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Kirkeby A, Nelander J, Hoban DB, Rogelius N, Bjartmarz H, Storm P, Fiorenzano A, Adler AF, Vale S, Mudannayake J, Zhang Y, Cardoso T, Mattsson B, Landau AM, Glud AN, Sørensen JC, Lillethorup TP, Lowdell M, Carvalho C, Bain O, van Vliet T, Lindvall O, Björklund A, Harry B, Cutting E, Widner H, Paul G, Barker RA, Parmar M. Preclinical quality, safety, and efficacy of a human embryonic stem cell-derived product for the treatment of Parkinson's disease, STEM-PD. Cell Stem Cell 2023; 30:1299-1314.e9. [PMID: 37802036 DOI: 10.1016/j.stem.2023.08.014] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 07/06/2023] [Accepted: 08/31/2023] [Indexed: 10/08/2023]
Abstract
Cell replacement therapies for Parkinson's disease (PD) based on transplantation of pluripotent stem cell-derived dopaminergic neurons are now entering clinical trials. Here, we present quality, safety, and efficacy data supporting the first-in-human STEM-PD phase I/IIa clinical trial along with the trial design. The STEM-PD product was manufactured under GMP and quality tested in vitro and in vivo to meet regulatory requirements. Importantly, no adverse effects were observed upon testing of the product in a 39-week rat GLP safety study for toxicity, tumorigenicity, and biodistribution, and a non-GLP efficacy study confirmed that the transplanted cells mediated full functional recovery in a pre-clinical rat model of PD. We further observed highly comparable efficacy results between two different GMP batches, verifying that the product can be serially manufactured. A fully in vivo-tested batch of STEM-PD is now being used in a clinical trial of 8 patients with moderate PD, initiated in 2022.
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Affiliation(s)
- Agnete Kirkeby
- Wallenberg Neuroscience Center, Wallenberg Center for Molecular Medicine and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden; Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW) and Department of Neuroscience, University of Copenhagen, 2200 Copenhagen, Denmark.
| | - Jenny Nelander
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Deirdre B Hoban
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Nina Rogelius
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Hjálmar Bjartmarz
- Department of Neurosurgery, Skåne University Hospital, 221 85 Lund, Sweden
| | - Petter Storm
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Alessandro Fiorenzano
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Andrew F Adler
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Shelby Vale
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Janitha Mudannayake
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Yu Zhang
- Wallenberg Neuroscience Center, Wallenberg Center for Molecular Medicine and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden; Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Tiago Cardoso
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Bengt Mattsson
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Anne M Landau
- Department of Nuclear Medicine & PET-Center and Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark
| | - Andreas N Glud
- Center for Experimental Neuroscience (CENSE), Department of Neurosurgery, Department of Clinical Medicine, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Jens C Sørensen
- Center for Experimental Neuroscience (CENSE), Department of Neurosurgery, Department of Clinical Medicine, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Thea P Lillethorup
- Department of Nuclear Medicine & PET-Center and Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark
| | - Mark Lowdell
- Centre for Cell, Gene and Tissue Therapeutics, Royal Free NHS Foundation Trust, Royal Free Hospital, London NW3 2QG, UK
| | - Carla Carvalho
- Centre for Cell, Gene and Tissue Therapeutics, Royal Free NHS Foundation Trust, Royal Free Hospital, London NW3 2QG, UK
| | - Owen Bain
- Centre for Cell, Gene and Tissue Therapeutics, Royal Free NHS Foundation Trust, Royal Free Hospital, London NW3 2QG, UK
| | | | - Olle Lindvall
- Lund Stem Cell Center and Department of Clinical Sciences Lund, Lund University, 221 84 Lund, Sweden
| | - Anders Björklund
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Bronwen Harry
- Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0PY, UK
| | - Emma Cutting
- Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0PY, UK
| | - Håkan Widner
- Department of Neurology, Skåne University Hospital, 221 85 Lund, Sweden
| | - Gesine Paul
- Department of Neurology, Skåne University Hospital, 221 85 Lund, Sweden; Wallenberg Neuroscience Center, Wallenberg Center for Molecular Medicine, Department of Clinical Sciences, Lund University, 221 84 Lund, Sweden
| | - Roger A Barker
- Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0PY, UK; Wellcome-MRC Cambridge Stem Cell Institute, Cambridge CB2 0AW, UK
| | - Malin Parmar
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.
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Barker RA, Björklund A. Restorative cell and gene therapies for Parkinson's disease. HANDBOOK OF CLINICAL NEUROLOGY 2023; 193:211-226. [PMID: 36803812 DOI: 10.1016/b978-0-323-85555-6.00012-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/18/2023]
Abstract
One of the core pathological features of Parkinson's disease (PD) is the loss of the dopaminergic nigrostriatal pathway which lies at the heart of many of the motor features of this condition as well as some of the cognitive problems. The importance of this pathological event is evident through the clinical benefits that are seen when patients with PD are treated with dopaminergic agents, at least in early-stage disease. However, these agents create problems of their own through stimulation of more intact dopaminergic networks within the central nervous system causing major neuropsychiatric problems including dopamine dysregulation. In addition, over time the nonphysiological stimulation of striatal dopamine receptors by l-dopa containing drugs leads to the genesis of l-dopa-induced dyskinesias that can become very disabling in many cases. As such, there has been much interest in trying to better reconstitute the dopaminergic nigrostriatal pathway using either factors to regrow it, cells to replace it, or gene therapies to restore dopamine transmission in the striatum. In this chapter, we lay out the rationale, history and current status of these different therapies as well as highlighting where the field is heading and what new interventions might come to clinic in the coming years.
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Affiliation(s)
- Roger A Barker
- Department of Clinical Neuroscience, Cambridge Centre for Brain Repair, Cambridge, United Kingdom.
| | - Anders Björklund
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Lund, Sweden
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Li JY, Li W. Postmortem Studies of Fetal Grafts in Parkinson's Disease: What Lessons Have We Learned? Front Cell Dev Biol 2021; 9:666675. [PMID: 34055800 PMCID: PMC8155361 DOI: 10.3389/fcell.2021.666675] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 04/06/2021] [Indexed: 12/28/2022] Open
Abstract
Neural transplantation is a potential therapeutic method for Parkinson’s disease (PD). Fetal dopaminergic (DA) neurons have been important transplantation cell sources in the history of replacement therapy for PD. Several decades of preclinical animal experiments and clinical trials using fetal DA neuron transplantation in PD therapy have shown not only promising results but also problems. In order to reveal possible factors influencing the clinical outcomes, we reviewed fetal DA neuron transplantation therapies from 1970s to present, with a special focus on postmortem studies. Firstly, we gave a general description of the clinical outcomes and neuroanatomy of grafted cases; secondly, we summarized the main available postmortem studies, including the cell survival, reinnervation, and pathology development. In the end, we further discussed the link between function and structure of the grafts, seeking for the possible factors contributing to a functional graft. With our review, we hope to provide references for future transplantation trials from a histological point of view.
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Affiliation(s)
- Jia-Yi Li
- Laboratory of Neurodegenerative Diseases and Repair, Institute of Health Sciences, China Medical University, Shenyang, China.,Neural Plasticity and Repair Unit, Wallenberg Neuroscience Centre, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Wen Li
- Laboratory of Neurodegenerative Diseases and Repair, Institute of Health Sciences, China Medical University, Shenyang, China.,Neural Plasticity and Repair Unit, Wallenberg Neuroscience Centre, Department of Experimental Medical Science, Lund University, Lund, Sweden
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Esdaille CJ, Washington KS, Laurencin CT. Regenerative engineering: a review of recent advances and future directions. Regen Med 2021; 16:495-512. [PMID: 34030463 PMCID: PMC8356698 DOI: 10.2217/rme-2021-0016] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 05/06/2021] [Indexed: 12/20/2022] Open
Abstract
Regenerative engineering is defined as the convergence of the disciplines of advanced material science, stem cell science, physics, developmental biology and clinical translation for the regeneration of complex tissues and organ systems. It is an expansion of tissue engineering, which was first developed as a method of repair and restoration of human tissue. In the past three decades, advances in regenerative engineering have made it possible to treat a variety of clinical challenges by utilizing cutting-edge technology currently available to harness the body's healing and regenerative abilities. The emergence of new information in developmental biology, stem cell science, advanced material science and nanotechnology have provided promising concepts and approaches to regenerate complex tissues and structures.
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Affiliation(s)
- Caldon J Esdaille
- Howard University College of Medicine, Washington, DC 20011, USA
- Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut Health Center, Farmington, CT 06030, USA
- Raymond & Beverly Sackler Center for Biomedical, Biological, Physical & Engineering Sciences, University of Connecticut Health, Farmington, CT 06030, USA
| | - Kenyatta S Washington
- Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut Health Center, Farmington, CT 06030, USA
- Raymond & Beverly Sackler Center for Biomedical, Biological, Physical & Engineering Sciences, University of Connecticut Health, Farmington, CT 06030, USA
- Department of Orthopedic Surgery, University of Connecticut Health, Farmington, CT 06030, USA
| | - Cato T Laurencin
- Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut Health Center, Farmington, CT 06030, USA
- Raymond & Beverly Sackler Center for Biomedical, Biological, Physical & Engineering Sciences, University of Connecticut Health, Farmington, CT 06030, USA
- Department of Orthopedic Surgery, University of Connecticut Health, Farmington, CT 06030, USA
- Department of Chemical & Biomolecular Engineering, University of Connecticut, Storrs, CT 06269, USA
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT 06030, USA
- Department of Materials Science & Engineering, University of Connecticut, Storrs, CT 06269, USA
- Institute of Materials Science, University of Connecticut, Storrs, CT 06269, USA
- Department of Craniofacial Sciences, School of Dental Medicine, University of Connecticut Health, Farmington, CT 06030, USA
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Rocco M, Juri C. Is treatment with stem cells effective in Parkinson's disease? Medwave 2018; 18:e7242. [PMID: 30240387 DOI: 10.5867/medwave.2018.05.7241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Accepted: 08/14/2018] [Indexed: 11/27/2022] Open
Abstract
INTRODUCTION There are many patients with Parkinson's disease who have a limited response to conventional pharmacological treatment. The use of stem cells has been postulated as an alternative, although its effectiveness remains a matter of controversy. METHODS To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS We identified two systematic reviews including 21 studies overall, of which three were randomized trials. We concluded it is not clear whether stem cells have any effect on the symptoms of Parkinson's disease because the certainty of the available evidence is very low.
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Affiliation(s)
- Matías Rocco
- Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Proyecto Epistemonikos, Santiago, Chile
| | - Carlos Juri
- Proyecto Epistemonikos, Santiago, Chile; Departamento de Neurología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile. . Address: Centro Evidencia UC, Pontificia Universidad Católica de Chile, Av. Diagonal Paraguay 476, Santiago, Chile
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Mortada I, Mortada R, Al Bazzal M. Dental pulp stem cells and the management of neurological diseases: An update. J Neurosci Res 2017; 96:265-272. [PMID: 28736906 DOI: 10.1002/jnr.24122] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 07/05/2017] [Accepted: 07/05/2017] [Indexed: 01/08/2023]
Abstract
Medical research in regenerative medicine has brought promising perspectives for the use of stem cells in clinical trials. Stem cells are undifferentiated cells capable of multilineage differentiation and available in numerous sources in the human body. Dental pulp constitutes an attractive source of these cells since collecting mesenchymal stem cells from this site is a noninvasive practice that can be performed after a common surgical extraction of supernumerary or wisdom teeth. Thus, tissue sacrifice is very low and several cytotypes can be obtained owing to these cells' multipotency, in addition to the fact that they can be cryopreserved and stored for long periods. Mesenchymal stem cells have high proliferation rates, making them favorable for clinical application. These multipotent cells, present in biological waste, constitute an appropriate resource in the treatment of many neurological diseases.
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Affiliation(s)
- Ibrahim Mortada
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Rola Mortada
- Lebanese University School of Dentistry, Beirut, Lebanon
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Niclis JC, Gantner CW, Alsanie WF, McDougall SJ, Bye CR, Elefanty AG, Stanley EG, Haynes JM, Pouton CW, Thompson LH, Parish CL. Efficiently Specified Ventral Midbrain Dopamine Neurons from Human Pluripotent Stem Cells Under Xeno-Free Conditions Restore Motor Deficits in Parkinsonian Rodents. Stem Cells Transl Med 2016; 6:937-948. [PMID: 28297587 PMCID: PMC5442782 DOI: 10.5966/sctm.2016-0073] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 09/01/2016] [Indexed: 01/04/2023] Open
Abstract
Recent studies have shown evidence for the functional integration of human pluripotent stem cell (hPSC)‐derived ventral midbrain dopamine (vmDA) neurons in animal models of Parkinson’s disease. Although these cells present a sustainable alternative to fetal mesencephalic grafts, a number of hurdles require attention prior to clinical translation. These include the persistent use of xenogeneic reagents and challenges associated with scalability and storage of differentiated cells. In this study, we describe the first fully defined feeder‐ and xenogeneic‐free protocol for the generation of vmDA neurons from hPSCs and utilize two novel reporter knock‐in lines (LMX1A‐eGFP and PITX3‐eGFP) for in‐depth in vitro and in vivo tracking. Across multiple embryonic and induced hPSC lines, this “next generation” protocol consistently increases both the yield and proportion of vmDA neural progenitors (OTX2/FOXA2/LMX1A) and neurons (FOXA2/TH/PITX3) that display classical vmDA metabolic and electrophysiological properties. We identify the mechanism underlying these improvements and demonstrate clinical applicability with the first report of scalability and cryopreservation of bona fide vmDA progenitors at a time amenable to transplantation. Finally, transplantation of xeno‐free vmDA progenitors from LMX1A‐ and PITX3‐eGFP reporter lines into Parkinsonian rodents demonstrates improved engraftment outcomes and restoration of motor deficits. These findings provide important and necessary advancements for the translation of hPSC‐derived neurons into the clinic. Stem Cells Translational Medicine2017;6:937–948
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Affiliation(s)
- Jonathan C. Niclis
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia
| | - Carlos W. Gantner
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia
| | - Walaa F. Alsanie
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia
| | - Stuart J. McDougall
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia
| | - Chris R. Bye
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia
| | - Andrew G. Elefanty
- Murdoch Children’s Research Institute, The Royal Children’s Hospital, Melbourne, Victoria, Australia
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
| | - Edouard G. Stanley
- Murdoch Children’s Research Institute, The Royal Children’s Hospital, Melbourne, Victoria, Australia
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
| | - John M. Haynes
- Monash Institute of Pharmaceutical Sciences, Monash University, Clayton, Victoria, Australia
| | - Colin W. Pouton
- Monash Institute of Pharmaceutical Sciences, Monash University, Clayton, Victoria, Australia
| | - Lachlan H. Thompson
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia
| | - Clare L. Parish
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia
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TAKAGI Y. History of Neural Stem Cell Research and Its Clinical Application. Neurol Med Chir (Tokyo) 2016; 56:110-24. [PMID: 26888043 PMCID: PMC4791305 DOI: 10.2176/nmc.ra.2015-0340] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 01/15/2016] [Indexed: 12/11/2022] Open
Abstract
"Once development was ended…in the adult centers, the nerve paths are something fixed and immutable. Everything may die, nothing may be regenerated," wrote Santiago Ramón y Cajal, a Spanish neuroanatomist and Nobel Prize winner and the father of modern neuroscience. This statement was the central dogma in neuroscience for a long time. However, in the 1960s, neural stem cells (NSCs) were discovered. Since then, our knowledge about NSCs has continued to grow. This review focuses on our current knowledge about NSCs and their surrounding microenvironment. In addition, the clinical application of NSCs for the treatment of various central nervous system diseases is also summarized.
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Affiliation(s)
- Yasushi TAKAGI
- Department of Neurosurgery, Kyoto University Graduate School of Medicine, Sakyo, Kyoto
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Racette BA, Willis AW. Time to change the blind men and the elephant approach to Parkinson disease? Neurology 2015; 85:190-6. [PMID: 26070339 PMCID: PMC4515036 DOI: 10.1212/wnl.0000000000001739] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 03/12/2015] [Indexed: 11/15/2022] Open
Abstract
Parkinson disease (PD) is a progressive neurodegenerative disease that is associated with substantial morbidity and early mortality. Disease-related costs exceed $10 billion, not including medications, out-of-pocket expenses, or societal costs. Symptomatic treatment with levodopa, which has been available for over 30 years, and advanced therapies such as deep brain stimulation improve outcomes. Yet most new medications for PD provide a therapeutic benefit that is relatively modest compared to the benefits from levodopa. Despite dozens of neuroprotective clinical trials, there are no medications proven to slow the progression of the disease. Given these limitations, we provide evidence of the potential public health impact of a research agenda that emphasizes identification of risk factors to reduce disease burden through exposure mitigation. In addition, we emphasize health care policy that focuses on increasing health care expenditures for neurologic evaluation and management services to increase access to specialists to improve disease outcomes and reduce costs through better disease management.
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Affiliation(s)
- Brad A Racette
- From the Department of Neurology (B.A.R.), Washington University School of Medicine, St. Louis, MO; the School of Public Health (B.A.R.), Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa; and the Department of Neurology (A.W.W.) and the Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics (A.W.W.), University of Pennsylvania School of Medicine, Philadelphia.
| | - Allison W Willis
- From the Department of Neurology (B.A.R.), Washington University School of Medicine, St. Louis, MO; the School of Public Health (B.A.R.), Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa; and the Department of Neurology (A.W.W.) and the Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics (A.W.W.), University of Pennsylvania School of Medicine, Philadelphia
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Suksuphew S, Noisa P. Neural stem cells could serve as a therapeutic material for age-related neurodegenerative diseases. World J Stem Cells 2015; 7:502-511. [PMID: 25815135 PMCID: PMC4369507 DOI: 10.4252/wjsc.v7.i2.502] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 09/18/2014] [Accepted: 10/27/2014] [Indexed: 02/06/2023] Open
Abstract
Progressively loss of neural and glial cells is the key event that leads to nervous system dysfunctions and diseases. Several neurodegenerative diseases, for instance Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, are associated to aging and suggested to be a consequence of deficiency of neural stem cell pool in the affected brain regions. Endogenous neural stem cells exist throughout life and are found in specific niches of human brain. These neural stem cells are responsible for the regeneration of new neurons to restore, in the normal circumstance, the functions of the brain. Endogenous neural stem cells can be isolated, propagated, and, notably, differentiated to most cell types of the brain. On the other hand, other types of stem cells, such as mesenchymal stem cells, embryonic stem cells, and induced pluripotent stem cells can also serve as a source for neural stem cell production, that hold a great promise for regeneration of the brain. The replacement of neural stem cells, either endogenous or stem cell-derived neural stem cells, into impaired brain is highly expected as a possible therapeutic mean for neurodegenerative diseases. In this review, clinical features and current routinely treatments of age-related neurodegenerative diseases are documented. Noteworthy, we presented the promising evidence of neural stem cells and their derivatives in curing such diseases, together with the remaining challenges to achieve the best outcome for patients.
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Kim SU, Lee HJ, Park IH, Chu K, Lee ST, Kim M, Roh JK, Kim SK, Wang KC. Human nerual stem cells for brain repair. Int J Stem Cells 2014; 1:27-35. [PMID: 24855505 DOI: 10.15283/ijsc.2008.1.1.27] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/02/2008] [Indexed: 01/17/2023] Open
Abstract
Cell replacement therapy and gene transfer to the diseased or injured brain have provided the basis for the development of potentially powerful new therapeutic strategies for a broad spectrum of human neurological diseases including Parkinson disease, Huntington disease, amyotrophic lateral sclerosis (ALS), Alzheimer disease, multiple sclerosis (MS), stroke, spinal cord injury and brain cancer. In recent years, neurons and glial cells have successfully been generated from neural stem cells, and extensive efforts by investigators to develop neural stem cell-based transplantation therapies have been carried out. We review here notable experimental and pre-clinical studies we have previously conducted involving human neural stem cell-based cell- and gene-therapies for Parkinson disease, Huntington disease, ALS, stroke and brain cancer.
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Affiliation(s)
- Seung U Kim
- Institute for Regenerative Medicine, Gachon Medical University Gil Hospital, Incheon, Korea ; Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, Canada
| | - Hong J Lee
- Institute for Regenerative Medicine, Gachon Medical University Gil Hospital, Incheon, Korea
| | - In H Park
- Institute for Regenerative Medicine, Gachon Medical University Gil Hospital, Incheon, Korea
| | - Kon Chu
- Department of Neurology Seoul National University Hospital, Seoul, Korea
| | - Soon T Lee
- Department of Neurology Seoul National University Hospital, Seoul, Korea
| | - Manho Kim
- Department of Neurology Seoul National University Hospital, Seoul, Korea
| | - Jae K Roh
- Department of Neurology Seoul National University Hospital, Seoul, Korea
| | - Seung K Kim
- Department of Neurosurgery, Seoul National University Hospital, Seoul, Korea
| | - Kyu C Wang
- Department of Neurosurgery, Seoul National University Hospital, Seoul, Korea
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Arias-Carrión O, Murillo-Rodríguez E. Effects of hypocretin/orexin cell transplantation on narcoleptic-like sleep behavior in rats. PLoS One 2014; 9:e95342. [PMID: 24736646 PMCID: PMC3988205 DOI: 10.1371/journal.pone.0095342] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2014] [Accepted: 03/25/2014] [Indexed: 11/22/2022] Open
Abstract
The sleep disorder narcolepsy is now considered a neurodegenerative disease because there is a massive loss of neurons containing the neuropeptide hypocretin/orexin (HCRT). In consequence, narcoleptic patients have very low cerebrospinal fluid (CSF) levels of HCRT. Studies in animal models of narcolepsy have shown the neurophysiological role of the HCRT system in the development of this disease. For example, the injection of the neurotoxin named hypocretin-2-saporin (HCRT2/SAP) into the lateral hypothalamus (LH) destroys the HCRT neurons, therefore diminishes the contents of HCRT in the CSF and induces narcoleptic-like behavior in rats. Transplants of various cell types have been used to induce recovery in a variety of neurodegenerative animal models. In models such as Parkinson's disease, cell survival has been shown to be small but satisfactory. Similarly, cell transplantation could be employed to implant grafts of HCRT cells into the LH or even other brain regions to treat narcolepsy. Here, we report for the first time that transplantation of HCRT neurons into the LH of HCRT2/SAP-lesioned rats diminishes narcoleptic-like sleep behavior. Therefore, cell transplantation may provide an effective method to treat narcolepsy.
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Affiliation(s)
- Oscar Arias-Carrión
- Unidad de Trastornos del Movimiento y Sueño (TMS), Hospital General Dr. Manuel Gea González, Mexico City, Mexico
- Unidad de Trastornos del Movimiento y Sueño (TMS), Hospital General Ajusco Medio, Mexico City, Mexico
- * E-mail: (OAC); (EMR)
| | - Eric Murillo-Rodríguez
- Laboratorio de Neurociencias Moleculares e Integrativas, Escuela de Medicina, División Ciencias de la Salud, Universidad Anáhuac Mayab, Mérida, Yucatán, Mexico
- * E-mail: (OAC); (EMR)
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Cordeiro KK, Cordeiro JG, Furlanetti LL, Garcia SJA, Tenório SB, Winkler C, Döbrössy MD, Nikkhah G. Subthalamic nucleus lesion improves cell survival and functional recovery following dopaminergic cell transplantation in parkinsonian rats. Eur J Neurosci 2014; 39:1474-84. [DOI: 10.1111/ejn.12541] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 01/31/2014] [Accepted: 02/03/2014] [Indexed: 11/28/2022]
Affiliation(s)
- Karina Kohn Cordeiro
- Department of Stereotactic and Functional Neurosurgery; Laboratory of Stereotaxy and Interventional Neurosciences; University Freiburg-Medical Center; Breisacher Str. 64 Freiburg 79106 Germany
- Federal University of Paraná; Hospital de Clínicas; Curitiba Brazil
| | - Joacir Graciolli Cordeiro
- Department of Stereotactic and Functional Neurosurgery; Laboratory of Stereotaxy and Interventional Neurosciences; University Freiburg-Medical Center; Breisacher Str. 64 Freiburg 79106 Germany
- Federal University of Paraná; Hospital de Clínicas; Curitiba Brazil
| | - Luciano Lopes Furlanetti
- Department of Stereotactic and Functional Neurosurgery; Laboratory of Stereotaxy and Interventional Neurosciences; University Freiburg-Medical Center; Breisacher Str. 64 Freiburg 79106 Germany
| | | | | | - Christian Winkler
- Department of Neurology; University Freiburg-Medical Center; Freiburg Germany
- Department of Neurology; Lindenbrunn Hospital; Coppenbrügge Germany
| | - Máté Daniel Döbrössy
- Department of Stereotactic and Functional Neurosurgery; Laboratory of Stereotaxy and Interventional Neurosciences; University Freiburg-Medical Center; Breisacher Str. 64 Freiburg 79106 Germany
| | - Guido Nikkhah
- Department of Neurosurgery; University Hospital of Erlangen; Erlangen Germany
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14
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Barker RA, de Beaufort I. Scientific and ethical issues related to stem cell research and interventions in neurodegenerative disorders of the brain. Prog Neurobiol 2013; 110:63-73. [DOI: 10.1016/j.pneurobio.2013.04.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2012] [Revised: 04/04/2013] [Accepted: 04/12/2013] [Indexed: 12/13/2022]
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15
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Kim SU, Lee HJ, Kim YB. Neural stem cell-based treatment for neurodegenerative diseases. Neuropathology 2013; 33:491-504. [PMID: 23384285 DOI: 10.1111/neup.12020] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Revised: 12/27/2012] [Accepted: 12/28/2012] [Indexed: 12/11/2022]
Abstract
Human neurodegenerative diseases such as Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) are caused by a loss of neurons and glia in the brain or spinal cord. Neurons and glial cells have successfully been generated from stem cells such as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs) and neural stem cells (NSCs), and stem cell-based cell therapies for neurodegenerative diseases have been developed. A recent advance in generation of a new class of pluripotent stem cells, induced pluripotent stem cells (iPSCs), derived from patients' own skin fibroblasts, opens doors for a totally new field of personalized medicine. Transplantation of NSCs, neurons or glia generated from stem cells in animal models of neurodegenerative diseases, including PD, HD, ALS and AD, demonstrates clinical improvement and also life extension of these animals. Additional therapeutic benefits in these animals can be provided by stem cell-mediated gene transfer of therapeutic genes such as neurotrophic factors and enzymes. Although further research is still needed, cell and gene therapy based on stem cells, particularly using neurons and glia derived from iPSCs, ESCs or NSCs, will become a routine treatment for patients suffering from neurodegenerative diseases and also stroke and spinal cord injury.
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Affiliation(s)
- Seung U Kim
- Medical Research Institute, Chung-Ang University College of Medicine, Seoul, Korea; Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, British Columbia, Canada
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16
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Neirinckx V, Coste C, Rogister B, Wislet-Gendebien S. Concise review: adult mesenchymal stem cells, adult neural crest stem cells, and therapy of neurological pathologies: a state of play. Stem Cells Transl Med 2013; 2:284-96. [PMID: 23486833 PMCID: PMC3659839 DOI: 10.5966/sctm.2012-0147] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Accepted: 01/16/2013] [Indexed: 12/14/2022] Open
Abstract
Adult stem cells are endowed with in vitro multilineage differentiation abilities and constitute an attractive autologous source of material for cell therapy in neurological disorders. With regard to lately published results, the ability of adult mesenchymal stem cells (MSCs) and neural crest stem cells (NCSCs) to integrate and differentiate into neurons once inside the central nervous system (CNS) is currently questioned. For this review, we collected exhaustive data on MSC/NCSC neural differentiation in vitro. We then analyzed preclinical cell therapy experiments in different models for neurological diseases and concluded that neural differentiation is probably not the leading property of adult MSCs and NCSCs concerning neurological pathology management. A fine analysis of the molecules that are secreted by MSCs and NCSCs would definitely be of significant interest regarding their important contribution to the clinical and pathological recovery after CNS lesions.
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Affiliation(s)
| | | | - Bernard Rogister
- Neurosciences Unit and
- Development, Stem Cells and Regenerative Medicine Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée, University of Liège, Liège, Belgium
- Neurology Department, Centre Hospitalier Universitaire de Liège, Liège, Belgium
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17
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Kim SU. Regenerative Medicine in the Central Nervous System: Stem Cell-Based Cell- and Gene-Therapy. Regen Med 2013. [DOI: 10.1007/978-94-007-5690-8_27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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18
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Nicoleau C, Viegas P, Peschanski M, Perrier AL. Human pluripotent stem cell therapy for Huntington's disease: technical, immunological, and safety challenges human pluripotent stem cell therapy for Huntington's disease: technical, immunological, and safety challenges. Neurotherapeutics 2011; 8:562-76. [PMID: 21976138 PMCID: PMC3250302 DOI: 10.1007/s13311-011-0079-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Intra-striatal transplantation of homotypic fetal tissue at the time of peak striatal neurogenesis can provide some functional benefit to patients suffering from Huntington's disease. Currently, the only approach shown to slow down the course of this condition is replacement of the neurons primarily targeted in this disorder, although it has been transient and has only worked with a limited number of patients. Otherwise, this dominantly inherited neurodegenerative disease inevitably results in the progressive decline of motricity, cognition, and behavior, and leads to death within 15 to 20 years of onset. However, fetal neural cell therapy of Huntington's disease, as with a similar approach in Parkinson's disease, is marred with both technical and biological hurdles related to the source of grafting material. This heavily restricts the number of patients who can be treated. A substitute cell source is therefore needed, but must perform at least as well as fetal neural graft in terms of brain recovery and reconstruction, while overcoming its major obstacles. Human pluripotent stem cells (embryonic in origin or induced from adult cells through genetic reprogramming) have the potential to meet those challenges. In this review, the therapeutic potential in view of 4 major issues is identified during fetal cell therapy clinical trials: 1) logistics of graft procurement, 2) quality control of the cell preparation, 3) immunogenicity of the graft, and 4) safety of the procedure.
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Affiliation(s)
- Camille Nicoleau
- INSERM U861, I-STEM, AFM, Evry Cedex, 91030 France
- UEVE U861, I-STEM, AFM, Evry Cedex, 91030 France
| | - Pedro Viegas
- INSERM U861, I-STEM, AFM, Evry Cedex, 91030 France
- UEVE U861, I-STEM, AFM, Evry Cedex, 91030 France
| | - Marc Peschanski
- INSERM U861, I-STEM, AFM, Evry Cedex, 91030 France
- UEVE U861, I-STEM, AFM, Evry Cedex, 91030 France
| | - Anselme L. Perrier
- INSERM U861, I-STEM, AFM, Evry Cedex, 91030 France
- UEVE U861, I-STEM, AFM, Evry Cedex, 91030 France
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19
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Wakeman DR, Dodiya HB, Kordower JH. Cell transplantation and gene therapy in Parkinson's disease. ACTA ACUST UNITED AC 2011; 78:126-58. [PMID: 21259269 DOI: 10.1002/msj.20233] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Parkinson's disease is a progressive neurodegenerative disorder affecting, in part, dopaminergic motor neurons of the ventral midbrain and their terminal projections that course to the striatum. Symptomatic strategies focused on dopamine replacement have proven effective at remediating some motor symptoms during the course of disease but ultimately fail to deliver long-term disease modification and lose effectiveness due to the emergence of side effects. Several strategies have been experimentally tested as alternatives for Parkinson's disease, including direct cell replacement and gene transfer through viral vectors. Cellular transplantation of dopamine-secreting cells was hypothesized as a substitute for pharmacotherapy to directly provide dopamine, whereas gene therapy has primarily focused on restoration of dopamine synthesis or neuroprotection and restoration of spared host dopaminergic circuitry through trophic factors as a means to enhance sustained controlled dopamine transmission. This seems now to have been verified in numerous studies in rodents and nonhuman primates, which have shown that grafts of fetal dopamine neurons or gene transfer through viral vector delivery can lead to improvements in biochemical and behavioral indices of dopamine deficiency. However, in clinical studies, the improvements in parkinsonism have been rather modest and variable and have been plagued by graft-induced dyskinesias. New developments in stem-cell transplantation and induced patient-derived cells have opened the doors for the advancement of cell-based therapeutics. In addition, viral-vector-derived therapies have been developed preclinically with excellent safety and efficacy profiles, showing promise in clinical trials thus far. Further progress and optimization of these therapies will be necessary to ensure safety and efficacy before widespread clinical use is deemed appropriate.
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20
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Lepski G, Jannes CE, Wessolleck J, Kobayashi E, Nikkhah G. Equivalent neurogenic potential of wild-type and GFP-labeled fetal-derived neural progenitor cells before and after transplantation into the rodent hippocampus. Transplantation 2011; 91:390-7. [PMID: 21169879 DOI: 10.1097/tp.0b013e3182063083] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
INTRODUCTION The hippocampal formation is a specific structure in the brain where neurogenesis occurs throughout adulthood and in which the neuronal cell loss causes various demential states. The main goal of this study was to verify whether fetal neural progenitor cells (NPCs) from transgenic rats expressing green fluorescent protein (GFP) retain the ability to differentiate into neuronal cells and to integrate into the hippocampal circuitry after transplantation. METHODS NPCs were isolated from E14 (gestational age: 14 days postconception) transgenic-Lewis and wild-type Sprague-Dawley rat embryos. Wild-type and transgenic cells were expanded and induced to differentiate into a neuronal lineage in vitro. Immunocytochemical and electrophysiological analysis were performed in both groups. GFP-expressing cells were implanted into the hippocampus and recorded electrophysiologically 3 months thereafter. Immunohistochemical analysis confirmed neuronal differentiation, and the yield of neuronal cells was determined stereologically. RESULTS NPCs derived from wild-type and transgenic animals are similar regarding their ability to generate neuronal cells in vitro. Neuronal maturity was confirmed by immunocytochemistry and electrophysiology, with demonstration of voltage-gated ionic currents, firing activity, and spontaneous synaptic currents. GFP-NPCs were also able to differentiate into mature neurons after implantation into the hippocampus, where they formed functional synaptic contacts. CONCLUSIONS GFP-transgenic cells represent an important tool in transplantation studies. Herein, we demonstrate their ability to generate functional neurons both in vitro and in vivo conditions. Neurons derived from fetal NPCs were able to integrate into the normal hippocampal circuitry. The high yield of mature neurons generated render these cells important candidates for restorative approaches based on cell therapy.
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Affiliation(s)
- Guilherme Lepski
- Department of Stereotactic and Functional Neurosurgery, University of Freiburg, Freiburg, Germany.
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21
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Delayed functional maturation of human neuronal progenitor cells in vitro. Mol Cell Neurosci 2011; 47:36-44. [PMID: 21362477 DOI: 10.1016/j.mcn.2011.02.011] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2010] [Revised: 02/19/2011] [Accepted: 02/21/2011] [Indexed: 01/19/2023] Open
Abstract
INTRODUCTION Differentiation of neuronal progenitor cells (NPCs) in vitro into functional neurons is dependent on a complex cascade of molecular signaling pathways, many of which remain unknown. More specifically, in human NPCs the relationship between the expression of typical neuronal marker proteins and functional properties, such as firing action potential and synaptic transmission, is not well understood. In the present report, the immunocytochemical, morphological and electrophysiological changes that human NPCs undergo during neuronal differentiation in vitro were investigated. METHODS Human NPCs were differentiated toward a neuronal phenotype. The time course of the expression of neuronal markers and morphological cell changes was mapped and passive and active electrophysiological membrane properties assessed, throughout the neuronal maturation process. RESULTS The acquisition of neuronal markers preceded functional physiological maturation by several weeks. Cell input resistance decreased in the first 2 weeks as cells became less sensitive to input current, while cell capacitance progressively increased with continued neuronal process growth. Functional maturation was observed only by the fifth/sixth week, preceded by a marked increase in Na+ and K+ currents. In contrast, electrophysiological maturation of rodent precursor cells was observed at the end of the first week in vitro. Functionally, human neuronal cells became capable of firing action potentials and forming active synaptic contacts. Many features of the firing pattern however remained immature. CONCLUSIONS The results showed that human NPCs develop remarkably slowly and retain immature neuronal features for a prolonged period. The importance of Na-dependent activity for proper neuronal maturation is emphasized.
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22
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Jin Y, Zhang C, Ziemba KS, Goldstein GA, Sullivan PG, Smith GM. Directing dopaminergic fiber growth along a preformed molecular pathway from embryonic ventral mesencephalon transplants in the rat brain. J Neurosci Res 2011; 89:619-27. [PMID: 21337366 DOI: 10.1002/jnr.22575] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2010] [Revised: 10/21/2010] [Accepted: 11/07/2010] [Indexed: 12/23/2022]
Abstract
To identify guidance molecules to promote long-distance growth of dopaminergic axons from transplanted embryonic ventral mesencephalon (VM) tissue, three pathways were created by expressing green fluorescent protein (GFP), glial cell line-derived neurotrophic factor (GDNF), or a combination of GDNF/GDNF receptor α1 (GFRα1) along the corpus callosum. To generate the guidance pathway, adenovirus encoding these transcripts was injected at four positions along the corpus callosum. In all groups, GDNF adenovirus was also injected on the right side 2.5 mm from the midline at the desired transplant site. Four days later, a piece of VM tissue from embryonic day 14 rats was injected at the transplant site. All rats also received daily subcutaneous injections of N-acetyl-L-cysteinamide (NACA; 100 μg per rat) as well as chondroitinase ABC at transplant site (10 U/ml, 2 μl). Two weeks after transplantation, the rats were perfused and the brains dissected out. Coronal sections were cut and immunostained with antibody to tyrosine hydroxylase (TH) to identify and count dopaminergic fibers in the corpus callosum. In GFP-expressing pathways, TH(+) fibers grew out of the transplants for a short distance in the corpus callosum. Very few TH(+) fibers grew across the midline. However, pathways expressing GDNF supported more TH(+) fiber growth across the midline into the contralateral hemisphere. Significantly greater numbers of TH(+) fibers grew across the midline in animals expressing a combination of GDNF and GFRα1 in the corpus callosum. These data suggest that expression of GDNF or a combination of GDNF and GFRα1 can support the long-distance dopaminergic fiber growth from a VM transplant, with the combination having a superior effect.
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Affiliation(s)
- Y Jin
- Department of Physiology, University of Kentucky, Lexington, Kentucky 40536, USA
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23
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Regenerative Medicine in the Central Nervous System: Stem Cell-Based Gene-Therapy. Regen Med 2011. [DOI: 10.1007/978-90-481-9075-1_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
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24
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Freeman TB, Cicchetti F, Bachoud-Lévi AC, Dunnett SB. Technical factors that influence neural transplant safety in Huntington's disease. Exp Neurol 2011; 227:1-9. [PMID: 20849848 DOI: 10.1016/j.expneurol.2010.08.031] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2010] [Revised: 08/18/2010] [Accepted: 08/21/2010] [Indexed: 01/30/2023]
Affiliation(s)
- T B Freeman
- Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL 33606-3571, USA.
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25
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Grafted dopamine neurons: Morphology, neurochemistry, and electrophysiology. Prog Neurobiol 2010; 90:190-7. [DOI: 10.1016/j.pneurobio.2009.10.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2009] [Revised: 04/23/2009] [Accepted: 10/09/2009] [Indexed: 01/02/2023]
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26
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Kim SU, de Vellis J. Stem cell-based cell therapy in neurological diseases: a review. J Neurosci Res 2009; 87:2183-200. [PMID: 19301431 DOI: 10.1002/jnr.22054] [Citation(s) in RCA: 310] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Human neurological disorders such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, multiple sclerosis (MS), stroke, and spinal cord injury are caused by a loss of neurons and glial cells in the brain or spinal cord. Cell replacement therapy and gene transfer to the diseased or injured brain have provided the basis for the development of potentially powerful new therapeutic strategies for a broad spectrum of human neurological diseases. However, the paucity of suitable cell types for cell replacement therapy in patients suffering from neurological disorders has hampered the development of this promising therapeutic approach. In recent years, neurons and glial cells have successfully been generated from stem cells such as embryonic stem cells, mesenchymal stem cells, and neural stem cells, and extensive efforts by investigators to develop stem cell-based brain transplantation therapies have been carried out. We review here notable experimental and preclinical studies previously published involving stem cell-based cell and gene therapies for Parkinson's disease, Huntington's disease, ALS, Alzheimer's disease, MS, stroke, spinal cord injury, brain tumor, and lysosomal storage diseases and discuss the future prospects for stem cell therapy of neurological disorders in the clinical setting. There are still many obstacles to be overcome before clinical application of cell therapy in neurological disease patients is adopted: 1) it is still uncertain what kind of stem cells would be an ideal source for cellular grafts, and 2) the mechanism by which transplantation of stem cells leads to an enhanced functional recovery and structural reorganization must to be better understood. Steady and solid progress in stem cell research in both basic and preclinical settings should support the hope for development of stem cell-based cell therapies for neurological diseases.
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Affiliation(s)
- Seung U Kim
- Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
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27
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Bolliet C, Bohn MC, Spector M. Non-viral delivery of the gene for glial cell line-derived neurotrophic factor to mesenchymal stem cells in vitro via a collagen scaffold. Tissue Eng Part C Methods 2009; 14:207-19. [PMID: 18721070 DOI: 10.1089/ten.tec.2008.0168] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Recent advances in tissue engineering that combine an extracellular matrix-like scaffold with therapeutic molecules, cells, DNA encoding therapeutic proteins, or a combination of the three hold promise for treating defects in the brain resulting from a penetrating injury or tumor resection. The purpose of this study was to investigate a porous sponge-like collagen scaffold for non-viral delivery of a plasmid encoding for glial cell line-derived neurotrophic factor (pGDNF) to rat marrow stromal stem cells (also referred to as mesenchymal stem cells, MSCs). The effects of the following parameters on GDNF synthesis in the three-dimensional (3D) constructs were evaluated and compared with results in monolayer culture: initial plasmid load (2-50 microg pGDNF), ratio of a lipid transfection reagent to plasmid (5:10), culture environment during the transfection (static and dynamic), and cell density. The level of gene expression in the collagen scaffolds achieved therapeutic levels that had previously been found to support survival of dopaminergic and trigeminal neurons in vitro. For the highest loading of plasmid (50 microg), the level of GDNF protein remained six to seven times above the control level after 2 weeks, a significant difference. Cell density in the scaffold was of importance for an early increase in GDNF production, with accumulated GDNF being approximately 60% greater after 9 days of culture when scaffolds were initially seeded with 2 million rat MSCs compared to 500,000 cells. Application of orbital shaking during the 4 h of transfection had a positive effect on the production of GDNF on 3D constructs but not of the same magnitude as reported in monolayer studies. Overall, these results demonstrate that the combination of tissue engineering and non-viral transfection of MSCs for the over-expression of GDNF is a promising approach for the long-term production of GDNF and probably for neurotrophic factors in general.
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Affiliation(s)
- Catherine Bolliet
- Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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28
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Olanow CW, Gracies JM, Goetz CG, Stoessl AJ, Freeman T, Kordower JH, Godbold J, Obeso JA. Clinical pattern and risk factors for dyskinesias following fetal nigral transplantation in Parkinson's disease: A double blind video-based analysis. Mov Disord 2008; 24:336-43. [PMID: 19006186 DOI: 10.1002/mds.22208] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Affiliation(s)
- C Warren Olanow
- Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029-6574, USA.
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29
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Gómez-Pinedo U, Félez MC, Sancho-Bielsa FJ, Vidueira S, Cabanes C, Soriano M, García-Verdugo JM, Barcia JA. Improved technique for stereotactic placement of nerve grafts between two locations inside the rat brain. J Neurosci Methods 2008; 174:194-201. [PMID: 18692091 DOI: 10.1016/j.jneumeth.2008.07.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2008] [Revised: 06/29/2008] [Accepted: 07/02/2008] [Indexed: 11/19/2022]
Abstract
Peripheral nerve grafts have shown the ability to facilitate central axonal growth and regenerate the adult central nervous system. However, the detailed description of a technique for atraumatic graft placement within the brain is lacking. We present a stereotactic procedure to implant a peripheral nerve graft within a rat's brain with minimal brain tissue damage. The procedure permits a correct graft placement joining two chosen points, and the survival and integration of the graft in the host tissue with a light glial reaction, with evidence of central axonal growth inside the graft, at least up to 8 weeks after its implantation.
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30
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Torres EM, Dowd E, Dunnett SB. Recovery of functional deficits following early donor age ventral mesencephalic grafts in a rat model of Parkinson's disease. Neuroscience 2008; 154:631-40. [PMID: 18468807 DOI: 10.1016/j.neuroscience.2008.03.048] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2007] [Revised: 03/10/2008] [Accepted: 03/20/2008] [Indexed: 12/12/2022]
Abstract
It has previously been reported that dopaminergic grafts derived from early donor age, embryonic age 12-day-old (E12) rat embryos produced a fivefold greater yield of dopamine neurons than those derived from conventional E14 donors. The present study addresses whether E12 grafts are able to ameliorate lesion-induced behavioral deficits to the same extent as E14 grafts. In a unilateral rat model of Parkinson's disease, animals received grafts derived from either E12 or E14 donor embryos, dispersed at four sites in the lesioned striatum. Both E12 and E14 grafts were able to induce recovery on both amphetamine and apomorphine rotation tests, and to ameliorate deficits in the cylinder, stepping test, and corridor tests, but were unable to restore function in the paw reaching task. E12 grafts were equivalent to E14 grafts in their effects on lesion-induced deficits. However, E12 grafts resulted in cell yields greater than previously reported for untreated primary tissue, with mean TH-positive cell counts in excess of 25,000 neurons, compared with E14 TH cell counts of 4000-5000 cells, representing survival rates of 75% and 12.5%, respectively, based on the expected adult complement. The equivalence of graft induced behavioral recovery between the two graft groups is attributed to a threshold number of cells, above which no further improvement is seen. Such high dopamine cell survival rates should mean that multiple, functioning grafts can be derived from a single embryonic donor, and if similar yields could be obtained from human tissues then the goal of one embryo per patient would be achieved.
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Affiliation(s)
- E M Torres
- Department of Biosciences, Biomedical Sciences Building, Museum Avenue, Cardiff University, PO Box 911 Cardiff South Glamorgan, UK.
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31
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Newman MB, Bakay RAE. Therapeutic potentials of human embryonic stem cells in Parkinson's disease. Neurotherapeutics 2008; 5:237-51. [PMID: 18394566 PMCID: PMC5084166 DOI: 10.1016/j.nurt.2008.02.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The loss of dopaminergic neurons of the substantia nigra is the pathological hallmark characteristic of Parkinson's disease (PD). The strategy of replacing these degenerating neurons with other cells that produce dopamine has been the main approach in the cell transplantation field for PD research. The isolation, differentiation, and long-term cultivation of human embryonic stem cells and the therapeutic research discovery made in relation to the beneficial properties of neurotrophic and neural growth factors has advanced the transplantation field beyond dopamine-producing cells. The present review addresses recent advances in human embryonic stem cell experimentation in relation to treating PD, as well as cell transplantation techniques in conjunction with alternative therapeutics.
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Affiliation(s)
- Mary B Newman
- Department of Neurosurgery, Rush University Medical Center, Chicago, Illinois 60612, USA.
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32
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Ormerod BK, Palmer TD, Caldwell MA. Neurodegeneration and cell replacement. Philos Trans R Soc Lond B Biol Sci 2008; 363:153-70. [PMID: 17331894 PMCID: PMC2605492 DOI: 10.1098/rstb.2006.2018] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The past decade has witnessed ground-breaking advances in human stem cell biology with scientists validating adult neurogenesis and establishing methods to isolate and propagate stem cell populations suitable for transplantation. These advances have forged promising strategies against human neurodegenerative diseases. For example, growth factor administration could stimulate intrinsic repair from endogenous neural stem cells, and cultured stem cells engineered into biopumps could be transplanted to deliver neuroprotective or restorative agents. Stem cells could also be transplanted to generate new neural elements that augment and potentially replace degenerating central nervous system (CNS) circuitry. Early efforts in neural tissue transplantation have shown that these strategies can improve functional outcome, but the ultimate success of clinical stem cell-based strategies will depend on detailed understanding of stem cell biology in the degenerating brain and detailed evaluation of their functional efficacy and safety in preclinical animal models.
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Affiliation(s)
- Brandi K Ormerod
- Department of Neurosurgery, Stanford University300 Pasteur Drive, Boswell Building, A301, Stanford, CA 94305-5327, USA
| | - Theo D Palmer
- Department of Neurosurgery, Stanford University300 Pasteur Drive, Boswell Building, A301, Stanford, CA 94305-5327, USA
| | - Maeve A Caldwell
- Centre for Brain Repair, University of Cambridge School of Clinical MedicineAddenbrooke's Hospital, Box 111, Hills Road, Cambridge CB2 2SP, UK
- Author and address for correspondence: Laboratory for Integrative Neuroscience and Endocrinology, Dorothy Hodgkin Building, University of Bristol, Whitson Street, Bristol BS1 3NY, UK ()
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Redmond DE, Vinuela A, Kordower JH, Isacson O. Influence of cell preparation and target location on the behavioral recovery after striatal transplantation of fetal dopaminergic neurons in a primate model of Parkinson's disease. Neurobiol Dis 2008; 29:103-16. [PMID: 17920901 PMCID: PMC2174366 DOI: 10.1016/j.nbd.2007.08.008] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2007] [Revised: 08/03/2007] [Accepted: 08/12/2007] [Indexed: 11/23/2022] Open
Abstract
Surgeries involving transplantation of fetal dopamine (DA) neurons into the caudate-putamen of patients with Parkinson's disease (PD) have been performed in various clinical trials to examine a potential restoration of motor function. The absence of studies in non-human primates to define the best transplantation protocols have lead to the use of a broad variety of techniques that potentially could have a major impact on the clinical outcome. The effects of using different cell and tissue preparation, and surgical targets, remain unknown. For this purpose, 20 St. Kitts African Green Monkeys (AFG) rendered parkinsonian by i.m. injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were balanced into 4 groups and unilaterally grafted in the (a) caudate or (b) putamen with fetal ventral mesencephalic (VM) tissue as (c) solid pieces or as a (d) cell suspension. By 9 months post-transplantation all animals showed significant and similar behavioral improvement as determined by a UPDRS based PD scale. Postmortem analyses showed that VM transplants survived in all animals. They were located in both surgical target sites, producing a broad DA reinnervation of the targeted nuclei that could also extend to the non-grafted nucleus on the ipsilateral side. Although no differences between groups were found in survival of DA neurons or degree of DA reinnervation, there was a significant correlation between striatal reinnervation and behavioral recovery only in animals transplanted in the putamen surgical target. Additionally, there was in general a stronger glial reaction to solid grafts than to cell suspensions. These studies provide data for the optimal time course, cell preparation and surgical targets for systematic examinations of both potential benefits and side effects of dopamine neuron cell transplantation in primate models of PD.
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Affiliation(s)
- D. E. Redmond
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510
| | - A Vinuela
- Udall Parkinson Disease Research Center of Excellence, Center for Neuroregeneration Research. McLean Hospital/Harvard Medical School, Belmont, MA 02478
| | - J. H. Kordower
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612
| | - O. Isacson
- Udall Parkinson Disease Research Center of Excellence, Center for Neuroregeneration Research. McLean Hospital/Harvard Medical School, Belmont, MA 02478
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Gustafson CJ, Birgisson A, Junker J, Huss F, Salemark L, Johnson H, Kratz G. Employing human keratinocytes cultured on macroporous gelatin spheres to treat full thickness-wounds: An in vivo study on athymic rats. Burns 2007; 33:726-35. [PMID: 17467913 DOI: 10.1016/j.burns.2006.10.382] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2006] [Accepted: 10/07/2006] [Indexed: 10/23/2022]
Abstract
Providing cutaneous wounds with sufficient epidermis to prevent infections and fluid loss is one of the most challenging tasks associated with surgical treatment of burns. Recently, application of cultured keratinocytes in this context has allowed this challenge to be met without several of the limitations connected with the use of split-thickness skin grafts. The continuous development of this novel approach has now revealed that transplantation of cultured autologous keratinocytes as single-cell suspensions exhibits several advantages over the use of cultured epidermal grafts. However, a number of methodological problems remain to be solved, primarily with regards to the complexity of culturing these cells; loss of viability and other negative effects during their preparation and transportation; the relatively long period of time required following transplantation to obtain a sufficiently protective epidermis. In the present investigation we attempted to eliminate these limitations by culturing the keratinocytes on macroporous gelatin spheres. Accordingly, the efficacies of normal human keratinocytes in single-cell suspension or growing on macroporous gelatin spheres, as well as of split-thickness skin grafts in healing wounds on athymic rats were compared. Human keratinocytes were found to adhere and proliferate efficiently both on the surface and within the pores of such spheres. Transplantation of such cells adherent to the spheres resulted in significantly more rapid formation of a stratified epidermis than did transplantation of single-cell suspensions or spheres alone. Twenty-three days after transplantation, the epidermis formed from the cells bound to the spheres was not as thick as the epidermis on wounds covered with split-thickness skin grafts, but significantly thicker than on wounds to which single-cell suspensions, spheres alone or no transplant at all was applied. Furthermore, fluorescence in situ hybridisation revealed that the transplanted keratinocytes, both those adherent to gelatin spheres and those in single-cell suspension, were components of the newly formed epidermis. These findings indicate that application of biodegradable macroporous spheres may prove to be of considerable value in designing cell-based therapies for the treatment of acute and persistent wounds.
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Affiliation(s)
- Carl-Johan Gustafson
- Department of Plastic and Reconstructive Surgery, Karolinska University Hospital, Stockholm, Sweden
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35
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Kim YM, Lee JJ, Park SK, Lim SC, Hwang BY, Lee CK, Lee MK. Effects of tri butyl tin acetate on dopamine biosynthesis and l-dopa-lnduced cytotoxicity in pc12 cells. Arch Pharm Res 2007; 30:858-65. [PMID: 17703738 DOI: 10.1007/bf02978837] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
The effects of tributyltin acetate (TBTA) on dopamine biosynthesis and L-3,4-dihydroxyphenylalanine (L-DOPA)-induced cytotoxicity in PC12 cells were examined. TBTA at concentrations of 0.1-0.2 microM inhibited dopamine biosynthesis by reducing tyrosine hydroxylase (TH) activity and TH gene expression in PC12 cells. TBTA at 0.1-0.4 microM also reduced L-DOPA (20-50 microM)-induced increases in dopamine content for 24 h in PC12 cells. TBTA at concentrations up to 0.3 microM did not affect cell viability. However, TBTA at concentrations higher than 0.4 microM caused apoptotic cytotoxicity. Exposure of PC12 cells to non-cytotoxic (0.1 and 0.2 microM) or cytotoxic (0.4 microM) concentrations of TBTA with L-DOPA (20, 50 and 100 microM) significantly increased the cell loss and the percentage of apoptotic cells after 24 or 48 h compared with TBTA or L-DOPA alone. These data suggest that TBTA inhibits dopamine biosynthesis and enhances L-DOPA-induced cytotoxicity in PC12 cells.
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Affiliation(s)
- Yu Mi Kim
- College of Pharmacy and Research Center for Bioresource and Health, Chungbuk National University, 12, Gaeshin-Dong, Heungduk-Gu, Cheongju 361-763, Korea
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36
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Torres EM, Monville C, Gates MA, Bagga V, Dunnett SB. Improved survival of young donor age dopamine grafts in a rat model of Parkinson's disease. Neuroscience 2007; 146:1606-17. [PMID: 17478050 DOI: 10.1016/j.neuroscience.2007.03.037] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2007] [Revised: 03/08/2007] [Accepted: 03/24/2007] [Indexed: 12/12/2022]
Abstract
In an attempt to improve the survival of implanted dopamine cells, we have readdressed the optimal embryonic donor age for dopamine grafts. In a rat model of Parkinson's disease, animals with unilateral 6-hydroxydopamine lesions of the median forebrain bundle received dopamine-rich ventral mesencephalic grafts derived from embryos of crown to rump length 4, 6, 9, or 10.5 mm (estimated embryonic age (E) 11, E12, E13 and E14 days post-coitus, respectively). Grafts derived from 4 mm embryos survived poorly, with less than 1% of the implanted dopamine cells surviving. Grafts derived from 9 mm and 10.5 mm embryos were similar to those seen in previous experiments with survival rates of 8% and 7% respectively. The best survival was seen in the group that received 6 mm grafts, which were significantly larger than all other graft groups. Mean dopamine cell survival in the 6 mm group (E12) was 36%, an extremely high survival rate for primary, untreated ventral mesencephalic grafts applied as a single placement, and more than fivefold larger than the survival rate observed in the 10.5 mm (E14) group. As E12 ventral mesencephalic tissues contain few, if any, differentiated dopamine cells we conclude that the large numbers of dopamine cells seen in the 6 mm grafts must have differentiated post-implantation. We consider the in vivo conditions which allow this differentiation to occur, and the implications for the future of clinical trials based on dopamine cell replacement therapy.
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Affiliation(s)
- E M Torres
- Department of Biosciences, Cardiff University, Museum Avenue, PO Box 911, Cardiff CF10 3US, UK.
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37
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Abstract
Cell transplantation for Huntington's disease has developed over the last decade to clinical application in pilot trials in the USA, France and the UK. Although the procedures are feasible, and under appropriate conditions safe, evidence for efficacy is still limited, which has led to some calls that further development should be discontinued. We review the background of striatal cell transplantation in experimental animal models of Huntington's disease and the rationale for applying similar strategies in the human disease, and we survey the present status of the preliminary studies that have so far been undertaken in patients. When we consider the variety of parameters and principles that remain poorly defined -- such as the optimal source, age, dissection, preparation, implantation, immunoprotection and assessment protocols -- it is not surprising that clinical efficacy is still unreliable. However, since these protocols are all tractable to experimental refinement, we consider that the potential for cell transplantation in Huntington's disease is greater than has yet been realised, and remains a therapeutic strategy worthy of investigation and pursuit.
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38
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Bähr M, Lingor P. Brain repair: Experimental treatment strategies, neuroprotective and repair strategies in the lesioned adult CNS. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2007; 557:148-63. [PMID: 16955709 DOI: 10.1007/0-387-30128-3_9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Affiliation(s)
- Mathias Bähr
- Department of Neurology, University of Göttingen, Germany
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39
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Kim SU, Park IH, Kim TH, Kim KS, Choi HB, Hong SH, Bang JH, Lee MA, Joo IS, Lee CS, Kim YS. Brain transplantation of human neural stem cells transduced with tyrosine hydroxylase and GTP cyclohydrolase 1 provides functional improvement in animal models of Parkinson disease. Neuropathology 2006; 26:129-40. [PMID: 16708545 DOI: 10.1111/j.1440-1789.2006.00688.x] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Parkinson disease is a neurodegenerative disease characterized by loss of midbrain dopaminergic neurons resulting in movement disorder. Neural stem cells (NSC) of the CNS have recently aroused a great deal of interest, not only because of their importance in basic research of neural development, but also for their therapeutic potential in neurological disorders. We have recently generated an immortalized human NSC cell line, HB1.F3, via retrovirus-mediated v-myc transfer. This line is capable of self-renewal, is multipotent, and expresses cell specific markers for NSC, ATP-binding cassettes transporter (ABCG2) and nestin. Next, we co-transduced the F3 NSC line with genes encoding tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GTPCH1) in order to generate dopamine-producing NSC. The F3.TH.GTPCH human NSC line expresses TH and GTPCH phenotypes as determined by RT-PCR, western blotting and immunocytochemistry, and shows a 800 to 2000-fold increase in production of L-dihydroxyphenyl alanine in HPLC analysis. A marked improvement in amphetamine-induced turning behavior was observed in parkinsonian rats implanted with F3.TH.GTPCH cells, but not in control rats receiving F3 NSC. In the animals showing functional improvement, a large number of TH-positive F3.TH.GTPCH NSC were found at injection sites. These results indicate that human NSC, genetically transduced with TH and GTPCH1 genes, have great potential in clinical utility for cell replacement therapy in patients suffering from Parkinson disease.
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Affiliation(s)
- Seung U Kim
- Brain Disease Research Center, Ajou University School of Medicine, Suwon, Korea.
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40
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Arias-Carrión O, Drucker-Colín R, Murillo-Rodríguez E. Survival rates through time of hypocretin grafted neurons within their projection site. Neurosci Lett 2006; 404:93-7. [PMID: 16762505 DOI: 10.1016/j.neulet.2006.05.017] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2006] [Revised: 04/07/2006] [Accepted: 05/08/2006] [Indexed: 11/16/2022]
Abstract
Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, inadvertent transitions from wakefulness to rapid eye movement sleep (so called "sleep-onset REMS period") and cataplexy (sudden bilateral skeletal muscle weakness during waking without impairment of consciousness). This disorder has been recently linked to a loss of hypocretin (HCRT) neurons making narcolepsy a neurodegenerative disease. Neuronal replacement could be used to reverse the symptoms of narcolepsy. Towards this end, we have recently reported that HCRT neurons from rat pups can survive when grafted into the pons of adult rats. Here, we investigate the time-course of survival of grafted HCRT neurons into the pons of adult rats. The HCRT neurons are present only in the lateral hypothalamus, and therefore suspension of cells from this region was derived from 8- to 10-day-old rat pups (donor), and grafted into the pons of adult (60 days old) host rats. Control rats received a transplant that consisted of cells from the cerebellum where no HCRT neurons are present. All adult host rats were sacrificed 1, 3, 6, 9, 12, 24, or 36 days after grafting. Immunohistochemistry was used to identify and count the presence of the HCRT grafted neurons in the target area. The tally of HCRT neurons present in the graft zone 1 day post-grafting was considered to be the baseline. From day 3 to 36 post-transplant there was a steady decline in the number of HCRT neurons. We also noted that on day 36, the HCRT neurons that survived in the pons had morphological features that were similar to mature HCRT neurons in the adult lateral hypothalamus, suggesting that these neurons might be functionally active. Control rats that received grafts of cerebellar tissue did not show HCRT neurons in the target area. These results demonstrate that there is a progressive decline in the number of transplanted neurons, but a significant percentage of HCRT neurons do survive until day 36. This study highlights the potential use of transplants as a therapeutical tool in order to treat narcolepsy.
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Affiliation(s)
- Oscar Arias-Carrión
- Depto. de Neurociencias/Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Circuito Interior, Ciudad Universitaria, México DF, México
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41
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Torres EM, Monville C, Lowenstein PR, Castro MG, Dunnett SB. Delivery of sonic hedgehog or glial derived neurotrophic factor to dopamine-rich grafts in a rat model of Parkinson's disease using adenoviral vectors Increased yield of dopamine cells is dependent on embryonic donor age. Brain Res Bull 2005; 68:31-41. [PMID: 16325002 PMCID: PMC2902250 DOI: 10.1016/j.brainresbull.2005.08.021] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The poor survival of dopamine grafts in Parkinson's disease is one of the main obstacles to the widespread application of this therapy. One hypothesis is that implanted neurons, once removed from the embryonic environment, lack the differentiation factors needed to develop the dopaminergic phenotype. In an effort to improve the numbers of dopamine neurons surviving in the grafts, we have investigated the potential of adenoviral vectors to deliver the differentiation factor sonic hedgehog or the glial cell line-derived neurotrophic factor GDNF to dopamine-rich grafts in a rat model of Parkinson's disease. Adenoviral vectors containing sonic hedgehog, GDNF, or the marker gene LacZ were injected into the dopamine depleted striatum of hemiparkinsonian rats. Two weeks later, ventral mesencephalic cell suspensions were prepared from embryos of donor ages E12, E13, E14 or E15 and implanted into the vector-transduced striatum. Pre-treatment with the sonic hedgehog vector produced a three-fold increase in the numbers of tyrosine hydroxylase-positive (presumed dopaminergic) cells in grafts derived from E12 donors, but had no effect on E13-E15 grafts. By contrast, pre-treatment with the GDNF vector increased yields of dopamine cells in grafts derived from E14 and E15 donors but had no effect on grafts from younger donors. The results indicate that provision of both trophic and differentiation factors can enhance the yields of dopamine neurons in ventral mesencephalic grafts, but that the two factors differ in the age and stage of embryonic development at which they have maximal effects.
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Affiliation(s)
- E M Torres
- Department of Biosciences, Cardiff University, Biomedical Sciences Building, Museum Avenue, PO Box 911, Cardiff CF10 3US, UK.
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42
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Jin G, Tan X, Tian M, Qin J, Zhu H, Huang Z, Xu H. The controlled differentiation of human neural stem cells into TH-immunoreactive (ir) neurons in vitro. Neurosci Lett 2005; 386:105-10. [PMID: 16046065 DOI: 10.1016/j.neulet.2005.04.065] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2005] [Revised: 03/08/2005] [Accepted: 04/01/2005] [Indexed: 10/25/2022]
Abstract
The expansion of human neural stem cells in vitro might overcome the poor donor supply of human fetal neural tissue in transplantation for Parkinson's disease. However, the differentiation of human neural stem cells into dopaminergic neurons has proven difficult. In the present study, we investigated the effects of cytokines, trophic factors of developmental striatum and Ginkgolide on differentiation of human neural stem cells (hNSCs) into TH-ir neurons. The immunoreactivity to tyrosine hydroxylase (TH), a distinctive marker for dopamine neurons was used to assess dopaminergic neuronal phenotype. We demonstrate that human neural stem cells expanded in vitro can efficiently differentiate into TH-ir neurons by induction. These stem cells might serve as a continuous, on-demand source of cells for therapeutic transplantation in patients with Parkinson's disease.
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Affiliation(s)
- Guohua Jin
- Department of Anatomy and Neurobiology, The Jiangsu Key Lab of Neuroregeneration, School of Basic Medical Science, Nantong University, Nantong, Jiangsu 226001, PR China.
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43
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Interaction between dopaminergic and cholinergic systems under conditions of deficiency of mesencephalo-striatal dopamine in rats. NEUROPHYSIOLOGY+ 2005. [DOI: 10.1007/s11062-006-0017-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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44
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Affiliation(s)
- Pierre Cesaro
- Department of Clinical Neurosciences and Institut National de la Santé et de la Recherche Médicale U 421 Hospital Henri Mondor, 94000 Créteil, France.
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45
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Dinsmore JH. Treatment of neurodegenerative diseases with neural cell transplantation. Expert Opin Investig Drugs 2005; 7:527-34. [PMID: 15991990 DOI: 10.1517/13543784.7.4.527] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Neural cell transplantation is an emerging therapy that may provide an effective treatment for neurodegenerative disorders. The most extensive work with neural transplants has been carried out for Parkinson's and Huntington's diseases. However, intensive efforts are also being made for the treatment of other neurological indications, such as spinal cord repair, stroke, epilepsy, multiple sclerosis (MS), Alzheimer's disease and amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), to name just a few. The major barrier for the successful application of cells as therapeutics is achieving long-term survival and function. The CNS has proven to be ideal for transplantation, in part because immune rejection is attenuated in the CNS compared to peripheral locations. However, some form of immunosuppression is desirable for optimal allograft survival and required for xenograft survival. This review will focus on the challenges of restoring function to something as intricate as the CNS and on the limitations imposed by this complexity on any cellular therapeutic.
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Affiliation(s)
- J H Dinsmore
- Diacrin, Inc., Building 96, Thirteenth St., Charlestown, MA 02129, USA
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46
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Lang AE, Obeso JA. Challenges in Parkinson's disease: restoration of the nigrostriatal dopamine system is not enough. Lancet Neurol 2004; 3:309-16. [PMID: 15099546 DOI: 10.1016/s1474-4422(04)00740-9] [Citation(s) in RCA: 205] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Levodopa remains the most effective treatment for Parkinson's disease (PD). However, the drug is complicated by a wide range of adverse effects, most notably motor fluctuations and dyskinesias. Long-acting dopamine agonists are associated with a reduced incidence of these complications and modern surgical approaches and pharmacological methods of providing more continuous dopaminergic stimulation have a substantial ameliorative effect on these problems. Despite these advances, disease progression remains unaffected. For this reason there has been much enthusiasm for cellular therapies designed to replace degenerating nigrostriatal dopaminergic neurons. However, recent fetal transplant trials have failed to show expected benefit and have been complicated by medication dyskinesias". Even if successful, such treatment may be predestined to provide no better outcome than available treatments given current medical and surgical experience that emphasises the increasingly critical role of "non-dopaminergic" symptoms to quality of life in late-stage PD. Knowledge of the widespread, multisystem nature of the neurodegeneration that accounts for these problems suggests that restoration of the nigrostriatal dopamine system should not be the ultimate goal of future research.
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Affiliation(s)
- Anthony E Lang
- Movement Disorders Clinic, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada.
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47
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Storch A, Lester HA, Boehm BO, Schwarz J. Functional characterization of dopaminergic neurons derived from rodent mesencephalic progenitor cells. J Chem Neuroanat 2003; 26:133-42. [PMID: 14599663 DOI: 10.1016/s0891-0618(03)00067-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Neural progenitor cells existing in the developing and adult brain retain the capacity to self renew and to produce the major cell types of the brain opening new avenues for restorative therapy of neuropsychiatric disorders. These cells can be grown in vitro while retaining the potential to differentiate into nervous tissue. A primary target for neurorestoration is Parkinson's disease, characterized by a continuous loss of the dopaminergic neurons in the substantia nigra pars compacta leading to dopamine depletion in the striatum and subsequent clinical symptoms including bradykinesia, rigidity and tremor. We established a protocol for long-term expansion and dopaminergic differentiation of rodent and human mesencephalic neural progenitor cells. Here we perform functional studies using both biochemical and electrophysiological techniques on dopaminergic neurons derived from rodent mesencephalic progenitor cells labeled with tyrosine hydroxylase (TH) gene promotor-driven expression of enhanced green fluorescence protein (EGFP). Thus, we demonstrate that these cells produce and release dopamine, express voltage-gated potassium and sodium currents, and fire action potentials. Furthermore, we detect a slowly activating hyperpolarization-activated inward cation current (I(h)), which is specific for dopaminergic neurons among present midbrain neurons. Our results demonstrate that differentiated mesencephalic progenitors exhibit some major morphological and functional characteristics of dopaminergic neurons. Therefore, these neural progenitor cells might serve as a useful source of dopaminergic neurons for studying the development and degeneration of these cells and may further serve as a continuous, on-demand source of cells for therapeutic transplantation in Parkinson's disease.
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Affiliation(s)
- Alexander Storch
- Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany.
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48
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Abstract
Following injury to the CNS, severed axons undergo a phase of abortive sprouting in the vicinity of the wound, but do not spontaneously re-grow or regenerate. From a long history of attempts to stimulate regeneraion, a major strategy that has been developed clinically is the implantation of tissue into denervated target regions. Unfortunately trials have so far not borne out the promise that this would prove a useful therapy for disorders such as Parkinson's disease. Many strategies have also been developed to stimulate the regeneration of axons across sites of injury, particularly in the spinal cord. Animal data have demonstrated that some of these approaches hold promise and that the spinal cord has a remarkable degree of intrinsic plasticity. Attempts are now being made to utilize experimental techniques in spinal patients.
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Affiliation(s)
- Peter E Batchelor
- Departments of Medicine and Neurology, University of Melbourne, Austin and Repatriation Medical Centre, Vic. 3084, Heidelberg, Australia
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49
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Zietlow R, Sinclair SR, Schwiening CJ, Dunnett SB, Fawcettt JW. The release of excitatory amino acids, dopamine, and potassium following transplantation of embryonic mesencephalic dopaminergic grafts to the rat striatum, and their effects on dopaminergic neuronal survival in vitro. Cell Transplant 2003; 11:637-52. [PMID: 12518891 DOI: 10.3727/000000002783985396] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
A major limitation to the effectiveness of grafts of fetal ventral mesencephalic tissue for parkinsonism is that about 90-95% of grafted dopaminergic neurones die. In rats, many of the cells are dead within 1 day and most cell death is complete within 1 week. Our previous results suggest that a major cause of this cell death is the release of toxins from the injured CNS tissue surrounding the graft, and that many of these toxins have dissipated within 1 h of inserting the grafting cannula. In the present experiments we measured the change over time in the concentration of several potential toxins around an acutely implanted grafting cannula. We also measured the additional effect of injecting suspensions of embryonic mesencephalon, latex microspheres, or vehicle on these concentrations. Measurements of glutamate, aspartate, and dopamine by microdialysis showed elevated levels during the first 20-60 min, which then declined to baseline. In the first 20 min glutamate levels were 10.7 times, aspartate levels 5 times, and dopamine levels 24.3 times baseline. Potassium levels increased to a peak of 33 +/- 10.6 mM 4-5 min after cannula insertion, returning to baseline of <5 mM by 30 min. Injection of cell suspension, latex microspheres, or vehicle had no significant effect on these levels. We then assayed the effect of high concentrations of glutamate, aspartate, dopamine, and potassium on dopaminergic neuronal survival in E14 ventral mesencephalic cultures. In monolayer cultures only dopamine at 200 microM showed toxicity. In three-dimensional cultures only the combination of raised potassium, dopamine, glutamate, and aspartate together decreased dopaminergic neuronal survival. We conclude that toxins other than the ones measured are the main cause of dopaminergic cell death after transplantation, or the effects of the toxins measured are enhanced by anoxia and metabolic challenges affecting newly inserted grafts.
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Affiliation(s)
- Rike Zietlow
- Cambridge University Centre for Brain Repair, Cambridge CB2 2PY, UK.
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50
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Love RM, Branton RL, Karlsson J, Brundin P, Clarke DJ. Effects of antioxidant pretreatment on the survival of embryonic dopaminergic neurons in vitro and following grafting in an animal model of Parkinson's disease. Cell Transplant 2003; 11:653-62. [PMID: 12518892 DOI: 10.3727/000000002783985431] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
The effect of pretreating cell suspensions of embryonic rat ventral mesencephala (VM) with antioxidant combinations on the survival of dopaminergic (DA) neurons was studied in vitro and following transplantation into the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease. The in vitro experiments examined the effects of two thiol antioxidants, N-acetyl-L-cysteine (NAC) and reduced glutathione (GSH), and a member of the lazaroid family of 21-aminosteroids, U-83836E, singly and in combination, on survival of DA neurons derived from dissociated E14 rat VM tissue. For in vivo studies, cell suspensions were pretreated with combinations of NAC, GSH, and U-83836E prior to transplanting into 6-OHDA-lesioned rats to investigate whether DA neuron survival could be further improved. NAC, GSH, and U-83836E individually increased DA neuron survival in vitro and a combination of all three resulted in the greatest survival. In vivo, pretreatment with U-83836E alone resulted in a significantly greater reduction in amphetamine-induced rotation 6 weeks postgrafting compared with a control group receiving nontreated graft tissue. This functional effect correlated with a significant improvement in DA neuron survival 6 weeks postgrafting. The thiol combination pretreatment of NAC and GSH, and the triple combination of NAC, GSH, and U-83836E, however, failed to improve both functional recovery and DA neuron survival when compared with the nontreated control grafts.
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Affiliation(s)
- R M Love
- Department of Human Anatomy and Genetics, University of Oxford, Oxford, OX1 3QX, UK
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