1932

Abstract

Age-associated neurological diseases represent a profound challenge in biomedical research as we are still struggling to understand the interface between the aging process and the manifestation of disease. Various pathologies in the elderly do not directly result from genetic mutations, toxins, or infectious agents but are primarily driven by the many manifestations of biological aging. Therefore, the generation of appropriate model systems to study human aging in the nervous system demands new concepts that lie beyond transgenic and drug-induced models. Although access to viable human brain specimens is limited and induced pluripotent stem cell models face limitations due to reprogramming-associated cellular rejuvenation, the direct conversion of somatic cells into induced neurons allows for the generation of human neurons that capture many aspects of aging. Here, we review advances in exploring age-associated neurodegenerative diseases using human cell reprogramming models, and we discuss general concepts, promises, and limitations of the field.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-genet-120417-031534
2018-11-23
2024-06-15
Loading full text...

Full text loading...

/deliver/fulltext/genet/52/1/annurev-genet-120417-031534.html?itemId=/content/journals/10.1146/annurev-genet-120417-031534&mimeType=html&fmt=ahah

Literature Cited

  1. 1.  Aasen T, Raya A, Barrero MJ, Garreta E, Consiglio A et al. 2008. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat. Biotechnol. 26:111276–84
    [Google Scholar]
  2. 2.  Abyzov A, Mariani J, Palejev D, Zhang Y, Haney MS et al. 2012. Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells. Nature 492:7429438–42
    [Google Scholar]
  3. 3.  Adler AF, Grigsby CL, Kulangara K, Wang H, Yasuda R, Leong KW 2012. Nonviral direct conversion of primary mouse embryonic fibroblasts to neuronal cells. Mol. Ther. Nucleic Acids 1:7e32
    [Google Scholar]
  4. 4.  Ambasudhan R, Talantova M, Coleman R, Yuan X, Zhu S et al. 2011. Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. Cell Stem Cell 9:2113–18
    [Google Scholar]
  5. 5.  Aubry L, Bugi A, Lefort N, Rousseau F, Peschanski M, Perrier AL 2008. Striatal progenitors derived from human ES cells mature into DARPP32 neurons in vitro and in quinolinic acid-lesioned rats. PNAS 105:4316707–12
    [Google Scholar]
  6. 6.  Bahar R, Hartmann CH, Rodriguez KA, Denny AD, Busuttil RA et al. 2006. Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature 441:70961011–14
    [Google Scholar]
  7. 7.  Bellin M, Marchetto MC, Gage FH, Mummery CL 2012. Induced pluripotent stem cells: the new patient?. Nat. Rev. Mol. Cell Biol. 13:11713–26
    [Google Scholar]
  8. 8.  Blanchard JW, Eade KT, Szűcs A, Sardo Lo V, Tsunemoto RK et al. 2015. Selective conversion of fibroblasts into peripheral sensory neurons. Nat. Neurosci. 18:125–35
    [Google Scholar]
  9. 9.  Deleted in proof
  10. 10.  Bormann F, Rodríguez-Paredes M, Hagemann S, Manchanda H, Kristof B et al. 2016. Reduced DNA methylation patterning and transcriptional connectivity define human skin aging. Aging Cell 15:3563–71
    [Google Scholar]
  11. 11.  Bozdag S, Li A, Riddick G, Kotliarov Y, Baysan M et al. 2013. Age-specific signatures of glioblastoma at the genomic, genetic, and epigenetic levels. PLOS ONE 8:4e62982
    [Google Scholar]
  12. 12.  Bratic A, Larsson N-G 2013. The role of mitochondria in aging. J. Clin. Invest 123:3951–57
    [Google Scholar]
  13. 13.  Briggs JA, Li VC, Lee S, Woolf CJ, Klein A, Kirschner MW 2017. Mouse embryonic stem cells can differentiate via multiple paths to the same state. eLife 6:e26945
    [Google Scholar]
  14. 14.  Burns LT, Wente SR 2014. From hypothesis to mechanism: uncovering nuclear pore complex links to gene expression. Mol. Cell. Biol. 34:122114–20
    [Google Scholar]
  15. 15.  Bushman DM, Kaeser GE, Siddoway B, Westra JW, Rivera RR et al. 2015. Genomic mosaicism with increased amyloid precursor protein (APP) gene copy number in single neurons from sporadic Alzheimer's disease brains. eLife 4:e05116
    [Google Scholar]
  16. 16.  Caiazzo M, Dell'Anno MT, Dvoretskova E, Lazarevic D, Taverna S et al. 2011. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476:7359224–27
    [Google Scholar]
  17. 17.  Caiazzo M, Giannelli S, Valente P, Lignani G, Carissimo A et al. 2015. Direct conversion of fibroblasts into functional astrocytes by defined transcription factors. Stem Cell Rep 4:125–36
    [Google Scholar]
  18. 18.  Capelson M, Hetzer MW 2009. The role of nuclear pores in gene regulation, development and disease. EMBO Rep 10:7697–705
    [Google Scholar]
  19. 19.  Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L 2009. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat. Biotechnol. 27:3275–80
    [Google Scholar]
  20. 20.  Chambers SM, Studer L 2011. Cell fate plug and play: direct reprogramming and induced pluripotency. Cell 145:6827–30
    [Google Scholar]
  21. 21.  Chow H-M, Herrup K 2015. Genomic integrity and the ageing brain. Nat. Rev. Neurosci. 16:11672–84
    [Google Scholar]
  22. 22.  D'Angelo MA, Raices M, Panowski SH, Hetzer MW 2009. Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells. Cell 136:2284–95
    [Google Scholar]
  23. 23.  Davis RL, Weintraub H, Lassar AB 1987. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51:6987–1000
    [Google Scholar]
  24. 24.  Dong X, Milholland B, Vijg J 2016. Evidence for a limit to human lifespan. Nature 538:7624257–59
    [Google Scholar]
  25. 25.  Drouin-Ouellet J, Lau S, Brattås PL, Rylander Ottosson D, Pircs K et al. 2017. REST suppression mediates neural conversion of adult human fibroblasts via microRNA-dependent and -independent pathways. EMBO Mol. Med. 9:1117–31
    [Google Scholar]
  26. 26.  Duan L, Bhattacharyya BJ, Belmadani A, Pan L, Miller RJ, Kessler JA 2014. Stem cell derived basal forebrain cholinergic neurons from Alzheimer's disease patients are more susceptible to cell death. Mol. Neurodegener. 9:3
    [Google Scholar]
  27. 27.  Eitan E, Hutchison ER, Mattson MP 2014. Telomere shortening in neurological disorders: an abundance of unanswered questions. Trends Neurosci 37:5256–63
    [Google Scholar]
  28. 28.  Enge M, Arda HE, Mignardi M, Beausang J, Bottino R et al. 2017. Single-cell analysis of human pancreas reveals transcriptional signatures of aging and somatic mutation patterns. Cell 171:2321–330.e14
    [Google Scholar]
  29. 29.  Eriksson PS, Perfilieva E, Björk-Eriksson T, Alborn AM, Nordborg C et al. 1998. Neurogenesis in the adult human hippocampus. Nat. Med. 4:111313–17
    [Google Scholar]
  30. 30.  Fang EF, Lautrup S, Hou Y, Demarest TG, Croteau DL et al. 2017. NAD+ in aging: molecular mechanisms and translational implications. Trends Mol. Med. 23:10899–916
    [Google Scholar]
  31. 31.  Fang EF, Scheibye-Knudsen M, Chua KF, Mattson MP, Croteau DL, Bohr VA 2016. Nuclear DNA damage signalling to mitochondria in ageing. Nat. Rev. Mol. Cell Biol. 17:5308–21
    [Google Scholar]
  32. 32.  Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S et al. 2015. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525:7567129–33
    [Google Scholar]
  33. 33.  Frobel J, Hemeda H, Lenz M, Abagnale G, Joussen S et al. 2014. Epigenetic rejuvenation of mesenchymal stromal cells derived from induced pluripotent stem cells. Stem Cell Rep 3:3414–22
    [Google Scholar]
  34. 34.  Fumagalli M, Rossiello F, Clerici M, Barozzi S, Cittaro D et al. 2012. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14:4355–65
    [Google Scholar]
  35. 35.  Gladyshev TV, Gladyshev VN 2016. A disease or not a disease? Aging as a pathology. Trends Mol. Med. 22:12995–96
    [Google Scholar]
  36. 36.  Gladyshev VN 2016. Aging: progressive decline in fitness due to the rising deleteriome adjusted by genetic, environmental, and stochastic processes. Aging Cell 15:4594–602
    [Google Scholar]
  37. 37.  Gonzalo S, Kreienkamp R 2015. DNA repair defects and genome instability in Hutchinson–Gilford Progeria Syndrome. Curr. Opin. Cell Biol. 34:75–83
    [Google Scholar]
  38. 38.  Graf T, Enver T 2009. Forcing cells to change lineages. Nature 462:7273587–94
    [Google Scholar]
  39. 39.  Grima JC, Daigle JG, Arbez N, Cunningham KC, Zhang K et al. 2017. Mutant Huntingtin disrupts the nuclear pore complex. Neuron 94:193–107.e6
    [Google Scholar]
  40. 40.  Hanawalt PC, Spivak G 2008. Transcription-coupled DNA repair: two decades of progress and surprises. Nat. Rev. Mol. Cell Biol. 9:12958–70
    [Google Scholar]
  41. 41.  Hansson J, Rafiee MR, Reiland S, Polo JM, Gehring J et al. 2012. Highly coordinated proteome dynamics during reprogramming of somatic cells to pluripotency. Cell Rep 2:61579–92
    [Google Scholar]
  42. 42.  Harries LW, Hernandez D, Henley W, Wood AR, Holly AC et al. 2011. Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing. Aging Cell 10:5868–78
    [Google Scholar]
  43. 43.  Heinrich C, Bergami M, Gascón S, Lepier A, Viganò F et al. 2014. Sox2-mediated conversion of NG2 glia into induced neurons in the injured adult cerebral cortex. Stem Cell Rep 3:61000–14
    [Google Scholar]
  44. 44.  Hernández-Vega A, Braun M, Scharrel L, Jahnel M, Wegmann S et al. 2017. Local nucleation of microtubule bundles through tubulin concentration into a condensed tau phase. Cell Rep 20:102304–12
    [Google Scholar]
  45. 45.  Hoelz A, Debler EW, Blobel G 2011. The structure of the nuclear pore complex. Annu. Rev. Biochem. 80:613–43
    [Google Scholar]
  46. 46.  Horvath S 2013. DNA methylation age of human tissues and cell types. Genome Biol 14:10R115
    [Google Scholar]
  47. 47.  Hu B-Y, Du Z-W, Zhang S-C 2009. Differentiation of human oligodendrocytes from pluripotent stem cells. Nat. Protoc 4:111614–22
    [Google Scholar]
  48. 48.  Hu W, Qiu B, Guan W, Wang Q, Wang M et al. 2015. Direct conversion of normal and Alzheimer's disease human fibroblasts into neuronal cells by small molecules. Cell Stem Cell 17:2204–12
    [Google Scholar]
  49. 49.  Huang P, Zhang L, Gao Y, He Z, Yao D et al. 2014. Direct reprogramming of human fibroblasts to functional and expandable hepatocytes. Cell Stem Cell 14:3370–84
    [Google Scholar]
  50. 50.  Huh CJ, Zhang B, Victor M, Dahiya S, Batista LF et al. 2016. Maintenance of age in human neurons generated by microRNA-based neuronal conversion of fibroblasts. eLife 5:e18648
    [Google Scholar]
  51. 51.  Ibarra A, Benner C, Tyagi S, Cool J, Hetzer MW 2016. Nucleoporin-mediated regulation of cell identity genes. Genes Dev 30:202253–58
    [Google Scholar]
  52. 52.  Ieda M, Fu J-D, Delgado-Olguin P, Vedantham V, Hayashi Y et al. 2010. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142:3375–86
    [Google Scholar]
  53. 53.  Inak G, Lorenz C, Lisowski P, Zink A, Mlody B, Prigione A 2017. Concise review: induced pluripotent stem cell-based drug discovery for mitochondrial disease. Stem Cells 35:71655–62
    [Google Scholar]
  54. 54.  Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y et al. 2012. Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature 482:7384216–20
    [Google Scholar]
  55. 55.  Jaarsma D, van der Pluijm I, de Waard MC, Haasdijk ED, Brandt R et al. 2011. Age-related neuronal degeneration: complementary roles of nucleotide excision repair and transcription-coupled repair in preventing neuropathology. PLOS Genet 7:12e1002405
    [Google Scholar]
  56. 56.  Jovičić A, Mertens J, Boeynaems S, Bogaert E, Chai N et al. 2015. Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat. Neurosci. 18:91226–29
    [Google Scholar]
  57. 57.  Jovičić A, Paul JW, Gitler AD 2016. Nuclear transport dysfunction: a common theme in amyotrophic lateral sclerosis and frontotemporal dementia. J. Neurochem. 138:S1134–44
    [Google Scholar]
  58. 58.  Kang E, Wang X, Tippner-Hedges R, Ma H, Folmes CDL et al. 2016. Age-related accumulation of somatic mitochondrial DNA mutations in adult-derived human iPSCs. Cell Stem Cell 18:5625–36
    [Google Scholar]
  59. 59.  Karch CM, Goate AM 2015. Alzheimer's disease risk genes and mechanisms of disease pathogenesis. Biol. Psychiatry 77:143–51
    [Google Scholar]
  60. 60.  Karow M, Sánchez R, Schichor C, Masserdotti G, Ortega F et al. 2012. Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells. Cell Stem Cell 11:4471–76
    [Google Scholar]
  61. 61.  Kim D, Kim C-H, Moon J-I, Chung Y-G, Chang M-Y et al. 2009. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4:6472–76
    [Google Scholar]
  62. 62.  Kim HJ, Taylor JP 2017. Lost in transportation: nucleocytoplasmic transport defects in ALS and other neurodegenerative diseases. Neuron 96:2285–97
    [Google Scholar]
  63. 63.  Kim Y, Zheng X, Ansari Z, Bunnell MC, Herdy JR et al. 2018. Mitochondrial aging defects emerge in directly reprogrammed human neurons due to their metabolic profile. Cell Rep 23:92550–58
    [Google Scholar]
  64. 64.  Koch P, Breuer P, Peitz M, Jungverdorben J, Kesavan J et al. 2011. Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease. Nature 480:543–46
    [Google Scholar]
  65. 65.  Koch P, Optiz T, Steinbeck JA, Ladewig J,, Brüstle O 2009. A rosette-type, self-renewing human ES cell-derived neural stem cell with potential for in vitro instruction and synaptic integration. PNAS 106:3225–30
    [Google Scholar]
  66. 66.  Koch P, Tamboli IY, Mertens J, Wunderlich P, Ladewig J et al. 2012. Presenilin-1 L166P mutant human pluripotent stem cell-derived neurons exhibit partial loss of γ-secretase activity in endogenous amyloid-β generation. Am. J. Pathol. 180:62404–16
    [Google Scholar]
  67. 67.  Krencik R, Weick JP, Liu Y, Zhang Z-J, Zhang S-C 2011. Specification of transplantable astroglial subtypes from human pluripotent stem cells. Nat. Biotechnol 29:6528–34
    [Google Scholar]
  68. 68.  Kriks S, Shim J-W, Piao J, Ganat YM, Wakeman DR et al. 2011. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature 480:547–51
    [Google Scholar]
  69. 69.  Ladewig J, Mertens J, Kesavan J, Doerr J, Poppe D et al. 2012. Small molecules enable highly efficient neuronal conversion of human fibroblasts. Nat. Methods 9:575–78
    [Google Scholar]
  70. 70.  Laiosa CV, Stadtfeld M, Xie H, de Andres-Aguayo L, Graf T 2006. Reprogramming of committed T cell progenitors to macrophages and dendritic cells by C/EBPα and PU.1 transcription factors. Immunity 25:5731–44
    [Google Scholar]
  71. 71.  Lancaster MA, Knoblich JA 2014. Organogenesis in a dish: modeling development and disease using organoid technologies. Science 345:61941247125
    [Google Scholar]
  72. 72.  Lapasset L, Milhavet O, Prieur A, Besnard E, Babled A et al. 2011. Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes Dev 25:212248–53
    [Google Scholar]
  73. 73.  Lau S, Rylander Ottosson D, Jakobsson J, Parmar M 2014. Direct neural conversion from human fibroblasts using self-regulating and nonintegrating viral vectors. Cell Rep 9:51673–80
    [Google Scholar]
  74. 74.  Li X, Zuo X, Jing J, Ma Y, Wang J et al. 2015. Small-molecule-driven direct reprogramming of mouse fibroblasts into functional neurons. Cell Stem Cell 17:2195–203
    [Google Scholar]
  75. 75.  Lindahl T, Barnes DE 2000. Repair of endogenous DNA damage. Cold Spring Harb. Symp. Quant. Biol. 65:127–33
    [Google Scholar]
  76. 76.  Liu H, Zhang S-C 2011. Specification of neuronal and glial subtypes from human pluripotent stem cells. Cell. Mol. Life Sci 68:243995–4008
    [Google Scholar]
  77. 77.  Liu M-L, Zang T, Zhang C-L 2016. Direct lineage reprogramming reveals disease-specific phenotypes of motor neurons from human ALS patients. Cell Rep 14:1115–28
    [Google Scholar]
  78. 78.  Liu M-L, Zang T, Zou Y, Chang JC, Gibson JR et al. 2013. Small molecules enable neurogenin 2 to efficiently convert human fibroblasts into cholinergic neurons. Nat. Commun. 4:2183
    [Google Scholar]
  79. 79.  Lo Sardo V, Ferguson W, Erikson GA, Topol EJ, Baldwin KK, Torkamani A 2016. Influence of donor age on induced pluripotent stem cells. Nat. Biotechnol. 35:169–74
    [Google Scholar]
  80. 80.  Lodato MA, Rodin RE, Bohrson CL, Coulter ME, Barton AR et al. 2017. Aging and neurodegeneration are associated with increased mutations in single human neurons. Science 359:555–59
    [Google Scholar]
  81. 81.  López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G 2013. The hallmarks of aging. Cell 153:61194–217
    [Google Scholar]
  82. 82.  Lu T, Pan Y, Kao S-Y, Li C, Kohane I et al. 2004. Gene regulation and DNA damage in the ageing human brain. Nature 429:6994883–91
    [Google Scholar]
  83. 83.  Madabhushi R, Gao F, Pfenning AR, Pan L, Yamakawa S et al. 2015. Activity-induced DNA breaks govern the expression of neuronal early-response genes. Cell 161:71592–605
    [Google Scholar]
  84. 84.  Marion RM, Strati K, Li H, Tejera A, Schoeftner S et al. 2009. Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells. Cell Stem Cell 4:2141–54
    [Google Scholar]
  85. 85.  Marro S, Pang ZP, Yang N, Tsai M-C, Qu K et al. 2011. Direct lineage conversion of terminally differentiated hepatocytes to functional neurons. Cell Stem Cell 9:4374–82
    [Google Scholar]
  86. 86.  Mattis VB, Svendsen SP, Ebert A, Svendsen CN, King AR et al. (HD iPSC Consort.) 2012. Induced pluripotent stem cells from patients with Huntington's disease show CAG-repeat-expansion-associated phenotypes. Cell Stem Cell 11:2264–78
    [Google Scholar]
  87. 87.  McConnell MJ, Lindberg MR, Brennand KJ, Piper JC, Voet T et al. 2013. Mosaic copy number variation in human neurons. Science 342:6158632–37
    [Google Scholar]
  88. 88.  McKinnon PJ 2017. Genome integrity and disease prevention in the nervous system. Genes Dev 31:121180–94
    [Google Scholar]
  89. 89.  Meissner A, Mikkelsen TS, Gu H, Wernig M, Hanna J et al. 2008. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454:7205766–70
    [Google Scholar]
  90. 90.  Mertens J, Marchetto MC, Bardy C, Gage FH 2016. Evaluating cell reprogramming, differentiation and conversion technologies in neuroscience. Nat. Rev. Neurosci. 17:7424–37
    [Google Scholar]
  91. 91.  Mertens J, Paquola ACM, Ku M, Hatch E, Böhnke L et al. 2015. Directly reprogrammed human neurons retain aging-associated transcriptomic signatures and reveal age-related nucleocytoplasmic defects. Cell Stem Cell 17:6705–18
    [Google Scholar]
  92. 92.  Mertens J, Stüber K, Poppe D, Doerr J, Ladewig J et al. 2013. Embryonic stem cell-based modeling of tau pathology in human neurons. Am. J. Pathol. 182:51769–79
    [Google Scholar]
  93. 93.  Mertens J, Stüber K, Wunderlich P, Ladewig J, Kesavan JC et al. 2013. APP processing in human pluripotent stem cell-derived neurons is resistant to NSAID-based γ-secretase modulation. Stem Cell Rep 1:491–98
    [Google Scholar]
  94. 94.  Miller JD, Ganat YM, Kishinevsky S, Bowman RL, Liu B et al. 2013. Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell 13:6691–705
    [Google Scholar]
  95. 95.  Mong J, Panman L, Alekseenko Z, Kee N, Stanton LW et al. 2014. Transcription factor-induced lineage programming of noradrenaline and motor neurons from embryonic stem cells. Stem Cells 32:3609–22
    [Google Scholar]
  96. 96.  Murry CE, Keller G 2008. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 132:4661–80
    [Google Scholar]
  97. 97.  Nekrasov ED, Vigont VA, Klyushnikov SA, Lebedeva OS, Vassina EM et al. 2016. Manifestation of Huntington's disease pathology in human induced pluripotent stem cell-derived neurons. Mol. Neurodegener. 11:27
    [Google Scholar]
  98. 98.  Nguyen HN, Byers B, Cord B, Shcheglovitov A, Byrne J et al. 2011. LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8:3267–80
    [Google Scholar]
  99. 99.  Nicholas CR, Chen J, Tang Y, Southwell DG, Chalmers N et al. 2013. Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. Cell Stem Cell 12:5573–86
    [Google Scholar]
  100. 100.  Nishimura T, Kaneko S, Kawana-Tachikawa A, Tajima Y, Goto H et al. 2013. Generation of rejuvenated antigen-specific T cells by reprogramming to pluripotency and redifferentiation. Cell Stem Cell 12:1114–26
    [Google Scholar]
  101. 101.  Ocampo A, Reddy P, Martinez-Redondo P, Platero-Luengo A, Hatanaka F et al. 2016. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell 167:1719–33.e12
    [Google Scholar]
  102. 102.  Okita K, Yamanaka S 2011. Induced pluripotent stem cells: opportunities and challenges. Philos. Trans. R. Soc. B 366:15752198–207
    [Google Scholar]
  103. 103.  Pang ZP, Yang N, Vierbuchen T, Ostermeier A, Fuentes DR et al. 2011. Induction of human neuronal cells by defined transcription factors. Nature 476:220–23
    [Google Scholar]
  104. 104.  Deleted in proof
  105. 105.  Pereira M, Pfisterer U, Rylander D, Torper O, Lau S et al. 2014. Highly efficient generation of induced neurons from human fibroblasts that survive transplantation into the adult rat brain. Sci. Rep. 4:16330
    [Google Scholar]
  106. 106.  Pfisterer U, Kirkeby A, Torper O, Wood J, Nelander J et al. 2011. Direct conversion of human fibroblasts to dopaminergic neurons. PNAS 108:2510343–48
    [Google Scholar]
  107. 107.  Prigione A, Hossini AM, Lichtner B, Serin A, Fauler B et al. 2011. Mitochondrial-associated cell death mechanisms are reset to an embryonic-like state in aged donor-derived iPS cells harboring chromosomal aberrations. PLOS ONE 6:11e27352
    [Google Scholar]
  108. 108.  Puzzo D, Gulisano W, Palmeri A, Arancio O 2015. Rodent models for Alzheimer's disease drug discovery. Expert Opin. Drug Discov. 10:7703–11
    [Google Scholar]
  109. 109.  Rakovic A, Shurkewitsch K, Seibler P, Grünewald A, Zanon A et al. 2013. Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)-dependent ubiquitination of endogenous Parkin attenuates mitophagy: study in human primary fibroblasts and induced pluripotent stem cell-derived neurons. J. Biol. Chem. 288:42223–37
    [Google Scholar]
  110. 110.  Rando TA, Chang HY 2012. Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. Cell 148:46–57
    [Google Scholar]
  111. 111.  Reinhardt P, Schmid B, Burbulla LF, Schöndorf DC, Wagner L et al. 2013. Genetic correction of a LRRK2 mutation in human iPSCs links Parkinsonian neurodegeneration to ERK-dependent changes in gene expression. Cell Stem Cell 12:3354–67
    [Google Scholar]
  112. 112.  Rivetti di Val Cervo P, Romanov RA, Spigolon G, Masini D, Martín-Montañez E et al. 2017. Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model. Nat. Biotechnol. 35:5444–52
    [Google Scholar]
  113. 113.  Savas JN, Toyama BH, Xu T, Yates JR, Hetzer MW 2012. Extremely long-lived nuclear pore proteins in the rat brain. Science 335:6071942–42
    [Google Scholar]
  114. 114.  Scheibye-Knudsen M, Mitchell SJ, Fang EF, Iyama T, Ward T et al. 2014. A high-fat diet and NAD+ activate Sirt1 to rescue premature aging in Cockayne syndrome. Cell Metab 20:5840–55
    [Google Scholar]
  115. 115.  Scheibye-Knudsen M, Tseng A, Borch Jensen M, Scheibye-Alsing K, Fang EF et al. 2016. Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA. PNAS 113:4412502–7
    [Google Scholar]
  116. 116.  Seibler P, Graziotto J, Jeong H, Simunovic F, Klein C, Krainc D 2011. Mitochondrial Parkin recruitment is impaired in neurons derived from mutant PINK1 induced pluripotent stem cells. J. Neurosci. 31:165970–76
    [Google Scholar]
  117. 117.  Sepe S, Milanese C, Gabriels S, Derks KWJ, Payan-Gomez C et al. 2016. Inefficient DNA repair is an aging-related modifier of Parkinson's disease. Cell Rep 15:91866–75
    [Google Scholar]
  118. 118.  Shi KY, Mori E, Nizami ZF, Lin Y, Kato M et al. 2017. Toxic PRn poly-dipeptides encoded by the C9orf72 repeat expansion block nuclear import and export. PNAS 114:7E1111–17
    [Google Scholar]
  119. 119.  Smith DK, Yang J, Liu M-L, Zhang C-L 2016. Small molecules modulate chromatin accessibility to promote NEUROG2-mediated fibroblast-to-neuron reprogramming. Stem Cell Rep 7:955–69
    [Google Scholar]
  120. 120.  Son EY, Ichida JK, Wainger BJ, Toma JS, Rafuse VF et al. 2011. Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell 9:205–18
    [Google Scholar]
  121. 121.  Studer L, Vera E, Cornacchia D 2015. Programming and reprogramming cellular age in the era of induced pluripotency. Cell Stem Cell 16:6591–600
    [Google Scholar]
  122. 122.  Suberbielle E, Sanchez PE, Kravitz AV, Wang X, Ho K et al. 2013. Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β. Nat. Neurosci. 16:5613–21
    [Google Scholar]
  123. 123.  Sugiura M, Kasama Y, Araki R, Hoki Y, Sunayama M et al. 2014. Induced pluripotent stem cell generation-associated point mutations arise during the initial stages of the conversion of these cells. Stem Cell Rep 2:152–63
    [Google Scholar]
  124. 124.  Suhr ST, Chang E-A, Rodriguez RM, Wang K, Ross PJ et al. 2009. Telomere dynamics in human cells reprogrammed to pluripotency. PLOS ONE 4:12e8124
    [Google Scholar]
  125. 125.  Suhr ST, Chang E-A, Tjong J, Alcasid N, Perkins GA et al. 2010. Mitochondrial rejuvenation after induced pluripotency. PLOS ONE 5:11e14095
    [Google Scholar]
  126. 126.  Tabar V, Studer L 2014. Pluripotent stem cells in regenerative medicine: challenges and recent progress. Nat. Rev. Genet. 15:282–92
    [Google Scholar]
  127. 127.  Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T et al. 2007. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:5861–72
    [Google Scholar]
  128. 128.  Tang Y, Liu M-L, Zang T, Zhang C-L 2017. Direct reprogramming rather than iPSC-based reprogramming maintains aging hallmarks in human motor neurons. Front. Mol. Neurosci 10:359
    [Google Scholar]
  129. 129.  Teschendorff AE, West J, Beck S 2013. Age-associated epigenetic drift: implications, and a case of epigenetic thrift?. Hum. Mol. Genet. 22:R7–15
    [Google Scholar]
  130. 130.  Theka I, Caiazzo M, Dvoretskova E, Leo D, Ungaro F et al. 2013. Rapid generation of functional dopaminergic neurons from human induced pluripotent stem cells through a single-step procedure using cell lineage transcription factors. Stem Cells Transl. Med. 2:6473–79
    [Google Scholar]
  131. 131.  Thier M, Wörsdörfer P, Lakes YB, Gorris R, Herms S et al. 2012. Direct conversion of fibroblasts into stably expandable neural stem cells. Cell Stem Cell 10:4473–79
    [Google Scholar]
  132. 132.  Thoma EC, Wischmeyer E, Offen N, Maurus K, Sirén A-L et al. 2012. Ectopic expression of neurogenin 2 alone is sufficient to induce differentiation of embryonic stem cells into mature neurons. PLOS ONE 7:6e38651
    [Google Scholar]
  133. 133.  Toda T, Hsu JY, Linker SB, Hu L, Schafer ST et al. 2017. Nup153 interacts with Sox2 to enable bimodal gene regulation and maintenance of neural progenitor cells. Cell Stem Cell 21:618–634.e7
    [Google Scholar]
  134. 134.  Torper O, Pfisterer U, Wolf DA, Pereira M, Lau S et al. 2013. Generation of induced neurons via direct conversion in vivo. PNAS 110:177038–43
    [Google Scholar]
  135. 135.  Toyama BH, Hetzer MW 2013. Protein homeostasis: live long, won't prosper. Nat. Rev. Mol. Cell Biol. 14:155–61
    [Google Scholar]
  136. 136.  Toyama BH, Savas JN, Park SK, Harris MS, Ingolia NT et al. 2013. Identification of long-lived proteins reveals exceptional stability of essential cellular structures. Cell 154:5971–82
    [Google Scholar]
  137. 137.  Treutlein B, Lee QY, Camp JG, Mall M, Koh W et al. 2016. Dissecting direct reprogramming from fibroblast to neuron using single-cell RNA-seq. Nature 534:7607391–95
    [Google Scholar]
  138. 138.  Vadodaria KC, Marchetto MC, Mertens J, Gage FH 2016. Generating human serotonergic neurons in vitro: methodological advances. BioEssays 38:111123–29
    [Google Scholar]
  139. 139.  Vadodaria KC, Mertens J, Paquola A, Bardy C, Li X et al. 2016. Generation of functional human serotonergic neurons from fibroblasts. Mol. Psychiatry 21:149–61
    [Google Scholar]
  140. 140.  Vera E, Bosco N, Studer L 2016. Generating late-onset human iPSC-based disease models by inducing neuronal age-related phenotypes through telomerase manipulation. Cell Rep 17:41184–92
    [Google Scholar]
  141. 141.  Vermeij WP, Dollé MET, Reiling E, Jaarsma D, Payan-Gomez C et al. 2016. Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice. Nature 537:7620427–31
    [Google Scholar]
  142. 142.  Victor MB, Richner M, Hermanstyne TO, Ransdell JL, Sobieski C et al. 2014. Generation of human striatal neurons by microRNA-dependent direct conversion of fibroblasts. Neuron 84:2311–23
    [Google Scholar]
  143. 143.  Victor MB, Richner M, Olsen HE, Lee SW, Monteys AM et al. 2018. Striatal neurons directly converted from Huntington's disease patient fibroblasts recapitulate age-associated disease phenotypes. Nat. Neurosci. 21:341–52
    [Google Scholar]
  144. 144.  Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Südhof TC, Wernig M 2010. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463:72841035–41
    [Google Scholar]
  145. 145.  Wapinski OL, Lee QY, Chen AC, Li R, Corces MR et al. 2017. Rapid chromatin switch in the direct reprogramming of fibroblasts to neurons. Cell Rep 20:133236–47
    [Google Scholar]
  146. 146.  Wapinski OL, Vierbuchen T, Qu K, Lee QY, Chanda S et al. 2013. Hierarchical mechanisms for direct reprogramming of fibroblasts to neurons. Cell 155:3621–35
    [Google Scholar]
  147. 147.  Warren L, Manos PD, Ahfeldt T, Loh Y-H, Li H et al. 2010. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7:5618–30
    [Google Scholar]
  148. 148.  Woodruff G, Young JE, Martinez FJ, Buen F, Gore A et al. 2013. The presenilin-1 ΔE9 mutation results in reduced γ-secretase activity, but not total loss of PS1 function, in isogenic human stem cells. Cell Rep 5:4974–85
    [Google Scholar]
  149. 149.  Xu Z, Jiang H, Zhong P, Yan Z, Chen S, Feng J 2016. Direct conversion of human fibroblasts to induced serotonergic neurons. Mol. Psychiatry 21:162–70
    [Google Scholar]
  150. 150.  Xue Y, Ouyang K, Huang J, Zhou Y, Ouyang H et al. 2013. Direct conversion of fibroblasts to neurons by reprogramming PTB-regulated microRNA circuits. Cell 152:82–96
    [Google Scholar]
  151. 151.  Yagi T, Ito D, Okada Y, Akamatsu W, Nihei Y et al. 2011. Modeling familial Alzheimer's disease with induced pluripotent stem cells. Hum. Mol. Genet. 20:234530–39
    [Google Scholar]
  152. 152.  Yang N, Chanda S, Marro S, Ng YH, Janas JA et al. 2017. Generation of pure GABAergic neurons by transcription factor programming. Nat. Methods 14:6621–28
    [Google Scholar]
  153. 153.  Yang N, Zuchero JB, Ahlenius H, Marro S, Ng YH et al. 2013. Generation of oligodendroglial cells by direct lineage conversion. Nat. Biotechnol. 31:5434–39
    [Google Scholar]
  154. 154.  Yang Y, Jiao J, Gao R, Le R, Kou X et al. 2015. Enhanced rejuvenation in induced pluripotent stem cell-derived neurons compared with directly converted neurons from an aged mouse. Stem Cells Dev 24:232767–77
    [Google Scholar]
  155. 155.  Yang Y, Jiao J, Gao R, Yao H, Sun X-F, Gao S 2013. Direct conversion of adipocyte progenitors into functional neurons. Cell. Reprogramming 15:6484–89
    [Google Scholar]
  156. 156.  Yoo AS, Sun AX, Li L, Shcheglovitov A, Portmann T et al. 2011. MicroRNA-mediated conversion of human fibroblasts to neurons. Nature 476:7359228–31
    [Google Scholar]
  157. 157.  Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB et al. 2015. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525:756756–61
    [Google Scholar]
  158. 158.  Zhang K, Liu G-H, Yi F, Montserrat N, Hishida T et al. 2014. Direct conversion of human fibroblasts into retinal pigment epithelium-like cells by defined factors. Protein Cell 5:148–58
    [Google Scholar]
  159. 159.  Zeng H, Guo M, Martins-Taylor K, Wang X, Zhang Z et al. 2010. Specification of region-specific neurons including forebrain glutamatergic neurons from human induced pluripotent stem cells. PLOS ONE 5:7e11853
    [Google Scholar]
  160. 160.  Zhao J, He H, Zhou K, Ren Y, Shi Z et al. 2012. Neuronal transcription factors induce conversion of human glioma cells to neurons and inhibit tumorigenesis. PLOS ONE 7:7e41506
    [Google Scholar]
  161. 161.  Zheng SC, Widschwendter M, Teschendorff AE 2016. Epigenetic drift, epigenetic clocks and cancer risk. Epigenomics 8:5705–19
    [Google Scholar]
  162. 162.  Zhou T, Benda C, Duzinger S, Huang Y, Li X et al. 2011. Generation of induced pluripotent stem cells from urine. J. Am. Soc. Nephrol. 22:71221–28
    [Google Scholar]
  163. 163.  Zhu S, Russ HA, Wang X, Zhang M, Ma T et al. 2016. Human pancreatic beta-like cells converted from fibroblasts. Nat. Commun. 7:10080
    [Google Scholar]
/content/journals/10.1146/annurev-genet-120417-031534
Loading
/content/journals/10.1146/annurev-genet-120417-031534
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error