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Talukdar G, Duvick L, Yang P, O'Callaghan B, Fuchs GJ, Cvetanovic M, Orr HT. An expanded polyglutamine in ATAXIN1 results in a loss-of-function that exacerbates severity of Multiple Sclerosis in an EAE mouse model. J Neuroinflammation 2025; 22:127. [PMID: 40307815 PMCID: PMC12044863 DOI: 10.1186/s12974-025-03450-2] [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: 12/17/2024] [Accepted: 04/18/2025] [Indexed: 05/02/2025] Open
Abstract
BACKGROUND AND OBJECTIVES Ataxin-1 (ATXN1) is a protein in which expansion of its polyglutamine tract causes the neurodegenerative disorder spinocerebellar ataxia type 1 (SCA1) via a gain-of-function. Wild type ATXN1 was recently shown to have a protective role in regulating severity of experimental autoimmune encephalomyelitis (EAE), a well-established mouse model for Multiple sclerosis (MS). This study further investigates the role of ATXN1 with an expanded polyglutamine tract in the context of MS using an EAE mouse model. METHODS Hemizygous Atxn1 (Atxn12Q/-) mice or f-ATXN1146Q/2Q, heterozygous mice that have one copy of the endogenous mouse gene replaced with a polyQ expanded pathogenic human ATXN1 gene, were injected with myelin oligodendrocytes glycoprotein (MOG35 - 55) peptide to induce EAE. Immunohistochemical and biochemical approaches were used to analyze the degree of demyelination, cell loss, axonal degeneration as well as detecting the activated immune cells and inflammatory cytokines upon EAE induction in Atxn12Q/- and f-ATXN1146Q/2Q mice. RESULTS Our findings reveal that a loss-of-function of wild type Atxn1 in Atxn12Q/- and f-ATXN1146Q/2Q mice significantly exacerbates the EAE symptoms, leading to increased demyelination, oligodendrocytes loss, heightened axon degeneration, and greater clinical disability in affected mice. Importantly, the data reveals that neurotoxic astrocytes are activated at acute stage of disease (PID-14) and at the chronic stage of disease (PID-30) neurotoxic astrocytes no longer show signs of activation. The data also demonstrated enhanced infiltration of immune cells into the lesions of mutant mice. DISCUSSION These results indicate that ATXN1 plays a protective role in modulating immune responses and maintaining neural integrity during MS. Importantly, expansion of the polyQ tract in ATXN1 results in a loss-of-function in ATXN1's ability to dampen the immune response. Understanding the functional role of ATXN1 in MS pathogenesis may open new avenues for therapeutic strategies aimed at mitigating disease progression.
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MESH Headings
- Animals
- Encephalomyelitis, Autoimmune, Experimental/pathology
- Encephalomyelitis, Autoimmune, Experimental/genetics
- Encephalomyelitis, Autoimmune, Experimental/chemically induced
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Mice
- Ataxin-1/genetics
- Ataxin-1/metabolism
- Peptides/genetics
- Peptides/metabolism
- Mice, Transgenic
- Disease Models, Animal
- Mice, Inbred C57BL
- Female
- Multiple Sclerosis/pathology
- Multiple Sclerosis/genetics
- Multiple Sclerosis/metabolism
- Humans
- Myelin-Oligodendrocyte Glycoprotein/toxicity
- Peptide Fragments/toxicity
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Affiliation(s)
- Gourango Talukdar
- Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA
- Department of Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Lisa Duvick
- Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Praseuth Yang
- Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Brennon O'Callaghan
- Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Gavin J Fuchs
- Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA
- Department of Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Marija Cvetanovic
- Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA.
- Department of Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA.
| | - Harry T Orr
- Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA.
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA.
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Talukdar G, Duvick L, Yang P, O'Callaghan B, Fuchs GJ, Cvetanovic M, Orr HT. An expanded polyglutamine in ATAXIN1 results in a loss-of-function that exacerbates severity of Multiple Sclerosis in an EAE mouse model. RESEARCH SQUARE 2025:rs.3.rs-5664390. [PMID: 40321775 PMCID: PMC12047985 DOI: 10.21203/rs.3.rs-5664390/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/08/2025]
Abstract
Background and Objectives Ataxin-1 (ATXN1) is a protein in which expansion of its polyglutamine tract causes the neurodegenerative disorder spinocerebellar ataxia type 1 (SCA1) via a gain-of-function. Wild type ATXN1 was recently shown to have a protective role in regulating severity of experimental autoimmune encephalomyelitis (EAE), a well-established mouse model for Multiple sclerosis (MS). This study further investigates the role of ATXN1 with an expanded polyglutamine tract in the context of MS using an EAE mouse model. Methods Hemizygous Atxn1 (Atxn1 2Q/-) mice or f-ATXN1 146Q/2Q , heterozygous mice that have one copy of the endogenous mouse gene replaced with a polyQ expanded pathogenic human ATXN1 gene, were injected with myelin oligodendrocytes glycoprotein (MOG35 - 55) peptide to induce EAE. Immunohistochemical and biochemical approaches were used to analyze the degree of demyelination, cell loss, axonal degeneration as well as detecting the activated immune cells and inflammatory cytokines upon EAE induction in Atxn1 2Q/- and f-ATXN1 146Q/2Q mice. Results Our findings reveal that a loss-of-function of wild type Atxn1 in Atxn1 2Q/- and f-ATXN1 146Q/2Q mice significantly exacerbates the EAE symptoms, leading to increased demyelination, oligodendrocytes loss, heightened axon degeneration, and greater clinical disability in affected mice. Importantly, the data reveals that neurotoxic astrocytes are activated at acute stage of disease (PID-14) and at the chronic stage of disease (PID-30) neurotoxic astrocytes no longer show signs of activation. The data also demonstrated enhanced infiltration of immune cells into the lesions of mutant mice. Discussion These results indicate that ATXN1 plays a protective role in modulating immune responses and maintaining neural integrity during MS. Importantly, expansion of the polyQ tract in ATXN1 results in a loss-of-function in ATXN1's ability to dampen the immune response. Understanding the functional role of ATXN1 in MS pathogenesis may open new avenues for therapeutic strategies aimed at mitigating disease progression.
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Dai X, Fan Y, Zhao X. Systemic lupus erythematosus: updated insights on the pathogenesis, diagnosis, prevention and therapeutics. Signal Transduct Target Ther 2025; 10:102. [PMID: 40097390 PMCID: PMC11914703 DOI: 10.1038/s41392-025-02168-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 11/26/2024] [Accepted: 01/26/2025] [Indexed: 03/19/2025] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic inflammatory illness with heterogeneous clinical manifestations covering multiple organs. Diversified types of medications have been shown effective for alleviating SLE syndromes, ranging from cytokines, antibodies, hormones, molecular inhibitors or antagonists, to cell transfusion. Drugs developed for treating other diseases may benefit SLE patients, and agents established as SLE therapeutics may be SLE-inductive. Complexities regarding SLE therapeutics render it essential and urgent to identify the mechanisms-of-action and pivotal signaling axis driving SLE pathogenesis, and to establish innovative SLE-targeting approaches with desirable therapeutic outcome and safety. After introducing the research history of SLE and its epidemiology, we categorized primary determinants driving SLE pathogenesis by their mechanisms; combed through current knowledge on SLE diagnosis and grouped them by disease onset, activity and comorbidity; introduced the genetic, epigenetic, hormonal and environmental factors predisposing SLE; and comprehensively categorized preventive strategies and available SLE therapeutics according to their functioning mechanisms. In summary, we proposed three mechanisms with determinant roles on SLE initiation and progression, i.e., attenuating the immune system, restoring the cytokine microenvironment homeostasis, and rescuing the impaired debris clearance machinery; and provided updated insights on current understandings of SLE regarding its pathogenesis, diagnosis, prevention and therapeutics, which may open an innovative avenue in the fields of SLE management.
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Affiliation(s)
- Xiaofeng Dai
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P. R. China.
| | - Yuting Fan
- Tissue Engineering and Stem Cell Experiment Center, Tumor Immunotherapy Technology Engineering Research Center, Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550004, P. R. China
- Department of Gastroenterology, the Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, P. R. China
| | - Xing Zhao
- Tissue Engineering and Stem Cell Experiment Center, Tumor Immunotherapy Technology Engineering Research Center, Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550004, P. R. China.
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Li L, He Y, Zhao J, Yin H, Feng X, Fan X, Wu W, Lu Q. Mesenchymal Stromal Cell-Based Therapy: A Promising Approach for Autoimmune Diseases. Clin Rev Allergy Immunol 2025; 68:21. [PMID: 39982546 DOI: 10.1007/s12016-025-09030-9] [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] [Accepted: 02/04/2025] [Indexed: 02/22/2025]
Abstract
Autoimmune diseases are characterized by immune dysregulation, resulting in aberrant reactivity of T cells and antibodies to self-antigens, leading to various patterns of inflammation and organ dysfunction. However, current therapeutic agents exhibit broad-spectrum activity and lack disease-specific selectivity, leading to enduring adverse effects, notably severe infections, and malignancies, and patients often fail to achieve the intended clinical goals. Mesenchymal stromal cells (MSCs) are multipotent stromal cells that can be easily derived from various tissues, such as adipose tissue, umbilical cords, Wharton's jelly, placenta, and dental tissues. MSCs offer advantages due to their immunomodulatory and anti-inflammatory abilities, low immunogenicity, and a high capacity for proliferation and multipotent differentiation, making them excellent candidates for cell-based treatment in autoimmune disorders. This review will cover preclinical studies and clinical trials involving MSCs in autoimmune diseases, as well as the primary challenges associated with the clinical application of MSC therapies and strategies for maximizing their therapeutic potential.
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Affiliation(s)
- Liming Li
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research On Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
| | - Yong He
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Junpeng Zhao
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research On Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, China
| | - Huiqi Yin
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research On Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
| | - Xiwei Feng
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research On Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
| | - Xinyu Fan
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research On Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
| | - Wei Wu
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research On Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
| | - Qianjin Lu
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.
- Key Laboratory of Basic and Translational Research On Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China.
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Zhang Y, Gu J, Wang X, Li L, Fu L, Wang D, Wang X, Han X. Opportunities and challenges: mesenchymal stem cells in the treatment of multiple sclerosis. Int J Neurosci 2023; 133:1031-1044. [PMID: 35579409 DOI: 10.1080/00207454.2022.2042690] [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: 09/17/2021] [Revised: 01/08/2022] [Accepted: 02/09/2022] [Indexed: 10/18/2022]
Abstract
Multiple sclerosis (MS) was once considered an untreatable disease. Through years of research, many drugs have been discovered and are widely used for the treatment of MS. However, the current treatment can only alleviate the clinical symptoms of MS and has serious side effects. Mesenchymal stem cells (MSCs) provide neuroprotection by migrating to injured tissues, suppressing inflammation, and fostering neuronal repair. Therefore, MSCs therapy holds great promise for MS treatment. This review aimed to assess the feasibility and safety of use of MSCs in MS treatment as well as its development prospect in clinical treatment by analysing the existing clinical studies.
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Affiliation(s)
- Yingyu Zhang
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
| | - Jiebing Gu
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
| | - Xiaoshuang Wang
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
| | - Linfang Li
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
| | - Lingling Fu
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
| | - Di Wang
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
| | - Xiuting Wang
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
| | - Xuemei Han
- Department of Neurology, China-Japan Union hospital of Jilin University, Changchun city, Jilin, P.R. China
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Gugjoo MB, Sakeena Q, Wani MY, Abdel-Baset Ismail A, Ahmad SM, Shah RA. Mesenchymal stem cells: A promising antimicrobial therapy in veterinary medicine. Microb Pathog 2023; 182:106234. [PMID: 37442216 DOI: 10.1016/j.micpath.2023.106234] [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: 02/23/2023] [Revised: 05/18/2023] [Accepted: 07/04/2023] [Indexed: 07/15/2023]
Abstract
Growing antimicrobial resistance (AMR) is a threat to human and animal populations citing the limited available options. Alternative antimicrobial options or functional enhancement of currently available antimicrobials remains only options. One of the potential options seems stem cells especially the mesenchymal stem cells (MSCs) that show antimicrobial properties. These cells additionally have pro-healing effects that may plausibly improve healing outcomes. MSCs antimicrobial actions are mediated either through direct cell-cell contact or their secretome that enhances innate immune mediated antimicrobial activities. These cells synergistically enhance efficacy of currently available antimicrobials especially against the biofilms. Reciprocal action from antimicrobials on the MSCs functionality remains poorly understood. Currently, the main limitation with MSCs based therapy is their limited efficacy. This demands further understanding and can be enhanced through biotechnological interventions. One of the interventional options is the 'priming' to enhance MSCs resistance and specific expression potential. The available literature shows potential antimicrobial actions of MSCs both ex vivo as well as in vivo. The studies on veterinary species are very promising although limited by number and extensiveness in details for their utility as standard therapeutic agents. The current review aims to discuss the role of animals in AMR and the potential antimicrobial actions of MSCs in veterinary medicine. The review also discusses the limitations in their utilization as standard therapeutics.
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Affiliation(s)
| | - Qumaila Sakeena
- Division of Veterinary Surgery & Radiology, FVSc & AH, Shuhama, J&K, 190006, India
| | - Mohd Yaqoob Wani
- Directorate of Extension Education, SKUAST-K, Shalimar, J&K, 190025, India
| | - Ahmed Abdel-Baset Ismail
- Department of Surgery, Anaesthesiology and Radiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Sharkia, 44511, Egypt
| | - Syed Mudasir Ahmad
- Division of Animal Biotechnology, FVSc & AH, Shuhama, J&K, 190006, India
| | - Riaz Ahmad Shah
- Division of Animal Biotechnology, FVSc & AH, Shuhama, J&K, 190006, India
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Monsour M, Gordon J, Lockard G, Borlongan CV. Stem Cells Attenuate the Inflammation Crosstalk Between Ischemic Stroke and Multiple Sclerosis: A Review. Cell Transplant 2023; 32:9636897231184596. [PMID: 37515536 PMCID: PMC10387781 DOI: 10.1177/09636897231184596] [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: 01/17/2023] [Revised: 06/06/2023] [Accepted: 06/11/2023] [Indexed: 07/31/2023] Open
Abstract
The immense neuroinflammation induced by multiple sclerosis (MS) promotes a favorable environment for ischemic stroke (IS) development, making IS a deadly complication of MS. The overlapping inflammation in MS and IS is a prelude to the vascular pathology, and an inherent cell death mechanism that exacerbates neurovascular unit (NVU) impairment in the disease progression. Despite this consequence, no therapies focus on reducing IS incidence in patients with MS. To this end, the preclinical and clinical evidence we review here argues for cell-based regenerative medicine that will augment the NVU dysfunction and inflammation to ameliorate IS risk.
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Affiliation(s)
- Molly Monsour
- Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Jonah Gordon
- Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Gavin Lockard
- Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Cesar V Borlongan
- Center of Excellence for Aging & Brain Repair, Department of Neurosurgery & Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
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Human Fallopian Tube - Derived Mesenchymal Stem Cells Inhibit Experimental Autoimmune Encephalomyelitis by Suppressing Th1/Th17 Activation and Migration to Central Nervous System. Stem Cell Rev Rep 2021; 18:609-625. [PMID: 34453694 DOI: 10.1007/s12015-021-10226-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2021] [Indexed: 10/20/2022]
Abstract
Mesenchymal stem cells comprise a natural reservoir of undifferentiated cells within adult tissues. Given their self-renewal, multipotency, regenerative potential and immunomodulatory properties, MSCs have been reported as a promising cell therapy for the treatment of different diseases, including neurodegenerative and autoimmune diseases. In this study, we investigated the immunomodulatory properties of human tubal mesenchymal stem cells (htMSCs) using the EAE model. htMSCs were able to suppress dendritic cells activation downregulating antigen presentation-related molecules, such as MHCII, CD80 and CD86, while impairing IFN-γ and IL-17 and increasing IL-10 and IL-4 secretion. It further correlated with milder disease scores when compared to the control group due to fewer leukocytes infiltrating the CNS, specially Th1 and Th17 lymphocytes, associated with increased IL-10 secreting Tr1 cells. Conversely, microglia were less activated and infiltrating mononuclear cells secreted higher levels of IL-4 and IL-10 and expressed reduced chemokine receptors as CCR4, CCR6 and CCR8. qPCR of the spinal cords revealed upregulation of indoleamine-2,3-dioxygenase (IDO) and brain derived neurotrophic factor (BDNF). Taken together, here evidenced the potential of htMSCs as an alternative for the treatment of inflammatory, autoimmune or neurodegenerative diseases.
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Progress in Mesenchymal Stem Cell Therapy for Ischemic Stroke. Stem Cells Int 2021; 2021:9923566. [PMID: 34221026 PMCID: PMC8219421 DOI: 10.1155/2021/9923566] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/27/2021] [Accepted: 06/03/2021] [Indexed: 12/12/2022] Open
Abstract
Ischemic stroke (IS) is a serious cerebrovascular disease with high morbidity and disability worldwide. Despite the great efforts that have been made, the prognosis of patients with IS remains unsatisfactory. Notably, recent studies indicated that mesenchymal stem cell (MSCs) therapy is becoming a novel research hotspot with large potential in treating multiple human diseases including IS. The current article is aimed at reviewing the progress of MSC treatment on IS. The mechanism of MSCs in the treatment of IS involved with immune regulation, neuroprotection, angiogenesis, and neural circuit reconstruction. In addition, nutritional cytokines, mitochondria, and extracellular vesicles (EVs) may be the main mediators of the therapeutic effect of MSCs. Transplantation of MSCs-derived EVs (MSCs-EVs) affords a better neuroprotective against IS when compared with transplantation of MSCs alone. MSC therapy can prolong the treatment time window of ischemic stroke, and early administration within 7 days after stroke may be the best treatment opportunity. The deliver routine consists of intraventricular, intravascular, intranasal, and intraperitoneal. Furthermore, several methods such as hypoxic preconditioning and gene technology could increase the homing and survival ability of MSCs after transplantation. In addition, MSCs combined with some drugs or physical therapy measures also show better neurological improvement. These data supported the notion that MSC therapy might be a promising therapeutic strategy for IS. And the application of new technology will promote MSC therapy of IS.
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Failed, Interrupted, or Inconclusive Trials on Neuroprotective and Neuroregenerative Treatment Strategies in Multiple Sclerosis: Update 2015-2020. Drugs 2021; 81:1031-1063. [PMID: 34086251 PMCID: PMC8217012 DOI: 10.1007/s40265-021-01526-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/15/2021] [Indexed: 02/06/2023]
Abstract
In the recent past, a plethora of drugs have been approved for the treatment of multiple sclerosis (MS). These therapeutics are mainly confined to immunomodulatory or immunosuppressive strategies but do not sufficiently address remyelination and neuroprotection. However, several neuroregenerative agents have shown potential in pre-clinical research and entered Phase I to III clinical trials. Although none of these compounds have yet proceeded to approval, understanding the causes of failure can broaden our knowledge about neuroprotection and neuroregeneration in MS. Moreover, most of the investigated approaches are characterised by consistent mechanisms of action and proved convincing efficacy in animal studies. Therefore, learning from their failure will help us to enforce the translation of findings acquired in pre-clinical studies into clinical application. Here, we summarise trials on MS treatment published since 2015 that have either failed or were interrupted due to a lack of efficacy, adverse events, or for other reasons. We further outline the rationale underlying these drugs and analyse the background of failure to gather new insights into MS pathophysiology and optimise future study designs. For conciseness, this review focuses on agents promoting remyelination and medications with primarily neuroprotective properties or unconventional approaches. Failed clinical trials that pursue immunomodulation are presented in a separate article.
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Zhang L, Lu X, Gong L, Cui L, Zhang H, Zhao W, Jiang P, Hou G, Hou Y. Tetramethylpyrazine Protects Blood-Spinal Cord Barrier Integrity by Modulating Microglia Polarization Through Activation of STAT3/SOCS3 and Inhibition of NF-кB Signaling Pathways in Experimental Autoimmune Encephalomyelitis Mice. Cell Mol Neurobiol 2021; 41:717-731. [PMID: 32424774 PMCID: PMC11448626 DOI: 10.1007/s10571-020-00878-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 05/12/2020] [Indexed: 01/24/2023]
Abstract
We previously reported that tetramethylpyrazine (TMP) alleviates experimental autoimmune encephalomyelitis (EAE) by decreasing glia activation. Activated microglia has been shown to mediate blood-spinal cord barrier (BSCB) disruption, which is a primary and continuous pathological characteristic of multiple sclerosis (MS). Therefore, in this study, we further investigated whether TMP protects the BSCB integrity by inhibition of glia activation to alleviate EAE. Extravasation of evans blue was used to detect the BSCB disruption. Tumor necrosis factor-α (TNF-α)/interlukine-1β (IL-1β) and interlukine-4 (IL-4)/interlukine-10 (IL-10) were determined by enzyme-linked immunosorbent assay. BV2 glial cells stimulated by interferon-γ (IFN-γ) were co-cultured with human brain microvascular endothelial cells to investigate the effect of TMP on the BSCB disruption. Flow cytometry was used to analyze the microglia phenotype. Western blot was performed to reveal the signaling pathways involved in the microglia activation. In this study, most importantly, we found that TMP protects the BSCB integrity by modulating microglia polarization from M1 phenotype to M2 phenotype through activation of STAT3/SOCS3 and inhibition of NF-кB signaling pathways. Moreover, TMP significantly preserves the tight junction proteins, reduces the secretion of pro-inflammatory cytokines (TNF-α, IL-1β) and increases the secretion of anti-inflammatory cytokines (IL-4, IL-10) from IFN-γ-stimulated BV2 microglia cells. Consequently, protection of the BSCB integrity leads to alleviation of clinical symptoms and demyelination in EAE mice. Therefore, TMP might be an effective therapeutic agent for cerebral disorders with BBB or BSCB disruption, such as ischemic stroke, MS, and traumatic brain injury.
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Affiliation(s)
- Lianshuang Zhang
- Department of Histology and Embryology, Binzhou Medical University, Yantai, 264003, People's Republic of China
| | - Xueyan Lu
- Department of Histology and Embryology, Binzhou Medical University, Yantai, 264003, People's Republic of China
| | - Lihua Gong
- Department of Histology and Embryology, Binzhou Medical University, Yantai, 264003, People's Republic of China
| | - Linlu Cui
- Department of Histology and Embryology, Binzhou Medical University, Yantai, 264003, People's Republic of China
| | - Hongqin Zhang
- Department of Histology and Embryology, Binzhou Medical University, Yantai, 264003, People's Republic of China
| | - Wei Zhao
- Department of Histology and Embryology, Binzhou Medical University, Yantai, 264003, People's Republic of China
| | - Pengyu Jiang
- Department of Histology and Embryology, Binzhou Medical University, Yantai, 264003, People's Republic of China
| | - GuiGe Hou
- The Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, Binzhou Medical University, Yantai, 264003, People's Republic of China.
| | - Yun Hou
- Department of Histology and Embryology, Binzhou Medical University, Yantai, 264003, People's Republic of China.
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Sun Y, Zhou YQ, Liu YK, Zhang HQ, Hou GG, Meng QG, Hou Y. Potential anti-neuroinflammatory NF-кB inhibitors based on 3,4-dihydronaphthalen-1(2 H)-one derivatives. J Enzyme Inhib Med Chem 2021; 35:1631-1640. [PMID: 32781863 PMCID: PMC7470122 DOI: 10.1080/14756366.2020.1804899] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Nuclear factor kappa B (NF-кB) inhibition represents a new therapeutic strategy for the treatment of neuroinflammatory diseases. In this study, a series of 3,4-dihydronaphthalen-1(2H)-one (DHN; 6a-n, 7a-c) derivatives were synthesised and characterised by NMR and HRMS. We assessed the toxicity and anti-neuroinflammatory properties of these compounds and found that 6m showed the greatest anti-neuroinflammatory properties, with relatively low toxicity. Specifically, 6m significantly reduced reactive oxygen species production, down-regulated the expression of NOD-like receptor pyrin domain-containing protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), and caspase-1 and prevented lipopolysaccharide-stimulated BV2 microglia cells polarisation towards an M1 phenotype. Furthermore, 6m significantly decreased IκBα and NF-кB p65 phosphorylation, thus inhibiting the NF-кB signalling pathway. This suggests that 6m may be explored as a functional anti-neuroinflammatory agent for the treatment of inflammatory diseases in the central nervous system, such as multiple sclerosis, traumatic brain injury, stroke and spinal cord injury.
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Affiliation(s)
- Yue Sun
- The Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, School of Pharmacy, Binzhou Medical University, Yantai, P. R. China
| | - Yan-Qiu Zhou
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, P. R. China
| | - Yin-Kai Liu
- The Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, School of Pharmacy, Binzhou Medical University, Yantai, P. R. China
| | - Hong-Qin Zhang
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, P. R. China
| | - Gui-Ge Hou
- The Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, School of Pharmacy, Binzhou Medical University, Yantai, P. R. China
| | - Qing-Guo Meng
- School of Pharmacy, Yantai University, Yantai, P. R. China
| | - Yun Hou
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, P. R. China
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13
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Tsai MJ, Liou DY, Chu YC, Chen Y, Huang MC, Huang WC, Cheng H, Tsai SK, Huang SS. Minocycline exhibits synergism with conditioned medium of bone marrow mesenchymal stem cells against ischemic stroke. J Tissue Eng Regen Med 2021; 15:279-292. [PMID: 33470523 DOI: 10.1002/term.3171] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 11/29/2020] [Accepted: 12/15/2020] [Indexed: 12/15/2022]
Abstract
Several lines of evidence show that a conditioned medium of bone marrow mesenchymal stem cells (BM-MSCcm) improve functional recovery after ischemic stroke but do not reduce ischemic lesions. It is important to develop a treatment strategy that can exhibit a synergistic effect with BM-MSCcm against ischemic stroke. In this study, the effect of BM-MSCcm and/or minocycline was examined in culture and in a middle cerebral artery occlusion (MCAo) animal model. In neuron-glial cultures, BM-MSCcm and combined treatment, but not minocycline, effectively increased neuronal connection and oligodendroglial survival. In contrast, minocycline and combined treatment, but not BM-MSCcm, reduced toxin-induced free radical production in cultures. Either minocycline or BM-MSCcm, or in combination, conferred protective effects against oxygen glucose deprivation-induced cell damage. In an in vivo study, BM-MSCcm and minocycline were administered to rats 2 h after MCAo. Monotherapy with BM-MSCcm or minocycline after ischemic stroke resulted in 9.4% or 17.5% reduction in infarction volume, respectively, but there was no significant difference. Interestingly, there was a 33.9% significant reduction in infarction volume by combined treatment with BM-MSCcm and minocycline in an in vivo study. The combined therapy also significantly improved grasping power, which was not altered by monotherapy. Furthermore, combined therapy increased the expression of neuronal nuclei in the peri-infarct area and hippocampus, and concurrently decreased the expression of ED1 in rat brain and the peri-infarct zone. Our data suggest that minocycline exhibits a synergistic effect with BM-MSCcm against ischemic stroke not only to improve neurological functional outcome but also to reduce cerebral infarction.
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Affiliation(s)
- May-Jywan Tsai
- Department of Neurosurgery, Neural Regeneration Laboratory, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Dann-Ying Liou
- Department of Neurosurgery, Neural Regeneration Laboratory, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ya-Chun Chu
- Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Yi Chen
- Department of Neurosurgery, Neural Regeneration Laboratory, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ming-Chao Huang
- Department of Neurosurgery, Neural Regeneration Laboratory, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Wen-Cheng Huang
- Department of Neurosurgery, Neural Regeneration Laboratory, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, National Yang-Ming University, Taipei, Taiwan.,Center for Neural Regeneration, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Henrich Cheng
- Department of Neurosurgery, Neural Regeneration Laboratory, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, National Yang-Ming University, Taipei, Taiwan.,Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.,Center for Neural Regeneration, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shen-Kou Tsai
- Department of Anesthesiology, Cheng-Hsin General Hospital, Taipei, Taiwan
| | - Shiang-Suo Huang
- Department of Pharmacology and Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan
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14
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Zhang XF, Wang HY, Zhao SN, Zhang SN, Zhao FL, Meng QG. Crystal structure of ( E)-2-(4-fluoro-3-(trifluoromethyl)benzylidene)-7-methoxy-3,4-dihydronaphthalen-1(2 H)-one, C 19H 14F 4O 2. Z KRIST-NEW CRYST ST 2021. [DOI: 10.1515/ncrs-2020-0448] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Abstract
C
19
H
14
F
4
O
2
${\text{C}}_{19}{\text{H}}_{14}{\text{F}}_{4}{\text{O}}_{2}$
, triclinic,
P
1
‾
$P‾{1}$
(no. 2), a = 8.1539(7) Å, b = 8.8584(6) Å, c = 11.8025(9) Å, α = 73.186(7)°, β = 76.184(7)°, γ = 69.512(7)°, V = 755.39(11) Å3, Z = 2,
R
g
t
${R}_{gt}$
(F) = 0.0436,
w
R
ref
$w{R}_{\text{ref}}$
(F
2) = 0.0965, T = 100 K.
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Affiliation(s)
- Xiao-Fan Zhang
- School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University , Yantai , PR China
| | - Hui-yun Wang
- College of Pharmacy, Jining Medical University , Rizhao , 276826 , PR China
| | - Sheng-Nan Zhao
- School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University , Yantai , PR China
| | - Sheng-Nan Zhang
- School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University , Yantai , PR China
| | - Feng-Lan Zhao
- School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University , Yantai , PR China
| | - Qing-Guo Meng
- School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University , Yantai , PR China
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15
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Russell KA, Garbin LC, Wong JM, Koch TG. Mesenchymal Stromal Cells as Potential Antimicrobial for Veterinary Use-A Comprehensive Review. Front Microbiol 2020; 11:606404. [PMID: 33335522 PMCID: PMC7736177 DOI: 10.3389/fmicb.2020.606404] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 11/10/2020] [Indexed: 12/13/2022] Open
Abstract
The emergence of “superbugs” resistant to antimicrobial medications threatens populations both veterinary and human. The current crisis has come about from the widespread use of the limited number of antimicrobials available in the treatment of livestock, companion animal, and human patients. A different approach must be sought to find alternatives to or enhancements of present conventional antimicrobials. Mesenchymal stromal cells (MSC) have antimicrobial properties that may help solve this problem. In the first part of the review, we explore the various mechanisms at work across species that help explain how MSCs influence microbial survival. We then discuss the findings of recent equine, canine, and bovine studies examining MSC antimicrobial properties in which MSCs are found to have significant effects on a variety of bacterial species either alone or in combination with antibiotics. Finally, information on the influence that various antimicrobials may have on MSC function is reviewed. MSCs exert their effect directly through the secretion of various bioactive factors or indirectly through the recruitment and activation of host immune cells. MSCs may soon become a valuable tool for veterinarians treating antimicrobial resistant infections. However, a great deal of work remains for the development of optimal MSC production conditions and testing for efficacy on different indications and species.
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Affiliation(s)
- Keith A Russell
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
| | - Livia C Garbin
- Clinical Veterinary Sciences Department, School of Veterinary Medicine, Faculty of Medical Sciences, The University of the West Indies, St. Augustine, West Indies
| | - Jonathan M Wong
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
| | - Thomas G Koch
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
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16
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Yanwu Y, Meiling G, Yunxia Z, Qiukui H, Birong D. Mesenchymal stem cells in experimental autoimmune encephalomyelitis model of multiple sclerosis: A systematic review and meta-analysis. Mult Scler Relat Disord 2020; 44:102200. [PMID: 32535500 DOI: 10.1016/j.msard.2020.102200] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 05/05/2020] [Accepted: 05/11/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIMS Mesenchymal stem cells (MSCs) transplantation has been considered a possible therapeutic method for Multiple Sclerosis (MS). However, no quantitative data synthesis of MSCs therapy for MS exists. We conducted a systematic review and meta-analysis to evaluate the effects of MSCs in experimental autoimmune encephalomyelitis (EAE) animal model of MS. METHODS We identified eligible studies published from January 1980 to January 2017 by searching four electronic databases (PubMed, MEDLINE, Embase and Web of Science). The outcome was the effects of MSCs on clinical performance evaluated by the EAE clinical score. RESULTS 36 preclinical studies including 675 animals in MSCs treatment group, and 693 animals in control group were included in this meta-analysis. We found that MSCs transplantation significantly ameliorated the symptoms and delayed the disease progression (SMD = -1.25, 95% CI: -1.45 to -1.05, P < 0.001). However, no significant differences in effect sizes were unveiled relative to clinical score standard (P = 0.35), type of MSCs (P = 0.35), source of MSCs (P = 0.06), MSCs dose (P = 0.44), delivery methods (P = 0.31) and follow up period (P = 0.73). CONCLUSIONS The current study showed that MSCs transplantation could ameliorate clinical performance in EAE animal model of MS. These findings support the further studies translate MSCs to treat MS in humans.
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Affiliation(s)
- Yang Yanwu
- Department of Neurosurgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Ge Meiling
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37 Guoxue Lane, Wuhou District, Chengdu 610041, Sichuan, China
| | - Zhang Yunxia
- Department of Geriatric, Sichuan Science City Hospital, No. 64, Mianshan Road, Mianyang, Sichuan, China
| | - Hao Qiukui
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37 Guoxue Lane, Wuhou District, Chengdu 610041, Sichuan, China
| | - Dong Birong
- Department of Neurosurgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China; National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37 Guoxue Lane, Wuhou District, Chengdu 610041, Sichuan, China; Department of Geriatric, Sichuan Science City Hospital, No. 64, Mianshan Road, Mianyang, Sichuan, China.
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17
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Zhang L, Wang X, Lu X, Ma Y, Xin X, Xu X, Wang S, Hou Y. Tetramethylpyrazine enhanced the therapeutic effects of human umbilical cord mesenchymal stem cells in experimental autoimmune encephalomyelitis mice through Nrf2/HO-1 signaling pathway. Stem Cell Res Ther 2020; 11:186. [PMID: 32430010 PMCID: PMC7238657 DOI: 10.1186/s13287-020-01700-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 04/15/2020] [Accepted: 04/28/2020] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION The therapeutic effects of mesenchymal stem cells (MSCs) have been limited by their apoptosis induced by oxidative stress after delivery into the injured sites. Therefore, strategies designed to improve the MSC therapeutic efficacy need to be explored. Tetramethylpyrazine (TMP) can promote the proliferation and differentiation of neural stem cells. In this study, we first evaluated the effects and mechanism of TMP on H2O2-stimulated human umbilical cord MSCs (hUCMSCs) and then further investigated the therapeutic effects of TMP-stimulated hUCMSCs on experimental autoimmune encephalomyelitis (EAE) mice. METHODS The toxicity of hUCMSCs against of TMP was determined by cell count kit-8 (CCK-8) assay. The effects of TMP on the hUCMSC cell cycle, the reactive oxygen species (ROS) production, and the apoptosis of H2O2-stimulated hUCMSCs were determined by flow cytometry. The expression of malondialdehyde (MDA) and superoxide dismutase (SOD) were also measured by colorimetry. The signaling pathway of TMP induced on H2O2-stimulated hUCMSCs was investigated by western blot. EAE was induced using immunization with MOG35-55 in C57BL/6 mice. The inflammatory cell infiltration and demyelination were detected by immunofluorescence staining. The blood-brain barrier (BBB) disruption was detected by Evans blue (EB) stain and the expression of tight junction protein (ZO-1) by western blot. RESULTS TMP significantly increased cell viability and changed the cell cycle of hUCMSCs. In addition, TMP (100 μM) significantly reduced intracellular ROS production, expression of MDA, and apoptosis, but increased expression of SOD through nuclear factor-erythroid 2-related factor-2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathway in H2O2-stimulated hUCMSCs. Most importantly, compared with wild hUCMSCs, TMP-stimulated hUCMSCs significantly ameliorated EAE, by attenuation of inflammation, demyelination, and BBB disruption. CONCLUSION The TMP-stimulated hUCMSCs provide a potential therapeutical protocol to enhance the therapeutic effects of hUCMSCs in multiple sclerosis.
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Affiliation(s)
- Lianshuang Zhang
- Department of Histology and Embryology, College of Basic Medicine, Binzhou Medical University, Yantai, China
| | - Xifeng Wang
- Department of Critical Care Medicine, Yu Huang Ding Hospital, Qingdao University, Yantai, China
| | - Xueyan Lu
- Department of Histology and Embryology, College of Basic Medicine, Binzhou Medical University, Yantai, China
| | - Yanchao Ma
- Department of Immunology, College of Basic Medicine, Binzhou Medical University, Yantai, China
| | - Xin Xin
- Department of Histology and Embryology, College of Basic Medicine, Binzhou Medical University, Yantai, China
| | - Xiaomin Xu
- Department of Histology and Embryology, College of Basic Medicine, Binzhou Medical University, Yantai, China
| | - Siyuan Wang
- Department of Histology and Embryology, College of Basic Medicine, Binzhou Medical University, Yantai, China
| | - Yun Hou
- Department of Histology and Embryology, College of Basic Medicine, Binzhou Medical University, Yantai, China.
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18
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Hendricks K, Parrado MG, Bradley J. Opinion: An Existing Drug to Assess In Vivo for Potential Adjunctive Therapy of Ebola Virus Disease and Post-Ebola Syndrome. Front Pharmacol 2020; 10:1691. [PMID: 32082173 PMCID: PMC7002323 DOI: 10.3389/fphar.2019.01691] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 12/24/2019] [Indexed: 01/02/2023] Open
Affiliation(s)
| | | | - John Bradley
- Division of Infectious Diseases, Department of Pediatrics, UCSD School of Medicine, San Diego, CA, United States
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19
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Cho DY, Jeun SS. Combination therapy of human bone marrow-derived mesenchymal stem cells and minocycline improves neuronal function in a rat middle cerebral artery occlusion model. Stem Cell Res Ther 2018; 9:309. [PMID: 30413178 PMCID: PMC6230290 DOI: 10.1186/s13287-018-1011-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 09/07/2018] [Accepted: 09/17/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The positive effects of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) and minocycline on ischemic stroke models have been well described through numerous studies. The aim of this study was to evaluate the effectiveness of combination therapy of hBM-MSCs with minocycline in a middle cerebral artery occlusion rat model. METHODS Forty male Sprague-Dawley rats were enrolled in this study. After right middle cerebral artery occlusion, rats were randomly assigned to one of four groups: control, minocycline, hBM-MSCs, or hBM-MSCs with minocycline. Rotarod test, adhesive-removal test, and modified neurological severity score grading were performed before and 1, 7, 14, 21, and 28 days after right middle cerebral artery occlusion. All rats were sacrificed at day 28. The volume of the infarcted area was measured with triphenyl tetrazolium chloride staining. Neuronal nuclear antigen (NeuN)- and vascular endothelial growth factor (VEGF)-positive cells in the ischemic boundary zone were assessed by immunofluorescence. RESULTS Neurological outcome in the adhesive-removal test and rotarod test and modified neurological severity score were better in the combination therapy group than in the monotherapy and control groups. The volume of the infarcted area was smaller in the combination group compared with the others. The proportions of NeuN- and VEGF-positive cells in the ischemic boundary were highest in the combination therapy group. CONCLUSIONS Early combination therapy of hBM-MSCs with minocycline in an ischemic stroke model may enhance neurological recovery, reduce the volume of the infarcted area, and promote the expression of NeuN and VEGF in ischemic boundary cells.
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Affiliation(s)
- Dong Young Cho
- Department of Neurosurgery, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 137-701, Korea
| | - Sin-Soo Jeun
- Department of Neurosurgery, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 137-701, Korea. .,Department of Biomedical Science, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 137-701, Korea.
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20
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Leyendecker A, Pinheiro CCG, Amano MT, Bueno DF. The Use of Human Mesenchymal Stem Cells as Therapeutic Agents for the in vivo Treatment of Immune-Related Diseases: A Systematic Review. Front Immunol 2018; 9:2056. [PMID: 30254638 PMCID: PMC6141714 DOI: 10.3389/fimmu.2018.02056] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 08/21/2018] [Indexed: 12/13/2022] Open
Abstract
Background: One of the greatest challenges for medicine is to find a safe and effective treatment for immune-related diseases. However, due to the low efficacy of the treatment available and the occurrence of serious adverse effects, many groups are currently searching for alternatives to the traditional therapy. In this regard, the use of human mesenchymal stem cells (hMSCs) represents a great promise for the treatment of a variety of immune-related diseases due to their potent immunomodulatory properties. The main objective of this study is, therefore, to present and summarize, through a systematic review of the literature, in vivo studies in which the efficacy of the administration of hMSCs for the treatment of immune-related diseases was evaluated. Methods: The article search was conducted in PubMed/MEDLINE, Scopus and Web of Science databases. Original research articles assessing the therapeutic potential of hMSCs administration for the in vivo treatment immune-related diseases, published from 1984 to December 2017, were selected and evaluated. Results: A total of 132 manuscripts formed the basis of this systematic review. Most of the studies analyzed reported positive results after hMSCs administration. Clinical effects commonly observed include an increase in the survival rates and a reduction in the severity and incidence of the immune-related diseases studied. In addition, hMSCs administration resulted in an inhibition in the proliferation and activation of CD19+ B cells, CD4+ Th1 and Th17 cells, CD8+ T cells, NK cells, macrophages, monocytes, and neutrophils. The clonal expansion of both Bregs and Tregs cells, however, was stimulated. Administration of hMSCs also resulted in a reduction in the levels of pro-inflammatory cytokines such as IFN-γ, TNF-α, IL-1, IL-2, IL-12, and IL-17 and in an increase in the levels of immunoregulatory cytokines such as IL-4, IL-10, and IL-13. Conclusions: The results obtained in this study open new avenues for the treatment of immune-related diseases through the administration of hMSCs and emphasize the importance of the conduction of further studies in this area.
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21
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Bai XY, Wang XF, Zhang LS, Du PC, Cao Z, Hou Y. Tetramethylpyrazine ameliorates experimental autoimmune encephalomyelitis by modulating the inflammatory response. Biochem Biophys Res Commun 2018; 503:1968-1972. [PMID: 30078676 DOI: 10.1016/j.bbrc.2018.07.143] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 07/28/2018] [Indexed: 12/26/2022]
Abstract
Multiple sclerosis (MS) is a disabling inflammatory and demyelinating disorder of the central nervous system. Tetramethylpyrazine (TMP) has been demonstrated to ameliorate cerebral ischemic injury and spinal cord injury by inhibiting inflammatory cell activation and pro-inflammatory cytokine production. However, the effects of TMP on MS have not been studied. In this study, we evaluated the effects of TMP on the inflammatory response in experimental autoimmune encephalomyelitis (EAE), which is an animal model of MS. TMP (30 mg/kg) treatment significantly reduced the expression levels of NLR Family, Pyrin Domain-Containing 3 Protein inflammasome and caspase-1and decreased inflammatory infiltration and glial activation. Moreover, TMP (30 mg/kg) suppressed the expression of pro-inflammatory cytokines (interleukin-18 [IL-18] and IL-17) and promoted the expression of an anti-inflammatory cytokine (IL-10). The reduced inflammatory response resulted in improvement in clinical scores and decreased demyelination in EAE mice. Therefore, our results demonstrate that TMP (30 mg/kg) improved functional recovery in part by reducing inflammation in EAE mice. TMP may be a potential therapeutic agent for MS therapy.
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Affiliation(s)
- Xian-Yong Bai
- Department of Histology and Embryology, Binzhou Medical University, Yantai, PR China
| | - Xi-Feng Wang
- Department of Critical Care Medicine, Yu Huang Ding Hospital, Qingdao University, Yantai, PR China
| | - Lian-Shuang Zhang
- Department of Histology and Embryology, Binzhou Medical University, Yantai, PR China
| | - Peng-Chao Du
- Department of Pathology, Binzhou Medical University, Yantai, PR China
| | - Zhang Cao
- Department of Pathology, Binzhou Medical University, Yantai, PR China
| | - Yun Hou
- Department of Histology and Embryology, Binzhou Medical University, Yantai, PR China.
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22
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Stem Cells as Potential Targets of Polyphenols in Multiple Sclerosis and Alzheimer's Disease. BIOMED RESEARCH INTERNATIONAL 2018; 2018:1483791. [PMID: 30112360 PMCID: PMC6077677 DOI: 10.1155/2018/1483791] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 06/19/2018] [Indexed: 12/16/2022]
Abstract
Alzheimer's disease (AD) and multiple sclerosis are major neurodegenerative diseases, which are characterized by the accumulation of abnormal pathogenic proteins due to oxidative stress, mitochondrial dysfunction, impaired autophagy, and pathogens, leading to neurodegeneration and behavioral deficits. Herein, we reviewed the utility of plant polyphenols in regulating proliferation and differentiation of stem cells for inducing brain self-repair in AD and multiple sclerosis. Firstly, we discussed the genetic, physiological, and environmental factors involved in the pathophysiology of both the disorders. Next, we reviewed various stem cell therapies available and how they have proved useful in animal models of AD and multiple sclerosis. Lastly, we discussed how polyphenols utilize the potential of stem cells, either complementing their therapeutic effects or stimulating endogenous and exogenous neurogenesis, against these diseases. We suggest that polyphenols could be a potential candidate for stem cell therapy against neurodegenerative disorders.
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23
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Jankowsky JL, Zheng H. Practical considerations for choosing a mouse model of Alzheimer's disease. Mol Neurodegener 2017; 12:89. [PMID: 29273078 PMCID: PMC5741956 DOI: 10.1186/s13024-017-0231-7] [Citation(s) in RCA: 318] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Accepted: 12/07/2017] [Indexed: 01/06/2023] Open
Abstract
Alzheimer’s disease (AD) is behaviorally identified by progressive memory impairment and pathologically characterized by the triad of β-amyloid plaques, neurofibrillary tangles, and neurodegeneration. Genetic mutations and risk factors have been identified that are either causal or modify the disease progression. These genetic and pathological features serve as basis for the creation and validation of mouse models of AD. Efforts made in the past quarter-century have produced over 100 genetically engineered mouse lines that recapitulate some aspects of AD clinicopathology. These models have been valuable resources for understanding genetic interactions that contribute to disease and cellular reactions that are engaged in response. Here we focus on mouse models that have been widely used stalwarts of the field or that are recently developed bellwethers of the future. Rather than providing a summary of each model, we endeavor to compare and contrast the genetic approaches employed and to discuss their respective advantages and limitations. We offer a critical account of the variables which may contribute to inconsistent findings and the factors that should be considered when choosing a model and interpreting the results. We hope to present an insightful review of current AD mouse models and to provide a practical guide for selecting models best matched to the experimental question at hand.
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Affiliation(s)
- Joanna L Jankowsky
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, 77030, USA. .,Department of Neurology, Baylor College of Medicine, Houston, TX, 77030, USA. .,Department of Neurosurgery, Baylor College of Medicine, Houston, TX, 77030, USA. .,Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. .,Huffington Center on Aging, Baylor College of Medicine, Houston, TX, 77030, USA.
| | - Hui Zheng
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, 77030, USA. .,Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. .,Huffington Center on Aging, Baylor College of Medicine, Houston, TX, 77030, USA. .,Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
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Guerra AD, Rose WE, Hematti P, Kao WJ. Minocycline modulates NFκB phosphorylation and enhances antimicrobial activity against Staphylococcus aureus in mesenchymal stromal/stem cells. Stem Cell Res Ther 2017; 8:171. [PMID: 28732530 PMCID: PMC5521110 DOI: 10.1186/s13287-017-0623-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 06/05/2017] [Accepted: 06/28/2017] [Indexed: 02/06/2023] Open
Abstract
Background Mesenchymal stromal/stem cells (MSCs) have demonstrated pro-healing properties due to their anti-inflammatory, angiogenic, and even antibacterial properties. We have shown previously that minocycline enhances the wound healing phenotype of MSCs, and MSCs encapsulated in poly(ethylene glycol) and gelatin-based hydrogels with minocycline have antibacterial properties against Staphylococcus aureus (SA). Here, we investigated the signaling pathway that minocycline modulates in MSCs which results in their enhanced wound healing phenotype and determined whether preconditioning MSCs with minocycline has an effect on antimicrobial activity. We further investigated the in-vivo antimicrobial efficacy of MSC and antibiotic-loaded hydrogels in inoculated full-thickness cutaneous wounds. Methods Modulation of cell signaling pathways in MSCs with minocycline was analyzed via western blot, immunofluorescence, and ELISA. Antimicrobial efficacy of MSCs pretreated with minocycline was determined by direct and transwell coculture with SA. MSC viability after SA coculture was determined via a LIVE/DEAD® stain. Internalization of SA by MSCs pretreated with minocycline was determined via confocal imaging. All protein and cytokine analysis was done via ELISA. The in-vivo antimicrobial efficacy of MSC and antibiotic-loaded hydrogels was determined in Sprague–Dawley rats inoculated with SA. Two-way ANOVA for multiple comparisons was used with Bonferroni test assessment and an unpaired two-tailed Student’s t test was used to determine p values for all assays with multiple or two conditions, respectively. Results Minocycline leads to the phosphorylation of transcriptional nuclear factor-κB (NFκB), but not c-Jun NH2-terminal kinase (JNK) or mitogen-activated protein kinase (ERK). Inhibition of NFκB activation prevented the minocycline-induced increase in VEGF secretion. Preconditioning of MSCs with minocycline led to a reduced production of the antimicrobial peptide LL-37, but enhanced antimicrobial activity against SA via an increased production of IL-6 and SA internalization. MSC and antibiotic-loaded hydrogels reduced SA bioburden in inoculated wounds over 3 days and accelerated reepithelialization. Conclusions Minocycline modulates the NFκB pathway in MSCs that leads to an enhanced production of IL-6 and internalization of SA. This mechanism may have contributed to the in-vivo antibacterial efficacy of MSC and antibiotic-loaded hydrogels. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0623-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Alberto Daniel Guerra
- School of Pharmacy, Division of Pharmaceutical Sciences, Pharmacy Practice Division, University of Wisconsin-Madison, 777 Highland Avenue, 7123 Rennebohm Hall, Madison, WI, 53705, USA
| | - Warren E Rose
- School of Pharmacy, Division of Pharmaceutical Sciences, Pharmacy Practice Division, University of Wisconsin-Madison, 777 Highland Avenue, 7123 Rennebohm Hall, Madison, WI, 53705, USA
| | - Peiman Hematti
- School of Medicine and Public Health, Department of Medicine, Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, 1685 Highland Avenue, Madison, WI, 53705, USA
| | - W John Kao
- School of Pharmacy, Division of Pharmaceutical Sciences, Pharmacy Practice Division, University of Wisconsin-Madison, 777 Highland Avenue, 7123 Rennebohm Hall, Madison, WI, 53705, USA. .,College of Engineering, Department of Biomedical Engineering, University of Wisconsin-Madison, 1415 Engineering Drive, Madison, WI, 53706, USA. .,School of Medicine and Public Health, Department of Surgery, University of Wisconsin-Madison, 1685 Highland Avenue, Madison, WI, 53705, USA. .,Present Address: 10/F Knowles Building, Pokfulam, Hong Kong.
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Silva T, Grenho L, Barros J, Silva JC, Pinto RV, Matos A, Colaço B, Fernandes MH, Bettencourt A, Gomes PS. A minocycline-releasing PMMA system as a space maintainer for staged bone reconstructions-in vitro antibacterial, cytocompatibility and anti-inflammatory characterization. ACTA ACUST UNITED AC 2017; 12:035009. [PMID: 28333042 DOI: 10.1088/1748-605x/aa68b8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
In the present work, we study the development and biological characterization of a polymethyl methacrylate (PMMA)-based minocycline delivery system, to be used as a space maintainer within craniofacial staged regenerative interventions. The developed delivery systems were characterized regarding solid state characteristics and assayed in vitro for antibacterial and anti-inflammatory activity, and cytocompatibility with human bone cells. A drug release profile allowed for an initial burst release and a more sustained and controlled release over time, with minimum inhibitory concentrations for the assayed and relevant pathogenic bacteria (i.e., Staphylococcus aureus, slime-producer Staphylococcus epidermidis and Escherichia coli) being easily attained in the early time points, and sustained up to 72 h. Furthermore, an improved osteoblastic cell response-with enhancement of cell adhesion and cell proliferation-and increased anti-inflammatory activity were verified in developed systems, compared to a control (non minocycline-loaded PMMA cement). The obtained results converge to support the possible efficacy of the developed PMMA-based minocycline delivery systems for the clinical management of complex craniofacial trauma. Here, biomaterials with space maintenance properties are necessary for the management of staged reconstructive approaches, thus minimizing the risk of peri-operative infections and enhancing the local tissue healing and early stages of regeneration.
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Affiliation(s)
- Tiago Silva
- Laboratory for Bone Metabolism and Regeneration-Faculty of Dental Medicine, U. Porto-Porto, Portugal
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Togha M, Jahanshahi M, Alizadeh L, Jahromi SR, Vakilzadeh G, Alipour B, Gorji A, Ghaemi A. Rapamycin Augments Immunomodulatory Properties of Bone Marrow-Derived Mesenchymal Stem Cells in Experimental Autoimmune Encephalomyelitis. Mol Neurobiol 2017; 54:2445-2457. [PMID: 26971291 DOI: 10.1007/s12035-016-9840-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 03/04/2016] [Indexed: 12/29/2022]
Abstract
The immunomodulatory and anti-inflammatory properties of bone marrow-derived mesenchymal stem cells (BM-MSCs) have been considered as an appropriate candidate for treatment of autoimmune diseases. Previous studies have revealed that treatment with BM-MSCs may modulate immune responses and alleviate the symptoms in experimental autoimmune encephalomyelitis (EAE) mice, an animal model of multiple sclerosis. Therefore, the present study was designed to examine immunomodulatory effects of BM-MSCs in the treatment of myelin oligodendrocyte glycoprotein (MOG) 35-55-induced EAE in C57BL/6 mice. MSCs were obtained from the bone marrow of C57BL mice, cultured with DMEM/F12, and characterized with flow cytometry for the presence of cell surface markers for BM-MSCs. Following three passages, BM-MSCs were injected intraperitoneally into EAE mice alone or in combination with rapamycin. Immunological and histopathological effects of BM-MSCs and addition of rapamycin to BM-MSCs were evaluated. The results demonstrated that adding rapamycin to BM-MSCs transplantation in EAE mice significantly reduced inflammation infiltration and demyelination, enhanced the immunomodulatory functions, and inhibited progress of neurological impairments compared to BM-MSC transplantation and control groups. The immunological effects of rapamycin and BM-MSC treatments were associated with the inhibition of the Ag-specific lymphocyte proliferation, CD8+ cytolytic activity, and the Th1-type cytokine (gamma-interferon (IFN-γ)) and the increase of Th-2 cytokine (interleukin-4 (IL-4) and IL-10) production. Addition of rapamycin to BM-MSCs was able to ameliorate neurological deficits and provide neuroprotective effects in EAE. This suggests the potential of rapamycin and BM-MSC combined therapy to play neuroprotective roles in the treatment of neuroinflammatory disorders.
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Affiliation(s)
- Mansoureh Togha
- Iranian Center of Neurological Research, Neuroscience Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrdad Jahanshahi
- Neuroscience Research Center, Department of Anatomy, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | | | - Soodeh Razeghi Jahromi
- Shefa Neuroscience Research Center, Tehran, Iran
- Multiple Sclerosis Research Center-Neuroscience Institute, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Gelareh Vakilzadeh
- School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahram Alipour
- Iranian Blood Transfusion Organization Research Center, Tehran, Iran
| | - Ali Gorji
- Shefa Neuroscience Research Center, Tehran, Iran
- Epilepsy Research Center, Klinik und Poliklinik für Neurochirurgie, Department of Neurology, Westfälische Wilhelms-Universität Münster, Münster, Germany
| | - Amir Ghaemi
- Infectious Diseases Research Center, Department of Microbiology, Golestan University of Medical Sciences, P.O. Box 49175-1141, Gorgan, Iran.
- Department of Virology, Institute Pasteur of Iran, Tehran, Iran.
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Zorzopulos J, Opal SM, Hernando-Insúa A, Rodriguez JM, Elías F, Fló J, López RA, Chasseing NA, Lux-Lantos VA, Coronel MF, Franco R, Montaner AD, Horn DL. Immunomodulatory oligonucleotide IMT504: Effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy. World J Stem Cells 2017; 9:45-67. [PMID: 28396715 PMCID: PMC5368622 DOI: 10.4252/wjsc.v9.i3.45] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 10/12/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023] Open
Abstract
The immune responses of humans and animals to insults (i.e., infections, traumas, tumoral transformation and radiation) are based on an intricate network of cells and chemical messengers. Abnormally high inflammation immediately after insult or abnormally prolonged pro-inflammatory stimuli bringing about chronic inflammation can lead to life-threatening or severely debilitating diseases. Mesenchymal stem cell (MSC) transplant has proved to be an effective therapy in preclinical studies which evaluated a vast diversity of inflammatory conditions. MSCs lead to resolution of inflammation, preparation for regeneration and actual regeneration, and then ultimate return to normal baseline or homeostasis. However, in clinical trials of transplanted MSCs, the expectations of great medical benefit have not yet been fulfilled. As a practical alternative to MSC transplant, a synthetic drug with the capacity to boost endogenous MSC expansion and/or activation may also be effective. Regarding this, IMT504, the prototype of a major class of immunomodulatory oligonucleotides, induces in vivo expansion of MSCs, resulting in a marked improvement in preclinical models of neuropathic pain, osteoporosis, diabetes and sepsis. IMT504 is easily manufactured and has an excellent preclinical safety record. In the small number of patients studied thus far, IMT504 has been well-tolerated, even at very high dosage. Further clinical investigation is necessary to demonstrate the utility of IMT504 for resolution of inflammation and regeneration in a broad array of human diseases that would likely benefit from an immunoprotective/immunoregenerative therapy.
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Amelioration of experimental autoimmune encephalomyelitis through transplantation of placental derived mesenchymal stem cells. Sci Rep 2017; 7:41837. [PMID: 28186117 PMCID: PMC5301256 DOI: 10.1038/srep41837] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Accepted: 12/29/2016] [Indexed: 12/16/2022] Open
Abstract
Placental derived mesenchymal stem cells (PMSCs) have been suggested as a possible source of cells to treat multiple sclerosis (MS) due to their immunomodulatory functions, lack of ethical concerns, and potential to differentiate into neurons and oligodendrocytes. To investigate whether PMSCs share similar characteristics with embryonic mesenchymal stem cells (EMSCs), and if transplanted PMSCs have the ability to integrate and replace degenerated neural cells, we transplanted rat PMSCs and EMSCs into the central nervous system (CNS) of Lewis rats with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Our findings demonstrated that transplanted PMSCs, similar to EMSCs, were effective in decreasing infiltrating inflammatory cells, preserving axons, and ameliorating demyelination, thereby improving the neurological functions of animals. Moreover, both PMSCs and EMSCs had the ability to migrate into inflamed tissues and express neural–glial lineage markers. These findings suggest that PMSCs may replace EMSCs as a source of cells in MS stem cell therapy.
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Torkaman M, Ghollasi M, Mohammadnia-Afrouzi M, Salimi A, Amari A. The effect of transplanted human Wharton's jelly mesenchymal stem cells treated with IFN-γ on experimental autoimmune encephalomyelitis mice. Cell Immunol 2016; 311:1-12. [PMID: 27697286 DOI: 10.1016/j.cellimm.2016.09.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 09/26/2016] [Accepted: 09/26/2016] [Indexed: 12/29/2022]
Abstract
Interferon gamma (IFN-γ) increases the immunosuppressive property of human Wharton's jelly mesenchymal stem cells (hWJ-MSCs). In this study, we evaluated the therapeutic effects of IFN-γ primed WJ-MSCs in EAE mice. IFN-γ primed WJ-MSCs were injected on days 3 and 11 after EAE induction. 21 days after EAE induction, splenocytes and cervical lymph node cells were isolated and cell proliferation, secretion of inflammatory cytokines and frequency of regulatory T-cells was measured. On day 50 of the study, cell infiltration and gene expression of inflammatory cytokines in brain of mice were studied. Leukocyte infiltration and symptoms were significantly reduced in IFN-γ primed WJ-MSCs treated group compared to other groups. These cells showed significantly reduced proliferation and increased Treg cells as well as decreased secretion and gene expression of inflammatory cytokines in EAE mice. Our data suggest that IFN-γ may be used to stimulate the immunomodulatory property of WJ-MSCs in clinical situations.
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Affiliation(s)
- Mohammad Torkaman
- Department of Pediatrics, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Marzieh Ghollasi
- Department of Cell and Molecular Biology, Faculty of Biological Science, Kharazmi University, Tehran, Iran.
| | | | - Ali Salimi
- Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Afshin Amari
- Department of Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Cellular and Molecular Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Wang D, Li SP, Fu JS, Zhang S, Bai L, Guo L. Resveratrol defends blood-brain barrier integrity in experimental autoimmune encephalomyelitis mice. J Neurophysiol 2016; 116:2173-2179. [PMID: 27535376 DOI: 10.1152/jn.00510.2016] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Accepted: 08/15/2016] [Indexed: 11/22/2022] Open
Abstract
The mouse autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS), is primarily characterized as dysfunction of the blood-brain barrier (BBB). Resveratrol exhibits anti-inflammatory, antioxidative, and neuroprotective activities. We investigated the beneficial effects of resveratrol in protecting the integrity of the BBB in EAE mice and observed improved clinical outcome in the EAE mice after resveratrol treatment. Evans blue (EB) extravasation was used to detect the disruption of BBB. Western blot were used to detected the tight junction proteins and adhesion molecules zonula occludens-1 (ZO-1), occludin, ICAM-1, and VCAM-1. Inflammatory factors inducible nitric oxide synthase (iNOS), IL-1β, and arginase 1 were evaluated by quantitative RT-PCR (qPCR) and IL-10 by ELISA. NADPH oxidase (NOX) levels were evaluated by qPCR, and its activity was analyzed by lucigenin-derived chemiluminescence. Resveratrol at doses of 25 and 50 mg/kg produced a dose-dependent decrease in EAE paralysis and EB leakage, ameliorated EAE-induced loss of tight junction proteins ZO-1, occludin, and claudin-5, as well as repressed the EAE-induced increase in adhesion proteins ICAM-1 and VCAM-1. In addition, resveratrol suppressed the EAE-induced overexpression of proinflammatory transcripts iNOS and IL-1β and upregulated the expression of anti-inflammatory transcripts arginase 1 and IL-10 cytokine in the brain. Furthermore, resveratrol downregulated the overexpressed NOX2 and NOX4 in the brain and suppressed NADPH activity. Resveratrol ameliorates the clinical severity of MS through maintaining the BBB integrity in EAE mice.
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Affiliation(s)
- Dong Wang
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China; and
| | - Shi-Ping Li
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China; and
| | - Jin-Sheng Fu
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China; and
| | - Sheng Zhang
- Department of Emergency, Xingtai People's Hospital, Xingtai, Hebei, People's Republic of China
| | - Lin Bai
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China; and
| | - Li Guo
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China; and
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Gharibi T, Ahmadi M, Seyfizadeh N, Jadidi-Niaragh F, Yousefi M. Immunomodulatory characteristics of mesenchymal stem cells and their role in the treatment of multiple sclerosis. Cell Immunol 2015; 293:113-21. [PMID: 25596473 DOI: 10.1016/j.cellimm.2015.01.002] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2014] [Revised: 12/31/2014] [Accepted: 01/02/2015] [Indexed: 12/12/2022]
Abstract
Multiple Sclerosis (MS) is a chronic inflammatory neurodegenerative disease of central nervous system (CNS). Although the main cause of MS is not clear, studies suggest that MS is an autoimmune disease which attacks myelin sheath of neurons. There are different therapeutic regimens for MS patients including interferon (IFN)-β, glatiramer acetate (GA), and natalizumab. However, such therapies are not quite effective and are associated with some side effects. So which, there is no complete therapeutic method for MS patients. Regarding the potent immunomodulatory effects of mesenchymal stem cells (MSCs) and their ameliorative effects in experimental autoimmune encephalopathy (EAE), it seems that MSCs may be a new therapeutic method in MS therapy. MSC transplantation is an approach to regulate the immune system in the region of CNS lesions. In this review, we have tried to discuss about the immunomodulatory properties of MSCs and their therapeutic mechanisms in MS patients.
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Affiliation(s)
- Tohid Gharibi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Ahmadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Narges Seyfizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Jadidi-Niaragh
- Department of Immunology, School of Public Health, Tehran 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.
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Fransson M, Piras E, Wang H, Burman J, Duprez I, Harris RA, LeBlanc K, Magnusson PU, Brittebo E, Loskog ASI. Intranasal delivery of central nervous system-retargeted human mesenchymal stromal cells prolongs treatment efficacy of experimental autoimmune encephalomyelitis. Immunology 2014; 142:431-41. [PMID: 24588452 DOI: 10.1111/imm.12275] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Revised: 02/17/2014] [Accepted: 02/17/2014] [Indexed: 12/17/2022] Open
Abstract
Treatment with mesenchymal stromal cells (MSCs) is currently of interest for a number of diseases including multiple sclerosis. MSCs are known to target inflamed tissues, but in a therapeutic setting their systemic administration will lead to few cells reaching the brain. We hypothesized that MSCs may target the brain upon intranasal administration and persist in central nervous system (CNS) tissue if expressing a CNS-targeting receptor. To demonstrate proof of concept, MSCs were genetically engineered to express a myelin oligodendrocyte glycoprotein-specific receptor. Engineered MSCs retained their immunosuppressive capacity, infiltrated into the brain upon intranasal cell administration, and were able to significantly reduce disease symptoms of experimental autoimmune encephalomyelitis (EAE). Mice treated with CNS-targeting MSCs were resistant to further EAE induction whereas non-targeted MSCs did not give such persistent effects. Histological analysis revealed increased brain restoration in engineered MSC-treated mice. In conclusion, MSCs can be genetically engineered to target the brain and prolong therapeutic efficacy in an EAE model.
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Affiliation(s)
- Moa Fransson
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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Interferon β-secreting mesenchymal stem cells combined with minocycline attenuate experimental autoimmune encephalomyelitis. J Neuroimmunol 2014; 274:20-7. [DOI: 10.1016/j.jneuroim.2014.06.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Revised: 05/21/2014] [Accepted: 06/02/2014] [Indexed: 12/30/2022]
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Khosravizadeh Z, Razavi S, Bahramian H, Kazemi M. The beneficial effect of encapsulated human adipose-derived stem cells in alginate hydrogel on neural differentiation. J Biomed Mater Res B Appl Biomater 2013; 102:749-55. [PMID: 24142904 DOI: 10.1002/jbm.b.33055] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Revised: 09/07/2013] [Accepted: 09/22/2013] [Indexed: 12/21/2022]
Abstract
Tissue engineering employs combination of biomaterials and cell therapy to develop new therapeutic strategies for neurodegenerative diseases, spinal cord, and traumatic brain injuries. Alginate is a biocompatible hydrogel, which has been used broadly to encapsulate many types of cells. Human adipose-derived stem cells (hADSCs) have appropriate property to differentiate into neuron-like cells. Therefore, the aim of this study was to evaluate the effect of alginate hydrogel on the viability and neural differentiation potential of induced hADSCs. After neural induction of isolated hADSCs and encapsulated in alginate hydrogel, the cell viability using MTT assay and their neural differentiation potential by immunocytochemical and real time RT-PCR analysis for neural markers (Nestin, GFAP, and MAP2) were evaluated. Expression of Nestin, GFAP, and MAP2 markers was significantly increased compare to monolayer induced cells (p<0.001), but we did not found any significant effect on viability of induced cells relative to monolayer induced cells. Although neural differentiation of encapsulated cells was increased relative to monolayer induced cells, the viability of these cells was not significantly different in alginate hydrogel as compared with monolayer induced cells.
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Affiliation(s)
- Zahra Khosravizadeh
- Department of Anatomical Sciences and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, 81744-176, Iran
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