Abstract
Recent advances in somatic cell reprogramming is one of the most important developments in neuroscience in the last decades since it offers for the first time the opportunity to work with disease/patient-specific neurons or other neural cell types. Induced pluripotent stem cells (iPSCs) can be differentiated into all cell types of the body enabling investigations not only on neurons but also on muscle or endothelial cells which are cell types often also of great interest in neurodegenerative diseases. The novel technology of direct lineage conversion of somatic cells into neurons (induced neurons; iNs) or into expandable multipotent neural stem cells (induced neural stem cells; iNSCs) provides interesting alternatives to the iPSC technology. These techniques have the advantage of easier cell culture, but only neurons (iNs) or neuroectodermal cells (iNSCs) can be generated. Although there are several open questions coming along with these new neural cell types, they hold great promises for both cell replacement and cell modelling of neurodegenerative diseases.
Similar content being viewed by others
References
Alipio Z, Liao W, Roemer EJ, Waner M, Fink LM, Ward DC, Ma Y (2010) Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic beta-like cells. Proc Natl Acad Sci USA 107(30):13426–13431. doi:10.1073/pnas.1007884107
Caiazzo M, Dell’Anno MT, Dvoretskova E, Lazarevic D, Taverna S, Leo D, Sotnikova TD, Menegon A, Roncaglia P, Colciago G, Russo G, Carninci P, Pezzoli G, Gainetdinov RR, Gustincich S, Dityatev A, Broccoli V (2011) Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476(7359):224–227. doi:10.1038/nature10284
Corti S, Nizzardo M, Simone C, Falcone M, Donadoni C, Salani S, Rizzo F, Nardini M, Riboldi G, Magri F, Zanetta C, Faravelli I, Bresolin N, Comi GP (2012) Direct reprogramming of human astrocytes into neural stem cells and neurons. Exp Cell Res 318(13):1528–1541. doi:10.1016/j.yexcr.2012.02.040
Ebert AD, Yu J, Rose FF Jr, Mattis VB, Lorson CL, Thomson JA, Svendsen CN (2009) Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457(7227):277–280. doi:10.1038/nature07677
Gore A, Li Z, Fung HL, Young JE, Agarwal S, Antosiewicz-Bourget J, Canto I, Giorgetti A, Israel MA, Kiskinis E, Lee JH, Loh YH, Manos PD, Montserrat N, Panopoulos AD, Ruiz S, Wilbert ML, Yu J, Kirkness EF, Izpisua Belmonte JC, Rossi DJ, Thomson JA, Eggan K, Daley GQ, Goldstein LS, Zhang K (2011) Somatic coding mutations in human induced pluripotent stem cells. Nature 471(7336):63–67. doi:10.1038/nature09805
Han DW, Tapia N, Hermann A, Hemmer K, Hoing S, Arauzo-Bravo MJ, Zaehres H, Wu G, Frank S, Moritz S, Greber B, Yang JH, Lee HT, Schwamborn JC, Storch A, Scholer HR (2012) Direct reprogramming of fibroblasts into neural stem cells by defined factors. Cell Stem Cell 10(4):465–472. doi:10.1016/j.stem.2012.02.021
Hanna J, Wernig M, Markoulaki S, Sun CW, Meissner A, Cassady JP, Beard C, Brambrink T, Wu LC, Townes TM, Jaenisch R (2007) Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318(5858):1920–1923. doi:10.1126/science.1152092
Hargus G, Cooper O, Deleidi M, Levy A, Lee K, Marlow E, Yow A, Soldner F, Hockemeyer D, Hallett PJ, Osborn T, Jaenisch R, Isacson O (2010) Differentiated Parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats. Proc Natl Acad Sci USA 107(36):15921–15926. doi:10.1073/pnas.1010209107
Hermann A, Gastl R, Liebau S, Popa MO, Fiedler J, Boehm BO, Maisel M, Lerche H, Schwarz J, Brenner R, Storch A (2004) Efficient generation of neural stem cell-like cells from adult human bone marrow stromal cells. J Cell Sci 117(Pt 19):4411–4422. doi:10.1242/jcs.01307
Hermann A, Liebau S, Gastl R, Fickert S, Habisch HJ, Fiedler J, Schwarz J, Brenner R, Storch A (2006a) Comparative analysis of neuroectodermal differentiation capacity of human bone marrow stromal cells using various conversion protocols. J Neurosci Res 83(8):1502–1514. doi:10.1002/jnr.20840
Hermann A, Maisel M, Storch A (2006b) Epigenetic conversion of human adult bone mesodermal stromal cells into neuroectodermal cell types for replacement therapy of neurodegenerative disorders. Expert Opin Biol Ther 6(7):653–670. doi:10.1517/14712598.6.7.653
Hikichi T, Matoba R, Ikeda T, Watanabe A, Yamamoto T, Yoshitake S, Tamura-Nakano M, Kimura T, Kamon M, Shimura M, Kawakami K, Okuda A, Okochi H, Inoue T, Suzuki A, Masui S (2013) Transcription factors interfering with dedifferentiation induce cell type-specific transcriptional profiles. Proc Natl Acad Sci U S A. doi:10.1073/pnas.1220200110
Jaenisch R, Young R (2008) Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell 132(4):567–582. doi:10.1016/j.cell.2008.01.015
Kaji K, Norrby K, Paca A, Mileikovsky M, Mohseni P, Woltjen K (2009) Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 458(7239):771–775. doi:10.1038/nature07864
Karow M, Sanchez R, Schichor C, Masserdotti G, Ortega F, Heinrich C, Gascon S, Khan MA, Lie DC, Dellavalle A, Cossu G, Goldbrunner R, Gotz M, Berninger B (2012) Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells. Cell Stem Cell 11(4):471–476. doi:10.1016/j.stem.2012.07.007
Kim JB, Zaehres H, Wu G, Gentile L, Ko K, Sebastiano V, Arauzo-Bravo MJ, Ruau D, Han DW, Zenke M, Scholer HR (2008) Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature 454(7204):646–650. doi:10.1038/nature07061
Kim D, Kim CH, Moon JI, Chung YG, Chang MY, Han BS, Ko S, Yang E, Cha KY, Lanza R, Kim KS (2009a) Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4(6):472–476. doi:10.1016/j.stem.2009.05.005
Kim JB, Greber B, Arauzo-Bravo MJ, Meyer J, Park KI, Zaehres H, Scholer HR (2009b) Direct reprogramming of human neural stem cells by OCT4. Nature 461(7264):643–649. doi:10.1038/nature08436
Kim JB, Sebastiano V, Wu G, Arauzo-Bravo MJ, Sasse P, Gentile L, Ko K, Ruau D, Ehrich M, van den Boom D, Meyer J, Hubner K, Bernemann C, Ortmeier C, Zenke M, Fleischmann BK, Zaehres H, Scholer HR (2009c) Oct4-induced pluripotency in adult neural stem cells. Cell 136(3):411–419. doi:10.1016/j.cell.2009.01.023
Kim J, Efe JA, Zhu S, Talantova M, Yuan X, Wang S, Lipton SA, Zhang K, Ding S (2011a) Direct reprogramming of mouse fibroblasts to neural progenitors. Proc Natl Acad Sci USA 108(19):7838–7843. doi:10.1073/pnas.1103113108
Kim K, Zhao R, Doi A, Ng K, Unternaehrer J, Cahan P, Huo H, Loh YH, Aryee MJ, Lensch MW, Li H, Collins JJ, Feinberg AP, Daley GQ (2011b) Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells. Nat Biotechnol 29(12):1117–1119. doi:10.1038/nbt.2052
Kleger A, Mahaddalkar PU, Katz SF, Lechel A, Joo JY, Loya K, Lin Q, Hartmann D, Liebau S, Kraus JM, Cantz T, Kestler HA, Zaehres H, Scholer H, Rudolph KL (2012) Increased reprogramming capacity of mouse liver progenitor cells, compared with differentiated liver cells, requires the BAF complex. Gastroenterology 142(4):907–917. doi:10.1053/j.gastro.2012.01.004
Koch P, Breuer P, Peitz M, Jungverdorben J, Kesavan J, Poppe D, Doerr J, Ladewig J, Mertens J, Tuting T, Hoffmann P, Klockgether T, Evert BO, Wullner U, Brustle O (2011) Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease. Nature 480(7378):543–546. doi:10.1038/nature10671
Koch P, Tamboli IY, Mertens J, Wunderlich P, Ladewig J, Stuber K, Esselmann H, Wiltfang J, Brustle O, Walter J (2012) Presenilin-1 L166P mutant human pluripotent stem cell-derived neurons exhibit partial loss of gamma-secretase activity in endogenous amyloid-beta generation. Am J Pathol 180(6):2404–2416. doi:10.1016/j.ajpath.2012.02.012
Ladewig J, Mertens J, Kesavan J, Doerr J, Poppe D, Glaue F, Herms S, Wernet P, Kogler G, Muller FJ, Koch P, Brustle O (2012) Small molecules enable highly efficient neuronal conversion of human fibroblasts. Nat Methods 9(6):575–578. doi:10.1038/nmeth.1972
Lee J, Elkahloun AG, Messina SA, Ferrari N, Xi D, Smith CL, Cooper R Jr, Albert PS, Fine HA (2003) Cellular and genetic characterization of human adult bone marrow-derived neural stem-like cells: a potential anti glioma cellular vector. Cancer Res 63(24):8877–8889
Linta L, Stockmann M, Kleinhans KN, Bockers A, Storch A, Zaehres H, Lin Q, Barbi G, Bockers TM, Kleger A, Liebau S (2012) Rat embryonic fibroblasts improve reprogramming of human keratinocytes into induced pluripotent stem cells. Stem Cells Dev 21(6):965–976. doi:10.1089/scd.2011.0026
Lister R, Pelizzola M, Kida YS, Hawkins RD, Nery JR, Hon G, Antosiewicz-Bourget J, O’Malley R, Castanon R, Klugman S, Downes M, Yu R, Stewart R, Ren B, Thomson JA, Evans RM, Ecker JR (2011) Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471(7336):68–73. doi:10.1038/nature09798
Lohle M, Hermann A, Glass H, Kempe A, Schwarz SC, Kim JB, Poulet C, Ravens U, Schwarz J, Scholer HR, Storch A (2012) Differentiation efficiency of induced pluripotent stem cells depends on the number of reprogramming factors. Stem Cells 30(3):570–579. doi:10.1002/stem.1016
Lujan E, Chanda S, Ahlenius H, Sudhof TC, Wernig M (2012) Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells. Proc Natl Acad Sci USA 109(7):2527–2532. doi:10.1073/pnas.1121003109
Maisel M, Habisch HJ, Royer L, Herr A, Milosevic J, Hermann A, Liebau S, Brenner R, Schwarz J, Schroeder M, Storch A (2010) Genome-wide expression profiling and functional network analysis upon neuroectodermal conversion of human mesenchymal stem cells suggest HIF-1 and miR-124a as important regulators. Exp Cell Res 316(17):2760–2778. doi:10.1016/j.yexcr.2010.06.012
Miura K, Okada Y, Aoi T, Okada A, Takahashi K, Okita K, Nakagawa M, Koyanagi M, Tanabe K, Ohnuki M, Ogawa D, Ikeda E, Okano H, Yamanaka S (2009) Variation in the safety of induced pluripotent stem cell lines. Nat Biotechnol 27(8):743–745. doi:10.1038/nbt.1554
Nagamatsu G, Saito S, Kosaka T, Takubo K, Kinoshita T, Oya M, Horimoto K, Suda T (2012) Optimal ratio of transcription factors for somatic cell reprogramming. J Biol Chem 287(43):36273–36282. doi:10.1074/jbc.M112.380683
Nelson TJ, Martinez-Fernandez A, Yamada S, Perez-Terzic C, Ikeda Y, Terzic A (2009) Repair of acute myocardial infarction by human stemness factors induced pluripotent stem cells. Circulation 120(5):408–416. doi:10.1161/CIRCULATIONAHA.109.865154
Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S (2008) Generation of mouse induced pluripotent stem cells without viral vectors. Science 322(5903):949–953. doi:10.1126/science.1164270
Okita K, Yamakawa T, Matsumura Y, Sato Y, Amano N, Watanabe A, Goshima N, Yamanaka S (2013) An efficient nonviral method to generate integration-free human-induced pluripotent stem cells from cord blood and peripheral blood cells. Stem Cells 31(3):458–466. doi:10.1002/stem.1293
Pang ZP, Yang N, Vierbuchen T, Ostermeier A, Fuentes DR, Yang TQ, Citri A, Sebastiano V, Marro S, Sudhof TC, Wernig M (2011) Induction of human neuronal cells by defined transcription factors. Nature 476(7359):220–223. doi:10.1038/nature10202
Pankratz MT, Li XJ, Lavaute TM, Lyons EA, Chen X, Zhang SC (2007) Directed neural differentiation of human embryonic stem cells via an obligated primitive anterior stage. Stem Cells 25(6):1511–1520. doi:10.1634/stemcells.2006-0707
Pfisterer U, Kirkeby A, Torper O, Wood J, Nelander J, Dufour A, Bjorklund A, Lindvall O, Jakobsson J, Parmar M (2011) Direct conversion of human fibroblasts to dopaminergic neurons. Proc Natl Acad Sci USA 108(25):10343–10348. doi:10.1073/pnas.1105135108
Qiang L, Fujita R, Yamashita T, Angulo S, Rhinn H, Rhee D, Doege C, Chau L, Aubry L, Vanti WB, Moreno H, Abeliovich A (2011) Directed conversion of Alzheimer’s disease patient skin fibroblasts into functional neurons. Cell 146(3):359–371. doi:10.1016/j.cell.2011.07.007
Reinhardt P, Schmid B, Burbulla LF, Schondorf DC, Wagner L, Glatza M, Hoing S, Hargus G, Heck SA, Dhingra A, Wu G, Muller S, Brockmann K, Kluba T, Maisel M, Kruger R, Berg D, Tsytsyura Y, Thiel CS, Psathaki OE, Klingauf J, Kuhlmann T, Klewin M, Muller H, Gasser T, Scholer HR, Sterneckert J (2013) Genetic correction of a LRRK2 mutation in human iPSCs Links Parkinsonian neurodegeneration to ERK-dependent changes in gene expression. Cell Stem Cell 12(3):354–367. doi:10.1016/j.stem.2013.01.008
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. doi:10.1016/j.stem.2012.05.018
Sheng C, Zheng Q, Wu J, Xu Z, Wang L, Li W, Zhang H, Zhao XY, Liu L, Wang Z, Guo C, Wu HJ, Liu Z, He S, Wang XJ, Chen Z, Zhou Q (2012) Direct reprogramming of Sertoli cells into multipotent neural stem cells by defined factors. Cell Res 22(1):208–218. doi:10.1038/cr.2011.175
Soldner F, Hockemeyer D, Beard C, Gao Q, Bell GW, Cook EG, Hargus G, Blak A, Cooper O, Mitalipova M, Isacson O, Jaenisch R (2009) Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136(5):964–977. doi:10.1016/j.cell.2009.02.013
Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K (2008) Induced pluripotent stem cells generated without viral integration. Science 322(5903):945–949. doi:10.1126/science.1162494
Storch A, Schwarz J (2002) Neural stem cells and neurodegeneration. Curr Opin Investig Drugs 3(5):774–781
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. doi:10.1016/j.cell.2006.07.024
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872. doi:10.1016/j.cell.2007.11.019
Thier M, Worsdorfer P, Lakes YB, Gorris R, Herms S, Opitz T, Seiferling D, Quandel T, Hoffmann P, Nothen MM, Brustle O, Edenhofer F (2012) Direct conversion of fibroblasts into stably expandable neural stem cells. Cell Stem Cell 10(4):473–479. doi:10.1016/j.stem.2012.03.003
Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Sudhof TC, Wernig M (2010) Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463(7284):1035–1041. doi:10.1038/nature08797
Warren L, Manos PD, Ahfeldt T, Loh YH, Li H, Lau F, Ebina W, Mandal PK, Smith ZD, Meissner A, Daley GQ, Brack AS, Collins JJ, Cowan C, Schlaeger TM, Rossi DJ (2010) Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7(5):618–630. doi:10.1016/j.stem.2010.08.012
Xue Y, Ouyang K, Huang J, Zhou Y, Ouyang H, Li H, Wang G, Wu Q, Wei C, Bi Y, Jiang L, Cai Z, Sun H, Zhang K, Zhang Y, Chen J, Fu XD (2013) Direct conversion of fibroblasts to neurons by reprogramming PTB-regulated microRNA circuits. Cell 152(1–2):82–96. doi:10.1016/j.cell.2012.11.045
Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin II, Thomson JA (2009) Human induced pluripotent stem cells free of vector and transgene sequences. Science 324(5928):797–801. doi:10.1126/science.1172482
Zhou H, Wu S, Joo JY, Zhu S, Han DW, Lin T, Trauger S, Bien G, Yao S, Zhu Y, Siuzdak G, Scholer HR, Duan L, Ding S (2009) Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4(5):381–384. doi:10.1016/j.stem.2009.04.005
Acknowledgments
The research of the authors was supported by the Bundesministerium für Bildung und Forschung, the Deutsche Forschungsgemeinschaft (DFG) through the Collaborative Research Center 655 ‘Cells into tissues: stem cell and progenitor commitment and interactions during tissue formation’ (SFB 655, project A23) and the DFG-Research centre and Cluster of Excellence “Centre for Regenerative Therapies Dresden (CRTD)”, the Thyssen-Stiftung, and the Landesstiftung Baden-Württemberg.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Hermann, A., Storch, A. Induced neural stem cells (iNSCs) in neurodegenerative diseases. J Neural Transm 120 (Suppl 1), 19–25 (2013). https://doi.org/10.1007/s00702-013-1042-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-013-1042-9