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VEGF-expressing human umbilical cord mesenchymal stem cells, an improved therapy strategy for Parkinson’s disease

Gene Therapy volume 18, pages 394–402 (2011)Cite this article

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Abstract

The umbilical cord provides a rich source of primitive mesenchymal stem cells (human umbilical cord mesenchymal stem cells (HUMSCs)), which have the potential for transplantation-based treatments of Parkinson's Disease (PD). Our pervious study indicated that adenovirus-associated virus-mediated intrastriatal delivery of human vascular endothelial growth factor 165 (VEGF 165) conferred molecular protection to the dopaminergic system. As both VEGF and HUMSCs displayed limited neuroprotection, in this study we investigated whether HUMSCs combined with VEGF expression could offer enhanced neuroprotection. HUMSCs were modified by adenovirus-mediated VEGF gene transfer, and subsequently transplanted into rotenone-lesioned striatum of hemiparkinsonian rats. As a result, HUMSCs differentiated into dopaminergic neuron-like cells on the basis of neuron-specific enolase (NSE) (neuronal marker), glial fibrillary acidic protein (GFAP) (astrocyte marker), nestin (neural stem cell marker) and tyrosine hydroxylase (TH) (dopaminergic marker) expression. Further, VEGF expression significantly enhanced the dopaminergic differentiation of HUMSCs in vivo. HUMSC transplantation ameliorated apomorphine-evoked rotations and reduced the loss of dopaminergic neurons in the lesioned substantia nigra (SNc), which was enhanced significantly by VEGF expression in HUMSCs. These findings present the suitability of HUMSC as a vector for gene therapy and suggest that stem cell engineering with VEGF may improve the transplantation strategy for the treatment of PD.

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References

  1. Mayeux R, Marder K, Cote LJ, Denaro J, Hemenegildo N, Mejia H et al. The frequency of idiopathic Parkinson's disease by age, ethnic group, and sex in northern Manhattan, 1988-1993. Am J Epidemiol 1995; 142: 820–827.

    Article  CAS  Google Scholar 

  2. Zhang ZX, Roman GC, Hong Z, Wu CB, Qu QM, Huang JB et al. Parkinson's disease in China: prevalence in Beijing, Xian, and Shanghai. Lancet 2005; 365: 595–597.

    Article  Google Scholar 

  3. Toulouse A, Sullivan AM . Progress in Parkinson's disease-where do we stand? Prog Neurobiol 2008; 85: 376–392.

    Article  Google Scholar 

  4. Olanow CW, Kieburtz K, Schapira AH . Why have we failed to achieve neuroprotection in Parkinson's disease? Ann Neurol 2008; 64 (Suppl 2): S101–S110.

    CAS  PubMed  Google Scholar 

  5. Geraerts M, Krylyshkina O, Debyser Z, Baekelandt V . Concise review: therapeutic strategies for Parkinson disease based on the modulation of adult neurogenesis. Stem Cells 2007; 25: 263–270.

    Article  CAS  Google Scholar 

  6. Friedman R, Betancur M, Boissel L, Tuncer H, Cetrulo C, Klingemann H . Umbilical cord mesenchymal stem cells: adjuvants for human cell transplantation. Biol Blood Marrow Transplant 2007; 13: 1477–1486.

    Article  Google Scholar 

  7. Brederlau A, Correia AS, Anisimov SV, Elmi M, Paul G, Roybon L et al. Transplantation of human embryonic stem cell-derived cells to a rat model of Parkinson's disease: effect of in vitro differentiation on graft survival and teratoma formation. Stem Cells 2006; 24: 1433–1440.

    Article  CAS  Google Scholar 

  8. Weiss ML, Medicetty S, Bledsoe AR, Rachakatla RS, Choi M, Merchav S et al. Human umbilical cord matrix stem cells: preliminary characterization and effect of transplantation in a rodent model of Parkinson's disease. Stem Cells 2006; 24: 781–792.

    Article  CAS  Google Scholar 

  9. Rossi DJ, Weissman IL . Pten, tumorigenesis, and stem cell self-renewal. Cell 2006; 125: 229–231.

    Article  CAS  Google Scholar 

  10. Miura K, Okada Y, Aoi T, Okada A, Takahashi K, Okita K et al. Variation in the safety of induced pluripotent stem cell lines. Nat Biotechnol 2009; 27: 743–745.

    Article  CAS  Google Scholar 

  11. Greenway MJ, Andersen PM, Russ C, Ennis S, Cashman S, Donaghy C et al. ANG mutations segregate with familial and ‘sporadic’ amyotrophic lateral sclerosis. Nat Genet 2006; 38: 411–413.

    Article  CAS  Google Scholar 

  12. Silverman WF, Krum JM, Mani N, Rosenstein JM . Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explant cultures. Neuroscience 1999; 90: 1529–1541.

    Article  CAS  Google Scholar 

  13. Pitzer MR, Sortwell CE, Daley BF, McGuire SO, Marchionini D, Fleming M et al. Angiogenic and neurotrophic effects of vascular endothelial growth factor (VEGF165): studies of grafted and cultured embryonic ventral mesencephalic cells. Exp Neurol 2003; 182: 435–445.

    Article  CAS  Google Scholar 

  14. Yasuhara T, Shingo T, Kobayashi K, Takeuchi A, Yano A, Muraoka K et al. Neuroprotective effects of vascular endothelial growth factor (VEGF) upon dopaminergic neurons in a rat model of Parkinson's disease. 2004; 19: 1494–1504.

  15. Yasuhara T, Shingo T, Muraoka K, Kameda M, Agari T, Wen Ji Y et al. Neurorescue effects of VEGF on a rat model of Parkinson's disease. Brain Research 2005; 1053: 10–18.

    Article  CAS  Google Scholar 

  16. Tian YY, Tang CJ, Wang JN, Feng Y, Chen XW, Wang L et al. Favorable effects of VEGF gene transfer on a rat model of Parkinson disease using adeno-associated viral vectors. Neuroscience Letters 2007; 421: 239–244.

    Article  CAS  Google Scholar 

  17. Xiong N, Huang J, Zhang Z, Xiong J, Liu X, Jia M et al. Stereotaxical Infusion of Rotenone: A Reliable Rodent Model for Parkinson's Disease. PLoS One 2009; 4: e7878.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Azzouz M, Ralph GS, Storkebaum E, Walmsley LE, Mitrophanous KA, Kingsman SM et al. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 2004; 429: 413–417.

    Article  CAS  Google Scholar 

  20. Storkebaum E, Lambrechts D, Dewerchin M, Moreno-Murciano MP, Appelmans S, Oh H et al. Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nature Neuroscience 2005; 8: 85–92.

    Article  CAS  Google Scholar 

  21. Yasuhara T, Shingo T, Date I . The potential role of vascular endothelial growth factor in the central nervous system. Rev Neurosci 2004; 15: 293–307.

    Article  CAS  Google Scholar 

  22. Romanov YA, Svintsitskaya VA, Smirnov VN . Searching for alternative sources of postnatal human mesenchymal stem cells: candidate MSC-like cells from umbilical cord. Stem Cells 2003; 21: 105–110.

    Article  Google Scholar 

  23. Mitchell KE, Weiss ML, Mitchell BM, Martin P, Davis D, Morales L et al. Matrix cells from Wharton's jelly form neurons and glia. Stem Cells 2003; 21: 50–60.

    Article  CAS  Google Scholar 

  24. Fu YS, Cheng YC, Lin MY, Cheng H, Chu PM, Chou SC 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.

    Article  Google Scholar 

  25. Sarugaser R, Lickorish D, Baksh D, Hosseini MM, Davies JE . Human umbilical cord perivascular (HUCPV) cells: a source of mesenchymal progenitors. Stem Cells 2005; 23: 220–229.

    Article  Google Scholar 

  26. Wang HS, Hung SC, Peng ST, Huang CC, Wei HM, Guo YJ et al. Mesenchymal stem cells in the Wharton's jelly of the human umbilical cord. Stem Cells 2004; 22: 1330–1337.

    Article  Google Scholar 

  27. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002; 418: 41–49.

    Article  CAS  Google Scholar 

  28. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143–147.

    Article  CAS  Google Scholar 

  29. Jin KL, Mao XO, Greenberg DA . Vascular endothelial growth factor: direct neuroprotective effect in in vitro ischemia. Proc Natl Acad Sci USA 2000; 97: 10242–10247.

    Article  CAS  Google Scholar 

  30. Yang SP, Bae DG, Kang HJ, Gwag BJ, Gho YS, Chae CB . Co-accumulation of vascular endothelial growth factor with beta-amyloid in the brain of patients with Alzheimer's disease. Neurobiol Aging 2004; 25: 283–290.

    Article  Google Scholar 

  31. Radtke C, Spies M, Sasaki M, Vogt PM, Kocsis JD . Demyelinating diseases and potential repair strategies. Int J Dev Neurosci 2007; 25: 149–153.

    Article  CAS  Google Scholar 

  32. Lee ST, Chu K, Jung KH, Kim SJ, Kim DH, Kang KM et al. Anti-inflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke. Brain 2008; 131 (Part 3): 616–629.

    Article  Google Scholar 

  33. Karp JM, Leng Teo GS . Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell 2009; 4: 206–216.

    Article  CAS  Google Scholar 

  34. Huang J, Hao L, Xiong N, Cao X, Liang Z, Sun S et al. Involvement of glyceraldehyde-3-phosphate dehydrogenase in rotenone induced cell apoptosis: Relevance to protein misfolding and aggregation. Brain Research 2009; 1279: 1–8.

    Article  CAS  Google Scholar 

  35. Brazelton TR, Rossi FM, Keshet GI, Blau HM . From marrow to brain: expression of neuronal phenotypes in adult mice. Science 2000; 290: 1775–1779.

    Article  CAS  Google Scholar 

  36. Mezey E, Key S, Vogelsang G, Szalayova I, Lange GD, Crain B . Transplanted bone marrow generates new neurons in human brains. Proc Natl Acad Sci USA 2003; 100: 1364–1369.

    Article  CAS  Google Scholar 

  37. Trzaska KA, Kuzhikandathil EV, Rameshwar P . Specification of a dopaminergic phenotype from adult human mesenchymal stem cells. Stem cells 2007; 25: 2797–2808.

    Article  CAS  Google Scholar 

  38. Muhlhauser J, Merrill MJ, Pili R, Maeda H, Bacic M, Bewig B et al. VEGF165 expressed by a replication-deficient recombinant adenovirus vector induces angiogenesis in vivo. Circ Res 1995; 77: 1077–1086.

    Article  CAS  Google Scholar 

  39. Ma R, Xiong N, Huang C, Tang Q, Hu B, Xiang J et al. Erythropoietin protects PC12 cells from beta-amyloid(25-35)-induced apoptosis via PI3K/Akt signaling pathway. Neuropharmacology 2009; 56: 1027–1034.

    Article  CAS  Google Scholar 

  40. Zhang Z, Cao X, Xiong N, Wang H, Huang J, Sun S et al. DNA polymerase-beta is required for 1-methyl-4-phenylpyridinium-induced apoptotic death in neurons. Apoptosis: an international journal on programmed cell death 2010; 15: 105–115.

    Article  CAS  Google Scholar 

  41. Dai Y, Xu M, Wang Y, Pasha Z, Li T, Ashraf M . HIF-1alpha induced-VEGF overexpression in bone marrow stem cells protects cardiomyocytes against ischemia. J Mol Cell Cardiol 2007; 42: 1036–1044.

    Article  CAS  Google Scholar 

  42. Hedlund E, Pruszak J, Lardaro T, Ludwig W, Vinuela A, Kim KS et al. Embryonic stem cell-derived Pitx3-enhanced green fluorescent protein midbrain dopamine neurons survive enrichment by fluorescence-activated cell sorting and function in an animal model of Parkinson's disease. Stem cells 2008; 26: 1526–1536.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (30870866), the Wuhan Science and Technology Bureau, China (20066002100) and the Hubei Provincial Science and Technology Department, China (2006ABA130). We are grateful to Drs Li Zou and Weixiang Ouyang (Gynecology and Obstetrics department, Union Hospital, HUST) for assisting with umbilical cord collection, Dr William J Long (MIT Lab for Computer Science, Cambridge, MA, USA) for polishing this manuscript and Dr Edgar (Ned) A Butter (Department of Psychiatry, Harvard Medical School, Boston, MA, USA) for proofreading this manuscript.

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Authors and Affiliations

  1. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China

    N Xiong, Z Zhang, J Huang, C Chen, Z Zhang, M Jia, J Xiong, X Liu, F Wang, X Cao, Z Liang, S Sun & T Wang

  2. Department of Psychiatry, Harvard Medical School; Division of Alcohol and Drug Abuse, and Mailman Research Center, McLean Hospital, Belmont, MA, USA

    N Xiong & Z Lin

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Correspondence to T Wang.

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This manuscript presents original research and has been neither previously published nor submitted for publication elsewhere.

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Xiong, N., Zhang, Z., Huang, J. et al. VEGF-expressing human umbilical cord mesenchymal stem cells, an improved therapy strategy for Parkinson’s disease. Gene Ther 18, 394–402 (2011). https://doi.org/10.1038/gt.2010.152

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