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1
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Marcu IR, Rogoveanu OC, Pădureanu R, Pădureanu V, Dop D. Diagnostic elements in amyotrophic lateral sclerosis: A case report. Biomed Rep 2024; 21:141. [PMID: 39161942 PMCID: PMC11332115 DOI: 10.3892/br.2024.1829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Accepted: 07/04/2024] [Indexed: 08/21/2024] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a rare neurological disease that involves the degeneration of both upper and lower motor neurons responsible for controlling voluntary muscle activity. Most people with ALS die within 3-5 years due to respiratory failure. The current study presents the case of a 68-year-old woman diagnosed with ALS based on the subjective and objective findings from the patient's initial physiotherapy assessment and on neurophysiological tests. Physiotherapy interventions are aiming to maintain the patient's strength, balance and functional independence for as long as possible. The present case report aimed to highlight that a multidisciplinary team approach is necessary for the management of a progressive degenerative disease such as ALS.
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Affiliation(s)
- Iulia Rahela Marcu
- Department of Physical and Rehabilitation Medicine, University of Medicine and Pharmacy of Craiova, Craiova 200349, Romania
| | - Otilia Constantina Rogoveanu
- Department of Physical and Rehabilitation Medicine, University of Medicine and Pharmacy of Craiova, Craiova 200349, Romania
| | - Rodica Pădureanu
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, Craiova 200349, Romania
| | - Vlad Pădureanu
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, Craiova 200349, Romania
| | - Dalia Dop
- Department of Pediatrics, University of Medicine and Pharmacy of Craiova, Craiova 200349, Romania
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Montiel-Troya M, Mohamed-Mohamed H, Pardo-Moreno T, González-Díaz A, Ruger-Navarrete A, de la Mata Fernández M, Tovar-Gálvez MI, Ramos-Rodríguez JJ, García-Morales V. Advancements in Pharmacological Interventions and Novel Therapeutic Approaches for Amyotrophic Lateral Sclerosis. Biomedicines 2024; 12:2200. [PMID: 39457513 PMCID: PMC11505100 DOI: 10.3390/biomedicines12102200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 09/19/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024] Open
Abstract
(1) Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease in which the patient suffers from an affection of both upper and lower motor neurons at the spinal and brainstem level, causing a progressive paralysis that leads to the patient's demise. Gender is also considered a predisposing risk factor for developing the disease. A brief review of the pathophysiological mechanisms of the disease is also described in this work. Despite the fact that a cure for ALS is currently unknown, there exists a variety of pharmacological and non-pharmacological therapies that can help reduce the progression of the disease over a certain period of time and alleviate symptoms. (2) We aim to analyze these pharmacological and non-pharmacological therapies through a systematic review. A comprehensive, multidisciplinary approach to treatment is necessary. (3) Drugs such as riluzole, edaravone, and sodium phenylbutyrate, among others, have been investigated. Additionally, it is important to stay updated on research on new drugs, such as masitinib, from which very good results have been obtained. (4) Therapies aimed at psychological support, speech and language, and physical therapy for the patient are also available, which increase the quality of life of the patients.
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Affiliation(s)
- María Montiel-Troya
- Faculty of Health Sciences Ceuta, University of Granada, 51001 Ceuta, Spain; (M.M.-T.); (T.P.-M.); (A.G.-D.); (A.R.-N.)
| | - Himan Mohamed-Mohamed
- Department of Physiology, Faculty of Health Sciences Ceuta, University of Granada, 51001 Ceuta, Spain; (H.M.-M.); (M.d.l.M.F.); (J.J.R.-R.)
| | - Teresa Pardo-Moreno
- Faculty of Health Sciences Ceuta, University of Granada, 51001 Ceuta, Spain; (M.M.-T.); (T.P.-M.); (A.G.-D.); (A.R.-N.)
| | - Ana González-Díaz
- Faculty of Health Sciences Ceuta, University of Granada, 51001 Ceuta, Spain; (M.M.-T.); (T.P.-M.); (A.G.-D.); (A.R.-N.)
| | - Azahara Ruger-Navarrete
- Faculty of Health Sciences Ceuta, University of Granada, 51001 Ceuta, Spain; (M.M.-T.); (T.P.-M.); (A.G.-D.); (A.R.-N.)
| | - Mario de la Mata Fernández
- Department of Physiology, Faculty of Health Sciences Ceuta, University of Granada, 51001 Ceuta, Spain; (H.M.-M.); (M.d.l.M.F.); (J.J.R.-R.)
| | - María Isabel Tovar-Gálvez
- Nursing Department, Faculty of Health Sciences, University of Granada, Avda. Ilustración 69, 18071 Granada, Spain
| | - Juan José Ramos-Rodríguez
- Department of Physiology, Faculty of Health Sciences Ceuta, University of Granada, 51001 Ceuta, Spain; (H.M.-M.); (M.d.l.M.F.); (J.J.R.-R.)
| | - Victoria García-Morales
- Department of Biomedicine, Biotechnology and Public Health, Physiology Area, Faculty of Medicine, University of Cádiz, Pl. Falla, 9, 11003 Cádiz, Spain;
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3
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Seta Y, Kimura K, Masahiro G, Tatsumori K, Murakami Y. SHED-CM: The Safety and Efficacy of Conditioned Media from Human Exfoliated Deciduous Teeth Stem Cells in Amyotrophic Lateral Sclerosis Treatment: A Retrospective Cohort Analysis. Biomedicines 2024; 12:2193. [PMID: 39457505 PMCID: PMC11504253 DOI: 10.3390/biomedicines12102193] [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: 09/09/2024] [Revised: 09/20/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024] Open
Abstract
BACKGROUND/OBJECTIVES Amyotrophic lateral sclerosis (ALS) is a progressive and irreversible neurodegenerative disease with limited treatment options. Advances in regenerative medicine have opened up new treatment options. The primary and exploratory objectives of this retrospective cohort study were to evaluate the safety and efficacy of stem cells from human exfoliated deciduous teeth-conditioned media (SHED-CM). METHODS Safety assessments included adverse events, vital signs, and laboratory test changes before and after administration, and efficacy was measured using the ALS Functional Rating Scale-Revised (ALSFRS-R), grip strength, and forced vital capacity in 24 patients with ALS treated at a single facility between 1 January 2022, and 30 November 2023. RESULTS While ALSFRS-R scores typically decline over time, the progression rate in this cohort was slower, suggesting a potential delay in disease progression. Alternatively, improvements in muscle strength and mobility were observed in some patients. Although adverse events were reported in only 3% of cases (no serious allergic reactions), the treatment-induced changes in vital signs and laboratory results were not clinically significant. CONCLUSIONS The SHED-CM treatment is a safe and potentially effective therapeutic option for patients with ALS. Further research is needed to optimize the SHED-CM treatment; however, this study lays the groundwork for future exploration of regenerative therapies for ALS.
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Affiliation(s)
| | | | | | | | - Yasufumi Murakami
- Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, Noda 278-8510, Japan
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4
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Mazzini L, De Marchi F, Buzanska L, Follenzi A, Glover JC, Gelati M, Lombardi I, Maioli M, Mesa-Herrera F, Mitrečić D, Olgasi C, Pivoriūnas A, Sanchez-Pernaute R, Sgromo C, Zychowicz M, Vescovi A, Ferrari D. Current status and new avenues of stem cell-based preclinical and therapeutic approaches in amyotrophic lateral sclerosis. Expert Opin Biol Ther 2024; 24:933-954. [PMID: 39162129 DOI: 10.1080/14712598.2024.2392307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 08/10/2024] [Indexed: 08/21/2024]
Abstract
INTRODUCTION Cell therapy development represents a critical challenge in amyotrophic lateral sclerosis (ALS) research. Despite more than 20 years of basic and clinical research, no definitive safety and efficacy results of cell-based therapies for ALS have been published. AREAS COVERED This review summarizes advances using stem cells (SCs) in pre-clinical studies to promote clinical translation and in clinical trials to treat ALS. New technologies have been developed and new experimental in vitro and animal models are now available to facilitate pre-clinical research in this field and to determine the most promising approaches to pursue in patients. New clinical trial designs aimed at developing personalized SC-based treatment with biological endpoints are being defined. EXPERT OPINION Knowledge of the basic biology of ALS and on the use of SCs to study and potentially treat ALS continues to grow. However, a consensus has yet to emerge on how best to translate these results into therapeutic applications. The selection and follow-up of patients should be based on clinical, biological, and molecular criteria. Planning of SC-based clinical trials should be coordinated with patient profiling genetically and molecularly to achieve personalized treatment. Much work within basic and clinical research is still needed to successfully transition SC therapy in ALS.
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Affiliation(s)
- Letizia Mazzini
- ALS Center, Neurology Unit, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Fabiola De Marchi
- ALS Center, Neurology Unit, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Leonora Buzanska
- Department of Stem Cell Bioengineering, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Antonia Follenzi
- Dipartimento di Scienze della Salute, Università del Piemonte Orientale, Novara, Italy
- Dipartimento Attività Integrate Ricerca Innovazione, Azienda Ospedaliero-Universitaria SS. Antonio e Biagio e C. Arrigo, Alessandria, Italy
| | - Joel Clinton Glover
- Norwegian Center for Stem Cell Research, Department of Immunology and Transfusion Medicine, Oslo University Hospital; Laboratory of Neural Development and Optical Recording (NDEVOR), Oslo, Norway
- Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Maurizio Gelati
- Unità Produttiva per Terapie Avanzate (UPTA), IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Ivan Lombardi
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy
| | - Margherita Maioli
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
- Center for Developmental Biology and Reprogramming-CEDEBIOR, University of Sassari, Sassari, Italy
| | - Fatima Mesa-Herrera
- Reprogramming and Neural Regeneration Lab, BioBizkaia Health Research Institute, Barakaldo, Spain
| | - Dinko Mitrečić
- Laboratory for Stem Cells, Croatian Institute for Brain Research and Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Cristina Olgasi
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Augustas Pivoriūnas
- Department of Stem Cell Biology, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
| | - Rosario Sanchez-Pernaute
- Reprogramming and Neural Regeneration Lab, BioBizkaia Health Research Institute, Barakaldo, Spain
- Ikerbaske, Basque Foundation for Science, Bilbao, Spain
| | - Chiara Sgromo
- Dipartimento di Scienze della Salute, Università del Piemonte Orientale, Novara, Italy
| | - Marzena Zychowicz
- Department of Stem Cell Bioengineering, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Angelo Vescovi
- Unità Produttiva per Terapie Avanzate (UPTA), IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy
| | - Daniela Ferrari
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy
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Pirsadeghi A, Namakkoobi N, Behzadi MS, Pourzinolabedin H, Askari F, Shahabinejad E, Ghorbani S, Asadi F, Hosseini-Chegeni A, Yousefi-Ahmadipour A, Kamrani MH. Therapeutic approaches of cell therapy based on stem cells and terminally differentiated cells: Potential and effectiveness. Cells Dev 2024; 177:203904. [PMID: 38316293 DOI: 10.1016/j.cdev.2024.203904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 11/24/2023] [Accepted: 01/30/2024] [Indexed: 02/07/2024]
Abstract
Cell-based therapy, as a promising regenerative medicine approach, has been a promising and effective strategy to treat or even cure various kinds of diseases and conditions. Generally, two types of cells are used in cell therapy, the first is the stem cell, and the other is a fully differentiated cell. Initially, all cells in the body are derived from stem cells. Based on the capacity, potency and differentiation potential of stem cells, there are four types: totipotent (produces all somatic cells plus perinatal tissues), pluripotent (produces all somatic cells), multipotent (produces many types of cells), and unipotent (produces a particular type of cells). All non-totipotent stem cells can be used for cell therapy, depending on their potency and/or disease state/conditions. Adult fully differentiated cell is another cell type for cell therapy that is isolated from adult tissues or obtained following the differentiation of stem cells. The cells can then be transplanted back into the patient to replace damaged or malfunctioning cells, promote tissue repair, or enhance the targeted organ's overall function. With increasing science and knowledge in biology and medicine, different types of techniques have been developed to obtain efficient cells to use for therapeutic approaches. In this study, the potential and opportunity of use of all cell types, both stem cells and fully differentiated cells, are reviewed.
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Affiliation(s)
- Ali Pirsadeghi
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Negar Namakkoobi
- Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Student Research Committee, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mahtab Sharifzadeh Behzadi
- Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Hanieh Pourzinolabedin
- Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Fatemeh Askari
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; USERN Office, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Erfan Shahabinejad
- Student Research Committee, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; USERN Office, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Somayeh Ghorbani
- Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Fatemeh Asadi
- Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Cancer and Stem Cell Research Laboratory, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Ali Hosseini-Chegeni
- Cancer and Stem Cell Research Laboratory, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Aliakbar Yousefi-Ahmadipour
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Student Research Committee, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Cancer and Stem Cell Research Laboratory, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
| | - Mohammad Hossein Kamrani
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
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6
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Fang J, Wei H, Wang H, Wang J, Liu H, Chen Y, Chen L, Lu L, Zhang Q, Pan R, Cui E, Luo X. Human placenta-derived mesenchymal stem cell administration protects against acute lung injury in a mouse model. J Cell Biochem 2023; 124:1249-1258. [PMID: 37450693 DOI: 10.1002/jcb.30445] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/08/2023] [Accepted: 07/03/2023] [Indexed: 07/18/2023]
Abstract
This study aims to investigate the effect of placenta-derived mesenchymal stem cells (PMSCs) administration on tissue repair following acute lung injury (ALI). PMSCs were transplanted intravenously to a mouse model of lipopolysaccharide-induced ALI. The therapeutic effects were determined by evaluating several indicators, including pathology; the wet/dry ratio of the lungs; blood gas analysis; the total protein content, cell numbers, and the activity of myeloperoxidase (MPO) in bronchial alveolar lavage fluid (BALF); and the levels of anti-inflammatory and proinflammatory cytokines in serum and BALF. To investigate the underlying mechanism, PMSC-derived exosomes were used for ALI treatment. Administration of PMSCs improved the degree of lung injury, reduced inflammation, increased the expression levels of anti-inflammatory cytokines, and protected lung function. As expected, the effects of PMSC-derived exosomes in the ALI model were similar to those of PMSCs, both in terms of improved lung function and reduced inflammation. These findings suggest that PMSCs have ameliorating effects on ALI that are potentially mediated via their secreted exosomes.
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Affiliation(s)
- Junbiao Fang
- Department of Anesthesiology, Center for Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou medical College, Hangzhou, China
| | - Hanwei Wei
- Department of Anesthesiology, Center for Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou medical College, Hangzhou, China
| | - Hongfa Wang
- Department of Anesthesiology, Center for Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou medical College, Hangzhou, China
| | - Junkai Wang
- Department of Anesthesiology, Center for Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou medical College, Hangzhou, China
| | - Huizi Liu
- Department of Anesthesiology, Center for Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou medical College, Hangzhou, China
| | - Yue Chen
- Department of Anesthesiology, Center for Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou medical College, Hangzhou, China
| | - Long Chen
- Department of Anesthesiology, Center for Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou medical College, Hangzhou, China
| | - Ling Lu
- Department of Anesthesiology, Center for Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou medical College, Hangzhou, China
| | - Qiang Zhang
- Key Laboratory of Cell-Based Drug and Applied Technology Development in Zhejiang Province, Hangzhou, China
| | - Ruolang Pan
- Key Laboratory of Cell-Based Drug and Applied Technology Development in Zhejiang Province, Hangzhou, China
| | - Enhai Cui
- Huzhou Central Hospital, Zhejiang University Huzhou Hospital, Huzhou, China
| | - Xiaopan Luo
- Department of Anesthesiology, Center for Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou medical College, Hangzhou, China
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7
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Ciurea AV, Mohan AG, Covache-Busuioc RA, Costin HP, Glavan LA, Corlatescu AD, Saceleanu VM. Unraveling Molecular and Genetic Insights into Neurodegenerative Diseases: Advances in Understanding Alzheimer's, Parkinson's, and Huntington's Diseases and Amyotrophic Lateral Sclerosis. Int J Mol Sci 2023; 24:10809. [PMID: 37445986 DOI: 10.3390/ijms241310809] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/26/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
Neurodegenerative diseases are, according to recent studies, one of the main causes of disability and death worldwide. Interest in molecular genetics has started to experience exponential growth thanks to numerous advancements in technology, shifts in the understanding of the disease as a phenomenon, and the change in the perspective regarding gene editing and the advantages of this action. The aim of this paper is to analyze the newest approaches in genetics and molecular sciences regarding four of the most important neurodegenerative disorders: Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We intend through this review to focus on the newest treatment, diagnosis, and predictions regarding this large group of diseases, in order to obtain a more accurate analysis and to identify the emerging signs that could lead to a better outcome in order to increase both the quality and the life span of the patient. Moreover, this review could provide evidence of future possible novel therapies that target the specific genes and that could be useful to be taken into consideration when the classical approaches fail to shed light.
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Affiliation(s)
- Alexandru Vlad Ciurea
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Neurosurgery Department, Sanador Clinical Hospital, 010991 Bucharest, Romania
| | - Aurel George Mohan
- Department of Neurosurgery, Bihor County Emergency Clinical Hospital, 410167 Oradea, Romania
- Department of Neurosurgery, Faculty of Medicine, Oradea University, 410610 Oradea, Romania
| | | | - Horia-Petre Costin
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Luca-Andrei Glavan
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Antonio-Daniel Corlatescu
- Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Vicentiu Mircea Saceleanu
- Neurosurgery Department, Sibiu County Emergency Hospital, 550245 Sibiu, Romania
- Neurosurgery Department, "Lucian Blaga" University of Medicine, 550024 Sibiu, Romania
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Biglari N, Mehdizadeh A, Vafaei Mastanabad M, Gharaeikhezri MH, Gol Mohammad Pour Afrakoti L, Pourbala H, Yousefi M, Soltani-Zangbar MS. Application of mesenchymal stem cells (MSCs) in neurodegenerative disorders: History, findings, and prospective challenges. Pathol Res Pract 2023; 247:154541. [PMID: 37245265 DOI: 10.1016/j.prp.2023.154541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 05/12/2023] [Accepted: 05/16/2023] [Indexed: 05/30/2023]
Abstract
Over the past few decades, the application of mesenchymal stem cells has captured the attention of researchers and practitioners worldwide. These cells can be obtained from practically every tissue in the body and are used to treat a broad variety of conditions, most notably neurological diseases such as Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. Studies are still being conducted, and the results of these studies have led to the identification of several different molecular pathways involved in the neuroglial speciation process. These molecular systems are closely regulated and interconnected due to the coordinated efforts of many components that make up the machinery responsible for cell signaling. Within the scope of this study, we compared and contrasted the numerous mesenchymal cell sources and their cellular features. These many sources of mesenchymal cells included adipocyte cells, fetal umbilical cord tissue, and bone marrow. In addition, we investigated whether these cells can potentially treat and modify neurodegenerative illnesses.
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Affiliation(s)
- Negin Biglari
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Mehdizadeh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahsa Vafaei Mastanabad
- Neurosurgery Department, Faculty of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | | | | | - Hooman Pourbala
- Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Yousefi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Sadegh Soltani-Zangbar
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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9
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Sironi F, De Marchi F, Mazzini L, Bendotti C. Cell therapy in ALS: An update on preclinical and clinical studies. Brain Res Bull 2023; 194:64-81. [PMID: 36690163 DOI: 10.1016/j.brainresbull.2023.01.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 01/08/2023] [Accepted: 01/19/2023] [Indexed: 01/21/2023]
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons and neuromuscular impairment leading to complete paralysis, respiratory failure and premature death. The pathogenesis of the disease is multifactorial and noncell-autonomous involving the central and peripheral compartments of the neuromuscular axis and the skeletal muscle. Advanced clinical trials on specific ALS-related pathways have failed to significantly slow the disease. Therapy with stem cells from different sources has provided a promising strategy to protect the motor units exerting their effect through multiple mechanisms including neurotrophic support and excitotoxicity and neuroinflammation modulation, as evidenced from preclinical studies. Several phase I and II clinical trial of ALS patients have been developed showing positive effects in terms of safety and tolerability. However, the modest results on functional improvement in ALS patients suggest that only a coordinated effort between basic and clinical researchers could solve many problems, such as selecting the ideal stem cell source, identifying their mechanism of action and expected clinical outcomes. A promising approach may be stem cells selected or engineered to deliver optimal growth factor support at multiple sites along the neuromuscular pathway. This review covers recent advances in stem cell therapies in animal models of ALS, as well as detailing the human clinical trials that have been done and are currently undergoing development.
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Affiliation(s)
- Francesca Sironi
- Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, Milan 20156, Italy
| | - Fabiola De Marchi
- Department of Neurology and ALS Centre, University of Piemonte Orientale, Maggiore Della Carità Hospital, Corso Mazzini 18, Novara 28100, Italy
| | - Letizia Mazzini
- Department of Neurology and ALS Centre, University of Piemonte Orientale, Maggiore Della Carità Hospital, Corso Mazzini 18, Novara 28100, Italy.
| | - Caterina Bendotti
- Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, Milan 20156, Italy.
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10
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Stem Cell Therapies in Movement Disorders: Lessons from Clinical Trials. Biomedicines 2023; 11:biomedicines11020505. [PMID: 36831041 PMCID: PMC9953050 DOI: 10.3390/biomedicines11020505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 02/04/2023] [Accepted: 02/04/2023] [Indexed: 02/12/2023] Open
Abstract
Stem cell-based therapies (SCT) to treat neurodegenerative disorders have promise but clinical trials have only recently begun, and results are not expected for several years. While most SCTs largely lead to a symptomatic therapeutic effect by replacing lost cell types, there may also be disease-modifying therapeutic effects. In fact, SCT may complement a multi-drug, subtype-specific therapeutic approach, consistent with the idea of precision medicine, which matches molecular therapies to biological subtypes of disease. In this narrative review, we examine published and ongoing trials in SCT in Parkinson's Disease, atypical parkinsonian disorders, Huntington's disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia in humans. We discuss the benefits and pitfalls of using this treatment approach within the spectrum of disease-modification efforts in neurodegenerative diseases. SCT may hold greater promise in the treatment of neurodegenerative disorders, but much research is required to determine the feasibility, safety, and efficacy of these complementary aims of therapeutic efforts.
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Sarikidi A, Kefalakes E, Falk CS, Esser R, Ganser A, Thau-Habermann N, Petri S. Altered Immunomodulatory Responses in the CX3CL1/CX3CR1 Axis Mediated by hMSCs in an Early In Vitro SOD1 G93A Model of ALS. Biomedicines 2022; 10:biomedicines10112916. [PMID: 36428484 PMCID: PMC9688016 DOI: 10.3390/biomedicines10112916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/11/2022] [Accepted: 11/08/2022] [Indexed: 11/16/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron (MN) disease characterized by progressive MN loss and muscular atrophy resulting in rapidly progressive paralysis and respiratory failure. Human mesenchymal stem/stromal cell (hMSC)-based therapy has been suggested to prolong MN survival via secretion of growth factors and modulation of cytokines/chemokines. We investigated the effects of hMSCs and a hMSC-conditioned medium (CM) on Cu/Zn superoxidase dismutase 1G93A (SOD1G93A) transgenic primary MNs. We found that co-culture of hMSCs and MNs resulted in slightly higher MN numbers, but did not protect against staurosporine (STS)-induced toxicity, implying marginal direct trophic effects of hMSCs. Aiming to elucidate the crosstalk between hMSCs and MNs in vitro, we found high levels of vascular endothelial growth factor (VEGF) and C-X3-C motif chemokine 1 (CX3CL1) in the hMSC secretome. Co-culture of hMSCs and MNs resulted in altered gene expression of growth factors and cytokines/chemokines in both MNs and hMSCs. hMSCs showed upregulation of CX3CL1 and its receptor CX3CR1 and downregulation of interleukin-1 β (IL1β) and interleukin-8 (IL8) when co-cultured with SOD1G93A MNs. MNs, on the other hand, showed upregulation of growth factors as well as CX3CR1 upon hMSC co-culture. Our results indicate that hMSCs only provide moderate trophic support to MNs by growth factor gene regulation and may mediate anti-inflammatory responses through the CX3CL1/CX3CR1 axis, but also increase expression of pro-inflammatory cytokines, which limits their therapeutic potential.
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Affiliation(s)
- Anastasia Sarikidi
- Department of Neurology, Hannover Medical School, 30625 Hannover, Germany
| | - Ekaterini Kefalakes
- Department of Neurology, Hannover Medical School, 30625 Hannover, Germany
- Institute of Neuroanatomy and Cell Biology, Hannover Medical School, 30625 Hannover, Germany
| | - Christine S. Falk
- Institute of Transplant Immunology, Hannover Medical School, 30625 Hannover, Germany
| | - Ruth Esser
- Institute of Cellular Therapeutics, Hannover Medical School, 30625 Hannover, Germany
| | - Arnold Ganser
- Institute of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany
| | | | - Susanne Petri
- Department of Neurology, Hannover Medical School, 30625 Hannover, Germany
- Correspondence: ; Tel.: +49-511-532-3740
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12
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Saini R, Pahwa B, Agrawal D, Singh P, Gurjar H, Mishra S, Jagdevan A, Misra MC. Safety and feasibility of intramedullary injected bone marrow-derived mesenchymal stem cells in acute complete spinal cord injury: phase 1 trial. J Neurosurg Spine 2022; 37:331-338. [PMID: 35395638 DOI: 10.3171/2022.2.spine211021] [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: 07/31/2021] [Accepted: 02/10/2022] [Indexed: 11/06/2022]
Abstract
OBJECTIVE The intramedullary route holds the potential to provide the most concentration of stem cells in cases of spinal cord injury (SCI). However, the safety and feasibility of this route need to be studied in human subjects. The aim of this study was to evaluate the safety and feasibility of intramedullary injected bone marrow-derived mesenchymal stem cells (BM-MSCs) in acute complete SCI. METHODS In this prospective study conducted over a 2-year period, 27 patients with acute (defined as within 1 week of injury) and complete SCI were randomized to receive BM-MSC or placebo through an intramedullary route intraoperatively at the time of spinal decompression and fusion. Institutional ethics approval was obtained, and informed consent was obtained from all patients. Safety was assessed using laboratory and clinicoradiological parameters preoperatively and 3 and 6 months after surgery. RESULTS A total of 180 patients were screened during the study period. Of these, 27 were enrolled in the study. Three patients withdrew, 3 patients were lost to follow-up, and 8 patients died, leaving a total of 13 patients for final analysis. Seven of these patients were in the stem cell group, and 6 were in the control group. Both groups were well matched in terms of sex, age, and weight. No adverse events related to stem cell injection were noted for laboratory and radiological parameters. Five patients in the control group and 3 patients in the stem cell group died during the follow-up period. CONCLUSIONS Intramedullary injection of BM-MSCs was found to be safe and feasible for use in patients with acute complete SCI.
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Affiliation(s)
- Renu Saini
- 1Stem Cell & Translational Neurosciences Laboratory, Department of Neurosurgery, JPNA Trauma Center, All India Institute of Medical Sciences, New Delhi, India; and
| | - Bhavya Pahwa
- 2University College of Medical Sciences and GTB Hospital, Dilshad Garden, Delhi, India
| | - Deepak Agrawal
- 1Stem Cell & Translational Neurosciences Laboratory, Department of Neurosurgery, JPNA Trauma Center, All India Institute of Medical Sciences, New Delhi, India; and
| | - Pankaj Singh
- 1Stem Cell & Translational Neurosciences Laboratory, Department of Neurosurgery, JPNA Trauma Center, All India Institute of Medical Sciences, New Delhi, India; and
| | - Hitesh Gurjar
- 1Stem Cell & Translational Neurosciences Laboratory, Department of Neurosurgery, JPNA Trauma Center, All India Institute of Medical Sciences, New Delhi, India; and
| | - Shashwat Mishra
- 1Stem Cell & Translational Neurosciences Laboratory, Department of Neurosurgery, JPNA Trauma Center, All India Institute of Medical Sciences, New Delhi, India; and
| | - Aman Jagdevan
- 1Stem Cell & Translational Neurosciences Laboratory, Department of Neurosurgery, JPNA Trauma Center, All India Institute of Medical Sciences, New Delhi, India; and
| | - Mahesh Chandra Misra
- 1Stem Cell & Translational Neurosciences Laboratory, Department of Neurosurgery, JPNA Trauma Center, All India Institute of Medical Sciences, New Delhi, India; and
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13
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Durankuş F, Albayrak Y, Erdoğan F, Albayrak N, Erdoğan MA, Erbaş O. Granulocyte Colony-Stimulating Factor Has a Sex-Dependent Positive Effect in the Maternal Immune Activation-Induced Autism Model. Int J Dev Neurosci 2022; 82:716-726. [PMID: 35904498 DOI: 10.1002/jdn.10221] [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: 03/20/2022] [Revised: 07/18/2022] [Accepted: 07/25/2022] [Indexed: 11/05/2022] Open
Abstract
OBJECTIVE The medical intervention for autism spectrum disorder (ASD) is restricted to ameliorating comorbid situations. Granulocyte colony-stimulating factor (G-CSF) is a growth factor that enhances the proliferation, differentiation and survival of hematopoietic progenitor cells. In the present study, we aimed to investigate the effects of G-CSF in a maternal immune activation-induced autism model. METHODS Sixteen female and 6 male Wistar adult rats were included in the study. After 21 days, forty-eight littermates (8 male controls, 8 female controls, 16 male lipopolysaccharide (LPS)-exposed rats and 16 female LPS-exposed rats) were divided into groups. Sixteen male LPS-exposed and 16 female LPS-exposed rats were divided into saline and G-CSF treatment groups. RESULTS In male rats, the LPS-exposed group was found to have significantly higher levels of TNF-α, IL-2, and IL-17 than the LPS-exposed G-CSF group. Levels of nerve growth factor, brain PSD-95 and brain GAD67 were higher in the LPS-exposed G-CSF group than in the LPS-exposed group in male rats. In female rats, brain NGF levels were similar between groups. There was no difference between groups in terms of brain GAD 67 levels. Brain PSD-95 levels were higher in the control group than in both the LPS-exposed and LPS-exposed G-CSF groups in female rats. Both neuronal CA1 and neuronal CA2 levels were lower, and the GFAP immunostaining index (CA1) and GFAP immunostaining index (CA3) were higher in the LPS-exposed group than in the LPS-exposed G-CSF group in male rats. However, neuronal count CA1 and Neuronal count CA3 values were found to be similar between groups in female rats. CONCLUSIONS The present research is the first to demonstrate the beneficial effects of G-CSF on core symptoms of ASD experimentally depending on male sex. G-CSF can be a good candidate for ameliorating the core symptoms of ASD without serious side effects in males.
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Affiliation(s)
- Ferit Durankuş
- Department of Pediatrics, Istanbul Medeniyet University, İstanbul, Turkey
| | - Yakup Albayrak
- Faculty of Medicine, Department of Psychiatry, Tekirdağ Namık Kemal University, Tekirdağ, Turkey
| | - Fırat Erdoğan
- Department of Pediatrics, Istanbul Medeniyet University, İstanbul, Turkey
| | | | - Mümin Alper Erdoğan
- Department of Physiology, Katip Çelebi University Medical School, İzmir, Turkey
| | - Oytun Erbaş
- Medical School, Department of Physiology, Demiroğlu Bilim University, İstanbul, Turkey
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14
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Lin TJ, Cheng KC, Wu LY, Lai WY, Ling TY, Kuo YC, Huang YH. Potential of Cellular Therapy for ALS: Current Strategies and Future Prospects. Front Cell Dev Biol 2022; 10:851613. [PMID: 35372346 PMCID: PMC8966507 DOI: 10.3389/fcell.2022.851613] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 02/15/2022] [Indexed: 12/15/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive upper and lower motor neuron (MN) degeneration with unclear pathology. The worldwide prevalence of ALS is approximately 4.42 per 100,000 populations, and death occurs within 3-5 years after diagnosis. However, no effective therapeutic modality for ALS is currently available. In recent years, cellular therapy has shown considerable therapeutic potential because it exerts immunomodulatory effects and protects the MN circuit. However, the safety and efficacy of cellular therapy in ALS are still under debate. In this review, we summarize the current progress in cellular therapy for ALS. The underlying mechanism, current clinical trials, and the pros and cons of cellular therapy using different types of cell are discussed. In addition, clinical studies of mesenchymal stem cells (MSCs) in ALS are highlighted. The summarized findings of this review can facilitate the future clinical application of precision medicine using cellular therapy in ALS.
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Affiliation(s)
- Ting-Jung Lin
- School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Kuang-Chao Cheng
- School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Luo-Yun Wu
- School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Wei-Yu Lai
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- TMU Research Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan
| | - Thai-Yen Ling
- Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan
| | - Yung-Che Kuo
- TMU Research Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yen-Hua Huang
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- TMU Research Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan
- International Ph.D. Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
- Comprehensive Cancer Center of Taipei Medical University, Taipei, Taiwan
- PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
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15
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Liu E, Karpf L, Bohl D. Neuroinflammation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia and the Interest of Induced Pluripotent Stem Cells to Study Immune Cells Interactions With Neurons. Front Mol Neurosci 2022; 14:767041. [PMID: 34970118 PMCID: PMC8712677 DOI: 10.3389/fnmol.2021.767041] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 11/16/2021] [Indexed: 12/14/2022] Open
Abstract
Inflammation is a shared hallmark between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). For long, studies were conducted on tissues of post-mortem patients and neuroinflammation was thought to be only bystander result of the disease with the immune system reacting to dying neurons. In the last two decades, thanks to improving technologies, the identification of causal genes and the development of new tools and models, the involvement of inflammation has emerged as a potential driver of the diseases and evolved as a new area of intense research. In this review, we present the current knowledge about neuroinflammation in ALS, ALS-FTD, and FTD patients and animal models and we discuss reasons of failures linked to therapeutic trials with immunomodulator drugs. Then we present the induced pluripotent stem cell (iPSC) technology and its interest as a new tool to have a better immunopathological comprehension of both diseases in a human context. The iPSC technology giving the unique opportunity to study cells across differentiation and maturation times, brings the hope to shed light on the different mechanisms linking neurodegeneration and activation of the immune system. Protocols available to differentiate iPSC into different immune cell types are presented. Finally, we discuss the interest in studying monocultures of iPS-derived immune cells, co-cultures with neurons and 3D cultures with different cell types, as more integrated cellular approaches. The hope is that the future work with human iPS-derived cells helps not only to identify disease-specific defects in the different cell types but also to decipher the synergistic effects between neurons and immune cells. These new cellular tools could help to find new therapeutic approaches for all patients with ALS, ALS-FTD, and FTD.
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Affiliation(s)
- Elise Liu
- Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, INSERM, CNRS, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France
| | - Léa Karpf
- Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, INSERM, CNRS, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France
| | - Delphine Bohl
- Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, INSERM, CNRS, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France
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16
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Arad M, Brown RA, Khatri R, Taylor RJ, Zalzman M. Direct differentiation of tonsillar biopsy-derived stem cells to the neuronal lineage. Cell Mol Biol Lett 2021; 26:38. [PMID: 34407767 PMCID: PMC8371824 DOI: 10.1186/s11658-021-00279-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 07/27/2021] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Neurological disorders are considered one of the greatest burdens to global public health and a leading cause of death. Stem cell therapies hold great promise for the cure of neurological disorders, as stem cells can serve as cell replacement, while also secreting factors to enhance endogenous tissue regeneration. Adult human multipotent stem cells (MSCs) reside on blood vessels, and therefore can be found in many tissues throughout the body, including palatine tonsils. Several studies have reported the capacity of MSCs to differentiate into, among other cell types, the neuronal lineage. However, unlike the case with embryonic stem cells, it is unclear whether MSCs can develop into mature neurons. METHODS Human tonsillar MSCs (T-MSCs) were isolated from a small, 0.6-g sample, of tonsillar biopsies with high viability and yield as we recently reported. Then, these cells were differentiated by a rapid, multi-stage procedure, into committed, post-mitotic, neuron-like cells using defined conditions. RESULTS Here we describe for the first time the derivation and differentiation of tonsillar biopsy-derived MSCs (T-MSCs), by a rapid, multi-step protocol, into post-mitotic, neuron-like cells using defined conditions without genetic manipulation. We characterized our T-MSC-derived neuronal cells and demonstrate their robust differentiation in vitro. CONCLUSIONS Our procedure leads to a rapid neuronal lineage commitment and loss of stemness markers, as early as three days following neurogenic differentiation. Our studies identify biopsy-derived T-MSCs as a potential source for generating neuron-like cells which may have potential use for in vitro modeling of neurodegenerative diseases or cell replacement therapies.
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Affiliation(s)
- Michal Arad
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene Street, Baltimore, MD, 21201, USA
| | - Robert A Brown
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene Street, Baltimore, MD, 21201, USA
| | - Raju Khatri
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene Street, Baltimore, MD, 21201, USA
| | - Rodney J Taylor
- Marlene and Stewart Greenbaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.,Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Michal Zalzman
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene Street, Baltimore, MD, 21201, USA. .,The Center for Stem Cell Biology and Regenerative Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. .,Marlene and Stewart Greenbaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. .,Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
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17
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Sykova E, Cizkova D, Kubinova S. Mesenchymal Stem Cells in Treatment of Spinal Cord Injury and Amyotrophic Lateral Sclerosis. Front Cell Dev Biol 2021; 9:695900. [PMID: 34295897 PMCID: PMC8290345 DOI: 10.3389/fcell.2021.695900] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 05/31/2021] [Indexed: 01/01/2023] Open
Abstract
Preclinical and clinical studies with various stem cells, their secretomes, and extracellular vesicles (EVs) indicate their use as a promising strategy for the treatment of various diseases and tissue defects, including neurodegenerative diseases such as spinal cord injury (SCI) and amyotrophic lateral sclerosis (ALS). Autologous and allogenic mesenchymal stem cells (MSCs) are so far the best candidates for use in regenerative medicine. Here we review the effects of the implantation of MSCs (progenitors of mesodermal origin) in animal models of SCI and ALS and in clinical studies. MSCs possess multilineage differentiation potential and are easily expandable in vitro. These cells, obtained from bone marrow (BM), adipose tissue, Wharton jelly, or even other tissues, have immunomodulatory and paracrine potential, releasing a number of cytokines and factors which inhibit the proliferation of T cells, B cells, and natural killer cells and modify dendritic cell activity. They are hypoimmunogenic, migrate toward lesion sites, induce better regeneration, preserve perineuronal nets, and stimulate neural plasticity. There is a wide use of MSC systemic application or MSCs seeded on scaffolds and tissue bridges made from various synthetic and natural biomaterials, including human decellularized extracellular matrix (ECM) or nanofibers. The positive effects of MSC implantation have been recorded in animals with SCI lesions and ALS. Moreover, promising effects of autologous as well as allogenic MSCs for the treatment of SCI and ALS were demonstrated in recent clinical studies.
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Affiliation(s)
- Eva Sykova
- Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Dasa Cizkova
- Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia.,Centre for Experimental and Clinical Regenerative Medicine, University of Veterinary Medicine and Pharmacy in Kosice, Kosice, Slovakia
| | - Sarka Kubinova
- Department of Optical and Biophysical Systems, Institute of Physics of the Czech Academy of Sciences, Prague, Czechia
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18
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Ornelas-González A, González-González M, Rito-Palomares M. Microcarrier-based stem cell bioprocessing: GMP-grade culture challenges and future trends for regenerative medicine. Crit Rev Biotechnol 2021; 41:1081-1095. [PMID: 33730936 DOI: 10.1080/07388551.2021.1898328] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Recently, stem cell-based therapies have been proposed as an alternative for the treatment of many diseases. Stem cells (SCs) are well known for their capacity to preserve themselves, proliferate, and differentiate into multiple lineages. These characteristics allow stem cells to be a viable option for the treatment of diverse diseases. Traditional methodologies based on 2-dimensional culture techniques (T-flasks and Petri dishes) are simple and well standardized; however, they present disadvantages that limit the production of the cell yield required for regenerative medicine applications. Lately, microcarrier (MC)-based culture techniques have emerged as an attractive platform for expanding stem cells in suspension systems. Although the use of stem cell expansion on MCs has recently shown significant increase, their implementation for medical purposes is been hampered by bottlenecks in upstream and downstream processing. Therefore, there is an urgent need in the development of bioprocesses that simplify stem cell cultures under xeno-free conditions and detachment from MCs without diminishing their pluripotency and viability. A critical analysis of the factors that impact the up and downstream bioprocessing on MC-based stem cell cultures is presented in this review. This analysis aims to raise the awareness of the current drawbacks that limit MC-based stem cell bioprocessing in regenerative medicine and propose alternatives to overcome them.
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Affiliation(s)
| | | | - Marco Rito-Palomares
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Mexico
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19
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Ahani-Nahayati M, Shariati A, Mahmoodi M, Olegovna Zekiy A, Javidi K, Shamlou S, Mousakhani A, Zamani M, Hassanzadeh A. Stem cell in neurodegenerative disorders; an emerging strategy. Int J Dev Neurosci 2021; 81:291-311. [PMID: 33650716 DOI: 10.1002/jdn.10101] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/13/2021] [Accepted: 02/24/2021] [Indexed: 01/28/2023] Open
Abstract
Neurodegenerative disorders are a diversity of disorders, surrounding Alzheimer's (AD), Parkinson's (PD), Huntington's diseases (HD), and amyotrophic lateral sclerosis (ALS) accompanied by some other less common diseases generally characterized by either developed deterioration of central or peripheral nervous system structurally or functionally. Today, with the viewpoint of an increasingly aging society, the number of patients with neurodegenerative diseases and sociomedical burdens will spread intensely. During the last decade, stem cell technology has attracted great attention for treating neurodegenerative diseases worldwide because of its unique attributes. As acknowledged, there are several categories of stem cells being able to proliferate and differentiate into various cellular lineages, highlighting their significance in the context of regenerative medicine. In preclinical models, stem cell therapy using mesenchymal stem/stromal cells (MSCs), hematopoietic stem cells (HSCs), and neural progenitor or stem cells (NPCs or NSCs) along with pluripotent stem cells (PSCs)-derived neuronal cells could elicit desired therapeutic effects, enabling functional deficit rescue partially. Regardless of the noteworthy progress in our scientific awareness and understanding of stem cell biology, there still exist various challenges to defeat. In the present review, we provide a summary of the therapeutic potential of stem cells and discuss the current status and prospect of stem cell strategy in neurodegenerative diseases, in particular, AD, PD, ALS, and HD.
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Affiliation(s)
- Milad Ahani-Nahayati
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Ali Shariati
- Stem Cell Research Center, Tehran University of Medical Science, Tehran, Iran
| | - Mahnaz Mahmoodi
- Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Angelina Olegovna Zekiy
- Department of Prosthetic Dentistry, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Kamran Javidi
- School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran.,Immunology Research Center (IRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Somayeh Shamlou
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Akbar Mousakhani
- Department of Plant Sciences, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Majid Zamani
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Ali Hassanzadeh
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Neurosciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
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20
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Abstract
Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of upper and lower motor neurons with high burden on society. Despite tremendous efforts over the last several decades, there is still no definite cure for ALS. Up to now, only two disease-modifying agents, riluzole and edaravone, are approved by U.S. Food and Drug Administration (FDA) for ALS treatment, which only modestly improves survival and disease progression. Major challenging issues to find an effective therapy are heterogeneity in the pathogenesis and genetic variability of ALS. As such, stem cell therapy has been recently a focus of both preclinical and clinical investigations of ALS. This is because stem cells have multifaceted features that can potentially target multiple pathogenic mechanisms in ALS even though its underlying mechanisms are not completely elucidated. Methods & Results: Here, we will have an overview of stem cell therapy in ALS, including their therapeutic mechanisms, the results of recent clinical trials as well as ongoing clinical trials. In addition, we will further discuss complications and limitations of stem cell therapy in ALS. Conclusion: The determination of whether stem cells offer a viable treatment strategy for ALS rests on well-designed and appropriately powered future clinical trials. Randomized, double-blinded, and sham-controlled studies would be valuable.
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Affiliation(s)
- Goun Je
- Department of Neurology, University of Massachusetts Medical School, Worcester, MA USA
| | - Kiandokht Keyhanian
- Department of Neurology, University of Massachusetts Medical School, Worcester, MA USA
| | - Mehdi Ghasemi
- Department of Neurology, University of Massachusetts Medical School, Worcester, MA USA
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21
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Sharma A, Sane H, Paranjape A, Varghese R, Nair V, Biju H, Sawant D, Gokulchandran N, Badhe P. Improved survival in amyotrophic lateral sclerosis patients following autologous bone marrow mononuclear cell therapy: a long term 10-year retrospective study. JOURNAL OF NEURORESTORATOLOGY 2021. [DOI: 10.26599/jnr.2021.9040010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Background: Promising results from previous studies using cell therapy have paved the way for an innovative treatment option for amyotrophic lateral sclerosis (ALS). There is considerable evidence of immune and inflammatory abnormalities in ALS. Bone marrow mononuclear cells (BMMNCs) possess immunomodulatory properties and could contribute to slowing of disease progression. Objective: Aim of our study was to evaluate the long-term effect of autologous BMMNCs combined with standard treatment on survival duration in a large population and to evaluate effect of type of onset and hormonal status on survival duration in the intervention group. Methods: This controlled, retrospective study spanned over 10 years, 5 months; included 216 patients with probable or definite ALS, 150 in intervention group receiving autologous BMMNCs and standard treatment, and 66 in control group receiving only standard treatment. The estimated survival duration of control group and intervention group was computed and compared using Kaplan Meier analysis. Survival duration of patients with different types of onset and hormonal status was compared within the intervention group. Results: None of the patients reported any major adverse events related to cell administration or the procedure. Kaplan Meier analysis estimated survival duration in the intervention group to be 91.7 months while 49.7 months in the control group (p = 0.008). Within the intervention group, estimated survival was significantly higher (p = 0.013) in patients with limb onset (102.3 months) vs. bulbar onset (49.9 months); premenopausal women (93.1 months) vs. postmenopausal women (57.6 months) (p = 0.002); and preandropausal men (153.7 months) vs. postandropausal males (56.5 months) (p = 0.006). Conclusion: Cell therapy using autologous BMMNCs along with standard treatment offers a promising and safe option for ALS with the potential of long term beneficial effect and increased survival. Limb onset patients, premenopausal women and men ≤ 40 years of age demonstrated better treatment efficacy.
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Beard K, Meaney DF, Issadore D. Clinical Applications of Extracellular Vesicles in the Diagnosis and Treatment of Traumatic Brain Injury. J Neurotrauma 2020; 37:2045-2056. [PMID: 32312151 PMCID: PMC7502684 DOI: 10.1089/neu.2020.6990] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Extracellular vesicles (EVs) have emerged as key mediators of cell-cell communication during homeostasis and in pathology. Central nervous system (CNS)-derived EVs contain cell type-specific surface markers and intralumenal protein, RNA, DNA, and metabolite cargo that can be used to assess the biochemical and molecular state of neurons and glia during neurological injury and disease. The development of EV isolation strategies coupled with analysis of multi-plexed biomarker and clinical data have the potential to improve our ability to classify and treat traumatic brain injury (TBI) and resulting sequelae. Additionally, their ability to cross the blood-brain barrier (BBB) has implications for both EV-based diagnostic strategies and for potential EV-based therapeutics. In the present review, we discuss encouraging data for EV-based diagnostic, prognostic, and therapeutic strategies in the context of TBI monitoring and management.
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Affiliation(s)
- Kryshawna Beard
- Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - David F. Meaney
- Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - David Issadore
- Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Electrical and Systems Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Masrori P, Van Damme P. Amyotrophic lateral sclerosis: a clinical review. Eur J Neurol 2020; 27:1918-1929. [PMID: 32526057 PMCID: PMC7540334 DOI: 10.1111/ene.14393] [Citation(s) in RCA: 615] [Impact Index Per Article: 123.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 06/04/2020] [Indexed: 12/13/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily the motor system, but in which extra-motor manifestations are increasingly recognized. The loss of upper and lower motor neurons in the motor cortex, the brain stem nuclei and the anterior horn of the spinal cord gives rise to progressive muscle weakness and wasting. ALS often has a focal onset but subsequently spreads to different body regions, where failure of respiratory muscles typically limits survival to 2-5 years after disease onset. In up to 50% of cases, there are extra-motor manifestations such as changes in behaviour, executive dysfunction and language problems. In 10%-15% of patients, these problems are severe enough to meet the clinical criteria of frontotemporal dementia (FTD). In 10% of ALS patients, the family history suggests an autosomal dominant inheritance pattern. The remaining 90% have no affected family members and are classified as sporadic ALS. The causes of ALS appear to be heterogeneous and are only partially understood. To date, more than 20 genes have been associated with ALS. The most common genetic cause is a hexanucleotide repeat expansion in the C9orf72 gene, responsible for 30%-50% of familial ALS and 7% of sporadic ALS. These expansions are also a frequent cause of frontotemporal dementia, emphasizing the molecular overlap between ALS and FTD. To this day there is no cure or effective treatment for ALS and the cornerstone of treatment remains multidisciplinary care, including nutritional and respiratory support and symptom management. In this review, different aspects of ALS are discussed, including epidemiology, aetiology, pathogenesis, clinical features, differential diagnosis, investigations, treatment and future prospects.
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Affiliation(s)
- P Masrori
- Department of Neurosciences, Experimental Neurology, KU Leuven - University of Leuven, Leuven, Belgium.,Laboratory of Neurobiology, Center for Brain and Disease Research, VIB, Leuven, Belgium.,Department of Neurology, University Hospitals Leuven, Leuven, Belgium
| | - P Van Damme
- Department of Neurosciences, Experimental Neurology, KU Leuven - University of Leuven, Leuven, Belgium.,Laboratory of Neurobiology, Center for Brain and Disease Research, VIB, Leuven, Belgium.,Department of Neurology, University Hospitals Leuven, Leuven, Belgium
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24
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Disease-modifying therapies in amyotrophic lateral sclerosis. Neuropharmacology 2020; 167:107986. [DOI: 10.1016/j.neuropharm.2020.107986] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 01/21/2020] [Accepted: 01/31/2020] [Indexed: 02/08/2023]
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Salamone P, Fuda G, Casale F, Marrali G, Lunetta C, Caponnetto C, Mazzini L, La Bella V, Mandrioli J, Simone IL, Moglia C, Calvo A, Tarella C, Chio A. G-CSF (filgrastim) treatment for amyotrophic lateral sclerosis: protocol for a phase II randomised, double-blind, placebo-controlled, parallel group, multicentre clinical study (STEMALS-II trial). BMJ Open 2020; 10:e034049. [PMID: 32209625 PMCID: PMC7202695 DOI: 10.1136/bmjopen-2019-034049] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurological disorder characterised by a selective degeneration of motor neurons (MNs). Stem cell transplantation is considered as a promising strategy in neurological disorders therapy and the possibility of inducing bone marrow cells (BMCs) to circulate in the peripheral blood is suggested to investigate stem cells migration in degenerated ALS nerve tissues where potentially repair MN damage. Granulocyte-colony stimulating factor (G-CSF) is a growth factor which stimulates haematopoietic progenitor cells, mobilises BMCs into injured brain and it is itself a neurotrophic factor for MN. G-CSF safety in humans has been demonstrated and many observations suggest that it may affect neural cells. Therefore, we decided to use G-CSF to mobilise BMCs into the peripheral circulation in patients with ALS, planning a clinical trial to evaluate the effect of G-CSF administration in ALS patients compared with placebo. METHODS AND ANALYSIS STEMALS-II is a phase II multicentre, randomised double-blind, placebo-controlled, parallel group clinical trial on G-CSF (filgrastim) and mannitol in ALS patients. Specifically, we investigate safety, tolerability and efficacy of four repeated courses of intravenous G-CSF and mannitol administered in 76 ALS patients in comparison with placebo (indistinguishable glucose solution 5%). We determine increase of G-CSF levels in serum and cerebrospinal fluid as CD34+ cells and leucocyte count after treatment; reduction in ALS Functional Rating Scale-Revised Score, forced vital capacity, Scale for Testing Muscle Strength Score and quality of life; the adverse events/reactions during the treatment; changes in neuroinflammation biomarkers before and after treatment. ETHICS AND DISSEMINATION The study protocol was approved by the Ethics Committee of Azienda Ospedaliera Universitaria 'Città della Salute e della Scienza', Torino, Italy. Results will be presented during scientific symposia or published in scientific journals. TRIAL REGISTRATION NUMBER Eudract 2014-002228-28.
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Affiliation(s)
- Paolina Salamone
- 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Torino, Piemonte, Italy
| | - Giuseppe Fuda
- 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Torino, Piemonte, Italy
| | - Federico Casale
- 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Torino, Piemonte, Italy
| | - Giuseppe Marrali
- 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Torino, Piemonte, Italy
| | - Christian Lunetta
- NEuroMuscular Omnicentre (NEMO), Fondazione Serena Onlus, Milan, Italy
| | - Claudia Caponnetto
- Neurological Clinic, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Letizia Mazzini
- Department of Neurology, Maggiore della Carità Hospital, University of Piemonte Orientale, Novara, Italy
| | - Vincenzo La Bella
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Sicilia, Italy
| | - Jessica Mandrioli
- Department of Neuroscience, Azienda Ospedaliera Universitaria Modena, St. Agostino-Estense Hospital, Modena, Italy
| | - Isabella Laura Simone
- Neurology Unit, Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Puglia, Italy
| | - Cristina Moglia
- 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Torino, Piemonte, Italy
- ALS Center, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Piemonte, Italy
| | - Andrea Calvo
- 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Torino, Piemonte, Italy
- ALS Center, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Piemonte, Italy
| | - Corrado Tarella
- Oncohematology Division, IEO European Institute of Oncology, IRCCS, University of Milan, Milano, Lombardia, Italy
| | - Adriano Chio
- 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Torino, Piemonte, Italy
- ALS Center, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Piemonte, Italy
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Huang H, Chen L, Mao G, Sharma HS. Clinical neurorestorative cell therapies: Developmental process, current state and future prospective. JOURNAL OF NEURORESTORATOLOGY 2020. [DOI: 10.26599/jnr.2020.9040009] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Clinical cell therapies (CTs) for neurological diseases and cellular damage have been explored for more than 2 decades. According to the United States Food and Drug Administration, there are 2 types of cell categories for therapy, namely stem cell-derived CT products and mature/functionally differentiated cell-derived CT products. However, regardless of the type of CT used, the majority of reports of clinical CTs from either small sample sizes based on single-center phase 1 or 2 unblinded trials or retrospective clinical studies showed effects on neurological improvement and the ability to either partially or temporarily thwart the deteriorating cellular processes of the neurodegenerative diseases. There have been only a few prospective, multicenter, randomized, double- blind placebo-control clinical trials of CTs so far in this developing novel area that have shown negative results, and more clinical trials are needed. This will expand our knowledge in exploring the type of cells that yield promising results and restore damaged neurological structure and functions of the central nervous system based on higher level evidence-based medical data. In this review, we briefly introduce the developmental process, current state, and future prospective for clinical neurorestorative CT.
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Zhu Q, Lu P. Stem Cell Transplantation for Amyotrophic Lateral Sclerosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1266:71-97. [PMID: 33105496 DOI: 10.1007/978-981-15-4370-8_6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is a motor neuronal degeneration disease, in which the death of motor neurons causes lost control of voluntary muscles. The consequence is weakness of muscles with a wide range of disabilities and eventually death. Most patients died within 5 years after diagnosis, and there is no cure for this devastating neurodegenerative disease up to date. Stem cells, including non-neural stem cells and neural stem cells (NSCs) or neural progenitor cells (NPCs), are very attractive cell sources for potential neuroprotection and motor neuron replacement therapy which bases on the idea that transplant-derived and newly differentiated motor neurons can replace lost motor neurons to re-establish voluntary motor control of muscles in ALS. Our recent studies show that transplanted NSCs or NPCs not only survive well in injured spinal cord, but also function as neuronal relays to receive regenerated host axonal connection and extend their own axons to host for connectivity, including motor axons in ventral root. This reciprocal connection between host neurons and transplanted neurons provides a strong rationale for neuronal replacement therapy for ALS to re-establish voluntary motor control of muscles. In addition, a variety of new stem cell resources and the new methodologies to generate NSCs or motor neuron-specific progenitor cells have been discovered and developed. Together, it provides the basis for motor neuron replacement therapy with NSCs or NPCs in ALS.
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Affiliation(s)
- Qiang Zhu
- Ludwig Institute, University of California - San Diego, La Jolla, CA, USA
| | - Paul Lu
- Veterans Administration San Diego Healthcare System, San Diego, CA, USA. .,Department of Neurosciences, University of California - San Diego, La Jolla, CA, USA.
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28
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Abdul Wahid SF, Law ZK, Ismail NA, Lai NM, Cochrane Neuromuscular Group. Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev 2019; 12:CD011742. [PMID: 31853962 PMCID: PMC6920743 DOI: 10.1002/14651858.cd011742.pub3] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Amyotrophic lateral sclerosis (ALS), which is also known as motor neuron disease (MND), is a fatal disease associated with rapidly progressive disability, for which no definitive treatment exists. Current treatment approaches largely focus on relieving symptoms to improve the quality of life of those affected. The therapeutic potential of cell-based therapies in ALS/MND has not been fully evaluated, given the paucity of high-quality clinical trials. Based on data from preclinical studies, cell-based therapy is a promising treatment for ALS/MND. This review was first published in 2015 when the first clinical trials of cell-based therapies were still in progress. We undertook this update to incorporate evidence now available from randomised controlled trials (RCTs). OBJECTIVES To assess the effects of cell-based therapy for people with ALS/MND, compared with placebo or no treatment. SEARCH METHODS On 31 July 2019, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, and Embase. We also searched two clinical trials registries for ongoing or unpublished studies. SELECTION CRITERIA We included RCTs that assigned people with ALS/MND to receive cell-based therapy versus a placebo or no additional treatment. Co-interventions were allowed, provided that they were given to each group equally. DATA COLLECTION AND ANALYSIS We followed standard Cochrane methodology. MAIN RESULTS Two RCTs involving 112 participants were eligible for inclusion in this review. One study compared autologous bone marrow-mesenchymal stem cells (BM-MSC) plus riluzole versus control (riluzole only), while the other study compared combined intramuscular and intrathecal administration of autologous mesenchymal stem cells secreting neurotrophic factors (MSC-NTF) to placebo. The latter study was reported as an abstract and provided no numerical data. Both studies were funded by biotechnology companies. The only study that contributed to the outcome data in the review involved 64 participants, comparing BM-MSC plus riluzole versus control (riluzole only). It reported outcomes after four to six months. It had a low risk of selection bias, detection bias and reporting bias, but a high risk of performance bias and attrition bias. The certainty of evidence was low for all major efficacy outcomes, with imprecision as the main downgrading factor, because the range of plausible estimates, as shown by the 95% confidence intervals (CIs), encompassed a range that would likely result in different clinical decisions. Functional impairment, expressed as the mean change in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score from baseline to six months after cell injection was slightly reduced (better) in the BM-MSC group compared to the control group (mean difference (MD) 3.38, 95% CI 1.22 to 5.54; 1 RCT, 56 participants; low-certainty evidence). ALSFRS-R has a range from 48 (normal) to 0 (maximally impaired); a change of 4 or more points is considered clinically important. The trial did not report outcomes at 12 months. There was no clear difference between the BM-MSC and the no treatment group in change in respiratory function (per cent predicted forced vital capacity; FVC%; MD -0.53, 95% CI -5.37 to 4.31; 1 RCT, 56 participants; low-certainty evidence); overall survival at six months (risk ratio (RR) 1.07, 95% CI 0.94 to 1.22; 1 RCT, 64 participants; low-certainty evidence); risk of total adverse events (RR 0.86, 95% CI 0.62 to 1.19; 1 RCT, 64 participants; low-certainty evidence) or serious adverse events (RR 0.47, 95% CI 0.13 to 1.72; 1 RCT, 64 participants; low-certainty evidence). The study did not measure muscle strength. AUTHORS' CONCLUSIONS Currently, there is a lack of high-certainty evidence to guide practice on the use of cell-based therapy to treat ALS/MND. Uncertainties remain as to whether this mode of therapy is capable of restoring muscle function, slowing disease progression, and improving survival in people with ALS/MND. Although one RCT provided low-certainty evidence that BM-MSC may slightly reduce functional impairment measured on the ALSFRS-R after four to six months, this was a small phase II trial that cannot be used to establish efficacy. We need large, prospective RCTs with long-term follow-up to establish the efficacy and safety of cellular therapy and to determine patient-, disease- and cell treatment-related factors that may influence the outcome of cell-based therapy. The major goals of future research are to determine the appropriate cell source, phenotype, dose and method of delivery, as these will be key elements in designing an optimal cell-based therapy programme for people with ALS/MND. Future research should also explore novel treatment strategies, including combinations of cellular therapy and standard or novel neuroprotective agents, to find the best possible approach to prevent or reverse the neurological deficit in ALS/MND, and to prolong survival in this debilitating and fatal condition.
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Affiliation(s)
- S Fadilah Abdul Wahid
- Universiti Kebangsaan Malaysia Medical CentreCell Therapy CenterJalan Yaacob LatifKuala LumpurMalaysia56000
| | - Zhe Kang Law
- Universiti Kebangsaan Malaysia Medical CentreDepartment of Medicine, Faculty of MedicineKuala LumpurMalaysia
| | - Nor Azimah Ismail
- Universiti Kebangsaan Malaysia Medical CentreCell Therapy CenterJalan Yaacob LatifKuala LumpurMalaysia56000
| | - Nai Ming Lai
- Taylor's UniversitySchool of MedicineSubang JayaMalaysia
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Tang C, Zhu L, Zhou Q, Li M, Zhu Y, Xu Z, Lu Y, Xu R. Altered Features of Vimentin-containing Cells in Cerebrum of Tg(SOD1*G93A)1Gur Mice: A Preliminary Study on Cerebrum Endogenous Neural Precursor Cells in Amyotrophic Lateral Sclerosis. Int J Biol Sci 2019; 15:2830-2843. [PMID: 31853221 PMCID: PMC6909959 DOI: 10.7150/ijbs.33461] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 09/16/2019] [Indexed: 12/11/2022] Open
Abstract
Vimentin-containing cells (VCCs) are potential neural precursor cells in central nervous systems, Thus, we studied the alteration of VCCs proliferation, differentiation and migration in the cerebrum during different stages of Tg(SOD1*G93A)1Gur mice. It aims to search potential ways regulating the proliferation, differentiation and migration of endogenous VCCs, to enhance their neural repair function and to cure or prevent from the development of ALS. We observed and analyzed the proliferation, differentiation and migration of VCCs in different anatomic regions and cell types of cerebrum at different stages including the pre-onset (60-70 days), onset (90-100 days) and progression (120-130 days) of wild-type (WT) and Tg(SOD1*G93A)1Gur mice using the fluorescent immunohistochemical technology. Results showed that VCCs in the cerebrum were mostly distributed in the ventricular system, periventricular structures, the hippocampus and the cerebral cortex in WT mice. VCCs significantly reduced in the motor cortex and the cingulate cortex in Tg(SOD1*G93A)1Gur mice. All vimentin expressed in the extranuclear and almost all VCCs were astrocytes in WT mice and Tg(SOD1*G93A)1Gur mice. There were no significant difference in the number of Brdu and nestin positive cells in left and right brains of WT mice and Tg(SOD1*G93A)1Gur mice in the period of 60-130 days. Our data suggested that there existed extensively NPCs in the cerebrum of adult mice. In ALS-like Tg(SOD1*G93A)1Gur mice, VCCs in the motor cortex, the olfactory cortex and the cingulate cortex showed that no any proliferation and redistribution in neural cells of VCCs in the cerebrum occurred in all stages of ALS, might migrate to damaged regions.
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Affiliation(s)
- Chunyan Tang
- Department of Neurology, Jiangxi Provincial People's Hospital, Affiliated People's Hospital of Nanchang University, Nanchang 330006, Jiangxi, china
| | - Lei Zhu
- Department of Neurology, Jiangxi Provincial People's Hospital, Affiliated People's Hospital of Nanchang University, Nanchang 330006, Jiangxi, china
| | - Qi Zhou
- Department of Neurology, Jiangxi Provincial People's Hospital, Affiliated People's Hospital of Nanchang University, Nanchang 330006, Jiangxi, china
| | - Menghua Li
- Department of Neurology, Jiangxi Provincial People's Hospital, Affiliated People's Hospital of Nanchang University, Nanchang 330006, Jiangxi, china
| | - Yu Zhu
- Department of Neurology, Jiangxi Provincial People's Hospital, Affiliated People's Hospital of Nanchang University, Nanchang 330006, Jiangxi, china
| | - Zhenzhen Xu
- Department of Neurology, Jiangxi Provincial People's Hospital, Affiliated People's Hospital of Nanchang University, Nanchang 330006, Jiangxi, china
| | - Yi Lu
- Department of Neurology, Jiangxi Provincial People's Hospital, Affiliated People's Hospital of Nanchang University, Nanchang 330006, Jiangxi, china
| | - Renshi Xu
- Department of Neurology, Jiangxi Provincial People's Hospital, Affiliated People's Hospital of Nanchang University, Nanchang 330006, Jiangxi, china
- Department of Neurology, First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
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Satzer D, Warnke PC. Technical note: accuracy and precision in stereotactic stem cell transplantation. Acta Neurochir (Wien) 2019; 161:2059-2064. [PMID: 31273445 DOI: 10.1007/s00701-019-03964-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 05/24/2019] [Indexed: 11/28/2022]
Abstract
BACKGROUND While multiple trials have employed stereotactic stem cell transplantation, injection techniques have received little critical attention. Precise cell delivery is critical for certain applications, particularly when targeting deep nuclei. METHODS Ten patients with a history of ischemic stroke underwent CT-guided stem cell transplantation. Cells were delivered along 3 tracts adjacent to the infarcted area. Intraoperative air deposits and postoperative T2-weighted MRI fluid signals were mapped in relation to calculated targets. RESULTS The deepest air deposit was found 4.5 ± 1.0 mm (mean ± 2 SEM) from target. The apex of the T2-hyperintense tract was found 2.8 ± 0.8 mm from target. On average, air pockets were found anterior (1.2 ± 1.1 mm, p = 0.04) and superior (2.4 ± 1.0 mm, p < 0.001) to the target; no directional bias was noted for the apex of the T2-hyperintense tract. Location and distribution of air deposits were variable and were affected by the relationship of cannula trajectory to stroke cavity. CONCLUSIONS Precise stereotactic cell transplantation is a little-studied technical challenge. Reflux of cell suspension and air, and the structure of the injection tract affect delivery of cell suspensions. Intraoperative CT allows assessment of delivery and potential trajectory correction.
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Affiliation(s)
- David Satzer
- Department of Neurosurgery, University of Chicago, 5841 S. Maryland Avenue, MC 3026, Chicago, IL, 60637, USA.
| | - Peter C Warnke
- Department of Neurosurgery, University of Chicago, 5841 S. Maryland Avenue, MC 3026, Chicago, IL, 60637, USA
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Goutman SA, Savelieff MG, Sakowski SA, Feldman EL. Stem cell treatments for amyotrophic lateral sclerosis: a critical overview of early phase trials. Expert Opin Investig Drugs 2019; 28:525-543. [PMID: 31189354 DOI: 10.1080/13543784.2019.1627324] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of cortical, brainstem, and spinal motor neurons; it causes progressive muscle weakness and atrophy, respiratory failure, and death. No currently available treatment either stops or reverses this disease. Therapeutics to slow, stop, and reverse ALS are needed. Stem cells may be a viable solution to sustain and nurture diseased motor neurons. Several early-stage clinical trials have been launched to assess the potential of stem cells for ALS treatment. Areas covered: Expert opinion: AREAS COVERED This review covers the key advances from early phase clinical trials of stem cell therapy for ALS and identifies promising avenues and key challenges. EXPERT OPINION Clinical trials in humans are still in the nascent stages of development. It will be critical to ensure that powered, well-controlled trials are conducted, that optimal treatment windows are identified, and that the ideal cell type, cell dose, and delivery site and method are determined. Several trials have used more invasive procedures, and ethical concerns of sham procedures on patients in the control arm and on their safety should be considered.
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Affiliation(s)
- Stephen A Goutman
- a Department of Neurology , University of Michigan , Ann Arbor , MI , USA.,b Program for Neurology Research & Discovery , University of Michigan , Ann Arbor , MI , USA
| | - Masha G Savelieff
- a Department of Neurology , University of Michigan , Ann Arbor , MI , USA.,b Program for Neurology Research & Discovery , University of Michigan , Ann Arbor , MI , USA
| | - Stacey A Sakowski
- a Department of Neurology , University of Michigan , Ann Arbor , MI , USA.,b Program for Neurology Research & Discovery , University of Michigan , Ann Arbor , MI , USA
| | - Eva L Feldman
- a Department of Neurology , University of Michigan , Ann Arbor , MI , USA.,b Program for Neurology Research & Discovery , University of Michigan , Ann Arbor , MI , USA
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Neuroimaging and clinical trials with stem cells in amyotrophic lateral sclerosis: Present and future perspectives. RADIOLOGIA 2019. [DOI: 10.1016/j.rxeng.2019.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Review of the Current Knowledge on the Role of Stem Cell Transplantation in Neurorehabilitation. BIOMED RESEARCH INTERNATIONAL 2019; 2019:3290894. [PMID: 30931325 PMCID: PMC6413404 DOI: 10.1155/2019/3290894] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 10/05/2018] [Accepted: 01/30/2019] [Indexed: 12/14/2022]
Abstract
The management involving stem cell (SC) therapy along with physiotherapy offers tremendous chance for patients after spinal cord injury (SCI), traumatic brain injury (TBI), stroke, etc. However, there are still only a limited number of reports assessing the impact of stem cells (SCs) on the rehabilitation process and/or the results of the simultaneous use of SC and rehabilitation. Additionally, since there is still not enough convincing evidence about the effect of SCT on humans, e.g., in stroke, there have been no studies conducted concerning rehabilitation program formation and expected outcomes. It has been shown that bone marrow-derived mesenchymal stem cell (BMSCs) transplantation in rats combined with hyperbaric oxygen therapy (HBO) can promote the functional recovery of hind limbs after SCI. An anti-inflammatory effect has been shown. One case study showed that, after the simultaneous use of SCT and rehabilitation, an SCI patient progressed from ASIA Grade A to ASIA Grade C. Such promising data in the case of complete tetraplegia could be a breakthrough in the treatment of neurologic disorders in humans. Although SCT appears as a promising method for the treatment of neurological conditions, e.g., complete tetraplegia, much work should be done towards the development of rehabilitation protocols.
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Mazzini L, Ferrari D, Andjus PR, Buzanska L, Cantello R, De Marchi F, Gelati M, Giniatullin R, Glover JC, Grilli M, Kozlova EN, Maioli M, Mitrečić D, Pivoriunas A, Sanchez-Pernaute R, Sarnowska A, Vescovi AL. Advances in stem cell therapy for amyotrophic lateral sclerosis. Expert Opin Biol Ther 2019; 18:865-881. [PMID: 30025485 DOI: 10.1080/14712598.2018.1503248] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Amyotrophic Lateral Sclerosis (ALS) is a progressive, incurable neurodegenerative disease that targets motoneurons. Cell-based therapies have generated widespread interest as a potential therapeutic approach but no conclusive results have yet been reported either from pre-clinical or clinical studies. AREAS COVERED This is an integrated review of pre-clinical and clinical studies focused on the development of cell-based therapies for ALS. We analyze the biology of stem cell treatments and results obtained from pre-clinical models of ALS and examine the methods and the results obtained to date from clinical trials. We discuss scientific, clinical, and ethical issues and propose some directions for future studies. EXPERT OPINION While data from individual studies are encouraging, stem-cell-based therapies do not yet represent a satisfactory, reliable clinical option. The field will critically benefit from the introduction of well-designed, randomized and reproducible, powered clinical trials. Comparative studies addressing key issues such as the nature, properties, and number of donor cells, the delivery mode and the selection of proper patient populations that may benefit the most from cell-based therapies are now of the essence. Multidisciplinary networks of experts should be established to empower effective translation of research into the clinic.
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Affiliation(s)
- Letizia Mazzini
- a ALS Centre Department of Neurology , "Maggiore della Carità" University Hospital Novara , Novara , Italy
| | - Daniela Ferrari
- b Department of Biotechnology and Biosciences , University Milano Bicocca , Milano , Italy
| | - Pavle R Andjus
- c Center for laser microscopy, Faculty of Biology , University of Belgrade , Belgrade , Serbia
| | - Leonora Buzanska
- d Stem Cell Bioengineering Unit , Mossakowski Medical Research Center, Polish Academy of Sciences , Warsaw , Poland
| | - Roberto Cantello
- a ALS Centre Department of Neurology , "Maggiore della Carità" University Hospital Novara , Novara , Italy
| | - Fabiola De Marchi
- a ALS Centre Department of Neurology , "Maggiore della Carità" University Hospital Novara , Novara , Italy
| | - Maurizio Gelati
- e Scientific Direction , IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo , Foggia , Italy.,f Cell Factory e biobanca, Fondazione Cellule Staminali , Terni , Italy
| | - Rashid Giniatullin
- g A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland , Neulaniementie 2, Kuopio , FINLAND
| | - Joel C Glover
- h Department of Molecular Medicine , Institute of Basic Medical Sciences, University of Oslo and Norwegian Center for Stem Cell Research, Oslo University Hospital , Oslo , Norway
| | - Mariagrazia Grilli
- i Department Pharmaceutical Sciences , Laboratory of Neuroplasticity, University of Piemonte Orientale , Novara , Italy
| | - Elena N Kozlova
- j Department of Neuroscience , Uppsala University Biomedical Centre , Uppsala , Sweden
| | - Margherita Maioli
- k Department of Biomedical Sciences and Center for Developmental Biology and Reprogramming (CEDEBIOR) , University of Sassari, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR) , Sassari , Italy
| | - Dinko Mitrečić
- l Laboratory for Stem Cells, Croatian Institute for Brain Research , University of Zagreb School of Medicine , Zagreb , Croatia
| | - Augustas Pivoriunas
- m Department of Stem Cell Biology , State Research Institute Centre for Innovative Medicine , Vilnius , Lithuania
| | - Rosario Sanchez-Pernaute
- n Preclinical Research , Andalusian Initiative for Advanced Therapies, Andalusian Health Ministry , Sevilla , Spain
| | - Anna Sarnowska
- d Stem Cell Bioengineering Unit , Mossakowski Medical Research Center, Polish Academy of Sciences , Warsaw , Poland
| | - Angelo L Vescovi
- b Department of Biotechnology and Biosciences , University Milano Bicocca , Milano , Italy.,f Cell Factory e biobanca, Fondazione Cellule Staminali , Terni , Italy
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Neuroimaging and clinical trials with stem cells in amyotrophic lateral sclerosis: present and future perspectives. RADIOLOGIA 2019; 61:183-190. [PMID: 30606510 DOI: 10.1016/j.rx.2018.11.004] [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: 09/05/2018] [Revised: 11/01/2018] [Accepted: 11/17/2018] [Indexed: 11/20/2022]
Abstract
Amyotrophic lateral sclerosis is a rare neurodegenerative disease with a rapid fatal course. The absence of effective treatments has led to new lines of research, some of which are based on stem cells. Surgical injection into the spinal cord, the most common route of administration of stem cells, has proven safe in trials to test the safety of the procedure. Nevertheless, challenges remain, such as determining the best route of administration or the way of checking the survival of the cells and their interaction with the therapeutic target. To date, the mission of neuroimaging techniques has been to detect lesions and complications in the spine and spinal cord, but neuroimaging also has the potential to supplant histologic study in analyzing the relations between the implanted cells and the therapeutic target, and as biomarkers of the disease, by measuring morphological and functional changes after treatment. These developments would increase the role of radiologists in the clinical management of patients with amyotrophic lateral sclerosis.
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Intraspinal Transplantation of the Adipose Tissue-Derived Regenerative Cells in Amyotrophic Lateral Sclerosis in Accordance with the Current Experts' Recommendations: Choosing Optimal Monitoring Tools. Stem Cells Int 2018; 2018:4392017. [PMID: 30158984 PMCID: PMC6109475 DOI: 10.1155/2018/4392017] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Revised: 05/26/2018] [Accepted: 06/14/2018] [Indexed: 12/11/2022] Open
Abstract
Stem cells (SCs) may constitute a perspective alternative to pharmacological treatment in neurodegenerative diseases. Although the safety of SC transplantation has been widely shown, their clinical efficiency in amyotrophic lateral sclerosis (ALS) is still to be proved. It is not only due to a limited number of studies, small treatment groups, and fast but nonlinear disease progression but also due to lack of objective methods able to show subtle clinical changes. Preliminary guidelines for cell therapy have recently been proposed by a group of ALS experts. They combine clinical, neurophysiological, and functional assessment together with monitoring of the cytokine level. Here, we describe a pilot study on transplantation of autologous adipose-derived regenerative cells (ADRC) into the spinal cord of the patients with ALS and monitoring of the results in accordance with the current recommendations. To show early and/or subtle changes within the muscles of interest, a wide range of clinical and functional tests were used and compared in order to choose the most sensitive and optimal set. Additionally, an analysis of transplanted ADRC was provided to develop standards ensuring the derivation and verification of adequate quality of transplanted cells and to correlate ADRC properties with clinical outcome.
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Tang BL. The use of mesenchymal stem cells (MSCs) for amyotrophic lateral sclerosis (ALS) therapy – a perspective on cell biological mechanisms. Rev Neurosci 2017; 28:725-738. [DOI: 10.1515/revneuro-2017-0018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 04/04/2017] [Indexed: 12/12/2022]
Abstract
AbstractRecent clinical trials of mesenchymal stem cells (MSCs) transplantation have demonstrated procedural safety and clinical proof of principle with a modest indication of benefit in patients with amyotrophic lateral sclerosis (ALS). While replacement therapy remained unrealistic, the clinical efficacy of this therapeutic option could be potentially enhanced if we could better decipher the mechanisms underlying some of the beneficial effects of transplanted cells, and work toward augmenting or combining these in a strategic manner. Novel ways whereby MSCs could act in modifying disease progression should also be explored. In this review, I discuss the known, emerging and postulated mechanisms of action underlying effects that transplanted MSCs may exert to promote motor neuron survival and/or to encourage regeneration in ALS. I shall also speculate on how transplanted cells may alter the diseased environment so as to minimize non-neuron cell autonomous damages by immune cells and astrocytes.
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Affiliation(s)
- Bor Luen Tang
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University Health System, Singapore
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Medical Drive, Singapore 117597, Singapore
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Forostyak S, Sykova E. Neuroprotective Potential of Cell-Based Therapies in ALS: From Bench to Bedside. Front Neurosci 2017; 11:591. [PMID: 29114200 PMCID: PMC5660803 DOI: 10.3389/fnins.2017.00591] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 10/09/2017] [Indexed: 12/12/2022] Open
Abstract
Motor neurons (MN) degeneration is a main feature of amyotrophic lateral sclerosis (ALS), a neurological disorder with a progressive course. The diagnosis of ALS is essentially a clinical one. Most common symptoms include a gradual neurological deterioration that reflect the impairment and subsequent loss of muscle functions. Up-to-date ALS has no therapy that would prevent or cure a disease. Modern therapeutic strategies comprise of neuroprotective treatment focused on antiglutamatergic, antioxidant, antiapoptotic, and anti-inflammatory molecules. Stem cells application and gene therapy has provided researchers with a powerful tool for discovery of new mechanisms and therapeutic agents, as well as opened new perspectives for patients and family members. Here, we review latest progress made in basic, translational and clinical stem cell research related to the ALS. We overviewed results of preclinical and clinical studies employing cell-based therapy to treat neurodegenerative disorders. A special focus has been made on the neuroprotective properties of adult mesenchymal stromal cells (MSC) application into ALS patients. Finally, we overviewed latest progress in the field of embryonic and induced pluripotent stem cells used for the modeling and application during neurodegeneration in general and in ALS in particular.
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Affiliation(s)
- Serhiy Forostyak
- Centre of Reconstructive Neuroscience, Institute of Experimental Medicine (ASCR), Czech Academy of Sciences, Prague, Czechia.,Department of Neuroscience, 2nd Faculty of Medicine, Charles University, Prague, Czechia
| | - Eva Sykova
- Department of Neuroscience, 2nd Faculty of Medicine, Charles University, Prague, Czechia.,Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia
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Lo Furno D, Mannino G, Giuffrida R. Functional role of mesenchymal stem cells in the treatment of chronic neurodegenerative diseases. J Cell Physiol 2017; 233:3982-3999. [PMID: 28926091 DOI: 10.1002/jcp.26192] [Citation(s) in RCA: 118] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 09/15/2017] [Indexed: 12/14/2022]
Abstract
Mesenchymal stem cells (MSCs) can differentiate into not only cells of mesodermal lineages, but also into endodermal and ectodermal derived elements, including neurons and glial cells. For this reason, MSCs have been extensively investigated to develop cell-based therapeutic strategies, especially in pathologies whose pharmacological treatments give poor results, if any. As in the case of irreversible neurological disorders characterized by progressive neuronal death, in which behavioral and cognitive functions of patients inexorably decline as the disease progresses. In this review, we focus on the possible functional role exerted by MSCs in the treatment of some disabling neurodegenerative disorders such as Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Huntington's Disease, and Parkinson's Disease. Investigations have been mainly performed in vitro and in animal models by using MSCs generally originated from umbilical cord, bone marrow, or adipose tissue. Positive results obtained have prompted several clinical trials, the number of which is progressively increasing worldwide. To date, many of them have been primarily addressed to verify the safety of the procedures but some improvements have already been reported, fortunately. Although the exact mechanisms of MSC-induced beneficial activities are not entirely defined, they include neurogenesis and angiogenesis stimulation, antiapoptotic, immunomodulatory, and anti-inflammatory actions. Most effects would be exerted through their paracrine expression of neurotrophic factors and cytokines, mainly delivered at damaged regions, given the innate propensity of MSCs to home to injured sites. Hopefully, in the near future more efficacious cell-replacement therapies will be developed to substantially restore disease-disrupted brain circuitry.
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Affiliation(s)
- Debora Lo Furno
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, Italy
| | - Giuliana Mannino
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, Italy
| | - Rosario Giuffrida
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, Italy
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Garbuzova-Davis S, Ehrhart J, Sanberg PR. Cord blood as a potential therapeutic for amyotrophic lateral sclerosis. Expert Opin Biol Ther 2017; 17:837-851. [DOI: 10.1080/14712598.2017.1323862] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Svitlana Garbuzova-Davis
- Center of Excellence for Aging & Brain Repair, University of South Florida, Morsani College of Medicine, Tampa, FL, USA
- Department of Neurosurgery and Brain Repair, University of South Florida, Morsani College of Medicine, Tampa, FL, USA
- Department of Molecular Pharmacology and Physiology, University of South Florida, Morsani College of Medicine, Tampa, FL, USA
- Department of Pathology and Cell Biology, University of South Florida, Morsani College of Medicine, Tampa, FL, USA
| | - Jared Ehrhart
- Center of Excellence for Aging & Brain Repair, University of South Florida, Morsani College of Medicine, Tampa, FL, USA
| | - Paul R. Sanberg
- Center of Excellence for Aging & Brain Repair, University of South Florida, Morsani College of Medicine, Tampa, FL, USA
- Department of Neurosurgery and Brain Repair, University of South Florida, Morsani College of Medicine, Tampa, FL, USA
- Department of Pathology and Cell Biology, University of South Florida, Morsani College of Medicine, Tampa, FL, USA
- Department of Psychiatry, University of South Florida, Morsani College of Medicine, Tampa, FL, USA
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Bonafede R, Mariotti R. ALS Pathogenesis and Therapeutic Approaches: The Role of Mesenchymal Stem Cells and Extracellular Vesicles. Front Cell Neurosci 2017; 11:80. [PMID: 28377696 PMCID: PMC5359305 DOI: 10.3389/fncel.2017.00080] [Citation(s) in RCA: 133] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 03/08/2017] [Indexed: 12/13/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle paralysis determined by the degeneration of motoneurons in the motor cortex brainstem and spinal cord. The ALS pathogenetic mechanisms are still unclear, despite the wealth of studies demonstrating the involvement of several altered signaling pathways, such as mitochondrial dysfunction, glutamate excitotoxicity, oxidative stress and neuroinflammation. To date, the proposed therapeutic strategies are targeted to one or a few of these alterations, resulting in only a minimal effect on disease course and survival of ALS patients. The involvement of different mechanisms in ALS pathogenesis underlines the need for a therapeutic approach targeted to multiple aspects. Mesenchymal stem cells (MSC) can support motoneurons and surrounding cells, reduce inflammation, stimulate tissue regeneration and release growth factors. On this basis, MSC have been proposed as promising candidates to treat ALS. However, due to the drawbacks of cell therapy, the possible therapeutic use of extracellular vesicles (EVs) released by stem cells is raising increasing interest. The present review summarizes the main pathological mechanisms involved in ALS and the related therapeutic approaches proposed to date, focusing on MSC therapy and their preclinical and clinical applications. Moreover, the nature and characteristics of EVs and their role in recapitulating the effect of stem cells are discussed, elucidating how and why these vesicles could provide novel opportunities for ALS treatment.
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Affiliation(s)
- Roberta Bonafede
- Department of Neuroscience, Biomedicine and Movement Sciences, University of VeronaVerona, Italy
| | - Raffaella Mariotti
- Department of Neuroscience, Biomedicine and Movement Sciences, University of VeronaVerona, Italy
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Martinez A, Palomo Ruiz MDV, Perez DI, Gil C. Drugs in clinical development for the treatment of amyotrophic lateral sclerosis. Expert Opin Investig Drugs 2017; 26:403-414. [PMID: 28277881 DOI: 10.1080/13543784.2017.1302426] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron progressive disorder for which no treatment exists to date. However, there are other investigational drugs and therapies currently under clinical development may offer hope in the near future. Areas covered: We have reviewed all the ALS ongoing clinical trials (until November 2016) and collected in Clinicaltrials.gov or EudraCT. We have described them in a comprehensive way and have grouped them in the following sections: biomarkers, biological therapies, cell therapy, drug repurposing and new drugs. Expert opinion: Despite multiple obstacles that explain the absence of effective drugs for the treatment of ALS, joint efforts among patient's associations, public and private sectors have fueled innovative research in this field, resulting in several compounds that are in the late stages of clinical trials. Drug repositioning is also playing an important role, having achieved the approval of some orphan drug applications, in late phases of clinical development. Endaravone has been recently approved in Japan and is pending in USA.
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Affiliation(s)
- Ana Martinez
- a IPSBB Unit , Centro de Investigaciones Biologicas-CSIC , Madrid , Spain
| | | | - Daniel I Perez
- a IPSBB Unit , Centro de Investigaciones Biologicas-CSIC , Madrid , Spain
| | - Carmen Gil
- a IPSBB Unit , Centro de Investigaciones Biologicas-CSIC , Madrid , Spain
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Gonzalez-Garza MT, Cruz-Vega DE. Regenerative capacity of autologous stem cell transplantation in elderly: a report of biomedical outcomes. Regen Med 2017; 12:169-178. [DOI: 10.2217/rme-2016-0038] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The occurrence of chronic diseases such as neurological, metabolic and cardiovascular degenerative disorders increases with age. Cell therapy is an emerging approach to the treatment of these conditions. Of particular interest is the application of autologous stem cells because it eliminates post-transplantation immune rejection and there are less ethical concerns associated with their use. The regenerative capacity of stem cells harvested from elderly people is however controversial. In this review, we analyze if self-renewal potential, differentiation capability and expression of stemness genes in stem cells collected from elderly patients validate their application in clinical trials and examine the results.
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Affiliation(s)
| | - Delia Elva Cruz-Vega
- Tecnologico de Monterrey, Escuela Nacional de Medicina, Morones Prieto 3000 Pte, CP64710, Monterrey, Mexico
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Czarzasta J, Habich A, Siwek T, Czapliński A, Maksymowicz W, Wojtkiewicz J. Stem cells for ALS: An overview of possible therapeutic approaches. Int J Dev Neurosci 2017; 57:46-55. [PMID: 28088365 DOI: 10.1016/j.ijdevneu.2017.01.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 01/06/2017] [Accepted: 01/06/2017] [Indexed: 12/11/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is an unusual, fatal, neurodegenerative disorder leading to the loss of motor neurons. After diagnosis, the average lifespan ranges from 3 to 5 years, and death usually results from respiratory failure. Although the pathogenesis of ALS remains unclear, multiple factors are thought to contribute to the progression of ALS, such as network interactions between genes, environmental exposure, impaired molecular pathways and many others. The neuroprotective properties of neural stem cells (NSCs) and the paracrine signaling of mesenchymal stem cells (MSCs) have been examined in multiple pre-clinical trials of ALS with promising results. The data from these initial trials indicate a reduction in the rate of disease progression. The mechanism through which stem cells achieve this reduction is of major interest. Here, we review the to-date pre-clinical and clinical therapeutic approaches employing stem cells, and discuss the most promising ones.
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Affiliation(s)
- Joanna Czarzasta
- Department of Pathophysiology, Faculty of Medical Sciences, University of Warmia and Mazury, Olsztyn, Poland.
| | - Aleksandra Habich
- Department of Neurology and Neurosurgery, Faculty of Medical Sciences, University of Warmia and Mazury, Olsztyn, Poland
| | - Tomasz Siwek
- Department of Neurology and Neurosurgery, Faculty of Medical Sciences, University of Warmia and Mazury, Olsztyn, Poland
| | - Adam Czapliński
- Department of Neurology and Neurosurgery, Faculty of Medical Sciences, University of Warmia and Mazury, Olsztyn, Poland; Neurocentrum Bellevue, Neurology, Zurich, Switzerland
| | - Wojciech Maksymowicz
- Department of Neurology and Neurosurgery, Faculty of Medical Sciences, University of Warmia and Mazury, Olsztyn, Poland
| | - Joanna Wojtkiewicz
- Department of Pathophysiology, Faculty of Medical Sciences, University of Warmia and Mazury, Olsztyn, Poland; Laboratory of Regenerative Medicine, University of Warmia and Mazury, Olsztyn, Poland; Foundation for nerve cells regeneration, Olsztyn, Poland
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Abdul Wahid SF, Law ZK, Ismail NA, Azman Ali R, Lai NM. Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev 2016; 11:CD011742. [PMID: 27822919 PMCID: PMC6464737 DOI: 10.1002/14651858.cd011742.pub2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Amyotrophic lateral sclerosis (ALS), which is also known as motor neuron disease (MND) is a fatal disease associated with rapidly progressive disability, for which no definitive treatment as yet exists. Current treatment regimens largely focus on relieving symptoms to improve the quality of life of those affected. Based on data from preclinical studies, cell-based therapy is a promising treatment for ALS/MND. OBJECTIVES To assess the effects of cell-based therapy for people with ALS/MND, compared with placebo or no additional treatment. SEARCH METHODS On 21 June 2016, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, and Embase. We also searched two clinical trials' registries for ongoing or unpublished studies. SELECTION CRITERIA We planned to include randomised controlled trials (RCTs), quasi-RCTs and cluster RCTs that assigned people with ALS/MND to receive cell-based therapy versus a placebo or no additional treatment. Co-interventions were allowable, provided that they were given to each group equally. DATA COLLECTION AND ANALYSIS We followed standard Cochrane methodology. MAIN RESULTS No studies were eligible for inclusion in the review. We identified four ongoing trials. AUTHORS' CONCLUSIONS Currently, there is a lack of high-quality evidence to guide practice on the use of cell-based therapy to treat ALS/MND.We need large, prospective RCTs to establish the efficacy of cellular therapy and to determine patient-, disease- and cell treatment-related factors that may influence the outcome of cell-based therapy. The major goals of future research should be to determine the appropriate cell source, phenotype, dose, and route of delivery, as these will be key elements in designing an optimal cell-based therapy programme for people with ALS/MND. Future research should also explore novel treatment strategies, including combinations of cellular therapy and standard or novel neuroprotective agents, to find the best possible approach to prevent or reverse the neurological deficit in ALS/MND, and to prolong survival in this debilitating and fatal condition.
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Affiliation(s)
| | - Zhe Kang Law
- Universiti Kebangsaan Malaysia Medical CentreDepartment of MedicineJalan Yaacob LatifBandar Tun RazakKuala LumpurMalaysia56000
| | - Nor Azimah Ismail
- Universiti Kebangsaan Malaysia Medical CentreCell Therapy CenterJalan Yaacob LatifKuala LumpurMalaysia56000
| | - Raymond Azman Ali
- Universiti Kebangsaan Malaysia Medical CentreNeurology Unit, Department of MedicineJalan Yaacob LatifBandar Tun RazakKuala LumpurMalaysia56000
| | - Nai Ming Lai
- Taylor's UniversitySchool of MedicineSubang JayaMalaysia
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Syková E, Rychmach P, Drahorádová I, Konrádová Š, Růžičková K, Voříšek I, Forostyak S, Homola A, Bojar M. Transplantation of Mesenchymal Stromal Cells in Patients With Amyotrophic Lateral Sclerosis: Results of Phase I/IIa Clinical Trial. Cell Transplant 2016; 26:647-658. [PMID: 27938483 DOI: 10.3727/096368916x693716] [Citation(s) in RCA: 115] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive untreatable neurodegenerative disorder, leading to the death of the cortical and spinal motoneurons (MNs). Bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) may represent a new approach to slowing down the progression of ALS by providing neurotrophic support to host MNs and by having an anti-inflammatory effect. We have designed a prospective, nonrandomized, open-label clinical trial (phase I/IIa, EudraCT No. 2011-000362-35) to assess the safety and efficacy of autologous multipotent BM-MSCs in ALS treatment. Autologous BM-MSCs were isolated and expanded under GMP conditions. Patients received 15 ± 4.5 × 106 of BM-MSCs via lumbar puncture into the cerebrospinal fluid. Patients were monitored for 6 months before treatment and then for an 18-month follow-up period. Potential adverse reactions were assessed, and the clinical outcome was evaluated by the ALS functional rating scale (ALSFRS), forced vital capacity (FVC), and weakness scales (WSs) to assess muscle strength on the lower and upper extremities. In total, 26 patients were enrolled in the study and were assessed for safety; 23 patients were suitable for efficacy evaluation. After intrathecal BM-MSC application, about 30% of the patients experienced a mild to moderate headache, resembling the headaches after a standard lumbar puncture. No suspected serious adverse reactions (SUSAR) were observed. We found a reduction in ALSFRS decline at 3 months after application (p < 0.02) that, in some cases, persisted for 6 months ( p < 0.05). In about 80% of the patients, FVC values remained stable or above 70% for a time period of 9 months. Values of WS were stable in 75% of patients at 3 months after application. Our results demonstrate that the intrathecal application of BM-MSCs in ALS patients is a safe procedure and that it can slow down progression of the disease.
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García Santos JM, Inuggi A, Gómez Espuch J, Vázquez C, Iniesta F, Blanquer M, María Moraleda J, Martínez S. Spinal cord infusion of stem cells in amyotrophic lateral sclerosis: Magnetic resonance spectroscopy shows metabolite improvement in the precentral gyrus. Cytotherapy 2016; 18:785-96. [DOI: 10.1016/j.jcyt.2016.03.296] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Revised: 03/19/2016] [Accepted: 03/20/2016] [Indexed: 11/29/2022]
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Ruiz-López FJ, Blanquer M. Autologous bone marrow mononuclear cells as neuroprotective treatment of amyotrophic lateral sclerosis. Neural Regen Res 2016; 11:568-9. [PMID: 27212914 PMCID: PMC4870910 DOI: 10.4103/1673-5374.180730] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
| | - Miguel Blanquer
- Hematopoietic Progenitors Transplant and Cell Therapy Unit, Virgen de la Arrixaca Hospital, Murcia University, IMIB, Murcia, Spain
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Fujikawa A, Noda M. Role of pleiotrophin-protein tyrosine phosphatase receptor type Z signaling in myelination. Neural Regen Res 2016; 11:549-51. [PMID: 27212906 PMCID: PMC4870902 DOI: 10.4103/1673-5374.180761] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Affiliation(s)
- Akihiro Fujikawa
- Division of Molecular Neurobiology, National Institute for Basic Biology, The Graduate University for Advanced Studies (SOKENDAI), Okazaki, Aichi, Japan
| | - Masaharu Noda
- Division of Molecular Neurobiology, National Institute for Basic Biology, The Graduate University for Advanced Studies (SOKENDAI), Okazaki, Aichi, Japan; School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki, Aichi, Japan
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Altarche-Xifro W, di Vicino U, Muñoz-Martin MI, Bortolozzi A, Bové J, Vila M, Cosma MP. Functional Rescue of Dopaminergic Neuron Loss in Parkinson's Disease Mice After Transplantation of Hematopoietic Stem and Progenitor Cells. EBioMedicine 2016; 8:83-95. [PMID: 27428421 PMCID: PMC4919540 DOI: 10.1016/j.ebiom.2016.04.016] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 04/14/2016] [Indexed: 01/24/2023] Open
Abstract
Parkinson's disease is a common neurodegenerative disorder, which is due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and for which no definitive cure is currently available. Cellular functions in mouse and human tissues can be restored after fusion of bone marrow (BM)-derived cells with a variety of somatic cells. Here, after transplantation of hematopoietic stem and progenitor cells (HSPCs) in the SNpc of two different mouse models of Parkinson's disease, we significantly ameliorated the dopaminergic neuron loss and function. We show fusion of transplanted HSPCs with neurons and with glial cells in the ventral midbrain of Parkinson's disease mice. Interestingly, the hybrids can undergo reprogramming in vivo and survived up to 4 weeks after transplantation, while acquiring features of mature astroglia. These newly generated astroglia produced Wnt1 and were essential for functional rescue of the dopaminergic neurons. Our data suggest that glial-derived hybrids produced upon fusion of transplanted HSPCs in the SNpc can rescue the Parkinson's disease phenotype via a niche-mediated effect, and can be exploited as an efficient cell-therapy approach.
Transplantation of HSPCs into the substantia nigra of PD mice ameliorates dopaminergic neuron loss and function. Hybrids generated after fusion of transplanted HSPCs undergo reprogramming in vivo and acquire features of mature astroglia. Newly generated astroglia produced Wnt1 and can functionally rescue the dopaminergic neuron loss. A definitive therapy for Parkinson's disease is not available. Here, we transplanted hematopoietic stem and progenitor cells into the substantia nigra of brains of two different mouse models of Parkinson's disease. These transplanted cells fused with neurons and glial cells of the recipient mice. Four weeks after transplantation, the hybrids acquired features of mature astroglia, secreted Wnt1, and functionally ameliorated dopaminergic neuron loss. Current cell therapy approaches are being pursued in the striatum with the aim to increase dopamine levels. Here we show that the loss of dopaminergic neurons can be protected against by direct actions in the substantia nigra.
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Affiliation(s)
- Wassim Altarche-Xifro
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain
| | - Umberto di Vicino
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain
| | - Maria Isabel Muñoz-Martin
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain
| | - Analía Bortolozzi
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain; Department of Neurochemistry and Neuropharmacology, IIBB-CSIC (Consejo Superior de Investigaciones Científicas), Barcelona, Spain
| | - Jordi Bové
- Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute and Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain
| | - Miquel Vila
- Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute and Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain; Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona (UAB), Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
| | - Maria Pia Cosma
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.
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