Document Type : Review Article
Authors
1 Department of Anatomy, TMMC & RC, Teerthanker Mahaveer University, Moradabad, Uttar Pradesh, India
2 Department of Pharmacology, TMMC & RC, Teerthanker Mahaveer University, Moradabad, Uttar Pradesh, India
Abstract
Background: Neurodegenerative diseases impact millions of individuals globally. Over the years, brain research has predominantly focused on neurons, but attention is now shifting to glial cells, the brain's support cells, which play a vital role in neurodegenerative disorders. Therefore, glial cell transplantation represents a groundbreaking treatment approach for various neurodegenerative disorders, with the potential to restore neuronal function. We evaluated the evidence on the therapeutic effectiveness of human glial cell transplantation in neurodegenerative disorders.
Methods: The literature review was performed in PubMed, Scopus, and Web of Science from 2000 to 2024. The authors independently reviewed the screened articles. The study outcomes on cell differentiation, long survival restoration of neuron function, and adverse outcomes were analyzed.
Results: Study results highlight promising findings, including astrocytes improving motor function and slowing disease progression in neurodegenerative animal models through neurotrophic factor secretion and reduced inflammation. Similarly, microglia transplantation has demonstrated effectiveness in reducing α-synuclein toxicity in Parkinson's disease (PD), removing amyloid-β plaques in Alzheimer's disease (AD) models, and enhancing neuronal survival. Additionally, in demyelinating pathologies like multiple sclerosis (MS), oligodendrocyte transplantation promotes remyelination, restoring axonal conduction and enhancing functional outcomes. Cografting astrocytes with neuro progenitor cells significantly improved dopamine neuron engraftment and survival for at least 6 months post-transplantation.
Conclusion: The transplantation of human glial cells offers promising therapeutic potential for neurodegenerative disorders, improving neuronal survival, restoring damaged circuits, and reducing disease progression.
Keywords
Main Subjects
- Murray CJL, Lopez AD. The global burden of disease: A comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020. Cambridge, MA: Harvard School of Public Health; 1996.
- Buffalo EA, Movshon JA, Wurtz RH. From basic brain research to treating human brain disorders. Proc Natl Acad Sci U S A 2019; 116(52): 26167-72.
- Kempermann G. Adult Neurogenesis: Stem Cells and Neuronal Development in the Adult Brain. Oxford, England: Oxford University Press; 2006.
- Przedborski S, Vila M, Jackson-Lewis V. Neurodegeneration: what is it and where are we? J Clin Invest 2003; 111(1): 3-10.
- Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA, Grant MK, et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 2010; 68(6): 1067-81.
- Martin JB. Molecular basis of the neurodegenerative disorders. N Engl
J Med 1999; 340(25): 1970-80. - Stone WS, Phillips MR, Yang LH, Kegeles LS, Susser ES, Lieberman JA. Neurodegenerative model of schizophrenia: Growing evidence to support a revisit. Schizophr Res 2022; 243: 154-62.
- Liu H, Hu Y, Zhang Y, Zhang H, Gao S, Wang L, et al. Mendelian randomization highlights significant difference and genetic heterogeneity in clinically diagnosed Alzheimer's disease GWAS and self-report proxy phenotype GWAX. Alzheimers Res Ther 2022; 14(1): 17.
- Albert K, Goldsteins G, Kälvälä S, Jolkkonen J, Lehtonen Š. Glial cell transplant for brain diseases: the supportive saviours? Transl Med Commun 2024; 9(1): 22.
- Moreno-Jiménez EP, Terreros-Roncal J, Flor-García M, Rábano A, Llorens-Martín M. Evidences for Adult Hippocampal Neurogenesis in Humans. J Neurosci 2021; 41(12): 2541-53.
- Kobashi S, Terashima T, Katagi M, Nakae Y, Okano J, Suzuki Y, et al. Transplantation of M2-Deviated Microglia Promotes Recovery of Motor Function after Spinal Cord Injury in Mice. Mol Ther 2020; 28(1): 254-65.
- Kondo T, Funayama M, Tsukita K, Hotta A, Yasuda A, Nori S, et al. Focal transplantation of human iPSC-derived glial-rich neural progenitors improves lifespan of ALS mice. Stem Cell Reports 2014; 3(2): 242-9.
- Priller J, Prinz M. Targeting microglia in brain disorders. Science 2019; 365(6448): 32-3.
- Higgins JPT, Morgan RL, Rooney AA, Taylor KW, Thayer KA, Silva RA, et al. A tool to assess risk of bias in non-randomized follow-up studies of exposure effects (ROBINS-E). Environ Int 2024; 186: 108602.
- Oberheim NA, Takano T, Han X, He W, Lin JH, Wang F, et al. Uniquely hominid features of adult human astrocytes.
J Neurosci 2009; 29(10): 3276-87. - Oberheim NA, Wang X, Goldman S, Nedergaard M. Astrocytic complexity distinguishes the human brain. Trends Neurosci 2006; 29(10): 547-53.
- Von Bartheld CS, Bahney J, Herculano-Houzel S. The search for true numbers of neurons and glial cells in the human brain: A review of 150 years of cell counting. J Comp Neurol 2016; 524(18): 3865-95.
- Goldman SA. Progenitor cell-based treatment of glial disease. Prog Brain Res 2017; 231: 165-89.
- Walker LC, Jucker M. Neurodegenerative diseases: expanding the prion concept. Annu Rev Neurosci 2015; 38: 87-103.
- Kranich J, Krautler NJ, Falsig J, Ballmer B, Li S, Hutter G, et al. Engulfment of cerebral apoptotic bodies controls the course of prion disease in a mouse strain-dependent manner. J Exp Med 2010; 207(10): 2271-81.
- Terwel D, Steffensen KR, Verghese PB, Kummer MP, Gustafsson J, Holtzman DM, et al. Critical role of astroglial apolipoprotein E and liver X receptor-α expression for microglial Aβ phagocytosis. J Neurosci 2011; 31(19): 7049-59.
- Brites D, Fernandes A. Neuroinflammation and Depression: Microglia Activation, Extracellular Microvesicles and microRNA Dysregulation. Front Cell Neurosci 2015;
9: 476. - Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models.
Science 2016; 352(6286): 712-6. - Daher JP, Volpicelli-Daley LA, Blackburn JP, Moehle MS, West AB. Abrogation of α-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats. Proc Natl Acad Sci USA 2014; 111(25): 9289-94.
- Boillée S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 2006; 312(5778): 1389-92.
- Chen C, Guderyon MJ, Li Y, Ge G, Bhattacharjee A, Ballard C, et al. Non-toxic HSC Transplantation-Based Macrophage/Microglia-Mediated GDNF Delivery for Parkinson's Disease. Mol Ther Methods Clin Dev 2020; 17: 83-98.
- Ban YH, Park D, Choi EK, Kim TM, Joo SS, Kim YB. Effectiveness of Combinational Treatments for Alzheimer's disease with Human Neural Stem Cells and Microglial Cells Over-Expressing Functional Genes. Int J Mol Sci 2023; 24(11): 9561.
- Lepore AC, O'Donnell J, Kim AS, Williams T, Tuteja A, Rao MS, et al. Human glial-restricted progenitor transplantation into cervical spinal cord of the SOD1 mouse model of ALS. Plos One 2011; 6(10): e25968.
- Izrael M, Slutsky SG, Admoni T, Cohen L, Granit A, Hasson A, et al. Safety and efficacy of human embryonic stem cell-derived astrocytes following intrathecal transplantation in SOD1(G93A) and NSG animal models. Stem Cell Res Ther 2018; 9(1): 152.
- Gotkine M, Caraco Y, Lerner Y, Blotnick S, Wanounou M, Slutsky SG, et al. Safety and efficacy of first-in-man intrathecal injection of human astrocytes (AstroRx®) in ALS patients: phase I/IIa clinical trial results. J Transl Med 2023; 21(1): 122.
- Proschel C, Stripay JL, Shih CH, Munger JC, Noble MD. Delayed transplantation of precursor cell-derived astrocytes provides multiple benefits in a rat model of Parkinsons. EMBO Mol Med 2014; 6(4): 504-18.
- Song JJ, Oh SM, Kwon OC, Wulansari N, Lee HS, Chang MY, et al. Cografting astrocytes improves cell therapeutic outcomes in a Parkinson's disease model. J Clin Invest 2018; 128(1): 463-82.
- Windrem MS, Schanz SJ, Guo M, Tian GF, Washco V, Stanwood N, et al. Neonatal chimerization with human glial progenitor cells can both remyelinate and rescue the otherwise lethally hypomyelinated shiverer mouse. Cell Stem Cell 2008; 2(6): 553-65.
- Wang S, Bates J, Li X, Schanz S, Chandler-Militello D, Levine C, et al. Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell 2013; 12(2): 252-64.
- Yoo Y, Neumayer G, Shibuya Y, Mader MM, Wernig M. A cell therapy approach to restore microglial Trem2 function in a mouse model of Alzheimer's disease. Cell Stem Cell 2023; 30(8): 1043-53.e6.
- Lepore AC, Rauck B, Dejea C, Pardo AC, Rao MS, Rothstein JD, et al. Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease. Nat Neurosci 2008; 11(11): 1294-301.
- Bahat-Stroomza M, Barhum Y, Levy YS, Karpov O, Bulvik S, Melamed E, et al. Induction of adult human bone marrow mesenchymal stromal cells into functional astrocyte-like cells: potential for restorative treatment in Parkinson's disease. J Mol Neurosci 2009; 39(1-2): 199-210.
- Esposito G, Sarnelli G, Capoccia E, Cirillo C, Pesce M, Lu J, et al. Autologous transplantation of intestine-isolated glia cells improves neuropathology and restores cognitive deficits in β amyloid-induced neurodegeneration. Sci Rep 2016; 6: 22605.
- Hampton DW, Webber DJ, Bilican B, Goedert M, Spillantini MG, Chandran S. Cell-mediated neuroprotection in a mouse model of human tauopathy. J Neurosci 2010; 30(30): 9973-83.
- Waldvogel HJ, Kim EH, Tippett LJ, Vonsattel JP, Faull RL. The Neuropathology of Huntington's Disease. Curr Top Behav Neurosci 2015; 22: 33-80.
- Benraiss A, Wang S, Herrlinger S, Li X, Chandler-Militello D, Mauceri J, et al. Human glia can both induce and rescue aspects of disease phenotype in Huntington disease. Nat Commun 2016; 7: 11758.
- Temple S. Advancing cell therapy for neurodegenerative diseases. Cell Stem Cell 2023; 30(5): 512-29.
- Levison SW, Goldman JE. Both oligodendrocytes and astrocytes develop from progenitors in the subventricular zone of postnatal rat forebrain. Neuron 1993; 10(2): 201-12.
- Nistor GI, Totoiu MO, Haque N, Carpenter MK, Keirstead HS. Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia 2005; 49(3): 385-96.
- Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 2017; 541(7638): 481-7.
- Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 2017; 541(7638): 481-7.
- Xi H, Chen L, Huang H, Zhang F, Liu Y, Chen D, et al. Preliminary report of multiple cell therapy for patients with multiple system atrophy. Cell Transplant 2013; 22 Suppl 1: S93-9.
- Hastings N, Kuan WL, Osborne A, Kotter MRN. Therapeutic Potential of Astrocyte Transplantation. Cell Transplant 2022; 31: 9636897221105499.
- Xu L, Yan J, Chen D, Welsh AM, Hazel T, Johe K, et al. Human neural stem cell grafts ameliorate motor neuron disease in SOD-1 transgenic rats. Transplantation 2006; 82(7): 865-75.