Skip to main content

Advertisement

SpringerLink
Log in

Therapeutical Strategies for Spinal Cord Injury and a Promising Autologous Astrocyte-Based Therapy Using Efficient Reprogramming Techniques

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Spinal cord injury (SCI) is a traumatic event resulting in disturbances to normal sensory, motor, or autonomic functions, which ultimately impacts a patient’s physical, psychological, and social well-being. Until now, no available therapy for SCI can effectively slow down or halt the disease progression. Compared to traditional treatments, e.g., medication, surgery, and functional electrical stimulation, stem cell replacement therapy shows high potential for repair and functional plasticity. Thus, stem cell therapy may provide a promising strategy in curative treatment of SCI, specifically when considering the requirement of neuron replenishment in the spinal cord after distinct acute injuries. However, the therapeutic application of neural stem cells (NSCs) still faces enormous challenges, such as ethical issues, possible inflammatory reactions, graft rejection, and tumor formation. Therefore, it is of vital interest to identify more suitable sources of cells with stem cell potential, which might potentially be harnessed for local neural repair. Due to abovementioned possible drawbacks, these cells should be autologous. Reprogramming of astrocytes to generate the desired neuronal cell types would open the door to autologous cell transplantation and treatment of SCI without possible severe side effects. In this paper, we review the relevant therapeutic strategies for SCI, and conversion of astrocyte into NSCs, suggesting this procedure as a possible treatment option.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Singh A, Tetreault L, Kalsi-Ryan S, Nouri A, Fehlings MG (2014) Global prevalence and incidence of traumatic spinal cord injury. Clin Epidemiol 6:309–331

    PubMed  PubMed Central  Google Scholar 

  2. Jackson AB, Dijkers M, Devivo MJ, Poczatek RB (2004) A demographic profile of new traumatic spinal cord injury—changes and stability over 30 years. Arch Phys Med Rehabil 85(11):1740–1748

    Article  PubMed  Google Scholar 

  3. Behrman AL, Trimble SA (2012) Outcomes of spinal cord injuries in young children. Dev Med Child Neurol 54:1078

    Article  PubMed  Google Scholar 

  4. Sekhon LH, Fehlings MG (2001) Epidemiology, demographics, and pathophysiology of acute spinal cord injury. Spine 26(24 Suppl):S2–S12

    Article  CAS  PubMed  Google Scholar 

  5. Morawietz C, Moffat F (2013) Effects of locomotor training after incomplete spinal cord injury: a systematic review. Arch Phys Med Rehabil 94(11):2297–2308

    Article  PubMed  Google Scholar 

  6. Michailidou C, Marston L, De Souza LH, Sutherland I (2014) A systematic review of the prevalence of musculoskeletal pain, back and low back pain in people with spinal cord injury. Disabil Rehabil 36(9):705–715

    Article  PubMed  Google Scholar 

  7. Esposito E, Cuzzocrea S (2011) Anti-TNF therapy in the injured spinal cord. Trends in pharmacological Sci 32(2):107–115

    Article  CAS  Google Scholar 

  8. Jencsen TS, Madsen CS, Finnerup NB (2009) Pharmacology and treatment of neuropathic pains. Current opinion in Neurol 22(5):467–474

    Article  CAS  Google Scholar 

  9. Song FH, Tian M, and Zhang H (2014) Molecular imaging in stem cell therapy for spinal cord. BioMed Res Int 759514. doi: 10.1155/2014/759514.

  10. Wang X, Hasan O, Arzeno A, Arzeno A, Benowitz LI, Cafferty WB, Strittmatter SM (2012) Axonal regeneration induced by blockade of glial inhibitors coupled with activation of intrinsic neuronal growth pathways. Exp Neurol 237(1):55–69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cregg JM, Depaul MA, Filous AR, Lang BT, Tran A, Silver J (2014) Functional regeneration beyond the glial scar. Exp Neurol 253:197–207

    Article  PubMed  Google Scholar 

  12. Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32(12):638–647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hulsebosch CE (2002) Recent advances in pathophysiology and treatment of spinal cord injury. Adv Physiol Educ 26(1–4):238–255

    Article  PubMed  Google Scholar 

  14. Ladewig J, Mertens J, Kesavan J, Doerr J, Poppe D, Glaue F, Herms S, Wernet P et al (2012) Small molecules enable highly efficient neuronal conversion of human fibroblasts. Nat Methods 9(6):575–578

    Article  CAS  PubMed  Google Scholar 

  15. 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

    Article  CAS  PubMed  Google Scholar 

  16. Liu ML, Zang T, Zou Y, Chang JC, Gibson JR, Huber KM, Zhang CL (2013) Small molecules enable neurogenin 2 to efficiently convert human fibroblasts into cholinergic neurons. Nature Commun 4:2183

    Google Scholar 

  17. Amamoto R, Arlotta P (2014) Development-inspired reprogramming of the mammalian central nervous system. Science 343(6170):1239882

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Su ZD, Niu WZ, Liu ML, Zou YH, Zhang CL (2014) In vivo conversion of astrocytes to neurons in the injured adult spinal cord. Nat Commun 5:3338

    PubMed  PubMed Central  Google Scholar 

  19. Corti S, Nizzardo M, Simone C, Falcone M, Donadoni C, Salani S, Rizzo F, Nardini M et al (2012) Direct reprogramming of human astrocytes into neural stem cells and neurons. Exp Cell Res 318(13):1528–1541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Miller RH, Raff MC (1984) Fibrous and protoplasmic astrocytes are biochemically and developmentally distinct. J Neurosci 4(2):585–592

    CAS  PubMed  Google Scholar 

  21. Yang H, Ling W, Vitale A, Olivera C, Min Y, You S (2011) ErbB2 activation contributes to de-differentiation of astrocytes into radial glial cells following induction of scratch-insulted astrocyte conditioned medium. Neurochem Int 59(7):1010–1018

    Article  CAS  PubMed  Google Scholar 

  22. Leavitt BR, Hernit-Grant CS, Macklis JD (1999) Mature astrocytes transform into transitional radial glia with adult mouse neocortex tat support directed migration of transplanted immature neurons. Exp Neurol 157(1):43–57

    Article  CAS  PubMed  Google Scholar 

  23. Nagelhus EA, Mathiisen TM, Bateman AC, Haug FM, Ottersen OP, Grubb JH, Waheed A, Sly WS (2005) Carbonic anhydrase XIV is enriched in specific membrane domains of retinal pigment epithelium, Muller cells, and astrocytes. Proc Natl Acad Sci U S A 102(22):8030–8035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yamada K, Watanabe M (2002) Cytodifferentiation of Bergmann glia and its relationship with Purkinje cells. Anatomical Sci Int/Japanese Assoc Anatomists 77(2):94–108

    Google Scholar 

  25. Chan-Palay V, Palay S (1972) The form of velate astrocytes in the cerebellar cortex of monkey and rat: high voltage electron microscopy of rapid Golgi preparations. Anat Embryol 138(1):1–19

    CAS  Google Scholar 

  26. 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 17(13):5046–5061

    CAS  PubMed  Google Scholar 

  27. Faden AI (2002) Neuroprotection and traumatic brain injury: theoretical option or realistic proposition. Curr Opin Neurol 15(6):707–712

    Article  PubMed  Google Scholar 

  28. Zhang JM, Wang HK, Chang-quan YE, Ge WP, Wu CP, Poo MM, Duan SM (2003) ATP Released by astrocytes mediates glutamatergic activity-dependent heterosynaptic suppression. Neuron 40(5):971–982

    Article  CAS  PubMed  Google Scholar 

  29. Allan S (2005) The neurovascular unit and the key role of astrocytes in the regulation of cerebral blood flow. Cerebrovasc Dis 21(1–2):137–138

    PubMed  Google Scholar 

  30. Gallo F, Morale MC, Farinella Z, Avola R, Marchetti B (1996) Growth factors released from astroglial cells in primary culture participate in the cross talk between luteinizing hormone-releasing hormone (LHRH) neurons and astrocytes. Effects on LHRH neuronal proliferation and secretion. Ann N Y Acad Sci 784:513–516

    Article  CAS  PubMed  Google Scholar 

  31. Haberg A, Qu H, Sonnewald U (2006) Glutamate and GABA metabolism in transient and permanent middle cerebral artery occlusion in rat: importance of astrocytes for neuronal survival. Neurochem Int 48(6–7):531–540

    Article  CAS  PubMed  Google Scholar 

  32. Walz W (1987) Swelling and potassium uptake in cultured astrocytes. Can J Physiol Pharmacol 65(5):1051–1057

    Article  CAS  PubMed  Google Scholar 

  33. Lang B, Liu HL, Liu R, Feng GD, Jiao XY, Ju G (2004) Astrocytes in injured adult rat spinal cord may acquire the potential of neural stem cells. Neurosci 128(4):775–783

    Article  CAS  Google Scholar 

  34. Chang ML, Wu CH, Jiang-Shieh YF, Shieh JY, Wen CY (2007) Reactive changes of retinal astrocytes and Muller glial cells in kainate-induced neuroexcitotoxicity. J Anat 210(1):54–65

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chen J, Leonq SY, Schachner M (2005) Differential expression of cell fate determinants in neurons and glial cells of adult mouse spinal cord after compression injury. Eur J Neurosci 22(8):1895–1906

    Article  PubMed  Google Scholar 

  36. Ooto S, Akagi T, Kageyama R, Akita J, Mandai M, Honda Y et al (2004) Potential for neural regeneration after neurotoxic injury in the adult mammalian retina. Proc Natl Acad Sci U S A 101(37):13654–13659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Itoh T, Satou T, Nishida S, Hashimoto S, Ito H (2006) Cultured rat astrocytes give rise to neural stem cells. Neurochem Res 31(11):1381–1387

    Article  CAS  PubMed  Google Scholar 

  38. Feng GD, He BR, Fan L, Liu LH, Zhang LL, Chen B, He ZP, Hao DJ et al (2014) Fibroblast growth factor4 is required but not sufficient for the astrocyte dedifferentiation. Mol Neurobiol 50(3):997–1012

    Article  CAS  PubMed  Google Scholar 

  39. Yang H, Feng GD, Olivera C, Jiao XY, Vitale A, Ju G, You SW (2012) Sonic hedgehog released from scratch-injured astrocytes is a key signal necessary but not sufficient for the astrocyte de-differentiation. Stem Cell Res 9(2):156–166

    Article  CAS  PubMed  Google Scholar 

  40. Yang H, Liang Z, Li JW, Cheng XP, Luo N, Ju G (2006) Optimized and efficient preparation of astrocyte cultures from rat spinal cord. Cytotechnology 52(2):87–97

    Article  PubMed  PubMed Central  Google Scholar 

  41. Frangakis MV, Kimelberg HK (1984) Dissociation of neonatal rat brain by dispase for preparation of primary astrocyte cultures. Neurochem Res 9(12):1689–1698

    Article  CAS  PubMed  Google Scholar 

  42. McKerracher L (2001) Spinal cord repair: strategies to promote axon regeneration. Neurobiol Dis 8(1):11–18

    Article  CAS  PubMed  Google Scholar 

  43. Marino RJ, Barros T, Biering-Sorensen F, Burns SP, Donovan WH, Graves DE, Haak M, Hudson LM et al (2003) International standards for neurological classification of spinal cord injury. J Spinal Cord Med 26(Suppl 1):S50–S56

    Article  Google Scholar 

  44. Yuan QY (2005) Review: strategies for neuronal regeneration after spinal cord injury. J Young Invest

  45. Tohda C, Kuboyama T (2011) Current and future therapeutic strategies for functional repair of spinal cord injury. Pharmacol Ther 132(1):57–71

    Article  CAS  PubMed  Google Scholar 

  46. Ditunno JF Jr, Young W, Donovan WH, Creasey G (1994) The international standards booklet for neurological and functional classification of spinal cord injury American Spinal injury Association. Paraplegia 32(2):70–80

    Article  PubMed  Google Scholar 

  47. Sadowsky C, Volshteyn O, Schultz L, McDonald JW (2002) Spinal cord injury. Disab Rehab 24(13):680–687

    Article  CAS  Google Scholar 

  48. Schwab ME (2002) Repairing the injured spinal cord. Science 295(5557):1029–1031

    Article  CAS  PubMed  Google Scholar 

  49. Jone DG, Anderson ER, Galvin KA (2003) Spinal cord regeneration: moving tentatively towards new perspectives. NeuroRehab 18(4):339–351

    Google Scholar 

  50. Li S, Liu BP, Budel S, Li M, Ji B, Walus L, Li W, Jirik A et al (2004) Blockade of Nogo-66, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein by soluble Nogo-66 receptor promotes axonal sprouting and recovery after spinal injury. J Neurosci 24(46):10511–10520

    Article  CAS  PubMed  Google Scholar 

  51. Xu H, Zhang SL, Tan GW, Zhu HW, Huang CQ, Zhang FF, Wang ZX (2012) Reactive gliosis and neuroinflammation in rats with communicating hydrocephalus. Neurosci 218:317–325

    Article  CAS  Google Scholar 

  52. Hendriks WT, Ruitenberg MJ, Blits B, Boer GJ, Verhaagen J (2004) Viral vector-mediated gene transfer of neurotrophins to promote regeneration of the injured spinal cord. Prog Brain Res 146:451–476

    Article  CAS  PubMed  Google Scholar 

  53. Jin Y, Fischer I, Tessler A, Houle JD (2002) Transplants of fibroblasts genetically modified to express BDNF promote axonal regeneration from supraspinal neurons following chronic spinal cord injury. Exp Neurol 177(1):265–275

    Article  CAS  PubMed  Google Scholar 

  54. Ye JH, Houle JD (1997) Treatment of the chronically injured spinal cord with neurotrophic factors can promote axonal regeneration from supraspinal neurons. Exp Neurol 143(1):70–81

    Article  CAS  PubMed  Google Scholar 

  55. Strong MJ, Kesavapany S, Pant HC (2005) The pathobiology of amyotrophic lateral sclerosis: a proteinopathy? J Neuropath Exp Neurol 64(8):649–664

    Article  CAS  PubMed  Google Scholar 

  56. Liu Y, Tachibana T, Dai Y, Kondo E, Fukuoka T, Yamanaka H, Noguchi K (2002) Heme oxygenase-1 expression after spinal cord injury: the induction in activated neutrophils. J Neurotrauma 19(4):479–490

    Article  PubMed  Google Scholar 

  57. Kim YJ, Hwang SY, Oh ES, Oh S, Han IO (2006) IL-1beta, an immediate early protein secreted by activated microglia, induces iNOS/NO in C6 astrocytoma cells through p38 MAPK and NFkappaB pathways. J Neurosci Res 84(5):1037–1046

    Article  CAS  PubMed  Google Scholar 

  58. Wang X, Xu XM (2014) Long-term survival, axonal growth-promotion, and myelination of Schwann cells grafted into contused spinal cord in adult rats. Exp Neurol 261:308–319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ruff CA, Wilcox JT, Fehlings MG (2012) Cell-based transplantation strategies to promote plasticity following spinal cord injury. Exp Neurol 235(1):78–90

    Article  PubMed  Google Scholar 

  60. Mehrabi S, Eftekhari S, Moradi F, Delaviz H, Pourheidar B, Azizi M, Zendehdel A, Shahbazi A et al (2013) Cell therapy in spinal cord injury: a mini-review. Basic Clin Neurosci 4(2):172–176

    PubMed  PubMed Central  Google Scholar 

  61. Harrop JS, Hashimoto R, Norvell D, Raich A, Aarabi B, Grossman RG, Guest JD, Tator CH et al (2012) Evaluation of clinical experience using cell-based therapies in patients with spinal cord injury: a systematic review. J Neurosurg Spine 17(1 Suppl):230–246

    Article  PubMed  Google Scholar 

  62. Lakatos A, Franklin RJ (2002) Transplant mediated repair of the central nervous system: an imminent solution? Curr Opin Neurol 15(6):701–705

    Article  PubMed  Google Scholar 

  63. Park DY, Mayle RE, Smith RL, Corcoran-Schwartz I, Kharazi AI, Cheng I (2013) Combined transplantation of human neuronal and mesenchymal stem cells following spinal cord injury. Global Spine J 3(1):1–6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Karimi-Abdolrezaee S, Eftekharpour E, Wang J, Schut D, Fehlings MG (2010) Synergistic effects of transplanted adult neural stem/progenitor cells, chondroitinase, and growth factors promote functional repair and plasticity of the chronically injured spinal cord. J Neurosci 30(5):1657–1676

    Article  CAS  PubMed  Google Scholar 

  65. Parr AM, Kulbatski I, Tator CH (2007) Transplantation of adult rat spinal cord stem/progenitor cells for spinal cord injury. J Neurotrauma 24(5):835–845

    Article  PubMed  Google Scholar 

  66. Hong JY, Lee SH, Lee SC, Kim JW, Kim KP, Kim SM, Tapia N, Lim KT et al (2014) Therapeutic potential of induced neural stem cells for spinal cord injury. J Biol Chem 289(47):32512–32525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Pfisterer U, Wood J, Nihlberg K, Hallgren O, Bjermer L, Westergren-Thorsson G, Lindvall O, Parmar M (2011) Efficient induction of functional neurons from adult human fibroblasts. Cell Cycle 10(19):3311–3316

    Article  CAS  PubMed  Google Scholar 

  68. Thier M, Wörsdörfer P, Lakes YB, Gorris R, Herms S, Opitz T, Seiferling D, Quandel T et al (2012) Direct conversion of fibroblasts into stably expandable neural stem cells. Cell Stem Cell 10(4):473–479

    Article  CAS  PubMed  Google Scholar 

  69. Ruggieri M, Riboldi G, Brajkovic S, Bucchia M, Bresolin N, Comi GP, Corti S (2014) Induced neural stem cells: methods of reprogramming and potential therapeutic applications. Prog Neurobiol 114:15–24

    Article  CAS  PubMed  Google Scholar 

  70. Ruiz S, Brennand K, Panopoulos AD, Herrerías A, Gage FH, Izpisua-Belmonte JC (2010) High-efficient generation of induced pluripotent stem cells from human astrocytes. PLoS One 5(12):e15526

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Heinrich C, Blum R, Gascón S, Masserdotti G, Tripathi P, Sánchez R, Tiedt S, Schroeder T et al (2010) Directing astroglia from the cerebral cortex into subtype specific functional neurons. PLoS Biol 8(5):e1000373

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Sher F, Boddeke E, Copray S (2011) Ezh2 expression in astrocytes induces their dedifferentiation toward neural stem cells. Cell Reprogramming 13(1):1–6

    Article  CAS  Google Scholar 

  73. Yang H, Cheng XP, Li JW, Yao Q, Ju G (2009) De-differentiation response of cultured astrocytes to injury induced by scratch or conditioned culture medium of scratch-insulted astrocytes. Cell Mol Neurobiol 29(4):455–473

    Article  PubMed  CAS  Google Scholar 

  74. Yu T, Cao G, Feng L (2006) Low temperature induced de-differentiation of astrocytes. J Cell Biochem 99:1096–1107

    Article  CAS  PubMed  Google Scholar 

  75. Timiras PS, Yaghmaie F, Saeed O, Thung E, Chinn G (2005) The ageing phenome: caloric restriction and hormones promote neural cell survival, growth, and de-differentiation. Mech Ageing Dev 126(1):3–9

    Article  CAS  PubMed  Google Scholar 

  76. Dai C, Celestino JC, Okada Y, Louis DN, Fuller GN, Holland EC (2001) PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev 15(15):1913–1925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sharif A, Legendre P, Prévot V, Allet C, Romao L, Studler JM, Chneiweiss H, Junier MP (2007) Transforming growth factor alpha promotes sequential conversion of mature astrocytes into neural progenitors and stem cells. Oncogene 26(19):2695–2706

    Article  CAS  PubMed  Google Scholar 

  78. Heins N, Malatesta P, Cecconi F, Nakafuku M, Tucker KL, Hack MA, Chapouton P, Barde YA et al (2002) Glial cells generate neurons: the role of the transcription factor Pax6. Nature Neurosci 5(4):308–315

    Article  CAS  PubMed  Google Scholar 

  79. Heinrich C, Gascón S, Masserdotti G, Lepier A, Sanchez R, Simon-Ebert T, Schroeder T, Götz M et al (2011) Generation of subtype-specific neurons from postnatal astroglia of the mouse cerebral cortex. Nat Protoc 6(2):214–228

    Article  CAS  PubMed  Google Scholar 

  80. Marro S, Pang ZP, Yang N, Tsai MC, 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Karow M, Sánchez R, Schichor C, Masserdotti G, Ortega F, Heinrich C, Gascón S, Khan MA et al (2012) Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells. Cell Stem Cell 11(4):471–476

    Article  CAS  PubMed  Google Scholar 

  82. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bertrand N, Castro DS, Guillemot F (2002) Proneural genes and the specification of neural cell types. Nat Rev Neurosci 3(7):517–530

    Article  CAS  PubMed  Google Scholar 

  84. Orly LW, Wapinski OL, Vierbuchen T, Qu K, Lee QY, Chanda S, Fuentes DR, Giresi PG et al (2013) Hierarchical mechanisms for direct reprogramming of fibroblasts to neurons. Cell 155(3):621–635

    Article  CAS  Google Scholar 

  85. Berninger B, Costa MR, Koch U, Schroeder T, Sutor B, Grothe B, Götz M (2007) Functional properties of neurons derived from in vitro reprogrammed postnatal astroglia. J Neurosci 27(32):8654–8664

    Article  CAS  PubMed  Google Scholar 

  86. Alavian K, Scholz C, Simon H (2008) Transcriptional regulation of mesencephalic dopaminergic neurons: the full circle of life and death. Mov Disord 23(3):319–328

    Article  PubMed  Google Scholar 

  87. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 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

    Article  CAS  PubMed  Google Scholar 

  89. Chen JG, Rasin MR, Kwan K, Sestan N (2005) Zfp312 is required for subcortical axonal projections and dendritic morphology of deep-layer pyramidal neurons of the cerebral cortex. Proc Natl Acad Sci U S A 102(49):17792–17797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Pardo M, Lang B, Yu L, Prosser H, Bradley A, Babu MM, Choudhary J (2010) An expanded Oct4 interaction network: implications for stem cell biology development, and disease. Cell Stem Cell 6(4):382–395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Mega T, Lupia M, Amodio N, Horton SJ, Mesuraca M, Pelaggi D, Agosti V, Grieco M, Chiarella E, Spina R, Moore MA, Schuringa JJ, Bond HM, Morrone G (2011) Zinc finger protein 521 antagonizes early B-cell factor 1 and modulates the B-lymphoid differentiation of primary hematopoietic progenitors. Cell Cycle 10(13):2129–2139

    Article  CAS  PubMed  Google Scholar 

  92. Tian C, Gong Y, Yang Y, Shen W, Wang K, Liu J, Xu B, Zhao J, Zhao C (2012) Foxg1 has an essential role in postnatal development of the dentate gyrus. J Neurosci 32(9):2931–2949

    Article  CAS  PubMed  Google Scholar 

  93. Ghosh TK, Song FF, Packham EA, Buxton S, Robinson TE, Ronksley J, Self T, Bonser AJ, Brook JD (2009) Physical interaction between TBX5 and MEF2C is required for early heart development. Mol Cell Biol 29(8):2205–2218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Lüningschröra P, Hauserb S, Kaltschmidta B, Kaltschmidt C (2013) MicroRNAs in pluripotency, reprogramming and cell fate induction. Biochim Biophys Acta 1833(8):1894–1903

    Article  CAS  Google Scholar 

  96. Huntzinger E, Izaurralde E (2011) Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet 12(2):99–110

    Article  CAS  PubMed  Google Scholar 

  97. Lipchina I, Studer L, Betel D (2012) The expanding role of miR-302-367 in pluripotency and reprogramming. Cell Cycle 11(8):1517–1523

    Article  CAS  PubMed  Google Scholar 

  98. Anokye-Danso F, Trivedi CM, Juhr D, Gupta M, Cui Z, Tian Y, Zhang Y, Yang W et al (2011) Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell 8(4):376–388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Judson RL, Babiarz JE, Venere M, Blelloch R (2009) Embryonic stem ell-specific microRNAs promote induced pluripotency. Nat Biotechnol 27(5):459–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Yang CS, Li Z, Rana TM (2011) microRNAs modulate iPS cell generation. RNA 17(8):1451–1460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Choi YJ, Lin CP, Ho JJ, He X, Okada N, Bu P, Zhong Y, Kim SY et al (2011) miR-34miRNAs provide a barrier for somatic cell reprogramming. Nat Cell Biol 13(11):1353–1360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Akerblom M, Sachdeva R, Jakobsson J (2012) Functional studies of microRNAs in neural stem cells: problems and perspectives. Front Neurosci 6:14. doi:10.3389/fnins.2012.00014

  103. Zhao C, Sun G, Li S, Lang MF, Yang S, Li W, Shi Y (2010) MicroRNA let-7b regulates neural stem cell proliferation and differentiation by targeting nuclear receptor TLX signaling. Proc Natl Acad Sci U S A 107(5):1876–1881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. de Chevigny A, Core N, Follert P, Gaudin M, Barbry P, Beclin C, Cremer H (2012) miR-7a regulation of Pax6 controls spatial origin of forebrain dopaminergic neurons. Nat Neurosci 15(8):1120–1126

    Article  PubMed  CAS  Google Scholar 

  105. Zhao C, Sun G, Li S, Shi Y (2009) A feedback regulatory loop involving microRNA-9 and nuclear receptor TLX in neural stem cell fate determination. Nat Struct Mol Biol 16(4):365–371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Packer AN, Xing Y, Harper SQ, Jones L, Davidson BL (2008) The bifunctional microRNA miR-9/miR-9* regulates REST and CoREST and is downregulated in Huntington's disease. J Neurosci 28(53):14341–14346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Shibata M, Nakao H, Kiyonari H, Abe T, Aizawa S (2011) MicroRNA-9 regulates neurogenesis in mouse telencephalon by targeting multiple transcription factors. J Neurosci 31(9):3407–3422

    Article  CAS  PubMed  Google Scholar 

  108. Yoo AS, Staahl BT, Chen L, Crabtree GR (2009) MicroRNA-mediated switching of chromatin-remodelling complexes in neural development. Nature 460(7255):642–646

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Biyashev D, Veliceasa D, Topczewski J, Topczewska JM, Mizgirev I, Vinokour E, Reddi AL, Licht JD, Revskoy SY, Volpert OV (2012) miR-27b controls venous specification and tip cell fate. Blood 119(11):2679–2687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 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 humanfibroblasts to neurons. Nature 476(7359):228–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Cheng LC, Pastrana E, Tavazoie M, Doetsch F (2009) miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Na Neurosci 12(4):399–408

    Article  CAS  Google Scholar 

  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(3):435–448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Visvanathan J, Lee S, Lee B, Lee JW, Lee SK (2007) The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development. Genes Dev 21(7):744–749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Boissart C, Nissan X, Giraud-Triboult K, Peschanski M, Benchoua A (2012) miR-125 potentiates early neural specification of human embryonic stem cells. Development 139(7):1247–1257

    Article  CAS  PubMed  Google Scholar 

  115. Sun G, Ye P, Murai K, Lang MF, Li S, Zhang H, Li W, Fu C, Yin J, Wang A, Ma X, Shi Y (2011) miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells. Nat Commun 2:529

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Xu N, Papagiannakopoulos T, Pan G, Thomson JA, Kosik KS (2009) MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells. Cell 137(4):647–658

    Article  CAS  PubMed  Google Scholar 

  117. Sinkkonen L, Hugenschmidt T, Berninger P, Gaidatzis D, Mohn F, Artus-Revel CG, Zavolan M, Svoboda P, Filipowicz W (2008) MicroRNAs control de novo DNA methylation through regulation of transcriptional repressors in mouse embryonic stem cells. Nat Struct Mol Biol 15(3):259–267

    Article  CAS  PubMed  Google Scholar 

  118. Benetti R, Gonzalo S, Jaco I, Munoz P, Gonzalez S, Schoeftner S, Murchison E, Andl T, Chen T, Klatt P, Li E, Serrano M, Millar S, Hannon G, Blasco MA (2008) A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent regulation of DNA methyltransferases. Nat Struct Mol Biol 15(3):998

    Article  CAS  PubMed  Google Scholar 

  119. Gonzalo S, Garcia-Cao M, Fraga MF, Schotta G, Peters AH, Cotter SE, Eguia R, Dean DC, Esteller M, Jenuwein T, Blasco MA (2005) Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin. Nat Cell Biol 7(4):420–428

    Article  CAS  PubMed  Google Scholar 

  120. Wang Y, Baskerville S, Shenoy A, Babiarz JE, Baehner L, Blelloch R (2008) Embryonic stem cell-specific microRNAs regulate the G1-S transition and promote rapid proliferation. Nat Genet 40(12):1478–1483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Zheng GX, Ravi A, Calabrese JM, Medeiros LA, Kirak O, Dennis LM, Jaenisch R, Burge CB, Sharp PA (2011) A latent pro-survival function for the mir-290–295 cluster in mouse embryonic stem cell. PLoS Genet 7(5):e1002054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lüningschrör P, Stöcker B, Kaltschmidt B, Kaltschmidt C (2012) miR-290 cluster modulates pluripotency by repressing canonical NF-kappaB signaling. Stem Cells 30(4):655–664

    Article  PubMed  CAS  Google Scholar 

  123. Rosa A, Brivanlou AH (2011) A regulatory circuitry comprised of miR-302 and the transcription factors OCT4 and NR2F2 regulates human embryonic stem cell differentiation. EMBO J 30(2):237–248

    Article  CAS  PubMed  Google Scholar 

  124. Rosa A, Spagnoli FM, Brivanlou AH (2009) The miR-430/427/302 family controls mesendodermal fate specification via species-specific target selection. Dev Cell 16(4):517–527

    Article  CAS  PubMed  Google Scholar 

  125. Crippa S, Cassano M, Messina G, Galli D, Galvez BG, Curk T, Altomare C, Ronzoni F, Toelen J, Gijsbers R, Debyser Z, Janssens S, Zupan B, Zaza A, Cossu G, Sampaolesi M (2011) miR669a and miR669q prevent skeletal muscle differentiation in postnatal cardiac progenitors. J Cell Biol 193:1197–1212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Franzoni E, Booker SA, Parthasarathy S Rehfeld F, Grosser S, Srivatsa S, Fuchs HR, Tarabykin V, Vida I, Wulczyn FG (2015) miR-128 regulates neuronal migration, outgrowth and intrinsic excitability via the intellectual disability gene Phf6. Elife 4: doi: 10.7554/eLife.04263

  127. Hanina SA, Mifsud W, Down TA, Hayashi K, O'Carroll D, Lao K, Miska EA, Surani MA (2010) Genome-wide identification of targets and function of individual MicroRNAs in mouse embryonic stem cells. PLoS Genet 6(10):e1001163. r–294

    Article  CAS  Google Scholar 

  128. Fang L, Deng Z, Shatseva T, Yang J, Peng C, Du WW, Yee AJ, Ang LC, He C, Shan SW, Yang BB (2010) MicroRNA miR-93 promotes tumor growth and angiogenesis by targeting integrin-β8. Oncogene 30(7):806–821

    Article  PubMed  CAS  Google Scholar 

  129. Xu D, He XX, Chang Y, Sun SZ, Xu CR, Lin JS (2012) Downregulation of MiR-93 expression reduces cell proliferation and clonogenicity of HepG2 cells. Hepatogastroenterology 59(120):2367–2373

    CAS  PubMed  Google Scholar 

  130. Shen G, Jia H, Tai Q, Li Y, Chen D (2013) miR-106b downregulates adenomatous polyposis coli and promotes cell proliferation in human hepatocellular carcinoma. Arcinogenesis 34(1):211–219

    Article  CAS  Google Scholar 

  131. Kan T, Sato F, Ito T, Matsumura N, David S, Cheng Y, Agarwal R, Paun BC, Jin Z, Olaru AV, Selaru FM, Hamilton JP, Yang J, Abraham JM, Mori Y, Meltzer SJ (2009) The miR-106b-25 polycistron, activated by genomic amplification, functions as an oncogene by suppressing p21 and Bim. Gastroenterology 136(5):1689–1700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Smith AL, Iwanaga R, Drasin DJ, Micalizzi DS, Vartuli RL, Tan AC, Ford HL (2012) The miR-106b-25 cluster targets Smad7, activates TGF-β signaling, and induces EMT and tumor initiating cell characteristics downstream of Six1 in human breast cancer. Oncogene 31(50):5162–5171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Agostini M, Knight RA (2014) miR-34: from bench to bedside. Oncotarget 5(4):872–881

    Article  PubMed  PubMed Central  Google Scholar 

  134. Xu LF, Wu ZP, Chen Y, Zhu QS, Hamidi S, Navab R (2014) MicroRNA-21 (miR-21) regulates cellular proliferation, invasion, migration, and apoptosis by targeting PTEN, RECK and Bcl-2 in lung squamous carcinoma, Gejiu City, China. PLoS One 9(8):e103698

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, Galuppo P, Just S, Rottbauer W, Frantz S, Castoldi M, Soutschek J, Koteliansky V, Rosenwald A, Basson MA, Licht JD, Pena JT, Rouhanifard SH, Muckenthaler MU, Tuschl T, Martin GR, Bauersachs J, Engelhardt S (2008) MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456(7224):980–984

    Article  CAS  PubMed  Google Scholar 

  136. Ma XD, Kumar M, Choudhury SN, Becker Buscaglia LE, Barker JR, Kanakamedala K, Liu MF, Li Y (2011) Loss of the miR-21 allele elevates the expression of its target genes and reduces tumorigenesis. Proc Natl Acad Sci U S A 108(25):10144–10149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Jong HL, Mustafa MR, Vanhoutte PM, AbuBakar S, Wong PF (2013) MicroRNA 299-3p modulates replicative senescence in endothelial cells. Physiol Genomics 45(7):256–267

    Article  CAS  PubMed  Google Scholar 

  138. Hong SG, Dunbar CE, Winkler T (2013) Assessing the risks of genotoxicity in the therapeutic development of induced pluripotent stem cells. Mol Ther 21(2):272–281

    Article  CAS  PubMed  Google Scholar 

  139. Li W, Li K, Wei W, Ding S (2013) Chemical approaches to stem cell biology and therapeutics. Cell Stem Cell 13(3):270–283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Struhl K (1998) Histone acetylation and transcriptional regulatory mechanisms. Genes Dev 12(5):599–606

    Article  CAS  PubMed  Google Scholar 

  141. Kretsovali A, Hadjimichael C, Charmpilas N (2012) Histone deacetylase inhibitors in cell pluripotency, differentiation, and reprogramming. Stem Cells Int 2012:184154

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Knoepfler PS, Zhang XY, Cheng PF, Gafken PR, McMahon SB, Eisenman RN (2006) Myc influences global chromatin structure. EMBO J 25(12):2723–2734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Meshorer E, Yellajoshula D, George E, Scambler PJ, Brown DT, Misteli T (2006) Hyperdynamic plasticity of chromatin proteins in pluripotent embryonic stem cells. Dev Cell 10(1):105–116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Huangfu D, Osafune K, Maehr R, Guo W, Eijkelenboom A, Chen S, Muhlestein W, Melton DA (2008) Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol 26(11):1269–1275

    Article  CAS  PubMed  Google Scholar 

  145. Kubicek S, O'Sullivan RJ, August EM, Hickey ER, Zhang Q, Teodoro ML, Rea S, Mechtler K et al (2007) Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol Cell 25(3):473–481

    Article  CAS  PubMed  Google Scholar 

  146. Shi Y, Desponts C, Do JT, Hahm HS, Schöler HR, Ding S (2008) Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell 3(5):568–574

    Article  CAS  PubMed  Google Scholar 

  147. Shi Y, Do JT, Desponts C, Hahm HS, Schöler HR, Ding S (2008) A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell 2(6):525–528

    Article  CAS  PubMed  Google Scholar 

  148. Chen X, Xu H, Yuan P, Fang F, Huss M, Vega VB, Wong E, Orlov YL et al (2008) Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133(6):1106–1117

    Article  CAS  PubMed  Google Scholar 

  149. Lin T, Ambasudhan R, Yuan X, Li W, Hilcove S, Abujarour R, Lin X, Hahm HS et al (2009) A chemical platform for improved induction of human iPSCs. Nat Methods 6(11):805–808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Li R, Liang J, Ni S, Zhou T, Qing X, Li H, He W, Chen J et al (2010) A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell 7(1):51–63

    Article  CAS  PubMed  Google Scholar 

  151. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282(5391):1145–1147

    Article  CAS  PubMed  Google Scholar 

  152. Yuan X, Wan H, Zhao X, Zhu S, Zhou Q, Ding S (2011) Brief report: combined chemical treatment enables Oct4-induced reprogramming from mouse embryonic fibroblasts. Stem Cells 29(3):549–553

    Article  CAS  PubMed  Google Scholar 

  153. Xie M, Cao N, Ding S (2014) Small Molecules for Cell Reprogramming and Heart Repair: Progress and Perspective. ACS Chem Biol 9(1):34–44

  154. Ichida JK, Blanchard J, Lam K, Son EY, Chung JE, Egli D, Loh KM, Carter AC et al (2009) A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem Cell 5(5):491–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Zhu S, Li W, Zhou H, Wei W, Ambasudhan R, Lin T, Kim J, Zhang K et al (2010) Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell 7(6):651–655

    Article  CAS  PubMed  Google Scholar 

  156. Reya T, Clevers H (2005) Wnt signalling in stem cells and cancer. Nature 434:843–850

    Article  CAS  PubMed  Google Scholar 

  157. Li W, Zhou H, Abujarour R, Zhu S, Young Joo J, Lin T, Hao E, Schöler HR et al (2009) Generation of human-induced pluripotent stem cells in the absence of exogenous Sox2. Stem Cells 27(12):2992–3000

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Marson A, Foreman R, Chevalier B, Bilodeau S, Kahn M, Young RA, Jaenisch R (2008) Wnt signaling promotes reprogramming of somatic cells to pluripotency. Cell Stem Cell 3(2):132–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Li Y, Zhang Q, Yin X, Yang W, Du Y, Hou P, Ge J, Liu C et al (2011) Generation of iPSCs from mouse fibroblasts with a single gene, Oct4, and small molecules. Cell Res 21(1):196–204

    Article  CAS  PubMed  Google Scholar 

  160. Miranda TB, Cortez CC, Yoo CB, Liang G, Abe M, Kelly TK, Marquez VE, Jones PA (2009) DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. Mol Cancer Ther 8(6):1579–1588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Heng JCD, Feng B, Han J, Jiang J, Kraus P, Ng JH, Orlov YL, Huss M et al (2010) The nuclear receptor Nr5a2 can replace Oct4 in the reprogramming of murine somatic cells to pluripotent cells. Cell Stem Cell 6(2):167–174

    Article  CAS  PubMed  Google Scholar 

  162. Deleidi M, Cooper O, Hargus G, Levy A, Lsacson O (2011) Oct4-induced reprogramming is required for adult brain neural stem cell differentiation into midbrain dopaminergic neurons. PLoS One 6(5):e19926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Blum R, Heinrich C, Sanchez R, Lepier A, Gundelfinger ED, Berninger B, Götz M (2011) Neuronal network formation from reprogrammed early postnatal rat cortical glial cells. Cereb Cortex 21(2):413–424

    Article  PubMed  Google Scholar 

  164. O'Carroll D, Erhardt S, Pagani M, Barton SC, Surani MA, Jenuwein T (2001) The polycomb-group gene Ezh2 is required for early mouse development. Mol Cell Biol 21(13):4330–4336

    Article  PubMed  PubMed Central  Google Scholar 

  165. Ezhkova E, Pasolli HA, Parker JS, Stokes N, Su IH, Hannon G, Tarakhovsky A, Fuchs E (2009) Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell 136(6):1122–1135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Chou RH, Yu YL, Hung MC (2011) The roles of EZH2 in cell lineage commitment. Am J Transl Res 3(3):243–250

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Moon JH, Yoon BS, Kim B, Park G, Jung HY, Maeng I, Jun EK, Yoo SJ et al (2008) Induction of neural stem cell-like cells (NSCLCs) from mouse astrocytes by Bmi1. Biochem Biophys Res Commun 371(2):267–272

    Article  CAS  PubMed  Google Scholar 

  168. He S, Iwashita T, Buchstaller J, Molofsky AV, Thomas D, Morrison SJ (2009) Bmi-1 over-expression in neural stem/progenitor cells increases proliferation and neurogenesis in culture but has little effect on these functions in vivo. Dev Biol 328(2):257–272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF, Morrison SJ (2003) Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425(6961):962–967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Molofsky AV, He S, Bydon M, Morrison SJ, Pardal R (2005) Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the pl6Ink4a and pl9Arf senescence pathways. Genes Dev 19(12):1432–1437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Park IK, Morrison SJ, Clarke MR (2004) Bmi1, stem cells, and senescence regulation. J Clin Invest 113(2):175–179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Guo Z, Zhang L, Wu Z, Chen Y, Wan 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

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Dr. Sebastian Schmull for the critical reading of the manuscripts. This work was supported by the Natural Science Foundation of China (Grant Nos. 81472098, 81371411), a key grant for the Natural Science of Xi’an Honghui Hospital (Grant No. HY2014001), and a Cross Research Fund of Biomedical Engineering from Shanghai Jiaotong University (Grant No. YG2014MS45).

Author information

Authors and Affiliations

  1. Translational Medicine Center, Hong Hui Hospital, Xi’an Jiaotong University College of Medicine, Shaanxi, 710054, China

    Hao Yang, Cui-cui Liu, Qian Zhang, Jiang An, Lingling Zhang & Ding-Jun Hao

  2. Clinic Stem Cell Research Center, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200217, China

    Hao Yang

  3. Department of Endocrinology, Lanzhou General Hospital of Lanzhou Military Area Command of Chinese PLA, Lanzhou, 730050, China

    Chun-Yu Wang

  4. Department of Spine Surgery, Hong Hui Hospital, Xi’an Jiaotong University College of Medicine, Shaanxi, 710054, China

    Ding-Jun Hao

Authors
  1. Hao Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cui-cui Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chun-Yu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiang An
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lingling Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ding-Jun Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hao Yang or Ding-Jun Hao.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, H., Liu, Cc., Wang, CY. et al. Therapeutical Strategies for Spinal Cord Injury and a Promising Autologous Astrocyte-Based Therapy Using Efficient Reprogramming Techniques. Mol Neurobiol 53, 2826–2842 (2016). https://doi.org/10.1007/s12035-015-9157-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-015-9157-7

Keywords

Search

Navigation