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The Cell Autonomous and Non-Cell Autonomous Aspects of Neuronal Vulnerability and Resilience in Amyotrophic Lateral Sclerosis. BIOLOGY 2022; 11:biology11081191. [PMID: 36009818 PMCID: PMC9405388 DOI: 10.3390/biology11081191] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/14/2022] [Accepted: 07/30/2022] [Indexed: 11/17/2022]
Abstract
Simple Summary Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by a progressive paralysis due to the loss of particular neurons in our nervous system called motor neurons, that exert voluntary control of all our skeletal muscles. It is not entirely understood why motor neurons are particularly vulnerable in ALS, neither is it completely clear why certain groups of motor neurons, including those that regulate eye movement, are rather resilient to this disease. However, both vulnerability and resilience to ALS likely reflect cell intrinsic properties of different motor neuron subpopulations as well as non-cell autonomous events regulated by surrounding cell types. In this review we dissect the particular properties of different motor neuron types and their responses to disease that may underlie their respective vulnerabilities and resilience. Disease progression in ALS involves multiple cell types that are closely connected to motor neurons and we here also discuss their contributions to the differential vulnerability of motor neurons. Abstract Amyotrophic lateral sclerosis (ALS) is defined by the loss of upper motor neurons (MNs) that project from the cerebral cortex to the brain stem and spinal cord and of lower MNs in the brain stem and spinal cord which innervate skeletal muscles, leading to spasticity, muscle atrophy, and paralysis. ALS involves several disease stages, and multiple cell types show dysfunction and play important roles during distinct phases of disease initiation and progression, subsequently leading to selective MN loss. Why MNs are particularly vulnerable in this lethal disease is still not entirely clear. Neither is it fully understood why certain MNs are more resilient to degeneration in ALS than others. Brain stem MNs of cranial nerves III, IV, and VI, which innervate our eye muscles, are highly resistant and persist until the end-stage of the disease, enabling paralyzed patients to communicate through ocular tracking devices. MNs of the Onuf’s nucleus in the sacral spinal cord, that innervate sphincter muscles and control urogenital functions, are also spared throughout the disease. There is also a differential vulnerability among MNs that are intermingled throughout the spinal cord, that directly relate to their physiological properties. Here, fast-twitch fatigable (FF) MNs, which innervate type IIb muscle fibers, are affected early, before onset of clinical symptoms, while slow-twitch (S) MNs, that innervate type I muscle fibers, remain longer throughout the disease progression. The resilience of particular MN subpopulations has been attributed to intrinsic determinants and multiple studies have demonstrated their unique gene regulation and protein content in health and in response to disease. Identified factors within resilient MNs have been utilized to protect more vulnerable cells. Selective vulnerability may also, in part, be driven by non-cell autonomous processes and the unique surroundings and constantly changing environment close to particular MN groups. In this article, we review in detail the cell intrinsic properties of resilient and vulnerable MN groups, as well as multiple additional cell types involved in disease initiation and progression and explain how these may contribute to the selective MN resilience and vulnerability in ALS.
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Guo W, Fumagalli L, Prior R, Van Den Bosch L. Current Advances and Limitations in Modeling ALS/FTD in a Dish Using Induced Pluripotent Stem Cells. Front Neurosci 2017; 11:671. [PMID: 29326542 PMCID: PMC5733489 DOI: 10.3389/fnins.2017.00671] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 11/20/2017] [Indexed: 12/11/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two age-dependent multifactorial neurodegenerative disorders, which are typically characterized by the selective death of motor neurons and cerebral cortex neurons, respectively. These two diseases share many clinical, genetic and pathological aspects. During the past decade, cell reprogramming technologies enabled researchers to generate human induced pluripotent stem cells (iPSCs) from somatic cells. This resulted in the unique opportunity to obtain specific neuronal and non-neuronal cell types from patients which could be used for basic research. Moreover, these in vitro models can mimic not only the familial forms of ALS/FTD, but also sporadic cases without known genetic cause. At present, there have been extensive technical advances in the generation of iPSCs, as well as in the differentiation procedures to obtain iPSC-derived motor neurons, cortical neurons and non-neuronal cells. The major challenge at this moment is to determine whether these iPSC-derived cells show relevant phenotypes that recapitulate complex diseases. In this review, we will summarize the work related to iPSC models of ALS and FTD. In addition, we will discuss potential drawbacks and solutions for establishing more trustworthy iPSC models for both ALS and FTD.
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Affiliation(s)
- Wenting Guo
- KU Leuven-Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease, Leuven, Belgium.,Laboratory of Neurobiology, VIB & KU Leuven Center for Brain & Disease Research, Leuven, Belgium
| | - Laura Fumagalli
- KU Leuven-Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease, Leuven, Belgium.,Laboratory of Neurobiology, VIB & KU Leuven Center for Brain & Disease Research, Leuven, Belgium
| | - Robert Prior
- KU Leuven-Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease, Leuven, Belgium.,Laboratory of Neurobiology, VIB & KU Leuven Center for Brain & Disease Research, Leuven, Belgium
| | - Ludo Van Den Bosch
- KU Leuven-Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease, Leuven, Belgium.,Laboratory of Neurobiology, VIB & KU Leuven Center for Brain & Disease Research, Leuven, Belgium
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Nijssen J, Comley LH, Hedlund E. Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis. Acta Neuropathol 2017; 133:863-885. [PMID: 28409282 PMCID: PMC5427160 DOI: 10.1007/s00401-017-1708-8] [Citation(s) in RCA: 230] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 03/29/2017] [Accepted: 04/01/2017] [Indexed: 12/11/2022]
Abstract
In the fatal disease-amyotrophic lateral sclerosis (ALS)-upper (corticospinal) motor neurons (MNs) and lower somatic MNs, which innervate voluntary muscles, degenerate. Importantly, certain lower MN subgroups are relatively resistant to degeneration, even though pathogenic proteins are typically ubiquitously expressed. Ocular MNs (OMNs), including the oculomotor, trochlear and abducens nuclei (CNIII, IV and VI), which regulate eye movement, persist throughout the disease. Consequently, eye-tracking devices are used to enable paralysed ALS patients (who can no longer speak) to communicate. Additionally, there is a gradient of vulnerability among spinal MNs. Those innervating fast-twitch muscle are most severely affected and degenerate first. MNs innervating slow-twitch muscle can compensate temporarily for the loss of their neighbours by re-innervating denervated muscle until later in disease these too degenerate. The resistant OMNs and the associated extraocular muscles (EOMs) are anatomically and functionally very different from other motor units. The EOMs have a unique set of myosin heavy chains, placing them outside the classical characterization spectrum of all skeletal muscle. Moreover, EOMs have multiple neuromuscular innervation sites per single myofibre. Spinal fast and slow motor units show differences in their dendritic arborisations and the number of myofibres they innervate. These motor units also differ in their functionality and excitability. Identifying the molecular basis of cell-intrinsic pathways that are differentially activated between resistant and vulnerable MNs could reveal mechanisms of selective neuronal resistance, degeneration and regeneration and lead to therapies preventing progressive MN loss in ALS. Illustrating this, overexpression of OMN-enriched genes in spinal MNs, as well as suppression of fast spinal MN-enriched genes can increase the lifespan of ALS mice. Here, we discuss the pattern of lower MN degeneration in ALS and review the current literature on OMN resistance in ALS and differential spinal MN vulnerability. We also reflect upon the non-cell autonomous components that are involved in lower MN degeneration in ALS.
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Bailey JM, Colón-Rodríguez A, Atchison WD. Evaluating a Gene-Environment Interaction in Amyotrophic Lateral Sclerosis: Methylmercury Exposure and Mutated SOD1. Curr Environ Health Rep 2017; 4:200-207. [PMID: 28397096 PMCID: PMC5494256 DOI: 10.1007/s40572-017-0144-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW Gene-environment (GxE) interactions likely contribute to numerous diseases, but are often difficult to model in the laboratory. Such interactions have been widely hypothesized for amyotrophic lateral sclerosis (ALS); recent controlled laboratory studies are discussed here and hypotheses related to possible mechanisms of action are offered. Using methylmercury exposure and mutated SOD1 to model the impacts of such an interaction, we interpret evidence about their respective mechanisms of toxicity to interrogate the possibility of additive (or synergistic) effects when combined. RECENT FINDINGS Recent work has converged on mechanisms of calcium-mediated glutamate excitotoxicity as a likely contributor in one model of a gene-environment interaction affecting the onset and progression of ALS-like phenotype. The current experimental literature on mechanisms of metal-induced neuronal injury and their relevant interactions with genetic contributions in ALS is sparse, but we describe those studies here and offer several integrative hypotheses about the likely mechanisms involved.
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Affiliation(s)
- Jordan M Bailey
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, 48824-1317, USA
- Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, 48824-1317, USA
| | - Alexandra Colón-Rodríguez
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, 48824-1317, USA
- Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, 48824-1317, USA
- Comparative Medicine and Integrative Biology Program, Michigan State University, East Lansing, MI, 48824-1317, USA
| | - William D Atchison
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, 48824-1317, USA.
- Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, 48824-1317, USA.
- Comparative Medicine and Integrative Biology Program, Michigan State University, East Lansing, MI, 48824-1317, USA.
- , Life Science Building, 1355 Bogue St. Room B331A, East Lansing, MI, 48824-1317, USA.
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Benninger F, Glat MJ, Offen D, Steiner I. Glial fibrillary acidic protein as a marker of astrocytic activation in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis. J Clin Neurosci 2015; 26:75-8. [PMID: 26602604 DOI: 10.1016/j.jocn.2015.10.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 10/11/2015] [Indexed: 12/14/2022]
Abstract
Glial fibrillary acidic protein (GFAP) has been shown to be increased in the cerebrospinal fluid (CSF) of patients suffering from neurological diseases involving the activation of astrocytes, but has not been studied in amyotrophic lateral sclerosis (ALS) patients to our knowledge. CSF samples of patients with definite ALS and of those with other neurological diseases were evaluated for their GFAP concentrations. CSF-GFAP concentrations of patients with ALS were significantly elevated by 53% compared to patients with other neurologic diseases. GFAP might serve as a biomarker in ALS. Our findings support the concept that astrocytes play a role in ALS pathogenesis.
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Affiliation(s)
- Felix Benninger
- Department of Neurology, Rabin Medical Center, Beilinson Hospital, Petach Tikva 49100, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Felsenstein Medical Research Institut, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Micaela J Glat
- Felsenstein Medical Research Institut, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Daniel Offen
- Felsenstein Medical Research Institut, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Israel Steiner
- Department of Neurology, Rabin Medical Center, Beilinson Hospital, Petach Tikva 49100, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Bradford AB, McNutt PM. Importance of being Nernst: Synaptic activity and functional relevance in stem cell-derived neurons. World J Stem Cells 2015; 7:899-921. [PMID: 26240679 PMCID: PMC4515435 DOI: 10.4252/wjsc.v7.i6.899] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Revised: 02/28/2015] [Accepted: 05/11/2015] [Indexed: 02/06/2023] Open
Abstract
Functional synaptogenesis and network emergence are signature endpoints of neurogenesis. These behaviors provide higher-order confirmation that biochemical and cellular processes necessary for neurotransmitter release, post-synaptic detection and network propagation of neuronal activity have been properly expressed and coordinated among cells. The development of synaptic neurotransmission can therefore be considered a defining property of neurons. Although dissociated primary neuron cultures readily form functioning synapses and network behaviors in vitro, continuously cultured neurogenic cell lines have historically failed to meet these criteria. Therefore, in vitro-derived neuron models that develop synaptic transmission are critically needed for a wide array of studies, including molecular neuroscience, developmental neurogenesis, disease research and neurotoxicology. Over the last decade, neurons derived from various stem cell lines have shown varying ability to develop into functionally mature neurons. In this review, we will discuss the neurogenic potential of various stem cells populations, addressing strengths and weaknesses of each, with particular attention to the emergence of functional behaviors. We will propose methods to functionally characterize new stem cell-derived neuron (SCN) platforms to improve their reliability as physiological relevant models. Finally, we will review how synaptically active SCNs can be applied to accelerate research in a variety of areas. Ultimately, emphasizing the critical importance of synaptic activity and network responses as a marker of neuronal maturation is anticipated to result in in vitro findings that better translate to efficacious clinical treatments.
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Meamar R, Nasr-Esfahani MH, Mousavi SA, Basiri K. Stem cell therapy in amyotrophic lateral sclerosis. J Clin Neurosci 2013; 20:1659-63. [PMID: 24148693 DOI: 10.1016/j.jocn.2013.04.024] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2012] [Revised: 01/08/2013] [Accepted: 04/14/2013] [Indexed: 02/07/2023]
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of upper and lower motor neurons, characterized by progressive muscular atrophy and weakness which culminates in death within 2-5 years. Despite various hypotheses about the responsible mechanisms, the etiology of ALS remains incompletely understood. However, it has been recently postulated that stem cell therapy could potentially target several mechanisms responsible for the etiology of ALS and other nervous system disorders, and could be regarded as one of the most promising therapeutic strategies for ALS treatment. We present a brief review of different methods of stem cell therapy in ALS patients and discuss the results with different cell types and routes of administration.
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Affiliation(s)
- Rokhsareh Meamar
- Department of Medical Science, Najafabad Branch, Islamic Azad University, Isfahan, Iran
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Rizzo F, Riboldi G, Salani S, Nizzardo M, Simone C, Corti S, Hedlund E. Cellular therapy to target neuroinflammation in amyotrophic lateral sclerosis. Cell Mol Life Sci 2013; 71:999-1015. [PMID: 24100629 PMCID: PMC3928509 DOI: 10.1007/s00018-013-1480-4] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Revised: 08/27/2013] [Accepted: 09/16/2013] [Indexed: 12/13/2022]
Abstract
Neurodegenerative disorders are characterized by the selective vulnerability and progressive loss of discrete neuronal populations. Non-neuronal cells appear to significantly contribute to neuronal loss in diseases such as amyotrophic lateral sclerosis (ALS), Parkinson, and Alzheimer’s disease. In ALS, there is deterioration of motor neurons in the cortex, brainstem, and spinal cord, which control voluntary muscle groups. This results in muscle wasting, paralysis, and death. Neuroinflammation, characterized by the appearance of reactive astrocytes and microglia as well as macrophage and T-lymphocyte infiltration, appears to be highly involved in the disease pathogenesis, highlighting the involvement of non-neuronal cells in neurodegeneration. There appears to be cross-talk between motor neurons, astrocytes, and immune cells, including microglia and T-lymphocytes, which are subsequently activated. Currently, effective therapies for ALS are lacking; however, the non-cell autonomous nature of ALS may indicate potential therapeutic targets. Here, we review the mechanisms of action of astrocytes, microglia, and T-lymphocytes in the nervous system in health and during the pathogenesis of ALS. We also evaluate the therapeutic potential of these cellular populations, after transplantation into ALS patients and animal models of the disease, in modulating the environment surrounding motor neurons from pro-inflammatory to neuroprotective. We also thoroughly discuss the recent advances made in the field and caveats that need to be overcome for clinical translation of cell therapies aimed at modulating non-cell autonomous events to preserve remaining motor neurons in patients.
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Affiliation(s)
- Federica Rizzo
- Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, IRCCS Foundation Ca’Granda Ospedale Maggiore Policlinico, 20135 Milan, Italy
| | - Giulietta Riboldi
- Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, IRCCS Foundation Ca’Granda Ospedale Maggiore Policlinico, 20135 Milan, Italy
| | - Sabrina Salani
- Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, IRCCS Foundation Ca’Granda Ospedale Maggiore Policlinico, 20135 Milan, Italy
| | - Monica Nizzardo
- Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, IRCCS Foundation Ca’Granda Ospedale Maggiore Policlinico, 20135 Milan, Italy
| | - Chiara Simone
- Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, IRCCS Foundation Ca’Granda Ospedale Maggiore Policlinico, 20135 Milan, Italy
| | - Stefania Corti
- Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, IRCCS Foundation Ca’Granda Ospedale Maggiore Policlinico, 20135 Milan, Italy
| | - Eva Hedlund
- Department of Neuroscience, Karolinska Institutet, Retzius v. 8, 17177 Stockholm, Sweden
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Benkler C, Ben-Zur T, Barhum Y, Offen D. Altered astrocytic response to activation in SOD1G93Amice and its implications on amyotrophic lateral sclerosis pathogenesis. Glia 2012; 61:312-26. [DOI: 10.1002/glia.22428] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2012] [Accepted: 09/04/2012] [Indexed: 12/11/2022]
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Cardozo-Pelaez F, Bridges RJ. Coupling biomarkers and drug action for neurodegenerative disease therapies: does the nose know?: Commentary on Sattler et al.: human nasal olfactory epithelium as a dynamic marker for CNS therapy development. Exp Neurol 2012; 235:508-12. [PMID: 22465461 DOI: 10.1016/j.expneurol.2012.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2011] [Revised: 03/05/2012] [Accepted: 03/12/2012] [Indexed: 10/28/2022]
Affiliation(s)
- Fernando Cardozo-Pelaez
- Center for Structural and Functional Neuroscience, Center for Environmental Health Sciences, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA
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Gauthier M, Maury Y, Peschanski M, Martinat C. Human pluripotent stem cells for genetic disease modeling and drug screening. Regen Med 2012; 6:607-22. [PMID: 21916596 DOI: 10.2217/rme.11.46] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Considerable hope surrounds the use of disease-specific pluripotent stem cells, which can differentiate into any cell type, as starting materials to generate models of human disease that will allow exploration of pathological mechanisms and the search for new treatments. Disease-specific human embryonic stem cells have provided a useful source for studying certain disease states. However, reprogramming of human somatic cells that use readily accessible tissue, such as skin or blood, to generate embryonic-like induced pluripotent stem cells has opened new perspectives for modeling and understanding a larger number of human pathologies. Here, we examine the challenges in creating a disease model from human pluripotent stem cells, and describe their use to model both cell-autonomous and non-cell-autonomous mechanisms, the need for adequate control experiments and the genetic limitations of human induced pluripotent stem cells. Progress in these areas will substantially accelerate effective application of disease-specific human pluripotent stem cells for drug screening.
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Gamez J, Carmona F, Raguer N, Ferrer-Sancho J, Martín-Henao GA, Martí-Beltrán S, Badia M, Gratacós M, Rodriguez-Gónzalez E, Seoane JL, Pallero-Castillo M, Burgos R, Puiggros C, Pasarin A, Bori-Fortuny I. Cellular transplants in amyotrophic lateral sclerosis patients: an observational study. Cytotherapy 2011; 12:669-77. [PMID: 20586670 DOI: 10.3109/14653241003774037] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AIMS Cytotherapy is a promising option for neurodegenerative disease treatment. Because of the fatal prognosis and imperative need for effective treatment, amyotrophic lateral sclerosis (ALS) patients request this therapy before its effectiveness has been verified. The increase in clinics offering cytotherapies but providing little scientific information has prompted considerable medical tourism. We present an observational study of Spanish ALS patients receiving cytotherapy, analyzing the experiences arising from the treatment (TX) and considering two progression markers, FVC and ALSFRS-R. METHODS Twelve ALS patients with a mean age of 48.6 years (SD 12.8) received cytotherapy 26.9 months (SD 15.8) after clinical onset. ALSFRS-R and FVC at TX were 32.3 (SD 6.8) and 63.4% (SD 15.3), respectively. TX involved transplants of olfactory ensheathing cells in three patients, and autologous mesenchymal stromal cells in the remainder. RESULTS One patient died 33 months post-TX after surviving for 49 months. Five required mechanical non-invasive home ventilation 7.4 months post-TX. Two required invasive ventilation 13 months post-TX. Five patients needed gastrostomy feeding 23.3 months post-TX. Survival between clinical onset and the study end date was 50 months (SD 17.2). No significant adverse events or changes in the decline of FVC and ALSFRS-R compared with the disease's natural history were observed. CONCLUSIONS Our observations suggest that these therapies do not halt the course of the disease. Cytotherapy cannot yet be considered a curative treatment for ALS.
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Affiliation(s)
- Josep Gamez
- Neurology Department, Hospital Universitari Vall d'Hebron, Autonomous University of Barcelona, Barcelona, Spain.
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Abstract
Neurodegenerative diseases result from the gradual and progressive loss of neural cells and lead to nervous system dysfunction. The rapidly advancing stem cell field is providing attractive alternative options for fighting these diseases. Results have provided proof of principle that cell replacement can work in humans with Parkinson's disease (PD). However, three clinical studies of cell transplantation were published that found no net benefit, while patients in two of the studies developed dyskinesias that persisted despite reductions in treatment. Induced pluripotent stem cells (iPSC) have major potential advantages because patient-specific neuroblasts are suitable for transplantation, avoid immune reactions, and can be produced without the use of human ES cells (hESC). Although iPSCs have not been successfully used in clinical trials for PD, patients with amyotrophic lateral sclerosis (ALS) were treated with autologous stem cells and, though they had some degree of decline one year after treatment, they were still improved compared with the preoperative period or without any drug therapy. In addition, neural stem cells (NSCs), via brain-derived neurotrophic factor (BDNF), have been shown to ameliorate complex behavioral deficits associated with widespread Alzheimer's disease (AD) pathology in a transgenic mouse model of AD. So far, the FDA lists 18 clinical trials treating multiple sclerosis (MS), but most are in preliminary stages. This article serves as an overview of recent studies in stem cell and regenerative approaches to the above chronic neurodegenerative disorders. There are still many obstacles to the use of stem cells as a cure for neurodegenerative disease, especially because we still don't fully understand the true mechanisms of these diseases. However, there is hope in the potential of stem cells to help us learn and understand a great deal more about the mechanisms underlying these devastating neurodegenerative diseases.
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Affiliation(s)
- Zhongling Feng
- Bio Group, Nitto Denko Technical Corporation, Oceanside, CA 82058, USA.
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Hedlund E, Karlsson M, Osborn T, Ludwig W, Isacson O. Global gene expression profiling of somatic motor neuron populations with different vulnerability identify molecules and pathways of degeneration and protection. ACTA ACUST UNITED AC 2010; 133:2313-30. [PMID: 20826431 DOI: 10.1093/brain/awq167] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Different somatic motor neuron subpopulations show a differential vulnerability to degeneration in diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy and spinobulbar muscular atrophy. Studies in mutant superoxide dismutase 1 over-expressing amyotrophic lateral sclerosis model mice indicate that initiation of disease is intrinsic to motor neurons, while progression is promoted by astrocytes and microglia. Therefore, analysis of the normal transcriptional profile of motor neurons displaying differential vulnerability to degeneration in motor neuron disease could give important clues to the mechanisms of relative vulnerability. Global gene expression profiling of motor neurons isolated by laser capture microdissection from three anatomical nuclei of the normal rat, oculomotor/trochlear (cranial nerve 3/4), hypoglossal (cranial nerve 12) and lateral motor column of the cervical spinal cord, displaying differential vulnerability to degeneration in motor neuron disorders, identified enriched transcripts for each neuronal subpopulation. There were striking differences in the regulation of genes involved in endoplasmatic reticulum and mitochondrial function, ubiquitination, apoptosis regulation, nitrogen metabolism, calcium regulation, transport, growth and RNA processing; cellular pathways that have been implicated in motor neuron diseases. Confirmation of genes of immediate biological interest identified differential localization of insulin-like growth factor II, guanine deaminase, peripherin, early growth response 1, soluble guanylate cyclase 1A3 and placental growth factor protein. Furthermore, the cranial nerve 3/4-restricted genes insulin-like growth factor II and guanine deaminase protected spinal motor neurons from glutamate-induced toxicity (P < 0.001, ANOVA), indicating that our approach can identify factors that protect or make neurons more susceptible to degeneration.
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Affiliation(s)
- Eva Hedlund
- Center for Neuroregeneration Research, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
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Inoue H. Neurodegenerative disease-specific induced pluripotent stem cell research. Exp Cell Res 2010; 316:2560-4. [PMID: 20420829 DOI: 10.1016/j.yexcr.2010.04.022] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2010] [Accepted: 04/19/2010] [Indexed: 12/31/2022]
Abstract
Neurodegenerative disease-specific induced pluripotent stem cell (iPSC) research contributes to the following 3 areas; "Disease modeling", "Disease material" and "Disease therapy". "Disease modeling", by recapitulating the disease phenotype in vitro, will reveal the pathomechanisms. Neurodegenerative disease-specific iPSC-derived non-neuronal cells harboring disease-causative protein(s), which play critical roles in neurodegeneration including motor neuron degeneration in amyotrophic lateral sclerosis, could be "Disease material", the target cell(s) for drug screening. These differentiated cells also could be used for "Disease therapy", an autologous cellular replacement/neuroprotection strategy, for patients with neurodegenerative disease. Further progress in these areas of research can be made for currently incurable neurodegenerative diseases.
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Affiliation(s)
- Haruhisa Inoue
- Center for iPS Cell Research and Application, Kyoto University, 53, Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
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