Advertisement

Journal of Neural Transmission

, Volume 120, Supplement 1, pp 19–25 | Cite as

Induced neural stem cells (iNSCs) in neurodegenerative diseases

  • Andreas HermannEmail author
  • Alexander StorchEmail author
Translational Neurosciences - Review Article

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.

Keywords

Induced pluripotent stem cells (iPSCs) Direct lineage conversion Induced neurons (iNs) Induced neural stem cells (iNSCs) 

Notes

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.

References

  1. 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 PubMedCrossRefGoogle Scholar
  2. 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 PubMedCrossRefGoogle Scholar
  3. 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 PubMedCrossRefGoogle Scholar
  4. 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 PubMedCrossRefGoogle Scholar
  5. 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 PubMedCrossRefGoogle Scholar
  6. 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 PubMedCrossRefGoogle Scholar
  7. 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 PubMedCrossRefGoogle Scholar
  8. 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 PubMedCrossRefGoogle Scholar
  9. 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 PubMedCrossRefGoogle Scholar
  10. 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 PubMedCrossRefGoogle Scholar
  11. 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 PubMedCrossRefGoogle Scholar
  12. 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 PubMedGoogle Scholar
  13. 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 PubMedCrossRefGoogle Scholar
  14. 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 PubMedCrossRefGoogle Scholar
  15. 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 PubMedCrossRefGoogle Scholar
  16. 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 PubMedCrossRefGoogle Scholar
  17. 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 PubMedCrossRefGoogle Scholar
  18. 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 CrossRefGoogle Scholar
  19. 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 PubMedCrossRefGoogle Scholar
  20. 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 PubMedCrossRefGoogle Scholar
  21. 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 PubMedCrossRefGoogle Scholar
  22. 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 PubMedCrossRefGoogle Scholar
  23. 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 PubMedGoogle Scholar
  24. 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 PubMedCrossRefGoogle Scholar
  25. 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 PubMedCrossRefGoogle Scholar
  26. 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):8877–8889PubMedGoogle Scholar
  27. 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 PubMedCrossRefGoogle Scholar
  28. 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 PubMedCrossRefGoogle Scholar
  29. 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 PubMedCrossRefGoogle Scholar
  30. 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 PubMedCrossRefGoogle Scholar
  31. 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 PubMedCrossRefGoogle Scholar
  32. 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 PubMedCrossRefGoogle Scholar
  33. 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 PubMedCrossRefGoogle Scholar
  34. 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 PubMedCrossRefGoogle Scholar
  35. 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 PubMedCrossRefGoogle Scholar
  36. 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 PubMedCrossRefGoogle Scholar
  37. 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 PubMedGoogle Scholar
  38. 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 PubMedCrossRefGoogle Scholar
  39. 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 PubMedCrossRefGoogle Scholar
  40. 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 PubMedCrossRefGoogle Scholar
  41. 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 PubMedCrossRefGoogle Scholar
  42. 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 PubMedCrossRefGoogle Scholar
  43. 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 PubMedCrossRefGoogle Scholar
  44. 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 PubMedCrossRefGoogle Scholar
  45. 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 PubMedCrossRefGoogle Scholar
  46. Storch A, Schwarz J (2002) Neural stem cells and neurodegeneration. Curr Opin Investig Drugs 3(5):774–781PubMedGoogle Scholar
  47. 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 PubMedCrossRefGoogle Scholar
  48. 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 PubMedCrossRefGoogle Scholar
  49. 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 PubMedCrossRefGoogle Scholar
  50. 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 PubMedCrossRefGoogle Scholar
  51. 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 PubMedCrossRefGoogle Scholar
  52. 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 PubMedCrossRefGoogle Scholar
  53. 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 PubMedCrossRefGoogle Scholar
  54. 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 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2013

Authors and Affiliations

  1. 1.Division of Neurodegenerative Diseases, Department of NeurologyDresden University of TechnologyDresdenGermany
  2. 2.German Centre for Neurodegenerative Diseases (DZNE) DresdenDresdenGermany
  3. 3.Center for Regenerative Therapies Dresden (CRTD)Dresden University of TechnologyDresdenGermany

Personalised recommendations