Export file:


  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text


  • Citation Only
  • Citation and Abstract

Human Mutations Affecting Reprogramming into Induced Pluripotent Stem Cells

Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan

Special Issue: iPS Cell Technologies in Human Diseases

The development of induced pluripotent stem cells (iPSCs) provides unprecedented opportunities for life sciences, drug discovery, and regenerative medicine. iPSCs have been generated from somatic cells in many patients with various genetic diseases carrying specific mutations. However, the efficiency of iPSC generation is quite low. Less than 1% of human primary somatic cells can usually turn into iPSCs. Previous studies have revealed that cellular signaling pathways, epigenetic status, and cellular senescence were major barriers to iPSC generation. Serendipitously in some cases, human mutations themselves affect the reprogramming efficiency of iPSC generation as well as cellular phenotypes recapitulating their disease symptoms. Mutations, which cause altered DNA repair (e.g., Ataxia-Telangiectasia, fanconi anemia and DNA Ligase IV (LIG4) syndrome), premature aging (e.g., Hutchinson–Gilford progeria syndrome and Néstor–Guillermo progeria syndrome), altered telomere homeostasis (e.g., dyskeratosis congenita), mitochondrial respiratory dysfunction, chromosomal abnormalities, and fibrodysplasia ossificans progressiva, have all been shown to affect the reprogramming efficiency of somatic cells to iPSCs. In this review, the effects of such mutations are summarized and the methods which have been employed to rescue efficient iPSC generation from mutant cells is discussed. Although the mutations affecting reprogramming processes are rare, these mutations have been invaluable to the elucidation of reprogramming mechanisms and to the development of improved reprogramming technologies.
  Article Metrics


1. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126: 663-676.    

2. Takahashi K, Tanabe K, Ohnuki M, et al. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131: 861-872.    

3. Yamanaka S (2009) Elite and stochastic models for induced pluripotent stem cell generation. Nature 460: 49-52.    

4. Ichida JK, Blanchard J, Lam K, et al. (2009) A small-molecule inhibitor of tgf-beta signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem Cell 5: 491-503.    

5. Lin T, Ambasudhan R, Yuan X, et al. (2009) A chemical platform for improved induction of human iPSCs. Nat Methods 6: 805-808.    

6. Maherali N, Sridharan R, Xie W, et al. (2007) Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1: 55-70.    

7. Kim K, Doi A, Wen B, et al. (2010) Epigenetic memory in induced pluripotent stem cells. Nature 467: 285-290.    

8. Carey BW, Markoulaki S, Hanna JH, et al. (2011) Reprogramming factor stoichiometry influences the epigenetic state and biological properties of induced pluripotent stem cells. Cell Stem Cell 9: 588-598.    

9. Kawamura T, Suzuki J, Wang YV, et al. (2009) Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature 460: 1140-1144.    

10. Hong H, Takahashi K, Ichisaka T, et al. (2009) Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Nature 460: 1132-1135.    

11. Li H, Collado M, Villasante A, et al. (2009) The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 460: 1136-1139.    

12. Banito A, Rashid ST, Acosta JC, et al. (2009) Senescence impairs successful reprogramming to pluripotent stem cells. Genes Dev 23: 2134-2139.    

13. Marion RM, Strati K, Li H, et al. (2009) A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 460: 1149-1153.    

14. Park IH, Arora N, Huo H, et al. (2008) Disease-specific induced pluripotent stem cells. Cell 134: 877-886.    

15. Teive HA, Moro A, Moscovich M, et al. (2015) Ataxia-telangiectasia – A historical review and a proposal for a new designation: ATM syndrome. J Neurol Sci 355: 3-6.    

16. Savitsky K, Bar-Shira A, Gilad S, et al. (1995) A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268: 1749-1753.    

17. Shiloh Y (2006) The ATM-mediated DNA-damage response: taking shape. Trends Biochem Sci 31: 402-410.    

18. Lee JH, Paull TT (2007) Activation and regulation of ATM kinase activity in response to DNA double-strand breaks. Oncogene 26: 7741-7748.    

19. Nayler S, Gatei M, Kozlov S, et al. (2012) Induced pluripotent stem cells from ataxia-telangiectasia recapitulate the cellular phenotype. Stem Cells Transl Med 1: 523-535.    

20. Lin L, Swerdel MR, Lazaropoulos MP, et al. (2015) Spontaneous ATM Gene Reversion in A-T iPSC to Produce an Isogenic Cell Line. Stem Cell Reports 5: 1097-1108.    

21. Fukawatase Y, Toyoda M, Okamura K, et al. (2014) Ataxia telangiectasia derived iPS cells show preserved x-ray sensitivity and decreased chromosomal instability. Sci Rep 4: 5421.

22. Lee P, Martin NT, Nakamura K, et al. (2013) SMRT compounds abrogate cellular phenotypes of ataxia telangiectasia in neural derivatives of patient-specific hiPSCs. Nat Commun 4: 1824.    

23. Carlessi L, Fusar Poli E, Delia D (2013) Brain and induced pluripotent stem cell-derived neural stem cells as an in vitro model of neurodegeneration in ataxia-telangiectasia. Exp Biol Med (Maywood) 238: 301-307.    

24. Kinoshita T, Nagamatsu G, Kosaka T, et al. (2011) Ataxia-telangiectasia mutated (ATM) deficiency decreases reprogramming efficiency and leads to genomic instability in iPS cells. Biochem Biophys Res Commun 407: 321-326.    

25. Wen W, Zhang JP, Xu J, et al. (2016) Enhanced Generation of Integration-free iPSCs from Human Adult Peripheral Blood Mononuclear Cells with an Optimal Combination of Episomal Vectors. Stem Cell Reports 6: 873-884.    

26. Su RJ, Baylink DJ, Neises A, et al. (2013) Efficient generation of integration-free ips cells from human adult peripheral blood using BCL-XL together with Yamanaka factors. PLoS One 8: e64496.    

27. Chou BK, Gu H, Gao Y, et al. (2015) A facile method to establish human induced pluripotent stem cells from adult blood cells under feeder-free and xeno-free culture conditions: a clinically compliant approach. Stem Cells Transl Med 4: 320-332.    

28. Bhatt N, Ghosh R, Roy S, et al. (2016) Robust reprogramming of Ataxia-Telangiectasia patient and carrier erythroid cells to induced pluripotent stem cells. Stem Cell Res 17: 296-305.    

29. Lu J, Li H, Baccei A, et al. (2016) Influence of ATM-Mediated DNA Damage Response on Genomic Variation in Human Induced Pluripotent Stem Cells. Stem Cells Dev 25: 740-747.    

30. Ahnesorg P, Smith P, Jackson SP (2006) XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell 124: 301-313.    

31. Grawunder U, Wilm M, Wu X, et al. (1997) Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells. Nature 388: 492-495.    

32. Riballo E, Critchlow SE, Teo SH, et al. (1999) Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient. Curr Biol 9: 699-702.    

33. O'Driscoll M, Cerosaletti KM, Girard PM, et al. (2001) DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell 8: 1175-1185.    

34. Ben-Omran TI, Cerosaletti K, Concannon P, et al. (2005) A patient with mutations in DNA Ligase IV: clinical features and overlap with Nijmegen breakage syndrome. Am J Med Genet A 137A: 283-287.    

35. Tilgner K, Neganova I, Moreno-Gimeno I, et al. (2013) A human iPSC model of Ligase IV deficiency reveals an important role for NHEJ-mediated-DSB repair in the survival and genomic stability of induced pluripotent stem cells and emerging haematopoietic progenitors. Cell Death Differ 20: 1089-1100.    

36. Felgentreff K, Du L, Weinacht KG, et al. (2014) Differential role of nonhomologous end joining factors in the generation, DNA damage response, and myeloid differentiation of human induced pluripotent stem cells. Proc Natl Acad Sci U S A 111: 8889-8894.    

37. Tilgner K, Neganova I, Singhapol C, et al. (2013) Brief report: a human induced pluripotent stem cell model of cernunnos deficiency reveals an important role for XLF in the survival of the primitive hematopoietic progenitors. Stem Cells 31: 2015-2023.    

38. Tischkowitz MD, Hodgson SV (2003) Fanconi anaemia. J Med Genet 40: 1-10.    

39. Kutler DI, Singh B, Satagopan J, et al. (2003) A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Blood 101: 1249-1256.    

40. Moldovan GL, D'Andrea AD (2009) How the fanconi anemia pathway guards the genome. Annu Rev Genet 43: 223-249.    

41. Wang W (2007) Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Nat Rev Genet 8: 735-748.    

42. Auerbach AD, Wolman SR (1976) Susceptibility of Fanconi's anaemia fibroblasts to chromosome damage by carcinogens. Nature 261: 494-496.    

43. Raya A, Rodriguez-Piza I, Guenechea G, et al. (2009) Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460: 53-59.    

44. Rio P, Banos R, Lombardo A, et al. (2014) Targeted gene therapy and cell reprogramming in Fanconi anemia. EMBO Mol Med 6: 835-848.    

45. Liu GH, Suzuki K, Li M, et al. (2014) Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs. Nat Commun 5: 4330.

46. Chlon TM, Hoskins EE, Mayhew CN, et al. (2014) High-risk human papillomavirus E6 protein promotes reprogramming of Fanconi anemia patient cells through repression of p53 but does not allow for sustained growth of induced pluripotent stem cells. J Virol 88: 11315-11326.    

47. Yung SK, Tilgner K, Ledran MH, et al. (2013) Brief report: human pluripotent stem cell models of fanconi anemia deficiency reveal an important role for fanconi anemia proteins in cellular reprogramming and survival of hematopoietic progenitors. Stem Cells 31: 1022-1029.    

48. Muller LU, Milsom MD, Harris CE, et al. (2012) Overcoming Reprogramming Resistance of Fanconi Anemia Cells. Blood 119: 5449-5457.    

49. Suzuki NM, Niwa A, Yabe M, et al. (2015) Pluripotent cell models of fanconi anemia identify the early pathological defect in human hemoangiogenic progenitors. Stem Cells Transl Med 4: 333-338.    

50. Lee DF, Su J, Kim HS, et al. (2015) Modeling familial cancer with induced pluripotent stem cells. Cell 161: 240-254.    

51. Yi L, Lu C, Hu W, et al. (2012) Multiple roles of p53-related pathways in somatic cell reprogramming and stem cell differentiation. Cancer Res 72: 5635-5645.    

52. Barrett R, Ornelas L, Yeager N, et al. (2014) Reliable generation of induced pluripotent stem cells from human lymphoblastoid cell lines. Stem Cells Transl Med 3: 1429-1434.    

53. Hoshino H, Nagano H, Haraguchi N, et al. (2012) Hypoxia and TP53 deficiency for induced pluripotent stem cell-like properties in gastrointestinal cancer. Int J Oncol 40: 1423-1430.

54. De Sandre-Giovannoli A, Bernard R, Cau P, et al. (2003) Lamin a truncation in Hutchinson-Gilford progeria. Science 300: 2055.    

55. Puente XS, Quesada V, Osorio FG, et al. (2011) Exome sequencing and functional analysis identifies BANF1 mutation as the cause of a hereditary progeroid syndrome. Am J Hum Genet 88: 650-656.    

56. Cabanillas R, Cadinanos J, Villameytide JA, et al. (2011) Nestor-Guillermo progeria syndrome: a novel premature aging condition with early onset and chronic development caused by BANF1 mutations. Am J Med Genet A 155A: 2617-2625.

57. Zhang J, Lian Q, Zhu G, et al. (2011) A human iPSC model of Hutchinson Gilford Progeria reveals vascular smooth muscle and mesenchymal stem cell defects. Cell Stem Cell 8: 31-45.    

58. Liu GH, Barkho BZ, Ruiz S, et al. (2011) Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome. Nature 472: 221-225.    

59. Ho JC, Zhou T, Lai WH, et al. (2011) Generation of induced pluripotent stem cell lines from 3 distinct laminopathies bearing heterogeneous mutations in lamin A/C. Aging (Albany NY) 3: 380-390.

60. Nissan X, Blondel S, Navarro C, et al. (2012) Unique preservation of neural cells in Hutchinson- Gilford progeria syndrome is due to the expression of the neural-specific miR-9 microRNA. Cell Rep 2: 1-9.    

61. Soria-Valles C, Osorio FG, Gutierrez-Fernandez A, et al. (2015) NF-kappaB activation impairs somatic cell reprogramming in ageing. Nat Cell Biol 17: 1004-1013.    

62. Mason PJ, Wilson DB, Bessler M (2005) Dyskeratosis congenita -- a disease of dysfunctional telomere maintenance. Curr Mol Med 5: 159-170.    

63. Walne AJ, Dokal I (2009) Advances in the understanding of dyskeratosis congenita. Br J Haematol 145: 164-172.    

64. Agarwal S, Loh YH, McLoughlin EM, et al. (2010) Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients. Nature 464: 292-296.    

65. Winkler T, Hong SG, Decker JE, et al. (2013) Defective telomere elongation and hematopoiesis from telomerase-mutant aplastic anemia iPSCs. J Clin Invest 123: 1952-1963.    

66. Batista LF, Pech MF, Zhong FL, et al. (2011) Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells. Nature 474: 399-402.    

67. Gu BW, Apicella M, Mills J, et al. (2015) Impaired Telomere Maintenance and Decreased Canonical WNT Signaling but Normal Ribosome Biogenesis in Induced Pluripotent Stem Cells from X-Linked Dyskeratosis Congenita Patients. PLoS One 10: e0127414.    

68. Woo DH, Chen Q, Yang TL, et al. (2016) Enhancing a Wnt-Telomere Feedback Loop Restores Intestinal Stem Cell Function in a Human Organotypic Model of Dyskeratosis Congenita. Cell Stem Cell 19: 397-405.    

69. Yu Y, Chang L, Zhao H, et al. (2015) Chromosome microduplication in somatic cells decreases the genetic stability of human reprogrammed somatic cells and results in pluripotent stem cells. Sci Rep 5: 10114.    

70. Bershteyn M, Hayashi Y, Desachy G, et al. (2014) Cell-autonomous correction of ring chromosomes in human induced pluripotent stem cells. Nature 507: 99-103.    

71. Yokota M, Hatakeyama H, Okabe S, et al. (2015) Mitochondrial respiratory dysfunction caused by a heteroplasmic mitochondrial DNA mutation blocks cellular reprogramming. Hum Mol Genet 24: 4698-4709.    

72. Hung SS, Van Bergen NJ, Jackson S, et al. (2016) Study of mitochondrial respiratory defects on reprogramming to human induced pluripotent stem cells. Aging (Albany NY) 8: 945-957.

73. Zhou Y, Al-Saaidi RA, Fernandez-Guerra P, et al. (2017) Mitochondrial Spare Respiratory Capacity Is Negatively Correlated with Nuclear Reprogramming Efficiency. Stem Cells Dev 26: 166-176.    

74. Nishimura K, Aizawa S, Nugroho FL, et al. (2017) A Role for KLF4 in Promoting the Metabolic Shift via TCL1 during Induced Pluripotent Stem Cell Generation. Stem Cell Reports 8: 787-801.    

75. Mizuguchi Y, Hatakeyama H, Sueoka K, et al. (2017) Low dose resveratrol ameliorates mitochondrial respiratory dysfunction and enhances cellular reprogramming. Mitochondrion.

76. Shore EM, Xu M, Feldman GJ, et al. (2006) A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet 38: 525-527.    

77. Hamasaki M, Hashizume Y, Yamada Y, et al. (2012) Pathogenic mutation of Alk2 inhibits ips cell reprogramming and maintenance: mechanisms of reprogramming and strategy for drug identification. Stem Cells 30: 2437-2449.    

78. Cai J, Orlova VV, Cai X, et al. (2015) Induced Pluripotent Stem Cells to Model Human Fibrodysplasia Ossificans Progressiva. Stem Cell Reports 5: 963-970.    

79. Hildebrand L, Rossbach B, Kuhnen P, et al. (2016) Generation of integration free induced pluripotent stem cells from fibrodysplasia ossificans progressiva (FOP) patients from urine samples. Stem Cell Res 16: 54-58.    

80. Matsumoto Y, Hayashi Y, Schlieve CR, et al. (2013) Induced pluripotent stem cells from patients with human fibrodysplasia ossificans progressiva show increased mineralization and cartilage formation. Orphanet J Rare Dis 8: 190.    

81. Barruet E, Morales BM, Lwin W, et al. (2016) The ACVR1 R206H mutation found in fibrodysplasia ossificans progressiva increases human induced pluripotent stem cell-derived endothelial cell formation and collagen production through BMP-mediated SMAD1/5/8 signaling. Stem Cell Res Ther 7: 115.    

82. Ying QL, Nichols J, Chambers I, et al. (2003) BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell 115: 281-292.    

83. Qi X, Li TG, Hao J, et al. (2004) BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways. Proc Natl Acad Sci U S A 101: 6027-6032.    

84. Schuldiner M, Yanuka O, Itskovitz-Eldor J, et al. (2000) Effects of eight growth factors on the differentiation of cells derived from human embryonic stem cells. Proc Natl Acad Sci U S A 97: 11307-11312.    

85. Chadwick K, Wang L, Li L, et al. (2003) Cytokines and BMP-4 promote hematopoietic differentiation of human embryonic stem cells. Blood 102: 906-915.    

86. James D, Levine AJ, Besser D, et al. (2005) TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells. Development 132: 1273-1282.    

87. Xu RH, Peck RM, Li DS, et al. (2005) Basic FGF and suppression of BMP signaling sustain undifferentiated proliferation of human ES cells. Nat Methods 2: 185-190.    

88. Kennedy M, D'Souza SL, Lynch-Kattman M, et al. (2007) Development of the hemangioblast defines the onset of hematopoiesis in human ES cell differentiation cultures. Blood 109: 2679-2687.

89. Samavarchi-Tehrani P, Golipour A, David L, et al. (2010) Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell 7: 64-77.    

90. Hayashi Y, Hsiao EC, Sami S, et al. (2016) BMP-SMAD-ID promotes reprogramming to pluripotency by inhibiting p16/INK4A-dependent senescence. Proc Natl Acad Sci U S A 113: 13057-13062.    

91. Hatsell SJ, Idone V, Wolken DM, et al. (2015) ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med 7: 303ra137.

92. Hino K, Ikeya M, Horigome K, et al. (2015) Neofunction of ACVR1 in fibrodysplasia ossificans progressiva. Proc Natl Acad Sci U S A 112: 15438-15443.    

93. Takahashi K, Yamanaka S (2016) A decade of transcription factor-mediated reprogramming to pluripotency. Nat Rev Mol Cell Biol 17: 183-193.

94. Worringer KA, Rand TA, Hayashi Y, et al. (2014) The let-7/LIN-41 pathway regulates reprogramming to human induced pluripotent stem cells by controlling expression of prodifferentiation genes. Cell Stem Cell 14: 40-52.    

95. Nie B, Wang H, Laurent T, et al. (2012) Cellular reprogramming: a small molecule perspective. Curr Opin Cell Biol 24: 784-792.    

96. Lin T, Wu S (2015) Reprogramming with Small Molecules instead of Exogenous Transcription Factors. Stem Cells Int 2015: 794632.

97. Baranek M, Markiewicz WT, Barciszewski J (2016) Selected small molecules as inducers of pluripotency. Acta Biochim Pol 63: 709-716.    

98. Hayashi Y, Chan T, Warashina M, et al. (2010) Reduction of N-glycolylneuraminic acid in human induced pluripotent stem cells generated or cultured under feeder- and serum-free defined conditions. PLoS One 5: e14099.    

99. Hayashi Y, Furue MK (2016) Biological Effects of Culture Substrates on Human Pluripotent Stem Cells. Stem Cells Int 2016: 5380560.

100. Kime C, Sakaki-Yumoto M, Goodrich L, et al. (2016) Autotaxin-mediated lipid signaling intersects with LIF and BMP signaling to promote the naive pluripotency transcription factor program. Proc Natl Acad Sci U S A 113: 12478-12483.    

101. Yoshida Y, Takahashi K, Okita K, et al. (2009) Hypoxia enhances the generation of induced pluripotent stem cells. Cell Stem Cell 5: 237-241.    

Copyright Info: © 2017, Yohei Hayashi, licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Article outline

Show full outline
Copyright © AIMS Press All Rights Reserved