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1
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Wu Y, Zhao Y, Guan Z, Esmaeili S, Xiao Z, Kuriakose D. JNK3 inhibitors as promising pharmaceuticals with neuroprotective properties. Cell Adh Migr 2024; 18:1-11. [PMID: 38357988 PMCID: PMC10878020 DOI: 10.1080/19336918.2024.2316576] [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: 05/17/2023] [Accepted: 02/06/2024] [Indexed: 02/16/2024] Open
Abstract
The intensive study and investigation of neuroprotective therapy for central nervous system (CNS) diseases is ongoing. Due to shared mechanisms of neurodegeneration, a neuroprotective approach might offer benefits across multiple neurological disorders, despite variations in symptoms or injuries. C-Jun N-terminal Kinase 3 (JNK3) is found primarily in the CNS and is involved in physiological processes such as brain development, synapse formation, and memory formation. The potential of JNK3 as a target for pharmacological development holds promise for advancing neuroprotective therapies. Developing small molecule JNK3 inhibitors into drugs with neuroprotective qualities could facilitate neuronal restoration and self-repair. This review focuses on elucidating key neuroprotective mechanisms, exploring the interplay between neurodegenerative diseases and neuroprotection, and discussing advancements in JNK3 inhibitor drug development.
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Affiliation(s)
- Yibeini Wu
- Department of Anatomy and Developmental biology, Monash University, Clayton, Vic, Australia
| | - Yiling Zhao
- Shaoxing Institute, Zhejiang University, Shaoxing, China
| | - Ziman Guan
- Department of Anatomy and Developmental biology, Monash University, Clayton, Vic, Australia
| | - Sajjad Esmaeili
- Department of Anatomy and Developmental biology, Monash University, Clayton, Vic, Australia
| | - Zhicheng Xiao
- Department of Anatomy and Developmental biology, Monash University, Clayton, Vic, Australia
- Shaoxing Institute, Zhejiang University, Shaoxing, China
| | - Diji Kuriakose
- Department of Anatomy and Developmental biology, Monash University, Clayton, Vic, Australia
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2
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Zou XF, Zhang BZ, Qian WW, Cheng FM. Bone marrow mesenchymal stem cells in treatment of peripheral nerve injury. World J Stem Cells 2024; 16:799-810. [PMID: 39219723 PMCID: PMC11362854 DOI: 10.4252/wjsc.v16.i8.799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 05/20/2024] [Accepted: 08/05/2024] [Indexed: 08/26/2024] Open
Abstract
Peripheral nerve injury (PNI) is a common neurological disorder and complete functional recovery is difficult to achieve. In recent years, bone marrow mesenchymal stem cells (BMSCs) have emerged as ideal seed cells for PNI treatment due to their strong differentiation potential and autologous transplantation ability. This review aims to summarize the molecular mechanisms by which BMSCs mediate nerve repair in PNI. The key mechanisms discussed include the differentiation of BMSCs into multiple types of nerve cells to promote repair of nerve injury. BMSCs also create a microenvironment suitable for neuronal survival and regeneration through the secretion of neurotrophic factors, extracellular matrix molecules, and adhesion molecules. Additionally, BMSCs release pro-angiogenic factors to promote the formation of new blood vessels. They modulate cytokine expression and regulate macrophage polarization, leading to immunomodulation. Furthermore, BMSCs synthesize and release proteins related to myelin sheath formation and axonal regeneration, thereby promoting neuronal repair and regeneration. Moreover, this review explores methods of applying BMSCs in PNI treatment, including direct cell transplantation into the injured neural tissue, implantation of BMSCs into nerve conduits providing support, and the application of genetically modified BMSCs, among others. These findings confirm the potential of BMSCs in treating PNI. However, with the development of this field, it is crucial to address issues related to BMSC therapy, including establishing standards for extracting, identifying, and cultivating BMSCs, as well as selecting application methods for BMSCs in PNI such as direct transplantation, tissue engineering, and genetic engineering. Addressing these issues will help translate current preclinical research results into clinical practice, providing new and effective treatment strategies for patients with PNI.
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Affiliation(s)
- Xiong-Fei Zou
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Beijing 100730, China
| | - Bao-Zhong Zhang
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Beijing 100730, China.
| | - Wen-Wei Qian
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Beijing 100730, China
| | - Florence Mei Cheng
- College of Nursing, The Ohio State University, Ohio, OH 43210, United States
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3
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Subbarayan R, Murugan Girija D, Raja STK, Krishnamoorthy A, Srinivasan D, Shrestha R, Srivastava N, Ranga Rao S. Conditioned medium-enriched umbilical cord mesenchymal stem cells: a potential therapeutic strategy for spinal cord injury, unveiling transcriptomic and secretomic insights. Mol Biol Rep 2024; 51:570. [PMID: 38658405 DOI: 10.1007/s11033-024-09503-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 04/02/2024] [Indexed: 04/26/2024]
Abstract
INTRODUCTION Spinal cord injury (SCI) leads to significant destruction of nerve tissue, causing the degeneration of axons and the formation of cystic cavities. This study aimed to examine the characteristics of human umbilical cord-derived mesenchymal stem cells (HUCMSCs) cultured in a serum-free conditioned medium (CM) and assess their effectiveness in a well-established hemitransection SCI model. MATERIALS AND METHODS In this study, HUCMSCs cultured medium was collected and characterized by measuring IL-10 and identifying proteomics using mass spectroscopy. This collected serum-free CM was further used in the experiments to culture and characterize the HUMSCs. Later, neuronal cells derived from CM-enriched HUCMSC were tested sequentially using an injectable caffeic acid-bioconjugated gelatin (CBG), which was further transplanted in a hemitransection SCI model. In vitro, characterization of CM-enriched HUCMSCs and differentiated neuronal cells was performed using flow cytometry, immunofluorescence, electron microscopy, and post-transplant analysis using immunohistology analysis, qPCR, in vivo bioluminescence imaging, and behavioral analysis using an infrared actimeter. RESULTS The cells that were cultured in the conditioned media produced a pro-inflammatory cytokine called IL-10. Upon examining the secretome of the conditioned media, the Kruppel-like family of KRAB and zinc-finger proteins (C2H2 and C4) were found to be activated. Transcriptome analysis also revealed an increased expression of ELK-1, HOXD8, OTX2, YY1, STAT1, ETV7, and PATZ1 in the conditioned media. Furthermore, the expression of Human Stem-101 confirmed proliferation during the first 3 weeks after transplantation, along with the migration of CBG-UCNSC cells within the transplanted area. The gene analysis showed increased expression of Nestin, NeuN, Calb-2, Msi1, and Msi2. The group that received CBG-UCNSC therapy showed a smooth recovery by the end of week 2, with most rats regaining their walking abilities similar to those before the spinal cord injury by week 5. CONCLUSIONS In conclusion, the CBG-UCNSC method effectively preserved the integrity of the transplanted neuronal-like cells and improved locomotor function. Thus, CM-enriched cells can potentially reduce biosafety risks associated with animal content, making them a promising option for clinical applications in treating spinal cord injuries.
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Affiliation(s)
- Rajasekaran Subbarayan
- Centre for Advanced Biotherapeutics and Regenerative Medicine, Research-FAHS, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, 603013, India.
| | | | | | | | - Dhasarathdev Srinivasan
- Centre for Advanced Biotherapeutics and Regenerative Medicine, Research-FAHS, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, 603013, India
| | | | | | - Suresh Ranga Rao
- Department of Engineering Design, Indian Institute of Technology Madras, Chennai, India
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4
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Chen SY, Yang RL, Wu XC, Zhao DZ, Fu SP, Lin FQ, Li LY, Yu LM, Zhang Q, Zhang T. Mesenchymal Stem Cell Transplantation: Neuroprotection and Nerve Regeneration After Spinal Cord Injury. J Inflamm Res 2023; 16:4763-4776. [PMID: 37881652 PMCID: PMC10595983 DOI: 10.2147/jir.s428425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 10/03/2023] [Indexed: 10/27/2023] Open
Abstract
Spinal Cord Injury (SCI), with its morbidity characteristics of high disability rate and high mortality rate, is a disease that is highly destructive to both the physiology and psychology of the patient, and for which there is still a lack of effective treatment. Following spinal cord injury, a cascade of secondary injury reactions known as ischemia, peripheral inflammatory cell infiltration, oxidative stress, etc. create a microenvironment that is unfavorable to neural recovery and ultimately results in apoptosis and necrosis of neurons and glial cells. Mesenchymal stem cell (MSC) transplantation has emerged as a more promising therapeutic options in recent years. MSC can promote spinal cord injury repair through a variety of mechanisms, including immunomodulation, neuroprotection, and nerve regeneration, giving patients with spinal cord injury hope. In this paper, it is discussed the neuroprotection and nerve regeneration components of MSCs' therapeutic method for treating spinal cord injuries.
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Affiliation(s)
- Si-Yu Chen
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Rui-Lin Yang
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Xiang-Chong Wu
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - De-Zhi Zhao
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Sheng-Ping Fu
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Feng-Qin Lin
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Lin-Yan Li
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Li-Mei Yu
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Qian Zhang
- Department of Human Anatomy, Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
| | - Tao Zhang
- Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
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5
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Chouaib B, Haack-Sørensen M, Chaubron F, Cuisinier F, Collart-Dutilleul PY. Towards the Standardization of Mesenchymal Stem Cell Secretome-Derived Product Manufacturing for Tissue Regeneration. Int J Mol Sci 2023; 24:12594. [PMID: 37628774 PMCID: PMC10454619 DOI: 10.3390/ijms241612594] [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: 06/07/2023] [Revised: 07/29/2023] [Accepted: 08/05/2023] [Indexed: 08/27/2023] Open
Abstract
Mesenchymal stem cell secretome or conditioned medium (MSC-CM) is a combination of biomolecules and growth factors in cell culture growth medium, secreted by mesenchymal stem cells (MSCs), and the starting point of several derived products. MSC-CM and its derivatives could be applied after injuries and could mediate most of the beneficial regenerative effects of MSCs without the possible side effects of using MSCs themselves. However, before the clinical application of these promising biopharmaceuticals, several issues such as manufacturing protocols and quality control must be addressed. This review aims to underline the influence of the procedure for conditioned medium production on the quality of the secretome and its derivatives and highlights the questions considering cell sources and donors, cell expansion, cell passage number and confluency, conditioning period, cell culture medium, microenvironment cues, and secretome-derived product purification. A high degree of variability in MSC secretomes is revealed based on these parameters, confirming the need to standardize and optimize protocols. Understanding how bioprocessing and manufacturing conditions interact to determine the quantity, quality, and profile of MSC-CM is essential to the development of good manufacturing practice (GMP)-compliant procedures suitable for replacing mesenchymal stem cells in regenerative medicine.
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Affiliation(s)
- Batoul Chouaib
- LBN, University of Montpellier, 34000 Montpellier, France; (B.C.); (F.C.)
- Human Health Department, IRSN, French Institute for Radiological Protection and Nuclear Safety, SERAMED, LRMed, 92262 Fontenay-aux-Roses, France
| | - Mandana Haack-Sørensen
- Cardiology Stem Cell Centre 9302, Rigshospitalet University of Copenhagen, Henrik Harpestrengsvej 4C, 2100 Copenhagen, Denmark
| | - Franck Chaubron
- Institut Clinident BioPharma, Biopôle Clermont-Limagne, 63360 Saint Beauzire, France;
| | - Frederic Cuisinier
- LBN, University of Montpellier, 34000 Montpellier, France; (B.C.); (F.C.)
- Faculty of Dentistry, University of Montpellier, 34000 Montpellier, France
- Service Odontologie, CHU Montpellier, 34000 Montpellier, France
| | - Pierre-Yves Collart-Dutilleul
- LBN, University of Montpellier, 34000 Montpellier, France; (B.C.); (F.C.)
- Faculty of Dentistry, University of Montpellier, 34000 Montpellier, France
- Service Odontologie, CHU Montpellier, 34000 Montpellier, France
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6
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Nasiry D, Khalatbary AR. Stem cell-derived extracellular vesicle-based therapy for nerve injury: A review of the molecular mechanisms. World Neurosurg X 2023; 19:100201. [PMID: 37181584 PMCID: PMC10173266 DOI: 10.1016/j.wnsx.2023.100201] [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: 10/30/2022] [Revised: 04/10/2023] [Accepted: 04/19/2023] [Indexed: 05/16/2023] Open
Abstract
Recent evidence suggests that stem cell therapy has beneficial effects on nerve damage. These beneficial effects were subsequently found to be exerted in part in a paracrine manner by the release of extracellular vesicles. Stem cell-secreted extracellular vesicles have shown great potential to reduce inflammation and apoptosis, optimize the function of Schwann cells, regulate genes related to regeneration, and improve behavioral performance after nerve damage. This review summarizes the current knowledge on the effect of stem cell-derived extracellular vesicles on neuroprotection and regeneration along with their molecular mechanisms after nerve damage.
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Affiliation(s)
- Davood Nasiry
- Amol Faculty of Paramedicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Ali Reza Khalatbary
- Cellular and Molecular Research Center, Mazandaran University of Medical Sciences, Sari, Iran
- Corresponding author.
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7
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Han W, Meißner EM, Neunteibl S, Günther M, Kahnt J, Dolga A, Xie C, Plesnila N, Zhu C, Blomgren K, Culmsee C. Dying transplanted neural stem cells mediate survival bystander effects in the injured brain. Cell Death Dis 2023; 14:173. [PMID: 36854658 PMCID: PMC9975220 DOI: 10.1038/s41419-023-05698-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 02/02/2023] [Accepted: 02/20/2023] [Indexed: 03/02/2023]
Abstract
Neural stem and progenitor cell (NSPC) transplants provide neuroprotection in models of acute brain injury, but the underlying mechanisms are not fully understood. Here, we provide evidence that caspase-dependent apoptotic cell death of NSPCs is required for sending survival signals to the injured brain. The secretome of dying NSPCs contains heat-stable proteins, which protect neurons against glutamate-induced toxicity and trophic factor withdrawal in vitro, and from ischemic brain damage in vivo. Our findings support a new concept suggesting a bystander effect of apoptotic NSPCs, which actively promote neuronal survival through the release of a protective "farewell" secretome. Similar protective effects by the secretome of apoptotic NSPC were also confirmed in human neural progenitor cells and neural stem cells but not in mouse embryonic fibroblasts (MEF) or human dopaminergic neurons, suggesting that the observed effects are cell type specific and exist for neural progenitor/stem cells across species.
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Affiliation(s)
- Wei Han
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
- Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Eva-Maria Meißner
- Institute of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg, Germany
| | - Stefanie Neunteibl
- Institute of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg, Germany
| | - Madeline Günther
- Institute of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg, Germany
- Center for Mind, Brain and Behavior (CMBB), Universities of Marburg and Giessen, Marburg, Germany
| | - Jörg Kahnt
- Max-Planck-Institute for Terrestrial Microbiology, Department of Ecophysiology, Marburg, Germany
| | - Amalia Dolga
- Faculty of Science and Engineering, Molecular Pharmacology - Groningen Research Institute of Pharmacy, Groningen, The Netherlands
| | - Cuicui Xie
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Nikolaus Plesnila
- Institute for Stroke and Dementia Research (ISD), University Clinic Munich, Munich, Germany
| | - Changlian Zhu
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
- Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Klas Blomgren
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
- Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden.
| | - Carsten Culmsee
- Institute of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg, Germany.
- Center for Mind, Brain and Behavior (CMBB), Universities of Marburg and Giessen, Marburg, Germany.
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8
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Payal N, Sharma L, Sharma A, Hobanii YH, Hakami MA, Ali N, Rashid S, Sachdeva M, Gulati M, Yadav S, Chigurupati S, Singh A, Khan H, Behl T. Understanding the Therapeutic Approaches for Neuroprotection. Curr Pharm Des 2023; 29:3368-3384. [PMID: 38151849 DOI: 10.2174/0113816128275761231103102125] [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: 08/10/2023] [Accepted: 10/07/2023] [Indexed: 12/29/2023]
Abstract
The term "neurodegenerative disorders" refers to a group of illnesses in which deterioration of nerve structure and function is a prominent feature. Cognitive capacities such as memory and decision-making deteriorate as a result of neuronal damage. The primary difficulty that remains is safeguarding neurons since they do not proliferate or regenerate spontaneously and are therefore not substituted by the body after they have been damaged. Millions of individuals throughout the world suffer from neurodegenerative diseases. Various pathways lead to neurodegeneration, including endoplasmic reticulum stress, calcium ion overload, mitochondrial dysfunction, reactive oxygen species generation, and apoptosis. Although different treatments and therapies are available for neuroprotection after a brain injury or damage, the obstacles are inextricably connected. Several studies have revealed the pathogenic effects of hypothermia, different breathed gases, stem cell treatments, mitochondrial transplantation, multi-pharmacological therapy, and other therapies that have improved neurological recovery and survival outcomes after brain damage. The present review highlights the use of therapeutic approaches that can be targeted to develop and understand significant therapies for treating neurodegenerative diseases.
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Affiliation(s)
- Nazrana Payal
- Department of Pharmacy, School of Biotechnology, Shoolini University of Biotechnology and Management Sciences, Solan, Himachal Pradesh, India
| | - Lalit Sharma
- Department of Pharmacology, School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, India
| | - Aditi Sharma
- Department of Pharmacology, School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, India
| | - Yahya Hosan Hobanii
- Department of Pharmacy, College of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
| | | | - Nemat Ali
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Summya Rashid
- Department of Pharmacology & Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Monika Sachdeva
- Department of Pharmacy, Fatima College of Health Sciences, Al Ain, United Arab Emirates
| | - Monica Gulati
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 1444411, India
- ARCCIM, Faculty of Health, University of Technology, Sydney, Ultimo, NSW 2007, Australia
| | - Shivam Yadav
- School of Pharmacy, Babu Banarasi Das University, Lucknow, Uttar Pradesh, India
| | - Sridevi Chigurupati
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraydah 52571, Kingdom of Saudi Arabia
- Department of Biotechnology, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Saveetha Nagar, Thandalam, Chennai 602105, India
| | - Abhiav Singh
- Department of Pharmacy, Indian Council of Medical Research, New Delhi, India
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan
| | - Tapan Behl
- Department of Pharmacy, School of Health Sciences and Technology, University of Petroleum and Energy Studies, Bidholi, Dehradun, Uttarakhand, India
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9
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Ischemic Brain Stroke and Mesenchymal Stem Cells: An Overview of Molecular Mechanisms and Therapeutic Potential. Stem Cells Int 2022; 2022:5930244. [PMID: 35663353 PMCID: PMC9159823 DOI: 10.1155/2022/5930244] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 10/12/2021] [Accepted: 05/04/2022] [Indexed: 12/15/2022] Open
Abstract
Ischemic brain injury is associated with a high rate of mortality and disability with no effective therapeutic strategy. Recently, a growing number of studies are focusing on mesenchymal stem cell-based therapies for neurodegenerative disorders. However, despite having the promising outcome of preclinical studies, the clinical application of stem cell therapy remained elusive due to little or no progress in clinical trials. The objective of this study was to provide a generalized critique for the role of mesenchymal stem cell therapy in ischemic stroke injury, its underlying mechanisms, and constraints on its preclinical and clinical applications. Thus, we attempted to present an overview of previously published reports to evaluate the progress and provide molecular basis of mesenchymal stem cells (MSCs) therapy and its application in preclinical and clinical settings, which could aid in designing an effective regenerative therapeutic strategy in the future.
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10
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Chaplygina AV, Zhdanova DY, Kovalev VI, Poltavtseva RA, Medvinskaya NI, Bobkova NV. Cell Therapy as a Way to Correct Impaired Neurogenesis in the Adult Brain in a Model of Alzheimer’s Disease. J EVOL BIOCHEM PHYS+ 2022. [DOI: 10.1134/s0022093022010112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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11
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Venugopal C, Shobha K, Rai KS, Dhanushkodi A. Neurogenic and cognitive enhancing effects of human dental pulp stem cells and its secretome in animal model of hippocampal neurodegeneration. Brain Res Bull 2022; 180:46-58. [PMID: 34979238 DOI: 10.1016/j.brainresbull.2021.12.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 11/11/2021] [Accepted: 12/28/2021] [Indexed: 12/26/2022]
Abstract
Progressive hippocampal neuronal losses, neuroinflammation, declined neurogenesis and impaired hippocampal functions are pathological features of Alzheimer's disease and temporal lobe epilepsy (TLE). Halting neuroinflammation and progressive neurodegeneration in the hippocampus is a major challenge in treating such disease conditions which, if unsuccessful would lead to learning/memory dysfunction and co-morbidities like anxiety/depression. Mesenchymal stem cells (MSCs) therapy provides hope for treating neurodegenerative diseases by either replacing lost neurons by transplantation of MSCs which might differentiate into appropriate neuronal phenotypes or by stimulating the resident neural stem cells for proliferation/differentiation. In this current study, we demonstrate that the intrahippocampal transplantation of ectoderm originated dental pulp stem cells (DPSCs) or intrahippocampal injection of DPSCs condition medium (DPSCs-CM) in a mouse model of hippocampal neurodegeneration could efficiently prevent neurodegeneration, neuroinflammation, enhance hippocampal neurogenesis and spatial learning and memory functions much superior to commonly used bone marrow mesenchymal stem cells (BM-MSCs) or its secretome. Probing the possible mechanisms of neuroprotection revealed that DPSCs/DPSCs-CM treatment upregulated an array of hosts' endogenous neural survival factors expression, reduced pro-apoptotic caspase activity and upregulated the anti-apoptotic factors BCL-2 and phosphorylated PI3K prominently than BM-MSCs/BM-MSCs-CM, suggesting that among MSCs, neural crest originated DPSCs might be a better adult stem cell candidate for treating neurodegenerative diseases.
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Affiliation(s)
- Chaitra Venugopal
- Manipal Institute of Regenerative Medicine, Bangalore, Manipal Academy of Higher Education, Manipal, India
| | - K Shobha
- Manipal Institute of Regenerative Medicine, Bangalore, Manipal Academy of Higher Education, Manipal, India
| | - Kiranmai S Rai
- Dept. of Physiology, Melaka Manipal Medical College, Manipal Academy of Higher, Education, Manipal, Karnataka, India
| | - Anandh Dhanushkodi
- Manipal Institute of Regenerative Medicine, Bangalore, Manipal Academy of Higher Education, Manipal, India.
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12
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Selegiline Induces Adipose tissue-derived Stem Cells into Neuron-like cells through MAPK Signaling Pathway. PHYSIOLOGY AND PHARMACOLOGY 2021. [DOI: 10.52547/phypha.26.1.4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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13
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Khalatbary AR. Stem cell-derived exosomes as a cell free therapy against spinal cord injury. Tissue Cell 2021; 71:101559. [PMID: 34052745 DOI: 10.1016/j.tice.2021.101559] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 05/01/2021] [Accepted: 05/24/2021] [Indexed: 12/19/2022]
Abstract
Recent evidence suggests that stem cell therapy has beneficial effects on spinal cord injury. It was subsequently established that these beneficial effects may be mediated through release of paracrine factors, a kind of extracellular vesicle known as exosomes. Stem cell-secreted nano-sized exosomes have shown great potential to reduce apoptosis and inflammation, enhance angiogenesis, and improve functional behavioral recovery following spinal cord injury. This review summarizes current knowledge about the influence of exosomes derived from stem cells on spinal cord protection and regeneration with their molecular mechanisms after injury.
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Affiliation(s)
- Ali Reza Khalatbary
- Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
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14
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Zhang H, Gong M, Luo X. Methoxytetrahydro-2H-pyran-2-yl)methyl benzoate inhibits spinal cord injury in the rat model via PPAR-γ/PI3K/p-Akt activation. ENVIRONMENTAL TOXICOLOGY 2020; 35:714-721. [PMID: 32149473 DOI: 10.1002/tox.22902] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Revised: 12/28/2019] [Accepted: 01/17/2020] [Indexed: 06/10/2023]
Abstract
Spinal cord injury (SCI) is the most commonly seen trauma leading to disability in people worldwide. The purpose of current study was to determine the protective effect of methoxytetrahydro-2H-pyran-2-yl)methyl benzoate (HMPB) on SCI in rat model. TUNEL staining was used to examine apoptotic changes in spinal cord of SCI rats. The ELISA kits were employed to assess inflammatory processes and oxidative factors in the spinal cord tissues. Behavioral changes in SCI rats were assessed using Basso, Beattie, and Bresnahan (BBB) scoring system. Western blotting was used for assessment of proteins. The HMPB treatment of SCI rats reduced apoptotic cell number based on the concentration of dose administered. Treatment of SCI rats with HMPB enhanced BBB score and decreased accumulation of water content in SCI rats significantly. On treatment with HMPB the TNF-α and interleukin-6/1β/18 levels were suppressed in SCI rats. Treatment with HMPB induced excessive release of SOD, CAT, and GSH molecules and decreased overproduction of MDA. The SCI induced upregulation of caspase-3/9 activity was completely alleviated by HMPB at 2 mg/kg dose. The HMPB treatment of SCI rats promoted peroxisome proliferator-activated receptor γ (PPAR-γ) expression, reduced cyclooxygenase (COX)-2 production and increased expression of p-Akt and phosphoinositide 3-kinase (p-PI3K). The study demonstrated that HMPB suppressed apoptosis, raised BBB score and inhibited inflammation in SCI rats. Moreover, activation of PI3K/Akt in the spinal cord tissues of SCI rats was promoted by HMPB. Therefore, HMPB has protective effect on SCI in the rat model.
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Affiliation(s)
- Hao Zhang
- Department of Spinal surgery, The People's Hospital of Longhua, Shenzhen, China
| | - Ming Gong
- Department of Spinal surgery, The People's Hospital of Longhua, Shenzhen, China
| | - Xinle Luo
- Department of Spinal surgery, The People's Hospital of Longhua, Shenzhen, China
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15
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Willing AE, Das M, Howell M, Mohapatra SS, Mohapatra S. Potential of mesenchymal stem cells alone, or in combination, to treat traumatic brain injury. CNS Neurosci Ther 2020; 26:616-627. [PMID: 32157822 PMCID: PMC7248546 DOI: 10.1111/cns.13300] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 02/17/2020] [Accepted: 02/23/2020] [Indexed: 12/13/2022] Open
Abstract
Traumatic brain injury (TBI) causes death and disability in the United States and around the world. The traumatic insult causes the mechanical injury of the brain and primary cellular death. While a comprehensive pathological mechanism of TBI is still lacking, the focus of the TBI research is concentrated on understanding the pathophysiology and developing suitable therapeutic approaches. Given the complexities in pathophysiology involving interconnected immunologic, inflammatory, and neurological cascades occurring after TBI, the therapies directed to a single mechanism fail in the clinical trials. This has led to the development of the paradigm of a combination therapeutic approach against TBI. While there are no drugs available for the treatment of TBI, stem cell therapy has shown promising results in preclinical studies. But, the success of the therapy depends on the survival of the stem cells, which are limited by several factors including route of administration, health of the administered cells, and inflammatory microenvironment of the injured brain. Reducing the inflammation prior to cell administration may provide a better outcome of cell therapy following TBI. This review is focused on different therapeutic approaches of TBI and the present status of the clinical trials.
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Affiliation(s)
- Alison E Willing
- Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Mahasweta Das
- Department of Molecular Medicine, University of South Florida Morsani College of Medicine, Tampa, FL, USA.,James A. Haley Veterans Hospital, Tampa, FL, USA
| | - Mark Howell
- Department of Molecular Medicine, University of South Florida Morsani College of Medicine, Tampa, FL, USA.,James A. Haley Veterans Hospital, Tampa, FL, USA
| | - Shyam S Mohapatra
- James A. Haley Veterans Hospital, Tampa, FL, USA.,Department of Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Subhra Mohapatra
- Department of Molecular Medicine, University of South Florida Morsani College of Medicine, Tampa, FL, USA.,James A. Haley Veterans Hospital, Tampa, FL, USA
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16
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Vahidinia Z, Azami Tameh A, Nejati M, Beyer C, Talaei SA, Etehadi Moghadam S, Atlasi MA. The protective effect of bone marrow mesenchymal stem cells in a rat model of ischemic stroke via reducing the C-Jun N-terminal kinase expression. Pathol Res Pract 2019; 215:152519. [PMID: 31272760 DOI: 10.1016/j.prp.2019.152519] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 06/03/2019] [Accepted: 06/26/2019] [Indexed: 01/09/2023]
Abstract
Ischemic stroke is the main cause of disability and mortality worldwide. Apoptosis and inflammation have an important role in ischemic brain injury. Mesenchymal stem cells (MSCs) have protective effects on stroke treatment due to anti-inflammatory properties. The inhibition of the C-Jun N-terminal kinase (JNK) pathway may be one of the molecular mechanisms of the neuroprotective effect of MSCs in ischemic brain injury. Twenty-eight male Wistar rats were divided randomly into 3 groups. Except the sham group, others subjected to transient middle cerebral artery occlusion (tMCAO). Bone marrow MSCs or saline were injected 3 h after tMCAO. Sensorimotor behavioral tests were performed 24 and 72 h after ischemia and reperfusion (I/R). The rats were sacrificed 72 h after I/R and infarct volume was measured by TTC staining. The number of apoptotic neurons and astrocytes in the peri-infarct area was assessed by TUNEL assay. The morphology of cells was checked by Nissl staining, and the expression of p-JNK was detected by immunohistochemistry and Western blot. Behavioral scores were improved and infarct volume was reduced by MSCs 24 h and 72 h after tMCAO. TUNEL assay showed that neuronal apoptosis and astroglial activity in the penumbra region were reduced by MSCs. Also, Nissl staining showed lower neuronal apoptosis in BMSCs-treated rats compared to controls. JNK phosphorylation which was profoundly induced by ischemia was significantly decreased after MSCs treatment. We concluded that anti-apoptotic and anti-inflammatory effects of MSCs therapy after brain ischemia may be associated with the down-regulation of p-JNK.
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Affiliation(s)
- Zeinab Vahidinia
- Anatomical Sciences Research Center, Kashan University of Medical Sciences, Kashan, Iran; Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Abolfazl Azami Tameh
- Anatomical Sciences Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Majid Nejati
- Anatomical Sciences Research Center, Kashan University of Medical Sciences, Kashan, Iran.
| | - Cordian Beyer
- Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
| | | | | | - Mohammad Ali Atlasi
- Anatomical Sciences Research Center, Kashan University of Medical Sciences, Kashan, Iran.
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17
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Barati S, Kashani IR, Tahmasebi F, Mehrabi S, Joghataei MT. Effect of mesenchymal stem cells on glial cells population in cuprizone induced demyelination model. Neuropeptides 2019; 75:75-84. [PMID: 31030907 DOI: 10.1016/j.npep.2019.04.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 04/11/2019] [Accepted: 04/12/2019] [Indexed: 12/30/2022]
Abstract
Mesenchymal stem cells (MSCs) have a notable potential to modulate immune responses and protect the central nervous system (CNS), mostly by secreting factors that affect inflammation. MSCs have the ability to improve several autoimmune diseases in animal models including multiple sclerosis (MS). MS is a disease of the CNS among adult humans and it is characterized by demyelination, neuroinflammation and gliosis. In this study, we first induced chronic demyelination by cuprizone, followed by intraventricular injection of MSC. Our results showed that MSC significantly decreased microgliosis and astrocytosis by secreting cytokines that have neuroprotective activity including TGF-β and CX3CL1. Also, downregulation of IL-1β and TNF-α as inflammatory chemokines was seen along with decreased astrocytes and microglia activation. Finally, these results showed that trophic factors secreted by MSC can increase oligodendrocyte population and remyelination rate by reducing pro-inflammatory factors. These findings demonstrate that MSC could decrease inflammation, gliosis and demyelination with neuroprotective and immunomodulating properties in chronic cuprizone demyelination model. Therefore MSC transplantation can be considered as a suitable approach for enhancing myelination and reducing inflammation in diseases such as MS.
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Affiliation(s)
- Shirin Barati
- Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Iraj Ragerdi Kashani
- Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Tahmasebi
- Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Soraya Mehrabi
- Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Taghi Joghataei
- Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran; Cellular and Molecular Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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18
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Liu N, Wang H, Han G, Cheng J, Hu W, Zhang J. Enhanced proliferation and differentiation of HO-1 gene-modified bone marrow-derived mesenchymal stem cells in the acute injured kidney. Int J Mol Med 2018; 42:946-956. [PMID: 29749549 PMCID: PMC6034926 DOI: 10.3892/ijmm.2018.3670] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 02/20/2018] [Indexed: 12/12/2022] Open
Abstract
The aim of the present study was to investigate the effect of heme oxygenase-1 (HO-1) overexpression on the survival and differentiation ability of bone marrow‑derived mesenchymal stem cells (BMSCs) in the acute kidney injury (AKI) microenvironment. HO-1-BMSCs and enhanced green fluorescent protein (eGFP)-BMSCs were constructed. Rat ischemia/reperfusion (I/R)‑AKI-kidney homogenate supernatant was prep-ared to treat the BMSCs, eGFP-BMSCs and HO-1-BMSCs in vitro. In the AKI microenvironment, the HO-1-BMSCs exhibited a smaller proportion of cells at the G0/G1 phase, and a larger proportion of cells expressing proliferating cell nuclear antigen (PCNA) and cytokeratin 18 (CK18). Phosphorylated protein kinase B (Akt) and extracellular signal‑regulated kinase (ERK) protein levels were observed to be increased in the HO-1-BMSCs compared with the BMSCs. LY294002 and PD98059 each inhibited the above effects. BMSCs, eGFP-BMSCs and HO-1-BMSCs were implanted into an I/R-AKI rat model. The proportions of PCNA+ BMSCs and CK18+ BMSCs were higher in the HO-1-BMSCs group compared with the BMSCs group, which resulted in a decreased acute tubular necrosis score and improved renal function for the AKI rats. In conclusion, the enhanced proliferation and differentiation of HO-1-BMSCs suggest the beneficial effects of such cells in the BMSC-based therapy of AKI. The mechanism underlying these effects may involve the stimulation of Akt and ERK signaling.
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Affiliation(s)
- Nanmei Liu
- Department of Nephrology, The 455th Hospital of PLA, Shanghai 200052, P.R. China
| | - Huiling Wang
- Department of Nephrology, The 455th Hospital of PLA, Shanghai 200052, P.R. China
| | - Guofeng Han
- Department of Nephrology, The 455th Hospital of PLA, Shanghai 200052, P.R. China
| | - Jin Cheng
- Department of Nephrology, The 455th Hospital of PLA, Shanghai 200052, P.R. China
| | - Weifeng Hu
- Department of Nephrology, The 455th Hospital of PLA, Shanghai 200052, P.R. China
| | - Jinyuan Zhang
- Department of Nephrology, The 455th Hospital of PLA, Shanghai 200052, P.R. China
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19
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Chen Y, Wang B, Zhao H. Thymoquinone reduces spinal cord injury by inhibiting inflammatory response, oxidative stress and apoptosis via PPAR-γ and PI3K/Akt pathways. Exp Ther Med 2018; 15:4987-4994. [PMID: 29904397 DOI: 10.3892/etm.2018.6072] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 09/01/2017] [Indexed: 01/03/2023] Open
Abstract
The present study used a mild contusion injury in rat spinal cord to determine that thymoquinone reduces inflammatory response, oxidative stress and apoptosis in a spinal cord injury (SCI) rat model and to demonstrate its possible molecular mechanisms. The rats in the thymoquinone group received 30 mg/kg thymoquinone once daily by intragastric administration from 3 weeks after surgery. Hematoxylin and eosin staining, Basso, Beattie and Bresnahan (BBB) scale and tissue water content detection were used in the present study to analyze the effect of thymoquinone on SCI. The activity of inflammatory response mediators, oxidative stress factors and caspase-3/9 was measured using ELISA kits. Furthermore, western blotting was performed to analyzed the protein expression levels of prostaglandin E2, suppressed cyclooxygenase-2 (COX-2) and activated peroxisome proliferator-activated receptor γ (PPAR-γ), PI3K and Akt. The results from the study demonstrated that thymoquinone increased Basso, Beattie and Bresnahan score and decreased water content in spinal cord tissue. Treatment with thymoquinone decreased inflammatory response [measured by levels of tumor necrosis factor α, interleukin (IL)-1β, IL-6 and IL-18], oxidative stress (measured by levels of superoxide dismutase, catalase, glutathione and malondialdehyde) and cell apoptosis (measured by levels of caspase-3 and caspase-9) in SCI rats. Thymoquinone treatment inhibited prostaglandin E2 activity, suppressed COX-2 protein expression and activated PPAR-γ, PI3K and p-Akt protein expression in SCI rats. These data revealed that thymoquinone reduces inflammatory response, oxidative stress and apoptosis via PPAR-γ and PI3K/Akt pathways in an SCI rat model.
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Affiliation(s)
- Yinming Chen
- Department of Orthopedics, Zaozhuang Municipal Hospital, Zaozhuang, Shandong 277102, P.R. China
| | - Benlong Wang
- Department of Orthopedics, Zaozhuang Municipal Hospital, Zaozhuang, Shandong 277102, P.R. China
| | - Hai Zhao
- Department of Orthopedics, Zaozhuang Municipal Hospital, Zaozhuang, Shandong 277102, P.R. China
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20
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Mesenchymal Stem Cell Protection of Neurons against Glutamate Excitotoxicity Involves Reduction of NMDA-Triggered Calcium Responses and Surface GluR1, and Is Partly Mediated by TNF. Int J Mol Sci 2018; 19:ijms19030651. [PMID: 29495345 PMCID: PMC5877512 DOI: 10.3390/ijms19030651] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 02/14/2018] [Accepted: 02/14/2018] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem cells (MSC) provide therapeutic effects in experimental CNS disease models and show promise as cell-based therapies for humans, but their modes of action are not well understood. We previously show that MSC protect rodent neurons against glutamate excitotoxicity in vitro, and in vivo in an epilepsy model. Neuroprotection is associated with reduced NMDA glutamate receptor (NMDAR) subunit expression and neuronal glutamate-induced calcium (Ca2+) responses, and increased expression of stem cell-associated genes. Here, to investigate whether MSC-secreted factors modulate neuronal AMPA glutamate receptors (AMPAR) and gene expression, we performed longitudinal studies of enriched mouse cortical neurons treated with MSC conditioned medium (CM). MSC CM did not alter total levels of GluR1 AMPAR subunit in neurons, but its distribution, reducing cell surface levels compared to non-treated neurons. Proportions of NeuN-positive neurons, and of GFAP- and NG2-positive glia, were equal in untreated and MSC CM-treated cultures over time suggesting that neurons, rather than differentially-expanded glia, account for the immature gene profile previously reported in MSC CM-treated cultures. Lastly, MSC CM contained measurable amounts of tumor necrosis factor (TNF) bioactivity and pre-treatment of MSC CM with the TNF inhibitor etanercept reduced its ability to protect neurons. Together these results indicate that MSC-mediated neuroprotection against glutamate excitotoxicity involves reduced NMDAR and GluR1-containing AMPAR function, and TNF-mediated neuroprotection.
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21
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Venugopal C, Prasad YSHC, Shobha K, Pinnelli VB, Dhanushkodi A. HEK-293 secretome attenuates kainic acid neurotoxicity through insulin like growth factor-phosphatidylinositol-3-kinases pathway and by temporal regulation of antioxidant defense machineries. Neurotoxicology 2017; 69:189-200. [PMID: 29208536 DOI: 10.1016/j.neuro.2017.11.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 11/27/2017] [Accepted: 11/27/2017] [Indexed: 01/09/2023]
Abstract
A major impediment in the success of cell therapy for neurodegenerative diseases is the poor survival of grafted cells in the in vivo milieu, predominantly due to accumulated reactive oxygen species, thus prompting the search for suitable alternatives. Accumulating evidence suggests that the therapeutic potential of transplanted cells is partially attributed to the secretome released by them into the extracellular milieu. Studies that investigated the neuroprotective potential of the secretome attributes to the mere presence of growth factors without addressing other underlying cellular/molecular changes that occur upon post-secretome intervention like re-establishing the host cell's free radical scavenging machineries. In the present study, we investigated the neuroprotective effects of human embryonic kidney (HEK-293) cell line derived secretome (HEK-S) in an in vitro model of kainic acid (KA) induced neurodegeneration and explored the possible neuroprotective mechanism(s) of HEK-S. Murine hippocampal cells were exposed to toxic doses of KA (200μM) for 6hours (H) or 24H to induce excitotoxicity. Kainic acid exposed hippocampal cells were then treated with HEK-S either simultaneously or 6h post-KA exposure. Our results revealed that HEK-S confers significant neuroprotection in early/later stages of neurodegeneration through insulin like growth factor (IGF) - phosphatidylinositol-3-kinases (PI3K) pathway, efficiently restoring the host's free radical scavenging mechanisms at molecular-cellular-biochemical levels and also by modulating kainate receptor subunit expressions in host neurons.
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Affiliation(s)
- Chaitra Venugopal
- School of Regenerative Medicine, Manipal Academy of Higher Education, Yelahanka, Bangalore, 560065, India
| | - Y S Harish Chandra Prasad
- School of Regenerative Medicine, Manipal Academy of Higher Education, Yelahanka, Bangalore, 560065, India
| | - K Shobha
- School of Regenerative Medicine, Manipal Academy of Higher Education, Yelahanka, Bangalore, 560065, India
| | | | - Anandh Dhanushkodi
- School of Regenerative Medicine, Manipal Academy of Higher Education, Yelahanka, Bangalore, 560065, India.
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22
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Secretome released from hydrogel-embedded adipose mesenchymal stem cells protects against the Parkinson's disease related toxin 6-hydroxydopamine. Eur J Pharm Biopharm 2017; 121:113-120. [PMID: 28965958 PMCID: PMC5656105 DOI: 10.1016/j.ejpb.2017.09.014] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 09/20/2017] [Accepted: 09/26/2017] [Indexed: 12/21/2022]
Abstract
Neurodegenerative diseases, as Parkinson’s disease (PD), involve irreversible neural cell damage and impairment. In PD, there is a selective degeneration of the dopaminergic neurons leading to motor symptoms. A common finding in PD neurodegeneration is the increase of reactive oxygen species (ROS), leading to oxidative stress. To date there are only interventions to relieve PD symptoms, however progress has been made in the development of therapies that target the immune system or use its components as therapeutic agents; among these, mesenchymal stem cells (MSCs), which are able to express neuroprotective factors as cytokines, chemokines and angiogenic molecules, collectively named secretome, that accumulate in MSC culture medium. However, lasting cell-free administration of secretome in vitro or in vivo is challenging. We used the conditioned media from rat adipose tissue-derived MSCs (RAA-MSCs) to check for neuroprotective activity towards pro-oxidizing agents such as hydrogen peroxide (H2O2) or the dopaminergic selective toxin 6-hydroxydopamine (6-OHDA) that is commonly used to model PD neurodegeneration. When neuroblastoma SH-SY5Y cells were pre-conditioned with 100% RAA-MSC media, then treated with H2O2 and 6-OHDA, mortality and ROS generation were reduced. We implemented the controlled release of RAA-MSC secretome from injectable biodegradable hydrogels that offer a possible in situ implant with mini-invasive techniques. The hydrogels were composed of type I bovine collagen (COLL) and low-molecular-weight hyaluronic acid (LMWHA) or COLL and polyethylene glycol (PEG). Hydrogels were suitable for RAA-MSC embedding up to 48 h and secretome from these RAA-MSCs was active and counteracted 6-OHDA toxicity, with upregulation of the antioxidant enzyme sirtuin 3 (SIRT3). These results support a biomaterials-based approach for controlled delivery of MSC-produced neuroprotective factors in a PD-relevant experimental context.
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23
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Xiong LL, Liu F, Deng SK, Liu J, Dan QQ, Zhang P, Zou Y, Xia QJ, Wang TH. Transplantation of Hematopoietic Stem Cells Promotes Functional Improvement Associated with NT-3-MEK-1 Activation in Spinal Cord-Transected Rats. Front Cell Neurosci 2017; 11:213. [PMID: 28769769 PMCID: PMC5515877 DOI: 10.3389/fncel.2017.00213] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Accepted: 07/04/2017] [Indexed: 02/05/2023] Open
Abstract
Transected spinal cord injury (SCT) is a devastating clinical disease that strongly affects a patient’s daily life and remains a great challenge for clinicians. Stem-cell therapy has been proposed as a potential therapeutic modality for SCT. To investigate the effects of hematopoietic stem cells (HSCs) on the recovery of structure and function in SCT rats and to explore the mechanisms associated with recovery, 57 adult Sprague-Dawley rats were randomly divided into sham (n = 15), SCT (n = 24), and HSC transplantation groups (n = 15). HSCs (passage 3) labeled by Hoechst 33342, were transplanted intraspinally into the rostral, scar and caudal sites of the transected lesion at 14 days post-operation. Both in vitro and in vivo, HSCs exhibited a capacity for cell proliferation and differentiation. Following HSC transplantation, the animals’ Basso, Beattie, and Bresnahan (BBB). locomotion scale scores increased significantly between weeks 4 and 24 post-SCT, which corresponded to an increased number of 5-hydroxytryptamine (5-HT) fibers and oligodendrocytes. The amount of astrogliosis indicated by immunohistochemical staining, was markedly decreased. Moreover, the decreased expression of neurotrophin- 3 (NT-3) and mitogen-activated protein kinase kinase-1 (MEK-1) after SCT was effectively restored by HSC transplantation. The data from the current study indicate that intraspinally administered HSCs in the chronic phase of SCT results in an improvement in neurological function. Further, the results indicate that intraspinally administered HSCs benefit the underlying mechanisms involved in the enhancement of 5-HT-positive fibers and oligogenesis, the suppression of excessive astrogliosis and the upregulation of NT3-regulated MEK-1 activation in the spinal cord. These crucial findings reveal not only the mechanism of cell therapy, but may also contribute to a novel therapeutic target for the treatment of spinal cord injury (SCI).
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Affiliation(s)
- Liu-Lin Xiong
- Institute of Neurological Disease, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan UniversityChengdu, China
| | - Fei Liu
- Institute of Neurological Disease, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan UniversityChengdu, China
| | - Shi-Kang Deng
- Institute of Neuroscience, Kunming Medical UniversityKunming, China
| | - Jia Liu
- Institute of Neuroscience, Kunming Medical UniversityKunming, China
| | - Qi-Qin Dan
- Institute of Neurological Disease, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan UniversityChengdu, China
| | - Piao Zhang
- Institute of Neuroscience, Kunming Medical UniversityKunming, China
| | - Yu Zou
- Institute of Neurological Disease, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan UniversityChengdu, China
| | - Qing-Jie Xia
- Institute of Neurological Disease, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan UniversityChengdu, China
| | - Ting-Hua Wang
- Institute of Neurological Disease, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan UniversityChengdu, China.,Institute of Neuroscience, Kunming Medical UniversityKunming, China
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24
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Parga JA, García-Garrote M, Martínez S, Raya Á, Labandeira-García JL, Rodríguez-Pallares J. Prostaglandin EP2 Receptors Mediate Mesenchymal Stromal Cell-Neuroprotective Effects on Dopaminergic Neurons. Mol Neurobiol 2017; 55:4763-4776. [DOI: 10.1007/s12035-017-0681-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 06/29/2017] [Indexed: 12/20/2022]
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25
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Nakajima M, Nito C, Sowa K, Suda S, Nishiyama Y, Nakamura-Takahashi A, Nitahara-Kasahara Y, Imagawa K, Hirato T, Ueda M, Kimura K, Okada T. Mesenchymal Stem Cells Overexpressing Interleukin-10 Promote Neuroprotection in Experimental Acute Ischemic Stroke. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2017; 6:102-111. [PMID: 28725658 PMCID: PMC5502709 DOI: 10.1016/j.omtm.2017.06.005] [Citation(s) in RCA: 104] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 06/21/2017] [Indexed: 12/16/2022]
Abstract
Interleukin (IL)-10 is a contributing factor to neuroprotection of mesenchymal stem cell (MSC) transplantation after ischemic stroke. Our aim was to increase therapeutic effects by combining MSCs and ex vivo IL-10 gene transfer with an adeno-associated virus (AAV) vector using a rat transient middle cerebral artery occlusion (MCAO) model. Sprague-Dawley rats underwent 90 min MCAO followed by intravenous administration of MSCs alone or IL-10 gene-transferred MSCs (MSC/IL-10) at 0 or 3 hr after ischemia reperfusion. Infarct lesions, neurological deficits, and immunological analyses were performed within 7 days after MCAO. 0-hr transplantation of MSCs alone and MSC/IL-10 significantly reduced infarct volumes and improved motor function. Conversely, 3-hr transplantation of MSC/IL-10, but not MSCs alone, significantly reduced infarct volumes (p < 0.01) and improved motor function (p < 0.01) compared with vehicle groups at 72 hr and 7 days after MCAO. Immunological analysis showed that MSC/IL-10 transplantation significantly inhibits microglial activation and pro-inflammatory cytokine expression compared with MSCs alone. Moreover, overexpressing IL-10 suppressed neuronal degeneration and improved survival of engrafted MSCs in the ischemic hemisphere. These results suggest that overexpressing IL-10 enhances the neuroprotective effects of MSC transplantation by anti-inflammatory modulation and thereby supports neuronal survival during the acute ischemic phase.
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Affiliation(s)
- Masataka Nakajima
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan.,Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
| | - Chikako Nito
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
| | - Kota Sowa
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan.,Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
| | - Satoshi Suda
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
| | - Yasuhiro Nishiyama
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
| | - Aki Nakamura-Takahashi
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan.,Department of Pharmacology, Tokyo Dental College, Tokyo 101-0061, Japan
| | - Yuko Nitahara-Kasahara
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan.,Department of Cell and Gene Therapy, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
| | | | - Tohru Hirato
- JCR Pharmaceuticals Co., Ltd., Hyogo, 659-0021, Japan
| | - Masayuki Ueda
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
| | - Kazumi Kimura
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
| | - Takashi Okada
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan.,Department of Cell and Gene Therapy, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
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Abstract
Spinal cord injury (SCI) represents one of the most complicated and heterogeneous pathological processes of central nervous system (CNS) impairments, which is still beyond functional regeneration. Transplantation of mesenchymal stem cells (MSCs) has been shown to promote the repair of the injured spinal cord tissues in animal models, and therefore, there is much interest in the clinical use of these cells. However, many questions which are essential to improve the therapy effects remain unanswered. For instance, the functional roles and related molecular regulatory mechanisms of MSCs in vivo are not yet completely determined. It is important for transplanted cells to migrate into the injured tissue, to survive and undergo neural differentiation, or to play neural protection roles by various mechanisms after SCI. In this review, we will focus on some of the recent knowledge about the biological behavior and function of MSCs in SCI. Meanwhile, we highlight the function of biomaterials to direct the behavior of MSCs based on our series of work on silk fibroin biomaterials and attempt to emphasize combinational strategies such as tissue engineering for functional improvement of SCI.
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Li J, Guo W, Xiong M, Zhang S, Han H, Chen J, Mao D, Yu H, Zeng Y. Erythropoietin facilitates the recruitment of bone marrow mesenchymal stem cells to sites of spinal cord injury. Exp Ther Med 2017; 13:1806-1812. [PMID: 28565771 PMCID: PMC5443180 DOI: 10.3892/etm.2017.4182] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Accepted: 07/26/2016] [Indexed: 12/28/2022] Open
Abstract
Despite the successes of bone marrow mesenchymal stem cell (BMSC) transplantation for the treatment of spinal cord injuries, only a small fraction of grafted cells migrate to the target areas. Therefore, there remains a need for more efficient strategies of BMSC delivery. The present study was designed to explore this. Rat models of spinal cord injury (SCI) were established and exposed to phosphate buffered saline (control), BMSCs or BMSCs + erythropoietin (EPO). Basso, Beattie and Bresnahan (BBB) locomotor scale and grid walk tests were then utilized to estimate neurological rehabilitation. Additionally, the following assays were performed: Immunofluorescence localization of BMSCs to the site of SCI; the transwell migration assay to detect in vitro cellular migration; the terminal deoxynucleotidyl transferase dUTP nick end labeling assay to determine the apoptotic index of the lesion; and western blotting analysis to evaluate the expression of vascular endothelial growth factor (VEGF) and brain derived neurotrophic factor (BDNF) at the site of SCI. The BBB scores of the BMSC + EPO treated group were significantly increased compared with the BMSC treatment group (P<0.05). For example, BMSC + EPO treated rats had a significantly decreased number of hind limb slips compared with the BMSC treatment group (P<0.05). Furthermore, EPO significantly increased the migration capacity of BMSCs compared with the control group (P<0.001). In addition, the apoptotic index of the BMSC + EPO group was significantly decreased compared with the BMSC group (P<0.05). Green fluorescent protein-labeled BMSCs were detected at the site of SCI in the BMSC and BMSCs + EPO groups, with the signal being notably stronger in the latter. Moreover, the expression of VEGF and BDNF in the BMSCs + EPO group was significantly increased compared with the BMSC group (P<0.05). In conclusion, the results of the present study indicate that EPO can facilitate the recruitment of BMSCs to sites of SCI, increase expression of BDNF and VEGF, and accelerate recovery of neurological function following SCI.
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Affiliation(s)
- Jun Li
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Weichun Guo
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Min Xiong
- Department of Orthopedics, Dongfeng General Hospital of Hubei University of Medicine, Shiyan, Hubei 442008, P.R. China
| | - Shuangjie Zhang
- Department of Urology, Taihe Hospital of Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Heng Han
- Department of Orthopedics, Dongfeng General Hospital of Hubei University of Medicine, Shiyan, Hubei 442008, P.R. China
| | - Jie Chen
- Department of Orthopedics, Dongfeng General Hospital of Hubei University of Medicine, Shiyan, Hubei 442008, P.R. China
| | - Dan Mao
- Department of Orthopedics, Dongfeng General Hospital of Hubei University of Medicine, Shiyan, Hubei 442008, P.R. China
| | - Hualong Yu
- Department of Orthopedics, Dongfeng General Hospital of Hubei University of Medicine, Shiyan, Hubei 442008, P.R. China
| | - Yun Zeng
- Department of Orthopedics, Dongfeng General Hospital of Hubei University of Medicine, Shiyan, Hubei 442008, P.R. China
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Neuroprotective Effects of Bone Marrow Mesenchymal Stem Cells on Bilateral Common Carotid Arteries Occlusion Model of Cerebral Ischemia in Rat. Behav Neurol 2016; 2016:2964712. [PMID: 27847404 PMCID: PMC5101406 DOI: 10.1155/2016/2964712] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 08/07/2016] [Accepted: 09/07/2016] [Indexed: 12/13/2022] Open
Abstract
Cell therapy is the most advanced treatment of the cerebral ischemia, nowadays. Herein, we discuss the neuroprotective effects of bone marrow mesenchymal stem cells (BMSCs) on rat hippocampal cells following intravenous injection of these cells in an ischemia-reperfusion model. Adult male Wistar rats were divided into 5 groups: control, sham (surgery without blockage of common carotid arteries), ischemia (common carotid arteries were blocked for 30 min prior to reperfusion), vehicle (7 days after ischemia PBS was injected via the tail vein), and treatment (injections of BMSC into the tail veins 7 days after ischemia). We performed neuromuscular and vestibulomotor function tests to assess behavioral function and, finally, brains were subjected to hematoxylin and eosin (H&E), anti-Brdu immunohistochemistry, and TUNEL staining. The ischemia group had severe apoptosis. The group treated with BMSCs had a lower mortality rate and also had significant improvement in functional recovery (P < 0.001). Ischemia-reperfusion for 30 min causes damage and extensive neuronal death in the hippocampus, especially in CA1 and CA3 regions, leading to several functional and neurological deficits. In conclusion, intravenous injection of BMSCs can significantly decrease the number of apoptotic neurons and significantly improve functional recovery, which may be a beneficial treatment method for ischemic injuries.
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Miao MS, Guo L, Li RQ, Ma X. Radix Ilicis Pubescentis total flavonoids combined with mobilization of bone marrow stem cells to protect against cerebral ischemia/reperfusion injury. Neural Regen Res 2016; 11:278-84. [PMID: 27073381 PMCID: PMC4810992 DOI: 10.4103/1673-5374.177736] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Previous studies have shown that Radix Ilicis Pubescentis total flavonoids have a neuroprotective effect, but it remains unclear whether Radix Ilicis Pubescentis total flavonoids have a synergistic effect with the recombinant human granulocyte colony stimulating factor-mobilized bone marrow stem cell transplantation on cerebral ischemia/reperfusion injury. Rat ischemia models were administered 0.3, 0.15 and 0.075 g/kg Radix Ilicis Pubescentis total flavonoids from 3 days before modeling to 2 days after injury. Results showed that Radix Ilicis Pubescentis total flavonoids could reduce pathological injury in rats with cerebral ischemia/reperfusion injury. The number of Nissl bodies increased, Bax protein expression decreased, Bcl-2 protein expression increased and the number of CD34-positive cells increased. Therefore, Radix Ilicis Pubescentis total flavonoids can improve the bone marrow stem cell mobilization effect, enhance the anti-apoptotic ability of nerve cells, and have a neuroprotective effect on cerebral ischemia/reperfusion injury in rats.
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Affiliation(s)
- Ming-San Miao
- Henan University of Traditional Chinese Medicine, Zhengzhou, Henan Province, China
| | - Lin Guo
- Henan University of Traditional Chinese Medicine, Zhengzhou, Henan Province, China
| | - Rui-Qi Li
- Henan University of Traditional Chinese Medicine, Zhengzhou, Henan Province, China
| | - Xiao Ma
- Henan University of Traditional Chinese Medicine, Zhengzhou, Henan Province, China
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Wang J, Chen Y, Yang Y, Xiao X, Chen S, Zhang C, Jacobs B, Zhao B, Bihl J, Chen Y. Endothelial progenitor cells and neural progenitor cells synergistically protect cerebral endothelial cells from Hypoxia/reoxygenation-induced injury via activating the PI3K/Akt pathway. Mol Brain 2016; 9:12. [PMID: 26842559 PMCID: PMC4738765 DOI: 10.1186/s13041-016-0193-7] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Accepted: 01/28/2016] [Indexed: 01/24/2023] Open
Abstract
Background Protection of cerebral endothelial cells (ECs) from hypoxia/reoxygenation (H/R)-induced injury is an important strategy for treating ischemic stroke. In this study, we investigated whether co-culture with endothelial progenitor cells (EPCs) and neural progenitor cells (NPCs) synergistically protects cerebral ECs against H/R injury and the underlying mechanism. Results EPCs and NPCs were respectively generated from inducible pluripotent stem cells. Human brain ECs were used to produce an in vitro H/R-injury model. Data showed: 1) Co-culture with EPCs and NPCs synergistically inhibited H/R-induced reactive oxygen species (ROS) over-production, apoptosis, and improved the angiogenic and barrier functions (tube formation and permeability) in H/R-injured ECs. 2) Co-culture with NPCs up-regulated the expression of vascular endothelial growth factor receptor 2 (VEGFR2). 3) Co-culture with EPCs and NPCs complementarily increased vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) levels in conditioned medium, and synergistically up-regulated the expression of p-Akt/Akt and p-Flk1/VEGFR2 in H/R-injured ECs. 4) Those effects could be decreased or abolished by inhibition of both VEGFR2 and tyrosine kinase B (TrkB) or phosphatidylinositol-3-kinase (PI3K). Conclusions Our data demonstrate that EPCs and NPCs synergistically protect cerebral ECs from H/R-injury, via activating the PI3K/Akt pathway which mainly depends on VEGF and BDNF paracrine.
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Affiliation(s)
- Jinju Wang
- Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Hwy, Dayton, OH, 45435, USA.
| | - Yusen Chen
- Department of Neurology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, 524001, Guangdong, China.
| | - Yi Yang
- Wuhan Institute of Physical Education, College of Health Science, Wuhan, 430079, Hubei, China.
| | - Xiang Xiao
- Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Hwy, Dayton, OH, 45435, USA.
| | - Shuzhen Chen
- Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Hwy, Dayton, OH, 45435, USA.
| | - Cheng Zhang
- Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Hwy, Dayton, OH, 45435, USA.
| | - Bradley Jacobs
- Department of Neurology, Wright State University, 3640 Colonel Glenn Hwy, Dayton, 45435, Ohio, USA.
| | - Bin Zhao
- Department of Neurology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, 524001, Guangdong, China.
| | - Ji Bihl
- Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Hwy, Dayton, OH, 45435, USA.
| | - Yanfang Chen
- Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Hwy, Dayton, OH, 45435, USA. .,Department of Neurology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, 524001, Guangdong, China. .,Department of Neurology, Wright State University, 3640 Colonel Glenn Hwy, Dayton, 45435, Ohio, USA. .,Department of Internal Medicine, Wright State University, 3640 Colonel Glenn Hwy, Dayton, 45435, Ohio, USA.
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Aertker BM, Bedi S, Cox CS. Strategies for CNS repair following TBI. Exp Neurol 2016; 275 Pt 3:411-426. [DOI: 10.1016/j.expneurol.2015.01.008] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Revised: 01/08/2015] [Accepted: 01/22/2015] [Indexed: 12/20/2022]
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Li L, Zhao D, Jin Z, Zhang J, Paul C, Wang Y. Phosphodiesterase 5a Inhibition with Adenoviral Short Hairpin RNA Benefits Infarcted Heart Partially through Activation of Akt Signaling Pathway and Reduction of Inflammatory Cytokines. PLoS One 2015; 10:e0145766. [PMID: 26709517 PMCID: PMC4692549 DOI: 10.1371/journal.pone.0145766] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 12/08/2015] [Indexed: 01/28/2023] Open
Abstract
Introduction Treatment with short hairpin RNA (shRNA) interference therapy targeting phosphodiesterase 5a after myocardial infarction (MI) has been shown to mitigate post-MI heart failure. We investigated the mechanisms that underpin the beneficial effects of PDE5a inhibition through shRNA on post-MI heart failure. Methods An adenoviral vector with an shRNA sequence inserted was adopted for the inhibition of phosphodiesterase 5a (Ad-shPDE5a) in vivo and in vitro. Myocardial infarction (MI) was induced in male C57BL/6J mice by left coronary artery ligation, and immediately after that, the Ad-shPDE5a was injected intramyocardially around the MI region and border areas. Results Four weeks post-MI, the Ad-shPDE5a-treated mice showed significant mitigation of the left ventricular (LV) dilatation and dysfunction compared to control mice. Infarction size and fibrosis were also significantly reduced in Ad-shPDE5a-treated mice. Additionally, Ad-shPDE5a treatment decreased the MI-induced inflammatory cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and transforming growth factor-β1, which was confirmed in vitro in Ad-shPDE5a transfected myofibroblasts cultured under oxygen glucose deprivation. Finally, Ad-shPDE5a treatment was found to activate the myocardial Akt signaling pathway in both in vivo and in vitro experiments. Conclusion These findings indicate that PDE5a inhibition by Ad-shPDE5a via the Akt signal pathway could be of significant value in the design of future therapeutics for post-MI heart failure.
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Affiliation(s)
- Longhu Li
- Department of Cardiology, the First Hospital of Qiqihaer City, Qiqihaer, China
- Department of Cardiology, the Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Dong Zhao
- Collaborative Innovation Center of Judicial Civilization, China, Key Laboratory of Evidence Science (China University of Political Science and Law), Ministry of Education, Beijing, China
| | - Zhe Jin
- Department of Cardiology, the First Hospital of Qiqihaer City, Qiqihaer, China
| | - Jian Zhang
- Department of EICU, the Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Christian Paul
- Department of Pathology and Lab Medicine, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, Ohio, 45267, United States of America
| | - Yigang Wang
- Department of Pathology and Lab Medicine, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, Ohio, 45267, United States of America
- * E-mail:
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Ravanidis S, Bogie JFJ, Donders R, Craeye D, Mays RW, Deans R, Gijbels K, Bronckaers A, Stinissen P, Pinxteren J, Hellings N. Neuroinflammatory signals enhance the immunomodulatory and neuroprotective properties of multipotent adult progenitor cells. Stem Cell Res Ther 2015; 6:176. [PMID: 26377390 PMCID: PMC4573995 DOI: 10.1186/s13287-015-0169-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 08/26/2015] [Accepted: 08/26/2015] [Indexed: 01/06/2023] Open
Abstract
Introduction Stem cell-based therapies are currently widely explored as a tool to treat neuroimmune diseases. Multipotent adult progenitor cells (MAPC) have been suggested to have strong immunomodulatory and neuroprotective properties in several experimental models. In this study, we investigate whether MAPC are of therapeutic interest for neuroinflammatory disorders such as multiple sclerosis by evaluating their capacities to modulate crucial pathological features and gain insights into the molecular pathways involved. Methods Rat MAPC were treated with combinations of pro-inflammatory cytokines that are closely associated with neuroinflammatory conditions, a process called licensing. mRNA expression of immunomodulatory molecules, chemokines and chemokine receptors was investigated. The migratory potential of licensed rat MAPC towards a broad spectrum of chemokines was tested in a Transwell assay. Furthermore, the effect of licensing on the ability of rat MAPC to attract and suppress the proliferation of encephalitogenic T cells was assessed. Finally, neuroprotective properties of rat MAPC were determined in the context of protection from oxidative stress of oligodendrocytes. Therefore, rat MAPC were incubated with conditioned medium of OLN93 cells subjected to sublethal doses of hydrogen peroxide and the gene expression of neurotrophic factors was assessed. Results After licensing, a wide variety of immunomodulatory molecules and chemokines, including inducible nitric oxide synthase and fractalkine, were upregulated by rat MAPC. The migratory properties of rat MAPC towards various chemokines were also altered. In addition, rat MAPC were found to inhibit antigen-specific T-cell proliferation and this suppressive effect was further enhanced after pro-inflammatory treatment. This phenomenon was partially mediated through inducible nitric oxide synthase or cyclooxygenase-2. Activated rat MAPC secreted factors that led to attraction of myelin-specific T cells. Finally, exposure of rat MAPC to an in vitro simulated neurodegenerative environment induced the upregulation of mRNA levels of vascular endothelial growth factor and ciliary neurotrophic factor. Factors secreted by rat MAPC in response to this environment partially protected OLN93 cells from hydrogen peroxide-induced cell death. Conclusions Rat MAPC possess immune modulatory and neuroprotective properties which are enhanced in response to neuroinflammatory signals. These findings thereby warrant further research to evaluate MAPC transplantation as a therapeutic approach in diseases with an immunological and neurodegenerative component such as multiple sclerosis. Electronic supplementary material The online version of this article (doi:10.1186/s13287-015-0169-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Stylianos Ravanidis
- Hasselt University, Biomedical Research Institute/Transnational University Limburg, School of Life Sciences, Campus Diepenbeek, Agoralaan building C, 3590, Diepenbeek, Belgium.
| | - Jeroen F J Bogie
- Hasselt University, Biomedical Research Institute/Transnational University Limburg, School of Life Sciences, Campus Diepenbeek, Agoralaan building C, 3590, Diepenbeek, Belgium.
| | - Raf Donders
- Hasselt University, Biomedical Research Institute/Transnational University Limburg, School of Life Sciences, Campus Diepenbeek, Agoralaan building C, 3590, Diepenbeek, Belgium.
| | | | - Robert W Mays
- Department of Regenerative Medicine, Athersys Inc., Cleveland, OH, USA.
| | - Robert Deans
- Department of Regenerative Medicine, Athersys Inc., Cleveland, OH, USA.
| | | | - Annelies Bronckaers
- Hasselt University, Biomedical Research Institute/Transnational University Limburg, School of Life Sciences, Campus Diepenbeek, Agoralaan building C, 3590, Diepenbeek, Belgium.
| | - Piet Stinissen
- Hasselt University, Biomedical Research Institute/Transnational University Limburg, School of Life Sciences, Campus Diepenbeek, Agoralaan building C, 3590, Diepenbeek, Belgium.
| | | | - Niels Hellings
- Hasselt University, Biomedical Research Institute/Transnational University Limburg, School of Life Sciences, Campus Diepenbeek, Agoralaan building C, 3590, Diepenbeek, Belgium.
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Lin L, Chen H, Zhang Y, Lin W, Liu Y, Li T, Zeng Y, Chen J, Du H, Chen R, Tan Y, Liu N. IL-10 Protects Neurites in Oxygen-Glucose-Deprived Cortical Neurons through the PI3K/Akt Pathway. PLoS One 2015; 10:e0136959. [PMID: 26366999 PMCID: PMC4569574 DOI: 10.1371/journal.pone.0136959] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 08/10/2015] [Indexed: 12/15/2022] Open
Abstract
IL-10, as a cytokine, has an anti-inflammatory cascade following various injuries, but it remains blurred whether IL-10 protects neurites of cortical neurons after oxygen-glucose deprivation injury. Here, we reported that IL-10, in a concentration-dependent manner, reduced neuronal apoptosis and increased neuronal survival in oxygen-glucose-deprived primary cortical neurons, producing an optimal protective effect at 20ng/ml. After staining NF-H and GAP-43, we found that IL-10 significantly protected neurites in terms of axon length and dendrite number by confocal microscopy. Furthermore, it induced the phosphorylation of AKT, suppressed the activation of caspase-3, and up-regulated the protein expression of GAP-43. In contrast, LY294002, a specific inhibitor of PI3K/AKT, reduced the level of AKT phosphorylation and GAP-43 expression, increased active caspase-3 expression and thus significantly weakened IL-10-mediated protective effect in the OGD-induced injury model. IL-10NA, the IL-10 neutralizing antibody, reduced the level of p-PI3K phosphorylation and increased the expression of active caspase-3. These findings suggest that IL-10 provides neuroprotective effects by protecting neurites through PI3K/AKT signaling pathway in oxygen-glucose-deprived primary cortical neurons.
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Affiliation(s)
- Longzai Lin
- Department of Neurology, The Affiliated Union Hospital, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China
- Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, Fujian, People’s Republic of China
| | - Hongbin Chen
- Department of Neurology, The Affiliated Union Hospital, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China
- Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, Fujian, People’s Republic of China
| | - Yixian Zhang
- Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, Fujian, People’s Republic of China
- Department of Rehabilitation, The Affiliated Union Hospital, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China
| | - Wei Lin
- Department of Neurology, The Affiliated Union Hospital, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China
- Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, Fujian, People’s Republic of China
| | - Yong Liu
- Department of Neurology, The Affiliated Union Hospital, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China
- Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, Fujian, People’s Republic of China
| | - Tin Li
- Department of Neurology, The Affiliated Union Hospital, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China
- Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, Fujian, People’s Republic of China
| | - Yongping Zeng
- Department of Neurology, The Affiliated Union Hospital, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China
- Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, Fujian, People’s Republic of China
| | - Jianhao Chen
- Department of Neurology, The Affiliated Union Hospital, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China
- Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, Fujian, People’s Republic of China
| | - Houwei Du
- Department of Neurology, The Affiliated Union Hospital, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China
- Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, Fujian, People’s Republic of China
| | - Ronghua Chen
- Department of Neurology, The Affiliated Union Hospital, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China
- Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, Fujian, People’s Republic of China
| | - Yi Tan
- Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, Fujian, People’s Republic of China
| | - Nan Liu
- Department of Neurology, The Affiliated Union Hospital, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China
- Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, Fujian, People’s Republic of China
- Department of Rehabilitation, The Affiliated Union Hospital, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China
- * E-mail:
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Abstract
Heart failure remains a major cause of death and disability, requiring rapid development of new therapies. Bone marrow-derived mesenchymal stem cell (MSC)-based therapy is an emerging approach for the treatment of both acute and chronic heart failure. Following successful experimental studies in a range of models, more than 40 clinical trials of MSC-based therapy for heart failure have now been registered, and the results of completed clinical trials so far have shown feasibility and safety of this approach with therapeutic potential suggested (though preliminarily). However, there appear to be several critical issues to be solved before this treatment could become a widespread standard therapy for heart failure. In this review, we comprehensively and systemically summarize a total of 73 preclinical studies and 11 clinical trial reports published to date. By analyzing the data in these reports, (1) improvement in the cell delivery method to the heart in order to enhance donor cell engraftment, (2) elucidation of mechanisms underpinning the therapeutic effects of the treatment differentiation and/or treatment secretion, and (3) validation of the utility of allogeneic MSCs which could enhance the efficacy and expand the application/indication of this therapeutic approach are highlighted as future perspectives. These important respects are further discussed in this review article with referencing latest scientific and clinical information.
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Affiliation(s)
- Takuya Narita
- Cardiothoracic Surgery, National Heart Centre, Singapore, Singapore
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Venugopal C, Chandanala S, Prasad HC, Nayeem D, Bhonde RR, Dhanushkodi A. Regenerative therapy for hippocampal degenerative diseases: lessons from preclinical studies. J Tissue Eng Regen Med 2015; 11:321-333. [PMID: 26118731 DOI: 10.1002/term.2052] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Revised: 04/08/2015] [Accepted: 04/29/2015] [Indexed: 12/30/2022]
Abstract
Increase in life expectancy has put neurodegenerative diseases on the rise. Amongst these, degenerative diseases involving hippocampus like Alzheimer's disease (AD) and temporal lobe epilepsy (TLE) are ranked higher as it is vulnerable to excitotoxicity induced neuronal dysfunction and death resulting in cognitive impairment. Modern medicines have not succeeded in halting the progression of these diseases rendering them incurable and often fatal. Under such scenario, regenerative studies employing stem cells or their by-products in animal models of AD and TLE have yielded encourageing results. This review focuses on the distinct cell types, such as hippocampal cell lines, neural precursor cells, embryonic stem cells derived neural precursor cells, induced pluripotent stem cells, induced neurons and mesenchymal stem cells, which can be employed to rescue hippocampal functions in neurodegenerative diseases like AD and TLE. Besides, the divergent mechanisms through which cell based therapy confer neuroprotection, current impediments and possible improvements in stem cell transplantation strategies are discussed. Authors are aware of the voluminous literature available on this issue and have made a sincere attempt to put forth the current status of research in the field of cell based therapy concurrently discussing the promise it holds for combating neurodegenerative diseases like AD and TLE in the near future. Copyright © 2015 John Wiley & Sons, Ltd.
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Affiliation(s)
- Chaitra Venugopal
- School of Regenerative Medicine, Manipal University, Bangalore, India
| | | | | | - Danish Nayeem
- School of Regenerative Medicine, Manipal University, Bangalore, India
| | - Ramesh R Bhonde
- School of Regenerative Medicine, Manipal University, Bangalore, India
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Dhanushkodi A, Venugopal C, Bevinahal PKK, Rai KS, Trichur RR, Talakad SN, Bhonde RR. Infusion of human embryonic kidney cell line conditioned medium reverses kainic acid induced hippocampal damage in mice. Cytotherapy 2014; 16:1760-70. [DOI: 10.1016/j.jcyt.2014.07.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Revised: 06/19/2014] [Accepted: 07/12/2014] [Indexed: 12/31/2022]
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Conditioned Medium Reconditions Hippocampal Neurons against Kainic Acid Induced Excitotoxicity: An In Vitro Study. J Toxicol 2014; 2014:194967. [PMID: 25505907 PMCID: PMC4258312 DOI: 10.1155/2014/194967] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 10/20/2014] [Accepted: 10/27/2014] [Indexed: 01/09/2023] Open
Abstract
Stem cell therapy is gaining attention as a promising treatment option for neurodegenerative diseases. The functional efficacy of grafted cells is a matter of debate and the recent consensus is that the cellular and functional recoveries might be due to "by-stander" effects of grafted cells. In the present study, we investigated the neuroprotective effect of conditioned medium (CM) derived from human embryonic kidney (HEK) cells in a kainic acid (KA) induced hippocampal degeneration model system in in vitro condition. Hippocampal cell line was exposed to KA (200 µM) for 24 hrs (lesion group) whereas, in the treatment group, hippocampal cell line was exposed to KA in combination with HEK-CM (KA + HEK-CM). We observed that KA exposure to cells resulted in significant neuronal loss. Interestingly, HEK-CM cotreatment completely attenuated the excitotoxic effects of KA. In HEK-CM cotreatment group, the cell viability was ~85-95% as opposed to 47% in KA alone group. Further investigation demonstrated that treatment with HEK-CM stimulated the endogenous cell survival factors like brain derived neurotrophic factors (BDNF) and antiapoptotic factor Bcl-2, revealing the possible mechanism of neuroprotection. Our results suggest that HEK-CM protects hippocampal neurons against excitotoxicity by stimulating the host's endogenous cell survival mechanisms.
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Dasari VR, Veeravalli KK, Dinh DH. Mesenchymal stem cells in the treatment of spinal cord injuries: A review. World J Stem Cells 2014; 6:120-133. [PMID: 24772239 PMCID: PMC3999770 DOI: 10.4252/wjsc.v6.i2.120] [Citation(s) in RCA: 153] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Revised: 02/19/2014] [Accepted: 03/12/2014] [Indexed: 02/06/2023] Open
Abstract
With technological advances in basic research, the intricate mechanism of secondary delayed spinal cord injury (SCI) continues to unravel at a rapid pace. However, despite our deeper understanding of the molecular changes occurring after initial insult to the spinal cord, the cure for paralysis remains elusive. Current treatment of SCI is limited to early administration of high dose steroids to mitigate the harmful effect of cord edema that occurs after SCI and to reduce the cascade of secondary delayed SCI. Recent evident-based clinical studies have cast doubt on the clinical benefit of steroids in SCI and intense focus on stem cell-based therapy has yielded some encouraging results. An array of mesenchymal stem cells (MSCs) from various sources with novel and promising strategies are being developed to improve function after SCI. In this review, we briefly discuss the pathophysiology of spinal cord injuries and characteristics and the potential sources of MSCs that can be used in the treatment of SCI. We will discuss the progress of MSCs application in research, focusing on the neuroprotective properties of MSCs. Finally, we will discuss the results from preclinical and clinical trials involving stem cell-based therapy in SCI.
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Hawryluk GWJ, Spano S, Chew D, Wang S, Erwin M, Chamankhah M, Forgione N, Fehlings MG. An Examination of the Mechanisms by which Neural Precursors Augment Recovery following Spinal Cord Injury: A Key Role for Remyelination. Cell Transplant 2014; 23:365-80. [DOI: 10.3727/096368912x662408] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
The mechanisms by which neural precursor cells (NPCs) enhance functional recovery from spinal cord injury (SCI) remain unclear. Spinal cord injured rats were transplanted with wild-type mouse NPCs, shiverer NPCs unable to produce myelin, dead NPCs, or media. Most animals also received minocycline, cyclosporine, and perilesional infusion of trophins. Motor function was graded according to the BBB scale. H&E/LFB staining was used to assess gray and white matter, cyst, and lesional tissue. Mature oligodendrocytes and ED1+ inflammatory cells were quantitated. Confocal and electron microscopy were used to assess the relationship between the transplanted cells and axons. Pharmacotherapy and trophin infusion preserved gray matter, white matter, and oligodendrocytes. Trophin infusion also significantly increased cyst and lesional tissue volume as well as inflammatory infiltrate, and functional recovery was reduced. Animals transplanted with wild-type NPCs showed greatest functional recovery; animals transplanted with shiverer NPCs performed the worst. Wild-type NPCs remyelinated host axons. Shiverer NPCs ensheathed axons but did not produce MBP. These results suggest that remyelination by NPCs is an important contribution to functional recovery following SCI. Shiverer NPCs may prevent remyelination by endogenous cells capable of myelin formation. These findings suggest that remyelination is an important therapeutic target following SCI.
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Affiliation(s)
- Gregory W. J. Hawryluk
- Division of Genetics and Development, Toronto Western Research Institute, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Department of Surgery, Division of Neurosurgery, University of Toronto, Toronto, ON, Canada
| | - Stefania Spano
- Division of Genetics and Development, Toronto Western Research Institute, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Derek Chew
- Division of Genetics and Development, Toronto Western Research Institute, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Shelly Wang
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Mark Erwin
- Division of Genetics and Development, Toronto Western Research Institute, University Health Network, Toronto, ON, Canada
- Department of Surgery, Division of Neurosurgery, University of Toronto, Toronto, ON, Canada
- Department of Surgery, Division of Orthopedic Surgery, University of Toronto, Toronto, ON, Canada
| | - Mahmood Chamankhah
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Nicole Forgione
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Michael G. Fehlings
- Division of Genetics and Development, Toronto Western Research Institute, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Department of Surgery, Division of Neurosurgery, University of Toronto, Toronto, ON, Canada
- Gerald and Tootsie Halbert Chair, Neural Repair and Regeneration, Toronto Western Hospital, Toronto, ON, Canada
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Torres-Espín A, Redondo-Castro E, Hernández J, Navarro X. Bone marrow mesenchymal stromal cells and olfactory ensheathing cells transplantation after spinal cord injury--a morphological and functional comparison in rats. Eur J Neurosci 2014; 39:1704-17. [PMID: 24635194 DOI: 10.1111/ejn.12542] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Accepted: 02/04/2014] [Indexed: 12/13/2022]
Abstract
Cell therapy for spinal cord injury (SCI) is a promising strategy for clinical application. Both bone marrow mesenchymal stromal cells (MSCs; also known as bone marrow-derived 'mesenchymal stem cells') and olfactory ensheathing cells (OECs) have demonstrated beneficial effects following transplantation in animal models of SCI. However, due to the large number of affecting parameters that determine the therapy success and the lack of methodological consensus, the comparison of different works is difficult. Therefore, we compared the effects of MSC and OEC transplants at early or delayed time after a spinal cord contusion injury in the rat. Functional outcomes for locomotion, sensory perception and electrophysiological responses were assessed. Moreover, the grafted cells survival and the amount of cavity and spared tissue were studied. The findings indicate that grafted cells survived until 7 days post-injection, but markedly disappeared in the following 2 weeks. Despite the low survival of the cells, MSC and OEC grafts provided tissue protection after early and delayed transplantation. Nevertheless, only acute MSC grafts improved locomotion recovery in treadmill condition and electrophysiological outcomes with respect to the other injured groups. These results, together with previous works, indicate that the MSC seem a better option than OEC for treatment of contusion injuries.
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Affiliation(s)
- Abel Torres-Espín
- Department of Cell Biology, Physiology and Immunology, Group of Neuroplasticity and Regeneration, Institute of Neurosciences, Edif. M, Universitat Autònoma de Barcelona, Bellaterra, E-08193, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain
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Neirinckx V, Cantinieaux D, Coste C, Rogister B, Franzen R, Wislet-Gendebien S. Concise Review: Spinal Cord Injuries: How Could Adult Mesenchymal and Neural Crest Stem Cells Take Up the Challenge? Stem Cells 2014; 32:829-43. [DOI: 10.1002/stem.1579] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Accepted: 10/03/2013] [Indexed: 12/15/2022]
Affiliation(s)
- Virginie Neirinckx
- Groupe Interdisciplinaire de Génoprotéomique appliquée (GIGA); Neurosciences Unit; Liège Belgium
| | - Dorothée Cantinieaux
- Groupe Interdisciplinaire de Génoprotéomique appliquée (GIGA); Neurosciences Unit; Liège Belgium
| | - Cécile Coste
- Groupe Interdisciplinaire de Génoprotéomique appliquée (GIGA); Neurosciences Unit; Liège Belgium
| | - Bernard Rogister
- Groupe Interdisciplinaire de Génoprotéomique appliquée (GIGA); Neurosciences Unit; Liège Belgium
- GIGA, Development, Stem Cells and Regenerative Medicine Unit; University of Liège; Liège Belgium
- Department of Neurology; Centre Hospitalier Universitaire de Liège; Liège Belgium
| | - Rachelle Franzen
- Groupe Interdisciplinaire de Génoprotéomique appliquée (GIGA); Neurosciences Unit; Liège Belgium
| | - Sabine Wislet-Gendebien
- Groupe Interdisciplinaire de Génoprotéomique appliquée (GIGA); Neurosciences Unit; Liège Belgium
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Hao P, Liang Z, Piao H, Ji X, Wang Y, Liu Y, Liu R, Liu J. Conditioned medium of human adipose-derived mesenchymal stem cells mediates protection in neurons following glutamate excitotoxicity by regulating energy metabolism and GAP-43 expression. Metab Brain Dis 2014; 29:193-205. [PMID: 24458787 PMCID: PMC3930846 DOI: 10.1007/s11011-014-9490-y] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 01/15/2014] [Indexed: 11/26/2022]
Abstract
Glutamate excitotoxicity has been implicated as one of the pathological mechanisms contributing to neuronal cell death and is involved in many neurological disorders. Stem cell transplantation is a promising approach for the treatment of nervous system damage or diseases. Previous studies have shown that mesenchymal stem cells (MSCs) have important therapeutic effects in experimental animal and preclinical disease model of central nervous system pathology. However, it is not well understood whether neurogenesis of MSCs or MSC conditioned-medium (CM) containing microparticles mediates therapeutic effects. Here, we investigated the neuroprotective effects of human adipose-derived MSCs (AMSCs) on cortical neurons using models of glutamate excitotoxicity. Following exposure to glutamate (100 μM, 15 min), cortical neurons were co-cultured with either AMSCs separated by a semiporous membrane (prohibiting direct cell-cell contact) or with AMSC-CM for 18 h. Compared to untreated control groups, AMSCs and AMSC-CM partially and similarly reduced neuronal cell damages, as indicated by reduced LDH release, a decreased number of trypan-positive cells and a decline in the number of apoptotic nuclei. Protection by CM was associated with increased GAP-43 expression and an elevated number of GAP-43-positive neurites. Furthermore, CM increased levels of ATP, NAD(+) and NADH and the ratio of NAD(+)/NADH, while preventing a glutamate-induced decline in mitochondrial membrane potential. These results demonstrate that AMSC-CM mediates direct neuroprotection by inhibiting neuronal cell damage/apoptosis, promoting nerve regeneration and repair, and restoring bioenergy following energy depletion caused by glutamate excitotoxicity.
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Affiliation(s)
- Peng Hao
- Regenerative Medicine Centre, First Affiliated Hospital of Dalian Medical University, No.222 Zhongshan Road, Dalian, 116011 People’s Republic of China
- Institute of Integrative Medicine, Dalian Medical University, Dalian, 116044 People’s Republic of China
- Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069 People’s Republic of China
| | - Zhanhua Liang
- Department of Neuroscience, First Affiliated Hospital of Dalian Medical University, Dalian, 116011 People’s Republic of China
| | - Hua Piao
- College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044 People’s Republic of China
| | - Xiaofei Ji
- Regenerative Medicine Centre, First Affiliated Hospital of Dalian Medical University, No.222 Zhongshan Road, Dalian, 116011 People’s Republic of China
- Institute of Integrative Medicine, Dalian Medical University, Dalian, 116044 People’s Republic of China
- Department of Neuroscience, First Affiliated Hospital of Dalian Medical University, Dalian, 116011 People’s Republic of China
| | - Yachen Wang
- Department of Neuroscience, First Affiliated Hospital of Dalian Medical University, Dalian, 116011 People’s Republic of China
| | - Yong Liu
- Regenerative Medicine Centre, First Affiliated Hospital of Dalian Medical University, No.222 Zhongshan Road, Dalian, 116011 People’s Republic of China
- Institute of Integrative Medicine, Dalian Medical University, Dalian, 116044 People’s Republic of China
- Department of Traditional Chinese Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, 116011 People’s Republic of China
| | - Rutao Liu
- Regenerative Medicine Centre, First Affiliated Hospital of Dalian Medical University, No.222 Zhongshan Road, Dalian, 116011 People’s Republic of China
| | - Jing Liu
- Regenerative Medicine Centre, First Affiliated Hospital of Dalian Medical University, No.222 Zhongshan Road, Dalian, 116011 People’s Republic of China
- Institute of Integrative Medicine, Dalian Medical University, Dalian, 116044 People’s Republic of China
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Blockade of interleukin 6 signaling improves the survival rate of transplanted bone marrow stromal cells and increases locomotor function in mice with spinal cord injury. J Neuropathol Exp Neurol 2013; 72:980-93. [PMID: 24042200 DOI: 10.1097/nen.0b013e3182a79de9] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Bone marrow stromal cells (BMSCs) have the potential to improve functional recovery in patients with spinal cord injury (SCI); however, they are limited by low survival rates after transplantation in the injured tissue. Our objective was to clarify the effects of a temporal blockade of interleukin 6 (IL-6)/IL-6 receptor (IL-6R) engagement using an anti-mouse IL-6R monoclonal antibody (MR16-1) on the survival rate of BMSCs after their transplantation in a mouse model of contusion SCI. MR16-1 cotreatment improved the survival rate of transplanted BMSCs, allowing some BMSCs to differentiate into neurons and astrocytes, and improved locomotor function recovery compared with BMSC transplantation or MR16-1 treatment alone. The death of transplanted BMSCs could be mainly related to apoptosis rather than necrosis. Transplantation of BMSC with cotreatment of MR16-1 was associated with a decrease of some proinflammatory cytokines, an increase of neurotrophic factors, decreased apoptosis rates of transplanted BMSCs, and enhanced expression of survival factors Akt and extracellular signal-regulated protein kinases 1/2. We conclude that MR16-1 treatment combined with BMSC transplants helped rescue neuronal cells and axons after contusion SCI better than BMSCs alone by modulating the inflammatory/immune responses and decreasing apoptosis.
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Liu Y, Zhang Y, Lin L, Lin F, Li T, Du H, Chen R, Zheng W, Liu N. Effects of bone marrow-derived mesenchymal stem cells on the axonal outgrowth through activation of PI3K/AKT signaling in primary cortical neurons followed oxygen-glucose deprivation injury. PLoS One 2013; 8:e78514. [PMID: 24265694 PMCID: PMC3827028 DOI: 10.1371/journal.pone.0078514] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2013] [Accepted: 09/14/2013] [Indexed: 01/01/2023] Open
Abstract
Background Transplantation with bone marrow-derived mesenchymal stem cells (BMSCs) improves the survival of neurons and axonal outgrowth after stroke remains undetermined. Here, we investigated whether PI3K/AKT signaling pathway is involved in these therapeutic effects of BMSCs. Methodology/Principal Findings (1) BMSCs and cortical neurons were derived from Sprague-Dawley rats. The injured neurons were induced by Oxygen–Glucose Deprivation (OGD), and then were respectively co-cultured for 48 hours with BMSCs at different densities (5×103, 5×105/ml) in transwell co-culture system. The average length of axon and expression of GAP-43 were examined to assess the effect of BMSCs on axonal outgrowth after the damage of neurons induced by OGD. (2) The injured neurons were cultured with a conditioned medium (CM) of BMSCs cultured for 24 hours in neurobasal medium. During the process, we further identified whether PI3K/AKT signaling pathway is involved through the adjunction of LY294002 (a specific phosphatidylinositide-3-kinase (PI3K) inhibitor). Two hours later, the expression of pAKT (phosphorylated AKT) and AKT were analyzed by Western blotting. The length of axons, the expression of GAP-43 and the survival of neurons were measured at 48 hours. Results Both BMSCs and CM from BMSCs inreased the axonal length and GAP-43 expression in OGD-injured cortical neurons. There was no difference between the effects of BMSCs of 5×105/ml and of 5×103/ml on axonal outgrowth. Expression of pAKT enhanced significantly at 2 hours and the neuron survival increased at 48 hours after the injured neurons cultured with the CM, respectively. These effects of CM were prevented by inhibitor LY294002. Conclusions/Significance BMSCs promote axonal outgrowth and the survival of neurons against the damage from OGD in vitro by the paracrine effects through PI3K/AKT signaling pathway.
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Affiliation(s)
- Yong Liu
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian, People Republic of China
- Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, Fujian, People Republic of China
| | - Yixian Zhang
- Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, Fujian, People Republic of China
- Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, Fujian, People Republic of China
| | - Longzai Lin
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian, People Republic of China
- Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, Fujian, People Republic of China
| | - Feifei Lin
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian, People Republic of China
- Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, Fujian, People Republic of China
| | - Tin Li
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian, People Republic of China
- Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, Fujian, People Republic of China
| | - Houwei Du
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian, People Republic of China
- Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, Fujian, People Republic of China
| | - Ronghua Chen
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian, People Republic of China
- Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, Fujian, People Republic of China
| | - Wei Zheng
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian, People Republic of China
- Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, Fujian, People Republic of China
| | - Nan Liu
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian, People Republic of China
- Institute of Cerebral Vascular Disease of Fujian Province, Fuzhou, Fujian, People Republic of China
- Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, Fujian, People Republic of China
- * E-mail:
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Sun H, Bénardais K, Stanslowsky N, Thau-Habermann N, Hensel N, Huang D, Claus P, Dengler R, Stangel M, Petri S. Therapeutic potential of mesenchymal stromal cells and MSC conditioned medium in Amyotrophic Lateral Sclerosis (ALS)--in vitro evidence from primary motor neuron cultures, NSC-34 cells, astrocytes and microglia. PLoS One 2013; 8:e72926. [PMID: 24069165 PMCID: PMC3771979 DOI: 10.1371/journal.pone.0072926] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Accepted: 07/15/2013] [Indexed: 12/13/2022] Open
Abstract
Administration of mesenchymal stromal cells (MSC) improves functional outcome in the SOD1G93A mouse model of the degenerative motor neuron disorder amyotrophic lateral sclerosis (ALS) as well as in models of other neurological disorders. We have now investigated the effect of the interaction between MSC and motor neurons (derived from both non-transgenic and mutant SOD1G93A transgenic mice), NSC-34 cells and glial cells (astrocytes, microglia) (derived again from both non-transgenic and mutant SOD1G93A ALS transgenic mice) in vitro. In primary motor neurons, NSC-34 cells and astrocytes, MSC conditioned medium (MSC CM) attenuated staurosporine (STS) - induced apoptosis in a concentration-dependent manner. Studying MSC CM-induced expression of neurotrophic factors in astrocytes and NSC-34 cells, we found that glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) gene expression in astrocytes were significantly enhanced by MSC CM, with differential responses of non-transgenic and mutant astrocytes. Expression of Vascular Endothelial Growth Factor (VEGF) in NSC-34 cells was significantly upregulated upon MSC CM-treatment. MSC CM significantly reduced the expression of the cytokines TNFα and IL-6 and iNOS both in transgenic and non-transgenic astrocytes. Gene expression of the neuroprotective chemokine Fractalkine (CX3CL1) was also upregulated in mutant SOD1G93A transgenic astrocytes by MSC CM treatment. Correspondingly, MSC CM increased the respective receptor, CX3CR1, in mutant SOD1G93A transgenic microglia. Our data demonstrate that MSC modulate motor neuronal and glial response to apoptosis and inflammation. MSC therefore represent an interesting candidate for further preclinical and clinical evaluation in ALS.
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Affiliation(s)
- Hui Sun
- Department of Neurology, Hannover Medical School, Hannover, Germany
- Center for Systems Neuroscience, Hannover, Germany
| | - Karelle Bénardais
- Department of Neurology, Hannover Medical School, Hannover, Germany
- Center for Systems Neuroscience, Hannover, Germany
| | - Nancy Stanslowsky
- Department of Neurology, Hannover Medical School, Hannover, Germany
- Center for Systems Neuroscience, Hannover, Germany
| | - Nadine Thau-Habermann
- Department of Neurology, Hannover Medical School, Hannover, Germany
- Center for Systems Neuroscience, Hannover, Germany
| | - Niko Hensel
- Center for Systems Neuroscience, Hannover, Germany
- Department of Neuroanatomy, Hannover Medical School, Hannover, Germany
| | - DongYa Huang
- Department of Neurology, East Hospital, Tongji University, Shanghai, China
| | - Peter Claus
- Center for Systems Neuroscience, Hannover, Germany
- Department of Neuroanatomy, Hannover Medical School, Hannover, Germany
| | - Reinhard Dengler
- Department of Neurology, Hannover Medical School, Hannover, Germany
- Center for Systems Neuroscience, Hannover, Germany
| | - Martin Stangel
- Department of Neurology, Hannover Medical School, Hannover, Germany
- Center for Systems Neuroscience, Hannover, Germany
| | - Susanne Petri
- Department of Neurology, Hannover Medical School, Hannover, Germany
- Center for Systems Neuroscience, Hannover, Germany
- Integriertes Forschungs- und Behandlungszentrum Transplantation (IFB-Tx), Hannover, Germany
- * E-mail:
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48
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Uccelli A. Mesenchymal stem cells exert a remarkable regenerative effect requiring minimal CNS integration. Exp Neurol 2013; 247:292-5. [DOI: 10.1016/j.expneurol.2013.01.028] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2012] [Revised: 01/22/2013] [Accepted: 01/28/2013] [Indexed: 12/28/2022]
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Yuan J, Huang G, Xiao Z, Lin L, Han T. Overexpression of β-NGF promotes differentiation of bone marrow mesenchymal stem cells into neurons through regulation of AKT and MAPK pathway. Mol Cell Biochem 2013; 383:201-11. [PMID: 23934089 DOI: 10.1007/s11010-013-1768-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Accepted: 08/02/2013] [Indexed: 02/03/2023]
Abstract
Bone marrow stromal stem cells (BMSCs) are fibroblastic in shape and capable of self-renewal and have the potential for multi-directional differentiation. Nerve growth factor (NGF), a homodimeric polypeptide, plays an important role in the nervous system by supporting the survival and growth of neural cells, regulating cell growth, promoting differentiation into neuron, and neuron migration. Adenoviral vectors are DNA viruses that contain 36 kb of double-stranded DNA allowing for transmission of the genes to the host nucleus but not inserting them into the host chromosome. The present study aimed to investigate the induction efficiency and differentiation of neural cells from BMSCs by β-NGF gene transfection with recombinant adenoviral vector (Ad-β-NGF) in vitro. The results of immunochemical assay confirmed the induced cells as neuron cells. Moreover, flow cytometric analysis, Annexin-V-FITC/PI, and BrdU assay revealed that chemical inducer β-mercaptoethanol (β-met) triggered apoptosis of BMSCs, as evidenced by inhibition of DNA fragmentation, nuclear condensation, translocation of phospholipid phosphatidylserine, and activation of caspase-3. Furthermore, the results of western blotting showed that β-met suppressed AKT signaling pathway and regulated the MAPKs during differentiation of BMSCs. In contrast, Ad-β-NGF effectively induced the differentiation of BMSCs without causing any cytopathic phenomenon and apoptotic cell death. Moreover, Ad-β-NGF recovered the expression level of phosphorylated AKT and MAPKs in cells exposed to chemical reagents. Taken together, these results suggest that β-NGF gene transfection promotes the differentiation of BMSCs into neurons through regulation of AKT and MAPKs signaling pathways.
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Affiliation(s)
- Jun Yuan
- Department of Neurovascular Surgery, First Hospital Affiliated to Shantou University, 57# Changping Road, Jinping District, Shantou, 515041, China
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Paul G, Anisimov SV. The secretome of mesenchymal stem cells: potential implications for neuroregeneration. Biochimie 2013; 95:2246-56. [PMID: 23871834 DOI: 10.1016/j.biochi.2013.07.013] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2013] [Accepted: 07/10/2013] [Indexed: 12/14/2022]
Abstract
Mesenchymal stem cells have shown regenerative properties in many tissues. This feature had originally been ascribed to their multipotency and thus their ability to differentiate into tissue-specific cells. However, many researchers consider the secretome of mesenchymal stem cells the most important player in the observed reparative effects of these cells. In this review, we specifically focus on the potential neuroregenerative effect of mesenchymal stem cells, summarize several possible mechanisms of neuroregeneration and list key factors mediating this effect. We illustrate examples of mesenchymal stem cell treatment in central nervous system disorders including stroke, neurodegenerative disorders (such as Parkinson's disease, Huntington's disease, multiple system atrophy and cerebellar ataxia) and inflammatory disease (such as multiple sclerosis). We specifically highlight studies where mesenchymal stem cells have entered clinical trials.
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Affiliation(s)
- Gesine Paul
- Translational Neurology Group, Division of Neurology, Department of Clinical Sciences, Lund University, Lund, Sweden; Department of Neurology, Scania University Hospital, Lund, Sweden.
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