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Direct Lineage Reprogramming in the CNS

  • Justine Bajohr
  • Maryam FaizEmail author
Part of the Advances in Experimental Medicine and Biology book series


Direct lineage reprogramming is the conversion of one specialized cell type to another without the need for a pluripotent intermediate. To date, a wide variety of cell types have been successfully generated using direct reprogramming, both in vitro and in vivo. These newly converted cells have the potential to replace cells that are lost to disease and/or injury. In this chapter, we will focus on direct reprogramming in the central nervous system. We will review current progress in the field with regards to all the major neural cell types and explore how cellular heterogeneity, both in the starter cell and target cell population, may have implications for direct reprogramming. Finally, we will discuss new technologies that will improve our understanding of the reprogramming process and aid the development of more specific and efficient future CNS-based reprogramming strategies.


Cellular reprogramming Direct lineage conversion Cellular heterogeneity Neurological disease/Injury Central nervous system 





achaete-scute family bHLH transcription factor 1

BAM factors

combination of the transcription factors Ascl1, Brn2 and Mytl1


POU Class 3 Homeobox 2


Choline O-Acetyltransferase


cellular Myc


2′,3’-Cyclic Nucleotide 3’ Phosphodiesterase


central nervous system


clustered regularly interspaced short palindromic repeats


CRISPR activation


Dopamine transporter


DOPA Decarboxylase


Distal-Less Homeobox 2


Designer Receptors Exclusively Activated by Designer Drugs


transcription factor 3


Enhancer Of Zeste 2 Polycomb Repressive Complex 2 Subunit


FEZ Family Zinc Finger 2


Forkhead Box A2


forkhead box G1


Gamma-amino butyric acid


glucose transporter protein type 1


gene regulatory network


Motor Neuron And Pancreas Homeobox 1


induced pluripotent stem cell


Insulin gene enhancer protein ISL-1


Inositol 1,4,5-Trisphosphate Receptor Type 2


Kruppel Like Factor 4


LIM Homeobox 3


LIM Homeobox Transcription Factor 1 Alpha


myelin basic protein


MDS1 And EVI1 Complex Locus




mature oligodendrocytes expressing Grm3 (Glutamate Metabotropic Receptor 3) and Jph4 (Junctophilin 4)


multiple sclerosis


myogenic differentiation 1


myelin transcription factor 1 like protein


Nanog Homeobox


Neurogenic Differentiation Factor 1


Nuclear Factor I A


Nuclear Factor I B

NG2 glia

Neural/glial antigen 2 expressing glial cells


Neurogenin 2


NK6 Homeobox 2


neural stem cell


neural stem and progenitor cells


Nuclear receptor related 1 protein


octamer-binding transcription factor 4


Oligodendrocyte Transcription Factor 1


Oligodendrocyte Transcription Factor 2


oligodendrocyte progenitor cell


Paired Box 6


reactive oxygen species

S1 cortex

primary somatosensory cortex

sc RNA-seq

single cell RNA sequencing


SRY-Box 10


SRY-Box 2


SRY-box 9


Vesicular monoamine transporter 2


valproic acid


Zinc Finger Protein 536


  1. Amamoto R, Arlotta P (2014) Development-inspired reprogramming of the mammalian central nervous system. Science (New York, NY) 343(6170):1239882. Scholar
  2. 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(9):963–970. Scholar
  3. Bardy C, van den Hurk M, Kakaradov B, Erwin JA, Jaeger BN, Hernandez RV, Eames T, Paucar AA, Gorris M, Marchand C et al (2016) Predicting the functional states of human iPSC-derived neurons with single-cell RNA-seq and electrophysiology. Mol Psychiatry 21(11):1573–1588. Scholar
  4. Barker RA, Götz M, Parmar M (2018) New approaches for brain repair—from rescue to reprogramming. Nature 557(7705):329. Scholar
  5. Berninger B (2010) Making neurons from mature glia: a far-fetched dream? Neuropharmacology 58(6):894–902. Scholar
  6. Black JB, Adler AF, Wang H-G, D’Ippolito AM, Hutchinson HA, Reddy TE, Pitt GS, Leong KW, Gersbach CA (2016) Targeted epigenetic remodeling of endogenous loci by CRISPR/Cas9-based transcriptional activators directly converts fibroblasts to neuronal cells. Cell Stem Cell 19(3):406–414. Scholar
  7. Blakemore WF (1972) Observations on oligodendrocyte degeneration, the resolution of status spongiosus and remyelination in cuprizone intoxication in mice. J Neurocytol 1(4):413–426. Scholar
  8. Blau HM, Chiu CP, Webster C (1983) Cytoplasmic activation of human nuclear genes in stable heterocaryons. Cell 32(4):1171–1180Google Scholar
  9. Blau HM, Pavlath GK, Hardeman EC, Chiu CP, Silberstein L, Webster SG, Miller SC, Webster C (1985) Plasticity of the differentiated state. Science (New York, NY) 230(4727):758–766Google Scholar
  10. Boche D, Perry VH, Nicoll JAR (2013) Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol 39(1):3–18. Scholar
  11. Buffo A, Vosko MR, Ertürk D, Hamann GF, Jucker M, Rowitch D, Götz M (2005) Expression pattern of the transcription factor Olig2 in response to brain injuries: implications for neuronal repair. Proc Natl Acad Sci U S A 102(50):18183–18188. Scholar
  12. Burn DJ, Jaros E (2001) Multiple system atrophy: cellular and molecular pathology. Mol Pathol 54(6):419–426Google Scholar
  13. Cadwell CR, Palasantza A, Jiang X, Berens P, Deng Q, Yilmaz M, Reimer J, Shen S, Bethge M, Tolias KF et al (2016) Electrophysiological, transcriptomic and morphologic profiling of single neurons using Patch-seq. Nat Biotechnol 34(2):199–203. Scholar
  14. Cahan P, Li H, Morris SA, Lummertz da Rocha E, Daley GQ, Collins JJ (2014) CellNet: network biology applied to stem cell engineering. Cell 158(4):903–915. Scholar
  15. Caiazzo M, Dell’Anno MT, Dvoretskova E, Lazarevic D, Taverna S, Leo D, Sotnikova TD, Menegon A, Roncaglia P, Colciago G et al (2011) Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476(7359):224–227. Scholar
  16. Caiazzo M, Giannelli S, Valente P, Lignani G, Carissimo A, Sessa A, Colasante G, Bartolomeo R, Massimino L, Ferroni S et al (2015) Direct conversion of fibroblasts into functional astrocytes by defined transcription factors. Stem Cell Rep 4(1):25–36. Scholar
  17. Cassoli JS, Guest PC, Malchow B, Schmitt A, Falkai P, Martins-de-Souza D (2015) Disturbed macro-connectivity in schizophrenia linked to oligodendrocyte dysfunction: from structural findings to molecules. NPJ Schizophr 1:15034. Scholar
  18. Chakraborty S, Ji H, Kabadi AM, Gersbach CA, Christoforou N, Leong KW (2014) A CRISPR/Cas9-based system for reprogramming cell lineage specification. Stem Cell Rep 3(6):940–947. Scholar
  19. Chanda S, Ang CE, Davila J, Pak C, Mall M, Lee QY, Ahlenius H, Jung SW, Südhof TC, Wernig M (2014) Generation of induced neuronal cells by the single reprogramming factor ASCL1. Stem Cell Rep 3(2):282–296. Scholar
  20. Chen G, Wernig M, Berninger B, Nakafuku M, Parmar M, Zhang C-L (2015) In vivo reprogramming for brain and spinal cord repair. eNeuro 2(5).,
  21. Chen Y, Ma N, Pei Z, Wu Z, Do-Monte FH, Huang P, Yellin E, Chen M, Yin J, Lee G, Minier A, Hu Y, Bai Y, Lee K, Quirk G, Chen G (2018) Functional repair after ischemic injury through high effciency in situ astrocyte-to-neuron conversion. bioRxiv.
  22. Chernoff GF (1981) Shiverer: an autosomal recessive mutant mouse with myelin deficiency. J Hered 72(2):128Google Scholar
  23. Corti S, Nizzardo M, Simone C, Falcone M, Donadoni C, Salani S, Rizzo F, Nardini M, Riboldi G, Magri F et al (2012) Direct reprogramming of human astrocytes into neural stem cells and neurons. Exp Cell Res 318(13–16):1528–1541. Scholar
  24. Davis RL, Weintraub H, Lassar AB (1987) Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51(6):987–1000Google Scholar
  25. Deisseroth K (2011) Optogenetics. Nat Methods 8(1):26–29. Scholar
  26. Dell’Anno MT, Caiazzo M, Leo D, Dvoretskova E, Medrihan L, Colasante G, Giannelli S, Theka I, Russo G, Mus L et al (2014) Remote control of induced dopaminergic neurons in parkinsonian rats. J Clin Invest 124(7):3215–3229. Scholar
  27. Desai MK, Sudol KL, Janelsins MC, Mastrangelo MA, Frazer ME, Bowers WJ (2009) Triple-transgenic Alzheimer’s disease mice exhibit region-specific abnormalities in brain myelination patterns prior to appearance of amyloid and tau pathology. Glia 57(1):54–65. Scholar
  28. Desai MK, Mastrangelo MA, Ryan DA, Sudol KL, Narrow WC, Bowers WJ (2010) Early oligodendrocyte/myelin pathology in Alzheimer’s disease mice constitutes a novel therapeutic target. Am J Pathol 177(3):1422–1435. Scholar
  29. Faiz M, Nagy A (2013) Induced pluripotent stem cells and disorders of the nervous system: progress, problems, and prospects. Neuroscientist 19(6):567–577. Scholar
  30. Faiz M, Sachewsky N, Gascón S, Bang KWA, Morshead CM, Nagy A (2015) Adult neural stem cells from the subventricular zone give rise to reactive astrocytes in the cortex after stroke. Cell Stem Cell 17(5):624–634. Scholar
  31. Gascón S, Murenu E, Masserdotti G, Ortega F, Russo GL, Petrik D, Deshpande A, Heinrich C, Karow M, Robertson SP et al (2016) Identification and successful negotiation of a metabolic checkpoint in direct neuronal reprogramming. Cell Stem Cell 18(3):396–409. Scholar
  32. Gascón S, Masserdotti G, Russo GL, Götz M (2017a) Direct neuronal reprogramming: achievements, hurdles, and new roads to success. Cell Stem Cell 21(1):18–34. Scholar
  33. Gascón S, Ortega F, Götz M (2017b) Transient CREB-mediated transcription is key in direct neuronal reprogramming. Neurogenesis (Austin) 4(1):e1285383. Scholar
  34. Graf T, Enver T (2009) Forcing cells to change lineages. Nature 462(7273):587–594. Scholar
  35. Grande A, Sumiyoshi K, López-Juárez A, Howard J, Sakthivel B, Aronow B, Campbell K, Nakafuku M (2013) Environmental impact on direct neuronal reprogramming in vivo in the adult brain. Nat Commun 4:2373. Scholar
  36. 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(2):188–202. Scholar
  37. Gurdon JB (1962) Adult frogs derived from the nuclei of single somatic cells. Dev Biol 4(2):256–273. Scholar
  38. Han DW, Tapia N, Hermann A, Hemmer K, Höing S, Araúzo-Bravo MJ, Zaehres H, Wu G, Frank S, Moritz S et al (2012) Direct reprogramming of fibroblasts into neural stem cells by defined factors. Cell Stem Cell 10(4):465–472. Scholar
  39. Heinrich C, Blum R, Gascón S, Masserdotti G, Tripathi P, Sánchez R, Tiedt S, Schroeder T, Götz M, Berninger B (2010) Directing astroglia from the cerebral cortex into subtype specific functional neurons. PLoS Biol 8(5):e1000373. Scholar
  40. Heinrich C, Bergami M, Gascón S, Lepier A, Viganò F, Dimou L, Sutor B, Berninger B, Götz M (2014) Sox2-mediated conversion of NG2 glia into induced neurons in the injured adult cerebral cortex. Stem Cell Rep 3(6):1000–1014. Scholar
  41. Heins N, Malatesta P, Cecconi F, Nakafuku M, Tucker KL, Hack MA, Chapouton P, Barde Y-A, Götz M (2002) Glial cells generate neurons: the role of the transcription factor Pax6. Nat Neurosci 5(4):308–315. Scholar
  42. Hu W, Qiu B, Guan W, Wang Q, Wang M, Li W, Gao L, Shen L, Huang Y, Xie G et al (2015) Direct conversion of normal and Alzheimer’s disease human fibroblasts into neuronal cells by small molecules. Cell Stem Cell 17(2):204–212. Scholar
  43. Jäkel S, Agirre E, Falcão AM, van Bruggen D, Lee KW, Knuesel I, Malhotra D, Ffrench-Constant C, Williams A, Castelo-Branco G (2019) Altered human oligodendrocyte heterogeneity in multiple sclerosis. Nature 23:1. Scholar
  44. Karow M, Camp JG, Falk S, Gerber T, Pataskar A, Gac-Santel M, Kageyama J, Brazovskaja A, Garding A, Fan W et al (2018) Direct pericyte-to-neuron reprogramming via unfolding of a neural stem cell-like program. Nat Neurosci 21(7):932–940. Scholar
  45. Kim J, Su SC, Wang H, Cheng AW, Cassady JP, Lodato MA, Lengner CJ, Chung C-Y, Dawlaty MM, Tsai L-H et al (2011) Functional integration of dopaminergic neurons directly converted from mouse fibroblasts. Cell Stem Cell 9(5):413–419. Scholar
  46. Kuller LH, Longstreth WT, Arnold AM, Bernick C, Bryan RN, Beauchamp NJ (2004) Cardiovascular Health Study Collaborative Research Group. White matter hyperintensity on cranial magnetic resonance imaging: a predictor of stroke. Stroke 35(8):1821–1825. Scholar
  47. Lassmann H, van Horssen J, Mahad D (2012) Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol 8(11):647–656. Scholar
  48. Li X, Zuo X, Jing J, Ma Y, Wang J, Liu D, Zhu J, Du X, Xiong L, Du Y et al (2015) Small-molecule-driven direct reprogramming of mouse fibroblasts into functional neurons. Cell Stem Cell 17(2):195–203. Scholar
  49. Liang X-G, Tan C, Wang C-K, Tao R-R, Huang Y-J, Ma K-F, Fukunaga K, Huang M-Z, Han F (2018) Myt1l induced direct reprogramming of pericytes into cholinergic neurons. CNS Neurosci Ther 24(9):801–809. Scholar
  50. Liddelow SA, Barres BA (2017) Reactive astrocytes: production, function, and therapeutic potential. Immunity 46(6):957–967. Scholar
  51. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Münch AE, Chung W-S, Peterson TC et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541(7638):481–487. Scholar
  52. Liu M-L, Zang T, Zou Y, Chang JC, Gibson JR, Huber KM, Zhang C-L (2013) Small molecules enable neurogenin 2 to efficiently convert human fibroblasts into cholinergic neurons. Nat Commun 4:2183. Scholar
  53. Liu Y, Yu C, Daley TP, Wang F, Cao WS, Bhate S, Lin X, Still C, Liu H, Zhao D et al (2018) CRISPR activation screens systematically identify factors that drive neuronal fate and reprogramming. Cell Stem Cell 23(5):758–771.e8. Scholar
  54. Lujan E, Chanda S, Ahlenius H, Südhof TC, Wernig M (2012) Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells. Proc Natl Acad Sci 109(7):2527–2532. Scholar
  55. Ma K, Deng X, Xia X, Fan Z, Qi X, Wang Y, Li Y, Ma Y, Chen Q, Peng H et al (2018) Direct conversion of mouse astrocytes into neural progenitor cells and specific lineages of neurons. Transl Neurodegener 7:29. Scholar
  56. Marques S, Zeisel A, Codeluppi S, van Bruggen D, Mendanha Falcão A, Xiao L, Li H, Häring M, Hochgerner H, Romanov RA et al (2016) Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system. Science (New York, NY) 352(6291):1326–1329. Scholar
  57. Marro S, Pang ZP, Yang N, Tsai M-C, Qu K, Chang HY, Südhof TC, Wernig M (2011) Direct lineage conversion of terminally differentiated hepatocytes to functional neurons. Cell Stem Cell 9(4):374–382. Scholar
  58. Masserdotti G, Gillotin S, Sutor B, Drechsel D, Irmler M, Jørgensen HF, Sass S, Theis FJ, Beckers J, Berninger B et al (2015) Transcriptional mechanisms of proneural factors and REST in regulating neuronal reprogramming of astrocytes. Cell Stem Cell 17(1):74–88. Scholar
  59. Masserdotti G, Gascón S, Götz M (2016) Direct neuronal reprogramming: learning from and for development. Development 143(14):2494–2510. Scholar
  60. Matsuda T, Irie T, Katsurabayashi S, Hayashi Y, Nagai T, Hamazaki N, Adefuin AMD, Miura F, Ito T, Kimura H et al (2019) Pioneer Factor NeuroD1 rearranges transcriptional and epigenetic profiles to execute microglia-neuron conversion. Neuron 101(3):472–485.e7. Scholar
  61. Matsushima GK, Morell P (2001) The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol (Zurich, Switzerland) 11(1):107–116Google Scholar
  62. Mokhtarzadeh Khanghahi A, Satarian L, Deng W, Baharvand H, Javan M (2018) In vivo conversion of astrocytes into oligodendrocyte lineage cells with transcription factor Sox10; Promise for myelin repair in multiple sclerosis. PLoS One 13(9):e0203785. Scholar
  63. Morris SA (2016) Direct lineage reprogramming via pioneer factors; a detour through developmental gene regulatory networks. Development 143(15):2696–2705. Scholar
  64. Morris SA, Cahan P, Li H, Zhao AM, San Roman AK, Shivdasani RA, Collins JJ, Daley GQ (2014) Dissecting engineered cell types and enhancing cell fate conversion via CellNet. Cell 158(4):889–902. Scholar
  65. Najm FJ, Lager AM, Zaremba A, Wyatt K, Caprariello AV, Factor DC, Karl RT, Maeda T, Miller RH, Tesar PJ (2013) Transcription factor-mediated reprogramming of fibroblasts to expandable, myelinogenic oligodendrocyte progenitor cells. Nat Biotechnol 31(5):426–433. Scholar
  66. Ninkovic J, Götz M (2018) Understanding direct neuronal reprogramming-from pioneer factors to 3D chromatin. Curr Opin Genet Dev 52:65–69. Scholar
  67. Niu W, Zang T, Zou Y, Fang S, Smith DK, Bachoo R, Zhang C-L (2013) In vivo reprogramming of astrocytes to neuroblasts in the adult brain. Nat Cell Biol 15(10):1164–1175. Scholar
  68. Niu W, Zang T, Wang L-L, Zou Y, Zhang C-L (2018) Phenotypic reprogramming of striatal neurons into dopaminergic neuron-like cells in the adult mouse brain. Stem Cell Rep 11(5):1156–1170. Scholar
  69. Reich DS, Lucchinetti CF, Calabresi PA (2018) Multiple sclerosis. N Engl J Med 378(2):169–180. Scholar
  70. Ring KL, Tong LM, Balestra ME, Javier R, Andrews-Zwilling Y, Li G, Walker D, Zhang WR, Kreitzer AC, Huang Y (2012) Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor. Cell Stem Cell 11(1):100–109. Scholar
  71. Rivetti di Val Cervo P, Romanov RA, Spigolon G, Masini D, Martín-Montañez E, Toledo EM, La Manno G, Feyder M, Pifl C, Ng Y-H 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(5):444–452. Scholar
  72. Roth AD, Ramírez G, Alarcón R, Von Bernhardi R (2005) Oligodendrocytes damage in Alzheimer’s disease: beta amyloid toxicity and inflammation. Biol Res 38(4):381–387Google Scholar
  73. Rouaux C, Arlotta P (2013) Direct lineage reprogramming of post-mitotic callosal neurons into corticofugal neurons in vivo. Nat Cell Biol 15(2):214–221. Scholar
  74. Sawcer S, Franklin RJM, Ban M (2014) Multiple sclerosis genetics. Lancet Neurol 13(7):700–709. Scholar
  75. Sheng C, Zheng Q, Wu J, Xu Z, Sang L, Wang L, Guo C, Zhu W, Tong M, Liu L et al (2012) Generation of dopaminergic neurons directly from mouse fibroblasts and fibroblast-derived neural progenitors. Cell Res 22(4):769–772. Scholar
  76. Sieweke MH (2015) Waddington’s valleys and Captain Cook’s islands. Cell Stem Cell 16(1):7–8. Scholar
  77. Son EY, Ichida JK, Wainger BJ, Toma JS, Rafuse VF, Woolf CJ, Eggan K (2011) Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell 9(3):205–218. Scholar
  78. Steinbeck JA, Studer L (2015) Moving stem cells to the clinic: potential and limitations for brain repair. Neuron 86(1):187–206. Scholar
  79. 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. Scholar
  80. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676. Scholar
  81. Tang Y, Le W (2016) Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol 53(2):1181–1194. Scholar
  82. Thored P, Wood J, Arvidsson A, Cammenga J, Kokaia Z, Lindvall O (2007) Long-term neuroblast migration along blood vessels in an area with transient angiogenesis and increased vascularization after stroke. Stroke 38(11):3032–3039. Scholar
  83. Tian E, Sun G, Sun G, Chao J, Ye P, Warden C, Riggs AD, Shi Y (2016) Small-molecule-based lineage reprogramming creates functional astrocytes. Cell Rep 16(3):781–792. Scholar
  84. Toft-Hansen H, Füchtbauer L, Owens T (2011) Inhibition of reactive astrocytosis in established experimental autoimmune encephalomyelitis favors infiltration by myeloid cells over T cells and enhances severity of disease. Glia 59(1):166–176. Scholar
  85. Torper O, Pfisterer U, Wolf DA, Pereira M, Lau S, Jakobsson J, Björklund A, Grealish S, Parmar M (2013) Generation of induced neurons via direct conversion in vivo. Proc Natl Acad Sci 110(17):7038–7043. Scholar
  86. Torper O, Ottosson DR, Pereira M, Lau S, Cardoso T, Grealish S, Parmar M (2015) In vivo reprogramming of striatal NG2 glia into functional neurons that integrate into local host circuitry. Cell Rep 12(3):474–481. Scholar
  87. Vadodaria KC, Mertens J, Paquola A, Bardy C, Li X, Jappelli R, Fung L, Marchetto MC, Hamm M, Gorris M et al (2016) Generation of functional human serotonergic neurons from fibroblasts. Mol Psychiatry 21(1):49–61. Scholar
  88. Victor MB, Richner M, Hermanstyne TO, Ransdell JL, Sobieski C, Deng P-Y, Klyachko VA, Nerbonne JM, Yoo AS (2014) Generation of human striatal neurons by microRNA-dependent direct conversion of fibroblasts. Neuron 84(2):311–323. Scholar
  89. Vierbuchen T, Wernig M (2011) Direct lineage conversions: unnatural but useful? Nat Biotechnol 29(10):892–907. Scholar
  90. 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(7284):1035–1041. Scholar
  91. Waddington CH (1957) The strategy of the genes; a discussion of some aspects of theoretical biology. Routledge, London. Scholar
  92. Wang L-L, Zhang C-L (2018) Engineering new neurons: in vivo reprogramming in mammalian brain and spinal cord. Cell Tissue Res 371(1):201–212. Scholar
  93. Wapinski OL, Lee QY, Chen AC, Li R, Corces MR, Ang CE, Treutlein B, Xiang C, Baubet V, Suchy FP et al (2017) Rapid chromatin switch in the direct reprogramming of fibroblasts to neurons. Cell Rep 20(13):3236–3247. Scholar
  94. Xie H, Ye M, Feng R, Graf T (2004) Stepwise reprogramming of B cells into macrophages. Cell 117(5):663–676Google Scholar
  95. Xu J, Du Y, Deng H (2015) Direct lineage reprogramming: strategies, mechanisms, and applications. Cell Stem Cell 16(2):119–134. Scholar
  96. Yang N, Ng YH, Pang ZP, Südhof TC, Wernig M (2011) Induced neuronal (iN) cells: how to make and define a neuron. Cell Stem Cell 9(6):517–525. Scholar
  97. Yang N, Zuchero JB, Ahlenius H, Marro S, Ng YH, Vierbuchen T, Hawkins JS, Geissler R, Barres BA, Wernig M (2013) Generation of oligodendroglial cells by direct lineage conversion. Nat Biotechnol 31(5):434–439. Scholar
  98. Yoo AS, Sun AX, Li L, Shcheglovitov A, Portmann T, Li Y, Lee-Messer C, Dolmetsch RE, Tsien RW, Crabtree GR (2011) MicroRNA-mediated conversion of human fibroblasts to neurons. Nature 476(7359):228–231. Scholar
  99. Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, Barres BA (2012) Genomic analysis of reactive astrogliosis. J Neurosci 32(18):6391–6410Google Scholar
  100. Zhang L, Lei Z, Guo Z, Pei Z, Chen Y, Zhang F, Cai A, Mok YK, Lee G, Swaminathan V et al (2018) Reversing glial scar Back to neural tissue through NeuroD1-mediated astrocyte-to-neuron conversion. bioRxiv 7:261438. Scholar
  101. Zhu X, Zhou W, Jin H, Li T (2018) Brn2 alone is sufficient to convert astrocytes into neural progenitors and neurons. Stem Cells Dev 27(11):736–744. Scholar

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Authors and Affiliations

  1. 1.Department of SurgeryUniversity of TorontoTorontoCanada

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