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Vassal M, Martins F, Monteiro B, Tambaro S, Martinez-Murillo R, Rebelo S. Emerging Pro-neurogenic Therapeutic Strategies for Neurodegenerative Diseases: A Review of Pre-clinical and Clinical Research. Mol Neurobiol 2025; 62:46-76. [PMID: 38816676 PMCID: PMC11711580 DOI: 10.1007/s12035-024-04246-w] [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: 01/03/2024] [Accepted: 05/14/2024] [Indexed: 06/01/2024]
Abstract
The neuroscience community has largely accepted the notion that functional neurons can be generated from neural stem cells in the adult brain, especially in two brain regions: the subventricular zone of the lateral ventricles and the subgranular zone in the dentate gyrus of the hippocampus. However, impaired neurogenesis has been observed in some neurodegenerative diseases, particularly in Alzheimer's, Parkinson's, and Huntington's diseases, and also in Lewy Body dementia. Therefore, restoration of neurogenic function in neurodegenerative diseases emerges as a potential therapeutic strategy to counteract, or at least delay, disease progression. Considering this, the present study summarizes the different neuronal niches, provides a collection of the therapeutic potential of different pro-neurogenic strategies in pre-clinical and clinical research, providing details about their possible modes of action, to guide future research and clinical practice.
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Affiliation(s)
- Mariana Vassal
- Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal
| | - Filipa Martins
- Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal
| | - Bruno Monteiro
- Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal
| | - Simone Tambaro
- Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden
| | - Ricardo Martinez-Murillo
- Neurovascular Research Group, Department of Translational Neurobiology, Cajal Institute (CSIC), Madrid, Spain
| | - Sandra Rebelo
- Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal.
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2
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Li J, Zhang F, Zhao L, Dong C. Microbiota-gut-brain axis and related therapeutics in Alzheimer's disease: prospects for multitherapy and inflammation control. Rev Neurosci 2023:revneuro-2023-0006. [PMID: 37076953 DOI: 10.1515/revneuro-2023-0006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 03/26/2023] [Indexed: 04/21/2023]
Abstract
Alzheimer's disease (AD) is the most common type of dementia in the elderly and causes neurodegeneration, leading to memory loss, behavioral disorder, and psychiatric impairment. One potential mechanism contributing to the pathogenesis of AD may be the imbalance in gut microbiota, local and systemic inflammation, and dysregulation of the microbiota-gut-brain axis (MGBA). Most of the AD drugs approved for clinical use today are symptomatic treatments that do not improve AD pathologic changes. As a result, researchers are exploring novel therapeutic modalities. Treatments involving the MGBA include antibiotics, probiotics, transplantation of fecal microbiota, botanical products, and others. However, single-treatment modalities are not as effective as expected, and a combination therapy is gaining momentum. The purpose of this review is to summarize recent advances in MGBA-related pathological mechanisms and treatment modalities in AD and to propose a new concept of combination therapy. "MGBA-based multitherapy" is an emerging view of treatment in which classic symptomatic treatments and MGBA-based therapeutic modalities are used in combination. Donepezil and memantine are two commonly used drugs in AD treatment. On the basis of the single/combined use of these two drugs, two/more additional drugs and treatment modalities that target the MGBA are chosen based on the characteristics of the patient's condition as an adjuvant treatment, as well as the maintenance of good lifestyle habits. "MGBA-based multitherapy" offers new insights for the treatment of cognitive impairment in AD patients and is expected to show good therapeutic results.
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Affiliation(s)
- Jiahao Li
- Department of Neurology, The First Affiliated Hospital, Dalian Medical University, No. 222 Zhongshan Road, Dalian 116011, China
| | - Feng Zhang
- Department of Neurology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Li Zhao
- Department of Neurology, The First Affiliated Hospital, Dalian Medical University, No. 222 Zhongshan Road, Dalian 116011, China
| | - Chunbo Dong
- Department of Neurology, The First Affiliated Hospital, Dalian Medical University, No. 222 Zhongshan Road, Dalian 116011, China
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Valenzuela M, Duncan T, Abey A, Johnson A, Boulamatsis C, Dalton MA, Jacobson E, Brunel L, Child G, Simpson D, Buckland M, Lowe A, Siette J, Westbrook F, McGreevy P. Autologous skin-derived neural precursor cell therapy reverses canine Alzheimer dementia-like syndrome in a proof of concept veterinary trial. Stem Cell Res Ther 2022; 13:261. [PMID: 35715872 PMCID: PMC9205057 DOI: 10.1186/s13287-022-02933-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 06/01/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Older companion dogs naturally develop a dementia-like syndrome with biological, clinical and therapeutic similarities to Alzheimer disease (AD). Given there has been no new safe, clinically effective and widely accessible treatment for AD for almost 20 years, an all-new cell therapeutic approach was trialled in canine veterinary patients, and further modelled in aged rats for more detailed neurobiological analysis. METHODS A Phase 1/2A veterinary trial was conducted in N = 6 older companion dogs with definitive diagnosis of Canine Cognitive Dysfunction (CCD). Treatment comprised direct microinjection of 250,000 autologous skin-derived neuroprecursors (SKNs) into the bilateral hippocampus using MRI-guided stereotaxis. Safety was assessed clinically and efficacy using the validated Canine Cognitive Dysfunction Rating Scale (CCDR) at baseline and 3-month post treatment. Intention to treat analysis imputed a single patient that had a surgical adverse event requiring euthanasia. Three dog brains were donated following natural death and histology carried out to quantify Alzheimer pathology as well as immature neurons and synapses; these were compared to a brain bank (N = 12) of untreated aged dogs with and without CCD. Further, an age-related memory dysfunction rat model (N = 16) was used to more closely evaluate intrahippocampal engraftment of canine SKN cells, focusing on mnemonic and synaptic effects as well as donor cell survival, neurodifferentation and electrophysiologic circuit integration in a live hippocampal slice preparation. RESULTS Four out-of-five dogs improved on the primary clinical CCDR endpoint, three fell below diagnostic threshold, and remarkably, two underwent full syndromal reversal lasting up to 2 years. At post mortem, synaptic density in the hippocampus specifically was nine standard deviations above non-treated dogs, and intensity of new neurons also several fold higher. There was no impact on AD pathology or long-term safety signals. Modelling in aged rats replicated the main canine trial findings: hippocampally-dependent place memory deficits were reversed and synaptic depletion rescued. In addition, this model confirmed donor cell survival and migration throughout the hippocampus, neuronal differentiation in situ, and physiologically-correct integration into pyramidal layer circuits. CONCLUSIONS With further development, SKN cell therapy may have potential for treating carefully chosen AD patients based on neurosynaptic restoration in the hippocampus.
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Affiliation(s)
- Michael Valenzuela
- Skin2Neuron Pty Ltd, Sydney, Australia.
- University of New South Wales, Sydney, Australia.
| | - T Duncan
- University of New South Wales, Sydney, Australia
| | - A Abey
- University of Sydney, Sydney, Australia
| | - A Johnson
- Skin2Neuron Pty Ltd, Sydney, Australia
| | | | | | - E Jacobson
- Sydney Children's Hospital, Sydney, Australia
| | - L Brunel
- University of Sydney, Sydney, Australia
| | - G Child
- University of Sydney, Sydney, Australia
| | - D Simpson
- Animal Referral Hospital Homebush, Sydney, Australia
| | - M Buckland
- University of Sydney, Sydney, Australia
- Royal Prince Alfred Hospital, Sydney, Australia
| | - A Lowe
- University of New South Wales, Sydney, Australia
| | - J Siette
- Western Sydney University, Sydney, Australia
| | - F Westbrook
- University of New South Wales, Sydney, Australia
| | - P McGreevy
- University of New England, Armidale, Australia
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Xie WS, Shehzadi K, Ma HL, Liang JH. A Potential Strategy for Treatment of Neurodegenerative Disorders by Regulation of Adult Hippocampal Neurogenesis in Human Brain. Curr Med Chem 2022; 29:5315-5347. [DOI: 10.2174/0929867329666220509114232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/13/2022] [Accepted: 03/17/2022] [Indexed: 11/22/2022]
Abstract
Abstract:
Adult hippocampal neurogenesis is a multistage mechanism that continues throughout the lifespan of human and non-human mammals. These adult-born neurons in the central nervous system (CNS) play a significant role in various hippocampus-dependent processes, including learning, mood regulation, pattern recognition, etc. Reduction of adult hippocampal neurogenesis, caused by multiple factors such as neurological disorders and aging, would impair neuronal proliferation and differentiation and result in memory loss. Accumulating studies have indicated that functional neuron impairment could be restored by promoting adult hippocampal neurogenesis. In this review, we summarized the small molecules that could efficiently promote the process of adult neurogenesis, particularly the agents that have the capacity of crossing the blood-brain barrier (BBB), and showed in vivo efficacy in mammalian brains. This may pave the way for the rational design of drugs to treat humnan neurodegenerative disorders in the future.
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Affiliation(s)
- Wei-Song Xie
- Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 102488, China
| | - Kiran Shehzadi
- Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 102488, China
| | - Hong-Le Ma
- Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 102488, China
| | - Jian-Hua Liang
- Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 102488, China
- Yangtze Delta Region Academy of Beijing Institute of Technology, Jiaxing 314019, China
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Adult Hippocampal Neurogenesis in Alzheimer’s Disease: An Overview of Human and Animal Studies with Implications for Therapeutic Perspectives Aimed at Memory Recovery. Neural Plast 2022; 2022:9959044. [PMID: 35075360 PMCID: PMC8783751 DOI: 10.1155/2022/9959044] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 10/21/2021] [Accepted: 12/15/2021] [Indexed: 12/31/2022] Open
Abstract
The mammalian hippocampal dentate gyrus is a niche for adult neurogenesis from neural stem cells. Newborn neurons integrate into existing neuronal networks, where they play a key role in hippocampal functions, including learning and memory. In the ageing brain, neurogenic capability progressively declines while in parallel increases the risk for developing Alzheimer's disease (AD), the main neurodegenerative disorder associated with memory loss. Numerous studies have investigated whether impaired adult neurogenesis contributes to memory decline in AD. Here, we review the literature on adult hippocampal neurogenesis (AHN) and AD by focusing on both human and mouse model studies. First, we describe key steps of AHN, report recent evidence of this phenomenon in humans, and describe the specific contribution of newborn neurons to memory, as evinced by animal studies. Next, we review articles investigating AHN in AD patients and critically examine the discrepancies among different studies over the last two decades. Also, we summarize researches investigating AHN in AD mouse models, and from these studies, we extrapolate the contribution of molecular factors linking AD-related changes to impaired neurogenesis. Lastly, we examine animal studies that link impaired neurogenesis to specific memory dysfunctions in AD and review treatments that have the potential to rescue memory capacities in AD by stimulating AHN.
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6
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Jalali MS, Sarkaki A, Farbood Y, Azandeh SS, Mansouri E, Ghasemi Dehcheshmeh M, Saki G. Transplanted Wharton’s jelly mesenchymal stem cells improve memory and brain hippocampal electrophysiology in rat model of Parkinson’s disease. J Chem Neuroanat 2020; 110:101865. [DOI: 10.1016/j.jchemneu.2020.101865] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 09/23/2020] [Accepted: 09/23/2020] [Indexed: 12/14/2022]
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Liu XY, Yang LP, Zhao L. Stem cell therapy for Alzheimer's disease. World J Stem Cells 2020; 12:787-802. [PMID: 32952859 PMCID: PMC7477654 DOI: 10.4252/wjsc.v12.i8.787] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 04/10/2020] [Accepted: 07/26/2020] [Indexed: 02/07/2023] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and cognitive impairment. It is caused by synaptic failure and excessive accumulation of misfolded proteins. To date, almost all advanced clinical trials on specific AD-related pathways have failed mostly due to a large number of neurons lost in the brain of patients with AD. Also, currently available drug candidates intervene too late. Stem cells have improved characteristics of self-renewal, proliferation, differentiation, and recombination with the advent of stem cell technology and the transformation of these cells into different types of central nervous system neurons and glial cells. Stem cell treatment has been successful in AD animal models. Recent preclinical studies on stem cell therapy for AD have proved to be promising. Cell replacement therapies, such as human embryonic stem cells or induced pluripotent stem cell-derived neural cells, have the potential to treat patients with AD, and human clinical trials are ongoing in this regard. However, many steps still need to be taken before stem cell therapy becomes a clinically feasible treatment for human AD and related diseases. This paper reviews the pathophysiology of AD and the application prospects of related stem cells based on cell type.
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Affiliation(s)
- Xin-Yu Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
| | - Lin-Po Yang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
| | - Lan Zhao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- Tianjin Key Laboratory of Acupuncture and Moxibustion, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China.
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Shohayeb B, Diab M, Ahmed M, Ng DCH. Factors that influence adult neurogenesis as potential therapy. Transl Neurodegener 2018; 7:4. [PMID: 29484176 PMCID: PMC5822640 DOI: 10.1186/s40035-018-0109-9] [Citation(s) in RCA: 126] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 02/16/2018] [Indexed: 12/21/2022] Open
Abstract
Adult neurogenesis involves persistent proliferative neuroprogenitor populations that reside within distinct regions of the brain. This phenomenon was first described over 50 years ago and it is now firmly established that new neurons are continually generated in distinct regions of the adult brain. The potential of enhancing the neurogenic process lies in improved brain cognition and neuronal plasticity particularly in the context of neuronal injury and neurodegenerative disorders. In addition, adult neurogenesis might also play a role in mood and affective disorders. The factors that regulate adult neurogenesis have been broadly studied. However, the underlying molecular mechanisms of regulating neurogenesis are still not fully defined. In this review, we will provide critical analysis of our current understanding of the factors and molecular mechanisms that determine neurogenesis. We will further discuss pre-clinical and clinical studies that have investigated the potential of modulating neurogenesis as therapeutic intervention in neurodegeneration.
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Affiliation(s)
- Belal Shohayeb
- 1School of Biomedical Science, Faculty of Medicine, University of Queensland, St Lucia, QLD 4067 Australia
| | - Mohamed Diab
- 2Faculty of Pharmacy, Pharos University in Alexandria, P.O. Box Sidi Gaber, Alexandria, 21311 Egypt
| | - Mazen Ahmed
- 2Faculty of Pharmacy, Pharos University in Alexandria, P.O. Box Sidi Gaber, Alexandria, 21311 Egypt
| | - Dominic Chi Hiung Ng
- 1School of Biomedical Science, Faculty of Medicine, University of Queensland, St Lucia, QLD 4067 Australia
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Stem Cell Therapies for Neurodegenerative Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1056:61-84. [PMID: 29754175 DOI: 10.1007/978-3-319-74470-4_5] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Stem cell therapies have been proposed as a treatment option for neurodegenerative diseases, but the best stem cell source and therapeutic efficacy for neuroregeneration remain uncertain. Embryonic stem cells (ESCs) and neural stem cells (NSCs), which can efficiently generate neural cells, could be good candidates but they pose ethical and practical issues. Not only difficult to find the good source of those cells but also they alway pose immunorejection problem since they may not be an autologous cells. Even if we overcome the immunorejection problem, it has also been reported that transplantation of ESCs develop teratoma. Although adult stem cells are more accessible, they have a limited developmental potential. We developed technologies to increase potency of mesenchymal stem cells, which allow them to develop into neural cells, by over expression of the ESC gene, nanog. We also developed a small molecule compound, which significantly increases endogenous NSCs by peripheral administration, eliminating even the necessity of stem cell injection to the brain. These novel technologies may offer neuroregenerative therapies for Alzheimers disease (AD). However, we found that AD pathological condition prevent neurogenesis from NSCs. This chapter discusses how to overcome the problem associated stem cell therapy under AD pathology and introduces exosome as a tool to improve the modification of adult stem cells. These new technologies may open a door for the new era for AD therapy.
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10
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Pen AE, Jensen UB. Current status of treating neurodegenerative disease with induced pluripotent stem cells. Acta Neurol Scand 2017; 135:57-72. [PMID: 26748435 DOI: 10.1111/ane.12545] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/24/2015] [Indexed: 12/18/2022]
Abstract
Degenerative diseases of the brain have proven challenging to treat, let alone cure. One of the treatment options is the use of stem cell therapy, which has been under investigation for several years. However, treatment with stem cells comes with a number of drawbacks, for instance the source of these cells. Currently, a number of options are tested to produce stem cells, although the main issues of quantity and ethics remain for most of them. Over recent years, the potential of induced pluripotent stem cells (iPSCs) has been widely investigated and these cells seem promising for production of numerous different tissues both in vitro and in vivo. One of the major advantages of iPSCs is that they can be made autologous and can provide a sufficient quantity of cells by culturing, making the use of other stem cell sources unnecessary. As the first descriptions of iPSC production with the transcription factors Sox2, Klf4, Oct4 and C-Myc, called the Yamanaka factors, a variety of methods has been developed to convert somatic cells from all germ layers to pluripotent stem cells. Improvement of these methods is necessary to increase the efficiency of reprogramming, the quality of pluripotency and the safety of these cells before use in human trials. This review focusses on the current accomplishments and remaining challenges in the production and use of iPSCs for treatment of neurodegenerative diseases of the brain such as Alzheimer's disease and Parkinson's disease.
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Affiliation(s)
- A. E. Pen
- Department of Molecular Biology and Genetics; Aarhus University; Tjele Denmark
| | - U. B. Jensen
- Department of Clinical Genetics; Aarhus University Hospital; Skejby Denmark
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11
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Lee JH, Oh IH, Lim HK. Stem Cell Therapy: A Prospective Treatment for Alzheimer's Disease. Psychiatry Investig 2016; 13:583-589. [PMID: 27909447 PMCID: PMC5128344 DOI: 10.4306/pi.2016.13.6.583] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Revised: 05/25/2016] [Accepted: 05/26/2016] [Indexed: 12/20/2022] Open
Abstract
Alzheimer's disease (AD) without cure remains as a serious health issue in the modern society. The major neuropathological alterations in AD are characterized by chronic neuroinflammation and neuronal loss due to neurofibrillary tangles (NFTs) of abnormally hyperphosphorylated tau, plaques of β-amyloid (Aβ) and various metabolic dysfunctions. Due to the multifaceted nature of AD pathology and our limited understanding on its etiology, AD is difficult to be treated with currently available pharmaceuticals. This unmet need, however, could be met with stem cell technology that can be engineered to replace neuronal loss in AD patients. Although stem cell therapy for AD is only in its development stages, it has vast potential uses ranging from replacement therapy to disease modelling and drug development. Current progress with stem cells in animal model studies offers promising results for the new prospective treatment for AD. This review will discuss the characteristics of AD, current progress in stem cell therapy and remaining challenges and promises in its development.
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Affiliation(s)
- Ji Han Lee
- Washington University in St. Louis, St. Louis, MO, USA
| | - Il-Hoan Oh
- The Catholic High-Performance Cell Therapy Center & Department of Medical Lifescience, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyun Kook Lim
- Department of Psychiatry, St. Vincent Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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12
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Physical exercise induces hippocampal neurogenesis and prevents cognitive decline. Behav Brain Res 2016; 317:332-339. [PMID: 27702635 DOI: 10.1016/j.bbr.2016.09.067] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Revised: 09/24/2016] [Accepted: 09/30/2016] [Indexed: 12/30/2022]
Abstract
Accumulating evidence from animal and human research indicate that adult hippocampal neurogenesis plays a key role in cognition. Meanwhile, cognitive decline is well known to associate with ageing-related neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Therefore, prevention of hippocampal neurogenesis reduction should be critical for these diseases. Physical exercise, a potent enhancer of adult hippocampal neurogenesis, has emerged as a potential therapy or an adjunctive therapeutic strategy for cognitive decline. In this review, we discuss the recent findings on hippocampal neurogenesis and the incorporation of new born neurons into the neuronal network in humans and in rodents. By focusing on hippocampal neurogenesis, we illustrate the role and possible mechanisms of physical exercise in cognition preservation.
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13
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Nagaraj S. Resurrection of neurodegenerative diseases via stem cells. BIOMEDICAL RESEARCH AND THERAPY 2016. [DOI: 10.7603/s40730-016-0031-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Gu P, Zhang Z, Cui D, Wang Y, Ma L, Geng Y, Wang M. Intracerebroventricular transplanted bone marrow stem cells survive and migrate into the brain of rats with Parkinson's disease. Neural Regen Res 2015; 7:978-84. [PMID: 25722685 PMCID: PMC4341278 DOI: 10.3969/j.issn.1673-5374.2012.13.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2011] [Accepted: 03/09/2012] [Indexed: 11/18/2022] Open
Abstract
In this study, 6-hydroxydopamine was stereotaxically injected into the right substantia nigra compact and ventral tegmental area of rats to establish Parkinson's disease models. The rats then received a transplantation of bone marrow stromal cells that were previously isolated, cultured and labeled with 5-bromo-2'-deoxyuridine in vitro. Transplantation of the bone marrow stromal cells significantly decreased apomorphine-induced rotation time and the escape latency in the Morris water maze test as compared with rats with untreated Parkinson's disease. Immunohistochemical staining showed that, 5-bromo-2'-deoxyuridine-immunoreactive cells were present in the lateral ventricular wall and the choroid plexus 1 day after transplantation. These immunoreactive cells migrated to the surrounding areas of the lateral cerebral ventricle along the corpus callosum. The results indicated that bone marrow stromal cells could migrate to tissues surround the cerebral ventricle via the cerebrospinal fluid circulation and fuse with cells in the brain, thus altering the phenotype of cells or forming neuron-like cells or astrocytes capable of expressing neuron-specific proteins. Taken together, the present findings indicate that bone marrow stromal cells transplanted intracerebroventricularly could survive, migrate and significantly improve the rotational behavior and cognitive function of rats with experimentally induced Parkinson's disease.
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Affiliation(s)
- Ping Gu
- Brain Aging and Cognitive Neuroscience Laboratory of Hebei Province, Shijiazhuang 050031, Hebei Province, China ; Department of Neurology, First Hospital of Hebei Medical University, Shijiazhuang 050031, Hebei Province, China
| | - Zhongxia Zhang
- Brain Aging and Cognitive Neuroscience Laboratory of Hebei Province, Shijiazhuang 050031, Hebei Province, China ; Department of Neurology, First Hospital of Hebei Medical University, Shijiazhuang 050031, Hebei Province, China
| | - Dongsheng Cui
- Brain Aging and Cognitive Neuroscience Laboratory of Hebei Province, Shijiazhuang 050031, Hebei Province, China
| | - Yanyong Wang
- Department of Neurology, First Hospital of Hebei Medical University, Shijiazhuang 050031, Hebei Province, China
| | - Lin Ma
- Brain Aging and Cognitive Neuroscience Laboratory of Hebei Province, Shijiazhuang 050031, Hebei Province, China ; Department of Neurology, First Hospital of Hebei Medical University, Shijiazhuang 050031, Hebei Province, China
| | - Yuan Geng
- Brain Aging and Cognitive Neuroscience Laboratory of Hebei Province, Shijiazhuang 050031, Hebei Province, China
| | - Mingwei Wang
- Brain Aging and Cognitive Neuroscience Laboratory of Hebei Province, Shijiazhuang 050031, Hebei Province, China ; Department of Neurology, First Hospital of Hebei Medical University, Shijiazhuang 050031, Hebei Province, China
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15
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Li XY, Bao XJ, Wang RZ. Potential of neural stem cell-based therapies for Alzheimer's disease. J Neurosci Res 2015; 93:1313-24. [PMID: 25601591 DOI: 10.1002/jnr.23555] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Revised: 11/23/2014] [Accepted: 12/15/2014] [Indexed: 02/06/2023]
Abstract
Alzheimer's disease (AD), known to be a leading cause of dementia that causes heavy social and financial burdens worldwide, is characterized by progressive loss of neurons and synaptic connectivity after depositions of amyloid-β (Aβ) protein. Current therapies for AD patients can only alleviate symptoms but cannot deter the neural degeneration, thus providing no long-term recovery. Neural stem cells (NSCs), capable of self-renewal and of differentiation into functional neurons and glia, have been shown to repair damaged networks and reverse memory and learning deficits in animal studies, providing new hope for curing AD patients by cell transplantation. Under AD pathology, the microenvironment also undergoes great alterations that affect the propagation of NSCs and subsequent therapeutic efficiency, calling for measures to improve the hostile environment for cell transplantation. This article reviews the therapeutic potential of both endogenous and exogenous NSCs in the treatment of AD and the challenges to application of stem cells in AD treatment, particularly those from the microenvironmental alterations, in the hope of providing more information for future research in exploiting stem cell-based therapies for AD. © 2015 Wiley Periodicals, Inc.
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Affiliation(s)
- Xue-Yuan Li
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, People's Republic of China
| | - Xin-Jie Bao
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, People's Republic of China
| | - Ren-Zhi Wang
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, People's Republic of China
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Tobin MK, Bonds JA, Minshall RD, Pelligrino DA, Testai FD, Lazarov O. Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here. J Cereb Blood Flow Metab 2014; 34:1573-1584. [PMID: 25074747 PMCID: PMC4269726 DOI: 10.1038/jcbfm.2014.130] [Citation(s) in RCA: 272] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Revised: 06/28/2014] [Accepted: 06/30/2014] [Indexed: 12/18/2022]
Abstract
This review covers the pathogenesis of ischemic stroke and future directions regarding therapeutic options after injury. Ischemic stroke is a devastating disease process affecting millions of people worldwide every year. The mechanisms underlying the pathophysiology of stroke are not fully understood but there is increasing evidence demonstrating the contribution of inflammation to the drastic changes after cerebral ischemia. This inflammation not only immediately affects the infarcted tissue but also causes long-term damage in the ischemic penumbra. Furthermore, the interaction between inflammation and subsequent neurogenesis is not well understood but the close relationship between these two processes has garnered significant interest in the last decade or so. Current approved therapy for stroke involving pharmacological thrombolysis is limited in its efficacy and new treatment strategies need to be investigated. Research aimed at new therapies is largely about transplantation of neural stem cells and using endogenous progenitor cells to promote brain repair. By understanding the interaction between inflammation and neurogenesis, new potential therapies could be developed to further establish brain repair mechanisms.
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Affiliation(s)
- Matthew K Tobin
- Medical Scientist Training Program, University of Illinois at Chicago, Chicago, Illinois, USA
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois, USA
- Graduate Program in Neuroscience, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Jacqueline A Bonds
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois, USA
- Graduate Program in Neuroscience, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Richard D Minshall
- Department of Anesthesiology, University of Illinois at Chicago, Chicago, Illinois, USA
- Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Dale A Pelligrino
- Department of Anesthesiology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Fernando D Testai
- Department of Neurology and Rehabilitation Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Orly Lazarov
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois, USA
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17
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Upadhyay G, Shankar S, Srivastava RK. Stem Cells in Neurological Disorders: Emerging Therapy with Stunning Hopes. Mol Neurobiol 2014; 52:610-25. [DOI: 10.1007/s12035-014-8883-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2014] [Accepted: 08/27/2014] [Indexed: 12/14/2022]
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19
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Abstract
Alzheimer's disease (AD) is a progressive neurological disorder characterized by the aggregation of two proteins, amyloid-β and hyperphosphorylated tau, and by neuronal and synaptic loss. Although some drugs have been shown to slow the progression of the disease, at present no treatment has been developed that can stop or reverse the progression of the pathology. Recently, new therapeutic strategies have been proposed for the treatment of the disease. Among these, the development of stem cells and gene-modified cells is an especially promising therapeutic approach for AD. In this review we highlight the experimental and preclinical studies that have been focused on stem cell-based and gene-modified cell-based uses as potential therapies for AD. The potential clinical applications are also discussed.
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Affiliation(s)
- Micaela Johanna Glat
- Laboratory of Neuroscience, Sackler Faculty of Medicine, Felsenstein Medical Research Center, Tel Aviv University, Petah-Tikva, Israel
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20
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Ma K, Fox L, Shi G, Shen J, Liu Q, Pappas JD, Cheng J, Qu T. Generation of neural stem cell-like cells from bone marrow-derived human mesenchymal stem cells. Neurol Res 2012; 33:1083-93. [PMID: 22196762 DOI: 10.1179/1743132811y.0000000053] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Under appropriate culture conditions, bone marrow (BM)-derived mesenchymal stem cells are capable of differentiating into diverse cell types unrelated to their phenotypical embryonic origin, including neural cells. Here, we report the successful generation of neural stem cell (NSC)-like cells from BM-derived human mesenchymal stem cells (hMSCs). Initially, hMSCs were cultivated in a conditioned medium of human neural stem cells. In this culture system, hMSCs were induced to become NSC-like cells, which proliferate in neurosphere-like structures and express early NSC markers. Like central nervous system-derived NSCs, these BM-derived NSC-like cells were able to differentiate into cells expressing neural markers for neurons, astrocytes, and oligodendrocytes. Whole-cell patch clamp recording revealed that neuron-like cells, differentiated from NSC-like cells, exhibited electrophysiological properties of neurons, including action potentials. Transplantation of NSC-like cells into mouse brain confirmed that these NSC-like cells retained their capability to differentiate into neuronal and glial cells in vivo. Our data show that multipotent NSC-like cells can be efficiently produced from BM-derived hMSCs in culture and that these cells may serve as a useful alternative to human neural stem cells for potential clinical applications such as autologous neuroreplacement therapies.
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Affiliation(s)
- K Ma
- College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
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21
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Abstract
Although the adult human brain has a small number of neural stem cells, they are insufficient to repair the damaged brain to achieve significant functional recovery for neurodegenerative diseases and stroke. Stem cell therapy, by either enhancing endogenous neurogenesis, or transplanting stem cells, has been regarded as a promising solution. However, the harsh environment of the diseased brain posts a severe threat to the survival and correct differentiation of those new stem cells. Hormesis (or preconditioning, stress adaptation) is an adaptation mechanism by which cells or organisms are potentiated to survive an otherwise lethal condition, such as the harsh oxidative stress in the stroke brain. Stem cells treated by low levels of chemical, physical, or pharmacological stimuli have been shown to survive better in the neurodegenerative brain. Thus combining hormesis and stem cell therapy might improve the outcome for treatment of these diseases. In addition, since the cell death patterns and their underlying molecular mechanism may vary in different neurodegenerative diseases, even in different progression stages of the same disease, it is essential to design a suitable and optimum hormetic strategy that is tailored to the individual patient.
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Affiliation(s)
- Guanghu Wang
- Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Health Sciences University
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22
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Babaei P, Soltani Tehrani B, Alizadeh A. Transplanted bone marrow mesenchymal stem cells improve memory in rat models of Alzheimer's disease. Stem Cells Int 2012; 2012:369417. [PMID: 22754576 PMCID: PMC3382392 DOI: 10.1155/2012/369417] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2012] [Revised: 04/18/2012] [Accepted: 04/18/2012] [Indexed: 12/13/2022] Open
Abstract
The present study aims to evaluate the effect of bone marrow mesenchymal stem cells (MSCs) grafts on cognition deficit in chemically and age-induced Alzheimer's models of rats. In the first experiments aged animals (30 months) were tested in Morris water maze (MWM) and divided into two groups: impaired memory and unimpaired memory. Impaired groups were divided into two groups and cannulated bilaterally at the CA1 of the hippocampus for delivery of mesenchymal stem cells (500 × 10(3)/μL) and PBS (phosphate buffer saline). In the second experiment, Ibotenic acid (Ibo) was injected bilaterally into the nucleus basalis magnocellularis (NBM) of young rats (3 months) and animals were tested in MWM. Then, animals with memory impairment received the following treatments: MSCs (500 × 10(3)/μL) and PBS. Two months after the treatments, cognitive recovery was assessed by MWM in relearning paradigm in both experiments. Results showed that MSCs treatment significantly increased learning ability and memory in both age- and Ibo-induced memory impairment. Adult bone marrow mesenchymal stem cells show promise in treating cognitive decline associated with aging and NBM lesions.
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Affiliation(s)
- Parvin Babaei
- Cellular and Molecular Research Center, Faculty of Medecine, Guilan University Complex, Rasht 41996-13769, Iran
- Deptartment of Physiology, Faculty of Medecine, Guilan University Complex, Rasht 41996-13769, Iran
| | - Bahram Soltani Tehrani
- Cellular and Molecular Research Center, Faculty of Medecine, Guilan University Complex, Rasht 41996-13769, Iran
- Deptartment of Pharmacology, Faculty of Medecine, Guilan University Complex, Rasht 41996-13769, Iran
| | - Arsalan Alizadeh
- Cellular and Molecular Research Center, Faculty of Medecine, Guilan University Complex, Rasht 41996-13769, Iran
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23
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Cui YM, Wang H, Liu QR, Han M, Lu Y, Zhao CQ. Flavans from Iris tenuifolia and their effects on β-amyloid aggregation and neural stem cells proliferation in vitro. Bioorg Med Chem Lett 2011; 21:4400-3. [DOI: 10.1016/j.bmcl.2011.06.039] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2011] [Revised: 06/01/2011] [Accepted: 06/10/2011] [Indexed: 12/25/2022]
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Tunici P, Pellegatta S, Finocchiaro G. The potential of stem cells for the treatment of brain tumors and globoid cell leukodystrophy. Cytotechnology 2011; 41:93-101. [PMID: 19002946 DOI: 10.1023/a:1024818621377] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Stem cells of different origin are under careful scrutiny as potential new tools for the treatment of several neurological diseases. The major focus of these reaserches have been neurodegenerative disorders, such as Huntington Chorea or Parkinson Disease (Shihabuddin et al., 1999). More recently attention has been devoted to their use for brain repair after stroke (Savitz et al., 2002). In this review we will focus on the potential of stem cell treatments for glioblastoma multiforme (Holland, 2000), the most aggressive primary brain tumor, and globoid cell leukodystrophy (Krabbe disease), a metabolic disorder of the white matter (Berger et al., 2001). These two diseases may offer a paradigm of what the stem cell approach may offer in term of treatment, alone or in combination with other therapeutic approaches. Two kinds of stem cells will be consideredhere: neural stem cells and hematopoietic stem cells, both obtained after birth. The review will focus on experimental models, with an eye on clinical perspectives.
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Affiliation(s)
- Patrizia Tunici
- Istituto Nazionale Neurologico Besta, Unit of Neuro-Oncology and Gene Therapy, Milan, Italy (Author for correspondence)
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25
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Nivet E, Vignes M, Girard SD, Pierrisnard C, Baril N, Devèze A, Magnan J, Lanté F, Khrestchatisky M, Féron F, Roman FS. Engraftment of human nasal olfactory stem cells restores neuroplasticity in mice with hippocampal lesions. J Clin Invest 2011; 121:2808-20. [PMID: 21670501 DOI: 10.1172/jci44489] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2010] [Accepted: 04/27/2011] [Indexed: 12/15/2022] Open
Abstract
Stem cell-based therapy has been proposed as a potential means of treatment for a variety of brain disorders. Because ethical and technical issues have so far limited the clinical translation of research using embryonic/fetal cells and neural tissue, respectively, the search for alternative sources of therapeutic stem cells remains ongoing. Here, we report that upon transplantation into mice with chemically induced hippocampal lesions, human olfactory ecto-mesenchymal stem cells (OE-MSCs) - adult stem cells from human nasal olfactory lamina propria - migrated toward the sites of neural damage, where they differentiated into neurons. Additionally, transplanted OE-MSCs stimulated endogenous neurogenesis, restored synaptic transmission, and enhanced long-term potentiation. Mice that received transplanted OE-MSCs exhibited restoration of learning and memory on behavioral tests compared with lesioned, nontransplanted control mice. Similar results were obtained when OE-MSCs were injected into the cerebrospinal fluid. These data show that OE-MSCs can induce neurogenesis and contribute to restoration of hippocampal neuronal networks via trophic actions. They provide evidence that human olfactory tissue is a conceivable source of nervous system replacement cells. This stem cell subtype may be useful for a broad range of stem cell-related studies.
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Affiliation(s)
- Emmanuel Nivet
- Laboratoire de Neurobiologie des Processus Mnésiques, CNRS UMR-6149, Aix-Marseille Université; IFR Sciences du Cerveau et de Cognition, Marseille, France.
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26
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Turgeman G, Pinkas A, Slotkin TA, Tfilin M, Langford R, Yanai J. Reversal of chlorpyrifos neurobehavioral teratogenicity in mice by allographic transplantation of adult subventricular zone-derived neural stem cells. J Neurosci Res 2011; 89:1185-93. [PMID: 21520219 DOI: 10.1002/jnr.22631] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2010] [Revised: 12/07/2010] [Accepted: 01/27/2011] [Indexed: 01/25/2023]
Abstract
Neurobehavioral teratogenicity can be reversed with transplantation of neural stem cells. However, the usefulness of this therapy would be greatly enhanced by employing adult stem cells. In pursuit of this this goal, we developed a model that uses subventricular zone (SVZ) cells. HS/Ibg mice were exposed prenatally to chlorpyrifos on gestational days 9-18 (3 mg/kg/day, SC) in order to induce deficits in their performance in the Morris water maze test. Both the control and the exposed offspring were transplanted with SVZ cells (or vehicle) on postnatal day 35; this actually represents an allogenic transplantation, because the HS/Ibg strain is a heterogeneous stock. The transplanted cells were later observed in the host brain by DiI tracing, and their initial differentiation to cholinergic neurons and astrocytes was ascertained. On postnatal day 80, animals that had been exposed prenatally to chlorpyrifos displayed impaired Morris water maze performance, requiring more time to reach the platform. Transplantation of adult SVZ-derived neural stem cells (NSC) reversed the deficits. Applying autologous transplantation provides an important demonstration that the methodological obstacles of immunological rejection and the ethical concerns related to using embryonic stem cells may be successfully bypassed in developing stem cell therapies for neurodevelopmental disorders.
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Affiliation(s)
- Gadi Turgeman
- Department of Molecular Biology, Ariel University Center of Samaria, Ariel, Israel
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27
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Kwak YD, Marutle A, Dantuma E, Merchant S, Bushnev S, Sugaya K. Involvement of notch signaling pathway in amyloid precursor protein induced glial differentiation. Eur J Pharmacol 2011; 650:18-27. [PMID: 20883690 PMCID: PMC2997918 DOI: 10.1016/j.ejphar.2010.09.015] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2009] [Revised: 08/10/2010] [Accepted: 09/07/2010] [Indexed: 10/19/2022]
Abstract
The amyloid precursor protein (APP) has been mainly studied in its role in the production of amyloid β peptides (Aβ), because Aβ deposition is a hallmark of Alzheimer's disease. Although several studies suggest APP has physiological functions, it is still controversial. We previously reported that APP increased glial differentiation of neural progenitor cells (NPCs). In the current study, NPCs transplanted into APP23 transgenic mice primarily differentiated into glial cells. In vitro treatment with secreted APP (sAPP) dose-dependently increased glial fibrillary acidic protein (GFAP) immuno-positive cells in NPCs and over expression of APP caused most NPCs to differentiate into GFAP immuno-positive cells. Treatment with sAPP also dose-dependently increased expression levels of GFAP in NT-2/D1 cells along with the generation of Notch intracellular domain (NICD) and expression of Hairy and enhancer of split 1 (Hes1). Treatment with γ-secretase inhibitor suppressed the generation of NICD and reduced Hes1 and GFAP expressions. Treatment with the N-terminal domain of APP (APP 1-205) was enough to induce up regulation of GFAP and Hes1 expressions, and application of 22 C11 antibodies recognizing N-terminal APP suppressed these changes by sAPP. These results indicate APP induces glial differentiation of NPCs through Notch signaling.
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Affiliation(s)
- Young-Don Kwak
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827 USA
| | - Amelia Marutle
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827 USA
| | - Elise Dantuma
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827 USA
| | - Stephanie Merchant
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827 USA
| | - Sergey Bushnev
- Florida Hospital Orlando, 601 East Rollins Street, Orlando, FL 32803 USA
| | - Kiminobu Sugaya
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827 USA
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Dantuma E, Merchant S, Sugaya K. Stem cells for the treatment of neurodegenerative diseases. Stem Cell Res Ther 2010; 1:37. [PMID: 21144012 PMCID: PMC3025439 DOI: 10.1186/scrt37] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Stem cells offer an enormous pool of resources for the understanding of the human body. One proposed use of stem cells has been as an autologous therapy. The use of stem cells for neurodegenerative diseases has become of interest. Clinical applications of stem cells for Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis will increase in the coming years, and although great care will need to be taken when moving forward with prospective treatments, the application of stem cells is highly promising.
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Affiliation(s)
- Elise Dantuma
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Boulevard, Orlando, FL 32827, USA.
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29
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Mesenchymal stem cells increase hippocampal neurogenesis and counteract depressive-like behavior. Mol Psychiatry 2010; 15:1164-75. [PMID: 19859069 DOI: 10.1038/mp.2009.110] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Adult bone marrow-derived mesenchymal stem cells (MSCs) are regarded as potential candidates for treatment of neurodegenerative disorders, because of their ability to promote neurogenesis. MSCs promote neurogenesis by differentiating into neural lineages as well as by expressing neurotrophic factors that enhance the survival and differentiation of neural progenitor cells. Depression has been associated with impaired neurogenesis in the hippocampus and dentate gyrus. Therefore, the aim of this study was to analyze the therapeutic potential of MSCs in the Flinders sensitive line (FSL), a rat animal model for depression. Rats received an intracerebroventricular injection of culture-expanded and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-labeled bone marrow-derived MSCs (10⁵ cells). MSC-transplanted FSL rats showed significant improvement in their behavioral performance, as measured by the forced swim test and the dominant-submissive relationship (DSR) paradigm. After transplantation, MSCs migrated mainly to the ipsilateral dentate gyrus, CA1 and CA3 regions of the hippocampus, and to a lesser extent to the thalamus, hypothalamus, cortex and contralateral hippocampus. Neurogenesis was increased in the ipsilateral dentate gyrus and hippocampus of engrafted rats (granular cell layer) and was correlated with MSC engraftment and behavioral performance. We therefore postulate that MSCs may serve as a novel modality for treating depressive disorders.
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Lazarov O, Mattson MP, Peterson DA, Pimplikar SW, van Praag H. When neurogenesis encounters aging and disease. Trends Neurosci 2010; 33:569-79. [PMID: 20961627 PMCID: PMC2981641 DOI: 10.1016/j.tins.2010.09.003] [Citation(s) in RCA: 304] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2010] [Revised: 09/02/2010] [Accepted: 09/13/2010] [Indexed: 11/20/2022]
Abstract
In this review, we consider the evidence that a reduction in neurogenesis underlies aging-related cognitive deficits and impairments in disorders such as Alzheimer's disease (AD). The molecular and cellular alterations associated with impaired neurogenesis in the aging brain are discussed. Dysfunction of presenilin-1, misprocessing of amyloid precursor protein and toxic effects of hyperphosphorylated tau and β-amyloid probably contribute to impaired neurogenesis in AD. Because factors such as exercise, environmental enrichment and dietary energy restriction enhance neurogenesis, and protect against age-related cognitive decline and AD, knowledge of the underlying neurogenic signaling pathways could lead to novel therapeutic strategies for preserving brain function. In addition, manipulation of endogenous neural stem cells and stem cell transplantation, as stand-alone or adjunct treatments, seems promising.
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Affiliation(s)
- Orly Lazarov
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA.
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31
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Kazma M, Izrael M, Revel M, Chebath J, Yanai J. Survival, differentiation, and reversal of heroin neurobehavioral teratogenicity in mice by transplanted neural stem cells derived from embryonic stem cells. J Neurosci Res 2010; 88:315-23. [PMID: 19746435 DOI: 10.1002/jnr.22193] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Cell therapies in animal models of neurobehavioral defects are normally derived from neural stem cells (NSC) of the developing cortex. However, the clinical feasibility of NSC therapies would be greatly improved by deriving transplanted cells and from a tissue culture source that is self-renewing, containing cells that potentially differentiate into the desired neuronal phenotypes. These cultures can be engineered to contain the appropriate factors to support their therapeutic action and likely evoke lesser immune reactions. In the current study, we employed our model of mice neurobehaviorally impaired via prenatal exposure to heroin, to test the therapeutic efficacy of NSC derived from murine embryonic stem cells culture (ESC). The culture contained elongated bipolar cells, 90% of which are positive for nestin, the intermediate filament protein found in neural precursors. After removal of growth factors, the NSC differentiated into neurons (34.0% +/- 3.8% NF-160 positive), including cholinergic cells (ChAT positive), oligodendrocytes (29.9% +/- 4.2% O(4)), and astrocytes (36.1% +/- 4.7% GFAP positive). Reverse transcriptase polymerase chain reaction (RT-PCR) analysis confirmed the immunocytochemical findings. Mice made deficient in Morris maze behavior by prenatal heroin exposure (10 mg/kg heroin s.c. on gestational days 9-18) were transplanted into the hippocampus region on postnatal day 35 with the ES culture-derived NSC (ES-NSC) labeled with dialkylcarbocyanine (Dil) cell tracker. Dil+ and NF160+ cells were detected in the hippocampal region (50% +/- 8% survival). The transplantation completely restored maze performance to normal; e.g., on day 3, transplantation improved the behavior from the deficient level of 11.9-sec latency to the control of 5.6-sec latency (44.5% improvement).
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Affiliation(s)
- Meital Kazma
- The Ross Laboratory for Studies in Neural Birth Defects, Department of Medical Neurobiology, Institute for Medical Research, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
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Billauer-Haimovitch H, Slotkin TA, Dotan S, Langford R, Pinkas A, Yanai J. Reversal of chlorpyrifos neurobehavioral teratogenicity in mice by nicotine administration and neural stem cell transplantation. Behav Brain Res 2009; 205:499-504. [PMID: 19682500 PMCID: PMC2782724 DOI: 10.1016/j.bbr.2009.08.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2009] [Revised: 08/03/2009] [Accepted: 08/04/2009] [Indexed: 01/12/2023]
Abstract
Identifying the mechanisms underlying the adverse effects of developmental neurotoxicants enables the design of therapies that can potentially reverse neurobehavioral deficits in adulthood. We administered chlorpyrifos (CPF), a model organophosphate pesticide to pregnant mice and identified visuospatial deficits in adult offspring using performance in the Morris maze. We then evaluated two strategies to reverse the effects, nicotine administration and transplantation of neural stem cells. Daily administration of nicotine prior to behavioral testing did not alter maze performance by itself, but completely reversed the deficits evoked by prenatal CPF exposure. Similarly, control animals grafted with neural stem cells in adolescence did not show any alterations in behavioral performance as adults, but the grafts completely reversed the effects of prenatal CPF treatment. This study thus provides a model for the development and application of both pharmacologic and cell-based therapies to offset the effects of neurobehavioral teratogens.
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Affiliation(s)
- Hana Billauer-Haimovitch
- The Ross Laboratory for Studies in Neural Birth Defects, Department of Medical Neurobiology, Institute for Medical Research – Israel-Canada, The Hebrew University-Hadassah Medical School, Box 12272, 91120, Jerusalem, Israel
| | - Theodore A. Slotkin
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710 USA
| | - Sharon Dotan
- The Ross Laboratory for Studies in Neural Birth Defects, Department of Medical Neurobiology, Institute for Medical Research – Israel-Canada, The Hebrew University-Hadassah Medical School, Box 12272, 91120, Jerusalem, Israel
| | - Rachel Langford
- The Ross Laboratory for Studies in Neural Birth Defects, Department of Medical Neurobiology, Institute for Medical Research – Israel-Canada, The Hebrew University-Hadassah Medical School, Box 12272, 91120, Jerusalem, Israel
| | - Adi Pinkas
- The Ross Laboratory for Studies in Neural Birth Defects, Department of Medical Neurobiology, Institute for Medical Research – Israel-Canada, The Hebrew University-Hadassah Medical School, Box 12272, 91120, Jerusalem, Israel
| | - Joseph Yanai
- The Ross Laboratory for Studies in Neural Birth Defects, Department of Medical Neurobiology, Institute for Medical Research – Israel-Canada, The Hebrew University-Hadassah Medical School, Box 12272, 91120, Jerusalem, Israel
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710 USA
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Abstract
Stem cells, as subjects of study for use in treating neurological diseases, are envisioned as a replacement for lost neurons and glia, a means of trophic support, a therapeutic vehicle, and, more recently, a tool for in vitro modeling to understand disease and to screen and personalize treatments. In this review we analyze the requirements of stem cell-based therapy for clinical translation, advances in stem cell research toward clinical application for neurological disorders, and different animal models used for analysis of these potential therapies. We focus on Parkinson's disease (typically defined by the progressive loss of dopaminergic nigral neurons), stroke (neurodegeneration associated with decreased blood perfusion in the brain), and multiple sclerosis (an autoimmune disorder that generates demyelination, axonal damage, astrocytic scarring, and neurodegeneration in the brain and spinal cord). We chose these disorders for their diversity and the number of people affected by them. An additional important consideration was the availability of multiple animal models in which to test stem cell applications for these diseases. We also discuss the relationship between the limited number of systematic stem cell studies performed in animals, in particular nonhuman primates and the delayed progress in advancing stem cell therapies to clinical success.
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Affiliation(s)
- Valerie L Joers
- Neuroscience Training Program, University of Wisconsin, Madison, WI, USA
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34
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Shetty AK, Rao MS, Hattiangady B. Behavior of hippocampal stem/progenitor cells following grafting into the injured aged hippocampus. J Neurosci Res 2008; 86:3062-74. [PMID: 18618674 PMCID: PMC2575032 DOI: 10.1002/jnr.21764] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Multipotent neural stem/progenitor cells (NSCs) from the embryonic hippocampus are potentially useful as donor cells to repopulate the degenerated regions of the aged hippocampus after stroke, epilepsy, or Alzheimer's disease. However, the efficacy of the NSC grafting strategy for repairing the injured aged hippocampus is unknown. To address this issue, we expanded FGF-2-responsive NSCs from the hippocampus of embryonic day 14 green fluorescent protein-expressing transgenic mice as neurospheres in vitro and grafted them into the hippocampus of 24-month-old F344 rats 4 days after CA3 region injury. Engraftment, migration, and neuronal/glial differentiation of cells derived from NSCs were analyzed 1 month after grafting. Differentiation of neurospheres in culture dishes or after placement on organotypic hippocampal slice cultures demonstrated that these cells had the ability to generate considerable numbers of neurons, astrocytes, and oligodendrocytes. Following grafting into the injured aged hippocampus, cells derived from neurospheres survived and dispersed, but exhibited no directed migration into degenerated or intact hippocampal cell layers. Phenotypic analyses of graft-derived cells revealed neuronal differentiation in 3%-5% of cells, astrocytic differentiation in 28% of cells, and oligodendrocytic differentiation in 6%-10% cells. The results demonstrate for the first time that NSCs derived from the fetal hippocampus survive and give rise to all three CNS phenotypes following transplantation into the injured aged hippocampus. However, grafted NSCs do not exhibit directed migration into lesioned areas or widespread neuronal differentiation, suggesting that direct grafting of primitive NSCs is not adequate for repair of the injured aged brain without priming the microenvironment.
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Affiliation(s)
- Ashok K Shetty
- Department of Surgery (Neurosurgery), Duke University Medical Center, Durham, NC 27710, USA.
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Hou L, Hong T. Stem cells and neurodegenerative diseases. ACTA ACUST UNITED AC 2008; 51:287-94. [PMID: 18368305 DOI: 10.1007/s11427-008-0049-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2007] [Accepted: 12/04/2007] [Indexed: 01/01/2023]
Abstract
Neurodegenerative diseases are characterized by the neurodegenerative changes or apoptosis of neurons involved in networks, which are important to specific physiological functions. With the development of old-aging society, the incidence of neurodegenerative diseases is on the increase. However, it is difficult to diagnose for most of neurodegenerative diseases. At present, there are too few effective therapies. Advances in stem cell biology have raised the hope and possibility for the therapy of neurodegenerative diseases. Recently, stem cells have been widely attempted to treat neurodegenerative diseases of animal model. Here we review the progress and prospects of various stem cells, including embryonic stem cells, mesenchymal stem cell and neural stem cells and so on, for the treatments of neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, Huntington' disease and Amyotrophic lateral sclerosis/Lou Gehrig's disease.
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Affiliation(s)
- LingLing Hou
- Institute of Biological Science and Technology, Beijing Jiaotong University, Beijing 100044, China.
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Hildebrand MS, Newton SS, Gubbels SP, Sheffield AM, Kochhar A, de Silva MG, Dahl HHM, Rose SD, Behlke MA, Smith RJH. Advances in molecular and cellular therapies for hearing loss. Mol Ther 2008; 16:224-36. [PMID: 18223547 DOI: 10.1038/sj.mt.6300351] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2007] [Accepted: 10/10/2007] [Indexed: 02/07/2023] Open
Abstract
Development of effective therapeutics for hearing loss has proven to be a slow and difficult process, evidenced by the lack of restorative medicines and technologies currently available to the otolaryngologist. In large part this is attributable to the limited regenerative potential in cochlear cells and the secondary degeneration of the cochlear architecture that commonly follows sensorineural hearing impairment. Therapeutic advances have been made using animal models, particularly in regeneration and remodeling of spiral ganglion neurons, which retract and die following hair cell loss. Natural regeneration in avian and reptilian systems provides hope that replacement of hair cells is achievable in humans. The most exciting recent advancements in this field have been made in the relatively new areas of cellular replacement and gene therapy. In this review we discuss recent developments in gene- and cell-based therapy for hearing loss, including detailed analysis of therapeutic mechanisms such as RNA interference and stem cell transplantation, as well as in utero delivery to the mammalian inner ear. We explore the advantages and limitations associated with the use of these strategies for inner ear restoration.
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Affiliation(s)
- Michael S Hildebrand
- Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, Iowa 52242, USA.
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Ben-Shaanan TL, Ben-Hur T, Yanai J. Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain. Mol Psychiatry 2008; 13:222-31. [PMID: 17876325 DOI: 10.1038/sj.mp.4002084] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Grafting of neural progenitors has been shown to reverse a wide variety of neurobehavioral defects. While their role of replacing injured cells and restoring damaged circuitries has been shown, it is widely accepted that this cannot be the only mechanism, as therapy can occur even when an insufficient number of transplanted cells are found. We hypothesized that one major mechanism by which transplanted neural progenitors exert their therapeutic effect is by enhancing endogenous cells production. Consequently, in an allographic model of transplantation, prenatally heroin-exposed genetically heterogeneous (HS) mice were made defective in their hippocampal neurobehavioral function by exposing their mothers to heroin (10 mg kg(-1) heroin on gestation days 9-18). Hippocampal damage was confirmed by deficient performance in the Morris maze (P<0.009), and decreased production of endogenous cells in the dentate gyrus by 39% was observed. On postnatal day 35, they received an HS-derived neural progenitors transplant followed by repeated bromodeoxyuridine injections. The transplant returned endogenous cells production to normal levels (P<0.006) and reversed the behavioral defects (P<0.03), despite the fact that only 0.0334% of the transplanted neural progenitors survived and that they differentiated mainly to astrocytes. An immunological study demonstrated the presence of macrophages and T cells as a possible explanation for the paucity of the transplanted cells. This study suggests one mechanism for the therapeutic action of neural progenitors, the enhancement of the production of endogenous cells, pointing to future clinical applications in this direction by use of neural progenitors or by analogous cell-inducing techniques.
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Affiliation(s)
- T L Ben-Shaanan
- The Ross Laboratory for Studies in Neural Birth Defects, Department of Anatomy and Cell Biology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
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Katz S, Ben-Hur T, Ben-Shaanan TL, Yanai J. Reversal of heroin neurobehavioral teratogenicity by grafting of neural progenitors. J Neurochem 2007; 104:38-49. [PMID: 18004998 DOI: 10.1111/j.1471-4159.2007.05004.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
A major objective in identifying the mechanisms underlying neurobehavioral teratogenicity in an animal model is the possibility of designing therapies that reverse or offset teratogen-induced neural damage. In our previous studies, we identified deficits in hippocampal muscarinic cholinergic receptor-induced translocation of protein kinase C (PKC) gamma as the likely central factor responsible for the adverse behavioral effects of pre-natal heroin exposure. Neural progenitors (NP) have the ability to recover behavioral deficits after focal hippocampal damage. Therefore, we explored whether behavioral and synaptic defects could be reversed in adulthood by neural progenitor grafting. Pregnant mice were injected daily with 10 mg/kg of heroin on gestational days 9-18. In adulthood, offspring showed deficits in the Morris maze, a behavior dependent on the integrity of septohippocampal cholinergic synaptic function, along with the loss of the PKCgamma and PKCbetaII responses to cholinergic stimulation. Mice that were exposed pre-natally to heroin and vehicle control mice were then grafted in adulthood with NP. Importantly, most grafted cells differentiated to astrocytes. NP reversed the behavioral deficits (p = 0.0043) and restored the normal response of hippocampal PKCgamma and PKCbetaII (p = 0.0337 and p = 0.0265 respectively) to cholinergic receptor stimulation. The effects were specific as the PKCalpha isoform, which is unrelated to the behavioral deficits, showed almost no changes. Neural progenitor grafting thus offers an animal model for reversing neurobehavioral deficits originating in septohippocampal cholinergic defects elicited by pre-natal exposure to insults.
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Affiliation(s)
- Sophia Katz
- The Ross Laboratory for Studies in Neural Birth Defects, Department of Anatomy and Cell Biology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
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Marutle A, Ohmitsu M, Nilbratt M, Greig NH, Nordberg A, Sugaya K. Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine. Proc Natl Acad Sci U S A 2007; 104:12506-11. [PMID: 17640880 PMCID: PMC1941499 DOI: 10.1073/pnas.0705346104] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
In a previous study, we found that human neural stem cells (HNSCs) exposed to high concentrations of secreted amyloid-precursor protein (sAPP) in vitro differentiated into mainly astrocytes, suggesting that pathological alterations in APP processing during neurodegenerative conditions such as Alzheimer's disease (AD) may prevent neuronal differentiation of HNSCs. Thus, successful neuroplacement therapy for AD may require regulating APP expression to favorable levels to enhance neuronal differentiation of HNSCs. Phenserine, a recently developed cholinesterase inhibitor (ChEI), has been reported to reduce APP levels in vitro and in vivo. In this study, we found reductions of APP and glial fibrillary acidic protein (GFAP) levels in the hippocampus of APP23 mice after 14 days treatment with (+)-phenserine (25 mg/kg) lacking ChEI activity. No significant change in APP gene expression was detected, suggesting that (+)-phenserine decreases APP levels and reactive astrocytes by posttranscription regulation. HNSCs transplanted into (+)-phenserine-treated APP23 mice followed by an additional 7 days of treatment with (+)-phenserine migrated and differentiated into neurons in the hippocampus and cortex after 6 weeks. Moreover, (+)-phenserine significantly increased neuronal differentiation of implanted HNSCs in hippocampal and cortical regions of APP23 mice and in the CA1 region of control mice. These results indicate that (+)-phenserine reduces APP protein in vivo and increases neuronal differentiation of HNSCs. Combination use of HNSC transplantation and treatment with drugs such as (+)-phenserine that modulate APP levels in the brain may be a useful tool for understanding mechanisms regulating stem cell migration and differentiation during neurodegenerative conditions in AD.
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Affiliation(s)
- Amelia Marutle
- Biomolecular Sciences Center, Burnett College of Biomedical Sciences, University of Central Florida, Orlando, FL 32816, USA.
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Viktorov IV, Savchenko EA, Ukhova OV, Alekseyeva NY, Chekhonin VP. Multipotent stem and progenitor cells of the olfactory epithelium. Bull Exp Biol Med 2007; 142:495-502. [PMID: 17415447 DOI: 10.1007/s10517-006-0402-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
In recent decades, a wide spectrum of fetal and embryonic stem and progenitor cells were used for cell therapy of diseases of the central nervous system, but the olfactory glial ensheathing cells exhibited certain advantages due to their biological properties and capacity to stimulate regeneratory processes in spinal injury. The therapeutic effect of a heterogeneous complex of olfactory epithelial cells is more pronounced; apart from glial ensheathing cells, this complex includes fibroblasts, Schwann cells, stem and progenitor cells of this structure. The use of minimally invasive methods for isolation of human olfactory epithelial tissue is important for clinical practice, because they provide cells for autologous transplantation and rule out graft rejection immune reaction and the risk of transmission viral infection and transfer of genetic defects, which can be associated with allotransplantation.
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Affiliation(s)
- I V Viktorov
- V. P. Serbsky State Research Center of Social and Forensic Psychiatry, Moscow.
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Abstract
OBJECTIVE To conduct a comprehensive literature review of the area of neural stem cells and neuropsychiatry. METHODS 'Neural stem cells' (NSCs) and 'neurogenesis' were used as keywords in Medline (1966 - November 2006) to identify relevant papers in the areas of Alzheimer's disease (AD), depression, schizophrenia and Parkinson's disease (PD). This list was supplemented with papers from reference lists of seminal reviews. RESULTS The concept of a 'stem cell' continues to evolve and is currently defined by operational criteria related to symmetrical renewal, multipotency and functional viability. In vivo adult mammalian neurogenesis occurs in discrete niches in the subventricular and subgranular zones - however, functional precursor cells can be generated in vitro from a wide variety of biological sources. Both artificial and physiological microenvironment is therefore critical to the characteristics and behaviour of neural precursors, and it is not straightforward how results from the laboratory can be extrapolated to the living organism. Transplant strategies in PD have shown that it is possible for primitive neural tissue to engraft into neuropathic brain areas, become biologically functional and lead to amelioration of clinical signs and symptoms. However, with long-term follow-up, significant problems related to intractable side-effects and potential neoplastic growth have been reported. These are therefore the potentials and pitfalls for NSC technology in neuropsychiatry. In AD, the physiology of amyloid precursor protein may directly interact with NSCs, and a role in memory function has been speculated. The role of endogenous neurogenesis has also been implicated in the etiology of depression. The significance of NSCs and neurogenesis for schizophrenia is still emerging. CONCLUSIONS There are a number of technical and conceptual challenges ahead before the promise of NSCs can be harnessed for the understanding and treatment of neuropsychiatric disorders. Further research into fundamental NSC biology and how this interacts with the neuropsychiatric disease processes is required.
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Affiliation(s)
| | - Kuldip Sidhu
- 3Diabetes Transplant Unit, The Prince of Wales Hospital, Sydney Australia
| | - Sophia Dean
- 1School of Psychiatry, University of New South Wales, Sydney Australia
| | - Perminder Sachdev
- 1School of Psychiatry, University of New South Wales, Sydney Australia
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Pulido JS, Sugaya I, Comstock J, Sugaya K. Reelin expression is upregulated following ocular tissue injury. Graefes Arch Clin Exp Ophthalmol 2006; 245:889-93. [PMID: 17120005 DOI: 10.1007/s00417-006-0458-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2006] [Accepted: 09/12/2006] [Indexed: 10/23/2022] Open
Abstract
PURPOSE Reelin is important in the guidance of neuronal stem cells in the central nervous system during normal development. We wished to determine whether reelin is expressed in the retina and cornea after injury. METHODS Mice underwent laceration of their retina as well as corneal epithelial debridement. The mice were sacrificed at 3 days, and eyes were fixed and stained for reelin expression and reelin messenger ribonucleic acid (mRNA). RESULTS In normal eyes, reelin was expressed only at very low levels in the ganglion cell layer of the retina and the endothelial cell layer of the cornea. In injured eyes, there was marked expression in reelin immunoreactivity in the retina and cornea. Reelin gene expression was seen in the retina and cornea. CONCLUSIONS Reelin is expressed during normal retinogenesis. This study shows that reelin is also upregulated following injury to the retina and cornea. The expression of reelin following injury suggests that reelin may play an important role in regulating stem cell trafficking in neuronal and nonneuronal tissues following injury similar to its role in normal organogenesis.
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Affiliation(s)
- Jose S Pulido
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA
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Niidome T, Morimoto N, Iijima S, Akaike A, Kihara T, Sugimoto H. Mechanisms of cell death of neural progenitor cells caused by trophic support deprivation. Eur J Pharmacol 2006; 548:1-8. [PMID: 16965769 DOI: 10.1016/j.ejphar.2006.07.052] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2006] [Revised: 06/21/2006] [Accepted: 07/13/2006] [Indexed: 01/02/2023]
Abstract
Cell death of neural progenitor cells is the primary problem limiting the value of neural progenitor cell-based therapy for central nervous system disorders. However, little is known about the mechanism of cell death of neural progenitor cells. In this study, we investigated the mechanisms of cell death of a multipotent cell line, MEB5, caused by deprivation of epidermal growth factor (EGF). When EGF was removed from the culture medium, the total number of viable MEB5 cells reduced, and nuclear condensation and elevation of caspase-3-like enzyme activity were observed in MEB5 cells. Treatment with a broad-range caspase inhibitor reduced cell death in a concentration-dependent manner, indicating that MEB5 cells undergo caspase-mediated apoptotic cell death caused by EGF deprivation. We also investigated the effects of glutamate receptor antagonists, antioxidants and nitric oxide synthase inhibitor on EGF deprivation-induced cell death. N-methyl-D-aspartate (NMDA) glutamate receptor antagonists, alpha-amino-3-hydrozy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptor antagonist and nitric oxide synthase inhibitor failed to reduce cell death. In contrast, two antioxidants with different chemical structures reduced cell death in a concentration-dependent manner. The production of reactive oxygen species was detected in MEB5 cells after EGF deprivation by monitoring dichlorodihydrofluorescein fluorescence as a marker of reactive oxygen species-related radicals. Our results suggest that oxidative stress triggers caspase-mediated apoptosis of neural progenitor cells by trophic support deprivation.
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Affiliation(s)
- Tetsuhiro Niidome
- Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
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Roitberg BZ, Mangubat E, Chen EY, Sugaya K, Thulborn KR, Kordower JH, Pawar A, Konecny T, Emborg ME. Survival and early differentiation of human neural stem cells transplanted in a nonhuman primate model of stroke. J Neurosurg 2006; 105:96-102. [PMID: 16871883 DOI: 10.3171/jns.2006.105.1.96] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECT Neural cell transplantation has been proposed as a treatment after stroke. The purpose of this study was to establish if human neural stem cells (HNSCs) could survive in the nonhuman primate brain after an ischemic event. METHODS Three adult cynomolgus monkeys received a unilateral occlusion of the M, segment of the right middle cerebral artery (MCA). One week later each animal received five magnetic resonance (MR) image-guided stereotactic intracerebral injections of HNSC neurospheres labeled with bromodeoxyuridine (BrdU) in the areas surrounding the ischemic lesion as defined in T1- and T2-weighted images. On the day of transplantation and throughout the study the monkeys received oral cyclosporine (10 mg/kg twice a day), and plasma levels were monitored routinely. The animals were killed at 45, 75, or 105 days after transplantation. Magnetic resonance images revealed a cortical and subcortical infarction in the MCA distribution area. Postmortem morphological brain analyses confirmed the distribution of the infarcted area seen in the MR images, with loss of tissue and necrosis in the ischemic region. Cells that were positive for BrdU were present in the three experimental monkeys, mainly along injection tracks. Double-label immunofluorescence for BrdU and betaIII-tubulin (a marker of young neurons) revealed colocalization of few HNSCs, most of which were observed outside the immediate injection site. Colocalization with nestin was also observed, indicating an early neural/glial fate. CONCLUSIONS In a model of stroke in nonhuman primates, HNSCs can survive up to 105 days when transplanted 1 week after an ischemic event and can partly undergo neuronal differentiation.
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Affiliation(s)
- Ben Z Roitberg
- Department of Neurosurgery, University of Illinois, Chicago, Illinois 60612, USA.
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Kwak YD, Brannen CL, Qu T, Kim HM, Dong X, Soba P, Majumdar A, Kaplan A, Beyreuther K, Sugaya K. Amyloid precursor protein regulates differentiation of human neural stem cells. Stem Cells Dev 2006; 15:381-9. [PMID: 16846375 DOI: 10.1089/scd.2006.15.381] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Although amyloid beta (Abeta) deposition has been a hallmark of Alzheimer's disease (AD), the absence of a phenotype in the beta amyloid precursor protein (APP) knockout mouse, tends to detract our attention away from the physiological functions of APP. Although much attention has been focused on the neurotoxicity of Abeta, many studies suggest the involvement of APP in neuroplasticity. We found that secreted amyloid precursor protein (sAPP) increased the differentiation of human neural stem cells (hNSCs) in vitro, while an antibody-recognizing APP dose-dependently inhibited these activities. With a high dose of sAPP treatment or wild-type APP gene transfection, hNSCs were differentiated into astrocytes rather than neurons. In vivo, hNSCs transplanted into APP-transgenic mouse brain exhibited glial differentiation rather than neural differentiation. Our results suggest that APP regulates neural stem cell biology in the adult brain, and that altered APP metabolism in Down syndrome or AD may have implications for the pathophysiology of these diseases.
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Affiliation(s)
- Y-D Kwak
- Biomolecular Science Center, University of Central Florida, Orlando, 32816, USA
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An Y, Tsang KKS, Zhang H. Potential of stem cell based therapy and tissue engineering in the regeneration of the central nervous system. Biomed Mater 2006; 1:R38-44. [PMID: 18460755 DOI: 10.1088/1748-6041/1/2/r02] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The insufficiency of self-repair and regeneration of the central nervous system (CNS) leads to difficulty of rehabilitation of the injured brain. In the past few decades, the significant progress in cell therapy and tissue engineering has contributed to the functional recovery of the CNS to a great extent. The present review focuses on the potential role of stem cell based therapy and tissue engineering in the regeneration of the CNS.
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Affiliation(s)
- Yihua An
- Department of Neural Stem Cell, Beijing Neurosurgical Institute affiliated to Capital University of Medical Sciences, Beijing 100050, People's Republic of China
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Jain M, Armstrong RJE, Elneil S, Barker RA. Transplanted human neural precursor cells migrate widely but show no lesion-specific tropism in the 6-hydroxydopamine rat model of Parkinson's disease. Cell Transplant 2006; 15:579-93. [PMID: 17176610 DOI: 10.3727/000000006783981684] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Parkinson's disease (PD), while primarily associated with degeneration of nigrostriatal dopamine neurons, is now increasingly recognized to have more widespread cell loss and so the most effective cell replacement therapy should target all these neuronal losses. Neural precursor cells might be ideal in this regard as in certain circumstances they have been shown to migrate widely following transplantation into the CNS. The aim of this study was to investigate whether transplanted human expanded neural precursor cells (hENPs) could migrate to sites of established or evolving pathology in the adult brain using the 6-hydroxydopamine (6-OHDA) rat model of PD. hENPs were grafted into the striatum prior to, at the same time as, or after the animals received a 6-OHDA lesion to the medial forebrain bundle. The presence of donor cells was then assessed in a distant site of cell loss (substantia nigra) or sites where cell death would not be expected (frontal cortex and globus pallidus). Donor cells were found distant from the site of implantation but the migration of these hENPs was not significantly greater in the 6-OHDA-lesioned brain and the cells did not specifically target the site of cell loss in the substantia nigra. The temporal relationship of grafting relative to the lesion, and therefore dopaminergic cell death, did not affect the migration of hENPs nor their differentiation. We conclude that while transplanted hENPs are capable of migration away from the site of implantation, they show no specific tropism for sites of ongoing or established nigral dopaminergic cell loss in this lesion model. Therefore, the use of such cells to replace the range of neurons lost in PD is likely to require a deeper understanding of the migratory cues in the damaged adult brain and some manipulation of these cells prior to transplantation.
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Affiliation(s)
- M Jain
- Cambridge University Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge CB2 2PY, UK
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Millet P, Lages CS, Haïk S, Nowak E, Allemand I, Granotier C, Boussin FD. Amyloid-beta peptide triggers Fas-independent apoptosis and differentiation of neural progenitor cells. Neurobiol Dis 2005; 19:57-65. [PMID: 15837561 DOI: 10.1016/j.nbd.2004.11.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2004] [Revised: 10/28/2004] [Accepted: 11/09/2004] [Indexed: 12/13/2022] Open
Abstract
Amyloid-beta peptide (A beta), derived from the amyloid-beta precursor protein (APP), plays a central role in the pathogenesis of Alzheimer's disease and induces neuronal apoptosis. Neural progenitor cells persist in the adult mammalian brain and continue to produce new neurons throughout the life. The aim of our study was to establish the effects of A beta on neural progenitor cells (NPC). We found that the neurotoxic peptide A beta 25-35 induced apoptosis of both neurons and NPC in wild-type (wt) primary cortical cultures derived from mouse embryos. Contrary to neurons, NPC were also subjected to apoptosis in response to A beta 25-35 in both fas-/- and Z-VAD/fmk (the broad-spectrum caspase inhibitor)-treated wt cortical cultures indicating that A beta triggers a Fas- and caspase-independent apoptotic pathway in NPC. Interestingly, we also show that A beta induces neurospheres adherence and NPC neuronal differentiation. Further studies are thus needed in order to understand the role of A beta effects on NPC in AD pathology. Understanding the mechanisms involved may also be essential for the development of new regenerative therapies in AD.
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Affiliation(s)
- Pascal Millet
- Laboratoire de Radiopathologie, DRR/DSV, CEA, IPSC, Fontenay-aux-Roses, France
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Sun LY, Evans MS, Hsieh J, Panici J, Bartke A. Increased neurogenesis in dentate gyrus of long-lived Ames dwarf mice. Endocrinology 2005; 146:1138-44. [PMID: 15564324 DOI: 10.1210/en.2004-1115] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Neurogenesis occurs throughout adult life in the dentate gyrus of mammalian hippocampus and has been suggested to play an important role in cognitive function. Multiple trophic factors including IGF-I have been demonstrated to regulate hippocampal neurogenesis. Ames dwarf mice live considerably longer than normal animals and maintain physiological function at youthful levels, including cognitive function, despite a deficiency of circulating GH and IGF-I. Here we show an increase in numbers of newly generated cells [bromodeoxyuridine (BrdU) positive] and newborn neurons (neuronal nuclear antigen and BrdU positive) in the dentate gyrus of adult dwarf mice compared with normal mice using BrdU labeling. Despite the profound suppression of hippocampal GH expression, hippocampal IGF-I protein levels are up-regulated and the corresponding mRNAs are as high in Ames dwarf as in normal mice. Our results suggest that local/hippocampal IGF-I expression may have induced the increase in hippocampal neurogenesis, and increased neurogenesis might contribute to the maintenance of youthful levels of cognitive function during aging in these long-lived animals.
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Affiliation(s)
- Liou Y Sun
- Geriatrics Research, Department of Internal Medicine, Southern Illinois University School of Medicine, Room 4389, 801 North Rutledge, Springfield, Illinois 62794-9628, USA
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Revishchin AV, Aleksandrova MA, Podgornyi OV, Marei MV, Poltavtseva RA, Korochkin LI, Stepanov GA, Sukhikh GT. Human Fetal Neural Stem Cells in Rat Brain: Effects of Preculturing and Transplantation. Bull Exp Biol Med 2005; 139:213-6. [PMID: 16027810 DOI: 10.1007/s10517-005-0251-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
The fate of human fetal stem/progenitor cells transplanted into rat brain depends on conditions of preculturing (long or short) and state and site of transplantation. Human nestin-positive stem cells cultured according to the short protocol did not migrate into hypoxic and normal brain after transplantation, but actively migrated in damaged spinal cord. After transplantation of long-cultured cells into the brain mainly committed neuroblasts and solitary nestin-positive cells migrated from the site of transplantation into the brain.
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Affiliation(s)
- A V Revishchin
- Institute of Problems of Ecology and Evolution, Russian Academy of Sciences, Moscow.
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