Mesenchymal Stromal Cells| Volume 18, ISSUE 3, P307-319, March 2016

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Dopaminergic-primed fetal liver mesenchymal stromal–like cells can reverse parkinsonian symptoms in 6-hydroxydopamine-lesioned mice


      Background aims

      Cell replacement therapy is considered a promising alternative in the treatment of degenerative diseases, and in this context, mesenchymal stromal cells (MSCs) have been proposed for transplantation in Parkinson disease (PD). Thus far, the results of animal studies are found to be inconsistent and inconclusive regarding the therapeutic ability of the cells. This study investigated the efficacy of fetal liver (FL)-MSC-derived dopaminergic (DA) neuronal primed cells for correction of parkinsonian symptoms in mice.


      FL-MSCs were differentiated for 21 days in the presence of a combination of neurotropic factors. The extent of cellular reprogramming was analyzed by quantitative polymerase chain reaction for DA-specific neuronal gene expressions and protein expressions by immuno-cytochemistry. The functionality of the cells was determined by electrophysiology and dopamine release assays. Ten-day-primed neuron-like cells or unprimed MSCs were transplanted into the 6-hydroxydopamine (6-OHDA)-lesioned striatum using a stereotaxic device. Dopamine-secreting properties and behavioral studies were used to assess improvement of parkinsonian symptoms.


      The differentiated cells expressed DA-specific genes and proteins, while exhibiting a high level of voltage-gated potassium current. Furthermore, neuronal primed cells differentiated into tyrosine hydroxylase immunoreactive and dopamine-secreting functional neuron-like cells. Symptomatic correction of PD in the recipient mice within 2 months of transplantation was also observed.


      FL-MSC-derived primed neuron-like cells integrated into the striatum of PD mice, improving parkinsonian symptoms. This study demonstrates an effective cell-based therapy for PD.

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        • Lees A.J.
        • Hardy J.
        • Revesz T.
        Parkinson's disease.
        Lancet. 2009; 373: 2055-2066
        • Parent M.
        • Bedard C.
        • Pourcher E.
        Dopaminergic innervation of the human subventricular zone: a comparison between Huntington's chorea and Parkinson's disease.
        Am J Neurodegener Dis. 2013; 2: 221-227
        • Ernst A.
        • Alkass K.
        • Bernard S.
        • Salehpour M.
        • Perl S.
        • Tisdale J.
        • et al.
        Neurogenesis in the striatum of the adult human brain.
        Cell. 2014; 156: 1072-1083
        • Morgan J.C.
        • Currie L.J.
        • Harrison M.B.
        • Bennett Jr, J.P.
        • Trugman J.M.
        • Wooten G.F.
        Mortality in levodopa-treated Parkinson's disease.
        Parkinson Dis. 2014; 2014: 426976
        • Hauser R.A.
        • Kolle W.C.
        • Hubble J.P.
        • Malapira T.
        • Busenbark K.
        • Olanow C.W.
        Time course of loss of clinical benefit following withdrawal of levodopa/carbidopa and bromocriptine in early Parkinson's disease.
        Mov Disord. 2000; 15: 485-489
        • Pincus D.W.
        • Goodman R.R.
        • Fraser R.A.
        • Nedergaard M.
        • Goldman S.A.
        Neural stem and progenitor cells: a strategy for gene therapy and brain repair.
        Neurosurgery. 1998; 42: 858-867
        • Gage F.H.
        • Coates P.W.
        • Palmer T.D.
        • Kuhn H.G.
        • Fisher L.J.
        • Suhonen J.O.
        • et al.
        Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain.
        Proc Natl Acad Sci U S A. 1995; 92: 11879-11883
        • Clarkson E.D.
        • Zawada W.M.
        • Bell K.P.
        • Esplen J.E.
        • Choi P.K.
        • Heidenreich K.A.
        • et al.
        IGF-I and bFGF improve dopamine neuron survival and behavioral outcome in parkinsonian rats receiving cultured human fetal tissue strands.
        Exp Neurol. 2001; 168: 183-191
        • Lindvall O.
        • Brundin P.
        • Widner H.
        • Rehncrona S.
        • Gustavii B.
        • Frackowiak R.
        • et al.
        Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease.
        Science. 1990; 247: 574-577
        • Mendez I.
        • Vinuela A.
        • Astradsson A.
        • Mukhida K.
        • Hallett P.
        • Robertson H.
        • et al.
        Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years.
        Nat Med. 2008; 14: 507-509
        • Thompson L.H.
        • Kirik D.
        • Bjorklund A.
        Non-dopaminergic neurons in ventral mesencephalic transplants make widespread axonal connections in the host brain.
        Exp Neurol. 2008; 213: 220-228
        • Steece-Collier K.
        • Collier T.J.
        • Danielson P.D.
        • Kurlan R.
        • Yurek D.M.
        • Sladek Jr, J.R.
        Embryonic mesencephalic grafts increase levodopa-induced forelimb hyperkinesia in parkinsonian rats.
        Mov Disord. 2003; 18: 1442-1454
        • Kim J.H.
        • Auerbach J.M.
        • Rodriguez-Gomez J.A.
        • Velasco I.
        • Gavin D.
        • Lumelsky N.
        • et al.
        Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease.
        Nature. 2002; 418: 50-56
        • Kim J.
        • Su S.C.
        • Wang H.
        • Cheng A.W.
        • Cassady J.P.
        • Lodato M.A.
        • et al.
        Functional integration of dopaminergic neurons directly converted from mouse fibroblasts.
        Cell Stem Cell. 2011; 9: 413-419
        • Hellmann M.A.
        • Panet H.
        • Barhum Y.
        • Melamed E.
        • Offen D.
        Increased survival and migration of engrafted mesenchymal bone marrow stem cells in 6-hydroxydopamine-lesioned rodents.
        Neurosci Lett. 2006; 395: 124-128
        • Trzaska K.A.
        • Kuzhikandathil E.V.
        • Rameshwar P.
        Specification of a dopaminergic phenotype from adult human mesenchymal stem cells.
        Stem Cells. 2007; 25: 2797-2808
        • Yang S.
        • Xue D.D.
        • Wu B.
        • Sun H.M.
        • Li X.S.
        • Dong F.
        • et al.
        Pleiotrophin is involved in the amniotic epithelial cell-induced differentiation of human umbilical cord blood-derived mesenchymal stem cells into dopaminergic neuron-like cells.
        Neurosci Lett. 2013; 539: 86-91
        • Khoo M.L.
        • Tao H.
        • Meedeniya A.C.
        • Mackay-Sim A.
        • Ma D.D.
        Transplantation of neuronal-primed human bone marrow mesenchymal stem cells in hemiparkinsonian rodents.
        PLoS ONE. 2011; 6: e19025
        • Hayashi T.
        • Wakao S.
        • Kitada M.
        • Ose T.
        • Watabe H.
        • Kuroda Y.
        • et al.
        Autologous mesenchymal stem cell-derived dopaminergic neurons function in parkinsonian macaques.
        J Clin Invest. 2013; 123: 272-284
        • Glavaski-Joksimovic A.
        • Virag T.
        • Chang Q.A.
        • West N.C.
        • Mangatu T.A.
        • McGrogan M.P.
        • et al.
        Reversal of dopaminergic degeneration in a Parkinsonian rat following micrografting of human bone marrow-derived neural progenitors.
        Cell Transplant. 2009; 18: 801-814
        • Cova L.
        • Armentero M.T.
        • Zennaro E.
        • Calzarossa C.
        • Bossolasco P.
        • Busca G.
        • et al.
        Multiple neurogenic and neurorescue effects of human mesenchymal stem cell after transplantation in an experimental model of Parkinson's disease.
        Brain Res. 2010; 1311: 12e27
        • Park H.J.
        • Shin J.Y.
        • Lee B.R.
        • Kim H.O.
        • Lee P.H.
        Mesenchymal stem cells augment neurogenesis in the subventricular zone and enhance differentiation of neural precursor cells into dopaminergic neurons in the substantia nigra of parkinsonian model.
        Cell Transplant. 2012; 21: 1629e40
        • Schwerk A.
        • Altschuler J.
        • Roch M.
        • Gossen M.
        • Winter C.
        • Berg J.
        • et al.
        Human adipose-derived mesenchymal stromal cells increase endogenous neurogenesis in the rat subventricular zone acutely after 6-hydroxydopamine lesioning.
        Cytotherapy. 2015; 17: 199e214
        • Friedman M.S.
        • Long M.W.
        • Hankenson K.D.
        Osteogenic differentiation of human mesenchymal stem cells is regulated by bone morphogenetic protein-6.
        J Cell Biol. 2006; 98: 538-554
        • Fink T.
        • Zachar V.
        Adipogenic differentiation of human mesenchymal stem cells.
        Methods Mol Biol. 2011; 698: 243-251
        • Cuebde J.
        • Moreno S.
        • Bolanos JP.
        • Almedia A.
        Retinoic acid downregulates Raae1 leading to APCCdh1 activation and neuroblastoma SH-SY5Y differentiation.
        Oncogene. 2008; 27: 3339-3344
        • Gonzalez E.
        • van Liempd S.
        • Conde-Vancells J.
        • Gutierrez-de Juan V.
        • Perez-Cormenzana M.
        • Mayo R.
        • et al.
        Serum UPLC-MS/MS metabolic profiling in an experimental model for acute-liver injury reveals potential biomarkers for hepatotoxicity.
        Metabolomics. 2011; 8: 997-1011
        • Politis M.
        • Lindvall O.
        Clinical application of stem cell therapy in Parkinson's disease.
        BMC Med. 2012; 10: 1
        • Kitada M.
        • Dezawa M.
        Parkinson's disease and mesenchymal stem cells: Potential for cell-based therapy.
        Parkinson Dis. 2012; 2012: 873706
        • Niemeyer P.
        • Kornacker M.
        • Mehlhorn A.
        • Seckinger A.
        • Vohrer J.
        • Schmal H.
        • et al.
        Comparison of immunological properties of bone marrow stromal cells and adipose tissue-derived stem cells before and after osteogenic differentiation in vitro.
        Tissue Eng. 2007; 13: 111-121
        • Klyushnenkova E.
        • Mosca J.D.
        • Zernetkina V.
        • Majumdar M.K.
        • Beggs K.J.
        • Simonetti D.W.
        • et al.
        T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression.
        J Biomed Sci. 2005; 12: 47-57
        • Jang M.J.
        • Kim H.S.
        • Lee H.G.
        • Kim G.J.
        • Jeon H.G.
        • Shin H.S.
        • et al.
        Placenta-derived mesenchymal stem cells have an immunomodulatory effect that can control acute graft-versus-host disease in mice.
        Acta Haematol. 2013; 129: 197-206
        • Fu Y.S.
        • Cheng Y.C.
        • Lin M.Y.
        • et al.
        Conversion of human umbilical cord mesenchymal stem cells in Wharton's jelly to dopaminergic neurons in vitro—potential therapeutic application for Parkinsonism.
        Stem Cells. 2006; 24: 115-124
        • Guo L.
        • Yin F.
        • Meng H.Q.
        • et al.
        Differentiation of mesenchymal stem cells into dopaminergic neuron-like cells in vitro.
        Biomed Environ Sci. 2005; 18: 36-42
        • Jiang Y.
        • Henderson D.
        • Blackstad M.
        • et al.
        Neuroectodermal differentiation from mouse multipotent adult progenitor cells.
        Proc Natl Acad Sci, USA. 2003; 100: 11854-11860
        • Suon S.
        • Yang M.
        • Iacovitti L.
        Adult human bone marrow stromal spheres express neuronal traits in vitro and in a rat model of Parkinson's disease.
        Brain Res. 2006; 1106: 46-51
        • Ren Y.
        • Hu Z.
        • Fan K.
        • Wang J.
        • Janoschka S.X.
        • Ge S.
        • et al.
        Parkin mutations reduce the complexity of neuronal processes in iPSC-derived human neurons.
        Stem Cells. 2015; 33: 68-78
        • Picken Bahrey H.L.
        • Moody W.J.
        Early development of voltage-gated ion currents and firing properties in neurons of the mouse cerebral cortex.
        J Neurophysiol. 2003; 89: 1761-1773
        • Bahrey H.L.
        • Moody W.J.
        Voltage-gated currents, dye and electrical coupling in the embryonic mouse neocortex.
        Cereb Cortex. 2003; 13: 239-251
        • Munoz-Elias G.
        • Marcus A.J.
        • Coyne T.M.
        • Woodbury D.
        • Black I.B.
        Adult bone marrow stromal cells in the embryonic brain: engraftment, migration, differentiation, and long-term survival.
        J Neurosci. 2004; 24: 4585-4595
        • Kopen G.C.
        • Rrockop D.J.
        • Phinney D.G.
        Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains.
        Proc Natl Acad Sci USA. 1999; 96: 10711-10716
        • Sadan O.
        • Bahat-Stromza M.
        • Barhum Y.
        • Levy Y.S.
        • Pisnevsky A.
        • Peretz H.
        • et al.
        Protective effects of neurotrophic factor-secreting cells in a 6-OHDA rat model of Parkinson disease.
        Stem Cells Dev. 2009; 18: 1179-1190
        • Przedborski S.
        • Levivier M.
        • Jiang H.
        • Ferreira M.
        • Jackson-Lewis V.
        • Donaldson D.
        • et al.
        Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine.
        Neuroscience. 1995; 67: 631-647
        • Bouchez G.
        • Sensebe L.
        • Vourc'h P.
        • Garreau L.
        • Bodard S.
        • Rico A.
        • et al.
        Partial recovery of dopaminergic pathway after graft of adult mesenchymal stem cells in a rat model of Parkinson's disease.
        Neuchem Inter. 2008; 52: 1332-1342
        • Petrova P.S.
        • Raibekas A.
        • Pevsner J.
        • Vigo N.
        • Anafi M.
        • Moore M.K.
        • et al.
        MANF: A new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons.
        J Mol Neurosci. 2003; 20: 173-187
        • Wang F.
        • Yasuhara T.
        • Shingo T.
        • Kameda M.
        • Tajiri N.
        • Yuan W.J.
        • et al.
        Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: focusing on neuroprotective effects of stromal cell derived factor-1α.
        BMC Neurosci. 2010; 11: 52
        • Park H.J.
        • Lee P.H.
        • Bang O.Y.
        • Lee G.
        • Ahn Y.H.
        Mesenchymal stem cells therapy exerts neuroprotection in a progressive animal model of Parkinson's disease.
        J Neurochem. 2008; 107: 141e51
        • Shetty P.
        • Thakur A.M.
        • Viswanathan C.
        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 Biol Int. 2013; 37: 167-180
        • Iancu R.
        • Mohapel P.
        • Brundin P.
        • Gesine P.
        Behavioral characterization of a unilateral 6-OHDA-lesion model of Parkinson's disease in mice.
        Behav Brain Res. 2005; 162: 1-10