Stem Cells and Neuronal Differentiation

  • Indrani Datta
  • Debanjana Majumdar
  • Kavina Ganapathy
  • Ramesh R. Bhonde


Stem cells are being increasingly considered alternative and viable sources of treatment for debilitating nervous system disorders and neurodegenerative diseases. Stem cells specific to nervous tissue, i.e., neural stem cells (NSCs), exist in two neurogenic regions of the adult brain – subventricular zone (SVZ) in the lateral ventricle and the subgranular zone (SGZ) in hippocampal dentate gyrus [1–4]. The inaccessibility and unavailability of NSCs deep in the brain makes it a difficult proposition to use them in clinical applications. Different stem cells are thus being tested for their neuronal differentiation capability, as a cell source for generation of functional mature neurons and glial cells. The “gold standard” of stem cells are embryonic stem cells (ESCs) as they not only retain long-term self-renewal capacity but also exhibit pluripotency to all three germ lineages. Recent advances in technology have brought the advent of another pluripotent stem cells called “inducible pluripotent stem cells” (iPSc), derived through “reprogramming” of terminally differentiated cells by the addition of a select set of genes [5–7]. However, several limitations still exist for the use of iPScs in therapeutic applications, such as the use of viral vectors for transfer of genes, inclusion of oncogenes, and teratoma formation [5, 6, 8–10]. Stem cells may also be isolated from several tissue sources and these are termed as adult stem cells (ASCs). The first ASCs to be identified were the hematopoietic stem cells (HSCs) derived from bone marrow, but the second population of stem cells from bone marrow called mesenchymal stem cells (MSCs) gained prominence due to their unique properties [11–13]. MSCs are nontumorigenic and immunomodulatory in addition to possessing multilineage differentiation potential not only towards mesodermal lineage derivatives but also to phenotypes of other germ layer cells like neuronal, hepatocytes, and islet cells [14–17]. Although fetal and adult origin MSCs possess some common characteristics with respect to expression of mesenchymal markers and absence of hematopoietic and HLA-DR markers, their neuronal differentiation efficacy is still to be evaluated for consideration as suitable candidates for nervous system disorders and neurodegenerative diseases.


Tyrosine Hydroxylase Neural Stem Cell Pluripotent Stem Cell Spinal Muscular Atrophy Neural Progenitor 


  1. 1.
    Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–1710PubMedGoogle Scholar
  2. 2.
    Quinones-Hinojosa A, Sanai N, Soriano-Navarro M, Gonzalez-Perez O, Mirzadeh Z, Gil-Perotin S, Romero Rodriguez R, Berger MS, Garcia-Verdugo JM, Alvarez-Buylla A (2006) Cellular composition and cytoarchitecture of the adult human subventricular zone: a niche of neural stem cells. J Comp Neurol 494(3):415–434PubMedGoogle Scholar
  3. 3.
    Hsu YC, Lee DC, Chiu IM (2007) Neural stem cells, neural progenitors, and neurotrophic factors. Cell Transplant 16(2):133–150PubMedGoogle Scholar
  4. 4.
    Ma DK, Bonaguidi MA, Ming GL, Song H (2009) Adult neural stem cells in the mammalian central nervous system. Cell Res 19(6):672–682PubMedCentralPubMedGoogle Scholar
  5. 5.
    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676PubMedGoogle Scholar
  6. 6.
    Okita K, Ichisaka T, Yamanaka S (2007) Generation of germline-competent induced pluripotent stem cells. Nature 448:313–317PubMedGoogle Scholar
  7. 7.
    Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, Bernstein BE, Jaenisch R (2007) In-vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448:318–324PubMedGoogle Scholar
  8. 8.
    Mikkelsen TS, Hanna J, Zhang X, Ku M, Wernig M, Schorderet P, Bernstein BE, Jaenisch R, Lander ES, Meissner A (2008) Dissecting direct reprogramming through integrative genomic analysis. Nature 454:49–55PubMedCentralPubMedGoogle Scholar
  9. 9.
    Sridharan R, Tchieu J, Mason MJ, Yachechko R, Kuoy E, Horvath S, Zhou Q, Plath K (2009) Role of the murine reprogramming factors in the induction of pluripotency. Cell 136:364–377PubMedCentralPubMedGoogle Scholar
  10. 10.
    Sommer CA, Sommer AG, Longmire TA, Christodoulou C, Thomas DD, Gostissa M, Alt FW, Murphy GJ, Kotton DN, Mostoslavsky G (2010) Excision of reprogramming transgenes improves the differentiation potential of iPS cells generated with a single excisable vector. Stem Cells 28:64–74PubMedGoogle Scholar
  11. 11.
    Dezawa M, Kanno H, Hoshino M, Cho H, Matsumoto N, Itokazu Y, Tajima N, Yamada H, Sawada H, Ishikawa H, Mimura T, Kitada M, Suzuki Y, Ide C (2004) Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation. J Clin Invest 113(12):1701–1710PubMedCentralPubMedGoogle Scholar
  12. 12.
    Syková E, Homola A, Mazanec R, Lachmann H, Konrádová SL, Kobylka P, Pádr R, Neuwirth J, Komrska V, Vávra V, Stulík J, Bojar M (2006) Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury. Cell Transplant 15(8–9):675–687PubMedGoogle Scholar
  13. 13.
    Giordano A, Galderisi U, Marino IR (2007) From the laboratory bench to the patient’s bedside: an update on clinical trials with mesenchymal stem cells. J Cell Physiol 211(1):27–35PubMedGoogle Scholar
  14. 14.
    Keyser KA, Beagles KE, Kiem HP (2007) Comparison of mesenchymal stem cells from different tissues to suppress T-cell activation. Cell Transplant 16(5):555–562PubMedGoogle Scholar
  15. 15.
    Le Blanc K (2003) Immunomodulatory effects of fetal and adult mesenchymal stem cells. Cytotherapy 5:485–489PubMedGoogle Scholar
  16. 16.
    Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC (2003) Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 75:389–397PubMedGoogle Scholar
  17. 17.
    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147PubMedGoogle Scholar
  18. 18.
    Schoenwolf GC, Alvarez IS (1989) Roles of neuroepithelial cell rearrangement and division in shaping of the avian neural plate. Development 106(3):427–439PubMedGoogle Scholar
  19. 19.
    Keller R, Shih J, Sater AK, Moreno C (1992) Planar induction of convergence and extension of the neural plate by the organizer of Xenopus. Dev Dyn 193(3):218–234PubMedGoogle Scholar
  20. 20.
    Keller R, Davidson L, Edlund A, Elul T, Ezin M, Shook D, Skoglund P (2000) Mechanisms of convergence and extension by cell intercalation. Trans R Soc Lond B Biol Sci 355(1399):897–922Google Scholar
  21. 21.
    Wallingford JB, Harland RM (2001) Xenopus Dishevelled signaling regulates both neural and mesodermal convergent extension: parallel forces elongating the body axis. Development 128(13):2581–2592PubMedGoogle Scholar
  22. 22.
    Wallingford JB, Harland RM (2002) Neural tube closure requires Dishevelled-dependent convergent extension of the midline. Development 129(24):5815–5825PubMedGoogle Scholar
  23. 23.
    Smith JL, Schoenwolf GC (1987) Cell cycle and neuroepithelial cell shape during bending of the chick neural plate. Anat Rec 218(2):196–206PubMedGoogle Scholar
  24. 24.
    Smith JL, Schoenwolf GC (1988) Role of cell-cycle in regulating neuroepithelial cell shape during bending of the chick neural plate. Cell Tissue Res 252(3):491–500PubMedGoogle Scholar
  25. 25.
    Chenn A, McConnell SK (1995) Cleavage orientation and the asymmetric inheritance of notch1 immunoreactivity in mammalian neurogenesis. Cell 82(4):631–641PubMedGoogle Scholar
  26. 26.
    Maxwell SL, Li M (2005) Midbrain dopaminergic development in vivo and in vitro from embryonic stem cells. J Anat 207:209–218PubMedCentralPubMedGoogle Scholar
  27. 27.
    Frantz GD, McConnell SK (1996) Restriction of late cerebral cortical progenitors to an upper-layer fate. Neuron 17(1):55–61PubMedGoogle Scholar
  28. 28.
    Galli R, Gritti A, Bonfanti L, Vescovi AL (2003) Neural stem cells: an overview. Circ Res 92(6):598–608PubMedGoogle Scholar
  29. 29.
    Doetsch F, Caillé I, Lim DA, García-Verdugo JM, Alvarez-Buylla A (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97(6):703–716PubMedGoogle Scholar
  30. 30.
    Alvarez-Buylla A, García-Verdugo JM, Tramontin AD (2001) A unified hypothesis on the lineage of neural stem cells. Nat Rev Neurosci 2(4):287–293PubMedGoogle Scholar
  31. 31.
    Reynolds BA, Weiss S (1996) Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. Dev Biol 175:1–13PubMedGoogle Scholar
  32. 32.
    Seaberg RM, van der Kooy D (2002) Adult rodent neurogenic regions: the ventricular subependyma contains neural stem cells, but the dentate gyrus contains restricted progenitors. J Neurosci 22(5):1784–1793PubMedGoogle Scholar
  33. 33.
    Bull ND, Bartlett PF (2005) The adult mouse hippocampal progenitor is neurogenic but not a stem cell. J Neurosci 25(47):10815–10821PubMedGoogle Scholar
  34. 34.
    Nyfeler Y, Kirch RD, Mantei N, Leone DP, Radtke F, Suter U, Taylor V (2005) Jagged1 signals in the postnatal subventricular zone are required for neural stem cell self-renewal. EMBO J 24(19):3504–3515. Epub 2005 Sep 15PubMedCentralPubMedGoogle Scholar
  35. 35.
    Roy NS, Benraiss A, Wang S, Fraser RA, Goodman R, Couldwell WT, Nedergaard M, Kawaguchi A, Okano H, Goldman SA (2000) Promoter-targeted selection and isolation of neural progenitor cells from the adult human ventricular zone. J Neurosci Res 59(3):321–331PubMedGoogle Scholar
  36. 36.
    Keyoung HM, Roy NS, Benraiss A, Louissaint A Jr, Suzuki A, Hashimoto M, Rashbaum WK, Okano H, Goldman SA (2001) High-yield selection and extraction of two promoter-defined phenotypes of neural stem cells from the fetal human brain. Nat Biotechnol 19(9):843–850PubMedGoogle Scholar
  37. 37.
    Götz M (2003) Glial cells generate neurons–master control within CNS regions: developmental perspectives on neural stem cells. Neuroscientist 9(5):379–397PubMedGoogle Scholar
  38. 38.
    Rakic S, Zecevic N (2003) Early oligodendrocyte progenitor cells in the human fetal telencephalon. Glia 41(2):117–127PubMedGoogle Scholar
  39. 39.
    Johansson CB, Momma S, Clarke DL, Risling M, Lendahl U, Frisén J (1999) Identification of a neural stem cell in the adult mammalian central nervous system. Cell 96(1):25–34PubMedGoogle Scholar
  40. 40.
    Kageyama R, Ohtsuka T, Kobayashi T (2008) Roles of Hes genes in neural development. Dev Growth Differ 50(Suppl 1):S97–S103. doi: 10.1111/j.1440-169X.2008.00993.x. Epub 2008 Apr 22PubMedGoogle Scholar
  41. 41.
    Frederiksen K, McKay RD (1988) Proliferation and differentiation of rat neuro-epithelial precursor cells in vivo. J Neurosci 8(4):1144–1151PubMedGoogle Scholar
  42. 42.
    Lendahl U, Zimmerman LB, McKay RD (1990) CNS stem cells express a new class of intermediate filament protein. Cell 60(4):585–595PubMedGoogle Scholar
  43. 43.
    Ciceroni C, Mosillo P, Mastrantoni E, Sale P, Ricci-Vitiani L, Biagioni F, Stocchi F, Nicoletti F, Melchiorri D (2010) mGLU3 metabotropic glutamate receptors modulate the differentiation of SVZ-derived neural stem cells towards the astrocytic lineage. Glia 58(7):813–822. doi: 10.1002/glia.20965 PubMedGoogle Scholar
  44. 44.
    Andersson T, Duckworth JK, Fritz N, Lewicka M, Södersten E, Uhlén P, Hermanson O (2011) Noggin and Wnt3a enable BMP4-dependent differentiation of telencephalic stem cells into GluR-agonist responsive neurons. Mol Cell Neurosci 47(1):10–18. doi: 10.1016/j.mcn.2011.01.006. Epub 2011 Jan 14PubMedGoogle Scholar
  45. 45.
    Okano-Uchida T, Naruse M, Ikezawa T, Shibasaki K, Ishizaki Y (2013) Cerebellar neural stem cells differentiate into two distinct types of astrocytes in response to CNTF and BMP2. Neurosci Lett 552:15–20. doi: 10.1016/j.neulet.2013.07.021. Epub 2013 July 26PubMedGoogle Scholar
  46. 46.
    Glasser T, Pollard SM, Smith A, Brustle O (2007) Tripotential differentiation of adherently expandable neural stem (NS) cells. PLoS One 2(3):e298. doi: 10.1371/journal.pone.0000298 Google Scholar
  47. 47.
    Bonni A, Sun Y, Nadal-Vicens M, Bhatt A, Frank DA, Rozovsky I, Stahl N, Yancopoulos GD, Greenberg ME (1997) Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. Science 278(5337):477–483PubMedGoogle Scholar
  48. 48.
    Vallières L, Campbell IL, Gage FH, Sawchenko PE (2002) Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci 22(2):486–492PubMedGoogle Scholar
  49. 49.
    Ben-Hur T, Einstein O, Mizrachi-Kol R, Ben-Menachem O, Reinhartz E, Karussis D, Abramsky O (2003) Transplanted multipotential neural precursor cells migrate into the inflamed white matter in response to experimental autoimmune encephalomyelitis. Glia 41(1):73–80PubMedGoogle Scholar
  50. 50.
    Imitola J, Raddassi K, Park KI, Mueller FJ, Nieto M, Teng YD, Frenkel D, Li J, Sidman RL, Walsh CA, Snyder EY, Khoury SJ (2004) Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci U S A 101(52):18117–18122. Epub 2004 Dec 17PubMedCentralPubMedGoogle Scholar
  51. 51.
    Belmadani A, Tran PB, Ren D, Miller RJ (2006) Chemokines regulate the migration of neural progenitors to sites of neuroinflammation. J Neurosci 26(12):3182–3191PubMedCentralPubMedGoogle Scholar
  52. 52.
    Lalive PH, Paglinawan R, Biollaz G, Kappos EA, Leone DP, Malipiero U, Relvas JB, Moransard M, Suter T, Fontana A (2005) TGF-beta-treated microglia induce oligodendrocyte precursor cell chemotaxis through the HGF-c-Met pathway. Eur J Immunol 35(3):727–737PubMedGoogle Scholar
  53. 53.
    Vroemen M, Aigner L, Winkler J, Weidner N (2003) Adult neural progenitor cell grafts survive after acute spinal cord injury and integrate along axonal pathways. Eur J Neurosci 18(4):743–751PubMedGoogle Scholar
  54. 54.
    Anton R, Kordower JH, Maidment NT, Manaster JS, Kane DJ, Rabizadeh S, Schueller SB, Yang J, Rabizadeh S, Edwards RH et al (1994) Neural-targeted gene therapy for rodent and primate hemiparkinsonism. Exp Neurol 127(2):207–218PubMedGoogle Scholar
  55. 55.
    Lundberg C, Horellou P, Mallet J, Björklund A (1996) Generation of DOPA-producing astrocytes by retroviral transduction of the human tyrosine hydroxylase gene: in vitro characterization and in vivo effects in the rat Parkinson model. Exp Neurol 139(1):39–53PubMedGoogle Scholar
  56. 56.
    Zhang Y, Pak C, Han Y, Ahlenius H, Zhang Z, Chanda S, Marro S, Patzke C, Acuna C, Covy J, Xu W, Yang N, Danko T, Chen L, Wernig M, Südhof TC (2013) Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron 78(5):785–798PubMedCentralPubMedGoogle Scholar
  57. 57.
    Spemann H, Mangold H (1924) Induction of embryonic primordia by implantation of organizers from a different species. Roux’s Arch Entw Mech 100:599–638Google Scholar
  58. 58.
    De Robertis EM, Wessely O, Oelgeschläger M, Brizuela B, Pera E, Larraín J, Abreu J, Bachiller D (2001) Molecular mechanisms of cell-cell signaling by the Spemann-Mangold organizer. Int J Dev Biol 45(1):189–197PubMedGoogle Scholar
  59. 59.
    Niehrs C (2004) Regionally specific induction by the Spemann-Mangold organizer. Nat Rev Genet 5(6):425–434PubMedGoogle Scholar
  60. 60.
    Pal R, Totey S, Mamidi MK, Bhat VS, Totey S (2009) Propensity of human embryonic stem cell lines during early stage of lineage specification controls their terminal differentiation into mature cell types. Exp Biol Med (Maywood) 234(10):1230–1243Google Scholar
  61. 61.
    Player A, Wang Y, Rao M, Kawasaki E (2007) Gene expression analysis of RNA purified from embryonic stem cells and embryoid body-derived cells using a high-throughput microarray platform. Curr Protoc Stem Cell Biol Chapter 1: Unit 1B.2. doi: 10.1002/9780470151808.sc01b02s2
  62. 62.
    Datta I, Ganapathy K, Tattikota SM, Bhonde R (2013) Directed differentiation of human embryonic stem cell-line HUES9 to dopaminergic neurons in a serum-free defined culture niche. Cell Biol Int 37(1):54–64PubMedGoogle Scholar
  63. 63.
    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 25:1511–1520PubMedCentralPubMedGoogle Scholar
  64. 64.
    Swistowski A, Peng J, Han Y, Swistowska AM, Rao MS, Zeng X (2009) Xeno-free defined conditions for culture of human embryonic stem cells, neural stem cells and dopaminergic neurons derived from them. PLoS One 4(7):e6233PubMedCentralPubMedGoogle Scholar
  65. 65.
    Shin S, Mitalipova M, Noggle S, Tibbitts D, Venable A, Rao R, Stice SL (2006) Long-term proliferation of human embryonic stem cell-derived neuroepithelial cells using defined adherent culture conditions. Stem Cells 24(1):125–138PubMedGoogle Scholar
  66. 66.
    Parish CL, Castelo-Branco G, Rawal N, Tonnesen J, Sorensen AT, Salto C, Kokaia M, Lindvall O, Arenas E (2008) Wnt5a-treated midbrain neural stem cells improve dopamine cell replacement therapy in parkinsonian mice. J Clin Invest 118(1):149–160PubMedCentralPubMedGoogle Scholar
  67. 67.
    Ferrari D, Sanchez-Pernaute R, Lee H, Studer L, Isacson O (2006) Transplanted dopamine neurons derived from primate ES cells preferentially innervate DARPP-32 striatal progenitors within the graft. Eur J Neurosci 24(7):1885–1896PubMedCentralPubMedGoogle Scholar
  68. 68.
    Daadi MM, Grueter BA, Malenka RC, Redmond DE Jr, Steinberg GK (2012) Dopaminergic neurons from midbrain-specified human embryonic stem cell-derived neural stem cells engrafted in a monkey model of Parkinson’s disease. PLoS One 7(7):e41120PubMedCentralPubMedGoogle Scholar
  69. 69.
    Yan Y, Shin S, Jha BS, Liu Q, Sheng J, Li F, Zhan M, Davis J, Bharti K, Zeng X, Rao M, Malik N, Vemuri MC (2013) Efficient and rapid derivation of primitive neural stem cells and generation of brain subtype neurons from human pluripotent stem cells. Stem Cells Transl Med 2(11):862–870PubMedCentralPubMedGoogle Scholar
  70. 70.
    Li T, Zheng J, Xie Y, Wang S, Zhang X, Li J, Jin L, Ma Y, Wolf DP, Zhou Q, Ji W (2005) Transplantable neural progenitor populations derived from rhesus monkey embryonic stem cells. Stem Cells 23(9):1295–1303. Epub 2005 July 28PubMedGoogle Scholar
  71. 71.
    Eiraku M, Watanabe K, Matsuo-Takasaki M, Kawada M, Yonemura S, Matsumura M, Wataya T, Nishiyama A, Muguruma K, Sasai Y (2008) Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell 3:519–532PubMedGoogle Scholar
  72. 72.
    Vazin T, Ashton RS, Conway A, Rode NA, Lee SM, Bravo V, Healy KE, Kane RS, Schaffer DV (2014) The effect of multivalent Sonic hedgehog on differentiation of human embryonic stem cells into dopaminergic and GABAergic neurons. Biomaterials 35(3):941–948PubMedGoogle Scholar
  73. 73.
    Amirpour N, Karamali F, Rabiee F, Rezaei L, Esfandiari E, Razavi S, Dehghani A, Razmju H, Nasr-Esfahani MH, Baharvand H (2012) Differentiation of human embryonic stem cell-derived retinal progenitors into retinal cells by Sonic hedgehog and/or retinal pigmented epithelium and transplantation into the subretinal space of sodium iodate-injected rabbits. Stem Cells Dev 21(1):42–53. doi: 10.1089/scd.2011.0073. Epub 2011 June 1PubMedGoogle Scholar
  74. 74.
    Patani R, Hollins AJ, Wishart TM, Puddifoot CA, Alvarez S, de Lera AR, Wyllie DJ, Compston DA, Pedersen RA, Gillingwater TH, Hardingham GE, Allen ND, Chandran S (2011) Retinoid-independent motor neurogenesis from human embryonic stem cells reveals a medial columnar ground state. Nat Commun 2:214. doi: 10.1038/ncomms1216 PubMedCentralPubMedGoogle Scholar
  75. 75.
    Germain ND, Banda EC, Becker S, Naegele JR, Grabel LB (2013) Derivation and isolation of NKX2.1-positive basal forebrain progenitors from human embryonic stem cells. Stem Cells Dev 22(10):1477–1489PubMedGoogle Scholar
  76. 76.
    Nicholas CR, Chen J, Tang Y, Southwell DG, Chalmers N, Vogt D, Arnold CM, Chen YJ, Stanley EG, Elefanty AG, Sasai Y, Alvarez-Buylla A, Rubenstein JL, Kriegstein AR (2013) Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. Cell Stem Cell 12(5):573–586PubMedCentralPubMedGoogle Scholar
  77. 77.
    Liu Y, Weick JP, Liu H, Krencik R, Zhang X, Ma L, Zhou GM, Ayala M, Zhang SC (2013) Medial ganglionic eminence-like cells derived from human embryonic stem cells correct learning and memory deficits. Nat Biotechnol 31(5):440–447. doi: 10.1038/nbt.2565. Epub 2013 Apr 21PubMedCentralPubMedGoogle Scholar
  78. 78.
    Ma LX, Hu B, Liu Y, Liu H, Vermilyea SC, Liu H, Zhang X, Sun Y, Gao L, Li J, Ayala M, Zhang SC (2010) Specification of functional striatal GABAergic projection neurons from human stem cells. Soc Neurosci Abstr 331.7Google Scholar
  79. 79.
    Bissonnette CJ, Lyass L, Bhattacharyya BJ, Belmadani A, Miller RJ, Kessler JA (2011) The controlled generation of functional basal forebrain cholinergic neurons from human embryonic stem cells. Stem Cells 29(5):802–811PubMedCentralPubMedGoogle Scholar
  80. 80.
    Nilbratt M, Porras O, Marutle A, Hovatta O, Nordberg A (2010) Neurotrophic factors promote cholinergic differentiation in human embryonic stem cell-derived neurons. J Cell Mol Med 14(6B):1476–1484. doi: 10.1111/j.1582-4934.2009.00916.x. Epub 2009 Oct 3PubMedGoogle Scholar
  81. 81.
    Li XJ, Du ZW, Zarnowska ED, Pankratz M, Hansen LO, Pearce RA, Zhang SC (2005) Specification of motoneurons from human embryonic stem cells. Nat Biotechnol 23:215–221PubMedGoogle Scholar
  82. 82.
    Singh Roy N, Nakano T, Xuing L, Kang J, Nedergaard M, Goldman SA (2005) Enhancer-specified GFP based FACS purification of human spinal motor neurons from embryonic stem cells. Exp Neurol 196:224–234. [PubMed: 16198339]PubMedGoogle Scholar
  83. 83.
    Lee H, Shamy GA, Elkabetz Y, Schofield CM, Harrsion NL, Panagiotakos G, Socci ND, Tabar V, Studer L (2007) Directed differentiation and transplantation of human embryonic stem cell-derived motoneurons. Stem Cells 25:1931–1939PubMedGoogle Scholar
  84. 84.
    Diniz B, Thomas P, Thomas B, Ribeiro R, Hu Y, Brant R, Ahuja A, Zhu D, Liu L, Koss M, Maia M, Chader G, Hinton DR, Humayun MS (2013) Subretinal implantation of retinal pigment epithelial cells derived from human embryonic stem cells: improved survival when implanted as a monolayer. Invest Ophthalmol Vis Sci 54(7):5087–5096PubMedCentralPubMedGoogle Scholar
  85. 85.
    Li W, Sun W, Zhang Y, Wei W, Ambasudhan R, Xia P, Talantova M, Lin T, Kim J, Wang X, Kim WR, Lipton SA, Zhang K, Ding S (2011) Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by small molecule inhibitors. Proc Natl Acad Sci U S A 108(20):8299–8304PubMedCentralPubMedGoogle Scholar
  86. 86.
    Deneen B, Ho R, Lukaszewicz A, Hochstim CJ, Gronostajski RM, Anderson DJ (2006) The transcription factor NFIA controls the onset of gliogenesis in the developing spinal cord. Neuron 52:953–968PubMedGoogle Scholar
  87. 87.
    Jiang P, Selvaraj V, Deng W (2010) Differentiation of embryonic stem cells into oligodendrocyte precursors. J Vis Exp 39Google Scholar
  88. 88.
    Alsanie WF, Niclis JC, Petratos S (2013) Human embryonic stem cell-derived oligodendrocytes: protocols and perspectives. Stem Cells Dev 22(18):2459–2476PubMedCentralPubMedGoogle Scholar
  89. 89.
    Stappert L, Borghese L, Roese-Koerner B, Weinhold S, Koch P, Terstegge S, Uhrberg M, Wernet P, Brüstle O (2013) MicroRNA-based promotion of human neuronal differentiation and subtype specification. PLoS One 8(3):e59011PubMedCentralPubMedGoogle Scholar
  90. 90.
    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):861–872PubMedGoogle Scholar
  91. 91.
    Malchenko S, Xie J, de Fatima Bonaldo M, Vanin EF, Bhattacharyya BJ, Belmadani A, Xi G, Galat V, Goossens W, Seftor RE, Tomita T, Crispino J, Miller RJ, Bohn MC, Hendrix MJ, Soares MB (2014) Onset of rosette formation during spontaneous neural differentiation of hESC and hiPSC colonies. Gene 534(2):400–407PubMedGoogle Scholar
  92. 92.
    Salewski RP, Buttigieg J, Mitchell RA, van der Kooy D, Nagy A, Fehlings MG (2013) The generation of definitive neural stem cells from PiggyBac transposon-induced pluripotent stem cells can be enhanced by induction of the NOTCH signaling pathway. Stem Cells Dev 22(3):383–396PubMedCentralPubMedGoogle Scholar
  93. 93.
    Waschek JA (2012) Noggin on heaven’s door: a factor that promotes the selective production of serotonergic neurons from murine embryonic stem cells and induced pluripotent stem cells. J Neurochem 122(1):1–3PubMedGoogle Scholar
  94. 94.
    Verpelli C, Carlessi L, Bechi G, FusarPoli E, Orellana D, Heise C, Franceschetti S, Mantegazza R, Mantegazza M, Delia D, Sala C (2013) Comparative neuronal differentiation of self-renewing neural progenitor cell lines obtained from human induced pluripotent stem cells. Front Cell Neurosci 7:175PubMedCentralPubMedGoogle Scholar
  95. 95.
    Zeng H, Guo M, Martins-Taylor K, Wang X, Zhang Z, Park JW, Zhan S, Kronenberg MS, Lichtler A, Liu HX, Chen FP, Yue L, Li XJ, Xu RH (2010) Specification of region-specific neurons including forebrain glutamatergic neurons from human induced pluripotent stem cells. PLoS One 5:e11853PubMedCentralPubMedGoogle Scholar
  96. 96.
    Yan Y, Shin S, Jha BS, Liu Q, Sheng J, Li F, Zhan M, Davis J, Bharti K, Zeng X, Rao M, Malik N, Vemuri MC (2013) Efficient and rapid derivation of primitive neural stem cells and generation of brain subtype neurons from human pluripotent stem cells. Stem Cells Transl Med 2(11):862–870. doi: 10.5966/sctm.2013-0080. Epub 2013 Oct 10PubMedCentralPubMedGoogle Scholar
  97. 97.
    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 U S A 107(36):15921–15926. doi: 10.1073/pnas.1010209107. Epub 2010 Aug 23PubMedCentralPubMedGoogle Scholar
  98. 98.
    Wernig M, Zhao JP, Pruszak J, Hedlund E, Fu D, Soldner F, Broccoli V, Constantine-Paton M, Isacson O, Jaenisch R (2008) Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proc Natl Acad Sci U S A 105(15):5856–5861PubMedCentralPubMedGoogle Scholar
  99. 99.
    Linta L, Stockmann M, Lin Q, Lechel A, Proepper C, Boeckers TM, Kleger A, Liebau S (2013) Microarray-based comparisons of ion channel expression patterns: human keratinocytes to reprogrammed hiPSCs to differentiated neuronal and cardiac progeny. Stem Cells Int 2013:784629PubMedCentralPubMedGoogle Scholar
  100. 100.
    Oki K, Tatarishvili J, Wood J, Koch P, Wattananit S, Mine Y, Monni E, Tornero D, Ahlenius H, Ladewig J, Brüstle O, Lindvall O, Kokaia Z (2012) Human-induced pluripotent stem cells form functional neurons and improve recovery after grafting in stroke-damaged brain. Stem Cells 30(6):1120–1133. doi: 10.1002/stem.1104 PubMedGoogle Scholar
  101. 101.
    Qin J, Song B, Zhang H, Wang Y, Wang N, Ji Y, Qi J, Chandra A, Yang B, Zhang Y, Gong G, Xu Y (2013) Transplantation of human neuro-epithelial-like stem cells derived from induced pluripotent stem cells improves neurological function in rats with experimental intracerebral hemorrhage. Neurosci Lett 548:95–100. doi: 10.1016/j.neulet.2013.05.007. Epub 2013 May 13PubMedGoogle Scholar
  102. 102.
    Popescu IR, Nicaise C, Liu S, Bisch G, Knippenberg S, Daubie V, Bohl D, Pochet R (2013) Neural progenitors derived from human induced pluripotent stem cells survive and differentiate upon transplantation into a rat model of amyotrophic lateral sclerosis. Stem Cells Transl Med 2(3):167–174. doi: 10.5966/sctm.2012-0042. Epub 2013 Feb 14PubMedCentralPubMedGoogle Scholar
  103. 103.
    Riazifar H, Jia Y, Chen J, Lynch G, Huang T (2014) Chemically induced specification of retinal ganglion cells from human embryonic and induced pluripotent stem cells. Stem Cell Transl Med 3(4):424–432Google Scholar
  104. 104.
    Liu Q, Spusta SC, Mi R, Lassiter RN, Stark MR, Höke A, Rao MS, Zeng X (2012) Human neural crest stem cells derived from human ESCs and induced pluripotent stem cells: induction, maintenance, and differentiation into functional schwann cells. Stem Cells Transl Med 1(4):266–278PubMedCentralPubMedGoogle Scholar
  105. 105.
    Lu HF, Chai C, Lim TC, Leong MF, Lim JK, Gao S, Lim KL, Wan AC (2014) A defined xeno-free and feeder-free culture system for the derivation, expansion and direct differentiation of transgene-free patient-specific induced pluripotent stem cells. Biomaterials 35(9):2816–2826PubMedGoogle Scholar
  106. 106.
    Hick A, Wattenhofer-Donzé M, Chintawar S, Tropel P, Simard JP, Vaucamps N, Gall D, Lambot L, André C, Reutenauer L, Rai M, Teletin M, Messaddeq N, Schiffmann SN, Viville S, Pearson CE, Pandolfo M, Puccio H (2013) Neurons and cardiomyocytes derived from induced pluripotent stem cells as a model for mitochondrial defects in Friedreich’s ataxia. Dis Model Mech 6(3):608–621PubMedCentralPubMedGoogle Scholar
  107. 107.
    Panicker LM, Miller D, Park TS, Patel B, Azevedo JL, Awad O, Masood MA, Veenstra TD, Goldin E, Stubblefield BK, Tayebi N, Polumuri SK, Vogel SN, Sidransky E, Zambidis ET, Feldman RA (2012) Induced pluripotent stem cell model recapitulates pathologic hallmarks of Gaucher disease. Proc Natl Acad Sci U S A 109(44):18054–18059. doi: 10.1073/pnas.1207889109. Epub 2012 Oct 15PubMedCentralPubMedGoogle Scholar
  108. 108.
    Dimos JT, Rodolfa KT, Niakan KK, Weisenthal LM, Mitsumoto H, Chung W, Croft GF, Saphier G, Leibel R, Goland R, Wichterle H, Henderson CE, Eggan K (2008) Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321(5893):1218–1221PubMedGoogle Scholar
  109. 109.
    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):277–280PubMedCentralPubMedGoogle Scholar
  110. 110.
    Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, Lensch MW, Cowan C, Hochedlinger K, Daley GQ (2008) Disease-specific induced pluripotent stem cells. Cell 134(5):877–886. doi: 10.1016/j.cell.2008.07.041. Epub 2008 Aug 7PubMedCentralPubMedGoogle Scholar
  111. 111.
    Soldner F, Laganière J, Cheng AW, Hockemeyer D, Gao Q, Alagappan R, Khurana V, Golbe LI, Myers RH, Lindquist S, Zhang L, Guschin D, Fong LK, Vu BJ, Meng X, Urnov FD, Rebar EJ, Gregory PD, Zhang HS, Jaenisch R (2011) Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Cell 146(2):318–331. doi: 10.1016/j.cell.2011.06.019 PubMedCentralPubMedGoogle Scholar
  112. 112.
    Brennand KJ, Landek-Salgado MA, Sawa A (2013) Modeling Heterogeneous Patients with a Clinical Diagnosis of Schizophrenia with Induced Pluripotent Stem Cells. Biol Psychiatry pii:S0006–3223(13)01000-7Google Scholar
  113. 113.
    Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera C, Hefferan MP, Van Gorp S, Nazor KL, Boscolo FS, Carson CT, Laurent LC, Marsala M, Gage FH, Remes AM, Koo EH, Goldstein LS (2012) Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482(7384):216–220PubMedCentralPubMedGoogle Scholar
  114. 114.
    Yusa K, Zhou L, Li MA, Bradley A, Craig NL (2011) A hyperactive piggyBac transposase for mammalian applications. Proc Natl Acad Sci U S A 108(4):1531–1536PubMedCentralPubMedGoogle Scholar
  115. 115.
    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. Epub 2007 Dec 6PubMedGoogle Scholar
  116. 116.
    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 PubMedCentralPubMedGoogle Scholar
  117. 117.
    Brennand KJ, Gage FH (2012) Modeling psychiatric disorders through reprogramming. Dis Model Mech 5(1):26–32PubMedCentralPubMedGoogle Scholar
  118. 118.
    Marchetto MC, Gage FH (2012) Modeling brain disease in a dish: really? Cell Stem Cell 10(6):642–645PubMedGoogle Scholar
  119. 119.
    Xia G, Santostefano KE, Goodwin M, Liu J, Subramony SH, Swanson MS, Terada N, Ashizawa T (2013) Generation of neural cells from DM1 induced pluripotent stem cells as cellular model for the study of central nervous system neuropathogenesis. Cell Reprogram 15(2):166–177PubMedCentralPubMedGoogle Scholar
  120. 120.
    Soldner F, Jaenisch R (2012) Medicine iPSC disease modeling science. Science 338(6111):1155–1156. doi: 10.1126/science.1227682 PubMedGoogle Scholar
  121. 121.
    Thier M, Wörsdörfer P, Lakes YB, Gorris R, Herms S, Opitz T, Seiferling D, Quandel T, Hoffmann P, Nöthen MM, Brüstle 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. Epub 2012 Mar 22PubMedGoogle Scholar
  122. 122.
    Thomson M, Liu SJ, Zou LN, Smith Z, Meissner A, Ramanathan S (2011) Cell 145:875–889PubMedGoogle Scholar
  123. 123.
    Kim J, Efe JA, Zhu S, Talantova M, Yuan X, Wang S, Lipton SA, Zhang K, Ding S (2011) Proc Natl Acad Sci U S A 108:7838–7843PubMedCentralPubMedGoogle Scholar
  124. 124.
    Han DW, Tapia N, Hermann A, Hemmer K, Ho¨ ing S, Arau’zo- Bravo M, Zahres H, Wu G, Frank S, Moritz S et al (2012) Cell Stem Cell 10(this issue):465–472PubMedGoogle Scholar
  125. 125.
    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. Epub 2012 June 7PubMedCentralPubMedGoogle Scholar
  126. 126.
    Pang ZP, Yang N, Vierbuchen T, Ostermeier A, Fuentes DR, Yang TQ, Citri A, Sebastiano V, Marro S, Südhof TC, Wernig M (2011) Induction of human neuronal cells by defined transcription factors. Nature 476(7359):220–223. doi: 10.1038/nature10202 PubMedCentralPubMedGoogle Scholar
  127. 127.
    Lujan E, Chanda S, Ahlenius H, Su¨ dhof TC, Wernig M (2012) Proc Natl Acad Sci USA 109:2527–2532PubMedCentralPubMedGoogle Scholar
  128. 128.
    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 PubMedGoogle Scholar
  129. 129.
    Torper O, Pfisterer U, Wolf DA, Pereira M, Lau S, Jakobsson J, Björklund A, Grealish S, Parmar M (2013) Generation of induced neurons via direct conversion in vivo. Proc Natl Acad Sci U S A 110(17):7038–7043. doi: 10.1073/pnas.1303829110. Epub 2013 Mar 25PubMedCentralPubMedGoogle Scholar
  130. 130.
    Zou Q, Yan Q, Zhong J, Wang K, Sun H, Yi X, Lai L (2014) Direct conversion of human fibroblasts into neuronal restricted progenitors. J Biol Chem 289(8):5250–5260PubMedGoogle Scholar
  131. 131.
    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. Nat Commun 4:2183. doi: 10.1038/ncomms3183 PubMedGoogle Scholar
  132. 132.
    Reyes M, Lund T, Lenvik T, Aguiar D, Koodie L, Verfaillie CM (2001) Purification and ex vivo expansion of postnatal, human marrow mesodermal progenitor cells. Blood 98:2615–2625PubMedGoogle Scholar
  133. 133.
    Fibbe WE, Noort WA (2003) Mesenchymal stem cells and hematopoietic stem cells transplantation. Ann NY Acad Sci 996:235–244PubMedGoogle Scholar
  134. 134.
    Egusa H, Schweizer FE, Wang CC, Matsuka Y, Nishimura I (2005) Neuronal differentiation of bone marrow-derived stromal stem cells involves suppression of discordant phenotypes through gene silencing. J Biol Chem 280:23691–23697PubMedGoogle Scholar
  135. 135.
    Friedenstein AJ, Gorskaja U, Kalugina NN (1976) Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol 4:267–274PubMedGoogle Scholar
  136. 136.
    Dennis JE, Charbord P (2002) Origin and differentiation of human and murine stroma. Stem Cells 20(3):205–214PubMedGoogle Scholar
  137. 137.
    Gronthos S, Brahim J, Li W, Fisher LW, Cherman N, Boyde A, DenBesten P, Robey PG, Shi S (2002) Stem cell properties of human dental pulp stem cells. J Dent Res 81(8):531–535PubMedGoogle Scholar
  138. 138.
    Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH (2002) Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 13(12):4279–4295PubMedCentralPubMedGoogle Scholar
  139. 139.
    Gimble J, Guilak F (2003) Adipose-derived adult stem cells: isolation, characterization, and differentiation potential. Cytotherapy 5(5):362–369PubMedGoogle Scholar
  140. 140.
    Miura M, Gronthos S, Zhao M, Lu B, Fisher LW, Robey PG, Shi S (2003) SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci U S A 100:5807–5812PubMedCentralPubMedGoogle Scholar
  141. 141.
    Zvaifler NJ, Marinova-Mutafchieva L, Adams G, Edwards CJ, Moss J, Burger JA, Maini RN (2000) Mesenchymal precursor cells in the blood of normal individuals. Arthritis Res 2:477–488PubMedCentralPubMedGoogle Scholar
  142. 142.
    Mitchell KE, Weiss ML, Mitchell BM, Martin P, Davis D, Morales L, Helwig B, Beerenstrauch M, Abou-Easa K, Hildreth T, Troyer D, Medicetty S (2003) Matrix cells from Wharton’s jelly form neurons and glia. Stem Cells 21(1):50–60PubMedGoogle Scholar
  143. 143.
    Igura K, Zhang X, Takahashi K, Mitsuru A, Yamaguchi S, Takashi TA (2004) Isolation and characterization of mesenchymal progenitor cells from chorionic villi of human placenta. Cytotherapy 6:543–553PubMedGoogle Scholar
  144. 144.
    Wang HS, Hung SC, Peng ST, Huang CC, Wei HM, Guo YJ, Fu YS, Lai MC, Chen CC (2004) Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord. Stem Cells 22(7):1330–1337PubMedGoogle Scholar
  145. 145.
    Fu YS, Shih YT, Cheng YC, Min MY (2004) Transformation of human umbilical mesenchymal cells into neurons in vitro. J Biomed Sci 11(5):652–660PubMedGoogle Scholar
  146. 146.
    Tsai MS, Lee JL, Chang YJ, Hwang SM (2004) Isolation of human multipotent mesenchymal stem cells from second trimester amniotic fluid using a novel two-stage culture protocol. Hum Reprod 19:1450–1456PubMedGoogle Scholar
  147. 147.
    Campagnoli C, Roberts IA, Kumar S, Bennet PR, Bellantuono I, Fisk NM (2001) Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver and bone marrow. Blood 98:2396–2402PubMedGoogle Scholar
  148. 148.
    Gong X, Sun Z, Cui D, Xu X, Zhu H, Wang L, Qian W, Han X (2012) Isolation and characterization of lung resident mesenchymal stem cells capable of differentiating into alveolar epithelial type II cells. Cell Biol Int [Epub ahead of print]Google Scholar
  149. 149.
    Dominici M, Le Blanc K, Mueller S-C, Marini FC, Krause DS, Deans RJ, Keating A, Prockop DJ, Horwitz EM (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8(4):315–317PubMedGoogle Scholar
  150. 150.
    Makino S, Fukuda K, Miyoshi S, Konishi F, Kodama H, Pan J, Sano M, Takahashi T, Hori S, Abe H, Hata J, Umezawa A, Ogawa S (1999) Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest 103:697–705PubMedCentralPubMedGoogle Scholar
  151. 151.
    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simoneti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147PubMedGoogle Scholar
  152. 152.
    Jiang Y, Jahagirdar BN, Reinhardt RL, Shwartz RE, Keene CD, Oritz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low W, Largaespada DA, Verfaillie CM (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418:41–49PubMedGoogle Scholar
  153. 153.
    Xu W, Zhang X, Qian H, Zhu W, Sun X, Hu J, Zhou H, Chen Y (2004) Mesenchymal stem cells from adult human bone marrow differentiate into a cardiomyocyte phenotype in vitro. Exp Biol Med (Maywood) 229:623–631Google Scholar
  154. 154.
    Egusa H, Schweizer FE, Wang CC, Matsuka Y, Nishimura I (2005) Neuronal differentiation of bone marrow-derived stromal stem cells involves suppression of discordant phenotypes through gene silencing. J Biol Chem 280:23691–23697PubMedGoogle Scholar
  155. 155.
    Datta I, Mishra S, Mohanty L, Pulikkot S, Joshi PG (2011) Neuronal plasticity of human Wharton’s jelly mesenchymal stromal cells to the dopaminergic cell type compared with human bone marrow mesenchymal stromal cells. Cytotherapy 13:918–932PubMedGoogle Scholar
  156. 156.
    Kanafi M, Majumdar D, Bhonde R, Datta I (2014 Jan 29) Midbrain cues dictate differentiation of human dental pulp stem cells towards functional dopaminergic neurons. J Cell Physiol. doi: 10.1002/jcp.24570
  157. 157.
    Tremain N, Korkko J, Ibberson D, Kopen GC, DiGirolamo C, Phinney DG (2001) MicroSAGE analysis of 2,353 expressed genes in a single cell-derived colony of undifferentiated human mesenchymal stem cells reveals mRNAs of multiple cell lineages. Stem Cells 19(5):408–418PubMedGoogle Scholar
  158. 158.
    Swistowski A, Peng J, Liu Q, Mali P, Rao MS, Cheng L, Zeng X (2010) Efficient generation of functional dopaminergic neurons from human induced pluripotent stem cells under defined conditions. Stem Cells 28(10):1893–1904PubMedCentralPubMedGoogle Scholar
  159. 159.
    Malgrange B, Borgs L, Grobarczyk B, Purnelle A, Ernst P, Moonen G, Nguyen L (2011) Using human pluripotent stem cells to untangle neurodegenerative disease mechanisms. Cell Mol Life Sci 68(4):635–649PubMedGoogle Scholar
  160. 160.
    Krick K, Tammia M, Martin R, Höke A, Mao HQ (2011) Signaling cue presentation and cell delivery to promote nerve regeneration. Curr Opin Biotechnol 22(5):741–746. doi: 10.1016/j.copbio.2011.04.002. Epub 2011 Apr 29PubMedGoogle Scholar
  161. 161.
    Woodbury D, Schwarz EJ, Prockop DJ, Black IB (2000) Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 61:364–370PubMedGoogle Scholar
  162. 162.
    Barnabé GF, Schwindt TT, Calcagnotto ME, Motta FL, Martinez G, de Oliveira Jr AC, Keim LMN, D’Almeida V, Mendez-Otero R, Mello LE (2009) Chemically-induced rat mesenchymal stem cells adopt molecular properties of neuronal like cells but do not have basic neuronal properties. PLoSONE 44e5222. doi: 10.1371/journal.pone.0005222
  163. 163.
    Király M, Porcsalmy B, Pataki A, Kádár K, Jelitai M, Molnár B, Hermann P, Gera I, Grimm WD, Ganss B, Zsembery A, Varga G (2009) Simultaneous PKC and cAMP activation induces differentiation of human dental pulp stem cells into functionally active neurons. Neurochem Int 55(5):323–332. doi: 10.1016/j.neuint.2009.03.017. Epub 2009 Apr 5PubMedGoogle Scholar
  164. 164.
    Trazaska KA, Reddy BY, Munoz JL, Li KY, Ye JH, Rameshwar P (2008) Loss of RE-1 silencing factor in mesenchymal stem cell derived dopamine progenitors induces functional maturity. Mol Cell Neurosci 39:285–290Google Scholar
  165. 165.
    Lu P, Blesch A, Tuszynski MH (2004) Induction of bone marrow stromal cells to neurons: differentiation, transdifferentiation, or artifact? J Neurosci Res 77:174–191PubMedGoogle Scholar
  166. 166.
    Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, Silva AJ (1994) Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79(1):59–68PubMedGoogle Scholar
  167. 167.
    Lim J, Yang C, Hong SJ, Kim KS (2000) Regulation of tyrosine hydroxylase gene transcription by the cAMP-signaling pathway: involvement of multiple transcription factors. Mol Cell Biochem 212(1–2):51–60PubMedGoogle Scholar
  168. 168.
    Dworkin S, Heath JK, deJong-Curtain TA, Hogan BM, Lieschke GJ, Malaterre J, Ramsay RG, Mantamadiotis T (2007) CREB activity modulates neural cell proliferation, midbrain-hindbrain organization and patterning in zebrafish. Dev Biol 307(1):127–141PubMedGoogle Scholar
  169. 169.
    Wang TT, Tio M, Lee W, Beerheide W, Udolph G (2007) Neural differentiation of mesenchymal-like stem cells from cord blood is mediated by PKA. Biochem Biophys Res Commun 357(4):1021–1027PubMedGoogle Scholar
  170. 170.
    Lepski G, Jannes CE, Maciaczyk J, Papazoglou A, Mehlhorn AT, Kaiser S, Teixeira MJ, Marie SK, Bischofberger J, Nikkhah G (2010) Limited Ca2+ and PKA-pathway dependent neurogenic differentiation of human adult mesenchymal stem cells as compared to fetal neuronal stem cells. Exp Cell Res 316(2):216–231PubMedGoogle Scholar
  171. 171.
    Rooney GE, Howard L, O’Brien T, Windebank AJ, Barry FP (2009) Elevation of cAMP in mesenchymal stem cells transiently upregulates neural markers rather than inducing neural differentiation. Stem Cells Dev 18(3):387–398PubMedGoogle Scholar
  172. 172.
    Zhang L, Tan X, Dong C, Zou L, Zhao H, Zhang X, Tian M, Jin G (2012) In vitro differentiation of human umbilical cord mesenchymal stem cells (hUCMSCs), derived from Wharton’s jelly, into choline acetyltransferase (ChAT)-positive cells. Int J Dev Neurosci 30(6):471–477PubMedGoogle Scholar
  173. 173.
    Wand J, Wang X, Sun Z, Wang X, Yang H, Shi S, Wang S (2010) Stem cells from human-exfoliated deciduous teeth can differentiate into dopaminergic neuron-like cells. Stem Cells Dev 19:1375–1383Google Scholar
  174. 174.
    Alexanian AR, Liu QS, Zhang Z (2013) Enhancing the efficiency of direct reprogramming of human mesenchymal stem cells into mature neuronal-like cells with the combination of small molecule modulators of chromatin modifying enzymes, SMAD signaling and cyclic adenosine monophosphate levels. Int J Biochem Cell Biol 45(8):1633–1638. doi: 10.1016/j.biocel.2013.04.022. Epub 2013 May 9PubMedGoogle Scholar
  175. 175.
    Jang S, Cho HH, Cho YB, Park JS, Jeong HS (2010) Functional neural differentiation of human adipose tissue-derived stem cells using bFGF and forskolin. BMC Cell Biol 11:25. doi: 10.1186/1471-2121-11-25 PubMedCentralPubMedGoogle Scholar
  176. 176.
    Fu L, Zhu L, Huang Y, Lee TD, Forman SJ, Shih CC (2008) Derivation of neural stem cells from mesenchymal stem cells: evidence for a bipotential stem cell population. Stem Cells Dev 17:1109–1121PubMedCentralPubMedGoogle Scholar
  177. 177.
    Han YG, Spassky N, Romaguera-Ros M, Garcia-Verdugo JM, Aguilar A, Schneider- Maunoury S, Alvarez-Buylla A (2008) Hedgehog signalling and primary cilia are required for the formation of adult neural stem cells. Nat Neurosci 11:277–284PubMedGoogle Scholar
  178. 178.
    Balasubramanian S, Thej C, Venugopal P, Priya N, Zakaria Z, SundarRaj S, Majumdar AS (2013) Higher propensity of Wharton’s jelly derived mesenchymal stromal cells towards neuronal lineage in comparison to those derived from adipose and bone marrow. Cell Biol Int 37(5):507–515; ISSN 1065-6995. doi: 10.1002/cbin.10056
  179. 179.
    Arthur A, Rychkov G, Shi S, Koblar SA, Gronthos S (2008) Adult human dental pulp stem cells differentiate toward functionally active neurons under appropriate environmental cues. Stem Cells 26:1787–1795PubMedGoogle Scholar
  180. 180.
    Liang J, Wu S, Zhao H, Li SL, Liu ZX, Wu J, Zhou L (2013) Human umbilical cord mesenchymal stem cells derived from Wharton’s jelly differentiate into cholinergic-like neurons in vitro. Neurosci Lett 532:59–63. doi: 10.1016/j.neulet.2012.11.014. Epub 2012 Nov 21PubMedGoogle Scholar
  181. 181.
    Naghdi M, Tiraihi T, Namin SA, Arabkheradmand J (2009) Transdifferentiation of bone marrow stromal cells into cholinergic neuronal phenotype: a potential source for cell therapy in spinal cord injury. Cytotherapy 11:137–152PubMedGoogle Scholar
  182. 182.
    Zhang W, Zeng YS, Wang JM, Ding Y, Li Y, Wu W (2009) Neurotrophin-3 improves retinoic acid-induced neural differentiation of skin-derived precursors through a p75NTR-dependent signaling pathway. Neurosci Res 64(2):170–176PubMedGoogle Scholar
  183. 183.
    Darabi S, Tiraihi T, Delshad A, Sadeghizadeh M (2013) A new multistep induction protocol for the transdifferentiation of bone marrow stromal stem cells into GABAergic neuron-like cells. Iran Biomed J 17(1):8–14PubMedCentralPubMedGoogle Scholar
  184. 184.
    Safford KM, Hicok KC, Safford SD, Halvorsen YD, Wilkison WO, Gimble JM, Rice HE (2002) Neurogenic differentiation of murine and human adipose – derived stromal cells. Biochem Biophys Res Commun 294:371–379PubMedGoogle Scholar
  185. 185.
    Schaffler A, Buchler C (2007) Concise review: adipose tissue-derived stromal cells – basic and clinical implications for novel cell-based therapies. Stem Cells 25:818–827PubMedGoogle Scholar
  186. 186.
    Anghileri E, Marconi S, Pignatelli A, Cifelli P, Galie M, Sbarbati A, Krampera M, Belluzzi O et al (2008) Neuronal differentiation potential of human adipose-derived mesenchymal stem cells. Stem Cells Dev 17:909–916PubMedGoogle Scholar
  187. 187.
    Kim SS, Choi JM, Kim JW, Ham DS, Ghil SH, Kim MK, Kim-Kwon Y, Hong SY, Ahn SC, Kim SU, Lee YD, Suh-Kim H (2005) cAMP induces neuronal differentiation of mesenchymal stem cells via activation of extracellular signal-regulated kinase/MAPK. Neuroreport 16(12):1357–1361PubMedGoogle Scholar
  188. 188.
    Pavlova G, Lopatina T, Kalinina N, Rybalkina E, Parfyonova Y, Tkachuk V, Revishchin A (2012) In vitro neuronal induction of adipose-derived stem cells and their fate after transplantation into injured mouse brain. Curr Med Chem 19:5170–5177PubMedGoogle Scholar
  189. 189.
    Ying C, Hu W, Cheng B, Zheng X, Li S (2012) Neural differentiation of rat adipose-derived stem cells in vitro. Cell Mol Neurobiol 32(8):1255–1263PubMedGoogle Scholar
  190. 190.
    Hedvika D, Xiufang G, Stephen L, Maria S, James JH (2011) Small molecule induction of human umbilical stem cells into myelin basic protein positive oligodendrocytes in a defined three-dimensional environment. ACS Chem Neurosci 3:31–39Google Scholar
  191. 191.
    Mantovani C, Mahay D, Kingham M, Terenghi G, Shawcross SG, Wiberg M (2010) Bone marrow- and adipose-derived stem cells show expression of myelin mRNAs and proteins. Regen Med 5:403–410PubMedGoogle Scholar
  192. 192.
    Chang SJ, Shun-Long W, Jui-Yu H, Tao-Yeuan W, Margaret DTC, Hsei-Wei W (2011) MicroRNA – 34a modulates genes involved in cellular motility and oxidative phosphorylation in neural precursors derived from human umbilical cord mesenchymal stem cells. BMC Med Genomics 4:65PubMedCentralPubMedGoogle Scholar
  193. 193.
    Barzilay R, Ben-Zur T, Bulvik S, Melamed E, Offen D (2009) Lentiviral delivery of LMX1a enhances dopaminergic phenotype in differentiated human bone marrow mesenchymal stem cells. Stem Cells Dev 18:591–601PubMedGoogle Scholar
  194. 194.
    Barzilay R, Melamed E, Offen D (2009) Introducing transcription factors to multipotent mesenchymal stem cells: making transdifferentiation possible. Stem Cells 27:2509–2515PubMedGoogle Scholar
  195. 195.
    Yang Y, Li Y, Lv Y, Zhang S, Chen L, Bai C, Nan X, Yue W, Pei X (2008) NRSF silencing induces neuronal differentiation of human mesenchymal stem cells. Exp Cell Res 314(11–12):2257–2265. doi: 10.1016/j.yexcr.2008.04.008. Epub 2008 May 1PubMedGoogle Scholar
  196. 196.
    Choi SA, Hwang SK, Wang KC, Cho BK, Phi JH, Lee JY, Jung HW, Lee DH, Kim SK (2011) Therapeutic efficacy and safety of TRAIL-producing human adipose tissue-derived mesenchymal stem cells against experimental brainstem glioma. Neuro Oncol 13:61–69PubMedCentralPubMedGoogle Scholar
  197. 197.
    Muñoz-Elias G, Marcus AJ, Coyne TM, Woodbury D, Black IB (2004) Adult bone marrow stromal cells in the embryonic brain: engraftment, migration, differentiation, and long-term survival. J Neurosci 24(19):4585–4595PubMedGoogle Scholar
  198. 198.
    Kopen GC, Prockop DJ, Phinney DG (1999) Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci U S A 96(19):10711–10716PubMedCentralPubMedGoogle Scholar
  199. 199.
    Mezey E, Key S, Vogelsang G, Szalayova I, Lange GD, Crain B (2003) Transplanted bone marrow generates new neurons in human brains. Proc Natl Acad Sci U S A 100(3):1364–1369. Epub 2003 Jan 21PubMedCentralPubMedGoogle Scholar
  200. 200.
    Huang AH, Snyder BR, Cheng PH, Chan AW (2008) Putative dental pulp-derived stem/stromal cells promote proliferation and differentiation of endogenous neural cells in the hippocampus of mice. Stem Cells 26:2654–2663PubMedGoogle Scholar
  201. 201.
    Azizi SA, Stokes D, Augelli BJ, DiGirolamo C, Prockop DJ (1998) Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats–similarities to astrocyte grafts. Proc Natl Acad Sci U S A 95(7):3908–3913PubMedCentralPubMedGoogle Scholar
  202. 202.
    Dezawa M, Hayase M, Kitada M, Wakao S, Itokazu Y, Nozaki K, Hashimoto N, Takagi Y (2009) Committed neural progenitor cells derived from genetically modified bone marrow stromal cells ameliorate deficits in a rat model of stroke. J Cereb Blood Flow Metab 29(8):1409–1420PubMedGoogle Scholar
  203. 203.
    Khoo ML, Tao H, Meedeniya AC, Mackay-Sim A, Ma DD (2011) Transplantation of neuronal-primed human bone marrow mesenchymal stem cells in hemiparkinsonian rodents. PLoS One 6(5):e19025. doi: 10.1371/journal.pone.0019025 PubMedCentralPubMedGoogle Scholar
  204. 204.
    Levy YS, Bahat-Stroomza M, Barzilay R, Burshtein A, Bulvik S, Barhum Y, Panet H, Melamed E, Offen D (2008) Regenerative effect of neural-induced human mesenchymal stromal cells in rat models of Parkinson’s disease. Cytotherapy 10:340–352PubMedGoogle Scholar
  205. 205.
    Wang F, Yasuhara T, Shingo T, Kameda M, Tajiri N, Yuan WJ, Kondo A, Kadota T et al (2010) Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: focusing on neuroprotective effects of stromal cell-derived factor-1α. BMC Neurosci 11:52PubMedCentralPubMedGoogle Scholar
  206. 206.
    Park HJ, Lee PH, Bang OY, Lee G, Ahn YH (2008) Mesenchymal stem cells therapy exerts neuroprotection in a progressive animal model of Parkinson’s disease. J Neurochem 107(1):141–51. doi: 10.1111/j.1471-4159.2008.05589.x. Epub 2008 July 28PubMedGoogle Scholar
  207. 207.
    Yang H, Xie Z, Wei L, Yang H, Yang S, Zhu Z, Wang P, Zhao C, Bi J (2013) Human umbilical cord mesenchymal stem cell-derived neuron-like cells rescue memory deficits and reduce amyloid-beta deposition in an AβPP/PS1 transgenic mouse model. Stem Cell Res Ther 4(4):76PubMedCentralPubMedGoogle Scholar
  208. 208.
    Habisch HJ, Schmid B, Arnim CA, Ludolph AC, Brenner R, Storch A (2010) Efficient processing of Alzheimer’s Disease amyloid-beta peptides by neuroectodermally converted mesenchymal stem cells. Stem Cells Dev 19:629–633PubMedGoogle Scholar
  209. 209.
    McCoy MK, Martinez TN, Ruhn KA, Wrage PC, Keefer EW, Botterman BR, Tansey KE, Tansey MG (2008) Autologous transplants of Adipose-Derived Adult Stromal (ADAS) cells afford dopaminergic neuroprotection in a model of Parkinson’s disease. Exp Neurol 210(1):14–29. Epub 2007 Nov 1PubMedCentralPubMedGoogle Scholar
  210. 210.
    Weiss ML, Medicetty S, Bledsoe AR, Rachakatla RS, Choi M, Merchav S, Luo Y, Rao MS, Velagaleti G, Troyer D (2006) Human umbilical cord matrix stem cells: preliminary characterization and effect of transplantation in a rodent model of Parkinson’s disease. Stem Cells 24(3):781–92. Epub 2005 Oct 13PubMedGoogle Scholar
  211. 211.
    Pereira MC, Secco M, Suzuki DE, Janjoppi L, Rodini CO, Torres LB, Araujo BH, Cavalheiro EA et al (2011) Contamination of mesenchymal stem cells with fibroblasts accelerates neurodegeneration in an experimental model of Parkinson’s disease. Stem Cell Rev 7:1006–1017PubMedCentralPubMedGoogle Scholar
  212. 212.
    Maria D, Hiroshi K, Mikio H, Hirotomi C, Naoya M, Yutaka I, Nobuyoshi T, Hitoshi Y et al (2004) Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation. J Clin Invest 113:1701–1710Google Scholar
  213. 213.
    Harmening K, Heile A, Miller M, Johanson CE, Wallrapp C, Brinker T, Silverberg GD, Klinge PM (2009) Microglial downregulation in a double transgenic mouse model associated with early-onset Alzheimer’s disease (AD) after intraventricular implantation of alginate encapsulated glucagon-like-peptide-1 (GLP-1) producing human mesenchymal stem cells. Cerebrospinal Fluid Res 6:S15PubMedCentralGoogle Scholar
  214. 214.
    Ikegame Y, Yamashita K, Hayashi S, Mizuno H, Tawada M, You F, Yamada K, Tanaka Y (2011) Comparison of mesenchymal stem cells from adipose tissue and bone marrow for ischemic stroke therapy. Cytotherapy 13:675–685PubMedGoogle Scholar
  215. 215.
    Yasuhara T, Matsukawa N, Hara K, Maki M, Ali MM, Yu SJ, Bae E, Yu G, Xu L, McGrogan M, Bankiewicz K, Case C, Borlongan CV (2009) Notch-induced rat and human bone marrow stromal cell grafts reduce ischemic cell loss and ameliorate behavioral deficits in chronic stroke animals. Stem Cells Dev 18(10):1501–1514PubMedGoogle Scholar
  216. 216.
    Bang OY, Lee JS, Lee PH, Lee G (2005) Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol 57(6):874–882PubMedGoogle Scholar
  217. 217.
    Mazzini L, Mareschi K, Ferrero I, Vassallo E, Oliveri G, Nasuelli N, Oggioni GD, Testa L, Fagioli F (2008) Stem cell treatment in amyotrophic lateral sclerosis. J Neurol Sci 265(1–2):78–83. Epub 2007 June 19PubMedGoogle Scholar
  218. 218.
    Pedram MS, Dehghan MM, Soleimani M, Sharifi D, Marjanmehr SH, Nasiri Z (2010) Transplantation of a combination of autologous neural differentiated and undifferentiated mesenchymal stem cells into injured spinal cord of rats. Spinal Cord 48(6):457–463PubMedGoogle Scholar
  219. 219.
    Hu BY, Zhang SC (2009) Differentiation of spinal motor neurons from pluripotent human stem cells. Nat Protoc 4(9):1295–1304PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer India 2014

Authors and Affiliations

  • Indrani Datta
    • 1
  • Debanjana Majumdar
    • 1
  • Kavina Ganapathy
    • 1
  • Ramesh R. Bhonde
    • 1
  1. 1.School of Regenerative MedicineManipal Institute of Regenerative Medicine, Manipal UniversityBangaloreIndia

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