Molecular Neurobiology

, Volume 53, Issue 4, pp 2124–2131 | Cite as

Experimental Advances Towards Neural Regeneration from Induced Stem Cells to Direct In Vivo Reprogramming

  • Sara Dametti
  • Irene Faravelli
  • Margherita Ruggieri
  • Agnese Ramirez
  • Monica Nizzardo
  • Stefania Corti


Neuronal loss is a common substrate of many neurological diseases that still lack effective treatments and highly burden lives of affected individuals. The discovery of self-renewing stem cells within the central nervous system (CNS) has opened the doors to the possibility of using the plasticity of CNS as a potential strategy for the development of regenerative therapies after injuries. The role of neural progenitor cells appears to be crucial, but insufficient in reparative processes after damage. In addition, the mechanisms that regulate these events are still largely unknown. Stem cell-based therapeutic approaches have primarily focused on the use of either induced pluripotent stem cells or induced neural stem cells as sources for cell transplantation. More recently, in vivo direct reprogramming of endogenous CNS cells into multipotent neural stem/progenitor cells has been proposed as an alternative strategy that could overcome the limits connected with both the invasiveness of exogenous cell transplantation and the technical issues of in vitro reprogramming (i.e., the time requested and the limited available amount of directly induced neuronal cells). In this review, we aim to highlight the recent studies on in vivo direct reprogramming, focusing on astrocytes conversion to neurons or to neural stem/precursors cells, in the perspective of future therapeutic purposes for neurological disorders.


In vivo reprogramming Neural stem cells Neuronal loss Regeneration 



The financial support of the Cariplo research grant to SC is gratefully acknowledged. The support of the “Associazione Amici del Centro Dino Ferrari” is gratefully acknowledged.

Conflict of Interest

The authors declare that they have no competing interests. All authors have approved the manuscript and agree with its submission to Cellular and Molecular Life Sciences.


  1. 1.
    Rizzo F, Riboldi G, Salani S, Nizzardo M, Simone C, Corti S, Hedlund E (2014) Cellular therapy to target neuroinflammation in amyotrophic lateral sclerosis. Cell Mol Life Sci CMLS 71(6):999–1015. doi: 10.1007/s00018-013-1480-4 CrossRefPubMedGoogle Scholar
  2. 2.
    Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97(6):703–716CrossRefPubMedGoogle Scholar
  3. 3.
    Doetsch F, Garcia-Verdugo JM, Alvarez-Buylla A (1997) Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J Neurosci Off J Soc Neurosci 17(13):5046–5061Google Scholar
  4. 4.
    Temple S (2001) The development of neural stem cells. Nature 414(6859):112–117. doi: 10.1038/35102174 CrossRefPubMedGoogle Scholar
  5. 5.
    Lim DA, Tramontin AD, Trevejo JM, Herrera DG, Garcia-Verdugo JM, Alvarez-Buylla A (2000) Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron 28(3):713–726CrossRefPubMedGoogle Scholar
  6. 6.
    Sanai N, Tramontin AD, Quinones-Hinojosa A, Barbaro NM, Gupta N, Kunwar S, Lawton MT, McDermott MW, Parsa AT, Manuel-Garcia Verdugo J, Berger MS, Alvarez-Buylla A (2004) Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427(6976):740–744. doi: 10.1038/nature02301 CrossRefPubMedGoogle Scholar
  7. 7.
    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 CrossRefPubMedGoogle Scholar
  8. 8.
    Corti S, Nizzardo M, Simone C, Falcone M, Nardini M, Ronchi D, Donadoni C, Salani S, Riboldi G, Magri F, Menozzi G, Bonaglia C, Rizzo F, Bresolin N, Comi GP (2012) Genetic correction of human induced pluripotent stem cells from patients with spinal muscular atrophy. Sci Transl Med 4(165):165ra162. doi: 10.1126/scitranslmed.3004108 PubMedPubMedCentralGoogle Scholar
  9. 9.
    Sandoe J, Eggan K (2013) Opportunities and challenges of pluripotent stem cell neurodegenerative disease models. Nat Neurosci 16(7):780–789. doi: 10.1038/nn.3425 CrossRefPubMedGoogle Scholar
  10. 10.
    Fong CY, Gauthaman K, Bongso A (2010) Teratomas from pluripotent stem cells: a clinical hurdle. J Cell Biochem 111(4):769–781. doi: 10.1002/jcb.22775 CrossRefPubMedGoogle Scholar
  11. 11.
    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 CrossRefPubMedGoogle Scholar
  12. 12.
    Yamanaka S (2009) A fresh look at iPS cells. Cell 137(1):13–17. doi: 10.1016/j.cell.2009.03.034 CrossRefPubMedGoogle Scholar
  13. 13.
    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 CrossRefPubMedGoogle Scholar
  14. 14.
    Liu X, Li F, Stubblefield EA, Blanchard B, Richards TL, Larson GA, He Y, Huang Q, Tan AC, Zhang D, Benke TA, Sladek JR, Zahniser NR, Li CY (2012) Direct reprogramming of human fibroblasts into dopaminergic neuron-like cells. Cell Res 22(2):321–332. doi: 10.1038/cr.2011.181 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    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 U S A 108(25):10343–10348. doi: 10.1073/pnas.1105135108 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    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. doi: 10.1016/j.stem.2011.07.014 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kim J, Efe JA, Zhu S, Talantova M, Yuan X, Wang S, Lipton SA, Zhang K, Ding S (2011) Direct reprogramming of mouse fibroblasts to neural progenitors. Proc Natl Acad Sci U S A 108(19):7838–7843. doi: 10.1073/pnas.1103113108 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    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 U S A 109(7):2527–2532. doi: 10.1073/pnas.1121003109 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    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 CrossRefPubMedGoogle Scholar
  20. 20.
    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 CrossRefPubMedGoogle Scholar
  21. 21.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Berninger B, Costa MR, Koch U, Schroeder T, Sutor B, Grothe B, Gotz M (2007) Functional properties of neurons derived from in vitro reprogrammed postnatal astroglia. J Neurosci Off J Soc Neurosci 27(32):8654–8664. doi: 10.1523/JNEUROSCI.1615-07.2007 CrossRefGoogle Scholar
  23. 23.
    Heinrich C, Blum R, Gascon S, Masserdotti G, Tripathi P, Sanchez R, Tiedt S, Schroeder T, Gotz M, Berninger B (2010) Directing astroglia from the cerebral cortex into subtype specific functional neurons. PLoS Biol 8(5), e1000373. doi: 10.1371/journal.pbio.1000373 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Heins N, Malatesta P, Cecconi F, Nakafuku M, Tucker KL, Hack MA, Chapouton P, Barde YA, Gotz M (2002) Glial cells generate neurons: the role of the transcription factor Pax6. Nat Neurosci 5(4):308–315. doi: 10.1038/nn828 CrossRefPubMedGoogle Scholar
  25. 25.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Juopperi TA, Kim WR, Chiang CH, Yu H, Margolis RL, Ross CA, Ming GL, Song H (2012) Astrocytes generated from patient induced pluripotent stem cells recapitulate features of Huntington’s disease patient cells. Mol Brain 5:17. doi: 10.1186/1756-6606-5-17 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Haidet-Phillips AM, Hester ME, Miranda CJ, Meyer K, Braun L, Frakes A, Song S, Likhite S, Murtha MJ, Foust KD, Rao M, Eagle A, Kammesheidt A, Christensen A, Mendell JR, Burghes AH, Kaspar BK (2011) Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat Biotechnol 29(9):824–828. doi: 10.1038/nbt.1957 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Re DB, Le Verche V, Yu C, Amoroso MW, Politi KA, Phani S, Ikiz B, Hoffmann L, Koolen M, Nagata T, Papadimitriou D, Nagy P, Mitsumoto H, Kariya S, Wichterle H, Henderson CE, Przedborski S (2014) Necroptosis drives motor neuron death in models of both sporadic and familial ALS. Neuron 81(5):1001–1008. doi: 10.1016/j.neuron.2014.01.011 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Goldman SA, Nedergaard M, Windrem MS (2012) Glial progenitor cell-based treatment and modeling of neurological disease. Science 338(6106):491–495. doi: 10.1126/science.1218071 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Gupta K, Patani R, Baxter P, Serio A, Story D, Tsujita T, Hayes JD, Pedersen RA, Hardingham GE, Chandran S (2012) Human embryonic stem cell derived astrocytes mediate non-cell-autonomous neuroprotection through endogenous and drug-induced mechanisms. Cell Death Differ 19(5):779–787. doi: 10.1038/cdd.2011.154 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Torper O, Pfisterer U, Wolf DA, Pereira M, Lau S, Jakobsson J, Bjorklund A, Grealish S, Parmar M (2013) Generation of induced neurons via direct conversion in vivo. Proc Natl Acad Sci U S A 110(17):7038–7043. doi: 10.1073/pnas.1303829110 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Buffo A, Vosko MR, Erturk D, Hamann GF, Jucker M, Rowitch D, Gotz 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. doi: 10.1073/pnas.0506535102 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    De la Rossa A, Bellone C, Golding B, Vitali I, Moss J, Toni N, Luscher C, Jabaudon D (2013) In vivo reprogramming of circuit connectivity in postmitotic neocortical neurons. Nat Neurosci 16(2):193–200. doi: 10.1038/nn.3299 CrossRefPubMedGoogle Scholar
  34. 34.
    Grande A, Sumiyoshi K, Lopez-Juarez 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. doi: 10.1038/ncomms3373 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Niu W, Zang T, Zou Y, Fang S, Smith DK, Bachoo R, Zhang CL (2013) In vivo reprogramming of astrocytes to neuroblasts in the adult brain. Nat Cell Biol 15(10):1164–1175. doi: 10.1038/ncb2843 CrossRefPubMedGoogle Scholar
  36. 36.
    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. doi: 10.1038/ncb2660 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Su Z, Niu W, Liu ML, Zou Y, Zhang CL (2014) In vivo conversion of astrocytes to neurons in the injured adult spinal cord. Nat Commun 5:3338. doi: 10.1038/ncomms4338 PubMedPubMedCentralGoogle Scholar
  38. 38.
    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. doi: 10.1016/j.stem.2013.12.001 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Sara Dametti
    • 1
  • Irene Faravelli
    • 1
  • Margherita Ruggieri
    • 1
  • Agnese Ramirez
    • 1
  • Monica Nizzardo
    • 1
  • Stefania Corti
    • 1
  1. 1.Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), Neurology Unit, IRCCS Foundation Ca’ Granda Ospedale Maggiore PoliclinicoUniversity of MilanMilanItaly

Personalised recommendations