Stem cell delivery of therapies for brain disorders

Alexander Aleynik, Kevin M Gernavage, Yasmine Sh Mourad, Lauren S Sherman, Katherine Liu, Yuriy A Gubenko, Pranela Rameshwar, Alexander Aleynik, Kevin M Gernavage, Yasmine Sh Mourad, Lauren S Sherman, Katherine Liu, Yuriy A Gubenko, Pranela Rameshwar

Abstract

The blood brain barrier (BBB) poses a problem to deliver drugs for brain malignancies and neurodegenerative disorders. Stem cells such as neural stem cells (NSCs) and mesenchymal stem cells (MSCs) can be used to delivery drugs or RNA to the brain. This use of methods to bypass the hurdles of delivering drugs across the BBB is particularly important for diseases with poor prognosis such as glioblastoma multiforme (GBM). Stem cell treatment to deliver drugs to neural tumors is currently in clinical trial. This method, albeit in the early phase, could be an advantage because stem cells can cross the BBB into the brain. MSCs are particularly interesting because to date, the experimental and clinical evidence showed 'no alarm signal' with regards to safety. Additionally, MSCs do not form tumors as other more primitive stem cells such as embryonic stem cells. More importantly, MSCs showed pathotropism by migrating to sites of tissue insult. Due to the ability of MSCs to be transplanted across allogeneic barrier, drug-engineered MSCs can be available as off-the-shelf cells for rapid transplantation. This review discusses the advantages and disadvantages of stem cells to deliver prodrugs, genes and RNA to treat neural disorders.

Keywords: Glioblastoma; Mesenchymal stem cells; Neural stem cells; Therapy.

Figures

Figure 1
Figure 1
Transport mechanisms across the blood brain barrier (BBB) are depicted. I) Shows receptor-mediated transport, II) demonstrates non-specific uptake through adsorption-mediated transport, and III) displays carrier-mediated transport.
Figure 2
Figure 2
MSCs genetically engineered to secrete IFN-β injected into the rat internal carotid artery can penetrate the BBB and home to U87 glioblastoma cells within the central nervous system (CNS). Administration of these genetically engineered MSCs through the rat’s tail vein or subcutaneously does not lead to penetration of the BBB or MSC tumor homing. This tropic mechanism is mediated by several receptor ligand combinations and is correlated with bulk tumor size reduction.

References

    1. Banks WA. Brain meets body: the blood–brain barrier as an endocrine interface. Endocrinology. 2012;3:4111–4119.
    1. Glenner GG. Reprint of Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 2012;3:534–539.
    1. Gomez-Isla T, Hollister R, West H, Mui S, Growdon JH, Petersen RC, Parisi JE, Hyman BT. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol. 1997;3:17–24.
    1. Yankner BA, Duffy LK, Kirschner DA. Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science. 1990;3:279–282.
    1. Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet. 1998;3:106–108.
    1. Zhu C, Gao J, Karlsson N, Li Q, Zhang Y, Huang Z, Li H, Kuhn HG, Blomgren K. Isoflurane anesthesia induced persistent, progressive memory impairment, caused a loss of neural stem cells, and reduced neurogenesis in young, but not adult, rodents. J Cereb Blood Flow Metab. 2010;3:1017–1030.
    1. Pardridge WM. Molecular Trojan horses for blood–brain barrier drug delivery. Discov Med. 2006;3:139–143.
    1. Gauthier S, Herrmann N, Ferreri F, Agbokou C. Use of memantine to treat Alzheimer’s disease. CMAJ. 2006;3:501–502.
    1. Larrue V, von Kummer R, Muller A, Bluhmki E. Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary analysis of the European-Australasian Acute Stroke Study (ECASS II) Stroke. 2001;3:438–441.
    1. Bagiella E, Novack TA, Ansel B, Diaz-Arrastia R, Dikmen S, Hart T, Temkin N. Measuring outcome in traumatic brain injury treatment trials: recommendations from the traumatic brain injury clinical trials network. J Head Trauma Rehabil. 2010;3:375–382.
    1. Tapia-Arancibia L, Aliaga E, Silhol M, Arancibia S. New insights into brain BDNF function in normal aging and Alzheimer disease. Brain Res Rev. 2008;3:201–220.
    1. Aliaga E, Silhol M, Bonneau N, Maurice T, Arancibia S, Tapia-Arancibia L. Dual response of BDNF to sublethal concentrations of beta-amyloid peptides in cultured cortical neurons. Neurobiol Dis. 2010;3:208–217.
    1. Larsen JM, Martin DR, Byrne ME. Recent advances in delivery through the blood–brain barrier. Curr Top Med Chem. 2014;3:1148–1160.
    1. Hayek SM, Deer TR, Pope JE, Panchal SJ, Patel VB. Intrathecal therapy for cancer and non-cancer pain. Pain Physician. 2011;3:219–248.
    1. Treat LH, McDannold N, Vykhodtseva N, Zhang Y, Tam K, Hynynen K. Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound. Intl J Cancer. 2007;3:901–907.
    1. Liu HL, Fan CH, Ting CY, Yeh CK. Combining microbubbles and ultrasound for drug delivery to brain tumors: current progress and overview. Theranostics. 2014;3:432–444.
    1. Wang F, Cheng Y, Mei J, Song Y, Yang Y, Liu Y, Wang Z. Focused ultrasound microbubble destruction-mediated changes in blood–brain barrier permeability assessed by contrast-enhanced magnetic resonance imaging. J Ultrasound Med. 2009;3:1501–1509.
    1. Xie F, Boska MD, Lof J, Uberti MG, Tsutsui JM, Porter TR. Effects of transcranial ultrasound and intravenous microbubbles on blood brain barrier permeability in a large animal model. Ultrasound Med & Biol. 2008;3:2028.
    1. Egleton R, Davis T. Development of neuropeptide drugs that cross the blood–brain barrier. Neurotherapeutics. 2005;3:44–53.
    1. Abbruscato TJ, Thomas SA, Hruby VJ, Davis TP. Brain and spinal cord distribution of Biphalin: correlation with opioid receptor density and mechanism of CNS entry. J Neurochem. 1997;3:1236–1245.
    1. Patel MM, Goyal BR, Bhadada SV, Bhatt JS, Amin AF. Getting into the brain: approaches to enhance brain drug delivery. CNS Drugs. 2009;3:35–58.
    1. Scherrmann JM. Drug delivery to brain via the blood–brain barrier. Vas Pharmacol. 2002;3:349–354.
    1. Tucker IG. Drug delivery to the brain via the blood–brain barrier: a review of the literature and some recent patent disclosures. Ther Deliv. 2011;3:311–327.
    1. Pardridge WM, Boado RJ. In: Methods in Enzymology, Protein Engineering for Therapeutics, Part B, Volume 503. Gregory KDW, editor. Academic Press (Elsevier Inc); 2012. Reengineering biopharmaceuticals for targeted delivery across the blood–brain barrier; pp. 269–292.
    1. Tobias A, Ahmed A, Moon KS, Lesniak MS. The art of gene therapy for glioma: a review of the challenging road to the bedside. J Neurol Neurosurg Psychiatry. 2013;3:213–222.
    1. Juratli TA, Schackert G, Krex D. Current status of local therapy in malignant gliomas- a clinical review of three selected approaches. Pharmacol Therap. 2013;3:341–358.
    1. Bhujbal SV, de Vos P, Niclou SP. Drug and cell encapsulation: alternative delivery options for the treatment of malignant brain tumors. Adv Drug Deliv Rev. 2014;3:142–153.
    1. Gabathuler R. Approaches to transport therapeutic drugs across the blood–brain barrier to treat brain diseases. Neurobiol Dis. 2010;3:48–57.
    1. Tzeng SY, Green JJ. Therapeutic nanomedicine for brain cancer. Ther Deliv. 2013;3:687–704.
    1. Salahuddin TS, Johansson BB, Kalimo H, Olsson Y. Structural changes in the rat brain after carotid infusions of hyperosmolar solutions: a light microscopic and immunohistochemical study. Neuropathol Appl Neurobiol. 1988;3:467–482.
    1. Boado RJ, Pardridge WM. The Trojan horse liposome technology for nonviral gene transfer across the blood–brain barrier. J Drug Deliv. 2011;3:296151.
    1. Xiao G, Gan LS. Receptor-mediated endocytosis and brain delivery of therapeutic biologics. Int J Cell Biol. 2013;3:703545.
    1. Grossman SA, Ye X, Piantadosi S, Desideri S, Nabors LB, Rosenfeld M, Fisher J. for the NABTT CNS Consortium. Survival of patients with newly diagnosed Glioblastoma treated with radiation and Temozolomide in research studies in the United States. Clin Cancer Res. 2010;3:2443–2449.
    1. Yu MK, Park J, Jon S. Targeting strategies for multifunctional nanoparticles in cancer imaging and therapy. Theranostics. 2012;3:3–44.
    1. Osaka M, Honmou O, Murakami T, Nonaka T, Houkin K, Hamada H, Kocsis JD. Intravenous administration of mesenchymal stem cells derived from bone marrow after contusive spinal cord injury improves functional outcome. Brain Res. 2010;3:226–235.
    1. Akiyama Y, Radtke C, Honmou O, Kocsis JD. Remyelination of the spinal cord following intravenous delivery of bone marrow cells. Glia. 2002;3:229–236.
    1. Altaner C, Altanerova V. Stem cell based glioblastoma gene therapy. Neoplasma. 2012;3:756–760.
    1. Reagan MR, Kaplan DL. Concise review: mesenchymal stem cell tumor-homing: detection methods in disease model systems. Stem Cells. 2011;3:920–927.
    1. Liu L, Eckert MA, Riazifar H, Kang DK, Agalliu D, Zhao W. From blood to the brain: can systemically transplanted mesenchymal stem cells cross the blood–brain barrier? Stem Cells Int. 2013;3:435093.
    1. Bruder SP, Fink DJ, Caplan AI. Mesenchymal stem cells in bone development, bone repair, and skeletal regeneration therapy. J Cell Biochem. 1994;3:283–294.
    1. Huang B, Tabata Y, Gao JQ. Mesenchymal stem cells as therapeutic agents and potential targeted gene delivery vehicle for brain diseases. J Controlled Release. 2012;3:464–473.
    1. Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, Zhao RC, Shi Y. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of Chemokines and Nitric Oxide. Cell Stem Cell. 2008;3:141–150.
    1. da Silva Meirelles L, Caplan AI, Nardi NB. In search of the in vivo identity of Mesenchymal stem cells. Stem Cells. 2008;3:2287–2299.
    1. Yilmaz G, Vital S, Yilmaz CE, Stokes KY, Alexander JS, Granger DN. Selectin-mediated recruitment of bone marrow stromal cells in the Postischemic Cerebral Microvasculature. Stroke. 2011;3:806–811.
    1. Duebgen M, Martinez-Quintanilla J, Tamura K, Hingtgen S, Redjal N, Wakimoto H, Shah K. Stem cells loaded with multimechanistic oncolytic herpes simplex virus variants for brain tumor therapy. J Natl Cancer Inst. 2014;3:dju090.
    1. Munoz JL, Bliss SA, Greco SJ, Ramkissoon SH, Ligon KL, Rameshwar P. Delivery of functional anti-miR-9 by Mesenchymal Stem Cell-derived Exosomes to Glioblastoma Multiforme Cells Conferred Chemosensitivity. Mol Ther Nucleic Acids. 2013;3:e126.
    1. Xiong W, Candolfi M, Liu C, Muhammad AKMG, Yagiz K, Puntel M, Moore PF, Avalos J, Young JD, Khan D, Donelson R, Pluhar GE, Ohlfest JR, Wawrowsky K, Lowenstein PR, Castro MG. Human Flt3L generates dendritic cells from canine peripheral blood precursors: implications for a Dog Glioma clinical trial. PLoS ONE. 2010;3:e11074.
    1. Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E, Giunti D, Ceravolo A, Cazzanti F, Frassoni F, Mancardi G, Uccelli A. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood. 2005;3:1755–1761.
    1. Uccelli A, Milanese M, Principato MC, Morando S, Bonifacino T, Vergani L, Giunti D, Voci A, Carminati E, Giribaldi F, Caponnetto C, Bonanno G. Intravenous mesenchymal stem cells improve survival and motor function in experimental amyotrophic lateral sclerosis. Mol Med. 2012;3:794–804.
    1. Dey ND, Bombard MC, Roland BP, Davidson S, Lu M, Rossignol J, Sandstrom MI, Skeel RL, Lescaudron L, Dunbar GL. Genetically engineered mesenchymal stem cells reduce behavioral deficits in the YAC 128 mouse model of Huntington’s disease. Behav Brain Res. 2010;3:193–200.
    1. Choi SA, Lee JY, Wang KC, Phi JH, Song SH, Song J, Kim SK. Human adipose tissue-derived mesenchymal stem cells: characteristics and therapeutic potential as cellular vehicles for prodrug gene therapy against brainstem gliomas. Eur J Cancer. 2014;3:129–137.
    1. Altanerova V, Cihova M, Babic M, Rychly B, Ondicova K, Mravec B, Altaner C. Human adipose tissue-derived mesenchymal stem cells expressing yeast cytosinedeaminase::uracil phosphoribosyltransferase inhibit intracerebral rat glioblastoma. Intl J Cancer. 2012;3:2455–2463.
    1. Lee HK, Finniss S, Cazacu S, Bucris E, Ziv-Av A, Xiang C, Bobbitt K, Rempel S, Hasselbach L, Mikkelsen T, Slavin S, Brodie C. Mesenchymal stem cells deliver synthetic microRNA mimics to glioma cells and glioma stem cells and inhibit their cell migration and self-renewal. Oncotarget. 2013;3:346–361.
    1. Cristofanilli M, Harris VK, Zigelbaum A, Goossens AM, Lu A, Rosenthal H, Sadiq SA. Mesenchymal stem cells enhance the engraftment and myelinating ability of allogeneic oligodendrocyte progenitors in dysmyelinated mice. Stem Cells Dev. 2011;3:2065–2076.
    1. Ryu CH, Park KY, Hou Y, Jeong CH, Kim SM, Jeun SS. Gene therapy of multiple sclerosis using interferon beta-secreting human bone marrow mesenchymal stem cells. Biomed Res Int. 2013;3:696738.
    1. Binello E, Germano IM. Stem cells as therapeutic vehicles for the treatment of high-grade gliomas. Neuro-Oncol. 2012;3:256–265.
    1. Horn AP, Bernardi A, Luiz FR, Grudzinski PB, Hoppe JB, de Souza LF, Chagastelles P, de Souza Wyse AT, Bernard EA, Battastini AM, Campos NN, Lenz G, Nardi NB, Salbego C. Mesenchymal stem cell-conditioned medium triggers neuroinflammation and reactive species generation in organotypic cultures of rat hippocampus. Stem Cells Dev. 2011;3:1171–1181.
    1. Greco SJ, Rameshwar P. Mesenchymal stem cells in drug/gene delivery: implications for cell therapy. Ther Deliv. 2012;3:997–1004.
    1. Munoz JL, Rodriguez-Cruz V, Greco SJ, Ramkissoon SH, Ligon KL, Rameshwar P. Temozolomide resistance in glioblastoma cells occurs partly through epidermal growth factor receptor-mediated induction of connexin 43. Cell Death Dis. 2014;3:e1145.
    1. Natasha G, Gundogan B, Tan A, Farhatnia Y, Wu W, Rajadas J, Seifalian AM. Exosomes as Immunotheranostic Nanoparticles. Clin Ther. 2014;3:820–829.
    1. Atay S, Godwin AK. Tumor-derived exosomes: a message delivery system for tumor progression. Commun Integr Biol. 2014;3:e28231.
    1. Faur J, Lachenal G, Court M, Hirrlinger J, Chatellard-Causse C, Blot B, Grange J, Schoehn G, Goldberg Y, Boyer V, Kirchhoff F, Raposo G, Garin J, Sadoul R. Exosomes are released by cultured cortical neurones. Mol Cell Neurosci. 2006;3:642–648.
    1. Street J, Barran P, Mackay CL, Weidt S, Balmforth C, Walsh T, Chalmers R, Webb D, Dear J. Identification and proteomic profiling of exosomes in human cerebrospinal fluid. J Transl Med. 2012;3:5.
    1. Ansar M, Serrano D, Papademetriou I, Bhowmick TK, Muro S. Biological functionalization of drug delivery carriers to bypass size restrictions of receptor-mediated endocytosis independently from receptor targeting. ACS Nano. 2013;3:10597–10611.
    1. van Niel G, Porto-Carreiro I, Simoes S, Raposo G. Exosomes: a common pathway for a specialized function. J Biochem. 2006;3:13–21.
    1. Kobayashi T, Beuchat MH, Chevallier J, Makino A, Mayran N, Escola JM, Lebrand C, Cosson P, Kobayashi T, Gruenberg J. Separation and characterization of late endosomal membrane domains. J Biol Chem. 2002;3:32157–32164.
    1. Sobo K, Chevallier J, Parton RG, Gruenberg J, van der Goot FG. Diversity of raft-like domains in late endosomes. PLoS ONE. 2007;3:e391.
    1. Helms JB, Zurzolo C. Lipids as targeting signals: lipid rafts and intracellular trafficking. Traffic. 2004;3:247–254.
    1. Gregory LA, Ricart RA, Patel SA, Lim PK, Rameshwar P. MicroRNAs, Gap junctional intercellular communication and Mesenchymal stem cells in breast cancer metastasis. Curr Cancer Ther Rev. 2011;3:176–183.
    1. Hutvagner G, McLachlan J, Pasquinelli AE, Balint E, Tuschl T, Zamore PD. A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science. 2001;3:834–838.
    1. Gonzalez-Gomez P, Sanchez P, Mira H. MicroRNAs as regulators of neural stem cell-related pathways in Glioblastoma multiforme. Mol Neurobiol. 2011;3:235–249.
    1. Hoffman Y, Pilpel Y, Oren M. MicroRNAs and Alu elements in the p53-Mdm2-Mdm4 regulatory network. J Mol Cell Biol. 2014;3:192–197.
    1. Huang PH, Xu AM, White FM. Oncogenic EGFR signaling networks in glioma. Sci Signal. 2009;3:re6.
    1. Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, Lu KV, Yoshimoto K, Huang JHY, Chute DJ, Riggs BL, Horvath S, Liau LM, Cavenee WK, Rao PN, Beroukhim R, Peck TC, Lee JC, Sellers WR, Stokoe D, Prados M, Cloughesy TF, Sawyers CL, Mischel PS. Molecular determinants of the response of Glioblastomas to EGFR Kinase inhibitors. New England J Med. 2005;3:2012–2024.
    1. Zhou X, Ren Y, Moore L, Mei M, You Y, Xu P, Wang B, Wang G, Jia Z, Pu P, Zhang W, Kang C. Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status. Lab Invest. 2010;3:144–155.
    1. Huse JT, Brennan C, Hambardzumyan D, Wee B, Pena J, Rouhanifard SH, Sohn-Lee C, le Sage C, Agami R, Tuschl T, Holland EC. The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo. Genes Dev. 2009;3:1327–1337.
    1. Song L, Huang Q, Chen K, Liu L, Lin C, Dai T, Yu C, Wu Z, Li J. miR-218 inhibits the invasive ability of glioma cells by direct downregulation of IKK beta. Biochem Biophy Res Commun. 2010;3:135–140.
    1. Kefas B, Comeau L, Floyd DH, Seleverstov O, Godlewski J, Schmittgen T, Jiang J, diPierro CG, Li Y, Chiocca EA, Lee J, Fine H, Abounader R, Lawler S, Purow B. The neuronal microRNA miR-326 acts in a feedback loop with notch and has therapeutic potential against brain tumors. J Neurosci. 2009;3:15161–15168.
    1. Coolen M, Katz S, Bally-Cuif L. miR-9: a versatile regulator of neurogenesis. Frontiers Cell Neurosci. 2013;3:1–11.
    1. Webster RJ, Giles KM, Price KJ, Zhang PM, Mattick JS, Leedman PJ. Regulation of epidermal growth factor receptor signaling in human cancer cells by MicroRNA-7. J Biol Chem. 2009;3:5731–5741.
    1. Zhang C, Han L, Zhang A, Yang W, Zhou X, Pu P, Du Y, Zeng H, Kang C. Global changes of mRNA expression reveals an increased activity of the interferon-induced signal transducer and activator of transcription (STAT) pathway by repression of miR-221/222 in glioblastoma U251 cells. Int J Oncol. 2010;3:1503–1512.
    1. Silber J, Lim D, Petritsch C, Persson A, Maunakea A, Yu M, Vandenberg S, Ginzinger D, James CD, Costello J, Bergers G, Weiss W, Alvarez-Buylla A, Hodgson JG. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med. 2008;3:14.
    1. Godlewski J, Nowicki MO, Bronisz A, Williams S, Otsuki A, Nuovo G, RayChaudhury A, Newton HB, Chiocca EA, Lawler S. Targeting of the Bmi-1 oncogene/stem cell renewal factor by MicroRNA-128 inhibits Glioma proliferation and self-renewal. Cancer Res. 2008;3:9125–9130.
    1. Nan Y, Han L, Zhang A, Wang G, Jia Z, Yang Y, Yue X, Pu P, Zhong Y, Kang C. MiRNA-451 plays a role as tumor suppressor in human glioma cells. Brain Res. 2010;3:14–21.
    1. Danks MK, Yoon KJ, Bush RA, Remack JS, Wierdl M, Tsurkan L, Kim SU, Garcia E, Metz MZ, Najbauer J, Potter PM, Aboody KS. Tumor-targeted enzyme/prodrug therapy mediates long-term disease-free survival of mice bearing disseminated Neuroblastoma. Cancer Res. 2007;3:22–25.
    1. Kim SU, de Vellis J. Stem cell-based cell therapy in neurological diseases: a review. J Neurosci Res. 2009;3:2183–2200.
    1. Ohlsson LB, Varas L, Kjellman C, Edvardsen K, Lindvall M. Mesenchymal progenitor cell-mediated inhibition of tumor growth in vivo and in vitro in gelatin matrix. Exp Mol Pathol. 2003;3:248–255.
    1. Qiao L, Xu Z, Zhao T, Ye L, Zhang X. Dkk-1 secreted by mesenchymal stem cells inhibits growth of breast cancer cells via depression of Wnt signalling. Cancer Lett. 2008;3:67–77.
    1. Ramasamy R, Lam EWF, Soeiro I, Tisato V, Bonnet D, Dazzi F. Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: impact on in vivo tumor growth. Leukemia. 2006;3:304–310.
    1. van Eekelen M, Sasportas LS, Kasmieh R, Yip S, Figueiredo JL, Louis DN, Weissleder R, Shah K. Human stem cells expressing novel TSP-1 variant have anti-angiogenic effect on brain tumors. Oncogene. 2010;3:3185–3195.
    1. Sun B, Roh KH, Park JR, Lee SR, Park SB, Jung JW, Kang SK, Lee YS, Kang KS. Therapeutic potential of mesenchymal stromal cells in a mouse breast cancer metastasis model. Cytotherapy. 2009;3:289–298. 1.
    1. Miletic H, Fischer Y, Litwak S, Giroglou T, Waerzeggers Y, Winkeler A, Li H, Himmelreich U, Lange C, Stenzel W, Deckert M, Neumann H, Jacobs AH, von Laer D. Bystander killing of malignant glioma by bone marrow-derived tumor-infiltrating progenitor cells expressing a suicide gene. Mol Ther. 2007;3:1373–1381.
    1. Christian DA, Hunter CA. Particle-mediated delivery of cytokines for immunotherapy. Immunotherapy. 2012;3:425–441.
    1. Lim JY, Park SI, Kim SM, Jun JA, Oh JH, Ryu CH, Jeong CH, Park SH, Park SA, Oh W, Chang JW, Jeun SS. Neural differentiation of brain-derived neurotrophic factor-expressing human umbilical cord blood-derived mesenchymal stem cells in culture via TrkB-mediated ERK and beta-catenin phosphorylation and following transplantation into the developing brain. Cell Transplant. 2011;3:1855–1866.
    1. Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J, Chen J, Hentschel S, Vecil G, Dembinski J, Andreeff M, Lang FF. Human bone marrow-derived Mesenchymal stem cells in the treatment of Gliomas. Cancer Res. 2005;3:3307–3318.
    1. Rameshwar P. Current thoughts on the therapeutic potential of stem cell. Methods Mol Biol. 2012;3:3–26.

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