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Advances in Stem Cell Research for Parkinson Disease

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Handbook of Neurotoxicity

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Abstract

There is significant interest in using stem cells as a cell source for treatment against Parkinson’s and other diseases due to the limited self-repair ability of the central nervous system and the lack of a pharmacological treatment to replace lost neurons. Parkinson’s disease is one of the main neurodegenerative disorders, and it is characterized by the degeneration of the nigrostriatal pathway caused by loss of ventral midbrain dopaminergic neurons in the substantia nigra pars compacta. Currently, there are no treatments to halt disease progress; the treatments merely ameliorate motor symptoms for a time, but the treatments are often followed by severe side effects. Cell-replacement therapy has been proposed as a treatment to replace damaged neurons and protect the remaining cells. Preliminary studies have utilized adult tissues, embryonic/fetal tissues, and embryonic stem cells as a source of dopaminergic cells. However, the ethical issues related to this type of procedure, the high quantity of required cells, the risk of tumor formation, and the immunological rejection associated with it have prevented this technique from being an effective treatment against Parkinson’s disease. Researchers have been challenged to focus on new cell-replacement alternatives. In 2006, researchers found that only four transcription factors were necessary to reprogram an adult somatic cell to an induced pluripotent stem cell. This breakthrough revolutionized the scientific community, as this technique would allow scientists to obtain specific cells from the patient, avoiding rejection problems from non-autologous grafts and avoiding ethical problems. In addition, a large number of cells could be obtained. Although induced pluripotent stem (iPS) cells have great potential as a treatment against this disease, there are some obstacles for its clinical use such as the lack of standardized protocols that result in a dopaminergic cell phenotype that grafts without undifferentiated cells and without a risk of tumor formation. Currently, the iPS cell system is an ideal model of study for many other diseases besides Parkinson’s, and the system is also good for drug screening. Recently, the direct reprogramming of somatic cells to induce neuronal (iN) cells without generating a pluripotent stage could be the solution to avoiding tumor formation risk. However, as a result of the low quantity of cells obtained, more investigations are necessary to convert this technique into an efficient cell-replacement therapy. If we overcome these obstacles, the use of iPS and iN cells could be, without a doubt, a promising therapy in the near future.

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Abbreviations

ASCs:

Adult stem cells

ATRA:

All-trans-retinoic acid

BDNF:

Brain-derived neurotrophic factor

bFGF:

Basic fibroblast growth factor

CB-SCs:

Cord blood-derived multipotent stem cells

CNS:

Central nervous system

DA:

Dopamine

EGF:

Epidermal growth factor

ESCs:

Embryonic stem cells

FGF2:

Fibroblast growth factor 2

FGF20:

Fibroblast growth factor 20

FGF8:

Fibroblast growth factor 8

GDNF:

Glial cell line-derived neurotrophic factor

GSK-3:

Glycogen synthase kinase 3

hESCs:

Human embryonic stem cells

HGF:

Hepatocyte growth factor

HSCs:

Hematopoietic stem cells

HUVMSCs:

Human umbilical vein mesenchymal stem cells

ICM:

Inner cell mass

iN:

Induced neuronal

iPSCs:

Induced pluripotent stem cells

MSCs:

Mesenchymal stem cells

NP:

Neural progenitor

NPSCs:

Neural progenitor stem cells

NSCs:

Neural stem cells

NSPCs:

Neural stem cell and neural progenitor cell

PD:

Parkinson’s disease

PGCs:

Primordial germ cells

SCC:

Stem cell coactivator complex

SDF1α:

Stromal cell-derived factor-1α

SDIA:

Stromal cell-derived inducing activity

sFRP1:

Secreted frizzled-related protein 1

SHH:

Sonic hedgehog

SNpc:

Substantia nigra pars compacta

STEMCCA:

Single excisable polycistronic lentiviral stem cell cassette

SVZ:

Subventricular zone

VEGFD:

Vascular endothelial growth factor D

References

  • Abdanipour, A., Tiraihi, T., & Delshad, A. (2011). Trans-differentiation of the adipose tissue-derived stem cells into neuron-like cells expressing neurotrophins by selegiline. Iranian Biomedical Journal, 15, 113–121.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Adewumi, O., Aflatoonian, B., Ahrlund-Richter, L., Amit, M., Andrews, P. W., Beighton, G., Bello, P. A., Benvenisty, N., Berry, L. S., Bevan, S., et al. (2007). Characterization of human embryonic stem cell lines by the International Stem Cell Initiative. Nature Biotechnology, 25, 803–816.

    CAS  PubMed  Google Scholar 

  • Amit, M., Carpenter, M. K., Inokuma, M. S., Chiu, C. P., Harris, C. P., Waknitz, M. A., Itskovitz-Eldor, J., & Thomson, J. A. (2000). Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Developmental Biology, 227, 271–278.

    CAS  PubMed  Google Scholar 

  • Andersson, E. R., Saltó, C., Villaescusa, J. C., Cajanek, L., Yang, S., Bryjova, L., Nagy, I. I., Vainio, S. J., Ramirez, C., Bryja, V., & Arenas, E. (2013). Wnt5a cooperates with canonical Wnts to generate midbrain dopaminergic neurons in vivo and in stem cells. Proceedings of the National Academy of Sciences of the United States of America, 110, E602–E610.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ara, J., Fekete, S., Zhu, A., & Frank, M. (2010). Characterization of neural stem/progenitor cells expressing VEGF and its receptors in the subventricular zone of newborn piglet brain. Neurochemical Research, 35, 1455–1470.

    CAS  PubMed  Google Scholar 

  • Arias-Carrión, O., & Yuan, T. F. (2009). Autologous neural stem cell transplantation: A new treatment option for Parkinson’s disease? Medical Hypotheses, 73, 757–759.

    PubMed  Google Scholar 

  • Arjona, V., Mínguez-Castellanos, A., Montoro, R. J., Ortega, A., Escamilla, F., Toledo-Aral, J. J., Pardal, R., Méndez-Ferrer, S., Martín, J. M., Pérez, M., Katati, M. J., Valencia, E., García, T., & López-Barneo, J. (2003). Autotransplantation of human carotid body cell aggregates for treatment of Parkinson’s disease. Neurosurgery, 53, 321–328.

    PubMed  Google Scholar 

  • Avilion, A. A., Nicolis, S. K., Pevny, L. H., Perez, L., Vivian, N., & Lovell-Badge, R. (2003). Multipotent cell lineages in early mouse development depend on SOX2 function. Genes & Development, 17, 126–140.

    CAS  Google Scholar 

  • Bai, L., Caplan, A., Lennon, D., & Miller, R. H. (2007). Human mesenchymal stem cells signals regulate neural stem cell fate. Neurochemical Research, 32, 353–362.

    CAS  PubMed  Google Scholar 

  • Ballagi, A. E., Odin, P., Othberg-Cederström, A., Smits, A., Duan, W. M., Lindvall, O., & Funa, K. (1994). Platelet-derived growth factor receptor expression after neural grafting in a rat model of Parkinson’s disease. Cell Transplantation, 3, 453–460.

    CAS  PubMed  Google Scholar 

  • Bankiewicz, K. S., Plunkett, R. J., Jacobowitz, D. M., Porrino, L., di Porzio, U., London, W. T., Kopin, I. J., & Oldfield, E. H. (1990). The effect of fetal mesencephalon implants on primate MPTP-induced parkinsonism. Histochemical and behavioral studies. Journal of Neurosurgery, 72, 231–244.

    CAS  PubMed  Google Scholar 

  • Barinaga, M. (2000). Fetal neuron grafts pave the way for stem cell therapies. Science, 287, 1421–1422.

    CAS  PubMed  Google Scholar 

  • Bellin, M., Marchetto, M. C., Gage, F. H., & Mummery, C. L. (2012). Induced pluripotent stem cells: The new patient? Nature Reviews Molecular Cell Biology, 13, 713–726.

    PubMed  Google Scholar 

  • Beltrami, A. P., Cesselli, D., Bergamin, N., Marcon, P., Rigo, S., Puppato, E., D’Aurizio, F., Verardo, R., Piazza, S., Pignatelli, A., Poz, A., Baccarani, U., Damiani, D., Fanin, R., Mariuzzi, L., Finato, N., Masolini, P., Burelli, S., Belluzzi, O., Schneider, C., & Beltrami, C. A. (2007). Multipotent cells can be generated in vitro from several adult human organs (heart, liver, and bone marrow). Blood, 110, 3438–3446.

    CAS  PubMed  Google Scholar 

  • Berg, J. S., & Goodell, M. A. (2007). An argument against a role for Oct4 in somatic stem cells. Cell Stem Cell, 1, 359–360.

    CAS  PubMed  Google Scholar 

  • Bernhardt, M., Galach, M., Novak, D., & Utikal, J. (2012). Mediators of induced pluripotency and their role in cancer cells – current scientific knowledge and future perspectives. Biotechnology Journal, 7, 810–821.

    CAS  PubMed  Google Scholar 

  • Bernheimer, H., Birkmayer, W., Hornykiewicz, O., Jellinger, K., & Seitelberger, F. (1973). Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. Journal of Neurological Sciences, 20, 415–455.

    CAS  Google Scholar 

  • Bernstein, B. E., Mikkelsen, T. S., Xie, X., Kamal, M., Huebert, D. J., Cuff, J., Fry, B., Meissner, A., Wernig, M., Plath, K., Jaenisch, R., Wagschal, A., Feil, R., Schreiber, S. L., & Lander, E. S. (2006). A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell, 125, 315–326.

    CAS  PubMed  Google Scholar 

  • Bilodeau, S., Kagey, M. H., Frampton, G. M., Rahl, P. B., & Young, R. A. (2009). SetDB1 contributes to repression of genes encoding developmental regulators and maintenance of ES cell state. Genes & Development, 23, 2484–2489.

    CAS  Google Scholar 

  • Björklund, A., & Lindvall, O. (1999). Transplanted nerve cells survive and are functional for many years. Lakartidningen, 96, 3407–3412.

    PubMed  Google Scholar 

  • Bonnamain, V., Neveu, I., & Naveilhan, P. (2012). Neural stem/progenitor cells as a promising candidate for regenerative therapy of the central nervous system. Frontiers in Cellular Neuroscience, 6, 17.

    PubMed Central  PubMed  Google Scholar 

  • Boyer, L. A., Lee, T. I., Cole, M. F., Johnstone, S. E., Levine, S. S., Zucker, J. P., Guenther, M. G., Kumar, R. M., Murray, H. L., Jenner, R. G., Gifford, D. K., Melton, D. A., Jaenisch, R., & Young, R. A. (2005). Core transcriptional regulatory circuitry in human embryonic stem cells. Cell, 122, 947–956.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Boyer, L. A., Plath, K., Zeitlinger, J., Brambrink, T., Medeiros, L. A., Lee, T. I., Levine, S. S., Wernig, M., Tajonar, A., Ray, M. K., Bell, G. W., Otte, A. P., Vidal, M., Gifford, D. K., Young, R. A., & Jaenisch, R. (2006). Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature, 441, 349–353.

    CAS  PubMed  Google Scholar 

  • Brazel, C. Y., Limke, T. L., Osborne, J. K., Miura, T., Cai, J., Pevny, L., & Rao, M. S. (2005). Sox2 expression defines a heterogeneous population of neurosphere-forming cells in the adult murine brain. Aging Cell, 4, 197–207.

    CAS  PubMed  Google Scholar 

  • Brons, I. G., Smithers, L. E., Trotter, M. W., Rugg-Gunn, P., Sun, B., Chuva de Sousa Lopes, S. M., Howlett, S. K., Clarkson, A., Ahrlund-Richter, L., Pedersen, R. A., & Vallier, L. (2007). Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature, 448, 191–195.

    CAS  PubMed  Google Scholar 

  • Brundin, P., Strecker, R. E., Gage, F. H., Lindvall, O., & Björklund, A. (1988). Intracerebral transplantation of dopamine neurons: Understanding the functional role of the mesolimbocortical dopamine system and developing a therapy for Parkinson’s disease. Annals of the New York Academy of Sciences, 537, 148–160.

    CAS  PubMed  Google Scholar 

  • Byers, B., Lee, H. L., & Reijo Pera, R. (2012). Modeling Parkinson’s disease using induced pluripotent stem cells. Current Neurology and Neuroscience Reports, 12, 237–242.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cai, J., Schleidt, S., Pelta-Heller, J., Hutchings, D., Cannarsa, G., & Iacovitti, L. (2013). BMP and TGF-β pathway mediators are critical upstream regulators of Wnt signaling during midbrain dopamine differentiation in human pluripotent stem cells. Developmental Biology, 1606, 30–34.

    Google Scholar 

  • Caiazzo, M., Dell’Anno, M. T., Dvoretskova, E., Lazarevic, D., Taverna, S., Leo, D., Sotnikova, T. D., Menegon, A., Roncaglia, P., Colciago, G., Russo, G., Carninci, P., Pezzoli, G., Gainetdinov, R. R., Gustincich, S., Dityatev, A., & Broccoli, V. (2011). Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature, 476, 224–227.

    CAS  PubMed  Google Scholar 

  • Cavaleri, F., & Schöler, H. R. (2003). Nanog: A new recruit to the embryonic stem cell orchestra. Cell, 113, 551–552.

    CAS  PubMed  Google Scholar 

  • Chambers, I., Colby, D., Robertson, M., Nichols, J., Lee, S., Tweedie, S., & Smith, A. (2003). Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell, 113, 643–655.

    CAS  PubMed  Google Scholar 

  • Chang, Y. L., Chen, S. J., Kao, C. L., Hung, S. C., Ding, D. C., Yu, C. C., Chen, Y. J., Ku, H. H., Lin, C. P., Lee, K. H., Chen, Y. C., Wang, J. J., Hsu, C. C., Chen, L. K., Li, H. Y., & Chiou, S. H. (2012). Docosahexaenoic acid promotes dopaminergic differentiation in induced pluripotent stem cells and inhibits teratoma formation in rats with Parkinson-like pathology. Cell Transplantation, 21, 313–332.

    PubMed  Google Scholar 

  • Chen, B. Y., Wang, X., Wang, Z. Y., Wang, Y. Z., Chen, L. W., & Luo, Z. J. (2013). Brain-derived neurotrophic factor stimulates proliferation and differentiation of neural stem cells, possibly by triggering the Wnt/β-catenin signaling pathway. Journal of Neuroscience Research, 91, 30–41.

    CAS  PubMed  Google Scholar 

  • Chew, J. L., Loh, Y. H., Zhang, W., Chen, X., Tam, W. L., Yeap, L. S., Li, P., Ang, Y. S., Lim, B., Robson, P., & Ng, H. H. (2005). Reciprocal transcriptional regulation of Pou5f1 and Sox2 via the Oct4/Sox2 complex in embryonic stem cells. Molecular and cellular biology, 25, 6031–6046.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chiba, S., Lee, Y. M., Zhou, W., & Freed, C. R. (2008). Noggin enhances dopamine neuron production from human embryonic stem cells and improves behavioral outcome after transplantation into Parkinsonian rats. Stem Cells, 26, 2810–2820.

    CAS  PubMed  Google Scholar 

  • Cho, M. S., Lee, Y. E., Kim, J. Y., Chung, S., Cho, Y. H., Kim, D. S., Kang, S. M., Lee, H., Kim, M. H., Kim, J. H., Leem, J. W., Oh, S. K., Choi, Y. M., Hwang, D. Y., Chang, J. W., & Kim, D. W. (2008). Highly efficient and large scale generation of functional dopamine neurons from human embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America, 105, 3392–3397.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Choi, Y. K., Cho, H., Seo, Y. K., Yoon, H. H., & Park, J. K. (2012). Stimulation of sub-sonic vibration promotes the differentiation of adipose tissue-derived mesenchymal stem cells into neural cells. Life Sciences, 91, 329–337.

    CAS  PubMed  Google Scholar 

  • Chou, B. K., Mali, P., Huang, X., Ye, Z., Dowey, S. N., Resar, L. M., Zou, C., Zhang, Y. A., Tong, J., & Cheng, L. (2011). Efficient human iPS cell derivation by a non-integrating plasmid from blood cells with unique epigenetic and gene expression signatures. Cell Research, 21, 518–529.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Collier, T. J., Sortwell, C. E., & Daley, B. F. (1999). Diminished viability, growth, and behavioral efficacy of fetal dopamine neuron grafts in aging rats with long-term dopamine depletion: An argument for neurotrophic supplementation. Journal of Neuroscience, 19, 5563–5573.

    CAS  PubMed  Google Scholar 

  • Cooper, O., Hargus, G., Deleidi, M., Blak, A., Osborn, T., Marlow, E., Lee, K., Levy, A., Perez-Torres, E., Yow, A., & Isacson, O. (2010). Differentiation of human ES and Parkinson’s disease iPS cells into ventral midbrain dopaminergic neurons requires a high activity form of SHH, FGF8a and specific regionalization by retinoic acid. Molecular and Cellular Neuroscience, 45, 258–266.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Correia, A. S., Anisimov, S. V., Roybon, L., Li, J. Y., & Brundin, P. (2007). Fibroblast growth factor-20 increases the yield of midbrain dopaminergic neurons derived from human embryonic stem cells. Frontiers in Neuroanatomy, 1, 4.

    PubMed Central  PubMed  Google Scholar 

  • Cowan, C. A., Atienza, J., Melton, D. A., & Eggan, K. (2005). Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells. Science, 309, 1369–1373.

    CAS  PubMed  Google Scholar 

  • 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. Iranian Biomedical Journal, 17, 8–14.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Datta, I., Ganapathy, K., Tattikota, S. M., & Bhonde, R. (2013). Directed differentiation of human embryonic stem cell-line HUES9 to dopaminergic neurons in a serum-free defined culture niche. Cell Biology International, 37, 54–64.

    PubMed  Google Scholar 

  • de Jong, J., Stoop, H., Gillis, A. J., van Gurp, R. J., van de Geijn, G. J., Boer, M. D., Hersmus, R., Saunders, P. T., Anderson, R. A., Oosterhuis, J. W., & Looijenga, L. H. (2008). Differential expression of SOX17 and SOX2 in germ cells and stem cells has biological and clinical implications. The Journal of Pathology, 215, 21–30.

    CAS  PubMed  Google Scholar 

  • Dor, Y., Brown, J., Martinez, O. I., & Melton, D. A. (2004). Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature, 429, 41–46.

    CAS  PubMed  Google Scholar 

  • Dushnik-Levinson, M., & Benvenisty, N. (1995). Embryogenesis in vitro: Study of differentiation of embryonic stem cells. Biology of the Neonate, 67, 77–83.

    CAS  PubMed  Google Scholar 

  • Ebben, J. D., Zorniak, M., Clark, P. A., & Kuo, J. S. (2011). Introduction to induced pluripotent stem cells: Advancing the potential for personalized medicine. World Neurosurgery, 76, 270–275.

    PubMed Central  PubMed  Google Scholar 

  • Ellis, P., Fagan, B. M., Magness, S. T., Hutton, S., Taranova, O., Hayashi, S., McMahon, A., Rao, M., & Pevny, L. (2004). SOX2, a persistent marker for multipotential neural stem cells derived from embryonic stem cells, the embryo or the adult. Developmental Neuroscience, 26, 148–165.

    CAS  PubMed  Google Scholar 

  • Emgård, M., Karlsson, J., Hansson, O., & Brundin, P. (1999). Patterns of cell death and dopaminergic neuron survival in intrastriatal nigral grafts. Experimental Neurology, 160, 279–288.

    PubMed  Google Scholar 

  • Eminli, S., Utikal, J., Arnold, K., Jaenisch, R., & Hochedlinger, K. (2008). Reprogramming of neural progenitor cells into induced pluripotent stem cells in the absence of exogenous Sox2 expression. Stem Cells, 26, 2467–2474.

    CAS  PubMed  Google Scholar 

  • Esfandiari, F., Fathi, A., Gourabi, H., Kiani, S., Nemati, S., & Baharvand, H. (2012). Glycogen synthase kinase-3 inhibition promotes proliferation and neuronal differentiation of human-induced pluripotent stem cell-derived neural progenitors. Stem Cells and Development, 21, 3233–3243.

    CAS  PubMed  Google Scholar 

  • Espejo, E. F., Montoro, R. J., Armengol, J. A., & López-Barneo, J. (1998). Cellular and functional recovery of Parkinsonian rats after intrastriatal transplantation of carotid body cell aggregates. Neuron, 20, 197–206.

    CAS  PubMed  Google Scholar 

  • Evans, M., & Kaufman, M. (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature, 292, 154–156.

    CAS  PubMed  Google Scholar 

  • Ezeh, U. I., Turek, P. J., Reijo, R. A., & Clark, A. T. (2005). Human embryonic stem cell genes OCT4, NANOG, STELLAR, and GDF3 are expressed in both seminoma and breast carcinoma. Cancer, 104, 2255–2265.

    CAS  PubMed  Google Scholar 

  • Ferri, A. L., Cavallaro, M., Braida, D., Di Cristofano, A., Canta, A., Vezzani, A., Ottolenghi, S., Pandolfi, P. P., Sala, M., DeBiasi, S., & Nicolis, S. K. (2004). Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain. Development, 131, 3805–3819.

    CAS  PubMed  Google Scholar 

  • Fisone, G., & Bezard, E. (2011). Molecular mechanisms of l-DOPA-induced dyskinesia. International Review of Neurobiology, 98, 95–122.

    CAS  PubMed  Google Scholar 

  • Fong, Y. W., Inouye, C., Yamaguchi, T., Cattoglio, C., Grubisic, I., & Tjian, R. (2011). A DNA repair complex functions as an Oct4/Sox2 coactivator in embryonic stem cells. Cell, 147, 120–131.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Freed, C. R., Breeze, R. E., Rosenberg, N. L., Schneck, S. A., Wells, T. H., Barrett, J. N., Grafton, S. T., Huang, S. C., Eidelberg, D., & Rottenberg, D. A. (1990). Transplantation of human fetal dopamine cells for Parkinson’s disease. Results at 1 year. Archives of Neurology, 47, 505–512.

    CAS  PubMed  Google Scholar 

  • Freed, C. R., Breeze, R. E., Rosenberg, N. L., Schneck, S. A., Kriek, E., Qi, J. X., Lone, T., Zhang, Y. B., Snyder, J. A., & Wells, T. H. (1992). Survival of implanted fetal dopamine cells and neurologic improvement 12 to 46 months after transplantation for Parkinson’s disease. The New England Journal of Medicine, 327, 1549–1555.

    CAS  PubMed  Google Scholar 

  • Freed, C. R., Greene, P. E., Breeze, R. E., Tsai, W. Y., DuMouchel, W., Kao, R., Dillon, S., Winfield, H., Culver, S., Trojanowski, J. Q., Eidelberg, D., & Fahn, S. (2001). Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. The New England Journal of Medicine, 344, 710–719.

    CAS  PubMed  Google Scholar 

  • Fu, W., Lu, Y., & Piao, Y. (2002). Culture and pluripotentiality of human marrow mesenchymal stem cells. Zhonghua Xue Ye Xue Za Zhi, 23, 202–204.

    PubMed  Google Scholar 

  • Galpern, W. R., Burns, L. H., Deacon, T. W., Dinsmore, J., & Isacson, O. (1996). Xenotransplantation of porcine fetal ventral mesencephalon in a rat model of Parkinson’s disease: Functional recovery and graft morphology. Experimental Neurology, 140, 1–13.

    CAS  PubMed  Google Scholar 

  • González, F., Boué, S., & Izpisúa Belmonte, J. C. (2011). Methods for making induced pluripotent stem cells: Reprogramming à la carte. Nature Reviews Genetics, 12, 231–242.

    PubMed  Google Scholar 

  • Grad, I., Hibaoui, Y., Jaconi, M., Chicha, L., Bergström-Tengzelius, R., Sailani, M. R., Pelte, M. F., Dahoun, S., Mitsiadis, T. A., Töhönen, V., Bouillaguet, S., Antonarakis, S. E., Kere, J., Zucchelli, M., Hovatta, O., & Feki, A. (2011). NANOG priming before full reprogramming may generate germ cell tumours. European Cells & Materials, 22, 258–274.

    CAS  Google Scholar 

  • Grinnell, K. L., Yang, B., Eckert, R. L., & Bickenbach, J. R. (2007). De-differentiation of mouse interfollicular keratinocytes by the embryonic transcription factor Oct-4. The Journal of Investigative Dermatology, 127, 372–380.

    CAS  PubMed  Google Scholar 

  • Gronthos, S., Mankani, M., Brahim, J., Robey, P. G., & Shi, S. (2000). Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America, 97, 13625–13630.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Guo, Z., Li, H., Li, X., Yu, X., Wang, H., Tang, P., & Mao, N. (2006). In vitro characteristics and in vivo immunosuppressive activity of compact bone-derived murine mesenchymal progenitor cells. Stem Cells, 24, 992–1000.

    PubMed  Google Scholar 

  • Guo, G., Yang, J., Nichols, J., Hall, J. S., Eyres, I., Mansfield, W., & Smith, A. (2009). Klf4 reverts developmentally programmed restriction of ground state pluripotency. Development, 136, 1063–1069.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gurdon, J. B., & Melton, D. A. (2008). Nuclear reprogramming in cells. Review. Science, 322, 1811–1815.

    CAS  PubMed  Google Scholar 

  • Gurdon, J. B., Elsdale, T. R., & Fischberg, M. (1958). Sexually mature individuals of Xenopus laevis from the transplantation of single somatic nuclei. Nature, 182, 64–65.

    CAS  PubMed  Google Scholar 

  • Hagell, P., Schrag, A., Piccini, P., Jahanshahi, M., Brown, R., Rehncrona, S., Widner, H., Brundin, P., Rothwell, J. C., Odin, P., Wenning, G. K., Morrish, P., Gustavii, B., Björklund, A., Brooks, D. J., Marsden, C. D., Quinn, N. P., & Lindvall, O. (1999). Sequential bilateral transplantation in Parkinson’s disease: Effects of the second graft. Brain, 122, 1121–1132.

    PubMed  Google Scholar 

  • Hamazaki, T., Oka, M., Yamanaka, S., & Terada, N. (2004). Aggregation of embryonic stem cells induces Nanog repression and primitive endoderm differentiation. Journal of Cell Science, 117, 5681–5686.

    CAS  PubMed  Google Scholar 

  • Hammachi, F., Morrison, G. M., Sharov, A. A., Livigni, A., Narayan, S., Papapetrou, E. P., O’Malley, J., Kaji, K., Ko, M. S., Ptashne, M., & Brickman, J. M. (2012). Transcriptional activation by Oct4 is sufficient for the maintenance and induction of pluripotency. Cell Reports, 1, 99–109.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Han, S. S., Williams, L. A., & Eggan, K. C. (2011). Constructing and deconstructing stem cell models of neurological disease. Neuron, 70, 626–644.

    CAS  PubMed  Google Scholar 

  • Hara, K., Uchida, K., Fukunaga, A., Toya, S., & Kawase, T. (1997). Implantation of xenogeneic transgenic neural plate tissues into parkinsonian rat brain. Cell Transplantation, 6, 515–519.

    CAS  PubMed  Google Scholar 

  • Hargus, G., Cooper, O., Deleidi, M., Levy, A., Lee, K., Marlow, E., Yow, A., Soldner, F., Hockemeyer, D., Hallett, P. J., 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. Proceedings of the National Academy of Sciences of the United States of America, 107, 15921–15926.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Harrower, T. P., Tyers, P., Hooks, Y., & Barker, R. A. (2006). Long-term survival and integration of porcine expanded neural precursor cell grafts in a rat model of Parkinson’s disease. Experimental Neurology, 197, 56–69.

    CAS  PubMed  Google Scholar 

  • Hart, A. H., Hartley, L., Ibrahim, M., & Robb, L. (2004). Identification, cloning and expression analysis of the pluripotency promoting Nanog genes in mouse and human. Developmental Dynamics, 230, 187–198.

    CAS  PubMed  Google Scholar 

  • Hochedlinger, K., Yamada, Y., Beard, C., & Jaenisch, R. (2005). Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell, 121, 465–477.

    CAS  PubMed  Google Scholar 

  • Hoei-Hansen, C. E., Almstrup, K., Nielsen, J. E., Brask Sonne, S., Graem, N., Skakkebaek, N. E., Leffers, H., & Rajpert-De Meyts, E. (2005). Stem cell pluripotency factor NANOG is expressed in human fetal gonocytes, testicular carcinoma in situ and germ cell tumours. Histopathology, 47, 48–56.

    CAS  PubMed  Google Scholar 

  • Holm, K. H., Cicchetti, F., Bjorklund, L., Boonman, Z., Tandon, P., Costantini, L. C., Deacon, T. W., Huang, X., Chen, D. F., & Isacson, O. (2001). Enhanced axonal growth from fetal human bcl-2 transgenic mouse dopamine neurons transplanted to the adult rat striatum. Neuroscience, 104, 397–405.

    CAS  PubMed  Google Scholar 

  • Hu, B. Y., Weick, J. P., Yu, J., Ma, L. X., Zhang, X. Q., Thomson, J. A., & Zhang, S. C. (2010). Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proceedings of the National Academy of Sciences of the United States of America, 107, 4335–4340.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Huffaker, T. K., Boss, B. D., Morgan, A. S., Neff, N. T., Strecker, R. E., Spence, M. S., & Miao, R. (1989). Xenografting of fetal pig ventral mesencephalon corrects motor asymmetry in the rat model of Parkinson’s disease. Experimental Brain Research, 77, 329–336.

    CAS  PubMed  Google Scholar 

  • Hwang, D. Y., Kim, D. S., & Kim, D. W. (2010). Human ES and iPS cells as cell sources for the treatment of Parkinson’s disease: Current state and problems. Journal of Cellular Biochemistry, 109, 292–301.

    CAS  PubMed  Google Scholar 

  • Ivanova, N., Dobrin, R., Lu, R., Kotenko, I., Levorse, J., DeCoste, C., Schafer, X., Lun, Y., & Lemischka, I. R. (2006). Dissecting self-renewal in stem cells with RNA interference. Nature, 442, 533–538.

    CAS  PubMed  Google Scholar 

  • Jackson, J. S., Golding, J. P., Chapon, C., Jones, W. A., & Bhakoo, K. K. (2010). Homing of stem cells to sites of inflammatory brain injury after intracerebral and intravenous administration: A longitudinal imaging study. Stem Cell Research & Therapy, 1, 17.

    Google Scholar 

  • Jensen, P., Pedersen, E. G., Zimmer, J., Widmer, H. R., & Meyer, M. (2008). Functional effect of FGF2- and FGF8-expanded ventral mesencephalic precursor cells in a rat model of Parkinson’s disease. Brain Research, 1218, 13–20.

    CAS  PubMed  Google Scholar 

  • Jeter, C. R., Badeaux, M., Choy, G., Chandra, D., Patrawala, L., Liu, C., Calhoun-Davis, T., Zaehres, H., Daley, G. Q., & Tang, D. G. (2009). Functional evidence that the self-renewal gene NANOG regulates human tumor development. Stem Cells, 27, 993–1005.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jo, A. Y., Kim, M. Y., Lee, H. S., Rhee, Y. H., Lee, J. E., Baek, K. H., Park, C. H., Koh, H. C., Shin, I., Lee, Y. S., & Lee, S. H. (2009). Generation of dopamine neurons with improved cell survival and phenotype maintenance using a degradation-resistant nurr1 mutant. Stem Cells, 27, 2238–2246.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kaddis, F. G., Clarkson, E. D., Bell, K. P., Choi, P. K., & Freed, C. R. (2000). Co-grafts of muscle cells and mesencephalic tissue into hemiparkinsonian rats: Behavioral and histochemical effects. Brain Research Bulletin, 51, 203–211.

    CAS  PubMed  Google Scholar 

  • Kaji, K., Norrby, K., Paca, A., Mileikovsky, M., Mohseni, P., & Woltjen, K. (2009). Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature, 458, 771–775.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kakishita, K., Elwan, M. A., Nakao, N., Itakura, T., & Sakuragawa, N. (2000). Human amniotic epithelial cells produce dopamine and survive after implantation into the striatum of a rat model of Parkinson’s disease: A potential source of donor for transplantation therapy. Experimental Neurology, 165, 27–34.

    CAS  PubMed  Google Scholar 

  • Kaminski Schierle, G. S., Hansson, O., & Brundin, P. (1999). Flunarizine improves the survival of grafted dopaminergic neurons. Neuroscience, 94, 17–20.

    CAS  PubMed  Google Scholar 

  • Kashyap, V., Rezende, N. C., Scotland, K. B., Shaffer, S. M., Persson, J. L., Gudas, L. J., & Mongan, N. P. (2009). Regulation of stem cell pluripotency and differentiation involves a mutual regulatory circuit of the NANOG, OCT4, and SOX2 pluripotency transcription factors with polycomb repressive complexes and stem cell microRNAs. Stem Cells and Development, 18, 1093–1108.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kerr, C. L., Gearhart, J. D., Elliott, A. M., & Donovan, P. J. (2006). Embryonic germ cells: When germ cells become stem cells. Seminars in Reproductive Medicine, 24, 304–313.

    CAS  PubMed  Google Scholar 

  • Kestendjieva, S., Kyurkchiev, D., Tsvetkova, G., Mehandjiev, T., Dimitrov, A., Nikolov, A., & Kyurkchiev, S. (2008). Characterization of mesenchymal stem cells isolated from the human umbilical cord. Cell Biology International, 32, 724–732.

    CAS  PubMed  Google Scholar 

  • Kim, H. J. (2011). Stem cell potential in Parkinson’s disease and molecular factors for the generation of dopamine neurons. Biochimica et Biophysica Acta, 1812, 1–11.

    CAS  PubMed  Google Scholar 

  • Kim, J. H., Auerbach, J. M., Rodríguez-Gómez, J. A., Velasco, I., Gavin, D., Lumelsky, N., Lee, S. H., Nguyen, J., Sánchez-Pernaute, R., Bankiewicz, K., & McKay, R. (2002). Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease. Nature, 418, 50–56.

    CAS  PubMed  Google Scholar 

  • Kim, J. B., Zaehres, H., Wu, G., Gentile, L., Ko, K., Sebastiano, V., Araúzo-Bravo, M. J., Ruau, D., Han, D. W., Zenke, M., & Schöler, H. R. (2008). Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature, 454, 646–650.

    CAS  PubMed  Google Scholar 

  • Kim, J. B., Greber, B., Araúzo-Bravo, M. J., Meyer, J., Park, K. I., Zaehres, H., & Schöler, H. R. (2009a). Direct reprogramming of human neural stem cells by OCT4. Nature, 461, 649–653.

    CAS  PubMed  Google Scholar 

  • Kim, J. B., Sebastiano, V., Wu, G., Araúzo-Bravo, M. J., Sasse, P., Gentile, L., Ko, K., Ruau, D., Ehrich, M., van den Boom, D., Meyer, J., Hübner, K., Bernemann, C., Ortmeier, C., Zenke, M., Fleischmann, B. K., Zaehres, H., & Schöler, H. R. (2009b). Oct4-induced pluripotency in adult neural stem cells. Cell, 136, 411–419.

    CAS  PubMed  Google Scholar 

  • Kim, J. B., Zaehres, H., Araúzo-Bravo, M. J., & Schöler, H. R. (2009c). Generation of induced pluripotent stem cells from neural stem cells. Nature Protocols, 4, 1464–1470.

    CAS  PubMed  Google Scholar 

  • Ko, J. Y., Lee, H. S., Park, C. H., Koh, H. C., Lee, Y. S., & Lee, S. H. (2009). Conditions for tumor-free and dopamine neuron-enriched grafts after transplanting human ES cell-derived neural precursor cells. Molecular Therapy, 17, 1761–1770.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Komitova, M., & Eriksson, P. S. (2004). Sox-2 is expressed by neural progenitors and astroglia in the adult rat brain. Neuroscience Letters, 369, 24–27.

    CAS  PubMed  Google Scholar 

  • Kompoliti, K., Chu, Y., Shannon, K. M., & Kordower, J. H. (2007). Neuropathological study 16 years after autologous adrenal medullary transplantation in a Parkinson’s disease patient. Movement Disorders, 22, 1630–1633.

    PubMed  Google Scholar 

  • Kriks, S., Shim, J. W., Piao, J., Ganat, Y. M., Wakeman, D. R., Xie, Z., Carrillo-Reid, L., Auyeung, G., Antonacci, C., Buch, A., Yang, L., Beal, M. F., Surmeier, D. J., Kordower, J. H., Tabar, V., & Studer, L. (2011). Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature, 480, 547–551.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kubo, A., Yoshida, T., Kobayashi, N., Yokoyama, T., Mimura, T., Nishiguchi, T., Higashida, T., Yamamoto, I., & Kanno, H. (2009). Efficient generation of dopamine neuron-like cells from skin-derived precursors with a synthetic peptide derived from von Hippel- Lindau protein. Stem Cells and Development, 18, 1523–1532.

    CAS  PubMed  Google Scholar 

  • Kupsch, A., Oertel, W. H., Earl, C. D., & Sautter, J. (1995). Neuronal transplantation and neurotrophic factors in the treatment of Parkinson’s disease–update February 1995. Journal of Neural Transmission. Supplementum, 46, 193–207.

    CAS  PubMed  Google Scholar 

  • Kuroda, T., Tada, M., Kubota, H., Kimura, H., Hatano, S. Y., Suemori, H., Nakatsuji, N., & Tada, T. (2005). Octamer and Sox elements are required for transcriptional cis regulation of Nanog gene expression. Molecular and Cellular Biology, 25, 2475–2485.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kuroda, T., Yasuda, S., & Sato, Y. (2013). Tumorigenicity studies for human pluripotent stem cell-derived products. Biological and Pharmaceutical Bulletin, 36, 189–192.

    CAS  PubMed  Google Scholar 

  • Larsson, L. C., & Widner, H. (2000). Neural tissue xenografting. Scandinavian Journal of Immunology, 52, 249–256.

    CAS  PubMed  Google Scholar 

  • Lengerke, C., Fehm, T., Kurth, R., Neubauer, H., Scheble, V., Müller, F., Schneider, F., Petersen, K., Wallwiener, D., Kanz, L., Fend, F., Perner, S., Bareiss, P. M., & Staebler, A. (2011). Expression of the embryonic stem cell marker SOX2 in early-stage breast carcinoma. BMC Cancer, 11, 42.

    PubMed Central  PubMed  Google Scholar 

  • Lengner, C. J., Camargo, F. D., Hochedlinger, K., Welstead, G. G., Zaidi, S., Gokhale, S., Scholer, H. R., Tomilin, A., & Jaenisch, R. (2007). Oct4 expression is not required for mouse somatic stem cell self-renewal. Cell Stem Cell, 1, 403–415.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lévêque, X., Nerrière-Daguin, V., Neveu, I., & Naveilhan, P. (2012). Pig neural cells derived from foetal mesencephalon as cell source for intracerebral xenotransplantation. Methods in Molecular Biology, 885, 233–243.

    PubMed  Google Scholar 

  • Li, J., Pan, G., Cui, K., Liu, Y., Xu, S., & Pei, D. A. (2007). A dominant-negative form of mouse SOX2 induces trophectoderm differentiation and progressive polyploidy in mouse embryonic stem cells. Journal of Biological Chemistry, 282, 19481–19492.

    CAS  PubMed  Google Scholar 

  • Li, M., Zhang, S. Z., Guo, Y. W., Cai, Y. Q., Yan, Z. J., Zou, Z., Jiang, X. D., Ke, Y. Q., He, X. Y., Jin, Z. L., Lu, G. H., & Su, D. Q. (2010). Human umbilical vein-derived dopaminergic-like cell transplantation with nerve growth factor ameliorates motor dysfunction in a rat model of Parkinson’s disease. Neurochemical Research, 35, 1522–1529.

    CAS  PubMed  Google Scholar 

  • Li, Y., Zhang, Q., Yin, X., Yang, W., Du, Y., Hou, P., Ge, J., Liu, C., Zhang, W., Zhang, X., Wu, Y., Li, H., Liu, K., Wu, C., Song, Z., Zhao, Y., Shi, Y., & Deng, H. (2011). Generation of iPSCs from mouse fibroblasts with a single gene, Oct4, and small molecules. Cell Research, 21, 196–204.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Li, X., Li, H., Bi, J., Chen, Y., Jain, S., & Zhao, Y. (2012). Human cord blood-derived multipotent stem cells (CB-SCs) treated with all-trans-retinoic acid (ATRA) give rise to dopamine neurons. Biochemical and Biophysical Research Communications, 419, 110–116.

    CAS  PubMed  Google Scholar 

  • Liard, O., Segura, S., Pascual, A., Gaudreau, P., Fusai, T., & Moyse, E. (2009). In vitro isolation of neural precursor cells from the adult pig subventricular zone. Journal of Neuroscience Methods, 182, 172–179.

    PubMed  Google Scholar 

  • Lindvall, O., Sawle, G., Widner, H., Rothwell, J. C., Björklund, A., Brooks, D., Brundin, P., Frackowiak, R., Marsden, C. D., & Odin, P. (1994). Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson’s disease. Annals of Neurology, 35, 172–180.

    CAS  PubMed  Google Scholar 

  • Liu, X., Li, F., Stubblefield, E. A., Blanchard, B., Richards, T. L., Larson, G. A., He, Y., Huang, Q., Tan, A. C., Zhang, D., Benke, T. A., Sladek, J. R., Zahniser, N. R., & Li, C. Y. (2012). Direct reprogramming of human fibroblasts into dopaminergic neuron-like cells. Cell Research, 22, 321–332.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Loh, Y. H., Wu, Q., Chew, J. L., Vega, V. B., Zhang, W., Chen, X., Bourque, G., George, J., Leong, B., Liu, J., Wong, K. Y., Sung, K. W., Lee, C. W., Zhao, X. D., Chiu, K. P., Lipovich, L., Kuznetsov, V. A., Robson, P., Stanton, L. W., Wei, C. L., Ruan, Y., Lim, B., & Ng, H. H. (2006). The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nature Genetics, 38, 431–440.

    CAS  PubMed  Google Scholar 

  • López-Lozano, J. J., Mata, M., & Bravo, G. (2000). Neural transplants en Parkinson disease: Clinical results of 10 years of experience. Group of Neural Transplants of the CPH. Revista de Neurologia, 30, 1077–1083.

    PubMed  Google Scholar 

  • Lunn, J. S., Sakowski, S. A., Hur, J., & Feldman, E. L. (2011). Stem cell technology for neurodegenerative diseases. Annals of Neurology, 70, 353–361.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Luquin, M. R., Montoro, R. J., Guillén, J., Saldise, L., Insausti, R., Del Río, J., & López-Barneo, J. (1999). Recovery of chronic parkinsonian monkeys by autotransplants of carotid body cell aggregates into putamen. Neuron, 22, 743–750.

    CAS  PubMed  Google Scholar 

  • MacKenzie, T. C., & Flake, A. W. (2002). Human mesenchymal stem cells: Insights from a surrogate in vivo assay system. Cells, Tissues, Organs, 171, 90–95.

    PubMed  Google Scholar 

  • Madrazo, I., Franco-Bourland, R., Ostrosky-Solis, F., Aguilera, M., Cuevas, C., Zamorano, C., Morelos, A., Magallon, E., & Guizar-Sahagun, G. (1990). Fetal homotransplants (ventral mesencephalon and adrenal tissue) to the striatum of parkinsonian subjects. Archives of Neurology, 47, 1281–1285.

    CAS  PubMed  Google Scholar 

  • Major, T., Menon, J., Auyeung, G., Soldner, F., Hockemeyer, D., Jaenisch, R., & Tabar, V. (2011). Transgene excision has no impact on in vivo integration of human iPS derived neural precursors. PLoS One, 6, e24687.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Marsden, C. D. (1994). Problems with long-term levodopa therapy for Parkinson’s disease. Clinical Neuropharmacology, 17(Suppl 2), 32–44.

    Google Scholar 

  • Martin, G. (1981). Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proceedings of the National Academy of Sciences of the United States of America, 78, 7634–7638.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Masui, S., Nakatake, Y., Toyooka, Y., Shimosato, D., Yagi, R., Takahashi, K., Okochi, H., Okuda, A., Matoba, R., Sharov, A. A., Ko, M. S., & Niwa, H. (2007). Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nature Cell Biology, 9, 625–635.

    CAS  PubMed  Google Scholar 

  • Mathew, J. M., Garcia-Morales, R. O., Carreno, M., Jin, Y., Fuller, L., Blomberg, B., Cirocco, R., Burke, G. W., Ciancio, G., Ricordi, C., Esquenazi, V., Tzakis, A. G., & Miller, J. (2003). Immune responses and their regulation by donor bone marrow cells in clinical organ transplantation. Transplant Immunology, 11, 307–321.

    CAS  PubMed  Google Scholar 

  • Mendez, I., Sadi, D., & Hong, M. (1996). Reconstruction of the nigrostriatal pathway by simultaneous intrastriatal and intranigral dopaminergic transplants. Journal of Neuroscience, 16, 7216–7227.

    CAS  PubMed  Google Scholar 

  • Mendez, I., Sanchez-Pernaute, R., Cooper, O., Viñuela, A., Ferrari, D., Björklund, L., Dagher, A., & Isacson, O. (2005). Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson’s disease. Brain, 128, 1498–1510.

    PubMed Central  PubMed  Google Scholar 

  • Miller, R. A., & Ruddle, F. H. (1976). Pluripotent teratocarcinoma-thymus somatic cell hybrids. Cell, 9, 45–55.

    CAS  PubMed  Google Scholar 

  • Minguez-Castellanos, A., & Escamilla-Sevilla, F. (2005). Pallidal vs subthalamic deep brain stimulation for Parkinson disease: Winner and loser or a sharing of honors? Archives of Neurology, 62, 1642–1643.

    PubMed  Google Scholar 

  • Mínguez-Castellanos, A., Escamilla-Sevilla, F., Hotton, G. R., Toledo-Aral, J. J., Ortega-Moreno, A., Méndez-Ferrer, S., Martín-Linares, J. M., Katati, M. J., Mir, P., Villadiego, J., Meersmans, M., Pérez-García, M., Brooks, D. J., Arjona, V., & López-Barneo, J. (2007). Carotid body autotransplantation in Parkinson disease: A clinical and positron emission tomography study. Journal of Neurology, Neurosurgery, and Psychiatry, 7, 825–831.

    Google Scholar 

  • Mitsui, K., Tokuzawa, Y., Itoh, H., Segawa, K., Murakami, M., Takahashi, K., Maruyama, M., Maeda, M., & Yamanaka, S. (2003). The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell, 113, 631–642.

    CAS  PubMed  Google Scholar 

  • Miyagi, S., Masui, S., Niwa, H., Saito, T., Shimazaki, T., Okano, H., Nishimoto, M., Muramatsu, M., Iwama, A., & Okuda, A. (2008). Consequence of the loss of Sox2 in the developing brain of the mouse. FEBS Letters, 582, 2811–2815.

    CAS  PubMed  Google Scholar 

  • Molenaar, G. J., Hogenesch, R. I., Sprengers, M. E., & Staal, M. J. (1997). Ontogenesis of embryonic porcine ventral mesencephalon in the perspective of its potential use as a xenograft in Parkinson’s disease. The Journal of Comparative Neurology, 382, 19–28.

    CAS  PubMed  Google Scholar 

  • Momčilović, O., Montoya-Sack, J., & Zeng, X. (2012). Dopaminergic differentiation using pluripotent stem cells. Journal of Cellular Biochemistry, 113, 3610–3619.

    PubMed  Google Scholar 

  • Morigi, M., & Benigni, A. (2012). Mesenchymal stem cells and kidney repair. Nephrol Dial Transplant, 28, 788–793.

    Google Scholar 

  • Morizane, A., Darsalia, V., Guloglu, M. O., Hjalt, T., Carta, M., Li, J. Y., & Brundin, P. A. (2010). Simple method for large-scale generation of dopamine neurons from human embryonic stem cells. Journal of Neuroscience Research, 88, 3467–3478.

    CAS  PubMed  Google Scholar 

  • Mundra, V., Gerling, I. C., & Mahato, R. I. (2013). Mesenchymal stem cell-based therapy. Molecular Pharmaceutics, 10, 77–89.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nadig, R. R. J. (2009). Stem cell therapy – Hype or hope? A review. Journal of Conservative Dentistry: JCD, 12, 131–138.

    PubMed Central  PubMed  Google Scholar 

  • Nakagawa, M., Koyanagi, M., Tanabe, K., Takahashi, K., Ichisaka, T., Aoi, T., Okita, K., Mochiduki, Y., Takizawa, N., & Yamanaka, S. (2008). Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotechnology, 26, 101–106.

    CAS  PubMed  Google Scholar 

  • Nakagawa, E., Zhang, L., Kim, E. J., Shin, J. O., Cho, S. W., Ohshima, H., & Jung, H. S. (2012). The novel function of Oct3/4 in mouse tooth development. Histochemistry and Cell Biology, 137, 367–376.

    CAS  PubMed  Google Scholar 

  • Narayanan, G., Poonepalli, A., Chen, J., Sankaran, S., Hariharan, S., Yu, Y. H., Robson, P., Yang, H., & Ahmed, S. (2012). Single-cell mRNA profiling identifies progenitor subclasses in neurospheres. Stem Cells and Development, 21, 3351–3362.

    CAS  PubMed  Google Scholar 

  • Nesti, C., Pardini, C., Barachini, S., D’Alessandro, D., Siciliano, G., Murri, L., Petrini, M., & Vaglini, F. (2011). Human dental pulp stem cells protect mouse dopaminergic neurons against MPP+ or rotenone. Brain Research, 1367, 94–102.

    CAS  PubMed  Google Scholar 

  • Nissim-Eliraz, E., Zisman, S., Schatz, O., & Ben-Arie, N. (2012). Nato3 integrates with the Shh-Foxa2 transcriptional network regulating the differentiation of midbrain dopaminergic neurons. Journal of Molecular Neuroscience, 21. doi: 10.1007/s12031-012-9939-6.

    Google Scholar 

  • Niwa, H. (2007). How is pluripotency determined and maintained? Development, 134, 635–646.

    CAS  PubMed  Google Scholar 

  • O’Sullivan, S. S., Williams, D. R., Gallagher, D. A., Massey, L. A., Silveira-Moriyama, L., & Lees, A. J. (2008). Nonmotor symptoms as presenting complaints in Parkinson’s disease: A clinicopathological study. Movement Disorders, 23, 101–106.

    PubMed  Google Scholar 

  • Obeso, J. A., Rodriguez-Oroz, M. C., Goetz, C. G., Marin, C., Kordower, J. H., Rodriguez, M., Hirsch, E. C., Farrer, M., Schapira, A. H., & Halliday, G. (2010). Missing pieces in the Parkinson’s disease puzzle. Nature Medicine, 16, 653–661.

    CAS  PubMed  Google Scholar 

  • Odekerken, V. J., van Laar, T., Staal, M. J., Mosch, A., Hoffmann, C. F., Nijssen, P. C., Beute, G. N., van Vugt, J. P., Lenders, M. W., Contarino, M. F., Mink, M. S., Bour, L. J., van den Munckhof, P., Schmand, B. A., de Haan, R. J., Schuurman, P. R., & de Bie, R. M. (2013). Subthalamic nucleus versus globus pallidus bilateral deep brain stimulation for advanced Parkinson’s disease (NSTAPS study): A randomised controlled trial. Lancet Neurology, 12, 37–44.

    PubMed  Google Scholar 

  • Okabe, S., Forsberg-Nilsson, K., Spiro, A. C., Segal, M., & McKay, R. D. (1996). Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro. Mechanisms of Development, 59, 89–102.

    CAS  PubMed  Google Scholar 

  • Okita, K., Ichisaka, T., & Yamanaka, S. (2007). Generation of germline-competent induced pluripotent stem cells. Nature, 448, 313–317.

    CAS  PubMed  Google Scholar 

  • Okita, K., Nakagawa, M., Hyenjong, H., Ichisaka, T., & Yamanaka, S. (2008). Generation of mouse induced pluripotent stem cells without viral vectors. Science, 322, 949–953.

    CAS  PubMed  Google Scholar 

  • Okita, K., Hong, H., Takahashi, K., & Yamanaka, S. (2010). Generation of mouse-induced pluripotent stem cells with plasmid vectors. Nature Protocols, 5, 418–428.

    CAS  PubMed  Google Scholar 

  • Okumura-Nakanishi, S., Saito, M., Niwa, H., & Ishikawa, F. (2005). Oct-3/4 and Sox2 regulate Oct-3/4 gene in embryonic stem cells. Journal of Biological Chemistry, 280, 5307–5317.

    CAS  PubMed  Google Scholar 

  • Olanow, C. W. (2004). The scientific basis for the current treatment of Parkinson’s disease. Annual Review of Medicine, 55, 41–60.

    CAS  PubMed  Google Scholar 

  • Olanow, C. W., Goetz, C. G., Kordower, J. H., Stoessl, A. J., Sossi, V., Brin, M. F., Shannon, K. M., Nauert, G. M., Perl, D. P., Godbold, J., & Freeman, T. B. (2003). A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Annals of Neurology, 54, 403–414.

    PubMed  Google Scholar 

  • Palmieri, S. L., Peter, W., Hess, H., & Schöler, H. R. (1994). Oct-4 transcription factor is differentially expressed in the mouse embryo during establishment of the first two extraembryonic cell lineages involved in implantation. Developmental Biology, 166, 259–267.

    CAS  PubMed  Google Scholar 

  • Pan, G. J., & Pei, D. Q. (2003). Identification of two distinct transactivation domains in the pluripotency sustaining factor nanog. Cell Research, 13, 499–502.

    CAS  PubMed  Google Scholar 

  • Pan, G., & Thomson, J. A. (2007). Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Research, 17, 42–49.

    CAS  PubMed  Google Scholar 

  • Pang, Z. P., Yang, N., Vierbuchen, T., Ostermeier, A., Fuentes, D. R., Yang, T. Q., Citri, A., Sebastiano, V., Marro, S., Südhof, T. C., & Wernig, M. (2011). Induction of human neuronal cells by defined transcription factors. Nature, 476, 220–223.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pardal, R., & López-Barneo, J. (2012). Neural stem cells and transplantation studies in Parkinson’s disease. Advances in Experimental Medicine and Biology, 741, 206–216.

    CAS  PubMed  Google Scholar 

  • Pardal, R., Ortega-Sáenz, P., Durán, R., & López-Barneo, J. (2007). Glia-like stem cells sustain physiologic neurogenesis in the adult mammalian carotid body. Cell, 131, 364–377.

    CAS  PubMed  Google Scholar 

  • Parish, C. L., Castelo-Branco, G., Rawal, N., Tonnesen, J., Sorensen, A. T., Salto, C., Kokaia, M., Lindvall, O., & Arenas, E. (2008). Wnt5a-treated midbrain neural stem cells improve dopamine cell replacement therapy in parkinsonian mice. The Journal of Clinical Investigation, 118, 149–160.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Park, S., Lee, K. S., Lee, Y. J., Shin, H. A., Cho, H. Y., Wang, K. C., Kim, Y. S., Lee, H. T., Chung, K. S., Kim, E. Y., & Lim, J. (2004). Generation of dopaminergic neurons in vitro from human embryonic stem cells treated with neurotrophic factors. Neuroscience Letters, 359, 99–103.

    CAS  PubMed  Google Scholar 

  • Park, H. J., Lee, P. H., Bang, O. Y., Lee, G., & Ahn, Y. H. (2008). Mesenchymal stem cells therapy exerts neuroprotection in a progressive animal model of Parkinson’s disease. Journal of Neurochemistry, 107, 141–151.

    CAS  PubMed  Google Scholar 

  • Patel, M., & Yang, S. (2010). Advances in reprogramming somatic cells to induced pluripotent stem cells. Stem Cell Reviews, 6, 367–380.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pawitan, J. A. (2011). Prospect of cell therapy for Parkinson’s disease. Anatomy & Cell Biology, 44, 256–264.

    Google Scholar 

  • Perl, L., Weissler, A., Mekori, Y. A., & Mor, A. (2010). Cellular therapy in 2010: Focus on autoimmune and cardiac diseases. The Israel Medical Association Journal, 12, 110–115.

    PubMed  Google Scholar 

  • Perlow, M. J., Freed, W. J., Hoffer, B. J., Seiger, A., Olson, L., & Wyatt, R. J. (1979). Brain grafts reduce motor abnormalities produced by destruction of nigrostriatal dopamine system. Science, 1204, 643–647.

    Google Scholar 

  • Perrett, R. M., Turnpenny, L., Eckert, J. J., O’Shea, M., Sonne, S. B., Cameron, I. T., Wilson, D. I., Rajpert-De Meyts, E., & Hanley, N. A. (2008). The early human germ cell lineage does not express SOX2 during in vivo development or upon in vitro culture. Biology of Reproduction, 78, 852–858.

    CAS  PubMed  Google Scholar 

  • Perrier, A. L., Tabar, V., Barberi, T., Rubio, M. E., Bruses, J., Topf, N., Harrison, N. L., & Studer, L. (2004). Derivation of midbrain dopamine neurons from human embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America, 101, 12543–12548.

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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, 3311–3316.

    CAS  PubMed  Google Scholar 

  • Piccini, P., Brooks, D. J., Björklund, A., Gunn, R. N., Grasby, P. M., Rimoldi, O., Brundin, P., Hagell, P., Rehncrona, S., Widner, H., & Lindvall, O. (1999). Dopamine release from nigral transplants visualized in vivo in a Parkinson’s patient. Nature Neuroscience, 2, 1137–1140.

    CAS  PubMed  Google Scholar 

  • Politis, M., & Lindvall, O. (2012). Clinical application of stem cell therapy in Parkinson’s disease. BMC Medicine, 10, 1.

    PubMed Central  PubMed  Google Scholar 

  • Porzionato, A., Macchi, V., Parenti, A., & De Caro, R. (2008). Trophic factors in the carotid body. International Review of Cell and Molecular Biology, 269, 1–58.

    CAS  PubMed  Google Scholar 

  • Prakash, N., & Wurst, W. (2007). A Wnt signal regulates stem cell fate and differentiation in vivo. Neurodegenerative Diseases, 4, 333–338.

    CAS  PubMed  Google Scholar 

  • Puschban, Z., Stefanova, N., Petersén, A., Winkler, C., Brundin, P., Poewe, W., & Wenning, G. K. (2005). Evidence for dopaminergic re-innervation by embryonic allografts in an optimized rat model of the Parkinsonian variant of multiple system atrophy. Brain Research Bulletin, 68, 54–58.

    CAS  PubMed  Google Scholar 

  • Ramos-Moreno, T., Castillo, C. G., & Martínez-Serrano, A. (2012). Long term behavioral effects of functional dopaminergic neurons generated from human neural stem cells in the rat 6-OH-DA Parkinson’s disease model. Effects of the forced expression of BCL-X(L). Behavioural Brain Research, 232, 225–232.

    CAS  PubMed  Google Scholar 

  • Reimann, V., Creutzig, U., & Kögler, G. (2009). Stem cells derived from cord blood in transplantation and regenerative medicine. Deutsches Ärzteblatt International, 106, 831–836.

    PubMed Central  PubMed  Google Scholar 

  • Rhee, Y. H., Ko, J. Y., Chang, M. Y., Yi, S. H., Kim, D., Kim, C. H., Shim, J. W., Jo, A. Y., Kim, B. W., Lee, H., Lee, S. H., Suh, W., Park, C. H., Koh, H. C., Lee, Y. S., Lanza, R., Kim, K. S., & Lee, S. H. (2011). Protein-based human iPS cells efficiently generate functional dopamine neurons and can treat a rat model of Parkinson disease. The Journal of Clinical Investigation, 121, 2326–2335.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Riaz, S. S., Jauniaux, E., Stern, G. M., & Bradford, H. F. (2002). The controlled conversion of human neural progenitor cells derived from foetal ventral mesencephalon into dopaminergic neurons in vitro. Brain Research. Developmental Brain Research, 136, 27–34.

    CAS  PubMed  Google Scholar 

  • Rizzino, A. (2009). Sox2 and Oct-3/4: A versatile pair of master regulators that orchestrate the self-renewal and pluripotency of embryonic stem cells. Wiley Interdisciplinary Reviews. Systems Biology and Medicine, 1, 228–236.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Robinton, D. A., & Daley, G. Q. (2012). The promise of induced pluripotent stem cells in research and therapy. Nature, 481, 295–305.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Rodda, D. J., Chew, J. L., Lim, L. H., Loh, Y. H., Wang, B., Ng, H. H., & Robson, P. (2005). Transcriptional regulation of nanog by OCT4 and SOX2. Journal of Biological Chemistry, 280, 24731–24737.

    CAS  PubMed  Google Scholar 

  • Rodriguez-Pallares, J., Joglar, B., Muñoz-Manchado, A. B., Villadiego, J., Toledo-Aral, J. J., & Labandeira-Garcia, J. L. (2012). Cografting of carotid body cells improves the long-term survival, fiber outgrowth and functional effects of grafted dopaminergic neurons. Regenerative Medicine, 7, 309–322.

    CAS  PubMed  Google Scholar 

  • Sadan, O., Bahat-Stromza, M., Barhum, Y., Levy, Y. S., Pisnevsky, A., Peretz, H., Ilan, A. B., Bulvik, S., Shemesh, N., Krepel, D., Cohen, Y., Melamed, E., & Offen, D. (2009). Protective effects of neurotrophic factor-secreting cells in a 6-OHDA rat model of Parkinson disease. Stem Cells and Development, 18, 1179–1190.

    CAS  PubMed  Google Scholar 

  • Sánchez-Danés, A., Consiglio, A., Richaud, Y., Rodríguez-Pizà, I., Dehay, B., Edel, M., Bové, J., Memo, M., Vila, M., Raya, A., & Izpisua-Belmonte, J. C. (2012a). Efficient generation of A9 midbrain dopaminergic neurons by lentiviral delivery of LMX1A in human embryonic stem cells and induced pluripotent stem cells. Human Gene Therapy, 23, 56–69.

    PubMed Central  PubMed  Google Scholar 

  • Sánchez-Danés, A., Richaud-Patin, Y., Carballo-Carbajal, I., Jiménez-Delgado, S., Caig, C., Mora, S., Di Guglielmo, C., Ezquerra, M., Patel, B., Giralt, A., Canals, J. M., Memo, M., Alberch, J., López-Barneo, J., Vila, M., Cuervo, A. M., Tolosa, E., Consiglio, A., & Raya, A. (2012b). Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson’s disease. EMBO Molecular Medicine, 4, 380–395.

    PubMed Central  PubMed  Google Scholar 

  • Schöler, H. R., Hatzopoulos, A. K., Balling, R., Suzuki, N., & Gruss, P. (1989). A family of octamer-specific proteins present during mouse embryogenesis: Evidence for germline-specific expression of an Oct factor. EMBO Journal, 8, 2543–2550.

    PubMed Central  PubMed  Google Scholar 

  • Schumacher, J. M., Ellias, S. A., Palmer, E. P., Kott, H. S., Dinsmore, J., Dempsey, P. K., Fischman, A. J., Thomas, C., Feldman, R. G., Kassissieh, S., Raineri, R., Manhart, C., Penney, D., Fink, J. S., & Isacson, O. (2000). Transplantation of embryonic porcine mesencephalic tissue in patients with PD. Neurology, 54, 1042–1050.

    CAS  PubMed  Google Scholar 

  • Schwartz, C. M., Tavakoli, T., Jamias, C., Park, S. S., Maudsley, S., Martin, B., Phillips, T. M., Yao, P. J., Itoh, K., Ma, W., Rao, M. S., Arenas, E., & Mattson, M. P. (2012). Stromal factors SDF1α, sFRP1, and VEGFD induce dopaminergic neuron differentiation of human pluripotent stem cells. Journal of Neuroscience Research, 90, 1367–1381.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sheik Mohamed, J., Gaughwin, P. M., Lim, B., Robson, P., & Lipovich, L. (2010). Conserved long noncoding RNAs transcriptionally regulated by Oct4 and Nanog modulate pluripotency in mouse embryonic stem cells. RNA, 16, 324–337.

    PubMed Central  PubMed  Google Scholar 

  • Sheng, J. G., McShane, L. M., Plunkett, R. J., Cummins, A. C., Oldfield, E. H., Kopin, I. J., & Palmatier, M. A. (1993). Dopaminergic neuronal sprouting and behavioral recovery in hemi-parkinsonian rats after implantation of amnion cells. Experimental Neurology, 123, 192–203.

    CAS  PubMed  Google Scholar 

  • Shetty, P., Thakur, A. M., & Viswanathan, C. (2013). Dopaminergic cells, derived from a high efficiency differentiation protocol from umbilical cord derived mesenchymal stem cells, alleviate symptoms in a Parkinson’s disease rodent model. Cell Biology International, 37, 167–180.

    CAS  PubMed  Google Scholar 

  • Shi, W., Wang, H., Pan, G., Geng, Y., Guo, Y., & Pei, D. (2006). Regulation of the pluripotency marker Rex-1 by Nanog and Sox2. Journal of Biological Chemistry, 281, 23319–23325.

    CAS  PubMed  Google Scholar 

  • Shi, Y., Desponts, C., Do, J. T., Hahm, H. S., Schöler, H. R., & Ding, S. (2008). Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell, 3, 568–574.

    CAS  PubMed  Google Scholar 

  • Shim, J. W., Park, C. H., Bae, Y. C., Bae, J. Y., Chung, S., Chang, M. Y., Koh, H. C., Lee, H. S., Hwang, S. J., Lee, K. H., Lee, Y. S., Choi, C. Y., & Lee, S. H. (2007). Generation of functional dopamine neurons from neural precursor cells isolated from the subventricular zone and white matter of the adult rat brain using Nurr1 overexpression. Stem Cells, 25, 1252–1262.

    CAS  PubMed  Google Scholar 

  • Silva, J., Barrandon, O., Nichols, J., Kawaguchi, J., Theunissen, T. W., & Smith, A. (2008). Promotion of reprogramming to ground state pluripotency by signal inhibition. PLoS Biology, 6, e253.

    PubMed Central  PubMed  Google Scholar 

  • Sirinathsinghji, D. J., Dunnett, S. B., Northrop, A. J., & Morris, B. J. (1990). Experimental hemiparkinsonism in the rat following chronic unilateral infusion of MPP+ into the nigrostriatal dopamine pathway–III. Reversal by embryonic nigral dopamine grafts. Neuroscience, 37, 757–766.

    CAS  PubMed  Google Scholar 

  • Soldner, F., Hockemeyer, D., Beard, C., Gao, Q., Bell, G. W., Cook, E. G., Hargus, G., Blak, A., Cooper, O., Mitalipova, M., Isacson, O., & Jaenisch, R. (2009). Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell, 136, 964–977.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sommer, A. G., Rozelle, S. S., Sullivan, S., Mills, J. A., Park, S. M., Smith, B. W., Iyer, A. M., French, D. L., Kotton, D. N., Gadue, P., Murphy, G. J., & Mostoslavsky, G. (2012). Generation of human induced pluripotent stem cells from peripheral blood using the STEMCCA lentiviral vector. Journal of Visualized Experiments, 68. doi: 10.3791/4327.

    Google Scholar 

  • Sonntag, K. C., Pruszak, J., Yoshizaki, T., van Arensbergen, J., Sanchez-Pernaute, R., & Isacson, O. (2007). Enhanced yield of neuroepithelial precursors and midbrain-like dopaminergic neurons from human embryonic stem cells using the bone morphogenic protein antagonist noggin. Stem Cells, 25, 411–418.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sortwell, C. E., Collier, T. J., & Sladek, J. R., Jr. (1998). Co-grafted embryonic striatum increases the survival of grafted embryonic dopamine neurons. The Journal of Comparative Neurology, 399, 530–540.

    CAS  PubMed  Google Scholar 

  • Stacpoole, S. R., Bilican, B., Webber, D. J., Luzhynskaya, A., He, X. L., Compston, A., Karadottir, R., Franklin, R. J., & Chandran, S. (2011). Efficient derivation of NPCs, spinal motor neurons and midbrain dopaminergic neurons from hESCs at 3% oxygen. Nature Protocols, 6, 1229–1240.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Stadtfeld, M., & Hochedlinger, K. (2010). Induced pluripotency: History, mechanisms, and applications. Genes & Development, 24, 2239–22363.

    CAS  Google Scholar 

  • Stadtfeld, M., Brennand, K., & Hochedlinger, K. (2008a). Reprogramming of pancreatic beta cells into induced pluripotent stem cells. Current Biology, 18, 890–894.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Stadtfeld, M., Nagaya, M., Utikal, J., Weir, G., & Hochedlinger, K. (2008b). Induced pluripotent stem cells generated without viral integration. Science, 322, 945–949.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Steffenhagen, C., Kraus, S., Dechant, F. X., Kandasamy, M., Lehner, B., Poehler, A. M., Furtner, T., Siebzehnrubl, F. A., Couillard-Despres, S., Strauss, O., Aigner, L., & Rivera, F. J. (2011). Identity, fate and potential of cells grown as neurospheres: Species matters. Stem Cell Reviews, 7, 815–835.

    PubMed  Google Scholar 

  • Stevanovic, M. (2003). Modulation of SOX2 and SOX3 gene expression during differentiation of human neuronal precursor cell line NTERA2. Molecular Biology Reports, 30, 127–132.

    CAS  PubMed  Google Scholar 

  • Storch, A., Schneider, C. B., Wolz, M., Stürwald, Y., Nebe, A., Odin, P., Mahler, A., Fuchs, G., Jost, W. H., Chaudhuri, K. R., Koch, R., Reichmann, H., & Ebersbach, G. (2013). Nonmotor fluctuations in Parkinson disease: Severity and correlation with motor complications. Neurology, 80, 800–809.

    PubMed  Google Scholar 

  • Stover, N. P., & Watts, R. L. (2008). Spheramine for treatment of Parkinson’s disease. Neurotherapeutics, 5, 252–259.

    CAS  PubMed  Google Scholar 

  • Strömberg, I., Bygdeman, M., Goldstein, M., Seiger, A., & Olson, L. (1986). Human fetal substantia nigra grafted to the dopamine-denervated striatum of immunosuppressed rats: Evidence for functional reinnervation. Neuroscience Letters, 71, 271–276.

    PubMed  Google Scholar 

  • Sumer, H., Liu, J., Malaver-Ortega, L. F., Lim, M. L., Khodadadi, K., & Verma, P. J. (2011). NANOG is a key factor for induction of pluripotency in bovine adult fibroblasts. Journal of Animal Science, 89, 2708–2716.

    CAS  PubMed  Google Scholar 

  • Sun, N., Longaker, M. T., & Wu, J. C. (2010). Human iPS cell-based therapy: Considerations before clinical applications. Cell Cycle, 9, 880–885.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Svendsen, C. N., Caldwell, M. A., Shen, J., ter Borg, M. G., Rosser, A. E., Tyers, P., Karmiol, S., & Dunnett, S. B. (1997). Long-term survival of human central nervous system progenitor cells transplanted into a rat model of Parkinson’s disease. Experimental Neurology, 148, 135–146.

    CAS  PubMed  Google Scholar 

  • Tada, M., Takahama, Y., Abe, K., Nakatsuji, N., Tada, T. (2001). Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells. Curr Biol, 11, 1553–1558.

    CAS  PubMed  Google Scholar 

  • Tai, M. H., Chang, C. C., Kiupel, M., Webster, J. D., Olson, L. K., & Trosko, J. E. (2005). Oct4 Expression in adult human stem cells: Evidence in support of the stem cell theory of carcinogenesis. Carcinogenesis, 26, 495–502.

    CAS  PubMed  Google Scholar 

  • Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126, 663–676.

    CAS  PubMed  Google Scholar 

  • 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, 861–872.

    CAS  PubMed  Google Scholar 

  • Tay, Y., Zhang, J., Thomson, A. M., Lim, B., & Rigoutsos, I. (2008). MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature, 455, 1124–1128.

    CAS  PubMed  Google Scholar 

  • Tesar, P. J., Chenoweth, J. G., Brook, F. A., Davies, T. J., Evans, E. P., Mack, D. L., Gardner, R. L., & Mckay, R. D. (2007). New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature, 448, 196–199.

    CAS  PubMed  Google Scholar 

  • Thomson, J., Itskovitz-Eldor, J., Shapiro, S., Waknitz, M., Swiergiel, J., Marshall, V., & Jones, J. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282, 1145–1147.

    CAS  PubMed  Google Scholar 

  • Toledo-Aral, J. J., Méndez-Ferrer, S., Pardal, R., Echevarría, M., & López-Barneo, J. (2003). Trophic restoration of the nigrostriatal dopaminergic pathway in long-term carotid body-grafted parkinsonian rats. Journal of Neuroscience, 23, 141–148.

    CAS  PubMed  Google Scholar 

  • Tomioka, M., Nishimoto, M., Miyagi, S., Katayanagi, T., Fukui, N., Niwa, H., Muramatsu, M., & Okuda, A. (2002). Identification of Sox-2 regulatory region which is under the control of Oct-3/4-Sox-2 complex. Nucleic Acids Research, 30, 3202–3213.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Torres, E. M., Monville, C., Lowenstein, P. R., Castro, M. G., & Dunnett, S. B. (2005). Delivery of sonic hedgehog or glial derived neurotrophic factor to dopamine-rich grafts in a rat model of Parkinson’s disease using adenoviral vectors increased yield of dopamine cells is dependent on embryonic donor age. Brain Research Bulletin, 68, 31–41.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Twelves, D., Perkins, K. S., & Counsell, C. (2003). Systematic review of incidence studies of Parkinson’s disease. Movement Disorders, 18, 19–31.

    PubMed  Google Scholar 

  • Vawda, R., & Fehlings, M. G. (2012). Mesenchymal cells in the treatment of spinal cord injury: Current & future perspectives. Current Stem Cell Research & Therapy, 8, 25–38.

    Google Scholar 

  • Verma, R., Holland, M. K., Temple-Smith, P., & Verma, P. J. (2012). Inducing pluripotency in somatic cells from the snow leopard (Panthera uncia), an endangered felid. Theriogenology, 77, 220–228.

    CAS  PubMed  Google Scholar 

  • Vierbuchen, T., Ostermeier, A., Pang, Z. P., Kokubu, Y., Südhof, T. C., & Wernig, M. (2010). Direct conversion of fibroblasts to functional neurons by defined factors. Nature, 463, 1035–1041.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Volpicelli, F., Consales, C., Caiazzo, M., Colucci-D’Amato, L., Perrone-Capano, C., & di Porzio, U. (2004). Enhancement of dopaminergic differentiation in proliferating midbrain neuroblasts by sonic hedgehog and ascorbic acid. Neural Plasticity, 11, 45–57.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Walker, E., Ohishi, M., Davey, R. E., Zhang, W., Cassar, P. A., Tanaka, T. S., Der, S. D., Morris, Q., Hughes, T. R., Zandstra, P. W., & Stanford, W. L. (2007). Prediction and testing of novel transcriptional networks regulating embryonic stem cell self-renewal and commitment. Cell Stem Cell, 1, 71–86.

    CAS  PubMed  Google Scholar 

  • Wang, X., Lu, Y., Zhang, H., Wang, K., He, Q., Wang, Y., Liu, X., Li, L., & Wang, X. (2004). Distinct efficacy of pre-differentiated versus intact fetal mesencephalon-derived human neural progenitor cells in alleviating rat model of Parkinson’s disease. International Journal of Developmental Neuroscience, 22, 175–183.

    CAS  PubMed  Google Scholar 

  • Wang, J., Rao, S., Chu, J., Shen, X., Levasseur, D. N., Theunissen, T. W., & Orkin, S. H. (2006). A protein interaction network for pluripotency of embryonic stem cells. Nature, 444, 364–368.

    CAS  PubMed  Google Scholar 

  • Wang, J., Levasseur, D. N., & Orkin, S. H. (2008). Requirement of Nanog dimerization for stem cell self-renewal and pluripotency. Proceedings of the National Academy of Sciences of the United States of America, 105, 6326–6331.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wang, J., He, Q., Han, C., Gu, H., Jin, L., Li, Q., Mei, Y., & Wu, M. (2012). p53-facilitated miR-199a-3p regulates somatic cell reprogramming. Stem Cells, 30, 1405–1413.

    CAS  PubMed  Google Scholar 

  • Wang, Y., Yang, J., Li, H., Wang, X., Zhu, L., Fan, M., & Wang, X. (2013). Hypoxia promotes dopaminergic differentiation of mesenchymal stem cells and shows benefits for transplantation in a rat model of Parkinson’s disease. PLoS One, 8, e54296.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Warren, L., Manos, P. D., Ahfeldt, T., Loh, Y. H., Li, H., Lau, F., Ebina, W., Mandal, P. K., Smith, Z. D., Meissner, A., Daley, G. Q., Brack, A. S., Collins, J. J., Cowan, C., Schlaeger, T. M., & Rossi, D. J. (2010). Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell, 7, 618–630.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Watmuff, B., Pouton, C. W., & Haynes, J. M. (2012). In vitro maturation of dopaminergic neurons derived from mouse embryonic stem cells: Implications for transplantation. PLoS One, 7, e31999.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Watt, F. M., & Driskell, R. R. (2010). The therapeutic potential of stem cells. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 365, 155–163.

    PubMed Central  PubMed  Google Scholar 

  • Wenning, G. K., Odin, P., Morrish, P., Rehncrona, S., Widner, H., Brundin, P., Rothwell, J. C., Brown, R., Gustavii, B., Hagell, P., Jahanshahi, M., Sawle, G., Björklund, A., Brooks, D. J., Marsden, C. D., Quinn, N. P., & Lindvall, O. (1997). Short- and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson’s disease. Annals of Neurology, 42, 95–107.

    CAS  PubMed  Google Scholar 

  • Wernig, M., Meissner, A., Foreman, R., Brambrink, T., Ku, M., Hochedlinger, K., Bernstein, B. E., & Jaenisch, R. (2007). In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature, 448, 318–324.

    CAS  PubMed  Google Scholar 

  • Wernig, M., Zhao, J. P., 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. Proceedings of the National Academy of Sciences of the United States of America, 105, 5856–5861.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Whone, A. L., Kemp, K., Sun, M., Wilkins, A., & Scolding, N. J. (2012). Human bone marrow mesenchymal stem cells protect catecholaminergic and serotonergic neuronal perikarya and transporter function from oxidative stress by the secretion of glial-derived neurotrophic factor. Brain Research, 1431, 86–96.

    CAS  PubMed  Google Scholar 

  • Wilkins, A., Kemp, K., Ginty, M., Hares, K., Mallam, E., & Scolding, N. (2009). Human bone marrow-derived mesenchymal stem cells secrete brain-derived neurotrophic factor which promotes neuronal survival in vitro. Stem Cell Research, 3, 63–70.

    CAS  PubMed  Google Scholar 

  • Wilmut, I., Schnieke, A. E., McWhir, J., Kind, A. J., & Campbell, K. H. (1997). Viable offspring derived from fetal and adult mammalian cells. Nature, 385, 810–813.

    CAS  PubMed  Google Scholar 

  • Włodarski, K. H., Włodarski, P., Galus, R., & Mazur, S. (2012). Adipose mesenchymal stem cells. Their characteristics and potential application in tissue repair. Polish Orthopedics & Traumatology, 77, 97–99.

    Google Scholar 

  • Woltjen, K., Michael, I. P., Mohseni, P., Desai, R., Mileikovsky, M., Hämäläinen, R., Cowling, R., Wang, W., Liu, P., Gertsenstein, M., Kaji, K., Sung, H. K., & Nagy, A. (2009). PiggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature, 458, 766–770.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wright Willis, A., Evanoff, B. A., Lian, M., Criswell, S. R., & Racette, B. A. (2010). Geographic and ethnic variation in Parkinson disease: A population-based study of US medicare beneficiaries. Neuroepidemiology, 34, 143–151.

    PubMed Central  PubMed  Google Scholar 

  • Yan, Y., Yang, D., Zarnowska, E. D., Du, Z., Werbel, B., Valliere, C., Pearce, R. A., Thomson, J. A., & Zhang, S. C. (2005). Directed differentiation of dopaminergic neuronal subtypes from human embryonic stem cells. Stem Cells, 23, 781–790.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yang, X. X., Xue, S. R., Dong, W. L., & Kong, Y. (2009). Therapeutic effect of human amniotic epithelial cell transplantation into the lateral ventricle of hemiparkinsonian rats. Chinese Medical Journal, 122, 2449–2454.

    CAS  PubMed  Google Scholar 

  • Yang, X., Hou, J., Han, Z., Wang, Y., Hao, C., Wei, L., & Shi, Y. (2013). One cell, multiple roles: Contribution of mesenchymal stem cells to tumor development in tumor microenvironment. Cell & Bioscience, 3, 5, Epub ahead of print.

    CAS  Google Scholar 

  • Yong, V. W., Guttman, M., Kim, S. U., Calne, D. B., Turnbull, I., Watabe, K., & Tomlinson, R. W. (1989). Transplantation of human sympathetic neurons and adrenal chromaffin cells into parkinsonian monkeys: No reversal of clinical symptoms. Journal of Neurological Sciences, 94, 51–67.

    CAS  Google Scholar 

  • Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., Nie, J., Jonsdottir, G. A., Ruotti, V., Stewart, R., Slukvin, I. I., & Thomson, J. A. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, 318, 1917–1920.

    CAS  PubMed  Google Scholar 

  • Yu, J., Hu, K., Smuga-Otto, K., Tian, S., Stewart, R., Slukvin, I. I., & Thomson, J. A. (2009). Human induced pluripotent stem cells free of vector and transgene sequences. Science, 324, 797–801.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yuan, H., Corbi, N., Basilico, C., & Dailey, L. (1995). Developmental-specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3. Genes & Development, 9, 2635–2645.

    CAS  Google Scholar 

  • Yurek, D. M., & Fletcher-Turner, A. (2004). Comparison of embryonic stem cell-derived dopamine neuron grafts and fetal ventral mesencephalic tissue grafts: Morphology and function. Cell Transplantation, 3, 295–306.

    Google Scholar 

  • Zangrossi, S., Marabese, M., Broggini, M., Giordano, R., D’Erasmo, M., Montelatici, E., Intini, D., Neri, A., Pesce, M., Rebulla, P., & Lazzari, L. (2007). Oct-4 expression in adult human differentiated cells challenges its role as a pure stem cell marker. Stem Cells, 25, 1675–1680.

    CAS  PubMed  Google Scholar 

  • Zeng, X., Cai, J., Chen, J., Luo, Y., You, Z. B., Fotter, E., Wang, Y., Harvey, B., Miura, T., Backman, C., Chen, G. J., Rao, M. S., & Freed, W. J. (2004). Dopaminergic differentiation of human embryonic stem cells. Stem Cells, 22, 925–940.

    CAS  PubMed  Google Scholar 

  • Zhang, X. Q., & Zhang, S. C. (2010). Differentiation of neural precursors and dopaminergic neurons from human embryonic stem cells. Methods in Molecular Biology, 584, 355–366.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhao, C., Deng, W., & Gage, F. H. (2008). Mechanisms and functional implications of adult neurogenesis. Cell, 132, 645–660.

    CAS  PubMed  Google Scholar 

  • Zhou, W., & Freed, C. R. (2009). Adenoviral gene delivery can reprogram human fibroblasts to induced pluripotent stem cells. Stem Cells, 27, 2667–2674.

    CAS  PubMed  Google Scholar 

  • Zhou, H., Wu, S., Joo, J. Y., Zhu, S., Han, D. W., Lin, T., Trauger, S., Bien, G., Yao, S., Zhu, Y., Siuzdak, G., Schöler, H. R., Duan, L., & Ding, S. (2009). Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell, 4, 381–384.

    CAS  PubMed  Google Scholar 

  • Zhu, Q., Ma, J., Yu, L., & Yuan, C. (2009). Grafted neural stem cells migrate to substantia nigra and improve behavior in Parkinsonian rats. Neuroscience Letters, 462, 213–218.

    CAS  PubMed  Google Scholar 

  • Zou, Z., Jiang, X., Zhang, W., Zhou, Y., Ke, Y., Zhang, S., & Xu, R. (2010). Efficacy of Tyrosine Hydroxylase gene modified neural stem cells derived from bone marrow on Parkinson’s disease a rat model study. Brain Research, 1346, 279–286.

    CAS  PubMed  Google Scholar 

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Acknowledgments

Supported by FONDECYT 1120337, 1100165.

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Authors and Affiliations

  1. Program of Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile

    Irmgard Paris, Ulises Ahumada-Castro & Juan Segura-Aguilar

  2. Department Basic Sciences, Santo Tomas University, Viña del Mar, Chile

    Irmgard Paris

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  1. Irmgard Paris
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  2. Ulises Ahumada-Castro
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  3. Juan Segura-Aguilar
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Correspondence to Irmgard Paris .

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Editors and Affiliations

  1. Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee, USA

    Richard M. Kostrzewa

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Paris, I., Ahumada-Castro, U., Segura-Aguilar, J. (2014). Advances in Stem Cell Research for Parkinson Disease. In: Kostrzewa, R. (eds) Handbook of Neurotoxicity. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5836-4_177

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