Translation of stem cell therapy for neurological diseases

      “Regenerative medicine” hopefully will provide novel therapies for diseases that remain without effective therapy. This development is also true for most neurodegenerative disorders including Alzheimer’s disease, Huntington’s disease, or Parkinson’s disease. Transplantation of new neurons to the brain has been performed in Parkinson’s disease and in Huntington’s disease. The restoration of dopaminergic neurons in patients with Parkinson’s disease via implantation of embryonic midbrain tissue was taken from animal experiments to clinical applications, showing a limited efficacy. Clinical trials in patients with Huntington’s disease using fetal striatal tissue currently are underway. Today, it seems possible to generate functional dopaminergic or striatal neurons form a variety of stem cells including embryonic or neural stem cells as well as induced pluripotent stem cells. First clinical trials using neural stem cell or embryonic-stem-cell-derived tissue are approved or already underway. Such cells allow for extensive in vitro and in vivo testing as well as “good manufacturing production,” reducing the risks in clinical application.


      CNS (central nervous system), EGF (epidermal growth factor), ESC (embryonic stem cell), FDS (Food and Drug Administration), FGF-2 (fibroblast growth factor), iPS (induced pluripotent stem cells), NCL (neuronal ceroid lipofuscinosis), NSC (neural stem cell), PMD (Pelizaeus–Merzbacher disease)
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        • Madrazo I.
        • Drucker-Colin R.
        • Diaz V.
        • Martinez-Mata J.
        • Torres C.
        • Becerril J.J.
        Open microsurgical autograft of adrenal medulla to the right caudate nucleus in two patients with intractable Parkinson’s disease.
        N Engl J Med. 1987; 316: 831-834
        • Freed C.R.
        • Greene P.E.
        • Breeze R.E.
        • et al.
        Transplantation of embryonic dopamine neurons for severe Parkinson’s disease.
        N Engl J Med. 2001; 344: 710-719
        • Olanow C.W.
        • Goetz C.G.
        • Kordower J.H.
        • et al.
        A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease.
        Ann Neurol. 2003; 54: 403-414
        • Bachoud-Levi A.C.
        • Gaura V.
        • Brugieres P.
        • et al.
        Effect of fetal neural transplants in patients with Huntington’s disease 6 years after surgery: a long-term follow-up study.
        Lancet Neurol. 2006; 5: 303-309
        • Erdo F.
        • Buhrle C.
        • Blunk J.
        • et al.
        Host-dependent tumorigenesis of embryonic stem cell transplantation in experimental stroke.
        J Cereb Blood Flow Metab. 2003; 23: 780-785
        • Lee H.
        • Shamy G.A.
        • Elkabetz Y.
        • et al.
        Directed differentiation and transplantation of human embryonic stem cell-derived motoneurons.
        Stem Cells. 2007; 25: 1931-1939
        • Aubry L.
        • Bugi A.
        • Lefort N.
        • Rousseau F.
        • Peschanski M.
        • Perrier A.L.
        Striatal progenitors derived from human ES cells mature into DARPP32 neurons in vitro and in quinolinic acid-lesioned rats.
        Proc Natl Acad Sci U S A. 2008; 105: 16707-16712
        • Lee S.H.
        • Lumelsky N.
        • Studer L.
        • Auerbach J.M.
        • McKay R.D.
        Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells.
        Nat Biotechnol. 2000; 18: 675-679
        • Kawasaki H.
        • Mizuseki K.
        • Nishikawa S.
        • et al.
        Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity.
        Neuron. 2000; 28: 31-40
        • 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 U S A. 2002; 99: 1580-1585
        • Keirstead H.S.
        • Nistor G.
        • Bernal G.
        • et al.
        Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury.
        J Neurosci. 2005; 25: 4694-4705
        • Nistor G.I.
        • Totoiu M.O.
        • Haque N.
        • Carpenter M.K.
        • Keirstead H.S.
        Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation.
        Glia. 2005; 49: 385-396
        • Geron
        World’s first clinical trial of human embryonic stem cell therapy cleared.
        Regen Med. 2009; 4: 161
        • Lefort N.
        • Feyeux M.
        • Bas C.
        • et al.
        Human embryonic stem cells reveal recurrent genomic instability at 20q11.21.
        Nat Biotechnol. 2008; 26: 1364-1366
        • Lefort N.
        • Perrier A.L.
        • Laabi Y.
        • Varela C.
        • Peschanski M.
        Human embryonic stem cells and genomic instability.
        Regen Med. 2009; 4: 899-909
        • Takahashi K.
        • Yamanaka S.
        Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.
        Cell. 2006; 126: 663-676
        • Kim J.B.
        • Sebastiano V.
        • Wu G.
        • et al.
        Oct4-induced pluripotency in adult neural stem cells.
        Cell. 2009; 136: 411-419
        • Kim J.B.
        • Zaehres H.
        • Wu G.
        • et al.
        Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors.
        Nature. 2008; 454: 646-650
        • 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 Cell. 2009; 4: 472-476
        • Soldner F.
        • Hockemeyer D.
        • Beard C.
        • et al.
        Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors.
        Cell. 2009; 136: 964-977
        • Wernig M.
        • Zhao J.P.
        • 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 U S A. 2008; 105: 5856-5861
        • Vierbuchen T.
        • Ostermeier A.
        • Pang Z.P.
        • Kokubu Y.
        • Sudhof T.C.
        • Wernig M.
        Direct conversion of fibroblasts to functional neurons by defined factors.
        Nature. 2010; 463: 1031-1032
        • Gritti A.
        • Bonfanti L.
        • Doetsch F.
        • et al.
        Multipotent neural stem cells reside into the rostral extension and olfactory bulb of adult rodents.
        J Neurosci. 2002; 22: 437-445
        • Johe K.K.
        • Hazel T.G.
        • Muller T.
        • Dugich-Djordjevic M.M.
        • McKay R.D.
        Single factors direct the differentiation of stem cells from the fetal and adult central nervous system.
        Genes Dev. 1996; 10: 3129-3140
        • Storch A.
        • Paul G.
        • Csete M.
        • et al.
        Long-term proliferation and dopaminergic differentiation of human mesencephalic neural precursor cells.
        Exp Neurol. 2001; 170: 317-325
        • Milosevic J.
        • Adler I.
        • Manaenko A.
        • et al.
        Non-hypoxic stabilization of hypoxia-inducible factor alpha (HIF-alpha): relevance in neural progenitor/stem cells.
        Neurotox Res. 2009; 15: 367-380
        • Milosevic J.
        • Maisel M.
        • Wegner F.
        • et al.
        Lack of hypoxia-inducible factor-1 alpha impairs midbrain neural precursor cells involving vascular endothelial growth factor signaling.
        J Neurosci. 2007; 27: 412-421
        • Milosevic J.
        • Schwarz S.C.
        • Krohn K.
        • Poppe M.
        • Storch A.
        • Schwarz J.
        Low atmospheric oxygen avoids maturation, senescence and cell death of murine mesencephalic neural precursors.
        J Neurochem. 2005; 92: 718-729
        • Milosevic J.
        • Brandt A.
        • Roemuss U.
        • et al.
        Uracil nucleotides stimulate human neural precursor cell proliferation and dopaminergic differentiation: involvement of MEK/ERK signalling.
        J Neurochem. 2006; 99: 913-923
        • Sabolek M.
        • Baumann B.
        • Heinrich M.
        • et al.
        Initiation of dopaminergic differentiation of Nurr1(-) mesencephalic precursor cells depends on activation of multiple mitogen-activated protein kinase pathways.
        Stem Cells. 2009; 27: 2009-2021
        • Schaarschmidt G.
        • Schewtschik S.
        • Kraft R.
        • et al.
        A new culturing strategy improves functional neuronal development of human neural progenitor cells.
        J Neurochem. 2009; 109: 238-247
        • Wegner F.
        • Kraft R.
        • Busse K.
        • et al.
        Glutamate receptor properties of human mesencephalic neural progenitor cells: NMDA enhances dopaminergic neurogenesis in vitro.
        J Neurochem. 2009; 111: 204-216
        • Tamaki S.J.
        • Jacobs Y.
        • Dohse M.
        • et al.
        Neuroprotection of host cells by human central nervous system stem cells in a mouse model of infantile neuronal ceroid lipofuscinosis.
        Cell Stem Cell. 2009; 5: 310-319
        • Amariglio N.
        • Hirshberg A.
        • Scheithauer B.W.
        • et al.
        Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient.
        PLoS Med. 2009; 6: e1000029
        • Miljan E.A.
        • Sinden J.D.
        Stem cell treatment of ischemic brain injury.
        Curr Opin Mol Ther. 2009; 11: 394-403
        • Deng J.
        • Petersen B.E.
        • Steindler D.A.
        • Jorgensen M.L.
        • Laywell E.D.
        Mesenchymal stem cells spontaneously express neural proteins in culture and are neurogenic after transplantation.
        Stem Cells. 2006; 24: 1054-1064
        • Hermann A.
        • Gastl R.
        • Liebau S.
        • et al.
        Efficient generation of neural stem cell-like cells from adult human bone marrow stromal cells.
        J Cell Sci. 2004; 117: 4411-4422
        • Venkataramana N.K.
        • Kumar S.K.
        • Balaraju S.
        • et al.
        Open-labeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson’s disease.
        Transl Res. 2010; 155: 62-70
        • Schwarz J.
        • Storch A.
        Transplantation in Parkinson’s disease: will mesenchymal stem cells help to reenter the clinical arena?.
        Transl Res. 2010; 155: 55-56