Advertisement

Intrastriatal transplantation of stem cells from human exfoliated deciduous teeth reduces motor defects in Parkinsonian rats

  • Author Footnotes
    * These authors equally contributed to the work.
    Nan Zhang
    Footnotes
    * These authors equally contributed to the work.
    Affiliations
    The Institute for Tissue Engineering and Regenerative Medicine, Liaocheng University/Liaocheng People's Hospital, Liaocheng, Shandong, China
    Search for articles by this author
  • Author Footnotes
    * These authors equally contributed to the work.
    Xianjie Lu
    Footnotes
    * These authors equally contributed to the work.
    Affiliations
    The Institute for Tissue Engineering and Regenerative Medicine, Liaocheng University/Liaocheng People's Hospital, Liaocheng, Shandong, China
    Search for articles by this author
  • Author Footnotes
    * These authors equally contributed to the work.
    Shichao Wu
    Footnotes
    * These authors equally contributed to the work.
    Affiliations
    The Institute for Tissue Engineering and Regenerative Medicine, Liaocheng University/Liaocheng People's Hospital, Liaocheng, Shandong, China
    Search for articles by this author
  • Author Footnotes
    * These authors equally contributed to the work.
    Xueli Li
    Footnotes
    * These authors equally contributed to the work.
    Affiliations
    Department of Neurology, Liaocheng People's Hospital, Liaocheng, Shandong, China
    Search for articles by this author
  • Jing Duan
    Affiliations
    The Institute for Tissue Engineering and Regenerative Medicine, Liaocheng University/Liaocheng People's Hospital, Liaocheng, Shandong, China
    Search for articles by this author
  • Chao Chen
    Affiliations
    The Institute for Tissue Engineering and Regenerative Medicine, Liaocheng University/Liaocheng People's Hospital, Liaocheng, Shandong, China
    Search for articles by this author
  • Wei Wang
    Affiliations
    The Institute for Tissue Engineering and Regenerative Medicine, Liaocheng University/Liaocheng People's Hospital, Liaocheng, Shandong, China
    Search for articles by this author
  • Hao Song
    Affiliations
    The Institute for Tissue Engineering and Regenerative Medicine, Liaocheng University/Liaocheng People's Hospital, Liaocheng, Shandong, China
    Search for articles by this author
  • Jiabei Tong
    Affiliations
    The Institute for Tissue Engineering and Regenerative Medicine, Liaocheng University/Liaocheng People's Hospital, Liaocheng, Shandong, China
    Search for articles by this author
  • Sen Li
    Affiliations
    The Institute for Tissue Engineering and Regenerative Medicine, Liaocheng University/Liaocheng People's Hospital, Liaocheng, Shandong, China
    Search for articles by this author
  • Yanming Liu
    Affiliations
    College of Biological Science, Qingdao University, Qingdao, Shandong, China
    Search for articles by this author
  • Xinjiang Kang
    Affiliations
    College of Biological Science, Liaocheng University, Liaocheng, Shandong, China
    Search for articles by this author
  • Xuexiang Wang
    Affiliations
    The Institute for Translational Medicine, The Second Affiliated Hospital, Shandong University, Jinan, Shandong, China
    Search for articles by this author
  • Fabin Han
    Correspondence
    Correspondence: Fabin Han, MD, The Institute for Tissue Engineering and Regenerative Medicine, Liaocheng University/Liaocheng People's Hospital, Shandong 252000, China.
    Affiliations
    The Institute for Tissue Engineering and Regenerative Medicine, Liaocheng University/Liaocheng People's Hospital, Liaocheng, Shandong, China

    The Institute for Translational Medicine, The Second Affiliated Hospital, Shandong University, Jinan, Shandong, China
    Search for articles by this author
  • Author Footnotes
    * These authors equally contributed to the work.
Published:March 22, 2018DOI:https://doi.org/10.1016/j.jcyt.2018.02.371

      Abstract

      Background

      This study explored the neural differentiation and therapeutic effects of stem cells from human exfoliated deciduous teeth (SHED) in a rat model of Parkinson's disease (PD).

      Methods

      The SHED were isolated from fresh dental pulp and were induced to differentiate to neurons and dopamine neurons by inhibiting similar mothers against dpp (SMAD) signaling with Noggin and increase conversion of dopamine neurons from SHED with CHIR99021, Sonic Hedgehog (SHH) and FGF8 in vitro. The neural-primed SHED were transplanted to the striatum of 6-hydroxydopamine (6-OHDA)–induced PD rats to evaluate their neural differentiation and functions in vivo.

      Results

      These SHED were efficiently differentiated to neurons (62.7%) and dopamine neurons (42.3%) through a newly developed method. After transplantation, the neural-induced SHED significantly improved recovery of the motor deficits of the PD rats. The grafted SHED were differentiated into neurons (61%), including dopamine neurons (22.3%), and integrated into the host rat brain by forming synaptic connections. Patch clamp analysis showed that neurons derived from grafted SHED have the same membrane potential profile as dopamine neurons, indicating these cells are dopamine neuron-like cells. The potential molecular mechanism of SHED transplantation in alleviating motor deficits of the rats is likely to be mediated by neuronal replacement and immune-modulation as we detected the transplanted dopamine neurons and released immune cytokines from SHED.

      Conclusion

      Using neural-primed SHED to treat PD showed significant restorations of motor deficits in 6-OHDA–induced rats. These observations provide further evidence that SHED can be used for cell-based therapy of PD.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Cytotherapy
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Dawson T.M.
        • Ko H.S.
        • Dawson V.L.
        Genetic animal models of Parkinson's disease.
        Neuron. 2010; 66: 646-661
        • Evans J.R.
        • Mason S.L.
        • Barker R.A.
        Current status of clinical trials of neural transplantation in Parkinson's disease.
        Prog Brain Res. 2012; 200: 169-198
        • Chen C.
        • Duan J.
        • Shen A.
        • Wang W.
        • Song H.
        • Liu Y.
        • et al.
        Transplantation of human umbilical cord blood-derived mononuclear cells induces recovery of motor dysfunction in a rat model of Parkinson's disease.
        J Neurorestoratology. 2016; 4: 23-33
        • Olanow C.W.
        • Goetz C.G.
        • Kordower J.H.
        • Stoessl A.J.
        • Sossi V.
        • Brin M.F.
        • et al.
        A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease.
        Ann Neurol. 2003; 54: 403-414
        • Chen L.
        • Huang H.
        • Xi H.
        • Mao G.
        Clinical neurorestorative progress in amyotrophic lateral sclerosis.
        J Neurorestoratology. 2015; 3: 109-114
        • Li W.
        • Englund E.
        • Widner H.
        • Mattsson B.
        • van Westen D.
        • Latt J.
        • et al.
        Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain.
        Proc Natl Acad Sci USA. 2016; 113: 6544-6549
        • Lindvall O.
        Developing dopaminergic cell therapy for Parkinson's disease–give up or move forward?.
        Mov Disord. 2013; 28: 268-273
        • Sundberg M.
        • Bogetofte H.
        • Lawson T.
        • Jansson J.
        • Smith G.
        • Astradsson A.
        • et al.
        Improved cell therapy protocols for Parkinson's disease based on differentiation efficiency and safety of hESC-, hiPSC-, and non-human primate iPSC-derived dopaminergic neurons.
        Stem Cells. 2013; 31: 1548-1562
        • Lindvall O.
        Clinical translation of stem cell transplantation in Parkinson's disease.
        J Intern Med. 2016; 279: 30-40
        • Han F.
        • Baremberg D.
        • Gao J.
        • Duan J.
        • Lu X.
        • Zhang N.
        • et al.
        Development of stem cell-based therapy for Parkinson's disease.
        Transl Neurodegener. 2015; 4: 16
        • Danielyan L.
        • Schafer R.
        • von Ameln-Mayerhofer A.
        • Bernhard F.
        • Verleysdonk S.
        • Buadze M.
        • et al.
        Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease.
        Rejuvenation Res. 2011; 14: 3-16
        • Kan I.
        • Ben-Zur T.
        • Barhum Y.
        • Levy Y.S.
        • Burstein A.
        • Charlow T.
        • et al.
        Dopaminergic differentiation of human mesenchymal stem cells–utilization of bioassay for tyrosine hydroxylase expression.
        Neurosci Lett. 2007; 419: 28-33
        • Lu L.L.
        • Liu Y.J.
        • Yang S.G.
        • Zhao Q.J.
        • Wang X.
        • Gong W.
        • et al.
        Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials.
        Haematologica. 2006; 91: 1017-1026
        • Keyser K.A.
        • Beagles K.E.
        • Kiem H.P.
        Comparison of mesenchymal stem cells from different tissues to suppress T-cell activation.
        Cell Transplant. 2007; 16: 555-562
        • Seo Y.
        • Yang S.R.
        • Jee M.K.
        • Joo E.K.
        • Roh K.H.
        • Seo M.S.
        • et al.
        Human umbilical cord blood-derived mesenchymal stem cells protect against neuronal cell death and ameliorate motor deficits in Niemann Pick type C1 mice.
        Cell Transplant. 2011; 20: 1033-1047
        • Kanafi M.
        • Majumdar D.
        • Bhonde R.
        • Gupta P.
        • Datta I.
        Midbrain cues dictate differentiation of human dental pulp stem cells towards functional dopaminergic neurons.
        J Cell Physiol. 2014; 229: 1369-1377
        • Song M.
        • Lee J.H.
        • Bae J.
        • Bu Y.
        • Kim E.C.
        Human dental pulp stem cells are more effective than human bone marrow-derived mesenchymal stem cells in cerebral ischemic injury.
        Cell Transplant. 2017; 26: 1001-1016
        • Karaoz E.
        • Demircan P.C.
        • Saglam O.
        • Aksoy A.
        • Kaymaz F.
        • Duruksu G.
        Human dental pulp stem cells demonstrate better neural and epithelial stem cell properties than bone marrow-derived mesenchymal stem cells.
        Histochem Cell Biol. 2011; 136: 455-473
        • La Noce M.
        • Mele L.
        • Tirino V.
        • Paino F.
        • De Rosa A.
        • Naddeo P.
        • et al.
        Neural crest stem cell population in craniomaxillofacial development and tissue repair.
        Eur Cell Mater. 2014; 28: 348-357
        • Al-Zoubi A.
        • Altwal F.
        • Khalifeh F.
        • Hermas J.
        • Al-Zoubi Z.
        • Jafar E.
        • et al.
        Ex vivo differentiation of human bone marrow-derived stem cells into neuronal cell-like lineages.
        J Neurorestoratology. 2016; 4: 35-44
        • Yamagata M.
        • Yamamoto A.
        • Kako E.
        • Kaneko N.
        • Matsubara K.
        • Sakai K.
        • et al.
        Human dental pulp-derived stem cells protect against hypoxic-ischemic brain injury in neonatal mice.
        Stroke. 2013; 44: 551-554
        • da Silva Meirelles L.
        • Caplan A.I.
        • Nardi N.B.
        In search of the in vivo identity of mesenchymal stem cells.
        Stem Cells. 2008; 26: 2287-2299
        • Zhang N.
        • Chen B.
        • Wang W.
        • Chen C.
        • Kang J.
        • Deng S.Q.
        • et al.
        Isolation, characterization and multi-lineage differentiation of stem cells from human exfoliated deciduous teeth.
        Mol Med Rep. 2016; 14: 95-102
        • Alge D.L.
        • Zhou D.
        • Adams L.L.
        • Wyss B.K.
        • Shadday M.D.
        • Woods E.J.
        • et al.
        Donor-matched comparison of dental pulp stem cells and bone marrow-derived mesenchymal stem cells in a rat model.
        J Tissue Eng Regen Med. 2010; 4: 73-81
        • Wang X.
        • Sha X.J.
        • Li G.H.
        • Yang F.S.
        • Ji K.
        • Wen L.Y.
        • et al.
        Comparative characterization of stem cells from human exfoliated deciduous teeth and dental pulp stem cells.
        Arch Oral Biol. 2012; 57: 1231-1240
        • Han F.
        • Wang W.
        • Chen B.
        • Chen C.
        • Li S.
        • Lu X.
        • et al.
        Human induced pluripotent stem cell-derived neurons improve motor asymmetry in a 6-hydroxydopamine-induced rat model of Parkinson's disease.
        Cytotherapy. 2015; 17: 665-679
        • 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)
        • Chambers S.M.
        • Fasano C.A.
        • Papapetrou E.P.
        • Tomishima M.
        • Sadelain M.
        • Studer L.
        Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling.
        Nat Biotechnol. 2009; 27: 275-280
        • Suzuki M.
        • McHugh J.
        • Tork C.
        • Shelley B.
        • Klein S.M.
        • Aebischer P.
        • et al.
        GDNF secreting human neural progenitor cells protect dying motor neurons, but not their projection to muscle, in a rat model of familial ALS.
        PLoS ONE. 2007; 2 (e689)
        • Neher E.
        Correction for liquid junction potentials in patch clamp experiments.
        Methods Enzymol. 1992; 207: 123-131
        • Yan Y.
        • Yang D.
        • Zarnowska E.D.
        • Du Z.
        • Werbel B.
        • Valliere C.
        • et al.
        Directed differentiation of dopaminergic neuronal subtypes from human embryonic stem cells.
        Stem Cells. 2005; 23: 781-790
        • Kang X.
        • Xu H.
        • Teng S.
        • Zhang X.
        • Deng Z.
        • Zhou L.
        • et al.
        Dopamine release from transplanted neural stem cells in Parkinsonian rat striatum in vivo.
        Proc Natl Acad Sci USA. 2014; 111: 15804-15809
        • Hu W.
        • Qiu B.
        • Guan W.
        • Wang Q.
        • Wang M.
        • Li W.
        • et al.
        Direct conversion of normal and Alzheimer's disease human fibroblasts into neuronal cells by small molecules.
        Cell Stem Cell. 2015; 17: 204-212
        • Fujii H.
        • Matsubara K.
        • Sakai K.
        • Ito M.
        • Ohno K.
        • Ueda M.
        • et al.
        Dopaminergic differentiation of stem cells from human deciduous teeth and their therapeutic benefits for Parkinsonian rats.
        Brain Res. 2015; 1613: 59-72
        • Young F.
        • Sloan A.
        • Song B.
        Dental pulp stem cells and their potential roles in central nervous system regeneration and repair.
        J Neurosci Res. 2013; 91: 1383-1393
        • Lu P.
        • Wang Y.
        • Graham L.
        • McHale K.
        • Gao M.
        • Wu D.
        • et al.
        Long-distance growth and connectivity of neural stem cells after severe spinal cord injury.
        Cell. 2012; 150: 1264-1273
        • Kriks S.
        • Shim J.W.
        • Piao J.
        • Ganat Y.M.
        • Wakeman D.R.
        • Xie Z.
        • et al.
        Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease.
        Nature. 2011; 480: 547-551
        • Ludlow K.H.
        • Bradley K.D.
        • Allison D.W.
        • Taylor S.R.
        • Yorgason J.T.
        • Hansen D.M.
        • et al.
        Acute and chronic ethanol modulate dopamine D2-subtype receptor responses in ventral tegmental area GABA neurons.
        Alcohol Clin Exp Res. 2009; 33: 804-811
        • Astradsson A.
        • Cooper O.
        • Vinuela A.
        • Isacson O.
        Recent advances in cell-based therapy for Parkinson disease.
        Neurosurg Focus. 2008; 24: E6
        • Lindvall O.
        • Barker R.A.
        • Brüstle O.
        • Isacson O.
        • Svendsen C.N.
        Clinical translation of stem cells in neurodegenerative disorders.
        Cell Stem Cell. 2012; 10: 151-155
        • Gonzalez R.
        • Garitaonandia I.
        • Poustovoitov M.
        • Abramihina T.
        • McEntire C.
        • Culp B.
        • et al.
        Neural stem cells derived from human parthenogenetic stem cells engraft and promote recovery in a nonhuman primate model of Parkinsons disease.
        Cell Transplant. 2016; 25: 1945-1966
        • Miura M.
        • Gronthos S.
        • Zhao M.
        • Lu B.
        • Fisher L.W.
        • Robey P.G.
        • et al.
        SHED: stem cells from human exfoliated deciduous teeth.
        Proc Natl Acad Sci USA. 2003; 100: 5807-5812
        • Wang J.
        • Wang X.
        • Sun Z.
        • Yang H.
        • Shi S.
        • Wang S.
        Stem cells from human-exfoliated deciduous teeth can differentiate into dopaminergic neuron-like cells.
        Stem Cells Dev. 2010; 19: 1375-1383
        • Blandini F.
        • Cova L.
        • Armentero M.T.
        • Zennaro E.
        • Levandis G.
        • Bossolasco P.
        • et al.
        Transplantation of undifferentiated human mesenchymal stem cells protects against 6-hydroxydopamine neurotoxicity in the rat.
        Cell Transplant. 2010; 19: 203-217
        • Chun S.Y.
        • Soker S.
        • Jang Y.J.
        • Kwon T.G.
        • Yoo E.S.
        Differentiation of human dental pulp stem cells into dopaminergic neuron-like cells in vitro.
        J Korean Med Sci. 2016; 31: 171-177
        • Ying Q.L.
        • Wray J.
        • Nichols J.
        • Batlle-Morera L.
        • Doble B.
        • Woodgett J.
        • et al.
        The ground state of embryonic stem cell self-renewal.
        Nature. 2008; 453: 519-523
        • Xi J.
        • Liu Y.
        • Liu H.
        • Chen H.
        • Emborg M.E.
        • Zhang S.C.
        Specification of midbrain dopamine neurons from primate pluripotent stem cells.
        Stem Cells. 2012; 30: 1655-1663
        • Elkabetz Y.
        • Panagiotakos G.
        • Al Shamy G.
        • Socci N.D.
        • Tabar V.
        • Studer L.
        Human ES cell-derived neural rosettes reveal a functionally distinct early neural stem cell stage.
        Genes Dev. 2008; 22: 152-165
        • Zhang X.Q.
        • Zhang S.C.
        Differentiation of neural precursors and dopaminergic neurons from human embryonic stem cells.
        Methods Mol Biol. 2010; 584: 355-366
        • Nakajima K.
        • Hida H.
        • Shimano Y.
        • Fujimoto I.
        • Hashitani T.
        • Kumazaki M.
        • et al.
        GDNF is a major component of trophic activity in DA-depleted striatum for survival and neurite extension of DAergic neurons.
        Brain Res. 2001; 916: 76-84
        • Wang W.
        • Song H.
        • Shen A.
        • Chen C.
        • Liu Y.
        • Dong Y.
        • et al.
        Differentiated cells derived from fetal neural stem cells improve motor deficits in a rat model of Parkinson's disease.
        Translational Neurosci Clin. 2015; 1: 75-85
        • Apel C.
        • Forlenza O.V.
        • de Paula V.J.
        • Talib L.L.
        • Denecke B.
        • Eduardo C.P.
        • et al.
        The neuroprotective effect of dental pulp cells in models of Alzheimer's and Parkinson's disease.
        J Neural Transm (Vienna). 2009; 116: 71-78
        • Zwart I.
        • Hill A.J.
        • Al-Allaf F.
        • Shah M.
        • Girdlestone J.
        • Sanusi A.B.
        • et al.
        Umbilical cord blood mesenchymal stromal cells are neuroprotective and promote regeneration in a rat optic tract model.
        Exp Neurol. 2009; 216: 439-448
        • Kemp K.
        • Dey R.
        • Cook A.
        • Scolding N.
        • Wilkins A.
        Mesenchymal stem cell-derived factors restore function to human frataxin-deficient cells.
        Cerebellum. 2017; 16: 840-851
        • Cheng Z.
        • He X.
        Anti-inflammatory effect of stem cells against spinal cord injury via regulating macrophage polarization.
        J Neurorestoratology. 2017; 5: 31-38