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Gómez-Gálvez P, Navarro V, Castro AM, Paradas C, Escudero LM. Computational Analysis of SOD1-G93A Mouse Muscle Biomarkers for Comprehensive Assessment of ALS Progression. Neuropathol Appl Neurobiol 2025; 51:e70014. [PMID: 40164574 DOI: 10.1111/nan.70014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 03/10/2025] [Accepted: 03/20/2025] [Indexed: 04/02/2025]
Abstract
AIMS To identify potential image biomarkers of neuromuscular disease by analysing morphological and network-derived features in skeletal muscle biopsies from a murine model of amyotrophic lateral sclerosis (ALS), the SOD1G93A mouse and wild-type (WT) controls at distinct stages of disease progression. METHODS Using the NDICIA computational framework, we quantitatively evaluated histological differences between skeletal muscle biopsies from SOD1G93A and WT mice. The process involved the selection of a subset of features revealing these differences. A subset of discriminative features was selected to characterise these differences, and their temporal dynamics were assessed across disease stages. RESULTS Our findings demonstrate that muscle pathology in the mutant model evolves from early alterations in muscle fibre arrangement, detectable at the presymptomatic stage through graph theory features, to the subsequent development of the typical morphological pattern of neurogenic atrophy at more advanced disease stages. CONCLUSIONS Our assay identifies a neurogenic signature in mutant muscle biopsies, even when the disease is phenotypically imperceptible.
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Affiliation(s)
- Pedro Gómez-Gálvez
- MRC Laboratory of Molecular Biology, Cambridge, UK
- Department of Physiology, Development and Neurobiology, University of Cambridge, Cambridge, UK
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla and Departamento de Biología Celular, Facultad de Biología, Universidad de Sevilla, Seville, Spain
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
| | - Victoria Navarro
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío CSIC/Universidad de Sevilla, Seville, Spain
| | - Ana M Castro
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla and Departamento de Biología Celular, Facultad de Biología, Universidad de Sevilla, Seville, Spain
| | - Carmen Paradas
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío CSIC/Universidad de Sevilla, Seville, Spain
- Neuromuscular Disease Unit, Neurology Department, Hospital Universitario Virgen del Rocío, Seville, Spain
| | - Luis M Escudero
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla and Departamento de Biología Celular, Facultad de Biología, Universidad de Sevilla, Seville, Spain
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
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Nowicka N, Zglejc-Waszak K, Juranek J, Korytko A, Wąsowicz K, Chmielewska-Krzesińska M, Wojtkiewicz J. Novel insights into RAGE signaling pathways during the progression of amyotrophic lateral sclerosis in RAGE-deficient SOD1 G93A mice. PLoS One 2024; 19:e0299567. [PMID: 38457412 PMCID: PMC10923448 DOI: 10.1371/journal.pone.0299567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 02/13/2024] [Indexed: 03/10/2024] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is neurodegenerative disease characterized by a progressive loss of motor neurons resulting in paralysis and muscle atrophy. One of the most prospective hypothesis on the ALS pathogenesis suggests that excessive inflammation and advanced glycation end-products (AGEs) accumulation play a crucial role in the development of ALS in patients and SOD1 G93A mice. Hence, we may speculate that RAGE, receptor for advanced glycation end-products and its proinflammatory ligands such as: HMGB1, S100B and CML contribute to ALS pathogenesis. The aim of our studies was to decipher the role of RAGE as well as provide insight into RAGE signaling pathways during the progression of ALS in SOD1 G93A and RAGE-deficient SOD1 G93A mice. In our study, we observed alternations in molecular pattern of proinflammatory RAGE ligands during progression of disease in RAGE KO SOD1 G93A mice compared to SOD1 G93A mice. Moreover, we observed that the amount of beta actin (ACTB) as well as Glial fibrillary acidic protein (GFAP) was elevated in SOD1 G93A mice when compared to mice with deletion of RAGE. These data contributes to our understanding of implications of RAGE and its ligands in pathogenesis of ALS and highlight potential targeted therapeutic interventions at the early stage of this devastating disease. Moreover, inhibition of the molecular cross-talk between RAGE and its proinflammatory ligands may abolish neuroinflammation, gliosis and motor neuron damage in SOD1 G93A mice. Hence, we hypothesize that attenuated interaction of RAGE with its proinflammatory ligands may improve well-being and health status during ALS in SOD1 G93A mice. Therefore, we emphasize that the inhibition of RAGE signaling pathway may be a therapeutic target for neurodegenerative diseases.
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Affiliation(s)
- Natalia Nowicka
- Department of Human Physiology and Pathophysiology, Faculty of Medicine, Collegium Medium, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Kamila Zglejc-Waszak
- Department of Human Physiology and Pathophysiology, Faculty of Medicine, Collegium Medium, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Judyta Juranek
- Department of Human Physiology and Pathophysiology, Faculty of Medicine, Collegium Medium, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Agnieszka Korytko
- Department of Human Physiology and Pathophysiology, Faculty of Medicine, Collegium Medium, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Krzysztof Wąsowicz
- Department of Pathophysiology, Forensic Veterinary Medicine and Administration, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Małgorzata Chmielewska-Krzesińska
- Department of Pathophysiology, Forensic Veterinary Medicine and Administration, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Joanna Wojtkiewicz
- Department of Human Physiology and Pathophysiology, Faculty of Medicine, Collegium Medium, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
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Scarian E, Viola C, Dragoni F, Di Gerlando R, Rizzo B, Diamanti L, Gagliardi S, Bordoni M, Pansarasa O. New Insights into Oxidative Stress and Inflammatory Response in Neurodegenerative Diseases. Int J Mol Sci 2024; 25:2698. [PMID: 38473944 DOI: 10.3390/ijms25052698] [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: 12/18/2023] [Revised: 02/19/2024] [Accepted: 02/21/2024] [Indexed: 03/14/2024] Open
Abstract
Oxidative stress (OS) and inflammation are two important and well-studied pathological hallmarks of neurodegenerative diseases (NDDs). Due to elevated oxygen consumption, the high presence of easily oxidizable polyunsaturated fatty acids and the weak antioxidant defenses, the brain is particularly vulnerable to oxidative injury. Uncertainty exists over whether these deficits contribute to the development of NDDs or are solely a consequence of neuronal degeneration. Furthermore, these two pathological hallmarks are linked, and it is known that OS can affect the inflammatory response. In this review, we will overview the last findings about these two pathways in the principal NDDs. Moreover, we will focus more in depth on amyotrophic lateral sclerosis (ALS) to understand how anti-inflammatory and antioxidants drugs have been used for the treatment of this still incurable motor neuron (MN) disease. Finally, we will analyze the principal past and actual clinical trials and the future perspectives in the study of these two pathological mechanisms.
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Affiliation(s)
- Eveljn Scarian
- Cellular Models and Neuroepigenetics Unit, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy
| | - Camilla Viola
- Cellular Models and Neuroepigenetics Unit, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy
- Department of Brain and Behavioral Sciences, University of Pavia, Via Agostino Bassi 21, 27100 Pavia, Italy
| | - Francesca Dragoni
- Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, Via Adolfo Ferrata, 9, 27100 Pavia, Italy
- Molecular Biology and Transcriptomics Unit, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy
| | - Rosalinda Di Gerlando
- Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, Via Adolfo Ferrata, 9, 27100 Pavia, Italy
- Molecular Biology and Transcriptomics Unit, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy
| | - Bartolo Rizzo
- Molecular Biology and Transcriptomics Unit, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy
| | - Luca Diamanti
- Neuroncology Unit, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy
| | - Stella Gagliardi
- Molecular Biology and Transcriptomics Unit, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy
| | - Matteo Bordoni
- Cellular Models and Neuroepigenetics Unit, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy
| | - Orietta Pansarasa
- Cellular Models and Neuroepigenetics Unit, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy
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Lan J, Zhou Y, Wang H, Tang J, Kang Y, Wang P, Liu X, Peng Y. Protective effect of human umbilical cord mesenchymal stem cell derived conditioned medium in a mutant TDP-43 induced motoneuron-like cellular model of ALS. Brain Res Bull 2023; 193:106-116. [PMID: 36563944 DOI: 10.1016/j.brainresbull.2022.12.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 12/15/2022] [Accepted: 12/18/2022] [Indexed: 12/24/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is a multi-factor neurodegenerative disease, characterized by the loss of motor neurons. TAR DNA-binding protein 43 (TDP-43) mutation, accumulation and aggregation, as well as oxidative stress are recognized as major pathological denominators and biochemical markers for ALS. Recently, human umbilical cord mesenchymal stem cell-derived conditioned medium (UC-CM) has been introduced to treat ALS patients. However, there is no research for the protective effect of UC-CM on the TDP-43 model of ALS. In this study, we evaluated the potential neuroprotective effect of UC-CM on a cellular ALS model expressing TDP-43mutant M337V, as well as its underlying mechanism. We found that 24 h UC-CM treatment could protect M337V expressing motor neurons by increasing cell viability and reducing LDH leakage. Furthermore, the aggregation of M337V, generation of ROS, malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), protein carbonyl and 8-OHdG were also reduced by UC-CM, indicating that UC-CM protected cells by reducing oxidative damage. Moreover, UC-CM significantly increased the expression of nuclear Nrf2 and its downstream enzyme HO1. The Nrf2 translocation inhibitor ML385 could inhibit the effect of UC-CM on the cell viability and aggregate of M337V. Our results suggest that UC-CM protect cells against M337V expression by its strong antioxidative effect via Nrf-2/HO-1 axis activation.
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Affiliation(s)
- Jiaqi Lan
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Yujun Zhou
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Hongyue Wang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Jingshu Tang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Yuying Kang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Peishen Wang
- Department of Cell Transplantation, The third Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Xuebin Liu
- Department of Cell Transplantation, The third Medical Center of Chinese PLA General Hospital, Beijing 100039, China; Beijing Zhongguang Tianyi Biotechnology Co., Ltd, Beijing 100026, China.
| | - Ying Peng
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
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Nowicka N, Szymańska K, Juranek J, Zglejc-Waszak K, Korytko A, Załęcki M, Chmielewska-Krzesińska M, Wąsowicz K, Wojtkiewicz J. The Involvement of RAGE and Its Ligands during Progression of ALS in SOD1 G93A Transgenic Mice. Int J Mol Sci 2022; 23:ijms23042184. [PMID: 35216298 PMCID: PMC8880540 DOI: 10.3390/ijms23042184] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/10/2022] [Accepted: 02/12/2022] [Indexed: 02/05/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive degeneration of upper and lower motor neurons that causes paralysis and muscle atrophy. The pathogenesis of the disease is still not elucidated. Receptor for Advanced Glycation End Product (RAGE) is a major component of the innate immune system and has implications in ALS pathogenesis. Multiple studies suggest the role of RAGE and its ligands in ALS. RAGE and its ligands are overexpressed in human and murine ALS motor neurons, astrocytes, and microglia. Here, we demonstrated the expression of RAGE and its ligands during the progression of the disease in the transgenic SOD1 G93A mouse lumbar spinal cord. We observed the highest expression of HMGB1 and S100b proteins at ALS onset. Our results highlight the potential role of RAGE and its ligands in ALS pathogenesis and suggest that some of the RAGE ligands might be used as biomarkers in early ALS diagnosis and potentially be useful in targeted therapeutic interventions at the early stage of this devastating disease.
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Affiliation(s)
- Natalia Nowicka
- Department of Human Physiology and Pathophysiology, School of Medicine, University of Warmia and Mazury, 10-082 Olsztyn, Poland; (K.S.); (K.Z.-W.); (A.K.); (J.W.)
- Correspondence: (N.N.); (J.J.)
| | - Kamila Szymańska
- Department of Human Physiology and Pathophysiology, School of Medicine, University of Warmia and Mazury, 10-082 Olsztyn, Poland; (K.S.); (K.Z.-W.); (A.K.); (J.W.)
| | - Judyta Juranek
- Department of Human Physiology and Pathophysiology, School of Medicine, University of Warmia and Mazury, 10-082 Olsztyn, Poland; (K.S.); (K.Z.-W.); (A.K.); (J.W.)
- Correspondence: (N.N.); (J.J.)
| | - Kamila Zglejc-Waszak
- Department of Human Physiology and Pathophysiology, School of Medicine, University of Warmia and Mazury, 10-082 Olsztyn, Poland; (K.S.); (K.Z.-W.); (A.K.); (J.W.)
| | - Agnieszka Korytko
- Department of Human Physiology and Pathophysiology, School of Medicine, University of Warmia and Mazury, 10-082 Olsztyn, Poland; (K.S.); (K.Z.-W.); (A.K.); (J.W.)
| | - Michał Załęcki
- Department of Animal Anatomy, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland;
| | - Małgorzata Chmielewska-Krzesińska
- Department of Pathophysiology, Forensic Veterinary Medicine and Administration, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (M.C.-K.); (K.W.)
| | - Krzysztof Wąsowicz
- Department of Pathophysiology, Forensic Veterinary Medicine and Administration, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (M.C.-K.); (K.W.)
| | - Joanna Wojtkiewicz
- Department of Human Physiology and Pathophysiology, School of Medicine, University of Warmia and Mazury, 10-082 Olsztyn, Poland; (K.S.); (K.Z.-W.); (A.K.); (J.W.)
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Siwek T, Jezierska-Woźniak K, Maksymowicz S, Barczewska M, Sowa M, Badowska W, Maksymowicz W. Repeat Administration of Bone Marrow-Derived Mesenchymal Stem Cells for Treatment of Amyotrophic Lateral Sclerosis. Med Sci Monit 2020; 26:e927484. [PMID: 33301428 PMCID: PMC7737405 DOI: 10.12659/msm.927484] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Background The aim of this study was to investigate repeated intrathecal injection of autologous bone marrow-derived mesenchymal stem cells (BM-D MSCs) to patients for treatment of sporadic amyotrophic lateral sclerosis (ALS). Material/Methods Autologous MSCs were isolated from the patients’ bone marrow, plated, expanded, harvested, and passaged. Stem cells from a single bone marrow collection were used for 3 injections per patient, given over a 3-month period. Outcomes were measured with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Participants were observed for a minimum of 6 months before transplantation to assess the natural course of ALS and for the same amount of time after transplantation to compare the rate of disease progression, estimated based on average monthly changes in ALSFRS-R scores. Data from 8 of the 15 participants eligible for the study were analyzed. Results The safety of the MSC injections was confirmed and various effects of the therapy were documented. In patients who had ALS with an inherently slow course, there were no significant changes in the rate of disease progression. In patients who had ALS with an inherently rapid course, slowing of the disease was noted following treatment with MSCs. However, because that subgroup was so small, it was not possible to assess whether the changes were statistically significant. Conclusions Identifying groups of patients who are not responding or potentially responding negatively to injection of MSCs may help prevent it from being offered to individuals who may not benefit from the therapy. One of the limitations of this treatment method is the amount of time required for long-lasting preparation of bone marrow-derived MSCs for a disease that is rapidly progressive. Therefore, it is worth looking for other allogeneic sources of stromal cells for these types of injections.
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Affiliation(s)
- Tomasz Siwek
- Department of Neurology, School of Medicine, University of Warmia and Mazury, Olsztyn, Poland.,Department of Neurology, University Hospital in Olsztyn, Olsztyn, Poland
| | | | - Stanisław Maksymowicz
- Department of Psychology and Sociology of Health and Public Health, School of Public Health, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland
| | - Monika Barczewska
- Department of Neurosurgery, School of Medicine, University of Warmia and Mazury, Olsztyn, Poland.,Departament of Neurosurgery, University Hospital in Olsztyn, Olsztyn, Poland
| | - Mariusz Sowa
- Department of Neurosurgery, School of Medicine, University of Warmia and Mazury, Olsztyn, Poland.,Department of Neurosurgery, University Hospital in Olsztyn, Olsztyn, Poland
| | - Wanda Badowska
- Department of Clinical Paediatrics, School of Medicine, University of Warmia and Mazury, Olsztyn, Poland
| | - Wojciech Maksymowicz
- Department of Neurosurgery, School of Medicine, University of Warmia and Mazury, Olsztyn, Poland.,Department of Neurosurgery, University Hospital in Olsztyn, Olsztyn, Poland
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Shariati A, Nemati R, Sadeghipour Y, Yaghoubi Y, Baghbani R, Javidi K, Zamani M, Hassanzadeh A. Mesenchymal stromal cells (MSCs) for neurodegenerative disease: A promising frontier. Eur J Cell Biol 2020; 99:151097. [PMID: 32800276 DOI: 10.1016/j.ejcb.2020.151097] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 06/22/2020] [Accepted: 06/23/2020] [Indexed: 12/11/2022] Open
Abstract
Neurodegenerative disorders are a variety of diseases including Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) along with some other less common diseases generally described by the advanced deterioration of central or peripheral nervous system, structurally or functionally. In the last two decades, mesenchymal stromal cells (MSCs) due to their unique assets encompassing self-renewal, multipotency and accessibility in association with low ethical concern open new frontiers in the context of neurodegenerative diseases therapy. Interestingly, MSCs can be differentiated into endodermal and ectodermal lineages (e.g., neurons, oligodendrocyte, and astrocyte), and thus could be employed to advance cell-based therapeutic strategy. Additionally, as inflammation ordinarily ensues as a local response provoked by microglia in the neurodegenerative diseases, MSCs therapy because of their pronounced immunomodulatory properties is noticed as a rational approach for their treatment. Recently, varied types of studies have been mostly carried out in vitro and rodent models using MSCs upon their procurement from various sources and expansion. The promising results of the studies in rodent models have motivated researchers to design and perform several clinical trials, with a speedily rising number. In the current review, we aim to deliver a brief overview of MSCs sources, expansion strategies, and their immunosuppressive characteristics and discuss credible functional mechanisms exerted by MSCs to treat neurodegenerative disorders, covering AD, PD, ALS, MS, and HD.
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Affiliation(s)
- Ali Shariati
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Reza Nemati
- Department of Medical Emergencies, School of Allied Medical Sciences, Bushehr University of Medical Sciences, Bushehr, Iran.
| | - Yasin Sadeghipour
- Department of Medical Nanotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Yoda Yaghoubi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Reza Baghbani
- Department of Medical Emergencies, School of Allied Medical Sciences, Bushehr University of Medical Sciences, Bushehr, Iran.
| | - Kamran Javidi
- School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran.
| | - Majid Zamani
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Gonabad University of Medical Sciences, Gonabad, Iran.
| | - Ali Hassanzadeh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Cell Therapy and Regenerative Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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Wang J, Hu WW, Jiang Z, Feng MJ. Advances in treatment of neurodegenerative diseases: Perspectives for combination of stem cells with neurotrophic factors. World J Stem Cells 2020; 12:323-338. [PMID: 32547681 PMCID: PMC7280867 DOI: 10.4252/wjsc.v12.i5.323] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 03/31/2020] [Accepted: 04/07/2020] [Indexed: 02/06/2023] Open
Abstract
Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, are a group of incurable neurological disorders, characterized by the chronic progressive loss of different neuronal subtypes. However, despite its increasing prevalence among the ever-increasing aging population, little progress has been made in the coincident immense efforts towards development of therapeutic agents. Research interest has recently turned towards stem cells including stem cells-derived exosomes, neurotrophic factors, and their combination as potential therapeutic agents in neurodegenerative diseases. In this review, we summarize the progress in therapeutic strategies based on stem cells combined with neurotrophic factors and mesenchymal stem cells-derived exosomes for neurodegenerative diseases, with an emphasis on the combination therapy.
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Affiliation(s)
- Jie Wang
- Department of Geriatrics, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu Province, China
- Department of Neurology, the Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211100, Jiangsu Province, China
| | - Wei-Wei Hu
- Department of Geriatrics, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Zhi Jiang
- Department of Geriatrics, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu Province, China
| | - Mei-Jiang Feng
- Department of Geriatrics, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu Province, China
- Key Laboratory for Aging & Disease, Nanjing Medical University, Nanjing 210011, Jiangsu Province, China.
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9
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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: 3] [Impact Index Per Article: 0.6] [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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10
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Białkowska J, Mroczkowska D, Huflejt ME, Wojtkiewicz J, Siwek T, Barczewska M, Maksymowicz W. COMPLEX TREATMENT OF AMYOTROPHIC LATERAL SCLEROSIS PATIENT. Acta Clin Croat 2019; 58:757-766. [PMID: 32595261 PMCID: PMC7314291 DOI: 10.20471/acc.2019.58.04.24] [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] [Indexed: 11/24/2022] Open
Abstract
Amyotrophic lateral sclerosis is a progressive and fatal degenerative neuromuscular disease with few if any treatment options and physical rehabilitation addressing specific deficits is the most frequent form of therapy. Patients also suffer from depression and increased anxiety. Our purpose was to assess the neurorehabilitation effectiveness in a patient with amyotrophic lateral sclerosis who underwent stem cell transplantation but refused physiotherapy due to depression. Disease progression was followed using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale bimonthly for six months pre- and then post-stem cell transplantation. Psychological traits were assessed using six standardized tests. Quantitative electroencephalogram diagnostics was performed before the first and after the last neurofeedback session, and sessions were conducted on a 3-times-a-week basis. The physiotherapy protocol included proprioceptive neuromuscular facilitation, electrical modalities unit applied to the lumbar spine area, and breathing, relaxation and walking exercises, among others. Increased motivation and marked decrease in the pain level was associated with the patient's willingness to complete physiotherapy, which resulted in improvements in most neuromuscular deficits and in increased respiratory capacity. During the 12 post-rehabilitation months, progression of the disease decelerated, and a positive behavioral change was noted. The study suggested that neurofeedback could be used as a neurorehabilitation component of the personalized complex rehabilitation protocol in patients with amyotrophic lateral sclerosis.
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Affiliation(s)
| | - Dorota Mroczkowska
- 1Department of Public Health, Faculty of Health Sciences, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland; 2Clinical University Hospital, Olsztyn, Poland; 3Department of Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland; 4Department of Neurology and Neurosurgery, School of Medicine, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland
| | - Margaret E Huflejt
- 1Department of Public Health, Faculty of Health Sciences, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland; 2Clinical University Hospital, Olsztyn, Poland; 3Department of Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland; 4Department of Neurology and Neurosurgery, School of Medicine, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland
| | - Joanna Wojtkiewicz
- 1Department of Public Health, Faculty of Health Sciences, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland; 2Clinical University Hospital, Olsztyn, Poland; 3Department of Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland; 4Department of Neurology and Neurosurgery, School of Medicine, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland
| | - Tomasz Siwek
- 1Department of Public Health, Faculty of Health Sciences, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland; 2Clinical University Hospital, Olsztyn, Poland; 3Department of Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland; 4Department of Neurology and Neurosurgery, School of Medicine, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland
| | - Monika Barczewska
- 1Department of Public Health, Faculty of Health Sciences, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland; 2Clinical University Hospital, Olsztyn, Poland; 3Department of Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland; 4Department of Neurology and Neurosurgery, School of Medicine, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland
| | - Wojciech Maksymowicz
- 1Department of Public Health, Faculty of Health Sciences, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland; 2Clinical University Hospital, Olsztyn, Poland; 3Department of Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland; 4Department of Neurology and Neurosurgery, School of Medicine, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland
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Gouel F, Rolland AS, Devedjian JC, Burnouf T, Devos D. Past and Future of Neurotrophic Growth Factors Therapies in ALS: From Single Neurotrophic Growth Factor to Stem Cells and Human Platelet Lysates. Front Neurol 2019; 10:835. [PMID: 31428042 PMCID: PMC6688198 DOI: 10.3389/fneur.2019.00835] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 07/19/2019] [Indexed: 12/11/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that typically results in death within 3–5 years after diagnosis. To date, there is no curative treatment and therefore an urgent unmet need of neuroprotective and/or neurorestorative treatments. Due to their spectrum of capacities in the central nervous system—e.g., development, plasticity, maintenance, neurogenesis—neurotrophic growth factors (NTF) have been exploited for therapeutic strategies in ALS for decades. In this review we present the initial strategy of using single NTF by different routes of administration to the use of stem cells transplantation to express a multiple NTFs-rich secretome to finally focus on a new biotherapy based on the human platelet lysates, the natural healing system containing a mix of pleitropic NTF and having immunomodulatory function. This review highlights that this latter treatment may be crucial to power the neuroprotection and/or neurorestoration therapy requested in this devastating disease.
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Affiliation(s)
- Flore Gouel
- Department of Medical Pharmacology, Lille University, INSERM UMRS_1171, University Hospital Center, LICEND COEN Center, Lille, France
| | - Anne-Sophie Rolland
- Department of Medical Pharmacology, Lille University, INSERM UMRS_1171, University Hospital Center, LICEND COEN Center, Lille, France
| | - Jean-Christophe Devedjian
- Department of Medical Pharmacology, Lille University, INSERM UMRS_1171, University Hospital Center, LICEND COEN Center, Lille, France
| | - Thierry Burnouf
- Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan.,International PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan.,International PhD Program in Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - David Devos
- Department of Medical Pharmacology, Lille University, INSERM UMRS_1171, University Hospital Center, LICEND COEN Center, Lille, France.,Department of Neurology, Lille University, INSERM UMRS_1171, University Hospital Center, LICEND COEN Center, Lille, France
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12
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Influence of Lineage-Negative Stem Cell Therapy on Articulatory Functions in ALS Patients. Stem Cells Int 2019; 2019:7213854. [PMID: 31281384 PMCID: PMC6589318 DOI: 10.1155/2019/7213854] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 04/17/2019] [Accepted: 05/08/2019] [Indexed: 01/01/2023] Open
Abstract
Introduction Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease, leading to loss of muscle strength and motor control. Impaired speech and swallowing lower the quality of life and consequently may induce acute respiratory failure. Bone marrow-derived stem and progenitor cells (SPCs) may be a valuable source of trophic factors. In this study, we assessed whether adjuvant cellular therapy could affect the levels of selected neurotrophins and proinflammatory factors in the cerebrospinal fluid (CSF) and subsequently prevent the deterioration of articulation. Materials and Methods The study group consisted of 32 patients with sporadic ALS who underwent autologous lineage-negative (Lin−) stem cell intrathecal administration to the spinal canal. Lin− cells were aspirated from the bone marrow and isolated using immunomagnetic beads and a lineage cell depletion kit. Patients were examined for articulatory functions by means of the Voice Handicap Index (VHI) questionnaire and Frenchay Dysarthria Assessment (FDA). In parallel, we carried out the analysis of selected trophic and proinflammatory factors in CSF utilizing multiplex fluorescent bead-based immunoassays. Results Of the 32 patients who received the Lin− progenitor cell therapy, 6 (group I) showed improvement in articulatory functions, 23 remained stable (group II), and 3 deteriorated (group III) on the 28th day. The improvement was particularly noticeable in a better cough reflex, laryngeal time, and dribble reflex. A statistically significant lower level of brain-derived neurotrophic factor (BDNF) was observed on day 0 in group I compared to group II. The CSF concentrations of C-reactive protein (CRP) in group I significantly decreased 7 days after Lin− SPC transplantation. On the contrary, a significant increase in the tumor necrosis factor receptor (TNF-R) level was confirmed among patients from group I with improvement of dribble and coughing reflex, tongue movements, and respiration on the 7th day, as well as on day 28 including dribble reflex solely. Conclusions An application of Lin− stem cells could potentate the beneficial humoral effect. The prevention of deterioration of articulatory functions in ALS patients after applying adjuvant Lin− stem cell therapy seems to be promising. Although the procedure is safe and feasible, it requires further in-depth studies.
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Differentiation of Motor Neuron-Like Cells from Tonsil-Derived Mesenchymal Stem Cells and Their Possible Application to Neuromuscular Junction Formation. Int J Mol Sci 2019; 20:ijms20112702. [PMID: 31159418 PMCID: PMC6600529 DOI: 10.3390/ijms20112702] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/27/2019] [Accepted: 05/30/2019] [Indexed: 12/11/2022] Open
Abstract
Human tonsil-derived mesenchymal stem cells (T-MSCs) are newly identified MSCs and present typical features of MSCs, including having the differentiation capacity into the three germ layers and excellent proliferation capacity. They are easily sourced and are useful for stem cell therapy in various disease states. We previously reported that T-MSCs could be differentiated into skeletal myocytes and Schwann-like cells; therefore, they are a promising candidate for cell therapies for neuromuscular disease. Motor neurons (MNs), which regulate spontaneous behavior, are affected by a wide range of MN diseases (MNDs) for which there are no effective remedies. We investigated the differentiation potential of MN-like cells derived from T-MSCs (T-MSC-MNCs) for application to therapy of MNDs. After the process of MN differentiation, the expression of MN-related markers, including Islet 1, HB9/HLXB9 (HB9), and choline acetyltransferase (ChAT), was increased when compared with undifferentiated T-MSCs. The secretion of acetylcholine to the conditioned medium was significantly increased after MN differentiation. We cocultured T-MSC-MNCs and human skeletal muscle cells, and confirmed the presence of the acetylcholine receptor clusters, which demonstrated the formation of neuromuscular junctions. The potential functional improvements afforded by these T-MSC-MNCs could be useful in the treatment of MNDs caused by genetic mutation, viral infection, or environmental problems.
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14
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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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15
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Preclinical Evaluation of Long-Term Neuroprotective Effects of BDNF-Engineered Mesenchymal Stromal Cells as Intravitreal Therapy for Chronic Retinal Degeneration in Rd6 Mutant Mice. Int J Mol Sci 2019; 20:ijms20030777. [PMID: 30759764 PMCID: PMC6387230 DOI: 10.3390/ijms20030777] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 02/03/2019] [Accepted: 02/10/2019] [Indexed: 12/13/2022] Open
Abstract
This study aimed to investigate whether the transplantation of genetically engineered bone marrow-derived mesenchymal stromal cells (MSCs) to overexpress brain-derived neurotrophic factor (BDNF) could rescue the chronic degenerative process of slow retinal degeneration in the rd6 (retinal degeneration 6) mouse model and sought to identify the potential underlying mechanisms. Rd6 mice were subjected to the intravitreal injection of lentivirally modified MSC-BDNF or unmodified MSC or saline. In vivo morphology, electrophysiological retinal function (ERG), and the expression of apoptosis-related genes, as well as BDNF and its receptor (TrkB), were assessed in retinas collected at 28 days and three months after transplantation. We observed that cells survived for at least three months after transplantation. MSC-BDNF preferentially integrated into the outer retinal layers and considerably rescued damaged retinal cells, as evaluated by ERG and immunofluorescence staining. Additionally, compared with controls, the therapy with MSC-BDNF was associated with the induction of molecular changes related to anti-apoptotic signaling. In conclusion, BDNF overexpression observed in retinas after MSC-BDNF treatment could enhance the neuroprotective properties of transplanted autologous MSCs alone in the chronically degenerated retina. This research provides evidence for the long-term efficacy of genetically-modified MSC and may represent a strategy for treating various forms of degenerative retinopathies in the future.
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16
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Majchrzak M, Drela K, Andrzejewska A, Rogujski P, Figurska S, Fiedorowicz M, Walczak P, Janowski M, Lukomska B, Stanaszek L. SOD1/Rag2 Mice with Low Copy Number of SOD1 Gene as a New Long-Living Immunodeficient Model of ALS. Sci Rep 2019; 9:799. [PMID: 30692571 PMCID: PMC6349855 DOI: 10.1038/s41598-018-37235-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 11/30/2018] [Indexed: 02/07/2023] Open
Abstract
The most recent research concerning amyotrophic lateral sclerosis (ALS) emphasizes the role of glia in disease development. Thus, one can suspect that the effective therapeutic strategy in treatment of ALS would be replacement of defective glia. One of the basic problems with human glial progenitors (hGRPs) replacement strategies is the time needed for the cells to become fully functional in vivo. The lifespan of most popular high copy number SOD1 mutant mice might be too short to acknowledge benefits of transplanted cells. We focused on developing immunodeficient rag2-/- model of ALS with lower number of transgene copies and longer lifespan. The obtained hSOD1/rag2 double mutant mice have been characterized. QPCR analysis revealed that copy number of hSOD1 transgene varied in our colony (4-8 copies). The difference in transgene copy number may be translated to significant impact on the lifespan. The death of long- and short-living hSOD1/rag2 mice is preceded by muscular weakness as early as one month before death. Importantly, based on magnetic resonance imaging we identified that mutant mice demonstrated abnormalities within the medullar motor nuclei. To conclude, we developed long-living double mutant hSOD1/rag2 mice, which could be a promising model for testing therapeutic utility of human stem cells.
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Affiliation(s)
- M Majchrzak
- NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - K Drela
- NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - A Andrzejewska
- NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - P Rogujski
- NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - S Figurska
- Laboratory for Genetically Modified Animals, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - M Fiedorowicz
- Department of Experimental Pharmacology and Small Animal Magnetic Resonance Imaging Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - P Walczak
- Johns Hopkins University School of Medicine, Institute for Cell Engineering, Division of MR Research, The Russell H. Morgan Department of Radiology and Radiological Science, Baltimore, MD, USA
- Department of Neurosurgery, School of Medicine, Collegium Medicum, University of Warmia and Mazury, Olsztyn, 10-719, Poland
| | - M Janowski
- NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
- Johns Hopkins University School of Medicine, Institute for Cell Engineering, Division of MR Research, The Russell H. Morgan Department of Radiology and Radiological Science, Baltimore, MD, USA
| | - B Lukomska
- NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - L Stanaszek
- NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
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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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Barczewska M, Grudniak M, Maksymowicz S, Siwek T, Ołdak T, Jezierska-Woźniak K, Gładysz D, Maksymowicz W. Safety of intrathecal injection of Wharton's jelly-derived mesenchymal stem cells in amyotrophic lateral sclerosis therapy. Neural Regen Res 2019; 14:313-318. [PMID: 30531015 PMCID: PMC6301165 DOI: 10.4103/1673-5374.243723] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Animal experiments have confirmed that mesenchymal stem cells can inhibit motor neuron apoptosis and inflammatory factor expression and increase neurotrophic factor expression. Therefore, mesenchymal stem cells have been shown to exhibit prospects in the treatment of amyotrophic lateral sclerosis. However, the safety of their clinical application needs to be validated. To investigate the safety of intrathecal injection of Wharton's jelly-derived mesenchymal stem cells in amyotrophic lateral sclerosis therapy, 43 patients (16 females and 27 males, mean age of 57.3 years) received an average dose of 0.42 × 106 cells/kg through intrathecal administration at the cervical, thoracic or lumbar region depending on the clinical symptoms. There was a 2 month interval between two injections. The adverse events occurring during a 6-month treatment period were evaluated. No adverse events occurred. Headache occurred in one case only after first injection of stem cells. This suggests that intrathecal injection of Wharton's Jelly-derived mesenchymal stem cells is well tolerated in patients with amyotrophic lateral sclerosis. This study was approved by the Bioethical Committee of School of Medicine, University of Warmia and Mazury in Olsztyn, Poland (approval No. 36/2014 and approval No. 8/2016). This study was registered with the ClinicalTrials.gov (identifier: NCT02881476) on August 29, 2016.
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Affiliation(s)
- Monika Barczewska
- Department of Neurology and Neurosurgery, School of Medicine, Collegium Medicum - University of Warmia and Mazury in Olsztyn; University Clinical Hospital in Olsztyn; Instytut Terapii Komórkowych w Olsztynie (Cell Therapies Institute, FamiCord Group), Olsztyn, Poland
| | - Mariusz Grudniak
- Polski Bank Komórek Macierzystych (PBKM, FamiCord Group), Warszawa, Poland
| | - Stanisław Maksymowicz
- Department of Psychology, Clinical Logopedics and Social Science in Medicine, Faculty of Health Sciences, Collegium Medicum - University of Warmia and Mazury in Olsztyn; Instytut Terapii Komórkowych w Olsztynie (Cell Therapies Institute, FamiCord Group), Olsztyn, Poland
| | - Tomasz Siwek
- Department of Neurology and Neurosurgery, School of Medicine, Collegium Medicum - University of Warmia and Mazury in Olsztyn; University Clinical Hospital in Olsztyn; Instytut Terapii Komórkowych w Olsztynie (Cell Therapies Institute, FamiCord Group), Olsztyn, Poland
| | - Tomasz Ołdak
- Polski Bank Komórek Macierzystych (PBKM, FamiCord Group), Warszawa, Poland
| | - Katarzyna Jezierska-Woźniak
- Department of Neurology and Neurosurgery, Laboratory of Regenerative Medicine, School of Medicine, Collegium Medicum-University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Dominika Gładysz
- Polski Bank Komórek Macierzystych (PBKM, FamiCord Group), Warszawa, Poland
| | - Wojciech Maksymowicz
- Department of Neurology and Neurosurgery, School of Medicine, Collegium Medicum - University of Warmia and Mazury in Olsztyn; University Clinical Hospital in Olsztyn, Olsztyn, Poland
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Stephenson J, Nutma E, van der Valk P, Amor S. Inflammation in CNS neurodegenerative diseases. Immunology 2018; 154:204-219. [PMID: 29513402 PMCID: PMC5980185 DOI: 10.1111/imm.12922] [Citation(s) in RCA: 651] [Impact Index Per Article: 93.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 02/22/2018] [Accepted: 02/28/2018] [Indexed: 12/11/2022] Open
Abstract
Neurodegenerative diseases, the leading cause of morbidity and disability, are gaining increased attention as they impose a considerable socioeconomic impact, due in part to the ageing community. Neuronal damage is a pathological hallmark of Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia and multiple sclerosis, although such damage is also observed following neurotropic viral infections, stroke, genetic white matter diseases and paraneoplastic disorders. Despite the different aetiologies, for example, infections, genetic mutations, trauma and protein aggregations, neuronal damage is frequently associated with chronic activation of an innate immune response in the CNS. The growing awareness that the immune system is inextricably involved in shaping the brain during development as well as mediating damage, but also regeneration and repair, has stimulated therapeutic approaches to modulate the immune system in neurodegenerative diseases. Here, we review the current understanding of how astrocytes and microglia, as well as neurons and oligodendrocytes, shape the neuroimmune response during development, and how aberrant responses that arise due to genetic or environmental triggers may predispose the CNS to neurodegenerative diseases. We discuss the known interactions between the peripheral immune system and the brain, and review the current concepts on how immune cells enter and leave the CNS. A better understanding of neuroimmune interactions during development and disease will be key to further manipulating these responses and the development of effective therapies to improve quality of life, and reduce the impact of neuroinflammatory and degenerative diseases.
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Affiliation(s)
- Jodie Stephenson
- Centre for Neuroscience and TraumaBarts and the Blizard Institute, LondonSchool of Medicine and DentistryQueen Mary University of LondonLondonUK
- Department of PathologyVU University Medical CentreAmsterdamthe Netherlands
| | - Erik Nutma
- Department of PathologyVU University Medical CentreAmsterdamthe Netherlands
| | - Paul van der Valk
- Department of PathologyVU University Medical CentreAmsterdamthe Netherlands
| | - Sandra Amor
- Centre for Neuroscience and TraumaBarts and the Blizard Institute, LondonSchool of Medicine and DentistryQueen Mary University of LondonLondonUK
- Department of PathologyVU University Medical CentreAmsterdamthe Netherlands
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Safety and Feasibility of Lin- Cells Administration to ALS Patients: A Novel View on Humoral Factors and miRNA Profiles. Int J Mol Sci 2018; 19:ijms19051312. [PMID: 29702606 PMCID: PMC5983708 DOI: 10.3390/ijms19051312] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 04/20/2018] [Accepted: 04/24/2018] [Indexed: 12/27/2022] Open
Abstract
Therapeutic options for amyotrophic lateral sclerosis (ALS) are still limited. Great hopes, however, are placed in growth factors that show neuroprotective abilities (e.g., nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF)) and in the immune modulating features, in particular, the anti-inflammatory effects. In our study we aimed to investigate whether a bone marrow-derived lineage-negative (Lin-) cells population, after autologous application into cerebrospinal fluid (CSF), is able to produce noticeable concentrations of trophic factors and inflammatory-related proteins and thus influence the clinical course of ALS. To our knowledge, the evaluation of Lin- cells transplantation for ALS treatment has not been previously reported. Early hematopoietic Lin- cells were isolated from twelve ALS patients’ bone marrow, and later, the suspension of cells was administered into the subarachnoid space by lumbar puncture. Concentrations of selected proteins in the CSF and plasma were quantified by multiplex fluorescent bead-based immunoassays at different timepoints post-transplantation. We also chose microRNAs (miRNAs) related to muscle biology (miRNA-1, miRNA-133a, and miRNA-206) and angiogenesis and inflammation (miRNA-155 and miRNA-378) and tested, for the first time, their expression profiles in the CSF and plasma of ALS patients after Lin- cells transplantation. The injection of bone marrow cells resulted in decreased concentration of selected inflammatory proteins (C3) after Lin- cells injection, particularly in patients who had a better clinical outcome. Moreover, several analyzed miRNAs have changed expression levels in the CSF and plasma of ALS patients subsequent to Lin- cells administration. Interestingly, the expression of miR-206 increased in ALS patients, while miR-378 decreased both in the CSF and plasma one month after the cells’ injection. We propose that autologous lineage-negative early hematopoietic cells injected intrathecally may be a safe and feasible source of material for transplantations to the central nervous system (CNS) environment aimed at anti-inflammatory support provision for ALS adjuvant treatment strategies. Further research is needed to evaluate whether the observed effects could significantly influence the ALS progression.
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Dharmadasa T, Huynh W, Tsugawa J, Shimatani Y, Ma Y, Kiernan MC. Implications of structural and functional brain changes in amyotrophic lateral sclerosis. Expert Rev Neurother 2018; 18:407-419. [PMID: 29667443 DOI: 10.1080/14737175.2018.1464912] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes progressive muscle weakness and disability, eventually leading to death. Heterogeneity of disease has become a major barrier to understanding key clinical questions such as prognosis and disease spread, and has disadvantaged clinical trials in search of therapeutic intervention. Patterns of disease have been explored through recent advances in neuroimaging, elucidating structural, molecular and functional changes. Unique brain signatures have emerged that have lent a greater understanding of critical disease mechanisms, offering opportunities to improve diagnosis, guide prognosis, and establish candidate biomarkers to direct future therapeutic strategies. Areas covered: This review explores patterns of cortical and subcortical change in ALS through advanced neuroimaging techniques and discusses the implications of these findings. Expert commentary: Cortical and subcortical signatures and patterns of atrophy are now consistently recognised, providing important pathophysiological insight into this heterogenous disease. The spread of cortical change, particularly involving frontotemporal networks, correlates with cognitive impairment and poorer prognosis. Cortical differences are also evident between ALS phenotypes and genotypes, which may partly explain the heterogeneity of prognosis. Ultimately, multimodal approaches with larger cohorts will be needed to provide sensitive biomarkers of disease spread at the level of the individual patient.
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Affiliation(s)
| | - William Huynh
- a Brain and Mind Centre , The University of Sydney , Sydney , Australia
| | - Jun Tsugawa
- c Department of Neurology , Fukuoka University Hospital , Fukuoka city , Japan
| | - Yoshimitsu Shimatani
- d Department of Neurology , Tokushima Prefectural Hospital , Tokushima city , Japan
| | - Yan Ma
- a Brain and Mind Centre , The University of Sydney , Sydney , Australia
| | - Matthew C Kiernan
- a Brain and Mind Centre , The University of Sydney , Sydney , Australia.,b Department of Neurology , Royal Prince Alfred Hospital , Sydney , Australia
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Abe K. [An early history of Japanese amyotrophic lateral sclerosis (ALS)-related diseases and the current development]. Rinsho Shinkeigaku 2018; 58:141-165. [PMID: 29491329 DOI: 10.5692/clinicalneurol.cn-001095] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The present review focuses an early history of Japanese amyotrophic lateral sclerosis (ALS)-related diseases and the current development. In relation to foreign previous reports, five topics are introduced and discussed on ALS with dementia, ALS/Parkinsonism dementia complex (ALS/PDC), familial ALS (FALS), spinal bulbar muscular atrophy (SBMA), and multisystem involvement especially in cerebellar system of ALS including ALS/SCA (spinocerebellar ataxia) crossroad mutation Asidan. This review found the great contribution of Japanese reports on the above five topics, and confirmed the great development of ALS-related diseases over the past 120 years.
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Affiliation(s)
- Koji Abe
- Department of Neurology, Okayama University Medical School
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23
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Ghaffari LT, Starr A, Nelson AT, Sattler R. Representing Diversity in the Dish: Using Patient-Derived in Vitro Models to Recreate the Heterogeneity of Neurological Disease. Front Neurosci 2018; 12:56. [PMID: 29479303 PMCID: PMC5812426 DOI: 10.3389/fnins.2018.00056] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 01/23/2018] [Indexed: 12/14/2022] Open
Abstract
Neurological diseases, including dementias such as Alzheimer's disease (AD) and fronto-temporal dementia (FTD) and degenerative motor neuron diseases such as amyotrophic lateral sclerosis (ALS), are responsible for an increasing fraction of worldwide fatalities. Researching these heterogeneous diseases requires models that endogenously express the full array of genetic and epigenetic factors which may influence disease development in both familial and sporadic patients. Here, we discuss the two primary methods of developing patient-derived neurons and glia to model neurodegenerative disease: reprogramming somatic cells into induced pluripotent stem cells (iPSCs), which are differentiated into neurons or glial cells, or directly converting (DC) somatic cells into neurons (iNeurons) or glial cells. Distinct differentiation techniques for both models result in a variety of neuronal and glial cell types, which have been successful in displaying unique hallmarks of a variety of neurological diseases. Yield, length of differentiation, ease of genetic manipulation, expression of cell-specific markers, and recapitulation of disease pathogenesis are presented as determining factors in how these methods may be used separately or together to ascertain mechanisms of disease and identify therapeutics for distinct patient populations or for specific individuals in personalized medicine projects.
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Affiliation(s)
- Layla T Ghaffari
- Department of Neurobiology, Barrow Neurological Institute, Dignity Health-St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States
| | - Alexander Starr
- Department of Neurobiology, Barrow Neurological Institute, Dignity Health-St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States
| | - Andrew T Nelson
- Department of Neurobiology, Barrow Neurological Institute, Dignity Health-St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States
| | - Rita Sattler
- Department of Neurobiology, Barrow Neurological Institute, Dignity Health-St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States
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24
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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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25
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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: 114] [Impact Index Per Article: 14.3] [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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26
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Namestnikova D, Gubskiy I, Kholodenko I, Melnikov P, Sukhinich K, Gabashvili A, Vishnevskiy D, Soloveva A, Abakumov M, Vakhrushev I, Lupatov A, Chekhonin V, Gubsky L, Yarygin K. Methodological aspects of MRI of transplanted superparamagnetic iron oxide-labeled mesenchymal stem cells in live rat brain. PLoS One 2017; 12:e0186717. [PMID: 29049361 PMCID: PMC5648235 DOI: 10.1371/journal.pone.0186717] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2017] [Accepted: 10/08/2017] [Indexed: 12/22/2022] Open
Abstract
In vivo tracking of transplanted mesenchymal stem cells (MSCs) migration and homing is vital for understanding the mechanisms of beneficial effects of MSCs transplantation in animal models of diseases and in clinical trials. Transplanted cells can be labeled with superparamagnetic iron oxide (SPIO) particles and visualized in vivo using a number of iron sensitive MRI techniques. However, the applicability of those techniques for SPIO-labeled MSCs tracking in live brain has not been sufficiently investigated. The goal of this study was to estimate the efficiency of various MRI techniques of SPIO-labeled cell tracing in the brain. To achieve that goal, the precision and specificity of T2WI, T2*WI and SWI (Susceptibility-Weighted Imaging) techniques of SPIO-labeled MSCs tracing in vitro and in live rat brain were for the first time compared in the same experiment. We have shown that SWI presents the most sensitive pulse sequence for SPIO-labeled MSCs MR visualization. After intracerebral administration due to limitations caused by local micro-hemorrhages the visualization threshold was 102 cells, while after intra-arterial transplantation SWI permitted detection of several cells or even single cells. There is just one publication claiming detection of individual SPIO-labeled MSCs in live brain, while the other state much lower sensitivity, describe detection of different cell types or high resolution tracing of MSCs in other tissues. This study confirms the possibility of single cell tracing in live brain and outlines the necessary conditions. SWI is a method convenient for the detection of single SPIO labeled MSCs and small groups of SPIO labeled MSCs in brain tissue and can be appropriate for monitoring migration and homing of transplanted cells in basic and translational neuroscience.
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Affiliation(s)
| | - Ilya Gubskiy
- Pirogov Russian National Research Medical University, Moscow, Russia
| | | | - Pavel Melnikov
- Pirogov Russian National Research Medical University, Moscow, Russia.,Serbsky Federal Medical Research Centre of Psychiatry and Narcology, Moscow, Russia
| | | | | | | | | | - Maxim Abakumov
- Pirogov Russian National Research Medical University, Moscow, Russia.,National University of Science and Technology, Moscow, Russia
| | | | | | - Vladimir Chekhonin
- Pirogov Russian National Research Medical University, Moscow, Russia.,Serbsky Federal Medical Research Centre of Psychiatry and Narcology, Moscow, Russia
| | - Leonid Gubsky
- Pirogov Russian National Research Medical University, Moscow, Russia
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27
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Lopes LCG, Galhardoni R, Silva V, Jorge FMH, Yeng LT, Callegaro D, Chadi G, Teixeira MJ, Ciampi de Andrade D. Beyond weakness: Characterization of pain, sensory profile and conditioned pain modulation in patients with motor neuron disease: A controlled study. Eur J Pain 2017; 22:72-83. [PMID: 28833988 DOI: 10.1002/ejp.1091] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/09/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND Motor neuron diseases (MND) represent a group of disorders that evolve with inexorable muscle weakness and medical management is based on symptom control. However, deeper characterization of non-motor symptoms in these patients have been rarely reported. METHODS This cross-sectional study aimed to describe non-motor symptoms in MND and their impact on quality of life and functional status, with a focus on pain and sensory changes. Eighty patients (31 females, 55.7 ± 12.9 years old) with MND underwent a neurological examination, pain, mood, catastrophizing and psychophysics assessments [quantitative sensory testing (QST) and conditioned pain modulation (CPM)], and were compared to sex- and age-matched healthy controls (HC). RESULTS Chronic pain was present in 46% of patients (VAS =5.18 ± 2.0). Pain of musculoskeletal origin occurred in 40.5% and was mainly located in the head/neck (51%) and lower back (35%). Neuropathic pain was not present in this sample. Compared to HC, MND patients had a lower cold detection threshold (p < 0.002), and significantly lower CPM scores (4.9 ± 0.2% vs. 22.1 ± 0.2%, p = 0.012). QST/CPM results did not differ between MND patients with and without pain. Pain intensity was statistically correlated with anxiety, depression and catastrophism, and spasticity scores were inversely correlated with CPM (ρ = -0.30, p = 0.026). CONCLUSIONS Pain is frequently reported by patients with MNDs. Somatosensory and CPM changes exist in MNDs and may be related to the neurodegenerative nature of the disease. Further studies should investigate the most appropriate treatment strategies for these patients. SIGNIFICANCE We report a comprehensive evaluation of pain and sensory abnormalities in motor neuron disease (MND) patients. We assessed the different pain syndromes present in MND with validated tools, and described the QST and conditioned pain modulation profiles in a controlled design.
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Affiliation(s)
- L C G Lopes
- Pain Center, Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira, São Paulo, Brazil.,Neurology Division, Department of Neurology, São Paulo State University (Unesp) Medical School, Botucatu, Brazil
| | - R Galhardoni
- Pain Center, Department of Neurology, University of São Paulo, Brazil.,Transcranial Magnetic Stimulation Laboratory, Psychiatry Institute, University of São Paulo, Brazil
| | - V Silva
- Transcranial Magnetic Stimulation Laboratory, Psychiatry Institute, University of São Paulo, Brazil
| | - F M H Jorge
- Neuroregeneration Center and ALS Brazil Project, Department of Neurology, University of São Paulo School of Medicine, Brazil
| | - L T Yeng
- Instituto de Ortopedia e Traumatologia, Division of Physical Medicine and Rehabilitation, University of São Paulo, Brazil
| | - D Callegaro
- Neuroimmunology Group, Department of Neurology, University of São Paulo, Brazil
| | - G Chadi
- Neuroregeneration Center and ALS Brazil Project, Department of Neurology, University of São Paulo School of Medicine, Brazil
| | - M J Teixeira
- Pain Center, Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira, São Paulo, Brazil.,Pain Center, Department of Neurology, University of São Paulo, Brazil.,Transcranial Magnetic Stimulation Laboratory, Psychiatry Institute, University of São Paulo, Brazil
| | - D Ciampi de Andrade
- Pain Center, Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira, São Paulo, Brazil.,Pain Center, Department of Neurology, University of São Paulo, Brazil.,Transcranial Magnetic Stimulation Laboratory, Psychiatry Institute, University of São Paulo, Brazil
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28
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Liu J, Wang F. Role of Neuroinflammation in Amyotrophic Lateral Sclerosis: Cellular Mechanisms and Therapeutic Implications. Front Immunol 2017; 8:1005. [PMID: 28871262 PMCID: PMC5567007 DOI: 10.3389/fimmu.2017.01005] [Citation(s) in RCA: 254] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2017] [Accepted: 08/07/2017] [Indexed: 12/13/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects upper motor neurons (MNs) comprising the corticospinal tract and lower MNs arising from the brain stem nuclei and ventral roots of the spinal cord, leading to fatal paralysis. Currently, there are no effective therapies for ALS. Increasing evidence indicates that neuroinflammation plays an important role in ALS pathogenesis. The neuroinflammation in ALS is characterized by infiltration of lymphocytes and macrophages, activation of microglia and reactive astrocytes, as well as the involvement of complement. In this review, we focus on the key cellular players of neuroinflammation during the pathogenesis of ALS by discussing not only their detrimental roles but also their immunomodulatory actions. We will summarize the pharmacological therapies for ALS that target neuroinflammation, as well as recent advances in the field of stem cell therapy aimed at modulating the inflammatory environment to preserve the remaining MNs in ALS patients and animal models of the disease.
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Affiliation(s)
- Jia Liu
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Fei Wang
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China
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29
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Zhong SJ, Gong YH, Lin YC. Combined intranasal nerve growth factor and ventricle neural stem cell grafts prolong survival and improve disease outcome in amyotrophic lateral sclerosis transgenic mice. Neurosci Lett 2017; 656:1-8. [PMID: 28694091 DOI: 10.1016/j.neulet.2017.07.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 05/29/2017] [Accepted: 07/05/2017] [Indexed: 12/12/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal disease that selectively involves motor neurons. Neurotrophic factor supplementation and neural stem cell (NSC) alternative therapy have been used to treat ALS. The two approaches can affect each other in their pathways of action, and there is a possibility for synergism. However, to date, there have been no studies demonstrating the effects of combined therapy in the treatment of ALS. In this study, for the first time, we adopted a method involving the intranasal administration of nerve growth factor combined with lateral ventricle NSC transplantation using G93A-SOD1 transgenic mice as experimental subjects to explore the treatment effect of this combined therapy in ALS. We discover that the combined therapy increase the quantity of TrkA receptors, broaden the migration of exogenous NSCs, further promote active proliferation in neurogenic regions of the brain and enhance the preservation of motor neurons in the spinal cord. Regarding physical activity, the combined therapy improved motor functions, further postponed ALS onset and extended the survival time of the mice.
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Affiliation(s)
- Shi-Jiang Zhong
- Department of Neurology, Logistic University Affiliated Hospital, Logistic University of Chinese People's Armed Police Force, Tianjin 300162, PR China
| | - Yan-Hua Gong
- Department of Biochemistry and Molecular Biology, Logistic University of the Chinese People's Armed Police Force, Tianjin, PR China
| | - Yan-Chen Lin
- Department of Neurology, Logistic University Affiliated Hospital, Logistic University of Chinese People's Armed Police Force, Tianjin 300162, PR China.
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