshi myopathy in vitro. PLoS One. 2013;8(4):e61540.CrossRefGoogle Scholar
  29. 29.
    Darabi R, Perlingeiro RC. Derivation of skeletal myogenic precursors from human pluripotent stem cells using conditional expression of PAX7. Methods Mol Biol. 2016;1357:423–39.CrossRefGoogle Scholar
  30. 30.
    Akiyama T, Wakabayashi S, Soma A, Sato S, Nakatake Y, Oda M, et al. Transient ectopic expression of the histone demethylase JMJD3 accelerates the differentiation of human pluripotent stem cells. Development. 2016;143(20):3674–85.CrossRefGoogle Scholar
  31. 31.
    Albini S, Puri PL. Generation of myospheres from hESCs by epigenetic reprogramming. J Vis Exp. 2014;88:e51243.Google Scholar
  32. 32.
    Chal J, Oginuma M, Al Tanoury Z, Gobert B, Sumara O, Hick A, et al. Differentiation of pluripotent stem cells to muscle fiber to model Duchenne muscular dystrophy. Nat Biotechnol. 2016;33(9):962–9.CrossRefGoogle Scholar
  33. 33.
    Caron L, Kher D, Lee KL, McKernan R, Dumevska B, Hidalgo A, et al. A human pluripotent stem cell model of facioscapulohumeral muscular dystrophy-affected skeletal muscles. Stem Cells Transl Med. 2016;5(9):1145–61.CrossRefGoogle Scholar
  34. 34.
    Moxley RT, Meola G. The myotonic dystrophies. Philadelphia, PA: Wolters Kluwer; 2008.Google Scholar
  35. 35.
    Monckton DG, Wong LJ, Ashizawa T, Caskey CT. Somatic mosaicism, germline expansions, germline reversions and intergenerational reductions in myotonic dystrophy males: small pool PCR analyses. Hum Mol Genet. 1995;4(1):1–8.CrossRefGoogle Scholar
  36. 36.
    Ashizawa T, Anvret M, Baiget M, Barcelo JM, Brunner H, Cobo AM, et al. Characteristics of intergenerational contractions of the CTG repeat in myotonic dystrophy. Am J Hum Genet. 1994;54(3):414–23.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Musova Z, Mazanec R, Krepelova A, Ehler E, Vales J, Jaklova R, et al. Highly unstable sequence interruptions of the CTG repeat in the myotonic dystrophy gene. Am J Med Genet A. 2009;149A(7):1365–74.CrossRefGoogle Scholar
  38. 38.
    Panigrahi GB, Lau R, Montgomery SE, Leonard MR, Pearson CE. Slipped (CTG)*(CAG) repeats can be correctly repaired, escape repair or undergo error-prone repair. Nat Struct Mol Biol. 2005;12(8):654–62.CrossRefGoogle Scholar
  39. 39.
    Dion V. Tissue specificity in DNA repair: lessons from trinucleotide repeat instability. Trends Genet. 2014;30(6):220–9.CrossRefGoogle Scholar
  40. 40.
    Du J, Campau E, Soragni E, Jespersen C, Gottesfeld JM. Length-dependent CTG.CAG triplet-repeat expansion in myotonic dystrophy patient-derived induced pluripotent stem cells. Hum Mol Genet. 2013;22(25):5276–87.CrossRefGoogle Scholar
  41. 41.
    Gomes-Pereira M, Bidichandani SI, Monckton DG. Analysis of unstable triplet repeats using small-pool polymerase chain reaction. Methods Mol Biol. 2004;277:61–76.PubMedGoogle Scholar
  42. 42.
    Ueki J, Nakamori M, Nakamura M, Nishikawa M, Yoshida Y, Tanaka A, et al. Myotonic dystrophy type 1 patient-derived iPSCs for the investigation of CTG repeat instability. Sci Rep. 2017;7:42522.CrossRefGoogle Scholar
  43. 43.
    Pearson CE, Nichol Edamura K, Cleary JD. Repeat instability: mechanisms of dynamic mutations. Nat Rev Genet. 2005;6(10):729–42.CrossRefGoogle Scholar
  44. 44.
    Yum K, Wang ET, Kalsotra A. Myotonic dystrophy: disease repeat range, penetrance, age of onset, and relationship between repeat size and phenotypes. Curr Opin Genet Dev. 2017;44:30–7.CrossRefGoogle Scholar
  45. 45.
    Savouret C, Brisson E, Essers J, Kanaar R, Pastink A, te Riele H, et al. CTG repeat instability and size variation timing in DNA repair-deficient mice. EMBO J. 2003;22(9):2264–73.CrossRefGoogle Scholar
  46. 46.
    Savouret C, Garcia-Cordier C, Megret J, te Riele H, Junien C, Gourdon G. MSH2-dependent germinal CTG repeat expansions are produced continuously in spermatogonia from DM1 transgenic mice. Mol Cell Biol. 2004;24(2):629–37.CrossRefGoogle Scholar
  47. 47.
    van den Broek WJ, Nelen MR, Wansink DG, Coerwinkel MM, te Riele H, Groenen PJ, et al. Somatic expansion behaviour of the (CTG)n repeat in myotonic dystrophy knock-in mice is differentially affected by Msh3 and Msh6 mismatch-repair proteins. Hum Mol Genet. 2002;11(2):191–8.CrossRefGoogle Scholar
  48. 48.
    Wheeler VC, Lebel LA, Vrbanac V, Teed A, te Riele H, MacDonald ME. Mismatch repair gene Msh2 modifies the timing of early disease in Hdh(Q111) striatum. Hum Mol Genet. 2003;12(3):273–81.CrossRefGoogle Scholar
  49. 49.
    Manley K, Shirley TL, Flaherty L, Messer A. Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice. Nat Genet. 1999;23(4):471–3.CrossRefGoogle Scholar
  50. 50.
    Bellin M, Mummery CL. Inherited heart disease—what can we expect from the second decade of human iPS cell research? FEBS Lett. 2016;590(15):2482–93.CrossRefGoogle Scholar
  51. 51.
    Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani H, et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member. Cell. 1992;68(4):799–808.CrossRefGoogle Scholar
  52. 52.
    Otten AD, Tapscott SJ. Triplet repeat expansion in myotonic dystrophy alters the adjacent chromatin structure. Proc Natl Acad Sci U S A. 1995;92(12):5465–9.CrossRefGoogle Scholar
  53. 53.
    Jansen G, Groenen PJ, Bachner D, Jap PH, Coerwinkel M, Oerlemans F, et al. Abnormal myotonic dystrophy protein kinase levels produce only mild myopathy in mice. Nat Genet. 1996;13(3):316–24.CrossRefGoogle Scholar
  54. 54.
    Davis BM, McCurrach ME, Taneja KL, Singer RH, Housman DE. Expansion of a CUG trinucleotide repeat in the 3′ untranslated region of myotonic dystrophy protein kinase transcripts results in nuclear retention of transcripts. Proc Natl Acad Sci U S A. 1997;94(14):7388–93.CrossRefGoogle Scholar
  55. 55.
    Klesert TR, Cho DH, Clark JI, Maylie J, Adelman J, Snider L, et al. Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy. Nat Genet. 2000;25(1):105–9.CrossRefGoogle Scholar
  56. 56.
    Mahadevan MS, Yadava RS, Yu Q, Balijepalli S, Frenzel-McCardell CD, Bourne TD, et al. Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy. Nat Genet. 2006;38(9):1066–70.CrossRefGoogle Scholar
  57. 57.
    Carrell ST, Carrell EM, Auerbach D, Pandey SK, Bennett CF, Dirksen RT, et al. Dmpk gene deletion or antisense knockdown does not compromise cardiac or skeletal muscle function in mice. Hum Mol Genet. 2016;25(19):4328–38.CrossRefGoogle Scholar
  58. 58.
    Gao Z, Cooper TA. Antisense oligonucleotides: rising stars in eliminating RNA toxicity in myotonic dystrophy. Hum Gene Ther. 2013;24(5):499–507.CrossRefGoogle Scholar
  59. 59.
    Xia G, Gao Y, Jin S, Subramony SH, Terada N, Ranum LP, et al. Genome modification leads to phenotype reversal in human myotonic dystrophy type 1 induced pluripotent stem cell-derived neural stem cells. Stem Cells. 2015;33(6):1829–38.CrossRefGoogle Scholar
  60. 60.
    Coonrod LA, Nakamori M, Wang W, Carrell S, Hilton CL, Bodner MJ, et al. Reducing levels of toxic RNA with small molecules. ACS Chem Biol. 2013;8(11):2528–37.CrossRefGoogle Scholar
  61. 61.
    Warf MB, Nakamori M, Matthys CM, Thornton CA, Berglund JA. Pentamidine reverses the splicing defects associated with myotonic dystrophy. Proc Natl Acad Sci U S A. 2009;106(44):18551–6.CrossRefGoogle Scholar
  62. 62.
    Siboni RB, Bodner MJ, Khalifa MM, Docter AG, Choi JY, Nakamori M, et al. Biological efficacy and toxicity of diamidines in myotonic dystrophy type 1 models. J Med Chem. 2015;58(15):5770–80.CrossRefGoogle Scholar
  63. 63.
    Childs-Disney JL, Parkesh R, Nakamori M, Thornton CA, Disney MD. Rational design of bioactive, modularly assembled aminoglycosides targeting the RNA that causes myotonic dystrophy type 1. ACS Chem Biol. 2012;7(12):1984–93.CrossRefGoogle Scholar
  64. 64.
    Nakamori M, Taylor K, Mochizuki H, Sobczak K, Takahashi MP. Oral administration of erythromycin decreases RNA toxicity in myotonic dystrophy. Ann Clin Transl Neurol. 2016;3(1):42–54.CrossRefGoogle Scholar
  65. 65.
    Childs-Disney JL, Hoskins J, Rzuczek SG, Thornton CA, Disney MD. Rationally designed small molecules targeting the RNA that causes myotonic dystrophy type 1 are potently bioactive. ACS Chem Biol. 2012;7(5):856–62.CrossRefGoogle Scholar
  66. 66.
    Orengo JP, Bundman D, Cooper TA. A bichromatic fluorescent reporter for cell-based screens of alternative splicing. Nucleic Acids Res. 2006;34(22):e148.CrossRefGoogle Scholar
  67. 67.
    O’Leary DA, Vargas L, Sharif O, Garcia ME, Sigal YJ, Chow SK, et al. HTS-compatible patient-derived cell-based assay to identify small molecule modulators of aberrant splicing in myotonic dystrophy type 1. Curr Chem Genomics. 2010;4:9–18.CrossRefGoogle Scholar
  68. 68.
    Chen HY, Kathirvel P, Yee WC, Lai PS. Correction of dystrophia myotonica type 1 pre-mRNA transcripts by artificial trans-splicing. Gene Ther. 2009;16(2):211–7.CrossRefGoogle Scholar
  69. 69.
    Okita K, Matsumura Y, Sato Y, Okada A, Morizane A, Okamoto S, et al. A more efficient method to generate integration-free human iPS cells. Nat Methods. 2011;8(5):409–12.CrossRefGoogle Scholar
  70. 70.
    Fujioka T, Yasuchika K, Nakamura Y, Nakatsuji N, Suemori H. A simple and efficient cryopreservation method for primate embryonic stem cells. Int J Dev Biol. 2004;48(10):1149–54.CrossRefGoogle Scholar
  71. 71.
    Takahashi K, Okita K, Nakagawa M, Yamanaka S. Induction of pluripotent stem cells from fibroblast cultures. Nat Protoc. 2007;2(12):3081–9.CrossRefGoogle Scholar
  72. 72.
    Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin II, et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science. 2009;324(5928):797–801.CrossRefGoogle Scholar
  73. 73.
    Tanabe K, Nakamura M, Narita M, Takahashi K, Yamanaka S. Maturation, not initiation, is the major roadblock during reprogramming toward pluripotency from human fibroblasts. Proc Natl Acad Sci U S A. 2013;110(30):12172–9.CrossRefGoogle Scholar
  74. 74.
    Morizane A, Doi D, Takahashi J. Neural induction with a dopaminergic phenotype from human pluripotent stem cells through a feeder-free floating aggregation culture. Methods Mol Biol. 2013;1018:11–9.CrossRefGoogle Scholar
  75. 75.
    Funakoshi S, Miki K, Takaki T, Okubo C, Hatani T, Chonabayashi K, et al. Enhanced engraftment, proliferation, and therapeutic potential in heart using optimized human iPSC-derived cardiomyocytes. Sci Rep. 2016;6:19111.CrossRefGoogle Scholar
  76. 76.
    Nakamori M, Sobczak K, Puwanant A, Welle S, Eichinger K, Pandya S, et al. Splicing biomarkers of disease severity in myotonic dystrophy. Ann Neurol. 2013;74(6):862–72.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Toshiyuki Araki
    • 1
    Email author
  • Masayoshi Kamon
    • 1
  • Hidetoshi Sakurai
    • 2
  1. 1.Department of Peripheral Nervous System ResearchNational Institute of Neuroscience, National Center of Neurology and PsychiatryTokyoJapan
  2. 2.Center for iPS Cell Research and Application (CiRA)Kyoto UniversityKyotoJapan

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