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Trigo CM, Rodrigues JS, Camões SP, Solá S, Miranda JP. Mesenchymal stem cell secretome for regenerative medicine: Where do we stand? J Adv Res 2025; 70:103-124. [PMID: 38729561 PMCID: PMC11976416 DOI: 10.1016/j.jare.2024.05.004] [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: 08/15/2023] [Revised: 02/27/2024] [Accepted: 05/03/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND Mesenchymal stem cell (MSC)-based therapies have yielded beneficial effects in a broad range of preclinical models and clinical trials for human diseases. In the context of MSC transplantation, it is widely recognized that the main mechanism for the regenerative potential of MSCs is not their differentiation, with in vivo data revealing transient and low engraftment rates. Instead, MSCs therapeutic effects are mainly attributed to its secretome, i.e., paracrine factors secreted by these cells, further offering a more attractive and innovative approach due to the effectiveness and safety of a cell-free product. AIM OF REVIEW In this review, we will discuss the potential benefits of MSC-derived secretome in regenerative medicine with particular focus on respiratory, hepatic, and neurological diseases. Both free and vesicular factors of MSC secretome will be detailed. We will also address novel potential strategies capable of improving their healing potential, namely by delivering important regenerative molecules according to specific diseases and tissue needs, as well as non-clinical and clinical studies that allow us to dissect their mechanisms of action. KEY SCIENTIFIC CONCEPTS OF REVIEW MSC-derived secretome includes both soluble and non-soluble factors, organized in extracellular vesicles (EVs). Importantly, besides depending on the cell origin, the characteristics and therapeutic potential of MSC secretome is deeply influenced by external stimuli, highlighting the possibility of optimizing their characteristics through preconditioning approaches. Nevertheless, the clarity around their mechanisms of action remains ambiguous, whereas the need for standardized procedures for the successful translation of those products to the clinics urges.
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Affiliation(s)
- Catarina M Trigo
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Joana S Rodrigues
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Sérgio P Camões
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Susana Solá
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Joana P Miranda
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
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2
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Kim KM, D'Elia AM, Rodell CB. Hydrogel-based approaches to target hypersensitivity mechanisms underlying autoimmune disease. Adv Drug Deliv Rev 2024; 212:115395. [PMID: 39004347 DOI: 10.1016/j.addr.2024.115395] [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: 11/08/2023] [Revised: 06/23/2024] [Accepted: 07/08/2024] [Indexed: 07/16/2024]
Abstract
A robust adaptive immune response is essential for combatting pathogens. In the wrong context such as due to genetic and environmental factors, however, the same mechanisms crucial for self-preservation can lead to a loss of self-tolerance. Resulting autoimmunity manifests in the development of a host of organ-specific or systemic autoimmune diseases, hallmarked by aberrant immune responses and tissue damage. The prevalence of autoimmune diseases is on the rise, medical management of which focuses primarily on pharmacological immunosuppression that places patients at a risk of side effects, including opportunistic infections and tumorigenesis. Biomaterial-based drug delivery systems confer many opportunities to address challenges associated with conventional disease management. Hydrogels, in particular, can protect encapsulated cargo (drug or cell therapeutics) from the host environment, afford their presentation in a controlled manner, and can be tailored to respond to disease conditions or support treatment via multiplexed functionality. Moreover, localized delivery to affected sites by these approaches has the potential to concentrate drug action at the site, reduce off-target exposure, and enhance patient compliance by reducing the need for frequent administration. Despite their many benefits for the management of autoimmune disease, such biomaterial-based approaches focus largely on the downstream effects of hypersensitivity mechanisms and have a limited capacity to eradicate the disease. In contrast, direct targeting of mechanisms of hypersensitivity reactions uniquely enables prophylaxis or the arrest of disease progression by mitigating the basis of autoimmunity. One promising approach is to induce self-antigen-specific tolerance, which specifically subdues damaging autoreactivity while otherwise retaining the normal immune responses. In this review, we will discuss hydrogel-based systems for the treatment of autoimmune disease, with a focus on those that target hypersensitivity mechanisms head-on. As the field continues to advance, it will expand the range of therapeutic choices for people coping with autoimmune diseases, providing fresh prospects for better clinical outcomes and improved quality of life.
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Affiliation(s)
- Kenneth M Kim
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA.
| | - Arielle M D'Elia
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA.
| | - Christopher B Rodell
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA; School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA.
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3
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Ghareghani M, Arneaud A, Rivest S. The evolution of mesenchymal stem cell-derived neural progenitor therapy for Multiple Sclerosis: from concept to clinic. Front Cell Neurosci 2024; 18:1428652. [PMID: 39280795 PMCID: PMC11393827 DOI: 10.3389/fncel.2024.1428652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 08/12/2024] [Indexed: 09/18/2024] Open
Abstract
This review delves into the generation and therapeutic applications of mesenchymal stem cell-derived neural progenitors (MSC-NPs) in Multiple Sclerosis (MS), a chronic autoimmune disease characterized by demyelination, neuroinflammation, and progressive neurological dysfunction. Most current treatment paradigms primarily aimed at regulating the immune response show little success against the neurodegenerative aspect of MS. This calls for new therapies that would play a role in neurodegeneration and functional recovery of the central nervous system (CNS). While utilizing MSC was found to be a promising approach in MS therapy, the initiation of MSC-NPs therapy is an innovation that introduces a new perspective, a dual-action plan, that targets both the immune and neurodegenerative mechanisms of MS. The first preclinical studies using animal models of the disease showed that MSC-NPs could migrate to damaged sites, support remyelination, and possess immunomodulatory properties, thus, providing a solid basis for their human application. Based on pilot feasibility studies and phase I clinical trials, this review covers the transition from preclinical to clinical phases, where intrathecally administered autologous MSC-NPs has shown great hope in treating patients with progressive MS by providing safety, tolerability, and preliminary efficacy. This review, after addressing the role of MSCs in MS and its animal model of experimental autoimmune encephalomyelitis (EAE), highlights the significance of the MSC-NP therapy by organizing its advancement processes from experimental models to clinical translation in MS treatment. It points out the continuing obstacles, which require more studies to improve therapeutic protocols, uncovers the mechanisms of action, and establishes long-term efficacy and safety in larger controlled trials.
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Affiliation(s)
- Majid Ghareghani
- Neuroscience Laboratory, CHU de Québec Research Centre, Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec City, QC, Canada
| | - Ayanna Arneaud
- Neuroscience Laboratory, CHU de Québec Research Centre, Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec City, QC, Canada
| | - Serge Rivest
- Neuroscience Laboratory, CHU de Québec Research Centre, Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec City, QC, Canada
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4
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Park H, Song J, Jeong HW, Grönloh MLB, Koh BI, Bovay E, Kim KP, Klotz L, Thistlethwaite PA, van Buul JD, Sorokin L, Adams RH. Apelin modulates inflammation and leukocyte recruitment in experimental autoimmune encephalomyelitis. Nat Commun 2024; 15:6282. [PMID: 39060233 PMCID: PMC11282314 DOI: 10.1038/s41467-024-50540-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
Demyelination due to autoreactive T cells and inflammation in the central nervous system are principal features of multiple sclerosis (MS), a chronic and highly disabling human disease affecting brain and spinal cord. Here, we show that treatment with apelin, a secreted peptide ligand for the G protein-coupled receptor APJ/Aplnr, is protective in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Apelin reduces immune cell entry into the brain, delays the onset and reduces the severity of EAE. Apelin affects the trafficking of leukocytes through the lung by modulating the expression of cell adhesion molecules that mediate leukocyte recruitment. In addition, apelin induces the internalization and desensitization of its receptor in endothelial cells (ECs). Accordingly, protection against EAE major outcomes of apelin treatment are phenocopied by loss of APJ/Aplnr function, achieved by EC-specific gene inactivation in mice or knockdown experiments in cultured primary endothelial cells. Our findings highlight the importance of the lung-brain axis in neuroinflammation and indicate that apelin targets the transendothelial migration of immune cells into the lung during acute inflammation.
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Affiliation(s)
- Hongryeol Park
- Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, Münster, Germany.
| | - Jian Song
- Institute of Physiological Chemistry and Pathobiochemistry and Cells-in-Motion Interfaculty Centre (CIMIC), University of Münster, Münster, Germany
| | - Hyun-Woo Jeong
- Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, Münster, Germany
| | - Max L B Grönloh
- Vascular Cell Biology Lab, Department of Medical Biochemistry, Amsterdam UMC, and Section Molecular Cytology at Swammerdam Institute for Life Sciences, Leeuwenhoek Centre for Advanced Microscopy, University of Amsterdam, Amsterdam, The Netherlands
| | - Bong Ihn Koh
- Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, Münster, Germany
| | - Esther Bovay
- Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, Münster, Germany
| | - Kee-Pyo Kim
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Luisa Klotz
- Department of Neurology, University of Münster, Münster, Germany
| | | | - Jaap D van Buul
- Vascular Cell Biology Lab, Department of Medical Biochemistry, Amsterdam UMC, and Section Molecular Cytology at Swammerdam Institute for Life Sciences, Leeuwenhoek Centre for Advanced Microscopy, University of Amsterdam, Amsterdam, The Netherlands
| | - Lydia Sorokin
- Institute of Physiological Chemistry and Pathobiochemistry and Cells-in-Motion Interfaculty Centre (CIMIC), University of Münster, Münster, Germany
| | - Ralf H Adams
- Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, Münster, Germany.
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Chang Z, Wang QY, Li LH, Jiang B, Zhou XM, Zhu H, Sun YP, Pan X, Tu XX, Wang W, Liu CY, Kuang HX. Potential Plausible Role of Stem Cell for Treating Depressive Disorder: a Retrospective Review. Mol Neurobiol 2024; 61:4454-4472. [PMID: 38097915 DOI: 10.1007/s12035-023-03843-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 11/29/2023] [Indexed: 07/11/2024]
Abstract
Depression poses a significant threat to global physical and mental health, impacting around 3.8% of the population with a rising incidence. Current treatment options primarily involve medication and psychological support, yet their effectiveness remains limited, contributing to high relapse rates. There is an urgent need for innovative and more efficacious treatment modalities. Stem cell therapy, a promising avenue in regenerative medicine for a spectrum of neurodegenerative conditions, has recently garnered attention for its potential application in depression. While much of this work remains preclinical, it has demonstrated considerable promise. Identified mechanisms underlying the antidepressant effects of stem cell therapy encompass the stimulation of neurotrophic factors, immune function modulation, and augmented monoamine levels. Nonetheless, these pathways and other undiscovered mechanisms necessitate further investigation. Depression fundamentally manifests as a neurodegenerative disorder. Given stem cell therapy's success in addressing a range of neurodegenerative pathologies, it opens the door to explore its application in depression treatment. This exploration may include repairing damaged nerves directly or indirectly and inhibiting neurotoxicity. Nevertheless, significant challenges must be overcome before stem cell therapies can be applied clinically. Successful resolution of these issues will ultimately determine the feasibility of incorporating stem cell therapies into the clinical landscape. This narrative review provides insights into the progress of research, potential avenues for exploration, and the prevailing challenges in the implementation of stem cell therapy for treatment of depression.
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Affiliation(s)
- Zhuo Chang
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Qing-Yi Wang
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Lu-Hao Li
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Bei Jiang
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Xue-Ming Zhou
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Hui Zhu
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Yan-Ping Sun
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Xue Pan
- Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xu-Xu Tu
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Wei Wang
- First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
| | - Chen-Yue Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Hai-Xue Kuang
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China.
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Frid K, Usmann A, Markovits-Pachter T, Binyamin O, Petrou P, Kassis I, Karussis D, Gabizon R. Granagard administration prolongs the survival of human mesenchymal stem cells transplanted into a mouse model of multiple sclerosis. J Neuroimmunol 2024; 389:578313. [PMID: 38401393 DOI: 10.1016/j.jneuroim.2024.578313] [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: 09/06/2023] [Revised: 01/29/2024] [Accepted: 02/08/2024] [Indexed: 02/26/2024]
Abstract
The clinical effect of human Mesenchymal stem cells (hMSCs) transplanted into EAE mice/MS patients is short lived due to poor survival of the transplanted cells. Since Granagard, a nanoformulation of pomegranate seed oil, extended the presence of Neuronal Stem cells transplanted into CJD mice brains, we tested whether this safe food supplement can also elongate the survival of hMSCs transplanted into EAE mice. Indeed, pathological studies 60 days post transplantation identified human cells only in brains of Granagard treated mice, concomitant with increased clinical activity. We conclude that Granagard may prolong the activity of stem cell transplantation in neurological diseases.
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Affiliation(s)
- Kati Frid
- Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Hospital, Israel; Medical School, The Hebrew University, Jerusalem, Israel
| | - Areen Usmann
- Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Hospital, Israel; Medical School, The Hebrew University, Jerusalem, Israel
| | - Tsipora Markovits-Pachter
- Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Hospital, Israel; Medical School, The Hebrew University, Jerusalem, Israel
| | - Orli Binyamin
- Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Hospital, Israel; Medical School, The Hebrew University, Jerusalem, Israel
| | - Panayota Petrou
- Unit of Neuroimmunology and Cell therapies and Multiple Sclerosis Center, Hadassah-Hebrew University Hospital, Israel
| | - Ibrahim Kassis
- Unit of Neuroimmunology and Cell therapies and Multiple Sclerosis Center, Hadassah-Hebrew University Hospital, Israel
| | - Dimitri Karussis
- Medical School, The Hebrew University, Jerusalem, Israel; Unit of Neuroimmunology and Cell therapies and Multiple Sclerosis Center, Hadassah-Hebrew University Hospital, Israel
| | - Ruth Gabizon
- Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Hospital, Israel; Medical School, The Hebrew University, Jerusalem, Israel.
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7
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Turano E, Scambi I, Bonafede R, Dusi S, Angelini G, Lopez N, Marostica G, Rossi B, Furlan R, Constantin G, Mariotti R, Bonetti B. Extracellular vesicles from adipose mesenchymal stem cells target inflamed lymph nodes in experimental autoimmune encephalomyelitis. Cytotherapy 2024; 26:276-285. [PMID: 38231166 DOI: 10.1016/j.jcyt.2023.12.007] [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: 05/07/2023] [Revised: 11/29/2023] [Accepted: 12/26/2023] [Indexed: 01/18/2024]
Abstract
BACKGROUND AIMS Adipose mesenchymal stem cells (ASCs) represent a promising therapeutic approach in inflammatory neurological disorders, including multiple sclerosis (MS). Recent lines of evidence indicate that most biological activities of ASCs are mediated by the delivery of soluble factors enclosed in extracellular vesicles (EVs). Indeed, we have previously demonstrated that small EVs derived from ASCs (ASC-EVs) ameliorate experimental autoimmune encephalomyelitis (EAE), a murine model of MS. The precise mechanisms and molecular/cellular target of EVs during EAE are still unknown. METHODS To investigate the homing of ASC-EVs, we intravenously injected small EVs loaded with ultra-small superparamagnetic iron oxide nanoparticles (USPIO) at disease onset in EAE-induced C57Bl/6J mice. Histochemical analysis and transmission electron microscopy were carried out 48 h after EV treatment. Moreover, to assess the cellular target of EVs, flow cytometry on cells extracted ex vivo from EAE mouse lymph nodes was performed. RESULTS Histochemical and ultrastructural analysis showed the presence of labeled EVs in lymph nodes but not in lungs and spinal cord of EAE injected mice. Moreover, we identified the cellular target of EVs in EAE lymph nodes by flow cytometry: ASC-EVs were preferentially located in macrophages, with a consistent amount also noted in dendritic cells and CD4+ T lymphocytes. CONCLUSIONS This represents the first direct evidence of the privileged localization of ASC-EVs in draining lymph nodes of EAE after systemic injection. These data provide prominent information on the distribution, uptake and retention of ASC-EVs, which may help in the development of EV-based therapy in MS.
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Affiliation(s)
- Ermanna Turano
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Ilaria Scambi
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Roberta Bonafede
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Silvia Dusi
- Division of General Pathology, Department of Medicine, University of Verona, Verona, Italy
| | - Gabriele Angelini
- Division of General Pathology, Department of Medicine, University of Verona, Verona, Italy
| | - Nicola Lopez
- Division of General Pathology, Department of Medicine, University of Verona, Verona, Italy
| | - Giulia Marostica
- Clinical Neuroimmunology Unit, Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy
| | - Barbara Rossi
- Division of General Pathology, Department of Medicine, University of Verona, Verona, Italy
| | - Roberto Furlan
- Clinical Neuroimmunology Unit, Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy
| | - Gabriela Constantin
- Division of General Pathology, Department of Medicine, University of Verona, Verona, Italy
| | - Raffaella Mariotti
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Bruno Bonetti
- Neurology Unit, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy.
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Mehta JM, Hiremath SC, Chilimba C, Ghasemi A, Weaver JD. Translation of cell therapies to treat autoimmune disorders. Adv Drug Deliv Rev 2024; 205:115161. [PMID: 38142739 PMCID: PMC10843859 DOI: 10.1016/j.addr.2023.115161] [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: 09/15/2023] [Revised: 12/05/2023] [Accepted: 12/15/2023] [Indexed: 12/26/2023]
Abstract
Autoimmune diseases are a diverse and complex set of chronic disorders with a substantial impact on patient quality of life and a significant global healthcare burden. Current approaches to autoimmune disease treatment comprise broadly acting immunosuppressive drugs that lack disease specificity, possess limited efficacy, and confer undesirable side effects. Additionally, there are limited treatments available to restore organs and tissues damaged during the course of autoimmune disease progression. Cell therapies are an emergent area of therapeutics with the potential to address both autoimmune disease immune dysfunction as well as autoimmune disease-damaged tissue and organ systems. In this review, we discuss the pathogenesis of common autoimmune disorders and the state-of-the-art in cell therapy approaches to (1) regenerate or replace autoimmune disease-damaged tissue and (2) eliminate pathological immune responses in autoimmunity. Finally, we discuss critical considerations for the translation of cell products to the clinic.
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Affiliation(s)
- Jinal M Mehta
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, USA
| | - Shivani C Hiremath
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, USA
| | - Chishiba Chilimba
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, USA
| | - Azin Ghasemi
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, USA
| | - Jessica D Weaver
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, USA.
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9
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Huang R, Chen J, Guo B, Jiang C, Sun W. Diabetes-induced male infertility: potential mechanisms and treatment options. Mol Med 2024; 30:11. [PMID: 38225568 PMCID: PMC10790413 DOI: 10.1186/s10020-023-00771-x] [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: 08/12/2023] [Accepted: 12/14/2023] [Indexed: 01/17/2024] Open
Abstract
Male infertility is a physiological phenomenon in which a man is unable to impregnate a fertile woman during a 12-month period of continuous, unprotected sexual intercourse. A growing body of clinical and epidemiological evidence indicates that the increasing incidence of male reproductive problems, especially infertility, shows a very similar trend to the incidence of diabetes within the same age range. In addition, a large number of previous in vivo and in vitro experiments have also suggested that the complex pathophysiological changes caused by diabetes may induce male infertility in multiple aspects, including hypothalamic-pituitary-gonadal axis dysfunction, spermatogenesis and maturation disorders, testicular interstitial cell damage erectile dysfunction. Based on the above related mechanisms, a large number of studies have focused on the potential therapeutic association between diabetes progression and infertility in patients with diabetes and infertility, providing important clues for the treatment of this population. In this paper, we summarized the research results of the effects of diabetes on male reproductive function in recent 5 years, elaborated the potential pathophysiological mechanisms of male infertility induced by diabetes, and reviewed and prospected the therapeutic measures.
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Affiliation(s)
- Runchun Huang
- The First Clinical Medical College, Lanzhou University, Lanzhou, People's Republic of China, 730000
| | - Jiawang Chen
- The First Clinical Medical College, Lanzhou University, Lanzhou, People's Republic of China, 730000
| | - Buyu Guo
- The First Clinical Medical College, Lanzhou University, Lanzhou, People's Republic of China, 730000
| | - Chenjun Jiang
- The First Clinical Medical College, Lanzhou University, Lanzhou, People's Republic of China, 730000
| | - Weiming Sun
- The First Clinical Medical College, Lanzhou University, Lanzhou, People's Republic of China, 730000.
- Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China.
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10
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Christodoulou MV, Petkou E, Atzemoglou N, Gkorla E, Karamitrou A, Simos YV, Bellos S, Bekiari C, Kouklis P, Konitsiotis S, Vezyraki P, Peschos D, Tsamis KI. Cell replacement therapy with stem cells in multiple sclerosis, a systematic review. Hum Cell 2024; 37:9-53. [PMID: 37985645 PMCID: PMC10764451 DOI: 10.1007/s13577-023-01006-1] [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: 08/02/2023] [Accepted: 10/26/2023] [Indexed: 11/22/2023]
Abstract
Multiple sclerosis (MS) is a chronic inflammatory, autoimmune, and neurodegenerative disease of the central nervous system (CNS), characterized by demyelination and axonal loss. It is induced by attack of autoreactive lymphocytes on the myelin sheath and endogenous remyelination failure, eventually leading to accumulation of neurological disability. Disease-modifying agents can successfully address inflammatory relapses, but have low efficacy in progressive forms of MS, and cannot stop the progressive neurodegenerative process. Thus, the stem cell replacement therapy approach, which aims to overcome CNS cell loss and remyelination failure, is considered a promising alternative treatment. Although the mechanisms behind the beneficial effects of stem cell transplantation are not yet fully understood, neurotrophic support, immunomodulation, and cell replacement appear to play an important role, leading to a multifaceted fight against the pathology of the disease. The present systematic review is focusing on the efficacy of stem cells to migrate at the lesion sites of the CNS and develop functional oligodendrocytes remyelinating axons. While most studies confirm the improvement of neurological deficits after the administration of different stem cell types, many critical issues need to be clarified before they can be efficiently introduced into clinical practice.
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Affiliation(s)
- Maria Veatriki Christodoulou
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Ermioni Petkou
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Natalia Atzemoglou
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Eleni Gkorla
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Aikaterini Karamitrou
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Yannis V Simos
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Stefanos Bellos
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Chryssa Bekiari
- Laboratory of Anatomy and Histology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Panos Kouklis
- Laboratory of Biology, Department of Medicine, University of Ioannina, Ioannina, Greece
| | | | - Patra Vezyraki
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Dimitrios Peschos
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Konstantinos I Tsamis
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece.
- Department of Neurology, University Hospital of Ioannina, Ioannina, Greece.
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11
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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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12
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Khamis T, Abdelkhalek A, Abdellatif H, Dwidar N, Said A, Ahmed R, Wagdy K, Elgarhy R, Eltahan R, Mohamed H, Said Amer E, Hanna M, Ragab T, Kishk A, Wael J, Sarhan E, Saweres L, Reda M, Elkomy S, Mohamed A, Samy A, Khafaga A, Shaker Y, Yehia H, Alanazi A, Alassiri M, Tîrziu E, Bucur IM, Arisha AH. BM-MSCs alleviate diabetic nephropathy in male rats by regulating ER stress, oxidative stress, inflammation, and apoptotic pathways. Front Pharmacol 2023; 14:1265230. [PMID: 38044936 PMCID: PMC10690373 DOI: 10.3389/fphar.2023.1265230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Accepted: 10/12/2023] [Indexed: 12/05/2023] Open
Abstract
Introduction: Diabetic nephropathy (DN), a chronic kidney disease, is a major cause of end-stage kidney disease worldwide. Mesenchymal stem cells (MSCs) have become a promising option to mitigate several diabetic complications. Methods: In this study, we evaluated the therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) in a rat model of STZ-induced DN. After the confirmation of diabetes, rats were treated with BM-MSCs and sacrificed at week 12 after treatment. Results: Our results showed that STZ-induced DN rats had extensive histopathological changes, significant upregulation in mRNA expression of renal apoptotic markers, ER stress markers, inflammatory markers, fibronectin, and intermediate filament proteins, and reduction of positive immunostaining of PCNA and elevated P53 in kidney tissue compared to the control group. BM-MSC therapy significantly improved renal histopathological changes, reduced renal apoptosis, ER stress, inflammation, and intermediate filament proteins, as well as increased positive immunostaining of PCNA and reduced P53 in renal tissue compared to the STZ-induced DN group. Conclusion: In conclusion, our study indicates that BM-MSCs may have therapeutic potential for the treatment of DN and provide important insights into their potential use as a novel therapeutic approach for DN.
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Affiliation(s)
- Tarek Khamis
- Department of Pharmacology and Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Adel Abdelkhalek
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Hussein Abdellatif
- Department of Human and Clinical Anatomy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
- Anatomy and Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Nourelden Dwidar
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Ahmed Said
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Rama Ahmed
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Kerolos Wagdy
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Rowina Elgarhy
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Rawan Eltahan
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Hisham Mohamed
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Eman Said Amer
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Maria Hanna
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Tarek Ragab
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Abdallah Kishk
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Judy Wael
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Eyad Sarhan
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Linda Saweres
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Mohamed Reda
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Sara Elkomy
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Abdalah Mohamed
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Abdullah Samy
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Ateya Khafaga
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Youliana Shaker
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Hamdy Yehia
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Asma Alanazi
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Mohammed Alassiri
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- Department of Basic Sciences, College of Science and Health Professions, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia
- Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City (KAMC), Ministry of the National Guard—Health Affairs, Riyadh, Saudi Arabia
| | - Emil Tîrziu
- Department of Animal Production and Veterinary Public Health, Faculty of Veterinary Medicine, University of Life Sciences, “King Mihai I” from Timisoara [ULST], Timisoara, Romania
| | - Iulia Maria Bucur
- Department of Animal Production and Veterinary Public Health, Faculty of Veterinary Medicine, University of Life Sciences, “King Mihai I” from Timisoara [ULST], Timisoara, Romania
| | - Ahmed Hamed Arisha
- Department of Animal Physiology and Biochemistry, Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
- Department of Physiology, Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
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13
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Shelash Al-Hawary SI, Yahya Ali A, Mustafa YF, Margiana R, Maksuda Ilyasovna S, Ramadan MF, Almalki SG, Alwave M, Alkhayyat S, Alsalamy A. The microRNAs (miRs) overexpressing mesenchymal stem cells (MSCs) therapy in neurological disorders; hope or hype. Biotechnol Prog 2023; 39:e3383. [PMID: 37642165 DOI: 10.1002/btpr.3383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 07/30/2023] [Accepted: 08/09/2023] [Indexed: 08/31/2023]
Abstract
Altered expression of multiple miRNAs was found to be extensively involved in the pathogenesis of different neurological disorders including Alzheimer's disease, Parkinson's disease, stroke, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. One of the biggest concerns within gene-based therapy is the delivery of the therapeutic microRNAs to the intended place, which is obligated to surpass the biological barriers without undergoing degradation in the bloodstream or renal excretion. Hence, the delivery of modified and unmodified miRNA molecules using excellent vehicles is required. In this light, mesenchymal stem cells (MSCs) have attracted increasing attention. The MSCs can be genetically modified to express or overexpress a particular microRNA aimed with promote neurogenesis and neuroprotection. The current review has focused on the therapeutic capabilities of microRNAs-overexpressing MSCs to ameliorate functional deficits in neurological conditions.
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Affiliation(s)
| | - Anas Yahya Ali
- Department of Nursing, Al-maarif University College, Ramadi, Al-Anbar, Iraq
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq
| | - Ria Margiana
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | | | | | - Sami G Almalki
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah, Saudi Arabia
| | - Marim Alwave
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Safa Alkhayyat
- College of Pharmacy, The Islamic University, Najaf, Iraq
| | - Ali Alsalamy
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna, Iraq
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14
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Smith BC, Tinkey RA, Brock OD, Mariam A, Habean ML, Dutta R, Williams JL. Astrocyte interferon-gamma signaling dampens inflammation during chronic central nervous system autoimmunity via PD-L1. J Neuroinflammation 2023; 20:234. [PMID: 37828609 PMCID: PMC10568873 DOI: 10.1186/s12974-023-02917-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 10/01/2023] [Indexed: 10/14/2023] Open
Abstract
Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS). Infiltrating inflammatory immune cells perpetuate demyelination and axonal damage in the CNS and significantly contribute to pathology and clinical deficits. While the cytokine interferon (IFN)γ is classically described as deleterious in acute CNS autoimmunity, we and others have shown astrocytic IFNγ signaling also has a neuroprotective role. Here, we performed RNA sequencing and ingenuity pathway analysis on IFNγ-treated astrocytes and found that PD-L1 was prominently expressed. Interestingly, PD-1/PD-L1 antagonism reduced apoptosis in leukocytes exposed to IFNγ-treated astrocytes in vitro. To further elucidate the role of astrocytic IFNγ signaling on the PD-1/PD-L1 axis in vivo, we induced the experimental autoimmune encephalomyelitis (EAE) model of MS in Aldh1l1-CreERT2, Ifngr1fl/fl mice. Mice with conditional astrocytic deletion of IFNγ receptor exhibited a reduction in PD-L1 expression which corresponded to increased infiltrating leukocytes, particularly from the myeloid lineage, and exacerbated clinical disease. PD-1 agonism reduced EAE severity and CNS-infiltrating leukocytes. Importantly, PD-1 is expressed by myeloid cells surrounding MS lesions. These data support that IFNγ signaling in astrocytes diminishes inflammation during chronic autoimmunity via upregulation of PD-L1, suggesting potential therapeutic benefit for MS patients.
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Affiliation(s)
- Brandon C Smith
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue/NC30, Cleveland, OH, 44195, USA
- Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH, USA
| | - Rachel A Tinkey
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue/NC30, Cleveland, OH, 44195, USA
- School of Biomedical Sciences, Kent State University, Kent, OH, USA
| | - Orion D Brock
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue/NC30, Cleveland, OH, 44195, USA
- Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Arshiya Mariam
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Maria L Habean
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue/NC30, Cleveland, OH, 44195, USA
- Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Ranjan Dutta
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue/NC30, Cleveland, OH, 44195, USA
| | - Jessica L Williams
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue/NC30, Cleveland, OH, 44195, USA.
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15
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Cecerska-Heryć E, Pękała M, Serwin N, Gliźniewicz M, Grygorcewicz B, Michalczyk A, Heryć R, Budkowska M, Dołęgowska B. The Use of Stem Cells as a Potential Treatment Method for Selected Neurodegenerative Diseases: Review. Cell Mol Neurobiol 2023:10.1007/s10571-023-01344-6. [PMID: 37027074 DOI: 10.1007/s10571-023-01344-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 03/30/2023] [Indexed: 04/08/2023]
Abstract
Stem cells have been the subject of research for years due to their enormous therapeutic potential. Most neurological diseases such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are incurable or very difficult to treat. Therefore new therapies are sought in which autologous stem cells are used. They are often the patient's only hope for recovery or slowing down the progress of the disease symptoms. The most important conclusions arise after analyzing the literature on the use of stem cells in neurodegenerative diseases. The effectiveness of MSC cell therapy has been confirmed in ALS and HD therapy. MSC cells slow down ALS progression and show early promising signs of efficacy. In HD, they reduced huntingtin (Htt) aggregation and stimulation of endogenous neurogenesis. MS therapy with hematopoietic stem cells (HSCs) inducted significant recalibration of pro-inflammatory and immunoregulatory components of the immune system. iPSC cells allow for accurate PD modeling. They are patient-specific and therefore minimize the risk of immune rejection and, in long-term observation, did not form any tumors in the brain. Extracellular vesicles derived from bone marrow mesenchymal stromal cells (BM-MSC-EVs) and Human adipose-derived stromal/stem cells (hASCs) cells are widely used to treat AD. Due to the reduction of Aβ42 deposits and increasing the survival of neurons, they improve memory and learning abilities. Despite many animal models and clinical trial studies, cell therapy still needs to be refined to increase its effectiveness in the human body.
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Affiliation(s)
- Elżbieta Cecerska-Heryć
- Department of Laboratory Medicine, Pomeranian Medical University of Szczecin, PowstancowWielkopolskich 72, 70-111, Szczecin, Poland.
| | - Maja Pękała
- Department of Laboratory Medicine, Pomeranian Medical University of Szczecin, PowstancowWielkopolskich 72, 70-111, Szczecin, Poland
| | - Natalia Serwin
- Department of Laboratory Medicine, Pomeranian Medical University of Szczecin, PowstancowWielkopolskich 72, 70-111, Szczecin, Poland
| | - Marta Gliźniewicz
- Department of Laboratory Medicine, Pomeranian Medical University of Szczecin, PowstancowWielkopolskich 72, 70-111, Szczecin, Poland
| | - Bartłomiej Grygorcewicz
- Department of Laboratory Medicine, Pomeranian Medical University of Szczecin, PowstancowWielkopolskich 72, 70-111, Szczecin, Poland
| | - Anna Michalczyk
- Department of Psychiatry, Pomeranian Medical University of Szczecin, Broniewskiego 26, 71-460, Szczecin, Poland
| | - Rafał Heryć
- Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University of Szczecin, PowstancowWielkopolskich 72, 70-111, Szczecin, Poland
| | - Marta Budkowska
- Department of Medical Analytics, Pomeranian Medical University of Szczecin, PowstancowWielkopolskich 72, 70-111, Szczecin, Poland
| | - Barbara Dołęgowska
- Department of Laboratory Medicine, Pomeranian Medical University of Szczecin, PowstancowWielkopolskich 72, 70-111, Szczecin, Poland
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16
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Borda M, Aquino JB, Mazzone GL. Cell-based experimental strategies for myelin repair in multiple sclerosis. J Neurosci Res 2023; 101:86-111. [PMID: 36164729 DOI: 10.1002/jnr.25129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 08/21/2022] [Accepted: 09/09/2022] [Indexed: 11/10/2022]
Abstract
Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS), diagnosed at a mean age of 32 years. CNS glia are crucial players in the onset of MS, primarily involving astrocytes and microglia that can cause/allow massive oligodendroglial cells death, without immune cell infiltration. Current therapeutic approaches are aimed at modulating inflammatory reactions during relapsing episodes, but lack the ability to induce very significant repair mechanisms. In this review article, different experimental approaches based mainly on the application of different cell types as therapeutic strategies applied for the induction of myelin repair and/or the amelioration of the disease are discussed. Regarding this issue, different cell sources were applied in various experimental models of MS, with different results, both in significant improvements in remyelination and the reduction of neuroinflammation and glial activation, or in neuroprotection. All cell types tested have advantages and disadvantages, which makes it difficult to choose a better option for therapeutic application in MS. New strategies combining cell-based treatment with other applications would result in further improvements and would be good candidates for MS cell therapy and myelin repair.
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Affiliation(s)
- Maximiliano Borda
- Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Derqui, Pilar, Buenos Aires, Argentina
| | - Jorge B Aquino
- Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Derqui, Pilar, Buenos Aires, Argentina.,CONICET, Comisión Nacional de Investigaciones Científicas y Técnicas
| | - Graciela L Mazzone
- Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Derqui, Pilar, Buenos Aires, Argentina.,CONICET, Comisión Nacional de Investigaciones Científicas y Técnicas
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17
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Isaković J, Šerer K, Barišić B, Mitrečić D. Mesenchymal stem cell therapy for neurological disorders: The light or the dark side of the force? Front Bioeng Biotechnol 2023; 11:1139359. [PMID: 36926687 PMCID: PMC10011535 DOI: 10.3389/fbioe.2023.1139359] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 02/13/2023] [Indexed: 03/08/2023] Open
Abstract
Neurological disorders are recognized as major causes of death and disability worldwide. Because of this, they represent one of the largest public health challenges. With awareness of the massive burden associated with these disorders, came the recognition that treatment options were disproportionately scarce and, oftentimes, ineffective. To address these problems, modern research is increasingly looking into novel, more effective methods to treat neurological patients; one of which is cell-based therapies. In this review, we present a critical analysis of the features, challenges, and prospects of one of the stem cell types that can be employed to treat numerous neurological disorders-mesenchymal stem cells (MSCs). Despite the fact that several studies have already established the safety of MSC-based treatment approaches, there are still some reservations within the field regarding their immunocompatibility, heterogeneity, stemness stability, and a range of adverse effects-one of which is their tumor-promoting ability. We additionally examine MSCs' mechanisms of action with respect to in vitro and in vivo research as well as detail the findings of past and ongoing clinical trials for Parkinson's and Alzheimer's disease, ischemic stroke, glioblastoma multiforme, and multiple sclerosis. Finally, this review discusses prospects for MSC-based therapeutics in the form of biomaterials, as well as the use of electromagnetic fields to enhance MSCs' proliferation and differentiation into neuronal cells.
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Affiliation(s)
- Jasmina Isaković
- Omnion Research International, Zagreb, Croatia.,Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Klara Šerer
- University of Zagreb School of Medicine, Zagreb, Croatia
| | - Barbara Barišić
- University of Zagreb School of Dental Medicine, Zagreb, Croatia
| | - Dinko Mitrečić
- Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia.,Laboratory for Stem Cells, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
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18
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Zayed MA, Sultan S, Alsaab HO, Yousof SM, Alrefaei GI, Alsubhi NH, Alkarim S, Al Ghamdi KS, Bagabir SA, Jana A, Alghamdi BS, Atta HM, Ashraf GM. Stem-Cell-Based Therapy: The Celestial Weapon against Neurological Disorders. Cells 2022; 11:3476. [PMID: 36359871 PMCID: PMC9655836 DOI: 10.3390/cells11213476] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 10/15/2022] [Accepted: 10/24/2022] [Indexed: 09/01/2023] Open
Abstract
Stem cells are a versatile source for cell therapy. Their use is particularly significant for the treatment of neurological disorders for which no definitive conventional medical treatment is available. Neurological disorders are of diverse etiology and pathogenesis. Alzheimer's disease (AD) is caused by abnormal protein deposits, leading to progressive dementia. Parkinson's disease (PD) is due to the specific degeneration of the dopaminergic neurons causing motor and sensory impairment. Huntington's disease (HD) includes a transmittable gene mutation, and any treatment should involve gene modulation of the transplanted cells. Multiple sclerosis (MS) is an autoimmune disorder affecting multiple neurons sporadically but induces progressive neuronal dysfunction. Amyotrophic lateral sclerosis (ALS) impacts upper and lower motor neurons, leading to progressive muscle degeneration. This shows the need to try to tailor different types of cells to repair the specific defect characteristic of each disease. In recent years, several types of stem cells were used in different animal models, including transgenic animals of various neurologic disorders. Based on some of the successful animal studies, some clinical trials were designed and approved. Some studies were successful, others were terminated and, still, a few are ongoing. In this manuscript, we aim to review the current information on both the experimental and clinical trials of stem cell therapy in neurological disorders of various disease mechanisms. The different types of cells used, their mode of transplantation and the molecular and physiologic effects are discussed. Recommendations for future use and hopes are highlighted.
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Affiliation(s)
- Mohamed A. Zayed
- Physiology Department, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Physiology Department, Faculty of Medicine, Menoufia University, Menoufia 32511, Egypt
| | - Samar Sultan
- Medical Laboratory Technology Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Regenerative Medicine Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Hashem O. Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taif University, Taif 21944, Saudi Arabia
| | - Shimaa Mohammad Yousof
- Physiology Department, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Medical Physiology Department, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Ghadeer I. Alrefaei
- Department of Biology, College of Science, University of Jeddah, Jeddah 21589, Saudi Arabia
| | - Nouf H. Alsubhi
- Department of Biological Sciences, College of Science & Arts, King Abdulaziz University, Rabigh 21911, Saudi Arabia
| | - Saleh Alkarim
- Embryonic and Cancer Stem Cell Research Group, King Fahad Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Biology Department, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Embryonic Stem Cells Research Unit, Biology Department, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Kholoud S. Al Ghamdi
- Department of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
| | - Sali Abubaker Bagabir
- Genetic Unit, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Jazan University, Jazan 45142, Saudi Arabia
| | - Ankit Jana
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT) Deemed to be University, Campus-11, Patia, Bhubaneswar 751024, Odisha, India
| | - Badrah S. Alghamdi
- Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Hazem M. Atta
- Clinical Biochemistry Department, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo 11562, Egypt
| | - Ghulam Md Ashraf
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, University City, Sharjah 27272, United Arab Emirates
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19
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Bone marrow-derived mesenchymal stem cells overexpressed with miR-182-5p protects against brain injury in a mouse model of cerebral ischemia. J Stroke Cerebrovasc Dis 2022; 31:106748. [PMID: 36087376 DOI: 10.1016/j.jstrokecerebrovasdis.2022.106748] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 08/17/2022] [Accepted: 08/23/2022] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Toll-like receptor 4 (TLR4) plays a critical role in ischemic brain injury by mediating the inflammatory response. The microRNA miR-185-5p suppresses inflammatory signaling by targeting TLR4. This study investigates whether overexpressing miR-182-5p in bone marrow-derived mesenchymal stem cells (BM-MSCs) could potentiate the neuroprotective effects of BM-MSCs in a mouse model of ischemic brain injury. METHODS We isolated BM-MSCs from mice, transfected the cells with miR-182-5p mimic, determined their MSC lineage through flow cytometry analysis of surface markers, examined miR-182-5p and TLR4 expression levels, and injected them into mice undergone middle cerebral artery occlusion (MCAO). MSC transplanted mice were subjected to behavior assays to determine cognitive and motor functions and biochemical analysis to determine neuroinflammation and TLR4/NF-κB in the ischemic hemisphere. RESULTS We found that BM-MSCs overexpressing miR-182-5p showed reduced TLR4 expression without affecting their MSC lineage. Mice transplanted with miR-182-5p overexpressing BM-MSCs after MCAO showed significantly improved cognitive and motor functions and reduced neuroinflammation, including suppressed microglial M1 polarization, reduced inflammatory cytokines, and inhibited TLR4/ NF-κB signaling. CONCLUSION Our findings suggest that overexpressing miR-182-5p in BM-MSCs can enhance the neuroprotective effects of BM-MSCs against ischemic brain injury by suppressing TLR4-mediated inflammatory response.
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20
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Khalil HMA, Mahmoud DB, El-Shiekh RA, Bakr AF, Boseila AA, Mehanna S, Naggar RA, Eliwa HA. Antidepressant and Cardioprotective Effects of Self-Nanoemulsifying Self-Nanosuspension Loaded with Hypericum perforatum on Post-Myocardial Infarction Depression in Rats. AAPS PharmSciTech 2022; 23:243. [PMID: 36028598 DOI: 10.1208/s12249-022-02387-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 07/31/2022] [Indexed: 11/30/2022] Open
Abstract
Hypericum perforatum (HP) is characterized by potent medicinal activity. However, the poor water solubility of many HP constituents limits their therapeutic effectiveness. Self-nanoemulsifying self-nanosuspension loaded with HP (HP.SNESNS) was formulated to improve the bioefficacy of HP. It was prepared using 10% triacetin, 57% Tween 20, and 33% PEG 400 and then incorporated with HP extract (100 mg/mL). HP.SNESNS demonstrated a bimodal size distribution (258.65 ± 29.35 and 9.08 ± 0.01 nm) corresponding to nanosuspension and nanoemulsion, respectively, a zeta potential of -8.03 mV, and an enhanced dissolution profile. Compared to the unformulated HP (100 mg/kg), HP.SNESNS significantly improved cardiac functions by decreasing the serum myocardial enzymes, nitric oxide (NO), and tumor necrosis factor- α (TNF-α) as well as restoring the heart tissue's normal architecture. Furthermore, it ameliorates anxiety, depressive-like behavior, and cognitive dysfunction by decreasing brain TNF-α, elevating neurotransmitters (norepinephrine and serotonin), and brain-derived neurotrophic factor (BDNF). In addition, HP.SNESNS augmented the immunohistochemical expression of cortical and hippocampal glial fibrillary acidic protein (GFAP) levels while downregulating the cortical Bcl-2-associated X protein (Bax) expression levels. Surprisingly, these protective activities were comparable to the HP (300 mg/kg). In conclusion, HP.SNESNS (100 mg/kg) exerted antidepressant and cardioprotective activities in the post-MI depression rat model.
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Affiliation(s)
- Heba M A Khalil
- Veterinary Hygiene and Management Department, Faculty of Vet. Medicine, Cairo University, Giza, 12211, Egypt.
| | - Dina B Mahmoud
- Department of Pharmaceutics, Egyptian Drug Authority Formerly Known As National Organization for Drug Control and Research (NODCAR), Giza, Egypt.,Pharmaceutical Technology, Institute of Pharmacy, Leipzig University, 04317, Leipzig, Germany
| | - Riham A El-Shiekh
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Kasr el Aini st, Cairo, 11562, Egypt
| | - Alaa F Bakr
- Pathology Department, Faculty of Vet. Medicine, Cairo University, Giza, 12211, Egypt
| | - Amira A Boseila
- Department of Pharmaceutics, Egyptian Drug Authority Formerly Known As National Organization for Drug Control and Research (NODCAR), Giza, Egypt.,Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Sinai University, Kantara branch, Sinai, 41636, Egypt
| | - Sally Mehanna
- Veterinary Hygiene and Management Department, Faculty of Vet. Medicine, Cairo University, Giza, 12211, Egypt
| | - Reham A Naggar
- Department of Pharmacology and Toxicology, College of Pharmacy and Drug Manufacturing, Misr University of Science and Technology (MUST), 6th October, Giza, 12566, Egypt
| | - Hesham A Eliwa
- Department of Pharmacology and Toxicology, College of Pharmacy and Drug Manufacturing, Misr University of Science and Technology (MUST), 6th October, Giza, 12566, Egypt
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21
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Robinson AM, Stavely R, Miller S, Eri R, Nurgali K. Mesenchymal stem cell treatment for enteric neuropathy in the Winnie mouse model of spontaneous chronic colitis. Cell Tissue Res 2022; 389:41-70. [PMID: 35536444 DOI: 10.1007/s00441-022-03633-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 04/26/2022] [Indexed: 11/30/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic gut inflammation with periods of acute flares and remission. Beneficial effects of a single dose of mesenchymal stem cell (MSC)-based treatment have been demonstrated in acute models of colitis. No studies investigated therapeutic effects of MSCs for the attenuation of enteric neuropathy in a chronic model of colitis. The short and long-term effects of MSC treatment in modulating inflammation and damage to the enteric nervous system (ENS) were studied in the Winnie mouse model of spontaneous chronic colitis highly representative of human IBD. Winnie mice received a single dose of either 1 × 106 human bone marrow-derived MSCs or 100µL PBS by intracolonic enema. C57BL/6 mice received 100µL PBS. Colon tissues were collected at 3 and 60 days post MSC administration to evaluate the short-term and long-term effects of MSCs on inflammation and enteric neuropathy by histological and immunohistochemical analyses. In a separate set of experiments, multiple treatments with 4 × 106 and 2 × 106 MSCs were performed and tissue collected at 3 days post treatment. Chronic intestinal inflammation in Winnie mice was associated with persistent diarrhea, perianal bleeding, morphological changes, and immune cell infiltration in the colon. Significant changes to the ENS, including impairment of cholinergic, noradrenergic and sensory innervation, and myenteric neuronal loss were prominent in Winnie mice. Treatment with a single dose of bone marrow-derived MSCs was ineffective in attenuating chronic inflammation and enteric neuropathy in Winnie.
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Affiliation(s)
- Ainsley M Robinson
- Institute for Health and Sport, Victoria University; Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia
| | - Rhian Stavely
- Institute for Health and Sport, Victoria University; Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia.,Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Sarah Miller
- Institute for Health and Sport, Victoria University; Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia
| | - Rajaraman Eri
- University of Tasmania, School of Health Sciences, Launceston, TAS, Australia
| | - Kulmira Nurgali
- Institute for Health and Sport, Victoria University; Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia. .,Department of Medicine Western Health, The University of Melbourne, Melbourne, VIC, Australia. .,Regenerative Medicine and Stem Cells Program, Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC, Australia.
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22
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Efficacy and Safety of Mesenchymal Stem Cell Transplantation in the Treatment of Autoimmune Diseases (Rheumatoid Arthritis, Systemic Lupus Erythematosus, Inflammatory Bowel Disease, Multiple Sclerosis, and Ankylosing Spondylitis): A Systematic Review and Meta-Analysis of Randomized Controlled Trial. Stem Cells Int 2022; 2022:9463314. [PMID: 35371265 PMCID: PMC8970953 DOI: 10.1155/2022/9463314] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 12/05/2021] [Accepted: 01/04/2022] [Indexed: 01/30/2023] Open
Abstract
Objective To evaluate the efficacy and safety of mesenchymal stem cell (MSC) transplantation in the treatment of autoimmune diseases. Methods The Chinese and English databases were searched for clinical research on the treatment of autoimmune diseases with mesenchymal stem cells. The search time range is from a self-built database to October 1, 2021. Two reviewers independently screened the literature according to the inclusion and exclusion criteria, extracted data, and evaluated the bias of the included studies. RevMan 5.3 analysis software was used for meta-analysis. Results A total of 18 RCTs involving 5 autoimmune diseases were included. The 5 autoimmune disease were rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease, ankylosing spondylitis, and multiple sclerosis. For RA, the current randomized controlled trials (RCTs) still believe that stem cell transplantation may reduce disease activity, improve the clinical symptoms (such as DAS28), and the percentage of CD4+CD 25+Foxp3+Tregs in the response group increased and the percentage of CD4+IL-17A+Th17 cells decreased. The total clinical effective rate of RA is 54%. For SLE, the results showed that mesenchymal stem cell transplantation may improve SLEDAI [-2.18 (-3.62, -0.75), P = 0.003], urine protein [-0.93 (-1.04, -0.81), P < 0.00001], and complement C3 [0.31 (0.19, 0.42), P < 0.00001]. For inflammatory bowel disease, the results showed that mesenchymal stem cell transplantation may improve clinical efficacy [2.50 (1.07, 5.84), P = 0.03]. For ankylosing spondylitis, MSC treatment for 6 months may increase the total effective rate; reduce erythrocyte sedimentation rate, intercellular adhesion molecules, and serum TNF-α; and improve pain and activity. For multiple sclerosis, the current research results are still controversial, so more RCTs are needed to amend or confirm the conclusions. No obvious adverse events of mesenchymal stem cell transplantation were found in all RCTs. Conclusion MSCs have a certain effect on different autoimmune diseases, but more RCTs are needed to further modify or confirm the conclusion.
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23
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Thompson KK, Tsirka SE. Immunosuppression in Multiple Sclerosis and Other Neurologic Disorders. Handb Exp Pharmacol 2021; 272:245-265. [PMID: 34595582 DOI: 10.1007/164_2021_545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by peripheral immune cell infiltration into the brain and spinal cord, demyelination, glial cell activation, and neuronal damage. Currently there is no cure for MS, however, available disease-modifying agents minimize inflammation in the CNS by various mechanisms. Approved drugs lessen severity of the disease and delay disease progression, however, they are still suboptimal as patients experience adverse effects and varying efficacies. Additionally, there is only one disease-modifying therapy available for the more debilitating, progressive form of MS. This chapter focuses on the presently-available therapeutics and, importantly, the future directions of MS therapy based on preclinical studies and early clinical trials. Immunosuppression in other neurological disorders including neuromyelitis optica spectrum disorders, myasthenia gravis, and Guillain-Barré syndrome is also discussed.
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Affiliation(s)
| | - Stella E Tsirka
- Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA.
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24
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Lotfy A, Ali NS, Abdelgawad M, Salama M. Mesenchymal stem cells as a treatment for multiple sclerosis: a focus on experimental animal studies. Rev Neurosci 2021; 31:161-179. [PMID: 31605598 DOI: 10.1515/revneuro-2019-0040] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Accepted: 06/14/2019] [Indexed: 12/18/2022]
Abstract
Multiple sclerosis (MS) is a progressive and debilitating neurological condition in which the immune system abnormally attacks the myelin sheath insulating the nerves. Mesenchymal stem cells (MSCs) are found in most adult tissues and play a significant systemic role in self-repair. MSCs have promising therapeutic effects in many diseases, such as autoimmune diseases, including MS. MSCs have been tested in MS animal models, such as experimental autoimmune encephalomyelitis. Other studies have combined other agents with MSCs, genetically modified MSCs, or used culture medium from MSCs. In this review, we will summarize these studies and compare the main factors in each study, such as the source of MSCs, the type of animal model, the route of injection, the number of injected cells, and the mechanism of action.
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Affiliation(s)
- Ahmed Lotfy
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), Beni-Suef University, Beni-Suef 62511, Egypt, e-mail:
| | - Nourhan S Ali
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), Beni-Suef University, Beni-Suef 62511, Egypt
| | - Mai Abdelgawad
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), Beni-Suef University, Beni-Suef 62511, Egypt
| | - Mohamed Salama
- Medical Experimental Research Center (MERC), Faculty of Medicine, Mansoura University, Mansourah, Ad Daqahliyah, Egypt.,Institute of Global Health and Human Ecology (IGHHE), American University in Cairo (AUC), Cairo, Egypt
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25
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Khamis T, Abdelalim AF, Saeed AA, Edress NM, Nafea A, Ebian HF, Algendy R, Hendawy DM, Arisha AH, Abdallah SH. Breast milk MSCs upregulated β-cells PDX1, Ngn3, and PCNA expression via remodeling ER stress /inflammatory /apoptotic signaling pathways in type 1 diabetic rats. Eur J Pharmacol 2021; 905:174188. [PMID: 34004210 DOI: 10.1016/j.ejphar.2021.174188] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 04/30/2021] [Accepted: 05/12/2021] [Indexed: 01/01/2023]
Abstract
Type 1 diabetes mellitus (T1DM) is one of the autoimmune diseases characterized by beta-cell dysfunction with serious health complications. Br-MSCs represent a novel valid candidate in regenerative medicine disciplines. Yet, the full potential of Br-MSCs in managing type 1 diabetes remains elusive. Indeed, this study was designed to explore a novel approach investigating the possible regenerative capacity of Br-MSCs in type1 diabetic islet on the level of the cellular mRNA expression of different molecular pathways involved in pancreatic beta-cell dysfunction. Sixty adult male Sprague-Dawley rats were randomly assigned into 3 groups (20 rats each); the control group, type1 diabetic group, and the type 1 diabetic Br-MSCs treated group. And, for the first time, our results revealed that intraperitoneally transplanted Br-MSCs homed to the diabetic islet and improved fasting blood glucose, serum insulin level, pancreatic oxidative stress, upregulated pancreatic mRNA expression for: regenerative markers (Pdx1, Ngn3, PCNA), INS, beta-cell receptors (IRS1, IRβ, PPARγ), pancreatic growth factors (IGF-1, VEGFβ1, FGFβ), anti-inflammatory cytokine (IL10) and anti-apoptotic marker (BCL2) too, Br-MSCs downregulated pancreatic mRNA expression for: inflammatory markers (NFKβ, TNFα, IL1β, IL6, IL8, MCP1), apoptotic markers for both intrinsic and extrinsic pathways (FAS, FAS-L, P53, P38, BAX, Caspase3), ER stress markers (ATF6, ATF3, ATF4, BIP, CHOP, JNK, XBP1) and autophagy inhibitor (mTOR). In conclusion, Br-MSCs could be considered as a new insight in beta cell regenerative therapy improving the deteriorated diabetic islet microenvironment via modulating; ER stress, inflammatory, and apoptotic signaling pathways besides, switching on the cellular quality control system (autophagy) thus enhancing beta-cell function.
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Affiliation(s)
- Tarek Khamis
- Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, 44519, Zagazig, Egypt; Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, 44519, Zagazig, Egypt.
| | - Abdelalim F Abdelalim
- Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, 44519, Zagazig, Egypt
| | - Ahmed A Saeed
- Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, 44519, Zagazig, Egypt
| | - Nagah M Edress
- Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, 44519, Zagazig, Egypt
| | - Alaa Nafea
- Department of Pediatrics, Faculty of Medicine, Zagazig University, 44519, Zagazig, Egypt
| | - Huda F Ebian
- Department of Clinical Pathology, Faculty of Medicine, Zagazig University, 44519, Zagazig, Egypt
| | - Reem Algendy
- Department of Milk Hygiene, Food Control Department, Faculty of Veterinary Medicine, Zagazig University, 44519, Zagazig, Egypt
| | - Doaa M Hendawy
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Zagazig University, 44511, Zagazig, Egypt
| | - Ahmed Hamed Arisha
- Department of Animal Physiology and Biochemistry, Faculty of Veterinary Medicine, Badr University in Cairo (BUC), Badr City, Cairo, Egypt; Department of Physiology, Faculty of Veterinary Medicine, Zagazig University, 44519, Zagazig, Egypt; Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, 44519, Zagazig, Egypt.
| | - Somia Hassan Abdallah
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Zagazig University, 44511, Zagazig, Egypt
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26
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Nasirishargh A, Kumar P, Ramasubramanian L, Clark K, Hao D, Lazar SV, Wang A. Exosomal microRNAs from mesenchymal stem/stromal cells: Biology and applications in neuroprotection. World J Stem Cells 2021; 13:776-794. [PMID: 34367477 PMCID: PMC8316862 DOI: 10.4252/wjsc.v13.i7.776] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 04/29/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are extensively studied as cell-therapy agents for neurological diseases. Recent studies consider exosomes secreted by MSCs as important mediators for MSCs' neuroprotective functions. Exosomes transfer functional molecules including proteins, lipids, metabolites, DNAs, and coding and non-coding RNAs from MSCs to their target cells. Emerging evidence shows that exosomal microRNAs (miRNAs) play a key role in the neuroprotective properties of these exosomes by targeting several genes and regulating various biological processes. Multiple exosomal miRNAs have been identified to have neuroprotective effects by promoting neurogenesis, neurite remodeling and survival, and neuroplasticity. Thus, exosomal miRNAs have significant therapeutic potential for neurological disorders such as stroke, traumatic brain injury, and neuroinflammatory or neurodegenerative diseases and disorders. This review discusses the neuroprotective effects of selected miRNAs (miR-21, miR-17-92, miR-133, miR-138, miR-124, miR-30, miR146a, and miR-29b) and explores their mechanisms of action and applications for the treatment of various neurological disease and disorders. It also provides an overview of state-of-the-art bioengineering approaches for isolating exosomes, optimizing their yield and manipulating the miRNA content of their cargo to improve their therapeutic potential.
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Affiliation(s)
- Aida Nasirishargh
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
| | - Priyadarsini Kumar
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, United States
| | - Lalithasri Ramasubramanian
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, United States
| | - Kaitlin Clark
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, United States
| | - Dake Hao
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, United States
| | - Sabrina V Lazar
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
| | - Aijun Wang
- Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine, Sacramento, CA 95817, United States
- Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, United States
- Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, United States.
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27
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Petrou P, Kassis I, Ginzberg A, Halimi M, Yaghmour N, Abramsky O, Karussis D. Long-Term Clinical and Immunological Effects of Repeated Mesenchymal Stem Cell Injections in Patients With Progressive Forms of Multiple Sclerosis. Front Neurol 2021; 12:639315. [PMID: 34135843 PMCID: PMC8202001 DOI: 10.3389/fneur.2021.639315] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 04/16/2021] [Indexed: 12/13/2022] Open
Abstract
Background: Mesenchymal stem cells (MSC) were shown to possess immunomodulatory and neurotrophic effects. Our previous trials, have shown that intrathecal (IT) and intravenous (IV) administration of MSCs were safe and provided indications of beneficial clinical effects. Methods: This is an open prospective study to evaluate the safety and the long-term clinical and immunological effects of multiple injections of autologous MSCs in 24 patients with active-progressive MS. At inclusion, the mean age of the patients was 47.0 ± 9.22, and the mean EDSS score was 6.75 ± 0.68 (range: 5.5–7.5). Patients were initially treated with 1 ×106 MSCS/kg of body weight (IT + IV) and subsequently with up to additional eight courses of MSCs, at intervals of 6–12 months. The duration of the trial was 4 years. Results: No serious, treatment-related adverse events were observed during the follow-up period. Twenty-two of the 24 patients were either stable or improved at the last follow-up visit. Ten patients had a lower than baseline EDSS at the last follow-up (nine were among those who received >2 treatments and one in the subgroup of ≤ 2 treatments, p = 0.04). The mean EDSS score reduced from 6.75 ± 0.68 at baseline to 6.42 ± 0.84 at the last visit, during a median follow-up period of 27.8 months (p = 0.028). Immunological follow-up showed a transient upregulation of CD4+CD25+FoxP3+ cells and downregulation of the proliferative ability of lymphocytes. Conclusions: Repeated MSC treatments in patients with progressive MS were shown safe at the short/intermediate term and induced clinical benefits (especially in patients treated with >2 injections) that lasted for up to 4 years, paralleled by short-term immunomodulatory effects. Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT04823000.
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Affiliation(s)
- Panayiota Petrou
- Multiple Sclerosis Center/Neuroimmunology Unit, Department of Neurology, The Agnes-Ginges Center for Neurogenetics, Hadassah University Hospital, Jerusalem, Israel
| | - Ibrahim Kassis
- Multiple Sclerosis Center/Neuroimmunology Unit, Department of Neurology, The Agnes-Ginges Center for Neurogenetics, Hadassah University Hospital, Jerusalem, Israel
| | - Ariel Ginzberg
- Multiple Sclerosis Center/Neuroimmunology Unit, Department of Neurology, The Agnes-Ginges Center for Neurogenetics, Hadassah University Hospital, Jerusalem, Israel
| | - Michel Halimi
- Multiple Sclerosis Center/Neuroimmunology Unit, Department of Neurology, The Agnes-Ginges Center for Neurogenetics, Hadassah University Hospital, Jerusalem, Israel
| | - Nour Yaghmour
- Multiple Sclerosis Center/Neuroimmunology Unit, Department of Neurology, The Agnes-Ginges Center for Neurogenetics, Hadassah University Hospital, Jerusalem, Israel
| | - Oded Abramsky
- Multiple Sclerosis Center/Neuroimmunology Unit, Department of Neurology, The Agnes-Ginges Center for Neurogenetics, Hadassah University Hospital, Jerusalem, Israel
| | - Dimitrios Karussis
- Multiple Sclerosis Center/Neuroimmunology Unit, Department of Neurology, The Agnes-Ginges Center for Neurogenetics, Hadassah University Hospital, Jerusalem, Israel
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28
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Benhamron S, Nitzan K, Valitsky M, Lax N, Karussis D, Kassis I, Rosenmann H. Cerebrospinal Fluid (CSF) Exchange Therapy with Artificial CSF Enriched with Mesenchymal Stem Cell Secretions Ameliorates Cognitive Deficits and Brain Pathology in Alzheimer's Disease Mice. J Alzheimers Dis 2021; 76:369-385. [PMID: 32474465 DOI: 10.3233/jad-191219] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND The high complexity of neurodegenerative diseases, including Alzheimer's disease (AD), and the lack of effective treatments point to the need for a broader therapeutic approach to target multiple components involved in the disease pathogenesis. OBJECTIVE To test the efficacy of 'cerebrospinal fluid (CSF) exchange therapy' in AD-mice. This novel therapeutic approach we recently proposed is based on the exchange of the endogenous pathogenic CSF with a new and healthy one by drainage of the endogenous CSF and its continuous replacement with artificial CSF (aCSF) enriched with secretions from human mesenchymal stem cells (MSCs). METHODS We treated AD-mice (amyloid-beta injected) with MSC secretions-enriched-aCSF using an intracerebroventricular CSF exchange procedure. Cognitive and histological analysis were performed. RESULTS We show that the MSC secretions enriched CSF exchange therapy improved cognitive performance, paralleled with increased neuronal counts (NeuN positive cells), reduced astrocytic burden (GFAP positive cells), and increased cell proliferation and neurogenesis (Ki67 positive cells and DCX positive cells) in the hippocampus. This beneficial effect was noted on days 5-10 following 3-consecutive daily exchange treatments (3 hours a day). A stronger effect was noted using a more prolonged CSF exchange protocol (3-consecutive daily exchange treatments with 3 additional treatments twice weekly), with cognitive follow-up performed as early as 2-3 days after treatment. Some increase in hippocampal cell proliferation, but no change in the other histological parameters, was noticed when performing CSF exchange therapy using unenriched aCSF relative to untreated AD-mice, yet smaller than with the enriched aCSF treatment. CONCLUSION These findings point to the therapeutic potential of the CSF exchange therapy using MSC secretions-enriched aCSF in AD, and might be applied to other neurodegenerative and dementia diseases.
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Affiliation(s)
- Sandrine Benhamron
- The Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Keren Nitzan
- The Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Michael Valitsky
- The Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Neta Lax
- The Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Dimitrios Karussis
- The Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Ibrahim Kassis
- The Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Hanna Rosenmann
- The Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel
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29
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Andrzejewska A, Dabrowska S, Lukomska B, Janowski M. Mesenchymal Stem Cells for Neurological Disorders. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2002944. [PMID: 33854883 PMCID: PMC8024997 DOI: 10.1002/advs.202002944] [Citation(s) in RCA: 187] [Impact Index Per Article: 46.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 11/23/2020] [Indexed: 05/13/2023]
Abstract
Neurological disorders are becoming a growing burden as society ages, and there is a compelling need to address this spiraling problem. Stem cell-based regenerative medicine is becoming an increasingly attractive approach to designing therapies for such disorders. The unique characteristics of mesenchymal stem cells (MSCs) make them among the most sought after cell sources. Researchers have extensively studied the modulatory properties of MSCs and their engineering, labeling, and delivery methods to the brain. The first part of this review provides an overview of studies on the application of MSCs to various neurological diseases, including stroke, traumatic brain injury, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, and other less frequently studied clinical entities. In the second part, stem cell delivery to the brain is focused. This fundamental but still understudied problem needs to be overcome to apply stem cells to brain diseases successfully. Here the value of cell engineering is also emphasized to facilitate MSC diapedesis, migration, and homing to brain areas affected by the disease to implement precision medicine paradigms into stem cell-based therapies.
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Affiliation(s)
- Anna Andrzejewska
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
| | - Sylwia Dabrowska
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
| | - Barbara Lukomska
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
| | - Miroslaw Janowski
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
- Center for Advanced Imaging ResearchDepartment of Diagnostic Radiology and Nuclear MedicineUniversity of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer CenterUniversity of MarylandBaltimoreMD21201‐1595USA
- Tumor Immunology and Immunotherapy ProgramUniversity of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer CenterUniversity of MarylandBaltimoreMD21201‐1595USA
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30
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Benallegue N, Kebir H, Kapoor R, Crockett A, Li C, Cheslow L, Abdel-Hakeem MS, Gesualdi J, Miller MC, Wherry EJ, Church ME, Blanco MA, Alvarez JI. The hedgehog pathway suppresses neuropathogenesis in CD4 T cell-driven inflammation. Brain 2021; 144:1670-1683. [PMID: 33723591 DOI: 10.1093/brain/awab083] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 12/08/2020] [Accepted: 12/17/2020] [Indexed: 12/13/2022] Open
Abstract
The concerted actions of the CNS and the immune system are essential to coordinating the outcome of neuroinflammatory responses. Yet, the precise mechanisms involved in this crosstalk and their contribution to the pathophysiology of neuroinflammatory diseases largely elude us. Here, we show that the CNS-endogenous hedgehog pathway, a signal triggered as part of the host response during the inflammatory phase of multiple sclerosis and experimental autoimmune encephalomyelitis, attenuates the pathogenicity of human and mouse effector CD4 T cells by regulating their production of inflammatory cytokines. Using a murine genetic model, in which the hedgehog signalling is compromised in CD4 T cells, we show that the hedgehog pathway acts on CD4 T cells to suppress the pathogenic hallmarks of autoimmune neuroinflammation, including demyelination and axonal damage, and thus mitigates the development of experimental autoimmune encephalomyelitis. Impairment of hedgehog signalling in CD4 T cells exacerbates brain-brainstem-cerebellum inflammation and leads to the development of atypical disease. Moreover, we present evidence that hedgehog signalling regulates the pathogenic profile of CD4 T cells by limiting their production of the inflammatory cytokines granulocyte-macrophage colony-stimulating factor and interferon-γ and by antagonizing their inflammatory program at the transcriptome level. Likewise, hedgehog signalling attenuates the inflammatory phenotype of human CD4 memory T cells. From a therapeutic point of view, our study underlines the potential of harnessing the hedgehog pathway to counteract ongoing excessive CNS inflammation, as systemic administration of a hedgehog agonist after disease onset effectively halts disease progression and significantly reduces neuroinflammation and the underlying neuropathology. We thus unveil a previously unrecognized role for the hedgehog pathway in regulating pathogenic inflammation within the CNS and propose to exploit its ability to modulate this neuroimmune network as a strategy to limit the progression of ongoing neuroinflammation.
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Affiliation(s)
- Nail Benallegue
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.,Inserm, Université de Nantes, CHU Nantes, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France
| | - Hania Kebir
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Richa Kapoor
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Alexis Crockett
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Cen Li
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.,Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China
| | - Lara Cheslow
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Mohamed S Abdel-Hakeem
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.,Department of Systems Pharmacology and Translational Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.,Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Kasr El-Aini, Cairo 11562, Egypt
| | - James Gesualdi
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Miles C Miller
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - E John Wherry
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.,Department of Systems Pharmacology and Translational Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Molly E Church
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - M Andres Blanco
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jorge I Alvarez
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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31
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Kassis I, Ben-Zwi M, Petrou P, Halimi M, Karussis D. Synergistic neuroprotective effects of Fingolimod and mesenchymal stem cells (MSC) in experimental autoimmune encephalomyelitis. Immunol Lett 2021; 233:11-19. [PMID: 33676976 DOI: 10.1016/j.imlet.2021.03.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 02/15/2021] [Accepted: 03/02/2021] [Indexed: 01/20/2023]
Abstract
Fingolimod (Gilenya™) is an effective oral medication approved for relapsing-remitting multiple sclerosis (MS), albeit less effective in chronic disease. Its main mechanism of action is through peripheral immunomodulation but neuroprotective effects may also be involved. Mesenchymal stem cells (MSC) were shown to exert immunomodulatory and neurotrophic effects in the model of multiple sclerosis (experimental autoimmune encephalomyelitis-EAE). The use of combination treatments in chronic diseases such as MS, has long been advocated and may result in improvement of the beneficial effects of each one of them. We tested the in vitro effects of Fingolimod (FTY720) on MSC and the in vivo effect of such combination treatment in the model of EAE. Fingolimod did not affect in any detrimental way the basic features of MSCs and it promoted their migration and proliferation ability .Moreover, Fingolimod induced neurotrophic factors secretion and suppressed the production of pro-inflammatory cytokines from astrocytes and microglia, in vitro. In vivo, the combined treatment of FTY720 and MSC (either by the intravenous or the intra-cerebroventricular route of administration) resulted in synergistic clinical beneficial effects compared to FTY720 or MSC alone, paralleled by a significant reduction of inflammatory CNS infiltrations and of axonal loss. These data may indicate a synergism of fingolimod with MSC and may support future combinations of immunomodulatory drugs with cellular therapies for the improvement of the benefits in progressive forms of MS.
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Affiliation(s)
- Ibrahim Kassis
- Unit of Neuroimmunology and Multiple Sclerosis Center, Hadassah University Hospital, Jerusalem, Ein-Kerem, Israel.
| | - Moriel Ben-Zwi
- Unit of Neuroimmunology and Multiple Sclerosis Center, Hadassah University Hospital, Jerusalem, Ein-Kerem, Israel
| | - Panayiota Petrou
- Unit of Neuroimmunology and Multiple Sclerosis Center, Hadassah University Hospital, Jerusalem, Ein-Kerem, Israel
| | - Michele Halimi
- Unit of Neuroimmunology and Multiple Sclerosis Center, Hadassah University Hospital, Jerusalem, Ein-Kerem, Israel
| | - Dimitrios Karussis
- Unit of Neuroimmunology and Multiple Sclerosis Center, Hadassah University Hospital, Jerusalem, Ein-Kerem, Israel
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32
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Petrou P, Kassis I, Levin N, Paul F, Backner Y, Benoliel T, Oertel FC, Scheel M, Hallimi M, Yaghmour N, Hur TB, Ginzberg A, Levy Y, Abramsky O, Karussis D. Beneficial effects of autologous mesenchymal stem cell transplantation in active progressive multiple sclerosis. Brain 2021; 143:3574-3588. [PMID: 33253391 DOI: 10.1093/brain/awaa333] [Citation(s) in RCA: 130] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 08/04/2020] [Accepted: 08/06/2020] [Indexed: 12/24/2022] Open
Abstract
In this study (trial registration: NCT02166021), we aimed to evaluate the optimal way of administration, the safety and the clinical efficacy of mesenchymal stem cell (MSC) transplantation in patients with active and progressive multiple sclerosis. Forty-eight patients (28 males and 20 females) with progressive multiple sclerosis (Expanded Disability Status Scale: 3.0-6.5, mean : 5.6 ± 0.8, mean age: 47.5 ± 12.3) and evidence of either clinical worsening or activity during the previous year, were enrolled (between 2015 and 2018). Patients were randomized into three groups and treated intrathecally (IT) or intravenously (IV) with autologous MSCs (1 × 106/kg) or sham injections. After 6 months, half of the patients from the MSC-IT and MSC-IV groups were retreated with MSCs, and the other half with sham injections. Patients initially assigned to sham treatment were divided into two subgroups and treated with either MSC-IT or MSC-IV. The study duration was 14 months. No serious treatment-related safety issues were detected. Significantly fewer patients experienced treatment failure in the MSC-IT and MSC-IV groups compared with those in the sham-treated group (6.7%, 9.7%, and 41.9%, respectively, P = 0.0003 and P = 0.0008). During the 1-year follow-up, 58.6% and 40.6% of patients treated with MSC-IT and MSC-IV, respectively, exhibited no evidence of disease activity compared with 9.7% in the sham-treated group (P < 0.0001 and P < 0.0048, respectively). MSC-IT transplantation induced additional benefits on the relapse rate, on the monthly changes of the T2 lesion load on MRI, and on the timed 25-foot walking test, 9-hole peg test, optical coherence tomography, functional MRI and cognitive tests. Treatment with MSCs was well-tolerated in progressive multiple sclerosis and induced short-term beneficial effects regarding the primary end points, especially in the patients with active disease. The intrathecal administration was more efficacious than the intravenous in several parameters of the disease. A phase III trial is warranted to confirm these findings.
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Affiliation(s)
- Panayiota Petrou
- Unit of Neuroimmunology and Multiple Sclerosis Center, Hadassah University Hospital, Jerusalem, Ein-Kerem, Israel
| | - Ibrahim Kassis
- Unit of Neuroimmunology and Multiple Sclerosis Center, Hadassah University Hospital, Jerusalem, Ein-Kerem, Israel
| | - Netta Levin
- Department of Neurology and The Agnes-Ginges Center for Neurogenetics, Hadassah University Hospital, Jerusalem, Ein-Kerem, Israel
| | - Friedemann Paul
- Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.,Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.,Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Yael Backner
- Department of Neurology and The Agnes-Ginges Center for Neurogenetics, Hadassah University Hospital, Jerusalem, Ein-Kerem, Israel
| | - Tal Benoliel
- Department of Neurology and The Agnes-Ginges Center for Neurogenetics, Hadassah University Hospital, Jerusalem, Ein-Kerem, Israel
| | - Frederike Cosima Oertel
- Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.,Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Michael Scheel
- Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.,Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.,Department of Neuroradiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Michelle Hallimi
- Unit of Neuroimmunology and Multiple Sclerosis Center, Hadassah University Hospital, Jerusalem, Ein-Kerem, Israel
| | - Nour Yaghmour
- Unit of Neuroimmunology and Multiple Sclerosis Center, Hadassah University Hospital, Jerusalem, Ein-Kerem, Israel
| | - Tamir Ben Hur
- Department of Neurology and The Agnes-Ginges Center for Neurogenetics, Hadassah University Hospital, Jerusalem, Ein-Kerem, Israel
| | - Ariel Ginzberg
- Unit of Neuroimmunology and Multiple Sclerosis Center, Hadassah University Hospital, Jerusalem, Ein-Kerem, Israel
| | - Yarden Levy
- Unit of Neuroimmunology and Multiple Sclerosis Center, Hadassah University Hospital, Jerusalem, Ein-Kerem, Israel
| | - Oded Abramsky
- Department of Neurology and The Agnes-Ginges Center for Neurogenetics, Hadassah University Hospital, Jerusalem, Ein-Kerem, Israel
| | - Dimitrios Karussis
- Unit of Neuroimmunology and Multiple Sclerosis Center, Hadassah University Hospital, Jerusalem, Ein-Kerem, Israel
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Willett K, Khan RS, Dine K, Wessel H, Kirshner ZZ, Sauer JL, Ellis A, Brown LR, Shindler KS. Neuroprotection mediated by ST266 requires full complement of proteins secreted by amnion-derived multipotent progenitor cells. PLoS One 2021; 16:e0243862. [PMID: 33406093 PMCID: PMC7787369 DOI: 10.1371/journal.pone.0243862] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 11/27/2020] [Indexed: 11/23/2022] Open
Abstract
ST266 is the biological secretome of cultured Amnion-derived Multipotent Progenitor cells containing multiple growth factors and cytokines. While intranasally-administered ST266 improves the phenotype in experimental optic neuritis, specific ST266 components mediating these effects are not known. We compared the effects of ST266 with and without removal of large molecular weight proteins both in vitro and in the multiple sclerosis model experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice. Mice were treated daily with intranasal vehicle, ST266 or lower molecular weight fraction of ST266. Retinal ganglion cells were counted in isolated retinas, and optic nerves were assessed for inflammation and demyelination. ST266 treatment significantly improved retinal ganglion cell survival and reduced optic nerve demyelination in EAE mice. The lower molecular weight ST266 fraction significantly improved optic nerve demyelination, but only showed a trend towards improved retinal ganglion cell survival. ST266 fractions below 50kDa increased Schwann cell proliferation in vitro, but were less effective than non-fractionated ST266. Demyelination attenuation was partially associated with the lower molecular weight ST266 fraction, but removal of higher molecular weight biomolecules from ST266 diminishes its neuroprotective effects, suggesting at least some high molecular weight proteins play a role in ST266-mediated neuroprotection.
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Affiliation(s)
- Keirnan Willett
- Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Reas S. Khan
- Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Kimberly Dine
- Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Howard Wessel
- Noveome Biotherapeutics, Inc., Pittsburgh, Pennsylvania, United States of America
| | - Ziv Z. Kirshner
- Noveome Biotherapeutics, Inc., Pittsburgh, Pennsylvania, United States of America
| | - Jodie L. Sauer
- Noveome Biotherapeutics, Inc., Pittsburgh, Pennsylvania, United States of America
| | - Ashley Ellis
- Noveome Biotherapeutics, Inc., Pittsburgh, Pennsylvania, United States of America
| | - Larry R. Brown
- Noveome Biotherapeutics, Inc., Pittsburgh, Pennsylvania, United States of America
| | - Kenneth S. Shindler
- Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
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34
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Jafarinia M, Alsahebfosoul F, Salehi H, Eskandari N, Azimzadeh M, Mahmoodi M, Asgary S, Ganjalikhani Hakemi M. Therapeutic effects of extracellular vesicles from human adipose-derived mesenchymal stem cells on chronic experimental autoimmune encephalomyelitis. J Cell Physiol 2020; 235:8779-8790. [PMID: 32329062 DOI: 10.1002/jcp.29721] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 04/05/2020] [Accepted: 04/06/2020] [Indexed: 02/05/2023]
Abstract
Since in cell therapy, there are always concerns about immune rejection, genetic disability, and malignancies, special attention has been paid to extracellular vesicles (EVs) which are secreted by mesenchymal stem cells (MSCs). In the present study, we assessed and compared the therapeutic effects of human adipose-derived mesenchymal stem cells (hADSC) and hADSC-EVs from adipose tissue on experimental autoimmune encephalomyelitis (EAE). After induction of EAE in C57Bl/6 mice, they were treated with hADSCs, hADSC-EVs, or vehicle intravenously. The clinical score of all mice was recorded every other day. Mice were killed at Day 30 and splenocytes were isolated for proliferation assay and determination of the frequency of Treg cells by flow cytometry. Leukocyte infiltration by hematoxylin and eosin, percentages of demyelination areas by luxol fast blue, and mean fluorescence intensity of oligodendrocyte transcription factor 2 (OLIG2) and myelin basic protein (MBP) by immunohistochemistry were assessed in the spinal cord. Our results showed that the maximum mean clinical score and myelin oligodendrocyte glycoprotein-induced proliferation of splenocytes in hADSC- and hADSC-EV-treated mice were significantly lower than the control mice (p < .05). We also demonstrated that the frequency of CD4+ CD25+ Foxp3+ cells was significantly higher in the spleen of hADSC-treated mice than EAE control mice (p = .023). The inflammation score and the percentages of demyelination areas in hADSC- and hADSC-EV-treated groups significantly declined compared with the untreated control group (p < .05). We also showed that there was no significant difference in MFI of MBP and OLIG2 in the spinal cord of studied groups. Overall, we suggest that intravenous administration of hADSC-EVs attenuates the induced EAE through diminishing proliferative potency of T cells, mean clinical score, leukocyte infiltration, and demyelination in a chronic model of multiple sclerosis.
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Affiliation(s)
- Morteza Jafarinia
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fereshteh Alsahebfosoul
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hossein Salehi
- Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nahid Eskandari
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maryam Azimzadeh
- Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Merat Mahmoodi
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Sedigheh Asgary
- Isfahan Cardiovascular Research Centre, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
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35
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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] [MESH Headings] [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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36
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Wu X, Jiang J, Gu Z, Zhang J, Chen Y, Liu X. Mesenchymal stromal cell therapies: immunomodulatory properties and clinical progress. Stem Cell Res Ther 2020; 11:345. [PMID: 32771052 PMCID: PMC7414268 DOI: 10.1186/s13287-020-01855-9] [Citation(s) in RCA: 187] [Impact Index Per Article: 37.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 07/09/2020] [Accepted: 07/27/2020] [Indexed: 02/08/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are a subset of heterogeneous non-hematopoietic fibroblast-like cells that can differentiate into cells of multiple lineages, such as chondrocytes, osteoblasts, adipocytes, myoblasts, and others. These multipotent MSCs can be found in nearly all tissues but mostly located in perivascular niches, playing a significant role in tissue repair and regeneration. Additionally, MSCs interact with immune cells both in innate and adaptive immune systems, modulating immune responses and enabling immunosuppression and tolerance induction. Understanding the biology of MSCs and their roles in clinical treatment is crucial for developing MSC-based cellular therapy for a variety of pathological conditions. Here, we review the progress in the study on the mechanisms underlying the immunomodulatory and regenerative effects of MSCs; update the medical translation of MSCs, focusing on the registration trials leading to regulatory approvals; and discuss how to improve therapeutic efficacy and safety of MSC applications for future.
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Affiliation(s)
- Xiaomo Wu
- Dermatology Institute of Fuzhou, Dermatology Hospital of Fuzhou, Xihong Road 243, Fuzhou, 350025, China
- Department of Biomedicine, University of Basel, Klingelbergstr 70, CH-4056, Basel, Switzerland
| | - Ju Jiang
- Dermatology Institute of Fuzhou, Dermatology Hospital of Fuzhou, Xihong Road 243, Fuzhou, 350025, China
| | - Zhongkai Gu
- The Institute of Biomedical Sciences, Fudan University, Mingdao Building, Dongan Road 131, Shanghai, 200032, China
| | - Jinyan Zhang
- Dermatology Institute of Fuzhou, Dermatology Hospital of Fuzhou, Xihong Road 243, Fuzhou, 350025, China
| | - Yang Chen
- Dermatology Institute of Fuzhou, Dermatology Hospital of Fuzhou, Xihong Road 243, Fuzhou, 350025, China.
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Xihong Road 312, Fuzhou, 350025, China.
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37
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Gramlich OW, Brown AJ, Godwin CR, Chimenti MS, Boland LK, Ankrum JA, Kardon RH. Systemic Mesenchymal Stem Cell Treatment Mitigates Structural and Functional Retinal Ganglion Cell Degeneration in a Mouse Model of Multiple Sclerosis. Transl Vis Sci Technol 2020; 9:16. [PMID: 32855863 PMCID: PMC7422913 DOI: 10.1167/tvst.9.8.16] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 05/26/2020] [Indexed: 01/14/2023] Open
Abstract
Purpose The purpose of this study was to determine mesenchymal stem cell (MSC) therapy efficacy on rescuing the visual system in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS) and to provide new mechanistic insights. Methods EAE was induced in female C57BL6 mice by immunization with myelin oligodendrocyte glycoprotein (MOG)35–55, complete Freund's adjuvant, and pertussis toxin. The findings were compared to sham-immunized mice. Half of the EAE mice received intraperitoneally delivered stem cells (EAE + MSC). Clinical progression was monitored according to a five-point EAE scoring scheme. Pattern electroretinogram (PERG) and retinal nerve fiber layer (RNFL) thickness were measured 32 days after induction. Retinas were harvested to determine retinal ganglion cell (RGC) density and prepared for RNA-sequencing. Results EAE animals that received MSC treatment seven days after EAE induction showed significantly lower motor-sensory impairment, improvement in the PERG amplitude, and preserved RNFL. Analysis of RNA-sequencing data demonstrated statistically significant differences in gene expression in the retina of MSC-treated EAE mice. Differentially expressed genes were enriched for pathways involved in endoplasmic reticulum stress, endothelial cell differentiation, HIF-1 signaling, and cholesterol transport in the MSC-treated EAE group. Conclusions Systemic MSC treatment positively affects RGC function and survival in EAE mice. Better cholesterol handling by increased expression of Abca1, the cholesterol efflux regulatory protein, paired with the resolution of HIF-1 signaling activation might explain the improvements seen in PERG of EAE animals after MSC treatment. Translational Relevance Using MSC therapy in a mouse model of MS, we discovered previously unappreciated biochemical pathways associated with RGC neuroprotection, which have the potential to be pharmacologically targeted as a new treatment regimen.
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Affiliation(s)
- Oliver W Gramlich
- Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, USA.,Center for the Prevention and Treatment of Visual Loss, Iowa City VA Health Care System, Iowa City, IA, USA
| | - Alexander J Brown
- Department of Biomedical Research, National Jewish Health, Denver, CO, USA.,Department of Immunology & Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Cheyanne R Godwin
- Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, USA.,Center for the Prevention and Treatment of Visual Loss, Iowa City VA Health Care System, Iowa City, IA, USA
| | - Michael S Chimenti
- Iowa Institute of Human Genetics, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA
| | - Lauren K Boland
- Roy J. Carver Department of Biomedical Engineering College, The University of Iowa, Iowa City, IA, USA
| | - James A Ankrum
- Roy J. Carver Department of Biomedical Engineering College, The University of Iowa, Iowa City, IA, USA
| | - Randy H Kardon
- Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, USA.,Center for the Prevention and Treatment of Visual Loss, Iowa City VA Health Care System, Iowa City, IA, USA
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38
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Secretome Analysis of Mesenchymal Stem Cell Factors Fostering Oligodendroglial Differentiation of Neural Stem Cells In Vivo. Int J Mol Sci 2020; 21:ijms21124350. [PMID: 32570968 PMCID: PMC7352621 DOI: 10.3390/ijms21124350] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 06/14/2020] [Accepted: 06/16/2020] [Indexed: 12/16/2022] Open
Abstract
Mesenchymal stem cell (MSC)-secreted factors have been shown to significantly promote oligodendrogenesis from cultured primary adult neural stem cells (aNSCs) and oligodendroglial precursor cells (OPCs). Revealing underlying mechanisms of how aNSCs can be fostered to differentiate into a specific cell lineage could provide important insights for the establishment of novel neuroregenerative treatment approaches aiming at myelin repair. However, the nature of MSC-derived differentiation and maturation factors acting on the oligodendroglial lineage has not been identified thus far. In addition to missing information on active ingredients, the degree to which MSC-dependent lineage instruction is functional in vivo also remains to be established. We here demonstrate that MSC-derived factors can indeed stimulate oligodendrogenesis and myelin sheath generation of aNSCs transplanted into different rodent central nervous system (CNS) regions, and furthermore, we provide insights into the underlying mechanism on the basis of a comparative mass spectrometry secretome analysis. We identified a number of secreted proteins known to act on oligodendroglia lineage differentiation. Among them, the tissue inhibitor of metalloproteinase type 1 (TIMP-1) was revealed to be an active component of the MSC-conditioned medium, thus validating our chosen secretome approach.
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Xin Y, Gao J, Hu R, Li H, Li Q, Han F, He Z, Lai L, Su M. Changes of immune parameters of T lymphocytes and macrophages in EAE mice after BM-MSCs transplantation. Immunol Lett 2020; 225:66-73. [PMID: 32544469 DOI: 10.1016/j.imlet.2020.05.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 04/21/2020] [Accepted: 05/14/2020] [Indexed: 12/15/2022]
Abstract
Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory infiltration, demyelination and axonal injury. Mesenchymal stem cells (MSCs) are pluripotent which can not only differentiate into many types of cells, but also have immunomodulatory effects. We show here that the transplantation of bone marrow MSCs (BM-MSCs) prevents the development of experimental autoimmune encephalomyelitis (EAE), the most common animal model of MS. Furthermore, we demonstrate that the immunologic mechanism by which BM-MSC transplantation ameliorates EAE involves inhibiting the proliferation and activation of T cells, reducing the production of inflammatory cytokines, and regulating macrophage responses, especially the macrophage polarization. The findings broaden our understanding about the regulation of T cell and macrophage immune responses by MSC transplantation.
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Affiliation(s)
- Ying Xin
- Department of Human Histology and Embryology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, 550025, China
| | - Jie Gao
- Department of Human Histology and Embryology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, 550025, China
| | - Rong Hu
- Department of Human Histology and Embryology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, 550025, China
| | - Hong Li
- Department of Human Histology and Embryology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, 550025, China
| | - Qian Li
- Department of Human Histology and Embryology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, 550025, China
| | - Feng Han
- Department of Neurosurgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550004, China.
| | - Zhixu He
- Key Laboratory for Adult Stem Cell Translational Research, Chinese Academy of Medical Sciences, Guiyang, Guizhou, 550004, China
| | - Laijun Lai
- Department of Allied Health Science, University of Connecticut, 1390 Storrs Road, Storrs, CT, 06269, USA
| | - Min Su
- Department of Human Histology and Embryology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, 550025, China; Key Laboratory for Adult Stem Cell Translational Research, Chinese Academy of Medical Sciences, Guiyang, Guizhou, 550004, China.
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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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Le Thi Bich P, Nguyen Thi H, Dang Ngo Chau H, Phan Van T, Do Q, Dong Khac H, Le Van D, Nguyen Huy L, Mai Cong K, Ta Ba T, Do Minh T, Vu Bich N, Truong Chau N, Van Pham P. Allogeneic umbilical cord-derived mesenchymal stem cell transplantation for treating chronic obstructive pulmonary disease: a pilot clinical study. Stem Cell Res Ther 2020; 11:60. [PMID: 32054512 PMCID: PMC7020576 DOI: 10.1186/s13287-020-1583-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 01/02/2020] [Accepted: 02/04/2020] [Indexed: 12/12/2022] Open
Abstract
Introduction Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. COPD results from chronic inflammation of the lungs. Current treatments, including physical and chemical therapies, provide limited results. Stem cells, particularly mesenchymal stem cells (MSCs), are used to treat COPD. Here, we evaluated the safety and efficacy of umbilical cord-derived (UC)-MSCs for treating COPD. Methods Twenty patients were enrolled, 9 at stage C and 11 at stage D per the Global Initiative for Obstructive Lung Disease (GOLD) classification. Patients were infused with 106 cells/kg of expanded allogeneic UC-MSCs. All patients were followed for 6 months after the first infusion. The treatment end-point included a comprehensive safety evaluation, pulmonary function testing (PFT), and quality-of-life indicators including questionnaires, the 6-min walk test (6MWT), and systemic inflammation assessments. All patients completed the full infusion and 6-month follow-up. Results No infusion-related toxicities, deaths, or severe adverse events occurred that were deemed related to UC-MSC administration. The UC-MSC-transplanted patients showed a significantly reduced Modified Medical Research Council score, COPD assessment test, and number of exacerbations. However, the forced expiratory volume in 1 s, C-reactive protein, and 6MWT values were nonsignificantly reduced after treatment (1, 3, and 6 months) compared with those before the treatment. Conclusion Systemic UC-MSC administration appears to be safe in patients with moderate-to-severe COPD, can significantly improve their quality of life, and provides a basis for subsequent cell therapy investigations. Trial registration ISRCTN, ISRCTN70443938. Registered 06 July 2019
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Affiliation(s)
| | - Ha Nguyen Thi
- Van Hanh General Hospital, Ho Chi Minh City, Viet Nam
| | | | - Tien Phan Van
- Van Hanh General Hospital, Ho Chi Minh City, Viet Nam
| | - Quyet Do
- Vietnam Millitay Academy 103, Ha Noi, Viet Nam
| | | | - Dong Le Van
- Vietnam Millitay Academy 103, Ha Noi, Viet Nam
| | | | | | - Thang Ta Ba
- Vietnam Millitay Academy 103, Ha Noi, Viet Nam
| | | | - Ngoc Vu Bich
- Stem Cell Institute, VNUHCM University of Science, Ho Chi Minh City, Viet Nam
| | - Nhat Truong Chau
- Stem Cell Institute, VNUHCM University of Science, Ho Chi Minh City, Viet Nam
| | - Phuc Van Pham
- Stem Cell Institute, VNUHCM University of Science, Ho Chi Minh City, Viet Nam. .,Laboratory of Stem Cell Research and Application, VNUHCM University of Science, Ho Chi Minh City, Viet Nam.
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Khamis T, Abdelalim AF, Abdallah SH, Saeed AA, Edress NM, Arisha AH. Early intervention with breast milk mesenchymal stem cells attenuates the development of diabetic-induced testicular dysfunction via hypothalamic Kisspeptin/Kiss1r-GnRH/GnIH system in male rats. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165577. [DOI: 10.1016/j.bbadis.2019.165577] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 10/22/2019] [Accepted: 10/23/2019] [Indexed: 02/07/2023]
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Short and Long Term Clinical and Immunologic Follow up after Bone Marrow Mesenchymal Stromal Cell Therapy in Progressive Multiple Sclerosis-A Phase I Study. J Clin Med 2019; 8:jcm8122102. [PMID: 31810187 PMCID: PMC6947442 DOI: 10.3390/jcm8122102] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 11/20/2019] [Accepted: 11/21/2019] [Indexed: 12/20/2022] Open
Abstract
Bone marrow derived mesenchymal stromal cells (BM-MSCs) have emerged as a possible new therapy for Multiple Sclerosis (MS), however studies regarding efficacy and in vivo immune response have been limited and inconclusive. We conducted a phase I clinical study assessing safety and clinical and peripheral immune responses after MSC therapy in MS. Seven patients with progressive MS were intravenously infused with a single dose of autologous MSC (1–2 × 106 MSCs/kg body weight). The infusions were safe and well tolerated when given during clinical remission. Five out of seven patients completed the follow up of 48 weeks post-infusion. Brain magnetic resonance imaging (MRI) showed the absence of new T2 lesions at 12 weeks in 5/6 patients, while 3/5 had accumulated new T2 lesions at 48 weeks. Patient expanded disability status scales (EDSS) were stable in 6/6 at 12 weeks but declined in 3/5 patients at 48 weeks. Early changes of circulating microRNA levels (2 h) and increased proportion of FOXP3+ Tregs were detected at 7 days post-infusion compared to baseline levels. In conclusion, MSC therapy was safe and well tolerated and is associated with possible transient beneficial clinical and peripheral immunotolerogenic effects.
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Richard SA. Elucidating the novel biomarker and therapeutic potentials of High-mobility group box 1 in Subarachnoid hemorrhage: A review. AIMS Neurosci 2019; 6:316-332. [PMID: 32341986 PMCID: PMC7179354 DOI: 10.3934/neuroscience.2019.4.316] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 11/21/2019] [Indexed: 12/13/2022] Open
Abstract
Subarachnoid hemorrhage (SAH) frequently arises after an aneurysm in a cerebral artery ruptures, resulting into bleeding as well as clot formation. High-mobility group box 1 (HMGB1) is an extremely preserved, universal protein secreted in the nuclei of all cell varieties. This review explores the biomarker as well as therapeutic potentials of HMBG1 in SAH especially during the occurrence of cerebral vasospasms. Plasma HMGB1 levels have proven to be very useful prognosticators of effective outcome as well as death after SAH. Correspondingly, higher HMGB1 levels in the cerebrospinal fluid (CSF) of SAH patients correlated well with poor outcome; signifying that, CSF level of HMGB1 is a novel predictor of outcome following SAH. Nonetheless, the degree of angiographic vasospasm does not always correlate with the degree of neurological deficits in SAH patients. HMGB1 stimulated cerebral vasospasm, augmented gene as well as protein secretory levels of receptor for advance glycation end product (RAGE) in neurons following SAH; which means that, silencing HMGB1 during SAH could be of therapeutic value. Compounds like resveratrol, glycyrrhizin, rhinacanthin, purpurogallin, 4′-O-β-D-Glucosyl-5-O-Methylvisamminol (4OGOMV) as well as receptor-interacting serine/threonine-protein kinase 3 (RIPK3) gene are capable of interacting with HMGB1 resulting in therapeutic benefits following SAH.
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Affiliation(s)
- Seidu A Richard
- Department of Medicine, Princefield University, P. O. Box MA 128, Ho-Volta Region, Ghana West Africa
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Neuralized mesenchymal stem cells (NMSC) exhibit phenotypical, and biological evidence of neuronal transdifferentiation and suppress EAE more effectively than unmodified MSC. Immunol Lett 2019; 212:6-13. [DOI: 10.1016/j.imlet.2019.05.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 05/15/2019] [Accepted: 05/20/2019] [Indexed: 12/22/2022]
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Ge S, Jiang X, Paul D, Song L, Wang X, Pachter JS. Human ES-derived MSCs correct TNF-α-mediated alterations in a blood-brain barrier model. Fluids Barriers CNS 2019; 16:18. [PMID: 31256757 PMCID: PMC6600885 DOI: 10.1186/s12987-019-0138-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 05/27/2019] [Indexed: 02/07/2023] Open
Abstract
Background Immune cell trafficking into the CNS is considered to contribute to pathogenesis in MS and its animal model, EAE. Disruption of the blood–brain barrier (BBB) is a hallmark of these pathologies and a potential target of therapeutics. Human embryonic stem cell-derived mesenchymal stem/stromal cells (hES-MSCs) have shown superior therapeutic efficacy, compared to bone marrow-derived MSCs, in reducing clinical symptoms and neuropathology of EAE. However, it has not yet been reported whether hES-MSCs inhibit and/or repair the BBB damage associated with neuroinflammation that accompanies EAE. Methods BMECs were cultured on Transwell inserts as a BBB model for all the experiments. Disruption of BBB models was induced by TNF-α, a pro-inflammatory cytokine that is a hallmark of acute and chronic neuroinflammation. Results Results indicated that hES-MSCs reversed the TNF-α-induced changes in tight junction proteins, permeability, transendothelial electrical resistance, and expression of adhesion molecules, especially when these cells were placed in direct contact with BMEC. Conclusions hES-MSCs and/or products derived from them could potentially serve as novel therapeutics to repair BBB disturbances in MS. Electronic supplementary material The online version of this article (10.1186/s12987-019-0138-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Shujun Ge
- Blood-Brain Barrier Laboratory, Dept. of Immunology, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA.
| | - Xi Jiang
- Blood-Brain Barrier Laboratory, Dept. of Immunology, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA.,Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Debayon Paul
- Blood-Brain Barrier Laboratory, Dept. of Immunology, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA
| | - Li Song
- ImStem Biotechnology, Inc., 400 Farmington Ave., Farmington, CT, 06030, USA
| | - Xiaofang Wang
- ImStem Biotechnology, Inc., 400 Farmington Ave., Farmington, CT, 06030, USA
| | - Joel S Pachter
- Blood-Brain Barrier Laboratory, Dept. of Immunology, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA
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Vaes JEG, Vink MA, de Theije CGM, Hoebeek FE, Benders MJNL, Nijboer CHA. The Potential of Stem Cell Therapy to Repair White Matter Injury in Preterm Infants: Lessons Learned From Experimental Models. Front Physiol 2019; 10:540. [PMID: 31143126 PMCID: PMC6521595 DOI: 10.3389/fphys.2019.00540] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 04/17/2019] [Indexed: 12/12/2022] Open
Abstract
Diffuse white matter injury (dWMI) is a major cause of morbidity in the extremely preterm born infant leading to life-long neurological impairments, including deficits in cognitive, motor, sensory, psychological, and behavioral functioning. At present, no treatment options are clinically available to combat dWMI and therefore exploration of novel strategies is urgently needed. In recent years, the pathophysiology underlying dWMI has slowly started to be unraveled, pointing towards the disturbed maturation of oligodendrocytes (OLs) as a key mechanism. Immature OL precursor cells in the developing brain are believed to be highly sensitive to perinatal inflammation and cerebral oxygen fluctuations, leading to impaired OL differentiation and eventually myelination failure. OL lineage development under normal and pathological circumstances and the process of (re)myelination have been studied extensively over the years, often in the context of other adult and pediatric white matter pathologies such as stroke and multiple sclerosis (MS). Various studies have proposed stem cell-based therapeutic strategies to boost white matter regeneration as a potential strategy against a wide range of neurological diseases. In this review we will discuss experimental studies focusing on mesenchymal stem cell (MSC) therapy to reduce white matter injury (WMI) in multiple adult and neonatal neurological diseases. What lessons have been learned from these previous studies and how can we translate this knowledge to application of MSCs for the injured white matter in the preterm infant? A perspective on the current state of stem cell therapy will be given and we will discuss different important considerations of MSCs including cellular sources, timing of treatment and administration routes. Furthermore, we reflect on optimization strategies that could potentially reinforce stem cell therapy, including preconditioning and genetic engineering of stem cells or using cell-free stem cell products, to optimize cell-based strategy for vulnerable preterm infants in the near future.
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Affiliation(s)
- Josine E G Vaes
- NIDOD Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Department of Neonatology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Marit A Vink
- NIDOD Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Caroline G M de Theije
- NIDOD Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Freek E Hoebeek
- NIDOD Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Manon J N L Benders
- Department of Neonatology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Cora H A Nijboer
- NIDOD Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
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Uccelli A, Laroni A, Brundin L, Clanet M, Fernandez O, Nabavi SM, Muraro PA, Oliveri RS, Radue EW, Sellner J, Soelberg Sorensen P, Sormani MP, Wuerfel JT, Battaglia MA, Freedman MS. MEsenchymal StEm cells for Multiple Sclerosis (MESEMS): a randomized, double blind, cross-over phase I/II clinical trial with autologous mesenchymal stem cells for the therapy of multiple sclerosis. Trials 2019; 20:263. [PMID: 31072380 PMCID: PMC6507027 DOI: 10.1186/s13063-019-3346-z] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 04/03/2019] [Indexed: 01/09/2023] Open
Abstract
Background Multiple sclerosis (MS) is an inflammatory disease of the central nervous system with a degenerative component, leading to irreversible disability. Mesenchymal stem cells (MSC) have been shown to prevent inflammation and neurodegeneration in animal models of MS, but no large phase II clinical trials have yet assessed the exploratory efficacy of MSC for MS. Methods/design This is an academic, investigator-initiated, randomized, double-blind, placebo-compared phase I/II clinical trial with autologous, bone-marrow derived MSC in MS. Enrolled subjects will receive autologous MSC at either baseline or at week 24, through a cross-over design. Primary co-objectives are to test safety and efficacy of MSC treatment compared to placebo at 6 months. Secondary objectives will evaluate the efficacy of MSC at clinical and MRI levels. In order to overcome funding constraints, the MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) study has been designed to merge partially independent clinical trials, following harmonized protocols and sharing some key centralized procedures, including data collection and analyses. Discussion Results will provide patients and the scientific community with data on the safety and efficacy of MSC for MS. The innovative approach utilized to obtain funds to support the MESEMS trial could represent a new model to circumvent limitation of funds encountered by academic trials. Trial registration Andalusia: NCT01745783, registered on Dec 10, 2012. Badalona: NCT02035514 EudraCT, 2010–024081–21. Registered on 2012. Canada: ClinicalTrials.gov, NCT02239393. Registered on September 12, 2014. Copenhagen: EudraCT, 2012–000518-13. Registered on June 21, 2012. Italy: EudraCT, 2011–001295-19, and ClinicalTrials.gov, NCT01854957. Retrospectively registered on May 16, 2013. London: Eudra CT 2012–002357-35, and ClinicalTrials.gov, NCT01606215. Registered on May 25, 2012. Salzburg: EudraCT, 2015–000137-78. Registered on September 15, 2015. Stockholm: ClinicalTrials.gov, NCT01730547. Registered on November 21, 2012. Toulouse: ClinicalTrials.gov, NCT02403947. Registered on March 31, 2015. Electronic supplementary material The online version of this article (10.1186/s13063-019-3346-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Antonio Uccelli
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and Center of Excellence for Biomedical Research (CEBR), University of Genova, Largo Daneo 3, 16132, Genoa, Italy. .,IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
| | - Alice Laroni
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and Center of Excellence for Biomedical Research (CEBR), University of Genova, Largo Daneo 3, 16132, Genoa, Italy.,IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Lou Brundin
- Karolinska Institutet, R3:04 Karolinska University Hospital 171 76, Stockholm, Sweden
| | - Michel Clanet
- CHU Toulouse, Université Paul Sabatier, INSERM UMR, 1043, Toulouse, France
| | - Oscar Fernandez
- Instituto de Investigación Biomédica de Málaga (IBIMA), Regional University Hospital of Malaga, Malaga, Spain
| | - Seyed Massood Nabavi
- Department of Brain and Cognitive Sciences, Royan Institute for Stem Cell Biology and Technology, Royan, Iran.,ACCR, Iran and Regenerative Biomedicine Center, MS, Neurology Clinic and Research Unit, Tehran, Iran
| | - Paolo A Muraro
- Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK
| | - Roberto S Oliveri
- Cell Therapy Unit, Department of Clinical Immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Ernst W Radue
- Medical Image Analysis Centre Basel (MIAC AG), Basel, Switzerland
| | - Johann Sellner
- Department of Neurology, Christian Doppler Medical Center, Paracelsus Medical University, Salzburg, Austria
| | - Per Soelberg Sorensen
- Danish MS Center Department of Neurology, University of Copenhagen and Rigshospitalet, Copenhagen, Denmark
| | | | - Jens Thomas Wuerfel
- Medical Image Analysis Centre Basel (MIAC AG), Basel, Switzerland.,Department of Biomedical Engineering, University Basel, Basel, Switzerland
| | - Mario A Battaglia
- Italian Multiple Sclerosis Foundation, Genoa, Italy.,Department of Life Sciences, University of Siena, Siena, Italy
| | - Mark S Freedman
- Department of Medicine (Neurology), University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
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Valitsky M, Benhamron S, Nitzan K, Karussis D, Ella E, Abramsky O, Kassis I, Rosenmann H. Cerebrospinal Fluid (CSF) Exchange with Artificial CSF Enriched with Mesenchymal Stem Cell Secretions Ameliorates Experimental Autoimmune Encephalomyelitis. Int J Mol Sci 2019; 20:ijms20071793. [PMID: 30978957 PMCID: PMC6480705 DOI: 10.3390/ijms20071793] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 03/28/2019] [Accepted: 04/08/2019] [Indexed: 12/13/2022] Open
Abstract
The complexity of central nervous system (CNS) degenerative/inflammatory diseases and the lack of substantially effective treatments point to the need for a broader therapeutic approach to target multiple components involved in the disease pathogenesis. We suggest a novel approach directed for the elimination of pathogenic agents from the CNS and, in parallel, its enrichment with an array of neuroprotective substances, using a "cerebrospinal fluid (CSF) exchange" procedure, in which endogenous (pathogenic) CSF is removed and replaced by artificial CSF (aCSF) enriched with secretions of human mesenchymal stem cells (MSCs). MSCs produce a variety of neuroprotective agents and have shown beneficial effects when cells are transplanted in animals and patients with CNS diseases. Our data show that MSCs grown in aCSF secrete neurotrophic factors, anti-inflammatory cytokines, and anti-oxidant agents; moreover, MSC-secretions-enriched-aCSF exerts neuroprotective and immunomodulatory effects in neuronal cell lines and spleen lymphocytes. Treatment of experimental-autoimmune-encephalomyelitis (EAE) mice with this enriched-aCSF using an intracerebroventricular (ICV) CSF exchange procedure ("CSF exchange therapy") caused a significant delay in the onset of EAE and amelioration of the clinical symptoms, paralleled by a reduction in axonal damage and demyelination. These findings point to the therapeutic potential of the CSF exchange therapy using MSC-secretions-enriched-aCSF in inflammatory/degenerative diseases of the CNS.
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Affiliation(s)
- Michael Valitsky
- The Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel.
| | - Sandrine Benhamron
- The Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel.
| | - Keren Nitzan
- The Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel.
| | - Dimitrios Karussis
- The Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel.
| | - Ezra Ella
- The Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel.
| | - Oded Abramsky
- The Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel.
| | - Ibrahim Kassis
- The Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel.
| | - Hanna Rosenmann
- The Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel.
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Cuascut FX, Hutton GJ. Stem Cell-Based Therapies for Multiple Sclerosis: Current Perspectives. Biomedicines 2019; 7:biomedicines7020026. [PMID: 30935074 PMCID: PMC6631931 DOI: 10.3390/biomedicines7020026] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 03/22/2019] [Accepted: 03/25/2019] [Indexed: 12/29/2022] Open
Abstract
Multiple sclerosis (MS) is an inflammatory and neurodegenerative autoimmune disease of the central nervous system (CNS). Disease-modifying therapies (DMT) targeting inflammation have been shown to reduce disease activity in patients with relapsing–remitting MS (RRMS). The current therapeutic challenge is to find an effective treatment to halt disease progression and reverse established neural damage. Stem cell-based therapies have emerged to address this dilemma. Several types of stem cells have been considered for clinical use, such as autologous hematopoietic (aHSC), mesenchymal (MSC), neuronal (NSC), human embryonic (hESC), and induced pluripotent (iPSC) stem cells. There is convincing evidence that immunoablation followed by hematopoietic therapy (aHSCT) has a high efficacy for suppressing inflammatory MS activity and improving neurological disability in patients with RRMS. In addition, MSC therapy may be a safe and tolerable treatment, but its clinical value is still under evaluation. Various studies have shown early promising results with other cellular therapies for CNS repair and decreasing inflammation. In this review, we discuss the current knowledge and limitations of different stem cell-based therapies for the treatment of patients with MS.
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Affiliation(s)
- Fernando X Cuascut
- Baylor College of Medicine, Maxine Mesigner Multiple Sclerosis Center, Houston, TX 77030, USA.
| | - George J Hutton
- Baylor College of Medicine, Maxine Mesigner Multiple Sclerosis Center, Houston, TX 77030, USA.
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