We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Adipose-derived human mesenchymal stem cells induce long-term neurogenic and anti-inflammatory effects and improve cognitive but not motor performance in a rat model of Parkinson's disease

    Anne Schwerk

    Department of Neurology, Charité University Medicine, Berlin, Germany

    ,
    Jennifer Altschüler

    Department of Neurology, Charité University Medicine, Berlin, Germany

    ,
    Manfred Roch

    Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany

    ,
    Manfred Gossen

    Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany

    Helmholtz-Zentrum Geesthacht (HZG), Institute of Biomaterial Science, Teltow, Germany

    ,
    Christine Winter

    Department of Psychiatry, Technical University Dresden, Germany

    ,
    Jürgen Berg

    Department of Neurology, Charité University Medicine, Berlin, Germany

    ,
    Andreas Kurtz

    Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany

    Helmholtz-Zentrum Geesthacht (HZG), Institute of Biomaterial Science, Teltow, Germany

    Seoul National University, College of Veterinary Medicine & Research Institute for Veterinary Science, Seoul 157–742, Republic of Korea

    ,
    Levent Akyüz

    Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany

    Institute for Medical Immunology, Berlin, Germany

    &
    Barbara Steiner

    *Author for correspondence:

    E-mail Address: barbara.steiner@charite.de

    Department of Neurology, Charité University Medicine, Berlin, Germany

    Published Online:https://doi.org/10.2217/rme.15.17

    Background: Mesenchymal stem cells (MSC) are easily harvested, and possess anti-inflammatory and trophic properties. Furthermore, MSC promote neuroprotection and neurogenesis, which could greatly benefit neurodegenerative disorders, such as Parkinson's disease. Methods: MSC were transplanted one week after 6-hydroxydopamine lesioning and effects were evaluated after 6 months. Results: MSC localized around the substantia nigra and the arachnoid mater, expressing pericyte and endothelial markers. MSC protected dopamine levels and upregulated peripheral anti-inflammatory cytokines. Furthermore, adipose-derived MSC increased neurogenesis in hippocampal and subventricular regions, and boosted memory functioning. Conclusion: Considering that hyposmia and loss of memory function are two major nonmotor symptoms in Parkinson's disease, transplants with modulatory effects on the hippocampus and subventricular zone could provide a disease-modifying therapy.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 Schapira AH. Neurobiology and treatment of Parkinson's disease. Trends Pharmacol. Sci. 30(1), 41–47 (2009).
    • 2 Braak H, Del Tredici K, Rub U, De Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24(2), 197–211 (2003).
    • 3 Ubeda-Banon I, Saiz-Sanchez D, De La Rosa-Prieto C et al. alpha-Synucleinopathy in the human olfactory system in Parkinson's disease: involvement of calcium-binding protein- and substance P-positive cells. Acta Neuropathol. 119(6), 723–735 (2010).
    • 4 Hoglinger GU, Rizk P, Muriel MP et al. Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nat. Neurosci. 7(7), 726–735 (2004).•• Essential study on neurogenesis, showing that precursor proliferation in the adult subependymal and subgranular zone depends on dopaminergic ennervation and is consequently reduced upon dopaminergic dennervation.
    • 5 Pearce RK, Hawkes CH, Daniel SE. The anterior olfactory nucleus in Parkinson's disease. Mov. Disord. 10(3), 283–287 (1995).
    • 6 Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sorensen P. Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch. Neurol. 60(3), 387–392 (2003).
    • 7 Camicioli R, Moore MM, Kinney A, Corbridge E, Glassberg K, Kaye JA. Parkinson's disease is associated with hippocampal atrophy. Mov. Disord. 18(7), 784–790 (2003).
    • 8 Doty RL. Olfactory dysfunction in Parkinson disease. Nat. Rev. Neurol. 8(6), 329–339 (2012).
    • 9 Lesemann A, Reinel C, Huhnchen P et al. MPTP-induced hippocampal effects on serotonin, dopamine, neurotrophins, adult neurogenesis and depression-like behavior are partially influenced by fluoxetine in adult mice. Brain Res. 1457, 51–69 (2012).
    • 10 Tansey MG, Goldberg MS. Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol. Dis. 37(3), 510–518 (2010).
    • 11 Yasuhara T, Shingo T, Muraoka K et al. Neurorescue effects of VEGF on a rat model of Parkinson's disease. Brain Res. 1053(1–2), 10–18 (2005).
    • 12 Zhou QH, Hui EK, Lu JZ, Boado RJ, Pardridge WM. Brain penetrating IgG-erythropoietin fusion protein is neuroprotective following intravenous treatment in Parkinson's disease in the mouse. Brain Res. 1382, 315–320 (2011).
    • 13 Ma S, Xie N, Li W, Yuan B, Shi Y, Wang Y. Immunobiology of mesenchymal stem cells. Cell Death Different. 21(2), 216–225 (2013).
    • 14 Boomsma RA, Geenen DL. Mesenchymal Stem Cells Secrete Multiple Cytokines That Promote Angiogenesis and Have Contrasting Effects on Chemotaxis and Apoptosis. PLoS ONE 7(4), e35685 (2012).
    • 15 Kilroy GE, Foster SJ, Wu X et al. Cytokine profile of human adipose-derived stem cells: expression of angiogenic, hematopoietic, and pro-inflammatory factors. J. Cell. Physiol. 212(3), 702–709 (2007).
    • 16 Abumaree M, Al Jumah M, Pace RA, Kalionis B. Immunosuppressive properties of mesenchymal stem cells. Stem Cell Rev. 8(2), 375–392 (2012).
    • 17 Devine SM, Bartholomew AM, Mahmud N et al. Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion. Exp. Hematol. 29(2), 244–255 (2001).
    • 18 Mogi M, Togari A, Kondo T et al. Glial cell line-derived neurotrophic factor in the substantia nigra from control and parkinsonian brains. Neurosci. Lett. 300(3), 179–181 (2001).
    • 19 Mogi M, Togari A, Kondo T et al. Brain-derived growth factor and nerve growth factor concentrations are decreased in the substantia nigra in Parkinson's disease. Neurosci. Lett. 270(1), 45–48 (1999).
    • 20 Cova L, Armentero MT, Zennaro E et al. Multiple neurogenic and neurorescue effects of human mesenchymal stem cell after transplantation in an experimental model of Parkinson's disease. Brain Res. 1311, 12–27 (2010).
    • 21 Park HJ, Shin JY, Lee BR, Kim HO, Lee PH. Mesenchymal stem cells augment neurogenesis in the subventricular zone and enhance differentiation of neural precursor cells into dopaminergic neurons in the substantia nigra of a parkinsonian model. Cell Transplant. 21(8), 1629–1640 (2012).
    • 22 Coquery N, Blesch A, Stroh A et al. Intrahippocampal transplantation of mesenchymal stromal cells promotes neuroplasticity. Cytotherapy 14(9), 1041–1053 (2012).
    • 23 Izadpanah R, Trygg C, Patel B et al. Biologic properties of mesenchymal stem cells derived from bone marrow and adipose tissue. J. Cell. Biochem. 99(5), 1285–1297 (2006).
    • 24 Vidal MA, Walker NJ, Napoli E, Borjesson DL. Evaluation of senescence in mesenchymal stem cells isolated from equine bone marrow, adipose tissue, and umbilical cord tissue. Stem Cells Dev. 21(2), 273–283 (2012).
    • 25 Zhang HT, Liu ZL, Yao XQ, Yang ZJ, Xu RX. Neural differentiation ability of mesenchymal stromal cells from bone marrow and adipose tissue: a comparative study. Cytotherapy 14(10), 1203–1214 (2012).
    • 26 Mccoy MK, Martinez TN, Ruhn KA et al. Autologous transplants of Adipose-Derived Adult Stromal (ADAS) cells afford dopaminergic neuroprotection in a model of Parkinson's disease. Exp. Neurol. 210(1), 14–29 (2008).
    • 27 Berg J, Roch M, Altschuler J et al. Human adipose-Derived Mesenchymal Stem Cells Improve Motor Functions and are Neuroprotective in the 6-Hydroxydopamine-Rat Model for Parkinson's Disease when Cultured in Monolayer Cultures but Suppress Hippocampal Neurogenesis and Hippocampal Memory Function when Cultured in Spheroids. Stem Cell Rev. 11(1), 133–149 (2014).•• Goundwork study for our study, which showed neuroprotective and effects of adipose-derived mesenchymal stem cells in a Parkinson's disease rat model.
    • 28 Ahmed H, Salem A, Atta H, Ghazy M, Aglan H. Do adipose tissue-derived mesenchymal stem cells ameliorate Parkinson's disease in rat model? Hum. Exp. Toxicol. 33(12), 1217–1231 (2014).
    • 29 Schwerk A, Altschüler J, Roch M et al. Human adipose-derived mesenchymal stromal cells increase endogenous neurogenesis in the rat subventricular zone acutely after 6-hydroxydopamine lesioning. Cytotherapy 17(2), 199–214 (2015).
    • 30 Frangioni JV, Hajjar RJ. In vivo tracking of stem cells for clinical trials in cardiovascular disease. Circulation 110(21), 3378–3383 (2004).
    • 31 Glavaski-Joksimovic A, Virag T, Chang QA et al. Reversal of dopaminergic degeneration in a parkinsonian rat following micrografting of human bone marrow-derived neural progenitors. Cell Transpl. 18(7), 801–814 (2009).
    • 32 Park HJ, Lee PH, Bang OY, Lee G, Ahn YH. Mesenchymal stem cells therapy exerts neuroprotection in a progressive animal model of Parkinson's disease. J. Neurochem. 107(1), 141–151 (2008).• Important study, which showed neuroprotective effects and a dopaminergic transdifferentiation of mesenchymal stem cells in a Parkinson's disease rat model.
    • 33 Wang W, Itaka K, Ohba S et al. 3D spheroid culture system on micropatterned substrates for improved differentiation efficiency of multipotent mesenchymal stem cells. Biomaterials 30(14), 2705–2715 (2009).
    • 34 Weiss ML, Medicetty S, Bledsoe AR et al. Human umbilical cord matrix stem cells: preliminary characterization and effect of transplantation in a rodent model of Parkinson's disease. Stem Cells 24(3), 781–792 (2006).
    • 35 Yuan H, Sarre S, Ebinger G, Michotte Y. Histological, behavioural and neurochemical evaluation of medial forebrain bundle and striatal 6-OHDA lesions as rat models of Parkinson's disease. J. Neurosci. Methods 144(1), 35–45 (2005).
    • 36 Blandini F, Cova L, Armentero MT et al. Transplantation of undifferentiated human mesenchymal stem cells protects against 6-hydroxydopamine neurotoxicity in the rat. Cell Transplant. 19(2), 203–217 (2010).
    • 37 Danielyan L, Schafer R, Von Ameln-Mayerhofer A et al. Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease. Rejuvenation Res. 14(1), 3–16 (2011).
    • 38 Tepper JM, Damlama M, Trent F. Postnatal changes in the distribution and morphology of rat substantia nigra dopaminergic neurons. Neuroscience 60(2), 469–477 (1994).
    • 39 Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates (5th Edition). Elsevier Academic Pres, Amsterdam, The Netherlands (2005).
    • 40 Ungerstedt U, Arbuthnott GW. Quantitative recording of rotational behavior in rats after 6-hydroxy-dopamine lesions of the nigrostriatal dopamine system. Brain Res. 24(3), 485–493 (1970).
    • 41 Balschun D, Manahan-Vaughan D, Wagner T, Behnisch T, Reymann KG, Wetzel W. A specific role for group I mGluRs in hippocampal LTP and hippocampus-dependent spatial learning. Learn. Mem. 6(2), 138–152 (1999).
    • 42 Decimo I, Fumagalli G, Berton V, Krampera M, Bifari F. Meninges. from protective membrane to stem cell niche. Am. J. Stem Cells 1(2), 92–105 (2012).
    • 43 Nakagomi T, Molnar Z, Taguchi A et al. Leptomeningeal-derived doublecortin-expressing cells in poststroke brain. Stem Cells Dev. 21(13), 2350–2354 (2012).
    • 44 Popescu BO, Gherghiceanu M, Kostin S, Ceafalan L, Popescu LM. Telocytes in meninges and choroid plexus. Neurosci. Lett. 516(2), 265–269 (2012).
    • 45 Mercier F, Hatton GI. Connexin 26 and basic fibroblast growth factor are expressed primarily in the subpial and subependymal layers in adult brain parenchyma. roles in stem cell proliferation and morphological plasticity? J. Compar. Neurol. 431(1), 88–104 (2001).
    • 46 Stylianopoulou F, Herbert J, Soares MB, Efstratiadis A. Expression of the insulin-like growth factor II gene in the choroid plexus and the leptomeninges of the adult rat central nervous system. Proc. Natl Acad. Sci. USA 85(1), 141–145 (1988).
    • 47 Steiner B, Kronenberg G, Jessberger S, Brandt MD, Reuter K, Kempermann G. Differential regulation of gliogenesis in the context of adult hippocampal neurogenesis in mice. Glia 46(1), 41–52 (2004).•• Key paper on neurogenesis, which assessed the amount of neuronal precursors in proliferating cells of the dentate gyrus.
    • 48 Campos FL, Carvalho MM, Cristovao AC et al. Rodent models of Parkinson's disease: beyond the motor symptomatology. Front. Behav. Neurosci. 7, 175 (2013).
    • 49 Domellof ME, Elgh E, Forsgren L. The relation between cognition and motor dysfunction in drug-naive newly diagnosed patients with Parkinson's disease. Mov. Disord. 26(12), 2183–2189 (2011).
    • 50 Janvin CC, Larsen JP, Aarsland D, Hugdahl K. Subtypes of mild cognitive impairment in Parkinson's disease: progression to dementia. Mov. Disord. 21(9), 1343–1349 (2006).
    • 51 Johnston LC, Su X, Maguire-Zeiss K et al. Human interleukin-10 gene transfer is protective in a rat model of Parkinson's disease. Mol. Ther. 16(8), 1392–1399 (2008).
    • 52 Lundblad M, Andersson M, Winkler C, Kirik D, Wierup N, Cenci MA. Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson's disease. Eur. J. Neurosci. 15(1), 120–132 (2002).
    • 53 Meredith GE, Kang UJ. Behavioral models of Parkinson's disease in rodents: a new look at an old problem. Mov. Disord. 21(10), 1595–1606 (2006).
    • 54 Chang JW, Wachtel SR, Young D, Kang UJ. Biochemical and anatomical characterization of forepaw adjusting steps in rat models of Parkinson's disease: studies on medial forebrain bundle and striatal lesions. Neuroscience 88(2), 617–628 (1999).
    • 55 Sakanaka M, Wen TC, Matsuda S et al. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc. Natl Acad. Sci. USA 95(8), 4635–4640 (1998).
    • 56 Wang L, Zhang ZG, Zhang RL et al. Matrix metalloproteinase 2 (MMP2) and MMP9 secreted by erythropoietin-activated endothelial cells promote neural progenitor cell migration. J. Neurosci. 26(22), 5996–6003 (2006).
    • 57 Kiyota T, Ingraham KL, Swan RJ, Jacobsen MT, Andrews SJ, Ikezu T. AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APP+PS1 mice. Gene Ther. 19(7), 724–733 (2012).
    • 58 Perez-Asensio FJ, Perpina U, Planas AM, Pozas E. Interleukin-10 regulates progenitor differentiation and modulates neurogenesis in adult brain. J. Cell Sci. 126(Pt 18), 4208–4219 (2013).
    • 59 Acquistapace A, Bru T, Lesault PF et al. Human mesenchymal stem cells reprogram adult cardiomyocytes toward a progenitor-like state through partial cell fusion and mitochondria transfer. Stem Cells 29(5), 812–824 (2011).
    • 60 Nygren JM, Jovinge S, Breitbach M et al. Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat. Med. 10(5), 494–501 (2004).
    • 61 Paredes MF, Li G, Berger O, Baraban SC, Pleasure SJ. Stromal-derived factor-1 (CXCL12) regulates laminar position of Cajal-Retzius cells in normal and dysplastic brains. J. Neurosci. 26(37), 9404–9412 (2006).
    • 62 Decimo I, Bifari F, Rodriguez FJ et al. Nestin- and doublecortin-positive cells reside in adult spinal cord meninges and participate in injury-induced parenchymal reaction. Stem Cells 29(12), 2062–2076 (2011).• Essential study on neurogenesis showing that precursor proliferation in the adult subependymal and subgranular zone depends on dopaminergic ennervation and is consequently reduced upon dopaminergic dennervation.
    • 63 Nakagomi T, Molnar Z, Nakano-Doi A et al. Ischemia-induced neural stem/progenitor cells in the pia mater following cortical infarction. Stem Cells Dev. 20(12), 2037–2051 (2011).
    • 64 Decimo I, Bifari F, Krampera M, Fumagalli G. Neural stem cell niches in health and diseases. Curr. Pharm. Des. 18(13), 1755–1783 (2012).
    • 65 Bestor TH. Gene silencing as a threat to the success of gene therapy. J. Clin. Invest. 105(4), 409–411 (2000).
    • 66 Ellis J, Yao S. Retrovirus silencing and vector design: relevance to normal and cancer stem cells? Curr. Gene Ther. 5(4), 367–373 (2005).
    • 67 Pannell D, Ellis J. Silencing of gene expression: implications for design of retrovirus vectors. Rev. Med. Virol. 11(4), 205–217 (2001).
    • 68 Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 3(4), 393–403 (1970).
    • 69 Karp JM, Leng Teo GS. Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell 4(3), 206–216 (2009).
    • 70 Pardridge WM, Boado RJ. Reengineering biopharmaceuticals for targeted delivery across the blood-brain barrier. Methods Enzymol. 503, 269–292 (2012).
    • 71 Nerem RM. Cell-based therapies: from basic biology to replacement, repair, and regeneration. Biomaterials 28(34), 5074–5077 (2007).
    • 72 Ikegame Y, Yamashita K, Hayashi S et al. Comparison of mesenchymal stem cells from adipose tissue and bone marrow for ischemic stroke therapy. Cytotherapy 13(6), 675–685 (2011).
    • 73 Mizuno H, Hyakusoku H. Mesengenic potential and future clinical perspective of human processed lipoaspirate cells. J. Nippon Med. Sch. 70(4), 300–306 (2003).
    • 74 Niemeyer P, Kornacker M, Mehlhorn A 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. 13(1), 111–121 (2007).