Stem cell-derived dopamine neurons for brain repair in Parkinson’s disease

Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

Bibliography

• 1  Lindvall O, Björklund A: Cell therapy in Parkinson’s disease. NeuroRx1,382–393 (2004).
  MedlineGoogle Scholar
• 2  Honegger P, Lenoir D, Favrod P: Growth and differentiation of aggregating fetal brain cells in a serum-free defined medium. Nature282,305–308 (1979).
  Medline CASGoogle Scholar
• 3  Eccleston PA, Gunton DJ, Silberberg DH: Requirements for brain cell attachment, survival and growth in serum-free medium: effects of extracellular matrix, epidermal growth factor and fibroblast growth factor. Dev. Neurosci.7,308–322 (1985).
  Medline CASGoogle Scholar
• 4  Pulliam L, Berens ME, Rosenblum ML: A normal human brain cell aggregate model for neurobiological studies. J. Neurosci. Res.21,521–530 (1988).
  Medline CASGoogle Scholar
• 5  Reynolds BA, Tetzlaff W, Weiss S: A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J. Neurosci.12,4565–4574 (1992).▪ Key paper describing the isolation and culture of neural stem cells.
  Medline CASGoogle Scholar
• 6  Rodriguez-Pallares J, Guerra MJ, Labandeira-Garcia JL: Angiotensin II and interleukin-1 interact to increase generation of dopaminergic neurons from neurospheres of mesencephalic precursors. Brain Res. Dev. Brain Res.158,120–122 (2005).
  Medline CASGoogle Scholar
• 7  Ling ZD, Potter ED, Lipton JW, Carvey PM: Differentiation of mesencephalic progenitor cells into dopaminergic neurons by cytokines. Exp. Neurol.149,411–423 (1998).
  Medline CASGoogle Scholar
• 8  Yu Y, Gu S, Huang H, Wen T: Combination of bFGF, heparin and laminin induce the generation of dopaminergic neurons from rat neural stem cells both in vitro and in vivo. J. Neurol. Sci.255,81–86 (2007).
  Medline CASGoogle Scholar
• 9  Pei Y, He X, Xie Z: Dopaminergic neuron differentiation of ventral mesencephalic progenitors regulated by developmental signals in vitro. NeuroReport14,1567–1570 (2003).
  Medline CASGoogle Scholar
• 10  Studer L, Csete M, Lee SH et al.: Enhanced proliferation, survival, and dopaminergic differentiation of CNS precursors in lowered oxygen. J. Neurosci.20,7377–7383 (2000).
  Medline CASGoogle Scholar
• 11  Rodriguez-Pallares J, Caruncho HJ, Guerra MJ, Labandeira-Garcia JL: Dipyridamole-induced increase in production of rat dopaminergic neurons from mesencephalic precursors. Neurosci. Lett.320,65–68 (2002).
  Medline CASGoogle Scholar
• 12  Volpicelli F, Consales C, Caiazzo M et al.: Enhancement of dopaminergic differentiation in proliferating midbrain neuroblasts by sonic hedgehog and ascorbic acid. Neural Plast.11,45–57 (2004).
  Medline CASGoogle Scholar
• 13  Peaire AE, Takeshima T, Johnston JM et al.: Production of dopaminergic neurons for cell therapy in the treatment of Parkinson’s disease. J. Neurosci. Methods124,61–74 (2003).
  Medline CASGoogle Scholar
• 14  Jin G, Tan X, Tian M et al.: The controlled differentiation of human neural stem cells into TH-immunoreactive (ir) neurons in vitro. Neurosci. Lett.386,105–110 (2005).
  Medline CASGoogle Scholar
• 15  Roybon L, Hjalt T, Christophersen NS, Li JY, Brundin P: Effects on differentiation of embryonic ventral midbrain progenitors by Lmx1a, Msx1, Ngn2, and Pitx3. J. Neurosci.28,3644–3656 (2008).
  Medline CASGoogle Scholar
• 16  Spitere K, Toulouse A, O’Sullivan DB, Sullivan AM: TAT-PAX6 protein transduction in neural progenitor cells: a novel approach for generation of dopaminergic neurones in vitro. Brain Res.1208,25–34 (2008).
  Medline CASGoogle Scholar
• 17  Kim HJ, Sugimori M, Nakafuku M, Svendsen CN: Control of neurogenesis and tyrosine hydroxylase expression in neural progenitor cells through bHLH proteins and Nurr1. Exp. Neurol.203,394–405 (2007).
  Medline CASGoogle Scholar
• 18  Andersson EK, Irvin DK, Ahlsio J, Parmar M: Ngn2 and Nurr1 act in synergy to induce midbrain dopaminergic neurons from expanded neural stem and progenitor cells. Exp. Cell Res.313,1172–1180 (2007).
  Medline CASGoogle Scholar
• 19  O’Keeffe GW, Sullivan AM: Donor age affects differentiation of rat ventral mesencephalic stem cells. Neurosci. Lett.375,101–106 (2005).
  MedlineGoogle Scholar
• 20  Rodriguez-Pallares J, Guerra MJ, Labandeira-Garcia JL: Elimination of serotonergic cells induces a marked increase in generation of dopaminergic neurons from mesencephalic precursors. Eur. J. Neurosci.18,2166–2174 (2003).
  MedlineGoogle Scholar
• 21  Svendsen CN, Clarke DJ, Rosser AE, Dunnett SB: Survival and differentiation of rat and human EGF responsive precursor cells following grafting into the lesioned adult CNS. Exp. Neurol.137,376–388 (1996).
  Medline CASGoogle Scholar
• 22  Svendsen CN, Caldwell MA, Shen J et al.: Long term survival of human central nervous system progenitor cells transplanted into a rat model of Parkinson’s disease. Exp. Neurol.148,135–146 (1997).
  Medline CASGoogle Scholar
• 23  Liste I, Garcia-Garcia E, Martinez-Serrano A: The generation of dopaminergic neurons by human neural stem cells is enhanced by Bcl-XL, both in vitro and in vivo. J. Neurosci.24,10786–10795 (2004).
  Medline CASGoogle Scholar
• 24  Studer L, Tabar V, McKay RDG: Transplantation of expanded mesencephalic precursors leads to recovery in parkinsonian rats. Nat. Neurosci.1,290–295 (1998).▪ Most successful study to produce functional dopaminergic neurons compared with previous reports.
  Medline CASGoogle Scholar
• 25  Parish CL, Castelo-Branco G, Rawal N et al.: Wnt5a-treated midbrain neural stem cells improve dopamine cell replacement therapy in parkinsonian mice. J. Clin. Invest.118,149–160 (2008).
  Medline CASGoogle Scholar
• 26  Sun J, Gao Q, Miller K et al.: Dopaminergic differentiation of grafted GFP transgenic neuroepithelial stem cells in the brain of a rat model of Parkinson’s disease. Neurosci. Lett.420,23–28 (2007).
  Medline CASGoogle Scholar
• 27  Wang X, Lu Y, Zhang H et al.: Distinct efficacy of pre-differentiated versus intact fetal mesencephalon-derived human neural progenitor cells in alleviating rat model of Parkinson’s disease. Int. J. Dev. Neurosci.22,175–183 (2004).
  Medline CASGoogle Scholar
• 28  Redmond DE Jr, Bjugstad KB, Teng YD et al.: Behavioral improvement in a primate Parkinson’s model is associated with multiple homeostatic effects of human neural stem cells. Proc. Natl Acad. Sci. USA104,12175–12180 (2007).
  Medline CASGoogle Scholar
• 29  Yang M, Donaldson AE, Marshall CE, Shen J, Iacovitti L: Studies on the differentiation of dopaminergic traits in human neural progenitor cells in vitro and in vivo. Cell Transplant.13,535–547 (2004).
  MedlineGoogle Scholar
• 30  Balasubramaniyan V, de Haas AH, Bakels R et al.: Functionally deficient neuronal differentiation of mouse embryonic neural stem cells in vitro. Neurosci. Res.49,261–265 (2004).
  Medline CASGoogle Scholar
• 31  Smith R, Bagga V, Fricker-Gates RA: Embryonic neural progenitor cells: the effects of species, region, and culture conditions on long-term proliferation and neuronal differentiation. J. Hematother. Stem Cell Res.12,713–725 (2003).
  Medline CASGoogle Scholar
• 32  Brundin P, Bjorklund A: Survival of expanded dopaminergic precursors is critical for clinical trials. Nat. Neurosci.1,537 (1998).▪ Important critique of current limitations in generating large numbers of dopamine neurons from cultured neural progenitors.
  Medline CASGoogle Scholar
• 33  Christophersen NS, Meijer X, Jorgensen JR et al.: Induction of dopaminergic neurons from growth factor expanded neural stem/progenitor cell cultures derived from human first trimester forebrain. Brain Res. Bull.70,457–466 (2006).
  Medline CASGoogle Scholar
• 34  Evans MJ, Kaufman MH: Establishment in culture of pluripotential cells from mouse embryos. Nature292,154–156 (1981).▪▪ First published report on the generation of embryonic stem cells.
  Medline CASGoogle Scholar
• 35  Martin GR, Evans MJ: Differentiation of clonal lines of teratocarcinoma cells: formation of embryoid bodies in vitro. Proc. Natl Acad. Sci. USA72,1441–1445 (1975).
  Medline CASGoogle Scholar
• 36  Rolletschek A, Chang H, Guan K et al.: Differentiation of embryonic stem cell-derived dopaminergic neurons is enhanced by survival-promoting factors. Mech. Dev.105,93–104 (2001).
  Medline CASGoogle Scholar
• 37  Lee SH, Lumelsky N, Studer L, Auerbach JM, McKay RD: Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat. Biotechnol.18,675–679 (2000).
  Medline CASGoogle Scholar
• 38  Kawasaki H, Mizuseki K, Nishikawa S et al.: Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity. Neuron28,31–40 (2000).
  Medline CASGoogle Scholar
• 39  Parmar M, Li M: Early specification of dopaminergic phenotype during ES cell differentiation. BMC Dev. Biol.7,86 (2007).
  MedlineGoogle Scholar
• 40  Baier PC, Schindehutte J, Thinyane K et al.: Behavioral changes in unilaterally 6-hydroxy-dopamine lesioned rats after transplantation of differentiated mouse embryonic stem cells without morphological integration. Stem Cells22,396–404 (2004).
  Medline CASGoogle Scholar
• 41  Kim DW: Efficient induction of dopaminergic neurons from embryonic stem cells for application to Parkinson’s disease. Yonsei Med. J.45(Suppl.),23–27 (2004).
  MedlineGoogle Scholar
• 42  Yoshizaki T, Inaji M, Kouike H et al.: Isolation and transplantation of dopaminergic neurons generated from mouse embryonic stem cells. Neurosci. Lett.363,33–37 (2004).
  Medline CASGoogle Scholar
• 43  Chung S, Shin BS, Hwang M et al.: Neural precursors derived from embryonic stem cells, but not those from fetal ventral mesencephalon, maintain the potential to differentiate into dopaminergic neurons after expansion in vitro. Stem Cells24,1583–1593 (2006).
  Medline CASGoogle Scholar
• 44  Nishimura F, Yoshikawa M, Kanda S et al.: Potential use of embryonic stem cells for the treatment of mouse parkinsonian models: improved behavior by transplantation of in vitro differentiated dopaminergic neurons from embryonic stem cells. Stem Cells21,171–180 (2003).
  MedlineGoogle Scholar
• 45  Rodriguez-Gomez JA, Lu JQ, Velasco I et al.: Persistent dopamine functions of neurons derived from embryonic stem cells in a rodent model of Parkinson disease. Stem Cells25,918–928 (2007).
  Medline CASGoogle Scholar
• 46  Sonntag KC, Simantov R, Kim KS, Isacson O: Temporally induced Nurr1 can induce a non-neuronal dopaminergic cell type in embryonic stem cell differentiation. Eur. J. Neurosci.19,1141–1152 (2004).
  MedlineGoogle Scholar
• 47  Martinat C, Bacci JJ, Leete T et al.: Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype. Proc. Natl Acad. Sci. USA103,2874–2879 (2006).
  Medline CASGoogle Scholar
• 48  Kim JH, Auerbach JM, Rodriguez-Gomez JA et al.: Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease. Nature418,50–56 (2002).▪▪ One of two seminal publications in 2002 showing embryonic stem cell (ESC)-derived dopaminergic neurons function to restore motor function in a rat model of Parkinson’s disease (PD)
  Medline CASGoogle Scholar
• 49  Chung S, Hedlund E, Hwang M et al.: The homeodomain transcription factor Pitx3 facilitates differentiation of mouse embryonic stem cells into AHD2-expressing dopaminergic neurons. Mol. Cell Neurosci.28,241–252 (2005).
  Medline CASGoogle Scholar
• 50  Hedlund E, Pruszak J, Lardaro T et al.: Embryonic stem cell-derived Pitx3-enhanced green fluorescent protein midbrain dopamine neurons survive enrichment by fluorescence-activated cell sorting and function in an animal model of Parkinson’s disease. Stem Cells26,1526–1536 (2008).
  Medline CASGoogle Scholar
• 51  Friling S, Andersson E, Thompson LH et al.: Efficient production of mesencephalic dopamine neurons by Lmx1a expression in embryonic stem cells. Proc. Natl Acad. Sci. USA106,7613–7618 (2009).
  Medline CASGoogle Scholar
• 52  Andersson E, Tryggvason U, Deng Q et al.: Identification of intrinsic determinants of midbrain dopamine neurons. Cell124,393–405 (2006).
  Medline CASGoogle Scholar
• 53  Chung S, Sonntag K-C, Andersson T et al.: Genetic engineering of mouse embryonic stem cells by Nurr1 enhances differentiation and maturation into dopaminergic neurons. Eur. J. Neurosci.16,1829–1838 (2002).
  MedlineGoogle Scholar
• 54  Bjorklund LM, Sanchez-Pernaute R, Chung S et al.: Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc. Natl Acad. Sci. USA99,2344–2349 (2002).▪▪ One of two seminal publications in 2002 showing ESC-derived dopaminergic neurons function to restore motor function in a rat model of PD.
  Medline CASGoogle Scholar
• 55  Inden M, Kim D, Gu Y et al.: Pharmacological characteristics of rotational behavior in hemiparkinsonian rats transplanted with mouse embryonic stem cell-derived neurons. J. Pharmacol. Sci.96,53–64 (2004).
  Medline CASGoogle Scholar
• 56  Inden M, Kim DH, Qi M et al.: Transplantation of mouse embryonic stem cell-derived neurons into the striatum, subthalamic nucleus and substantia nigra, and behavioral recovery in hemiparkinsonian rats. Neurosci. Lett.387,151–156 (2005).
  Medline CASGoogle Scholar
• 57  Takagi Y, Takahashi J, Saiki H et al.: Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model. J. Clin. Invest.115,102–109 (2005).
  Medline CASGoogle Scholar
• 58  Kawasaki H, Suemori H, Mizuseki K et al.: Generation of dopaminergic neurons and pigmented epithelia from primate ES cells by stromal cell-derived inducing activity. Proc. Natl Acad. Sci. USA99,1580–1585 (2002).
  Medline CASGoogle Scholar
• 59  Ferrari D, Sanchez-Pernaute R, Lee H, Studer L, Isacson O: Transplanted dopamine neurons derived from primate ES cells preferentially innervate DARPP-32 striatal progenitors within the graft. Eur. J. Neurosci.24,1885–1896 (2006).
  MedlineGoogle Scholar
• 60  Sanchez-Pernaute R, Lee H, Patterson M et al.: Parthenogenetic dopamine neurons from primate embryonic stem cells restore function in experimental Parkinson’s disease. Brain131,2127–2139 (2008).
  MedlineGoogle Scholar
• 61  Thomson JA, Itskovitz-Eldor J, Shapiro SS et al.: Embryonic stem cell lines derived from human blastocysts. Science282,1145–1147 (1998).▪▪ First isolation and generation of human ESCs.
  Medline CASGoogle Scholar
• 62  Schuldiner M, Eiges R, Eden A et al.: Induced neuronal differentiation of human embryonic stem cells. Brain Res.913,201–205 (2001).
  Medline CASGoogle Scholar
• 63  Park S, Lee KS, Lee YJ et al.: Generation of dopaminergic neurons in vitro from human embryonic stem cells treated with neurotrophic factors. Neurosci. Lett.359,99–103 (2004).
  Medline CASGoogle Scholar
• 64  Yan Y, Yang D, Zarnowska ED et al.: Directed differentiation of dopaminergic neuronal subtypes from human embryonic stem cells. Stem Cells23,781–790 (2005).
  Medline CASGoogle Scholar
• 65  Geeta R, Ramnath RL, Rao HS, Chandra V: One year survival and significant reversal of motor deficits in parkinsonian rats transplanted with hESC derived dopaminergic neurons. Biochem. Biophys. Res. Commun.373,258–264 (2008).
  Medline CASGoogle Scholar
• 66  Ben Hur T, Idelson M, Khaner H et al.: Transplantation of human embryonic stem cell-derived neural progenitors improves behavioral deficit in parkinsonian rats. Stem Cells22,1246–1255 (2004).
  MedlineGoogle Scholar
• 67  Carpenter M, Rao MS, Freed W, Zeng X: Derivation and characterization of neuronal precursors and dopaminergic neurons from human embryonic stem cells in vitro. Methods Mol. Biol.331,153–167 (2006).
  MedlineGoogle Scholar
• 68  Chiba S, Lee YM, Zhou W, Freed CR: Noggin enhances dopamine neuron production from human embryonic stem cells and improves behavioral outcome after transplantation into parkinsonian rats. Stem Cells26,2810–2820 (2008).
  Medline CASGoogle Scholar
• 69  Park CH, Lee SH: Efficient generation of dopamine neurons from human embryonic stem cells. Methods Mol. Biol.407,311–322 (2007).
  Medline CASGoogle Scholar
• 70  Ko JY, Park CH, Koh HC et al.: Human embryonic stem cell-derived neural precursors as a continuous, stable, and on-demand source for human dopamine neurons. J. Neurochem.103,1417–1429 (2007).
  Medline CASGoogle Scholar
• 71  Brederlau A, Correia AS, Anisimov SV et al.: Transplantation of human embryonic stem cell-derived cells to a rat model of Parkinson’s disease: effect of in vitro differentiation on graft survival and teratoma formation. Stem Cells24,1433–1440 (2006).
  Medline CASGoogle Scholar
• 72  Zeng X, Cai J, Chen J et al.: Dopaminergic differentiation of human embryonic stem cells. Stem Cells22,925–940 (2004).
  Medline CASGoogle Scholar
• 73  Perrier AL, Tabar V, Barberi T et al.: Derivation of midbrain dopamine neurons from human embryonic stem cells. Proc. Natl Acad. Sci. USA101,12543–12548 (2004).
  Medline CASGoogle Scholar
• 74  Buytaert-Hoefen KA, Alvarez E, Freed CR: Generation of tyrosine hydroxylase positive neurons from human embryonic stem cells after coculture with cellular substrates and exposure to GDNF. Stem Cells22,669–674 (2004).
  Medline CASGoogle Scholar
• 75  Song T, Chen G, Wang Y et al.: Chemically defined sequential culture media for TH⁺ cell derivation from human embryonic stem cells. Mol. Hum. Reprod.14,619–625 (2008).
  Medline CASGoogle Scholar
• 76  Iacovitti L, Donaldson AE, Marshall CE, Suon S, Yang M: A protocol for the differentiation of human embryonic stem cells into dopaminergic neurons using only chemically defined human additives: studies in vitro and in vivo. Brain Res.1127,19–25 (2007).
  Medline CASGoogle Scholar
• 77  Vazin T, Becker KG, Chen J et al.: A novel combination of factors, termed SPIE, which promotes dopaminergic neuron differentiation from human embryonic stem cells. PLoS One.4,E6606 (2009).
  MedlineGoogle Scholar
• 78  Schulz TC, Noggle SA, Palmarini GM et al.: Differentiation of human embryonic stem cells to dopaminergic neurons in serum-free suspension culture. Stem Cells22,1218–1238 (2004).
  Medline CASGoogle Scholar
• 79  Sonntag KC, Pruszak J, Yoshizaki T et al.: Enhanced yield of neuroepithelial precursors and midbrain-like dopaminergic neurons from human embryonic stem cells using the bone morphogenic protein antagonist noggin. Stem Cells25,411–418 (2007).
  Medline CASGoogle Scholar
• 80  Yang D, Zhang ZJ, Oldenburg M, Ayala M, Zhang SC: Human embryonic stem cell-derived dopaminergic neurons reverse functional deficit in parkinsonian rats. Stem Cells26,55–63 (2008).▪ Reports efficient generation of midbrain-like dopaminergic neurons in vivo and some associated recovery of motor function.
  Medline CASGoogle Scholar
• 81  Hayashi H, Morizane A, Koyanagi M et al.: Meningeal cells induce dopaminergic neurons from embryonic stem cells. Eur. J. Neurosci.27,261–268 (2008).
  MedlineGoogle Scholar
• 82  Shimada H, Yoshimura N, Tsuji A, Kunisada T: Differentiation of dopaminergic neurons from human embryonic stem cells: modulation of differentiation by FGF-20. J. Biosci. Bioeng.107,447–454 (2009).
  Medline CASGoogle Scholar
• 83  Hong S, Kang UJ, Isacson O et al.: Neural precursors derived from human embryonic stem cells maintain long term proliferation without losing the potential to differentiate into all three neural lineages, including dopaminergic neurons. J. Neurochem.104,316–324 (2008).
  Medline CASGoogle Scholar
• 84  Cho MS, Lee YE, Kim JY et al.: Highly efficient and large-scale generation of functional dopamine neurons from human embryonic stem cells. Proc. Natl Acad. Sci. USA105,3392–3397 (2008).
  Medline CASGoogle Scholar
• 85  Roy NS, Cleren C, Singh SK et al.: Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat. Med.12,1259–1268 (2006).
  Medline CASGoogle Scholar
• 86  Ben-Hur T, Idelson M, Khaner H et al.: Transplantation of human embryonic stem cell-derived neural progenitors improves behavioral deficit in parkinsonian rats. Stem Cells22,1246–1255 (2004).
  MedlineGoogle Scholar
• 87  Takahashi K, Yamanaka S: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell126,663–676 (2006).▪▪ Ground-breaking research demonstrating generation of induced pluripotent stem cells showing similar properties to ESCs.
  Medline CASGoogle Scholar
• 88  Wernig M, Meissner A, Foreman R et al.: In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature448,318–324 (2007).
  Medline CASGoogle Scholar
• 89  Okita K, Ichisaka T, Yamanaka S: Generation of germline-competent induced pluripotent stem cells. Nature448,313–317 (2007).
  Medline CASGoogle Scholar
• 90  Maherali N, Sridharan R, Xie W et al.: Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell1,55–70 (2007).
  Medline CASGoogle Scholar
• 91  Takahashi K, Tanabe K, Ohnuki M et al.: Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell131,861–872 (2007).
  Medline CASGoogle Scholar
• 92  Yu J, Vodyanik MA, Smuga-Otto K et al.: Induced pluripotent stem cell lines derived from human somatic cells. Science318,1917–1920 (2007).
  Medline CASGoogle Scholar
• 93  Lowry WE, Richter L, Yachechko R et al.: Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc. Natl Acad. Sci. USA105,2883–2888 (2008).
  Medline CASGoogle Scholar
• 94  Park IH, Zhao R, West JA et al.: Reprogramming of human somatic cells to pluripotency with defined factors. Nature451,141–146 (2008).
  Medline CASGoogle Scholar
• 95  Aasen T, Raya A, Barrero MJ et al.: Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat. Biotechnol.26,1276–1284 (2008).
  Medline CASGoogle Scholar
• 96  Huangfu D, Osafune K, Maehr R et al.: Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat. Biotechnol.26,1269–1275 (2008).
  Medline CASGoogle Scholar
• 97  Chambers SM, Fasano CA, Papapetrou EP et al.: Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat. Biotechnol.27,275–280 (2009).
  Medline CASGoogle Scholar
• 98  Wernig M, Zhao JP, Pruszak J et al.: Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proc. Natl Acad. Sci. USA105,5856–5861 (2008).
  Medline CASGoogle Scholar
• 99  Cai J, Yang M, Poremsky E et al.: Dopaminergic neurons derived from human induced pluripotent stem cells survive and integrate into 6-OHDA lesioned rats. Stem Cells Dev. (2009) (Epub ahead of print).
  Google Scholar
• 100  Soldner F, Hockemeyer D, Beard C et al.: Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell136,964–977 (2009).▪▪ First report of PD patient-derived induced pluripotent stem cells, a major step towards autologous transplants.
  Medline CASGoogle Scholar
• 101  Kim D, Kim C-H, Moon J-I et al.: Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell4,472–476 (2009).
  Medline CASGoogle Scholar
• 102  Zhou H, Wu S, Joo JY et al.: Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell4,381–384 (2009).
  Medline CASGoogle Scholar
• 103  Palmer TD, Takahashi J, Gage FH: The adult rat hippocampus contains primordial neural stem cells. Mol. Cell. Neurosci.8,389–404 (1997).
  Medline CASGoogle Scholar
• 104  Alvarez-Buylla A, Seri B, Doetsch F: Identification of neural stem cells in the adult vertebrate brain. Brain Res. Bull.57,751–758 (2002).
  MedlineGoogle Scholar
• 105  Papanikolaou T, Lennington JB, Betz A et al.: In vitro generation of dopaminergic neurons from adult subventricular zone neural progenitor cells. Stem Cells Dev.17,157–172 (2008).
  Medline CASGoogle Scholar
• 106  Dziewczapolski G, Lie DC, Ray J, Gage FH, Shults CW: Survival and differentiation of adult rat-derived neural progenitor cells transplanted to the striatum of hemiparkinsonian rats. Exp. Neurol.183,653–664 (2003).
  Medline CASGoogle Scholar
• 107  Richardson RM, Broaddus WC, Holloway KL, Fillmore HL: Grafts of adult subependymal zone neuronal progenitor cells rescue hemiparkinsonian behavioral decline. Brain Res.1032,11–22 (2005).
  Medline CASGoogle Scholar
• 108  Cooper O, Isacson O: Intrastriatal transforming growth factor a delivery to a model of Parkinson’s disease induces proliferation and migration of endogenous adult neural progenitor cells without differentiation into dopaminergic neurons. J. Neurosci.24,8924–8931 (2004).
  Medline CASGoogle Scholar
• 109  Zhao M, Momma S, Delfani K et al.: Evidence for neurogenesis in the adult mammalian substantia nigra. Proc. Natl Acad. Sci. USA100,7925–7930 (2003).
  Medline CASGoogle Scholar
• 110  Shan X, Chi L, Bishop M et al.: Enhanced de novo neurogenesis and dopaminergic neurogenesis in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease-like mice. Stem Cells24,1280–1287 (2006).
  Medline CASGoogle Scholar
• 111  Frielingsdorf H, Schwarz K, Brundin P, Mohapel P: No evidence for new dopaminergic neurons in the adult mammalian substantia nigra. Proc. Natl Acad. Sci. USA101,10177–10182 (2004).
  Medline CASGoogle Scholar
• 112  Lie DC, Dziewczapolski G, Willhoite AR et al.: The adult substantia nigra contains progenitor cells with neurogenic potential. J. Neurosci.22,6639–6649 (2002).
  Medline CASGoogle Scholar
• 113  Sanchez-Ramos J, Song S, Cardozo-Pelaez F et al.: Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp. Neurol.164,247–256 (2000).
  Medline CASGoogle Scholar
• 114  Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR: Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science290,1779–1782 (2000).
  Medline CASGoogle Scholar
• 115  Brazelton TR, Rossi FM, Keshet GI, Blau HM: From marrow to brain: expression of neuronal phenotypes in adult mice. Science290,1775–1779 (2000).
  Medline CASGoogle Scholar
• 116  Ying QL, Nichols J, Evans EP, Smith AG: Changing potency by spontaneous fusion. Nature416,545–548 (2002).▪ Important research to challenge the concept of transdifferentiation across lineages.
  Medline CASGoogle Scholar
• 117  Terada N, Hamazaki T, Oka M et al.: Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature416,542–545 (2002).▪ Important research to challenge the concept of transdifferentiation across lineages.
  Medline CASGoogle Scholar
• 118  Jiang Y, Henderson D, Blackstad M et al.: Neuroectodermal differentiation from mouse multipotent adult progenitor cells. Proc. Natl Acad. Sci. USA100(Suppl. 1),11854–11860 (2003).
  Medline CASGoogle Scholar
• 119  Trzaska KA, King CC, Li KY et al.: Brain-derived neurotrophic factor facilitates maturation of mesenchymal stem cell-derived dopamine progenitors to functional neurons. J. Neurochem.110,1058–1069 (2009).
  Medline CASGoogle Scholar
• 120  Trzaska KA, Kuzhikandathil EV, Rameshwar P: Specification of a dopaminergic phenotype from adult human mesenchymal stem cells. Stem Cells25,2797–2808 (2007).
  Medline CASGoogle Scholar
• 121  Dezawa M, Kanno H, Hoshino M et al.: Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation. J. Clin. Invest.113,1701–1710 (2004).
  Medline CASGoogle Scholar
• 122  Suon S, Yang M, Iacovitti L: Adult human bone marrow stromal spheres express neuronal traits in vitro and in a rat model of Parkinson’s disease. Brain Res.1106,46–51 (2006).
  Medline CASGoogle Scholar
• 123  Thompson L, Barraud P, Andersson E, Kirik D, Bjorklund A: Identification of dopaminergic neurons of nigral and ventral tegmental area subtypes in grafts of fetal ventral mesencephalon based on cell morphology, protein expression, and efferent projections. J. Neurosci.25,6467–6477 (2005).▪ Important finding that midbrain dopaminergic neurons are the subset of neurons in nigral grafts that reconnect with host circuitry and therefore, would be required in a stem cell-derived transplant.
  Medline CASGoogle Scholar
• 124  Fukuda H, Takahashi J, Watanabe K et al.: Fluorescence-activated cell sorting-based purification of embryonic stem cell-derived neural precursors averts tumor formation after transplantation. Stem Cells24,763–771 (2006).
  Medline CASGoogle Scholar
• 125  Zhou H, Wu S, Joo JY et al.: Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell4,381–384 (2009).
  Medline CASGoogle Scholar