1932

Abstract

Neurodegenerative diseases, characterized by progressive neural loss, have been some of the most challenging medical problems in aging societies. Treatment strategies such as symptom management have little impact on disease progression, while intervention with specific disease mechanisms may only slow down disease progression. One therapeutic strategy that has the potential to reverse the disease phenotype is to replenish neurons and rebuild the pathway lost to degeneration. Although it is generally believed that the central nervous system has lost the capability to regenerate, increasing evidence indicates that the brain is more plastic than previously thought, containing perhaps the biggest repertoire of cells with latent neurogenic programs in the body. This review focuses on key advances in generating new neurons through in situ neuronal reprogramming, which is tied to fundamental questions regarding adult neurogenesis, cell source, and mechanisms for neuronal reprogramming, as well as the ability of new neurons to integrate into the existing circuitry.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-genet-071719-023616
2021-11-23
2024-04-24
Loading full text...

Full text loading...

/deliver/fulltext/genet/55/1/annurev-genet-071719-023616.html?itemId=/content/journals/10.1146/annurev-genet-071719-023616&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Addis RC, Hsu F-C, Wright RL, Dichter MA, Coulter DA, Gearhart JD. 2011. Efficient conversion of astrocytes to functional midbrain dopaminergic neurons using a single polycistronic vector. PLOS ONE 6:e28719
    [Google Scholar]
  2. 2. 
    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 9:113–18
    [Google Scholar]
  3. 3. 
    Anacker C, Hen R. 2017. Adult hippocampal neurogenesis and cognitive flexibility—linking memory and mood. Nat. Rev. Neurosci. 18:335–46
    [Google Scholar]
  4. 4. 
    Anderson MA, Burda JE, Ren Y, Ao Y, O'Shea TM et al. 2016. Astrocyte scar formation aids central nervous system axon regeneration. Nature 532:195–200
    [Google Scholar]
  5. 5. 
    Andreotti JP, Silva WN, Costa AC, Picoli CC, Bitencourt FC et al. 2019. Neural stem cell niche heterogeneity. Semin. Cell Dev. Biol. 95:42–53
    [Google Scholar]
  6. 6. 
    Anthony TE, Klein C, Fishell G, Heintz N. 2004. Radial glia serve as neuronal progenitors in all regions of the central nervous system. Neuron 41:881–90
    [Google Scholar]
  7. 7. 
    Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O. 2002. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat. Med. 8:963–70
    [Google Scholar]
  8. 8. 
    Assinck P, Duncan GJ, Hilton BJ, Plemel JR, Tetzlaff W. 2017. Cell transplantation therapy for spinal cord injury. Nat. Neurosci. 20:637–47
    [Google Scholar]
  9. 9. 
    Ballas N, Grunseich C, Lu DD, Speh JC, Mandel G. 2005. REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell 121:645–57
    [Google Scholar]
  10. 10. 
    Barker RA. 2019. Designing stem-cell-based dopamine cell replacement trials for Parkinson's disease. Nat. Med. 25:1045–53
    [Google Scholar]
  11. 11. 
    Barker RA, Barrett J, Mason SL, Björklund A. 2013. Fetal dopaminergic transplantation trials and the future of neural grafting in Parkinson's disease. Lancet Neurol 12:84–91
    [Google Scholar]
  12. 12. 
    Barker RA, Parmar M, Studer L, Takahashi J. 2017. Human trials of stem cell-derived dopamine neurons for Parkinson's disease: dawn of a new era. Cell Stem Cell 21:569–73
    [Google Scholar]
  13. 13. 
    Batiuk MY, Martirosyan A, Wahis J, de Vin F, Marneffe C et al. 2020. Identification of region-specific astrocyte subtypes at single cell resolution. Nat. Commun. 11:1220
    [Google Scholar]
  14. 14. 
    Bayraktar OA, Fuentealba LC, Alvarez-Buylla A, Rowitch DH. 2015. Astrocyte development and heterogeneity. Cold Spring Harb. Perspect. Biol. 7:a020362
    [Google Scholar]
  15. 15. 
    Bennett CF, Krainer AR, Cleveland DW. 2019. Antisense oligonucleotide therapies for neurodegenerative diseases. Annu. Rev. Neurosci. 42:385–406
    [Google Scholar]
  16. 16. 
    Benraiss A, Wang S, Herrlinger S, Li X, Chandler-Militello D et al. 2016. Human glia can both induce and rescue aspects of disease phenotype in Huntington disease. Nat. Commun. 7:11758
    [Google Scholar]
  17. 17. 
    Berninger B, Costa MR, Koch U, Schroeder T, Sutor B et al. 2007. Functional properties of neurons derived from in vitro reprogrammed postnatal astroglia. J. Neurosci. 27:8654–64
    [Google Scholar]
  18. 18. 
    Biddy BA, Kong W, Kamimoto K, Guo C, Waye SE et al. 2018. Single-cell mapping of lineage and identity in direct reprogramming. Nature 564:219–24
    [Google Scholar]
  19. 19. 
    Björklund A, Stenevi U, Schmidt RH, Dunnett SB, Gage FH. 1983. Intracerebral grafting of neuronal cell suspensions. II. Survival and growth of nigral cell suspensions implanted in different brain sites. Acta Physiol. Scand. Suppl. 522:9–18
    [Google Scholar]
  20. 20. 
    Black DL. 2003. Mechanisms of alternative pre-messenger RNA splicing. Annu. Rev. Biochem. 72:291–336
    [Google Scholar]
  21. 21. 
    Blackshaw S, Sanes JR. 2021. Turning lead into gold: reprogramming retinal cells to cure blindness. J. Clin. Investig. 131:e146134
    [Google Scholar]
  22. 22. 
    Blanchard JW, Eade KT, Szűcs A, Lo Sardo V, Tsunemoto RK et al. 2015. Selective conversion of fibroblasts into peripheral sensory neurons. Nat. Neurosci. 18:25–35
    [Google Scholar]
  23. 23. 
    Boisvert MM, Erikson GA, Shokhirev MN, Allen NJ. 2018. The aging astrocyte transcriptome from multiple regions of the mouse brain. Cell Rep 22:269–85
    [Google Scholar]
  24. 24. 
    Boldrini M, Fulmore CA, Tartt AN, Simeon LR, Pavlova I et al. 2018. Human hippocampal neuro-genesis persists throughout aging. Cell Stem Cell 22:589–99.E5
    [Google Scholar]
  25. 25. 
    Boutz PL, Stoilov P, Li Q, Lin C-H, Chawla G et al. 2007. A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons. Genes Dev 21:1636–52
    [Google Scholar]
  26. 26. 
    Bradford J, Shin J-Y, Roberts M, Wang C-E, Li X-J, Li S 2009. Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms. PNAS 106:22480–85
    [Google Scholar]
  27. 27. 
    Brown AW, Marlowe KJ, Bjelke B. 2003. Age effect on motor recovery in a post-acute animal stroke model. Neurobiol. Aging 24:607–14
    [Google Scholar]
  28. 28. 
    Bruce AW, Donaldson IJ, Wood IC, Yerbury SA, Sadowski MI et al. 2004. Genome-wide analysis of repressor element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) target genes. PNAS 101:10458–63
    [Google Scholar]
  29. 29. 
    Brulet R, Matsuda T, Zhang L, Miranda C, Giacca M et al. 2017. NEUROD1 instructs neuronal conversion in non-reactive astrocytes. Stem Cell Rep 8:1506–15
    [Google Scholar]
  30. 30. 
    Buffo A, Vosko MR, Ertürk D, Hamann GF, Jucker M et al. 2005. Expression pattern of the transcription factor Olig2 in response to brain injuries: implications for neuronal repair. PNAS 102:18183–88
    [Google Scholar]
  31. 31. 
    Cahan P, Li H, Morris SA, da Rocha EL, Daley GQ, Collins JJ. 2014. CellNet: network biology applied to stem cell engineering. Cell 158:903–15
    [Google Scholar]
  32. 32. 
    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 476:224–27
    [Google Scholar]
  33. 33. 
    Caldwell AB, Liu Q, Schroth GP, Galasko DR, Yuan SH et al. 2020. Dedifferentiation and neuronal repression define familial Alzheimer's disease. Sci. Adv. 6:eaba5933
    [Google Scholar]
  34. 34. 
    Cates K, McCoy MJ, Kwon J-S, Liu Y, Abernathy DG et al. 2021. Deconstructing stepwise fate conversion of human fibroblasts to neurons by microRNAs. Cell Stem Cell 28:127–40.e9
    [Google Scholar]
  35. 35. 
    Chen R-L, Balami JS, Esiri MM, Chen L-K, Buchan AM. 2010. Ischemic stroke in the elderly: an overview of evidence. Nat. Rev. Neurol. 6:256–65
    [Google Scholar]
  36. 36. 
    Chen Y-C, Ma N-X, Pei Z-F, Wu Z, Do-Monte FH et al. 2020. A NeuroD1 AAV-based gene therapy for functional brain repair after ischemic injury through in vivo astrocyte-to-neuron conversion. Mol. Ther. 28:217–34
    [Google Scholar]
  37. 37. 
    Chong JA, Tapia-Ramirez J, Kim S, Toledo-Aral JJ, Zheng Y et al. 1995. REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell 80:949–57
    [Google Scholar]
  38. 38. 
    Clarke LE, Liddelow SA, Chakraborty C, Münch AE, Heiman M, Barres BA 2018. Normal aging induces A1-like astrocyte reactivity. PNAS 115:E1896–905
    [Google Scholar]
  39. 39. 
    Colasante G, Lignani G, Rubio A, Medrihan L, Yekhlef L et al. 2015. Rapid conversion of fibroblasts into functional forebrain GABAergic interneurons by direct genetic reprogramming. Cell Stem Cell 17:719–34
    [Google Scholar]
  40. 40. 
    Collier TJ, Sortwell CE, Elsworth JD, Taylor JR, Roth RH et al. 2002. Embryonic ventral mesencephalic grafts to the substantia nigra of MPTP-treated monkeys: feasibility relevant to multiple-target grafting as a therapy for Parkinson's disease. J. Comp. Neurol. 442:320–30
    [Google Scholar]
  41. 41. 
    Corey DR. 2017. Nusinersen, an antisense oligonucleotide drug for spinal muscular atrophy. Nat. Neurosci. 20:497–99
    [Google Scholar]
  42. 42. 
    Coutinho-Mansfield GC, Xue Y, Zhang Y, Fu X-D. 2007. PTB/nPTB switch: a post-transcriptional mechanism for programming neuronal differentiation. Genes Dev 21:1573–77
    [Google Scholar]
  43. 43. 
    Curtis MA, Kam M, Nannmark U, Anderson MF, Axell MZ et al. 2007. Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science 315:1243–49
    [Google Scholar]
  44. 44. 
    Davis RL, Weintraub H, Lassar AB. 1987. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51:987–1000
    [Google Scholar]
  45. 45. 
    De Gioia R, Biella F, Citterio G, Rizzo F, Abati E et al. 2020. Neural stem cell transplantation for neurodegenerative diseases. Int. J. Mol. Sci. 21:3103
    [Google Scholar]
  46. 46. 
    di Val Cervo PR, 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. 35:444–52
    [Google Scholar]
  47. 47. 
    Diaz-Castro B, Gangwani MR, Yu X, Coppola G, Khakh BS. 2019. Astrocyte molecular signatures in Huntington's disease. Sci. Transl. Med. 11:eaaw8546
    [Google Scholar]
  48. 48. 
    Doi D, Magotani H, Kikuchi T, Ikeda M, Hiramatsu S et al. 2020. Pre-clinical study of induced pluripotent stem cell-derived dopaminergic progenitor cells for Parkinson's disease. Nat. Commun. 11:3369
    [Google Scholar]
  49. 49. 
    Doty RL. 2012. Olfactory dysfunction in Parkinson disease. Nat. Rev. Neurol. 8:329–39
    [Google Scholar]
  50. 50. 
    Duan CL, Liu CW, Shen SW, Yu Z, Mo JL et al. 2015. Striatal astrocytes transdifferentiate into functional mature neurons following ischemic brain injury. Glia 63:1660–70
    [Google Scholar]
  51. 51. 
    Dunnett SB, Björklund A, Lindvall O. 2001. Cell therapy in Parkinson's disease—stop or go?. Nat. Rev. Neurosci. 2:365–69
    [Google Scholar]
  52. 52. 
    Ehm O, Göritz C, Covic M, Schäffner I, Schwarz TJ et al. 2010. RBPJκ-dependent signaling is essential for long-term maintenance of neural stem cells in the adult hippocampus. J. Neurosci. 30:13794–807
    [Google Scholar]
  53. 53. 
    Ernst A, Alkass K, Bernard S, Salehpour M, Perl S et al. 2014. Neurogenesis in the striatum of the adult human brain. Cell 156:1072–83
    [Google Scholar]
  54. 54. 
    Espay AJ, Brundin P, Lang AE. 2017. Precision medicine for disease modification in Parkinson disease. Nat. Rev. Neurol. 13:119–26
    [Google Scholar]
  55. 55. 
    Faideau M, Kim J, Cormier K, Gilmore R, Welch M et al. 2010. In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects. Hum. Mol. Genet. 19:3053–67
    [Google Scholar]
  56. 56. 
    Fandel TM, Trivedi A, Nicholas CR, Zhang H, Chen J et al. 2016. Transplanted human stem cell-derived interneuron precursors mitigate mouse bladder dysfunction and central neuropathic pain after spinal cord injury. Cell Stem Cell 19:544–57
    [Google Scholar]
  57. 57. 
    Farah MH, Olson JM, Sucic HB, Hume RI, Tapscott SJ, Turner DL. 2000. Generation of neurons by transient expression of neural bHLH proteins in mammalian cells. Development 127:693–702
    [Google Scholar]
  58. 58. 
    Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J et al. 2016. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet 388:3017–26
    [Google Scholar]
  59. 59. 
    Freed CR, Greene PE, Breeze RE, Tsai W-Y, DuMouchel W et al. 2001. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N. Engl. J. Med. 344:710–19
    [Google Scholar]
  60. 60. 
    Fu X, Zhu J, Duan Y, Li G, Cai H et al. 2020. Visual function restoration in genetically blind mice via endogenous cellular reprogramming. bioRxiv 2020.04.08.030981. https://doi.org/10.1101/2020.04.08.030981
    [Crossref]
  61. 61. 
    Gage FH, Temple S. 2013. Neural stem cells: generating and regenerating the brain. Neuron 80:588–601
    [Google Scholar]
  62. 62. 
    Gaillard A, Decressac M, Frappé I, Fernagut PO, Prestoz L et al. 2009. Anatomical and functional reconstruction of the nigrostriatal pathway by intranigral transplants. Neurobiol. Dis 35:477–88
    [Google Scholar]
  63. 63. 
    Gaillard A, Jaber M. 2011. Rewiring the brain with cell transplantation in Parkinson's disease. Trends Neurosci 34:124–33
    [Google Scholar]
  64. 64. 
    García-Blanco MA, Jamison SF, Sharp PA. 1989. Identification and purification of a 62,000-dalton protein that binds specifically to the polypyrimidine tract of introns. Genes Dev 3:1874–86
    [Google Scholar]
  65. 65. 
    Gascón S, Masserdotti G, Russo GL, Götz M. 2017. Direct neuronal reprogramming: achievements, hurdles, and new roads to success. Cell Stem Cell 21:18–34
    [Google Scholar]
  66. 66. 
    Gascón S, Murenu E, Masserdotti G, Ortega F, Russo GL et al. 2016. Identification and successful negotiation of a metabolic checkpoint in direct neuronal reprogramming. Cell Stem Cell 18:396–409
    [Google Scholar]
  67. 67. 
    Ge L-J, Yang F-H, Li W, Wang T, Lin Y et al. 2020. In vivo neuroregeneration to treat ischemic stroke through NeuroD1 AAV-based gene therapy in adult non-human primates. Front. Cell Dev. Biol 8:590008
    [Google Scholar]
  68. 68. 
    Golde TE, DeKosky ST, Galasko D. 2018. Alzheimer's disease: the right drug, the right time. Science 362:1250–51
    [Google Scholar]
  69. 69. 
    Gonçalves JT, Schafer ST, Gage FH. 2016. Adult neurogenesis in the hippocampus: from stem cells to behavior. Cell 167:897–914
    [Google Scholar]
  70. 70. 
    Götz M, Sirko S, Beckers J, Irmler M. 2015. Reactive astrocytes as neural stem or progenitor cells: in vivo lineage, in vitro potential, and genome-wide expression analysis. Glia 63:1452–68
    [Google Scholar]
  71. 71. 
    Grade S, Götz M. 2017. Neuronal replacement therapy: previous achievements and challenges ahead. NPJ Regen. Med. 2:29
    [Google Scholar]
  72. 72. 
    Grealish S, Diguet E, Kirkeby A, Mattsson B, Heuer A et al. 2014. Human ESC-derived dopamine neurons show similar preclinical efficacy and potency to fetal neurons when grafted in a rat model of Parkinson's disease. Cell Stem Cell 15:653–65
    [Google Scholar]
  73. 73. 
    Gresita A, Glavan DG, Udristoiu I, Catalin B, Hermann DM, Popa-Wagner A. 2019. Very low efficiency of direct reprogramming of astrocytes into neurons in the brains of young and aged mice after cerebral ischemia. Front. Aging Neurosci. 11:334
    [Google Scholar]
  74. 74. 
    Guo Z, Zhang L, Wu Z, Chen Y, Wang F, Chen G 2014. In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer's disease model. Cell Stem Cell 14:188–202
    [Google Scholar]
  75. 75. 
    Hallett PJ, Deleidi M, Astradsson A, Smith GA, Cooper O et al. 2015. Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson's disease. Cell Stem Cell 16:269–74
    [Google Scholar]
  76. 76. 
    Heinrich C, Blum R, Gascón S, Masserdotti G, Tripathi P et al. 2010. Directing astroglia from the cerebral cortex into subtype specific functional neurons. PLOS Biol 8:e1000373
    [Google Scholar]
  77. 77. 
    Heins N, Malatesta P, Cecconi F, Nakafuku M, Tucker KL et al. 2002. Glial cells generate neurons: the role of the transcription factor Pax6. Nat. Neurosci. 5:308–15
    [Google Scholar]
  78. 78. 
    Hou Y, Dan X, Babbar M, Wei Y, Hasselbalch SG et al. 2019. Ageing as a risk factor for neurodegenerative disease. Nat. Rev. Neurol. 15:565–81
    [Google Scholar]
  79. 79. 
    Hu J, Qian H, Xue Y, Fu X-D. 2018. PTB/nPTB: master regulators of neuronal fate in mammals. Biophys. Rep. 4:204–14
    [Google Scholar]
  80. 80. 
    Hu X, Qin S, Huang X, Yuan Y, Tan Z et al. 2019. Region-restrict astrocytes exhibit heterogeneous susceptibility to neuronal reprogramming. Stem Cell Rep 12:290–304
    [Google Scholar]
  81. 81. 
    Jin K, Wang X, Xie L, Mao XO, Zhu W et al. 2006. Evidence for stroke-induced neurogenesis in the human brain. PNAS 103:13198–202
    [Google Scholar]
  82. 82. 
    Johnson DS, Mortazavi A, Myers RM, Wold B. 2007. Genome-wide mapping of in vivo protein-DNA interactions. Science 316:1497–502
    [Google Scholar]
  83. 83. 
    Juopperi TA, Kim WR, Chiang C-H, Yu H, Margolis RL et al. 2012. Astrocytes generated from patient induced pluripotent stem cells recapitulate features of Huntington's disease patient cells. Mol. Brain 5:17
    [Google Scholar]
  84. 84. 
    Kane AE, Sinclair DA. 2019. Epigenetic changes during aging and their reprogramming potential. Crit. Rev. Biochem. Mol. Biol. 54:61–83
    [Google Scholar]
  85. 85. 
    Karow M, Camp JG, Falk S, Gerber T, Pataskar A et al. 2018. Direct pericyte-to-neuron reprogramming via unfolding of a neural stem cell-like program. Nat. Neurosci. 21:932–40
    [Google Scholar]
  86. 86. 
    Kaslin J, Ganz J, Brand M. 2008. Proliferation, neurogenesis and regeneration in the non-mammalian vertebrate brain. Philos. Trans. R. Soc. B 363:101–22
    [Google Scholar]
  87. 87. 
    Kempermann G, Gage FH, Aigner L, Song H, Curtis MA et al. 2018. Human adult neurogenesis: evidence and remaining questions. Cell Stem Cell 23:25–30
    [Google Scholar]
  88. 88. 
    Kikuchi T, Morizane A, Doi D, Magotani H, Onoe H et al. 2017. Human iPS cell-derived dopaminergic neurons function in a primate Parkinson's disease model. Nature 548:592–96
    [Google Scholar]
  89. 89. 
    Kizil C, Kaslin J, Kroehne V, Brand M. 2012. Adult neurogenesis and brain regeneration in zebrafish. Dev. Neurobiol. 72:429–61
    [Google Scholar]
  90. 90. 
    Koh S-H, Park H-H. 2017. Neurogenesis in stroke recovery. Transl. Stroke Res. 8:3–13
    [Google Scholar]
  91. 91. 
    Kokoeva MV, Yin H, Flier JS. 2007. Evidence for constitutive neural cell proliferation in the adult murine hypothalamus. J. Comp. Neurol. 505:209–20
    [Google Scholar]
  92. 92. 
    Kriegstein A, Alvarez-Buylla A. 2009. The glial nature of embryonic and adult neural stem cells. Annu. Rev. Neurosci. 32:149–84
    [Google Scholar]
  93. 93. 
    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]
  94. 94. 
    Kuhn HG, Dickinson-Anson H, Gage FH. 1996. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J. Neurosci. 16:2027–33
    [Google Scholar]
  95. 95. 
    Kumamaru H, Kadoya K, Adler AF, Takashima Y, Graham L et al. 2018. Generation and post-injury integration of human spinal cord neural stem cells. Nat. Methods 15:723–31
    [Google Scholar]
  96. 96. 
    La Manno G, Gyllborg D, Codeluppi S, Nishimura K, Salto C et al. 2016. Molecular diversity of midbrain development in mouse, human, and stem cells. Cell 167:566–80.e19
    [Google Scholar]
  97. 97. 
    Lai K, Kaspar BK, Gage FH, Schaffer DV. 2003. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat. Neurosci. 6:21–27
    [Google Scholar]
  98. 98. 
    Li K, Li J, Zheng J, Qin S. 2019. Reactive astrocytes in neurodegenerative diseases. Aging Dis 10:664–75
    [Google Scholar]
  99. 99. 
    Li Q, Zheng S, Han A, Lin C-H, Stoilov P et al. 2014. The splicing regulator PTBP2 controls a program of embryonic splicing required for neuronal maturation. eLife 3:e01201
    [Google Scholar]
  100. 100. 
    Li W, Sun W, Zhang Y, Wei W, Ambasudhan R et al. 2011. Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by small molecule inhibitors. PNAS 108:8299–304
    [Google Scholar]
  101. 101. 
    Liddelow SA, Barres BA. 2017. Reactive astrocytes: production, function, and therapeutic potential. Immunity 46:957–67
    [Google Scholar]
  102. 102. 
    Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ et al. 2017. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–87
    [Google Scholar]
  103. 103. 
    Lindvall O, Kokaia Z, Martinez-Serrano A. 2004. Stem cell therapy for human neurodegenerative disorders–how to make it work. Nat. Med. 10:S42–50
    [Google Scholar]
  104. 104. 
    Liu S, Zhen G, Meloni BP, Campbell K, Winn HR. 2009. Rodent stroke model guidelines for preclinical stroke trials. J. Exp. Stroke Transl. Med. 2:2–27
    [Google Scholar]
  105. 105. 
    Liu Y, Miao Q, Yuan J, Han S, Zhang P et al. 2015. Ascl1 converts dorsal midbrain astrocytes into functional neurons in vivo. J. Neurosci. 35:9336–55
    [Google Scholar]
  106. 106. 
    Long JM, Holtzman DM. 2019. Alzheimer disease: an update on pathobiology and treatment strategies. Cell 179:312–39
    [Google Scholar]
  107. 107. 
    Loria F, Vargas JY, Bousset L, Syan S, Salles A et al. 2017. α-Synuclein transfer between neurons and astrocytes indicates that astrocytes play a role in degradation rather than in spreading. Acta Neuropathol 134:789–808
    [Google Scholar]
  108. 108. 
    Lu T, Aron L, Zullo J, Pan Y, Kim H et al. 2014. REST and stress resistance in ageing and Alzheimer's disease. Nature 507:448–54
    [Google Scholar]
  109. 109. 
    Magnusson JP, Frisén J. 2016. Stars from the darkest night: unlocking the neurogenic potential of astrocytes in different brain regions. Development 143:1075–86
    [Google Scholar]
  110. 110. 
    Magnusson JP, Göritz C, Tatarishvili J, Dias DO, Smith EM et al. 2014. A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse. Science 346:237–41
    [Google Scholar]
  111. 111. 
    Magnusson JP, Zamboni M, Santopolo G, Mold JE, Barrientos-Somarribas M et al. 2020. Activation of a neural stem cell transcriptional program in parenchymal astrocytes. eLife 9:e59733
    [Google Scholar]
  112. 112. 
    Makeyev EV, Zhang J, Carrasco MA, Maniatis T. 2007. The microRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol. Cell 27:435–48
    [Google Scholar]
  113. 113. 
    Malatesta P, Hack MA, Hartfuss E, Kettenmann H, Klinkert W et al. 2003. Neuronal or glial progeny: regional differences in radial glia fate. Neuron 37:751–64
    [Google Scholar]
  114. 114. 
    Malatesta P, Hartfuss E, Götz M. 2000. Isolation of radial glial cells by fluorescent-activated cell sorting reveals a neuronal lineage. Development 127:5253–63
    [Google Scholar]
  115. 115. 
    Maliken BD, Molkentin JD. 2018. Undeniable evidence that the adult mammalian heart lacks an endogenous regenerative stem cell. Circulation 138:806–8
    [Google Scholar]
  116. 116. 
    Mall M, Kareta MS, Chanda S, Ahlenius H, Perotti N et al. 2017. Myt1l safeguards neuronal identity by actively repressing many non-neuronal fates. Nature 544:245–49
    [Google Scholar]
  117. 117. 
    Maslov AY, Barone TA, Plunkett RJ, Pruitt SC. 2004. Neural stem cell detection, characterization, and age-related changes in the subventricular zone of mice. J. Neurosci. 24:1726–33
    [Google Scholar]
  118. 118. 
    Masserdotti G, Gillotin S, Sutor B, Drechsel D, Irmler M et al. 2015. Transcriptional mechanisms of proneural factors and REST in regulating neuronal reprogramming of astrocytes. Cell Stem Cell 17:74–88
    [Google Scholar]
  119. 119. 
    Matsuda T, Irie T, Katsurabayashi S, Hayashi Y, Nagai T et al. 2019. Pioneer factor NeuroD1 rearranges transcriptional and epigenetic profiles to execute microglia-neuron conversion. Neuron 101:472–85.e7
    [Google Scholar]
  120. 120. 
    Mattugini N, Bocchi R, Scheuss V, Russo GL, Torper O et al. 2019. Inducing different neuronal subtypes from astrocytes in the injured mouse cerebral cortex. Neuron 103:1086–95.e5
    [Google Scholar]
  121. 121. 
    Merkle FT, Fuentealba LC, Sanders TA, Magno L, Kessaris N, Alvarez-Buylla A. 2014. Adult neural stem cells in distinct microdomains generate previously unknown interneuron types. Nat. Neurosci. 17:207–14
    [Google Scholar]
  122. 122. 
    Ming G-l, Song H. 2011. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70:687–702
    [Google Scholar]
  123. 123. 
    Mori T, Buffo A, Götz M. 2005. The novel roles of glial cells revisited: the contribution of radial glia and astrocytes to neurogenesis. Curr. Top. Dev. Biol. 69:67–99
    [Google Scholar]
  124. 124. 
    Morris SA, Cahan P, Li H, Zhao AM, San Roman AK et al. 2014. Dissecting engineered cell types and enhancing cell fate conversion via CellNet. Cell 158:889–902
    [Google Scholar]
  125. 125. 
    Murphy TH, Corbett D. 2009. Plasticity during stroke recovery: from synapse to behaviour. Nat. Rev. Neurosci. 10:861–72
    [Google Scholar]
  126. 126. 
    Negredo PN, Yeo RW, Brunet A. 2020. Aging and rejuvenation of neural stem cells and their niches. Cell Stem Cell 27:202–23
    [Google Scholar]
  127. 127. 
    Niu W, Zang T, Smith DK, Vue TY, Zou Y et al. 2015. SOX2 reprograms resident astrocytes into neural progenitors in the adult brain. Stem Cell Rep 4:780–94
    [Google Scholar]
  128. 128. 
    Niu W, Zang T, Zou Y, Fang S, Smith DK et al. 2013. In vivo reprogramming of astrocytes to neuro-blasts in the adult brain. Nat. Cell Biol. 15:1164–75
    [Google Scholar]
  129. 129. 
    Niv F, Keiner S, Krishna K, Witte OW, Lie DC, Redecker C. 2012. Aberrant neurogenesis after stroke: a retroviral cell labeling study. Stroke 43:2468–75
    [Google Scholar]
  130. 130. 
    Olanow C, Fahn S 2006. Fetal nigral transplantation as a therapy for Parkinson's disease. Restorative Therapies in Parkinson's Disease P Brundin, CW Olanow 93–118 Boston: Springer
    [Google Scholar]
  131. 131. 
    Olanow CW, Goetz CG, Kordower JH, Stoessl AJ, Sossi V et al. 2003. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease. Ann. Neurol. 54:403–14
    [Google Scholar]
  132. 132. 
    Palma-Tortosa S, Tornero D, Hansen MG, Monni E, Hajy M et al. 2020. Activity in grafted human iPS cell–derived cortical neurons integrated in stroke-injured rat brain regulates motor behavior. PNAS 117:9094–100
    [Google Scholar]
  133. 133. 
    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]
  134. 134. 
    Parish CL, Beljajeva A, Arenas E, Simon A. 2007. Midbrain dopaminergic neurogenesis and behavioural recovery in a salamander lesion-induced regeneration model. Development 134:2881–87
    [Google Scholar]
  135. 135. 
    Pfisterer U, Kirkeby A, Torper O, Wood J, Nelander J et al. 2011. Direct conversion of human fibroblasts to dopaminergic neurons. PNAS 108:10343–48
    [Google Scholar]
  136. 136. 
    Phatnani H, Maniatis T. 2015. Astrocytes in neurodegenerative disease. Cold Spring Harb. Perspect. Biol. 7:a020628
    [Google Scholar]
  137. 137. 
    Politis M, Wu K, Loane C, Quinn NP, Brooks DJ et al. 2010. Serotonergic neurons mediate dyskinesia side effects in Parkinson's patients with neural transplants. Sci. Transl. Med. 2:38ra46
    [Google Scholar]
  138. 138. 
    Polydorides AD, Okano HJ, Yang YYL, Stefani G, Darnell RB 2000. A brain-enriched polypyrimidine tract-binding protein antagonizes the ability of Nova to regulate neuron-specific alternative splicing. PNAS 97:6350–55
    [Google Scholar]
  139. 139. 
    Price JD, Park K-Y, Chen J, Salinas RD, Cho MJ et al. 2014. The Ink4a/Arf locus is a barrier to direct neuronal transdifferentiation. J. Neurosci. 34:12560–67
    [Google Scholar]
  140. 140. 
    Qian C, Dong B, Wang X-Y, Zhou F-Q. 2021. In vivo glial trans-differentiation for neuronal replacement and functional recovery in central nervous system. FEBS J. 288:477385
    [Google Scholar]
  141. 141. 
    Qian H, Kang X, Hu J, Zhang D, Liang Z et al. 2020. Reversing a model of Parkinson's disease with in situ converted nigral neurons. Nature 582:550–56
    [Google Scholar]
  142. 142. 
    Ramachandran R, Fausett BV, Goldman D. 2010. Ascl1a regulates Müller glia dedifferentiation and retinal regeneration through a Lin-28-dependent, let-7 microRNA signalling pathway. Nat. Cell Biol. 12:1101–7
    [Google Scholar]
  143. 143. 
    Rojczyk-Gołębiewska E, Pałasz A, Wiaderkiewicz R. 2014. Hypothalamic subependymal niche: a novel site of the adult neurogenesis. Cell. Mol. Neurobiol. 34:631–42
    [Google Scholar]
  144. 144. 
    Roussarie J-P, Yao V, Rodriguez-Rodriguez P, Oughtred R, Rust J et al. 2020. Selective neuronal vulnerability in Alzheimer's disease: a network-based analysis. Neuron 107:821–35.e12
    [Google Scholar]
  145. 145. 
    Sanai N, Tramontin AD, Quinones-Hinojosa A, Barbaro NM, Gupta N et al. 2004. Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427:740–44
    [Google Scholar]
  146. 146. 
    Schaar KL, Brenneman MM, Savitz SI. 2010. Functional assessments in the rodent stroke model. Exp. Transl. Stroke Med. 2:13
    [Google Scholar]
  147. 147. 
    Schiebinger G, Shu J, Tabaka M, Cleary B, Subramanian V et al. 2019. Optimal-transport analysis of single-cell gene expression identifies developmental trajectories in reprogramming. Cell 176:928–43.e22
    [Google Scholar]
  148. 148. 
    Schoenherr CJ, Anderson DJ. 1995. The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes. Science 267:1360–63
    [Google Scholar]
  149. 149. 
    Seib DR, Corsini NS, Ellwanger K, Plaas C, Mateos A et al. 2013. Loss of Dickkopf-1 restores neurogenesis in old age and counteracts cognitive decline. Cell Stem Cell 12:204–14
    [Google Scholar]
  150. 150. 
    Shu P, Wu C, Ruan X, Liu W, Hou L et al. 2019. Opposing gradients of microRNA expression temporally pattern layer formation in the developing neocortex. Dev. Cell 49:764–85.e4
    [Google Scholar]
  151. 151. 
    Simon C, Götz M, Dimou L. 2011. Progenitors in the adult cerebral cortex: cell cycle properties and regulation by physiological stimuli and injury. Glia 59:869–81
    [Google Scholar]
  152. 152. 
    Sirko S, Behrendt G, Johansson PA, Tripathi P, Costa MR et al. 2013. Reactive glia in the injured brain acquire stem cell properties in response to Sonic hedgehog. Cell Stem Cell 12:426–39
    [Google Scholar]
  153. 153. 
    Smethurst P, Risse E, Tyzack GE, Mitchell JS, Taha DM et al. 2020. Distinct responses of neurons and astrocytes to TDP-43 proteinopathy in amyotrophic lateral sclerosis. Brain 143:430–40
    [Google Scholar]
  154. 154. 
    Snyder JS. 2019. Recalibrating the relevance of adult neurogenesis. Trends Neurosci 42:164–78
    [Google Scholar]
  155. 155. 
    Sofroniew MV. 2020. Astrocyte reactivity: subtypes, states, and functions in CNS innate immunity. Trends Immunol 41:758–70
    [Google Scholar]
  156. 156. 
    Söllvander S, Nikitidou E, Brolin R, Söderberg L, Sehlin D et al. 2016. Accumulation of amyloid-β by astrocytes result in enlarged endosomes and microvesicle-induced apoptosis of neurons. Mol. Neurodegener. 11:38
    [Google Scholar]
  157. 157. 
    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]
  158. 158. 
    Sorrells SF, Paredes MF, Cebrian-Silla A, Sandoval K, Qi D et al. 2018. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 555:377–81
    [Google Scholar]
  159. 159. 
    Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M et al. 2013. Dynamics of hippocampal neurogenesis in adult humans. Cell 153:1219–27
    [Google Scholar]
  160. 160. 
    Spellman R, Llorian M, Smith CW. 2007. Crossregulation and functional redundancy between the splicing regulator PTB and its paralogs nPTB and ROD1. Mol. Cell 27:420–34
    [Google Scholar]
  161. 161. 
    Spencer DD, Robbins RJ, Naftolin F, Marek KL, Vollmer T et al. 1992. Unilateral transplantation of human fetal mesencephalic tissue into the caudate nucleus of patients with Parkinson's disease. N. Engl. J. Med. 327:1541–48
    [Google Scholar]
  162. 162. 
    Steinbeck JA, Studer L. 2015. Moving stem cells to the clinic: potential and limitations for brain repair. Neuron 86:187–206
    [Google Scholar]
  163. 163. 
    Su Z, Niu W, Liu M-L, Zou Y, Zhang C-L. 2014. In vivo conversion of astrocytes to neurons in the injured adult spinal cord. Nat. Commun. 5:3338
    [Google Scholar]
  164. 164. 
    Summerfield C, Junqué C, Tolosa E, Salgado-Pineda P, Gómez-Ansón B et al. 2005. Structural brain changes in Parkinson disease with dementia: a voxel-based morphometry study. Arch. Neurol. 62:281–85
    [Google Scholar]
  165. 165. 
    Sun X, Hu X, Wang D, Yuan Y, Qin S et al. 2017. Establishment and characterization of primary astrocyte culture from adult mouse brain. Brain Res. Bull. 132:10–19
    [Google Scholar]
  166. 166. 
    Sun Y, Nadal-Vicens M, Misono S, Lin MZ, Zubiaga A et al. 2001. Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell 104:365–76
    [Google Scholar]
  167. 167. 
    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 131:861–72
    [Google Scholar]
  168. 168. 
    Takahashi K, Yamanaka S. 2006. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–76
    [Google Scholar]
  169. 169. 
    Tapscott SJ, Davis RL, Thayer MJ, Cheng P-F, Weintraub H, Lassar AB. 1988. MyoD1: a nuclear phosphoprotein requiring a Myc homology region to convert fibroblasts to myoblasts. Science 242:405–11
    [Google Scholar]
  170. 170. 
    Torper O, Pfisterer U, Wolf DA, Pereira M, Lau S et al. 2013. Generation of induced neurons via direct conversion in vivo. PNAS 110:7038–43
    [Google Scholar]
  171. 171. 
    Trokovic R, Weltner J, Noisa P, Raivio T, Otonkoski T. 2015. Combined negative effect of donor age and time in culture on the reprogramming efficiency into induced pluripotent stem cells. Stem Cell Res 15:254–62
    [Google Scholar]
  172. 172. 
    Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Südhof TC, Wernig M. 2010. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463:1035–41
    [Google Scholar]
  173. 173. 
    Vierbuchen T, Wernig M. 2012. Molecular roadblocks for cellular reprogramming. Mol. Cell 47:827–38
    [Google Scholar]
  174. 174. 
    Wang C, Liu F, Liu Y-Y, Zhao C-H, You Y et al. 2011. Identification and characterization of neuroblasts in the subventricular zone and rostral migratory stream of the adult human brain. Cell Res 21:1534–50
    [Google Scholar]
  175. 175. 
    Wang L-L, Garcia CS, Zhong X, Ma S, Zhang C-L. 2020. Rapid and efficient in vivo astrocyte-to-neuron conversion with regional identity and connectivity?. bioRxiv 2020.08.16.253195. https://doi.org/10.1101/2020.08.16.253195
    [Crossref]
  176. 176. 
    Wapinski OL, Vierbuchen T, Qu K, Lee QY, Chanda S et al. 2013. Hierarchical mechanisms for direct reprogramming of fibroblasts to neurons. Cell 155:621–35
    [Google Scholar]
  177. 177. 
    Weinberg MS, Criswell HE, Powell SK, Bhatt AP, McCown TJ. 2017. Viral vector reprogramming of adult resident striatal oligodendrocytes into functional neurons. Mol. Ther. 25:928–34
    [Google Scholar]
  178. 178. 
    Wollerton MC, Gooding C, Wagner EJ, MA Garcia-Blanco, Smith CW. 2004. Autoregulation of polypyrimidine tract binding protein by alternative splicing leading to nonsense-mediated decay. Mol. Cell 13:91–100
    [Google Scholar]
  179. 179. 
    Wu Z, Parry M, Hou X-Y, Liu M-H, Wang H et al. 2020. Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington's disease. Nat. Commun. 11:1105
    [Google Scholar]
  180. 180. 
    Xiong M, Tao Y, Gao Q, Feng B, Yan W et al. 2020. Human stem cell-derived neurons repair circuits and restore neural function. Cell Stem Cell 28:112–26.e6
    [Google Scholar]
  181. 181. 
    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]
  182. 182. 
    Xue Y, Qian H, Hu J, Zhou B, Zhou Y et al. 2016. Sequential regulatory loops as key gatekeepers for neuronal reprogramming in human cells. Nat. Neurosci. 19:807–15
    [Google Scholar]
  183. 183. 
    Xue Y, Zhou Y, Wu T, Zhu T, Ji X et al. 2009. Genome-wide analysis of PTB-RNA interactions reveals a strategy used by the general splicing repressor to modulate exon inclusion or skipping. Mol. Cell 36:996–1006
    [Google Scholar]
  184. 184. 
    Yao K, Qiu S, Wang YV, Park SJH, Mohns EJ et al. 2018. Restoration of vision after de novo genesis of rod photoreceptors in mammalian retinas. Nature 560:484–88
    [Google Scholar]
  185. 185. 
    Yoo AS, Sun AX, Li L, Shcheglovitov A, Portmann T et al. 2011. MicroRNA-mediated conversion of human fibroblasts to neurons. Nature 476:228–31
    [Google Scholar]
  186. 186. 
    Yousef H, Morgenthaler A, Schlesinger C, Bugaj L, Conboy IM, Schaffer DV. 2015. Age-associated increase in BMP signaling inhibits hippocampal neurogenesis. Stem Cells 33:1577–88
    [Google Scholar]
  187. 187. 
    Yu X, Nagai J, Khakh BS. 2020. Improved tools to study astrocytes. Nat. Rev. Neurosci. 21:121–38
    [Google Scholar]
  188. 188. 
    Yun SP, Kam T-I, Panicker N, Kim S, Oh Y et al. 2018. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease. Nat. Med. 24:931–38
    [Google Scholar]
  189. 189. 
    Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L et al. 2012. Genomic analysis of reactive astrogliosis. J. Neurosci. 32:6391–410
    [Google Scholar]
  190. 190. 
    Zamboni M, Llorens-Bobadilla E, Magnusson JP, Frisén J. 2020. A widespread neurogenic potential of neocortical astrocytes is induced by injury. Cell Stem Cell 27:605–17.e5
    [Google Scholar]
  191. 191. 
    Zarei-Kheirabadi M, Hesaraki M, Kiani S, Baharvand H. 2019. In vivo conversion of rat astrocytes into neuronal cells through neural stem cells in injured spinal cord with a single zinc-finger transcription factor. Stem Cell Res. Ther. 10:380
    [Google Scholar]
  192. 192. 
    Zeiss C. 2005. Neuroanatomical phenotyping in the mouse: the dopaminergic system. Vet. Pathol. 42:753–73
    [Google Scholar]
  193. 193. 
    Zhang L, Lei Z, Guo Z, Pei Z, Chen Y et al. 2020. Development of neuroregenerative gene therapy to reverse glial scar tissue back to neuron-enriched tissue. Front. Cell. Neurosci. 14:594170
    [Google Scholar]
  194. 194. 
    Zhang M, Ergin V, Lin L, Stork C, Chen L, Zheng S 2019. Axonogenesis is coordinated by neuron-specific alternative splicing programming and splicing regulator PTBP2. Neuron 101:690–706.e10
    [Google Scholar]
  195. 195. 
    Zholudeva LV, Iyer N, Qiang L, Spruance VM, Randelman ML et al. 2018. Transplantation of neural progenitors and V2a interneurons after spinal cord injury. J. Neurotrauma 35:2883–903
    [Google Scholar]
  196. 196. 
    Zhou H, Su J, Hu X, Zhou C, Li H et al. 2020. Glia-to-neuron conversion by CRISPR-CasRx alleviates symptoms of neurological disease in mice. Cell 181:590–603.e16
    [Google Scholar]
  197. 197. 
    Zullo JM, Drake D, Aron L, O'Hern P, Dhamne SC et al. 2019. Regulation of lifespan by neural excitation and REST. Nature 574:359–64
    [Google Scholar]
/content/journals/10.1146/annurev-genet-071719-023616
Loading
/content/journals/10.1146/annurev-genet-071719-023616
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