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Yang L, Liu SC, Liu YY, Zhu FQ, Xiong MJ, Hu DX, Zhang WJ. Therapeutic role of neural stem cells in neurological diseases. Front Bioeng Biotechnol 2024; 12:1329712. [PMID: 38515621 PMCID: PMC10955145 DOI: 10.3389/fbioe.2024.1329712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 02/12/2024] [Indexed: 03/23/2024] Open
Abstract
The failure of endogenous repair is the main feature of neurological diseases that cannot recover the damaged tissue and the resulting dysfunction. Currently, the range of treatment options for neurological diseases is limited, and the approved drugs are used to treat neurological diseases, but the therapeutic effect is still not ideal. In recent years, different studies have revealed that neural stem cells (NSCs) have made exciting achievements in the treatment of neurological diseases. NSCs have the potential of self-renewal and differentiation, which shows great foreground as the replacement therapy of endogenous cells in neurological diseases, which broadens a new way of cell therapy. The biological functions of NSCs in the repair of nerve injury include neuroprotection, promoting axonal regeneration and remyelination, secretion of neurotrophic factors, immune regulation, and improve the inflammatory microenvironment of nerve injury. All these reveal that NSCs play an important role in improving the progression of neurological diseases. Therefore, it is of great significance to better understand the functional role of NSCs in the treatment of neurological diseases. In view of this, we comprehensively discussed the application and value of NSCs in neurological diseases as well as the existing problems and challenges.
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Affiliation(s)
- Ling Yang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
- Department of Physical Examination, The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Si-Cheng Liu
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Yi-Yi Liu
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Fu-Qi Zhu
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Mei-Juan Xiong
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Dong-Xia Hu
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Wen-Jun Zhang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
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The Nerve Growth Factor Receptor (NGFR/p75 NTR): A Major Player in Alzheimer's Disease. Int J Mol Sci 2023; 24:ijms24043200. [PMID: 36834612 PMCID: PMC9965628 DOI: 10.3390/ijms24043200] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 02/01/2023] [Accepted: 02/03/2023] [Indexed: 02/09/2023] Open
Abstract
Alzheimer's disease (AD) represents the most prevalent type of dementia in elderly people, primarily characterized by brain accumulation of beta-amyloid (Aβ) peptides, derived from Amyloid Precursor Protein (APP), in the extracellular space (amyloid plaques) and intracellular deposits of the hyperphosphorylated form of the protein tau (p-tau; tangles or neurofibrillary aggregates). The Nerve growth factor receptor (NGFR/p75NTR) represents a low-affinity receptor for all known mammalians neurotrophins (i.e., proNGF, NGF, BDNF, NT-3 e NT-4/5) and it is involved in pathways that determine both survival and death of neurons. Interestingly, also Aβ peptides can blind to NGFR/p75NTR making it the "ideal" candidate in mediating Aβ-induced neuropathology. In addition to pathogenesis and neuropathology, several data indicated that NGFR/p75NTR could play a key role in AD also from a genetic perspective. Other studies suggested that NGFR/p75NTR could represent a good diagnostic tool, as well as a promising therapeutic target for AD. Here, we comprehensively summarize and review the current experimental evidence on this topic.
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Nose-to-Brain: The Next Step for Stem Cell and Biomaterial Therapy in Neurological Disorders. Cells 2022; 11:cells11193095. [PMID: 36231058 PMCID: PMC9564248 DOI: 10.3390/cells11193095] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/28/2022] [Accepted: 09/29/2022] [Indexed: 11/18/2022] Open
Abstract
Neurological disorders are a leading cause of morbidity worldwide, giving rise to a growing need to develop treatments to revert their symptoms. This review highlights the great potential of recent advances in cell therapy for the treatment of neurological disorders. Through the administration of pluripotent or stem cells, this novel therapy may promote neuroprotection, neuroplasticity, and neuroregeneration in lesion areas. The review also addresses the administration of these therapeutic molecules by the intranasal route, a promising, non-conventional route that allows for direct access to the central nervous system without crossing the blood–brain barrier, avoiding potential adverse reactions and enabling the administration of large quantities of therapeutic molecules to the brain. Finally, we focus on the need to use biomaterials, which play an important role as nutrient carriers, scaffolds, and immune modulators in the administration of non-autologous cells. Little research has been conducted into the integration of biomaterials alongside intranasally administered cell therapy, a highly promising approach for the treatment of neurological disorders.
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Oxidative Stress in Ageing and Chronic Degenerative Pathologies: Molecular Mechanisms Involved in Counteracting Oxidative Stress and Chronic Inflammation. Int J Mol Sci 2022; 23:ijms23137273. [PMID: 35806275 PMCID: PMC9266760 DOI: 10.3390/ijms23137273] [Citation(s) in RCA: 140] [Impact Index Per Article: 46.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 06/24/2022] [Accepted: 06/24/2022] [Indexed: 12/17/2022] Open
Abstract
Ageing and chronic degenerative pathologies demonstrate the shared characteristics of high bioavailability of reactive oxygen species (ROS) and oxidative stress, chronic/persistent inflammation, glycation, and mitochondrial abnormalities. Excessive ROS production results in nucleic acid and protein destruction, thereby altering the cellular structure and functional outcome. To stabilise increased ROS production and modulate oxidative stress, the human body produces antioxidants, “free radical scavengers”, that inhibit or delay cell damage. Reinforcing the antioxidant defence system and/or counteracting the deleterious repercussions of immoderate reactive oxygen and nitrogen species (RONS) is critical and may curb the progression of ageing and chronic degenerative syndromes. Various therapeutic methods for ROS and oxidative stress reduction have been developed. However, scientific investigations are required to assess their efficacy. In this review, we summarise the interconnected mechanism of oxidative stress and chronic inflammation that contributes to ageing and chronic degenerative pathologies, including neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), cardiovascular diseases CVD, diabetes mellitus (DM), and chronic kidney disease (CKD). We also highlight potential counteractive measures to combat ageing and chronic degenerative diseases.
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Therapeutic potential of neurotrophic factors in Alzheimer's Disease. Mol Biol Rep 2021; 49:2345-2357. [PMID: 34826049 DOI: 10.1007/s11033-021-06968-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 11/17/2021] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia among the elderly population. AD is accompanied with the dysregulation of specific neurotrophic factors (NTFs) and their receptors, which plays a critical role in neuronal degeneration. NTFs are small proteins with therapeutic potential for human neurodegenerative diseases. These growth factors are categorized into four families: neurotrophins, neurokines, the glial cell line-derived NTF family of ligands, and the newly discovered cerebral dopamine NTF/mesencephalic astrocyte-derived NTF family. NTFs are capable of preventing cell death in degenerative conditions and can increase the neuronal growth and function in these disorders. Nevertheless, the adverse side effects of NTFs delivery and poor diffusion of these factors in the brain restrict the efficacy of NTFs therapy in clinical situations. MATERIALS AND METHODS In this review, we focus on the current advances in the use of NTFs to treat AD and summarize previous experimental and clinical studies for supporting the protective and therapeutic effects of these factors. CONCLUSION Based on reports, NTFs are considered as new and promising candidates for treating AD and AD-associated cognitive impairment.
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Gala D, Gurusamy V, Patel K, Damodar S, Swaminath G, Ullal G. Stem Cell Therapy for Post-Traumatic Stress Disorder: A Novel Therapeutic Approach. Diseases 2021; 9:diseases9040077. [PMID: 34842629 PMCID: PMC8628773 DOI: 10.3390/diseases9040077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 10/11/2021] [Accepted: 10/25/2021] [Indexed: 12/04/2022] Open
Abstract
Stem cell therapy is a rapidly evolving field of regenerative medicine being employed for the management of various central nervous system disorders. The ability to self-renew, differentiate into specialized cells, and integrate into neuronal networks has positioned stem cells as an ideal mechanism for the treatment of epilepsy. Epilepsy is characterized by repetitive seizures caused by imbalance in the GABA and glutamate neurotransmission following neuronal damage. Stem cells provide benefit by reducing the glutamate excitotoxicity and strengthening the GABAergic inter-neuron connections. Similar to the abnormal neuroanatomic location in epilepsy, post-traumatic stress disorder (PTSD) is caused by hyperarousal in the amygdala and decreased activity of the hippocampus and medial prefrontal cortex. Thus, stem cells could be used to modulate neuronal interconnectivity. In this review, we provide a rationale for the use of stem cell therapy in the treatment of PTSD.
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Applications of Xylosides in the Manipulation of Stem Cell Niche to Regulate Human Neural Stem Cell Differentiation and Neurite Outgrowth. Methods Mol Biol 2021. [PMID: 34626422 DOI: 10.1007/978-1-0716-1398-6_58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/29/2023]
Abstract
The extracellular matrix (ECM) plays a pivotal role in the regulation of neural stem cell differentiation, axon guidance and growth, and neural plasticity. Glycosaminoglycans, such as heparan sulfate and chondroitin sulfate, are significant components of brain ECM that dictates neurogenesis and neural repair. Herein, we describe a simple method to assess the effect of xylsoides, which serve as primers and inhibitors of GAG biosynthesis, on human neural stem cell differentiation and neurite outgrowth in in vitro culture conditions.
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Icariin Promotes Survival, Proliferation, and Differentiation of Neural Stem Cells In Vitro and in a Rat Model of Alzheimer's Disease. Stem Cells Int 2021; 2021:9974625. [PMID: 34257671 PMCID: PMC8249160 DOI: 10.1155/2021/9974625] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 06/08/2021] [Accepted: 06/12/2021] [Indexed: 11/18/2022] Open
Abstract
Alzheimer's disease (AD) involves the degeneration of cholinergic neurons in the basal forebrain. Neural stem cell (NSC) transplantation has emerged as a promising therapeutic approach for treating AD. Icariin (ICA) is the main active component in Epimedium, a traditional Chinese herb. The purpose of the present study was to investigate the effects and mechanisms of ICA on the proliferation and differentiation of NSCs in the basal forebrain of a fimbria-fornix transection (FFT) rat model. In the present study, ICA promoted the survival, proliferation, and migration of NSCs in vitro. In FFT rats, ICA promoted the proliferation and differentiation of NSCs into neurons and increased the number of cholinergic neurons in the MS and VDB of the basal forebrain. These results suggest that combination therapy of ICA oral administration and NSC transplantation may provide a new potential and effective approach for AD therapy.
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Srivastava S, Ahmad R, Khare SK. Alzheimer's disease and its treatment by different approaches: A review. Eur J Med Chem 2021; 216:113320. [PMID: 33652356 DOI: 10.1016/j.ejmech.2021.113320] [Citation(s) in RCA: 216] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 02/04/2021] [Accepted: 02/13/2021] [Indexed: 12/13/2022]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder that impairs mental ability development and interrupts neurocognitive function. This neuropathological condition is depicted by neurodegeneration, neural loss, and development of neurofibrillary tangles and Aβ plaques. There is also a greater risk of developing AD at a later age for people with cardiovascular diseases, hypertension and diabetes. In the biomedical sciences, effective treatment for Alzheimer's disease is a severe obstacle. There is no such treatment to cure Alzheimer's disease. The drug present in the market show only symptomatic relief. The cause of Alzheimer's disease is not fully understood and the blood-brain barrier restricts drug efficacy are two main factors that hamper research. Stem cell-based therapy has been seen as an effective, secure, and creative therapeutic solution to overcoming AD because of AD's multifactorial nature and inadequate care. Current developments in nanotechnology often offer possibilities for the delivery of active drug candidates to address certain limitations. The key nanoformulations being tested against AD include polymeric nanoparticles (NP), inorganic NPs and lipid-based NPs. Nano drug delivery systems are promising vehicles for targeting several therapeutic moieties by easing drug molecules' penetration across the CNS and improving their bioavailability. In this review, we focus on the causes of the AD and their treatment by different approaches.
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Affiliation(s)
- Sukriti Srivastava
- Enzyme and Microbial Biochemistry Laboratory, Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India
| | - Razi Ahmad
- Enzyme and Microbial Biochemistry Laboratory, Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India
| | - Sunil Kumar Khare
- Enzyme and Microbial Biochemistry Laboratory, Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India.
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Bagheri-Mohammadi S. Stem cell-based therapy as a promising approach in Alzheimer's disease: current perspectives on novel treatment. Cell Tissue Bank 2021; 22:339-353. [PMID: 33398492 DOI: 10.1007/s10561-020-09896-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 12/19/2020] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) is a neuronal disorder with insidious onset and slow progression, leading to growing global concern with huge implications for individuals and society. The occurrence of AD has been increased and has become an important health issue throughout the world. In recent years, the care of more than 35 million patients with AD costs over $ 600 billion per year, it is approximately 1 percent of the global Gross Domestic Product. Currently, the therapeutic approach is not effective for neurological deficits especially after the development of these major neurological disorders. The discovery of the technique called cell-based therapy has shown promising results and made important conclusions beyond AD using the stem cells approach. Here we review recent progress on stem cell-based therapy in the context of AD.
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Affiliation(s)
- Saeid Bagheri-Mohammadi
- Department of Physiology and Neurophysiology Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. .,Department of Physiology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran. .,Department of Applied Cell Sciences, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran.
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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: 86] [Impact Index Per Article: 17.2] [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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Human Neural Stem Cells Encoding ChAT Gene Restore Cognitive Function via Acetylcholine Synthesis, Aβ Elimination, and Neuroregeneration in APPswe/PS1dE9 Mice. Int J Mol Sci 2020; 21:ijms21113958. [PMID: 32486466 PMCID: PMC7313059 DOI: 10.3390/ijms21113958] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 05/29/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023] Open
Abstract
In Alzheimer disease (AD) patients, degeneration of the cholinergic system utilizing acetylcholine for memory acquisition is observed. Since AD therapy using acetylcholinesterase (AChE) inhibitors are only palliative for memory deficits without slowing or reversing disease progress, there is a need for effective therapies, and stem cell-based therapeutic approaches targeting AD should fulfill this requirement. We established a human neural stem cell (NSC) line encoding choline acetyltransferase (ChAT) gene, an acetylcholine-synthesizing enzyme. APPswe/PS1dE9 AD model mice transplanted with the F3.ChAT NSCs exhibited improved cognitive function and physical activity. Transplanted F3.ChAT NSCs in the AD mice differentiated into neurons and astrocytes, produced ChAT protein, increased the ACh level, and improved the learning and memory function. F3.ChAT cell transplantation reduced Aβ deposits by recovering microglial function; i.e., the down-regulation of β-secretase and inflammatory cytokines and up-regulation of Aβ-degrading enzyme neprilysin. F3.ChAT cells restored growth factors (GFs) and neurotrophic factors (NFs), and they induced the proliferation of NSCs in the host brain. These findings indicate that NSCs overexpressing ChAT can ameliorate complex cognitive and physical deficits of AD animals by releasing ACh, reducing Aβ deposit, and promoting neuroregeneration by the production of GFs/NFs. It is suggested that NSCs overexpressing ChAT could be a candidate for cell therapy in advanced AD therapy.
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Wang J, Hu WW, Jiang Z, Feng MJ. Advances in treatment of neurodegenerative diseases: Perspectives for combination of stem cells with neurotrophic factors. World J Stem Cells 2020; 12:323-338. [PMID: 32547681 PMCID: PMC7280867 DOI: 10.4252/wjsc.v12.i5.323] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 03/31/2020] [Accepted: 04/07/2020] [Indexed: 02/06/2023] Open
Abstract
Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, are a group of incurable neurological disorders, characterized by the chronic progressive loss of different neuronal subtypes. However, despite its increasing prevalence among the ever-increasing aging population, little progress has been made in the coincident immense efforts towards development of therapeutic agents. Research interest has recently turned towards stem cells including stem cells-derived exosomes, neurotrophic factors, and their combination as potential therapeutic agents in neurodegenerative diseases. In this review, we summarize the progress in therapeutic strategies based on stem cells combined with neurotrophic factors and mesenchymal stem cells-derived exosomes for neurodegenerative diseases, with an emphasis on the combination therapy.
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Affiliation(s)
- Jie Wang
- Department of Geriatrics, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu Province, China
- Department of Neurology, the Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211100, Jiangsu Province, China
| | - Wei-Wei Hu
- Department of Geriatrics, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Zhi Jiang
- Department of Geriatrics, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu Province, China
| | - Mei-Jiang Feng
- Department of Geriatrics, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu Province, China
- Key Laboratory for Aging & Disease, Nanjing Medical University, Nanjing 210011, Jiangsu Province, China.
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Kim J, Shin K, Cha Y, Ban YH, Park SK, Jeong HS, Park D, Choi EK, Kim YB. Neuroprotective effects of human neural stem cells over-expressing choline acetyltransferase in a middle cerebral artery occlusion model. J Chem Neuroanat 2019; 103:101730. [PMID: 31837389 DOI: 10.1016/j.jchemneu.2019.101730] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 12/09/2019] [Accepted: 12/10/2019] [Indexed: 10/25/2022]
Abstract
Stroke is one of the most-devastating brain diseases causing acute death or permanent disability. Although tissue-type plasminogen activator was approved by Food and Drug Administration for early reperfusion of the occluded vessels, oxidative injury may cause extensive brain infarction. Accordingly, there is a need for effective neuroprotection during reperfusion, and stem cell-based therapeutic approaches should fulfill this requirement. We established human neural stem cells (NSCs) encoding gene of choline acetyltransferase (F3.ChAT), an acetylcholine-synthesizing enzyme, and investigated whether infusion of the F3.ChAT cells attenuate the ischemia-reperfusion brain damage in a rat model of middle cerebral artery occlusion (MCAO). F3.ChAT cells were found to produce much higher amounts of ChAT as well as neuroprotective and anti-inflammatory neurotrophins than their parental F3 NSCs. After 2-h occlusion, the artery was reperfused, along with intravenous infusion of the stem cells (1 × 106 cells/rat). Administration of the F3.ChAT cells markedly reduced the infarction volume and improved both the cognitive dysfunction and behavioural deficits of MCAO animals, in which F3.ChAT cells were superior to F3 cells. F3.ChAT cells not only restored microtubule-associated protein-2, a neuronal cytoskeletal protein, and preserved microvessels, but also suppressed lipid peroxidation, pro-inflammatory cytokines, glial fibrillary acidic protein, and intercellular adhesion molecule-1 in the brain tissues. The results demonstrate that early intravenous infusion of NSCs expressing ChAT and neurotrophins attenuate brain and capillary injuries and restore neurobehavioural functions via neuroprotective and anti-inflammatory activities, and that F3.ChAT cells could be a candidate for the neuroprotection and functional recovery of acute stroke patients.
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Affiliation(s)
- Jihyun Kim
- College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Kyungha Shin
- College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Yeseul Cha
- College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Young-Hwan Ban
- College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Sung Kyeong Park
- Daejeon Health Institute of Technology, Daejeon, Republic of Korea
| | - Heon Sang Jeong
- Department of Food Science and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Dongsun Park
- Department of Biology Education, Korea National University of Education, Cheongju, Chungbuk, Republic of Korea
| | - Ehn-Kyoung Choi
- College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Yun-Bae Kim
- College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
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Zhang GL, Zhu ZH, Wang YZ. Neural stem cell transplantation therapy for brain ischemic stroke: Review and perspectives. World J Stem Cells 2019; 11:817-830. [PMID: 31692854 PMCID: PMC6828598 DOI: 10.4252/wjsc.v11.i10.817] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 08/11/2019] [Accepted: 09/11/2019] [Indexed: 02/06/2023] Open
Abstract
Brain ischemic stroke is one of the most common causes of death and disability, currently has no efficient therapeutic strategy in clinic. Due to irreversible functional neurons loss and neural tissue injury, stem cell transplantation may be the most promising treatment approach. Neural stem cells (NSCs) as the special type of stem cells only exist in the nervous system, can differentiate into neurons, astrocytes, and oligodendrocytes, and have the abilities to compensate insufficient endogenous nerve cells and improve the inflammatory microenvironment of cell survival. In this review, we focused on the important role of NSCs therapy for brain ischemic stroke, mainly introduced the methods of optimizing the therapeutic efficacy of NSC transplantation, such as transfection and overexpression of specific genes, pretreatment of NSCs with inflammatory factors, and co-transplantation with cytokines. Next, we discussed the potential problems of NSC transplantation which seriously limited their rapid clinical transformation and application. Finally, we expected a new research topic in the field of stem cell research. Based on the bystander effect, exosomes derived from NSCs can overcome many of the risks and difficulties associated with cell therapy. Thus, as natural seed resource of nervous system, NSCs-based cell-free treatment is a newly therapy strategy, will play more important role in treating ischemic stroke in the future.
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Affiliation(s)
- Gui-Long Zhang
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China
| | - Zhi-Han Zhu
- Department of Neurosurgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Ye-Zhong Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China
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Neurodegeneration and Neuro-Regeneration-Alzheimer's Disease and Stem Cell Therapy. Int J Mol Sci 2019; 20:ijms20174272. [PMID: 31480448 PMCID: PMC6747457 DOI: 10.3390/ijms20174272] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 08/27/2019] [Accepted: 08/28/2019] [Indexed: 12/17/2022] Open
Abstract
Aging causes many changes in the human body, and is a high risk for various diseases. Dementia, a common age-related disease, is a clinical disorder triggered by neurodegeneration. Brain damage caused by neuronal death leads to cognitive decline, memory loss, learning inabilities and mood changes. Numerous disease conditions may cause dementia; however, the most common one is Alzheimer’s disease (AD), a futile and yet untreatable illness. Adult neurogenesis carries the potential of brain self-repair by an endogenous formation of newly-born neurons in the adult brain; however it also declines with age. Strategies to improve the symptoms of aging and age-related diseases have included different means to stimulate neurogenesis, both pharmacologically and naturally. Finally, the regulatory mechanisms of stem cells neurogenesis or a functional integration of newborn neurons have been explored to provide the basis for grafted stem cell therapy. This review aims to provide an overview of AD pathology of different neural and glial cell types and summarizes current strategies of experimental stem cell treatments and their putative future use in clinical settings.
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Omrani MM, Ansari M, Kordestani SS, Kiaie N, Salati A. Enhanced bone marrow stem cell attachment and differentiation on PCL/CNT substrate. INORG NANO-MET CHEM 2019. [DOI: 10.1080/24701556.2019.1586723] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Affiliation(s)
| | - Mojtaba Ansari
- Department of Biomedical Engineering, Meybod University, Meybod, Iran
| | | | - Nasim Kiaie
- Department of Biomedical Engineering, Amirkabir University of Technology, Tehran, Iran
| | - Amir Salati
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Tissue Engineering and Applied Cell Sciences Group, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
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18
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Chakari-Khiavi F, Dolati S, Chakari-Khiavi A, Abbaszadeh H, Aghebati-Maleki L, Pourlak T, Mehdizadeh A, Yousefi M. Prospects for the application of mesenchymal stem cells in Alzheimer's disease treatment. Life Sci 2019; 231:116564. [PMID: 31202840 DOI: 10.1016/j.lfs.2019.116564] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Revised: 06/11/2019] [Accepted: 06/11/2019] [Indexed: 01/09/2023]
Abstract
Alzheimer's disease (AD) as a dementia and neurodegenerative disease, is mostly prevalent among people more than 65 years. AD is mostly manifested in the form of degraded mental function, such as losing memory and impaired cognitive function. Due to inefficiency of traditional pharmacological therapeutic approaches with no long-term cure, cell therapy can be considered as a capable approach in AD management. Therapies based on mesenchymal stem cells (MSCs) have provided hopeful results in experimental models regarding several disorders. MSCs enhance the levels of functional recoveries in pathologic experimental models of central nervous system (CNS) and are being investigated in clinical trials in neurological disorders. However, there is limited knowledge on the protective capabilities of MSCs in AD management. Almost, several experiments have suggested positive effects of MSCs and helped to better understand of AD-related dementia mechanism. MSCs have the potential to be used in AD treatment through amyloid-β peptide (AB), Tau protein and cholinergic system. This review aimed to clarify the promising perspective of MSCs in the context of AD.
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Affiliation(s)
- Forough Chakari-Khiavi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Pharmaceutical Chemistry, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sanam Dolati
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Aging Research Institute, Tabriz University of Medical Sciences Tabriz, Iran
| | - Aref Chakari-Khiavi
- Aging Research Institute, Tabriz University of Medical Sciences Tabriz, Iran
| | - Hossein Abbaszadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Tannaz Pourlak
- Aging Research Institute, Tabriz University of Medical Sciences Tabriz, Iran
| | - Amir Mehdizadeh
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Aging Research Institute, Tabriz University of Medical Sciences Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran..
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19
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Eremenko E, Mittal K, Berner O, Kamenetsky N, Nemirovsky A, Elyahu Y, Monsonego A. BDNF-producing, amyloid β-specific CD4 T cells as targeted drug-delivery vehicles in Alzheimer's disease. EBioMedicine 2019; 43:424-434. [PMID: 31085101 PMCID: PMC6557914 DOI: 10.1016/j.ebiom.2019.04.019] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 04/04/2019] [Accepted: 04/08/2019] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND The delivery of therapeutic proteins to selected sites within the central nervous system (CNS) parenchyma is a major challenge in the treatment of various neurodegenerative disorders. As brain-derived neurotrophic factor (BDNF) is reduced in the brain of people with Alzheimer's disease (AD) and its administration has shown promising therapeutic effects in mouse model of the disease, we generated a novel platform for T cell-based BDNF delivery into the brain parenchyma. METHODS We generated amyloid beta-protein (Aβ)-specific CD4 T cells (Aβ-T cells), genetically engineered to express BDNF, and injected them intracerebroventricularly into the 5XFAD mouse model of AD. FINDINGS The BDNF-secreting Aβ-T cells migrated efficiently to amyloid plaques, where they significantly increased the levels of BDNF, its receptor TrkB, and various synaptic proteins known to be reduced in AD. Furthermore, the injected mice demonstrated reduced levels of beta-secretase 1 (BACE1)-a protease essential in the cleavage process of the amyloid precursor protein-and ameliorated amyloid pathology and inflammation within the brain parenchyma. INTERPRETATION A T cell-based delivery of proteins into the brain can serve as a platform to modulate neurotoxic inflammation and to promote neuronal repair in neurodegenerative diseases.
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Affiliation(s)
- Ekaterina Eremenko
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; The National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
| | - Kritika Mittal
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; The National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
| | - Omer Berner
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; The National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
| | - Nikita Kamenetsky
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; The National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
| | - Anna Nemirovsky
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; The National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
| | - Yehezqel Elyahu
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; The National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
| | - Alon Monsonego
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; The National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
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20
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Li W, Huang L, Meng E, Wang X, Zhang D, Wang G. Effect of crude venom from the spider Chilobrachys jingzhao on the proliferation and differentiation of C17.2 neural stem cells. BIOTECHNOL BIOTEC EQ 2018. [DOI: 10.1080/13102818.2018.1496033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
- Wenying Li
- Department of Chemistry and Biology, College of Science, National University of Defense Technology, Changsha, Hunan, China
| | - Lixiang Huang
- Department of Chemistry and Biology, College of Science, National University of Defense Technology, Changsha, Hunan, China
| | - Er Meng
- Department of Chemistry and Biology, College of Science, National University of Defense Technology, Changsha, Hunan, China
| | - Xiaoyan Wang
- Department of Chemistry and Biology, College of Science, National University of Defense Technology, Changsha, Hunan, China
| | - Dongyi Zhang
- Department of Chemistry and Biology, College of Science, National University of Defense Technology, Changsha, Hunan, China
| | - Gan Wang
- Department of Chemistry and Biology, College of Science, National University of Defense Technology, Changsha, Hunan, China
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21
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Kwak KA, Lee SP, Yang JY, Park YS. Current Perspectives regarding Stem Cell-Based Therapy for Alzheimer's Disease. Stem Cells Int 2018; 2018:6392986. [PMID: 29686714 PMCID: PMC5852851 DOI: 10.1155/2018/6392986] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2017] [Accepted: 01/15/2018] [Indexed: 02/07/2023] Open
Abstract
Alzheimer's disease (AD), a progressive neurodegenerative disorder featuring memory loss and cognitive impairment, is caused by synaptic failure and the excessive accumulation of misfolded proteins. Many unsuccessful attempts have been made to develop new small molecules or antibodies to intervene in the disease's pathogenesis. Stem cell-based therapies cast a new hope for AD treatment as a replacement or regeneration strategy. The results from recent preclinical studies regarding stem cell-based therapies are promising. Human clinical trials are now underway. However, a number of questions remain to be answered prior to safe and effective clinical translation. This review explores the pathophysiology of AD and summarizes the relevant stem cell research according to cell type. We also briefly summarize related clinical trials. Finally, future perspectives are discussed with regard to their clinical applications.
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Affiliation(s)
- Kyeong-Ah Kwak
- Department of Oral Anatomy, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
| | - Seung-Pyo Lee
- Department of Oral Anatomy, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
| | - Jin-Young Yang
- Department of Dental Hygiene, Daejeon Institute of Science and Technology, Daejeon, Republic of Korea
| | - Young-Seok Park
- Department of Oral Anatomy, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
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22
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Kang JM, Yeon BK, Cho SJ, Suh YH. Stem Cell Therapy for Alzheimer's Disease: A Review of Recent Clinical Trials. J Alzheimers Dis 2018; 54:879-889. [PMID: 27567851 DOI: 10.3233/jad-160406] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Stem cell therapy has been noted to be a disease-modifying treatment for Alzheimer's disease (AD). After the failure to develop new drugs for AD, the number of studies on stem cells, such as mesenchymal stem cells (MSCs) and neural stem cells (NSCs), has increased from the early 2000 s. Issues pertaining to stem cells have been investigated in many animal studies in terms of stem cell origin, differentiation potency, method of culture, tumor formation, injection route, and mobility. Since 2010, mainly in East Asia, researchers began clinical trials investigating the use of stem cells for AD. Two phase I trials on moderate AD have been completed; though they revealed no severe acute or long-term side effects, no significant clinical efficacy was observed. Several studies, which involve more sophisticated study designs using different injection routes, well-established scales, and biomarkers such as amyloid positron emission tomography, are planned for mild to moderate AD patients. Here, we review the concept of stem cell therapy for AD and the progress of recent clinical trials.
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Affiliation(s)
- Jae Myeong Kang
- Department of Psychiatry, Gil Medical Center, Gachon University, College of Medicine, Incheon, Korea
| | - Byeong Kil Yeon
- Department of Psychiatry, Gil Medical Center, Gachon University, College of Medicine, Incheon, Korea.,Incheon Metropolitan Dementia Center, Incheon, Korea
| | - Seong-Jin Cho
- Department of Psychiatry, Gil Medical Center, Gachon University, College of Medicine, Incheon, Korea
| | - Yoo-Hun Suh
- Neuroscience Research Institute, Gachon University, College of Medicine, Incheon, Korea
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23
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Marei HE, Elnegiry AA, Zaghloul A, Althani A, Afifi N, Abd-Elmaksoud A, Farag A, Lashen S, Rezk S, Shouman Z, Cenciarelli C, Hasan A. Nanotubes impregnated human olfactory bulb neural stem cells promote neuronal differentiation in Trimethyltin-induced neurodegeneration rat model. J Cell Physiol 2017; 232:3586-3597. [PMID: 28121007 DOI: 10.1002/jcp.25826] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 01/03/2017] [Accepted: 01/24/2017] [Indexed: 12/12/2022]
Abstract
Neural stem cells (NSCs) are multipotent self-renewing cells that could be used in cellular-based therapy for a wide variety of neurodegenerative diseases including Alzheimer's diseases (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Being multipotent in nature, they are practically capable of giving rise to major cell types of the nervous tissue including neurons, astrocytes, and oligodendrocytes. This is in marked contrast to neural progenitor cells which are committed to a specific lineage fate. In previous studies, we have demonstrated the ability of NSCs isolated from human olfactory bulb (OB) to survive, proliferate, differentiate, and restore cognitive and motor deficits associated with AD, and PD rat models, respectively. The use of carbon nanotubes (CNTs) to enhance the survivability and differentiation potential of NSCs following their in vivo engraftment have been recently suggested. Here, in order to assess the ability of CNTs to enhance the therapeutic potential of human OBNSCs for restoring cognitive deficits and neurodegenerative lesions, we co-engrafted CNTs and human OBNSCs in TMT-neurodegeneration rat model. The present study revealed that engrafted human OBNSCS-CNTs restored cognitive deficits, and neurodegenerative changes associated with TMT-induced rat neurodegeneration model. Moreover, the CNTs seemed to provide a support for engrafted OBNSCs, with increasing their tendency to differentiate into neurons rather than into glia cells. The present study indicate the marked ability of CNTs to enhance the therapeutic potential of human OBNSCs which qualify this novel therapeutic paradigm as a promising candidate for cell-based therapy of different neurodegenerative diseases.
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Affiliation(s)
- Hany E Marei
- Biomedical Research Center, Qatar University, Doha, Qatar
| | - Ahmed A Elnegiry
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Aswan University, Aswan, Egypt
| | - Adel Zaghloul
- Department of Surgery, Anesthesiology and Radiology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Asma Althani
- Biomedical Research Center, Qatar University, Doha, Qatar
| | | | - Ahmed Abd-Elmaksoud
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Amany Farag
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Samah Lashen
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Shymaa Rezk
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Zeinab Shouman
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | | | - Anwarul Hasan
- Department of Mechanical and Industrial Engineering, Qatar University, Doha, Qatar
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24
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Nayernia Z, Colaianna M, Robledinos-Antón N, Gutzwiller E, Sloan-Béna F, Stathaki E, Hibaoui Y, Cuadrado A, Hescheler J, Stasia MJ, Saric T, Jaquet V, Krause KH. Decreased neural precursor cell pool in NADPH oxidase 2-deficiency: From mouse brain to neural differentiation of patient derived iPSC. Redox Biol 2017; 13:82-93. [PMID: 28575744 PMCID: PMC5454143 DOI: 10.1016/j.redox.2017.04.026] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 04/19/2017] [Accepted: 04/20/2017] [Indexed: 10/28/2022] Open
Abstract
There is emerging evidence for the involvement of reactive oxygen species (ROS) in the regulation of stem cells and cellular differentiation. Absence of the ROS-generating NADPH oxidase NOX2 in chronic granulomatous disease (CGD) patients, predominantly manifests as immune deficiency, but has also been associated with decreased cognition. Here, we investigate the role of NOX enzymes in neuronal homeostasis in adult mouse brain and in neural cells derived from human induced pluripotent stem cells (iPSC). High levels of NOX2 were found in mouse adult neurogenic regions. In NOX2-deficient mice, neurogenic regions showed diminished redox modifications, as well as decrease in neuroprecursor numbers and in expression of genes involved in neural differentiation including NES, BDNF and OTX2. iPSC from healthy subjects and patients with CGD were used to study the role of NOX2 in human in vitro neuronal development. Expression of NOX2 was low in undifferentiated iPSC, upregulated upon neural induction, and disappeared during neuronal differentiation. In human neurospheres, NOX2 protein and ROS generation were polarized within the inner cell layer of rosette structures. NOX2 deficiency in CGD-iPSCs resulted in an abnormal neural induction in vitro, as revealed by a reduced expression of neuroprogenitor markers (NES, BDNF, OTX2, NRSF/REST), and a decreased generation of mature neurons. Vector-mediated NOX2 expression in NOX2-deficient iPSCs rescued neurogenesis. Taken together, our study provides novel evidence for a regulatory role of NOX2 during early stages of neurogenesis in mouse and human.
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Affiliation(s)
- Zeynab Nayernia
- Department of Pathology and Immunology, University of Geneva Medical School, 1-rue Michel Servet, 1211 Geneva, Switzerland
| | - Marilena Colaianna
- Department of Pathology and Immunology, University of Geneva Medical School, 1-rue Michel Servet, 1211 Geneva, Switzerland
| | - Natalia Robledinos-Antón
- Instituto de Investigaciones Biomédicas "Alberto Sols", Faculty of Medicine, Autonomous University of Madrid (UAM), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Eveline Gutzwiller
- Department of Pathology and Immunology, University of Geneva Medical School, 1-rue Michel Servet, 1211 Geneva, Switzerland
| | - Frédérique Sloan-Béna
- Hôpitaux Universitaires de Genève HUG, Laboratoires de Cytogénétique Constitutionnelle, Service de Médecine Génétique, Geneva, Switzerland
| | - Elisavet Stathaki
- Hôpitaux Universitaires de Genève HUG, Laboratoires de Cytogénétique Constitutionnelle, Service de Médecine Génétique, Geneva, Switzerland
| | - Yousef Hibaoui
- Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel Servet, 1211 Geneva, Switzerland
| | - Antonio Cuadrado
- Instituto de Investigaciones Biomédicas "Alberto Sols", Faculty of Medicine, Autonomous University of Madrid (UAM), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Jürgen Hescheler
- Center for Physiology and Pathophysiology, Institute for Neurophysiology, Medical Faculty, University of Cologne, Cologne 50931, Germany
| | - Marie-José Stasia
- Université Grenoble Alpes, Techniques de l'Ingénierie Médicale et de la Complexité- Grenoble, F38000 Grenoble, France
| | - Tomo Saric
- Center for Physiology and Pathophysiology, Institute for Neurophysiology, Medical Faculty, University of Cologne, Cologne 50931, Germany
| | - Vincent Jaquet
- Department of Pathology and Immunology, University of Geneva Medical School, 1-rue Michel Servet, 1211 Geneva, Switzerland
| | - Karl-Heinz Krause
- Department of Pathology and Immunology, University of Geneva Medical School, 1-rue Michel Servet, 1211 Geneva, Switzerland.
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25
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Zheng XY, Wan QQ, Zheng CY, Zhou HL, Dong XY, Deng QS, Yao H, Fu Q, Gao M, Yan ZJ, Wang SS, You Y, Lv J, Wang XY, Chen KE, Zhang MY, Xu RX. Amniotic Mesenchymal Stem Cells Decrease Aβ Deposition and Improve Memory in APP/PS1 Transgenic Mice. Neurochem Res 2017; 42:2191-2207. [PMID: 28397068 DOI: 10.1007/s11064-017-2226-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Revised: 03/03/2017] [Accepted: 03/07/2017] [Indexed: 12/11/2022]
Abstract
Transplantation of human amniotic mesenchymal stem cells (hAM-MSCs) seems to be a promising strategy for the treatment of neurodegenerative disorders, including Alzheimer's disease (AD). However, the clinical therapeutic effects of hAM-MSCs and their mechanisms of action in AD remain to be determined. Here, we used amyloid precursor protein (APP) and presenilin1 (PS1) double-transgenic mice to evaluate the effects of hAM-MSC transplantation on AD-related neuropathology and cognitive dysfunction. We found that hAM-MSC transplantation into the hippocampus dramatically reduced amyloid-β peptide (Aβ) deposition and rescued spatial learning and memory deficits in APP/PS1 mice. Interestingly, these effects were associated with increasing in Aβ-degrading factors, elevations in activated microglia, and the modulation of neuroinflammation. Furthermore, enhanced hippocampal neurogenesis in the subgranular zone (SGZ) of the dentate gyrus (DG) and enhanced synaptic plasticity following hAM-MSC treatment could be another important factor in reversing the cognitive decline in APP/PS1 mice. Instead, the mechanism underlying the improved cognition apparently involves a robust increase in hippocampal synaptic density and neurogenesis that is mediated by brain-derived neurotrophic factor (BDNF). In conclusion, our data suggest that hAM-MSCs may be a new and effective therapy for the treatment of AD.
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Affiliation(s)
- Xiao-Yu Zheng
- Department of Intensive-Care Unit, Affiliated First Hospital, Jinan University, Guangzhou, China
| | - Qian-Quan Wan
- Department of Neurosurgery, Affiliated First Hospital, Jinan University, Region, No. 613, Huangpudadaoxi, Tianhe District, Guangzhou, 510630, China
| | - Chuan-Yi Zheng
- Affiliated Bayi Brain Hospital, General Hospital of Beijing Military Region, Beijing, China
| | - Hong-Long Zhou
- Affiliated Bayi Brain Hospital, General Hospital of Beijing Military Region, Beijing, China
| | - Xing-Yu Dong
- Affiliated Bayi Brain Hospital, General Hospital of Beijing Military Region, Beijing, China
| | - Qing-Shan Deng
- Affiliated Bayi Brain Hospital, General Hospital of Beijing Military Region, Beijing, China
| | - Hui Yao
- Affiliated Bayi Brain Hospital, General Hospital of Beijing Military Region, Beijing, China
| | - Qiang Fu
- Affiliated Bayi Brain Hospital, General Hospital of Beijing Military Region, Beijing, China
| | - Mou Gao
- Affiliated Bayi Brain Hospital, General Hospital of Beijing Military Region, Beijing, China
| | - Zhong-Jie Yan
- Affiliated Bayi Brain Hospital, General Hospital of Beijing Military Region, Beijing, China
| | - Shan-Shan Wang
- Affiliated Bayi Brain Hospital, General Hospital of Beijing Military Region, Beijing, China
| | - Yu You
- Affiliated Bayi Brain Hospital, General Hospital of Beijing Military Region, Beijing, China
| | - Jun Lv
- Affiliated Bayi Brain Hospital, General Hospital of Beijing Military Region, Beijing, China
| | - Xiang-Yu Wang
- Department of Neurosurgery, Affiliated First Hospital, Jinan University, Region, No. 613, Huangpudadaoxi, Tianhe District, Guangzhou, 510630, China.
| | - Ke-En Chen
- Department of Neurosurgery, Affiliated First Hospital, Jinan University, Region, No. 613, Huangpudadaoxi, Tianhe District, Guangzhou, 510630, China.
| | - Mao-Ying Zhang
- Department of Neurosurgery, Affiliated First Hospital, Jinan University, Region, No. 613, Huangpudadaoxi, Tianhe District, Guangzhou, 510630, China.
| | - Ru-Xiang Xu
- Affiliated Bayi Brain Hospital, General Hospital of Beijing Military Region, Beijing, China.
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26
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Zhao H, Alam A, San CY, Eguchi S, Chen Q, Lian Q, Ma D. Molecular mechanisms of brain-derived neurotrophic factor in neuro-protection: Recent developments. Brain Res 2017; 1665:1-21. [PMID: 28396009 DOI: 10.1016/j.brainres.2017.03.029] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Revised: 03/02/2017] [Accepted: 03/28/2017] [Indexed: 12/13/2022]
Abstract
Neuronal cell injury, as a consequence of acute or chronic neurological trauma, is a significant cause of mortality around the world. On a molecular level, the condition is characterized by widespread cell death and poor regeneration, which can result in severe morbidity in survivors. Potential therapeutics are of major interest, with a promising candidate being brain-derived neurotrophic factor (BDNF), a ubiquitous agent in the brain which has been associated with neural development and may facilitate protective and regenerative effects following injury. This review summarizes the available information on the potential benefits of BDNF and the molecular mechanisms involved in several pathological conditions, including hypoxic brain injury, stroke, Alzheimer's disease and Parkinson's disease. It further explores the methods in which BDNF can be applied in clinical and therapeutic settings, and the potential challenges to overcome.
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Affiliation(s)
- Hailin Zhao
- Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK
| | - Azeem Alam
- Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK
| | - Chun-Yin San
- Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK
| | - Shiori Eguchi
- Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK
| | - Qian Chen
- Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK; Department of Anaesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Qingquan Lian
- Department of Anesthesiology, Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
| | - Daqing Ma
- Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK.
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27
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Huang L, Wang G. The Effects of Different Factors on the Behavior of Neural Stem Cells. Stem Cells Int 2017; 2017:9497325. [PMID: 29358957 PMCID: PMC5735681 DOI: 10.1155/2017/9497325] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 10/18/2017] [Indexed: 02/07/2023] Open
Abstract
The repair of central nervous system (CNS) injury has been a worldwide problem in the biomedical field. How to reduce the damage to the CNS and promote the reconstruction of the damaged nervous system structure and function recovery has always been the concern of nerve tissue engineering. Multiple differentiation potentials of neural stem cell (NSC) determine the application value for the repair of the CNS injury. Thus, how to regulate the behavior of NSCs becomes the key to treating the CNS injury. So far, a large number of researchers have devoted themselves to searching for a better way to regulate the behavior of NSCs. This paper summarizes the effects of different factors on the behavior of NSCs in the past 10 years, especially on the proliferation and differentiation of NSCs. The final purpose of this review is to provide a more detailed theoretical basis for the clinical repair of the CNS injury by nerve tissue engineering.
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Affiliation(s)
- Lixiang Huang
- Department of Chemistry and Biology, College of Science, National University of Defense Technology, Changsha, Hunan 410073, China
| | - Gan Wang
- Department of Chemistry and Biology, College of Science, National University of Defense Technology, Changsha, Hunan 410073, China
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Ammar AS, Osman Y, Hendam AT, Hasen MA, Al Rubaish FA, Al Nujaidi DY, Al Abbas FM. A Method for Reconstruction of Severely Damaged Spinal Cord using Autologous Hematopoietic Stem Cells and Platelet-rich Protein as a Biological Scaffold. Asian J Neurosurg 2017; 12:681-690. [PMID: 29114283 PMCID: PMC5652095 DOI: 10.4103/ajns.ajns_351_16] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Introduction: There have been attempts to alter the prognosis of severe spinal cord injury in different centers, but none of which have reliably altered the outcome. Some trials use stem cells (SCs) that produced widely differing results. We hereby add our experience in our center of a surgical reconstruction of the damaged spinal cord using a mixture of SCs and Platelet-Rich Protein (PRP) with fibrin coated as a biological scaffold. Materials and Methods: Four cases of severely damaged spinal cord have been operated for neurolysis and reconstruction of the spinal cord using SCs and platelet-rich protein (PRP) with fibrin coated harvested from the peripheral circulation of the patient. PRP serves to maintain the position of the SCs. One milliliter suspension contains an average of 2.8 × 106 of autologous hematopoietic SCs. Patients were intraoperatively monitored by somatosensory evoked potential, motor evoked potentials, and delta wave. They are clinically followed postoperatively and electromyogram was repeated every 2 weeks. Magnetic resonance imaging (MRI) was repeated regularly. The patients are followed up for a period between 2 and 3 years. Results: One patient demonstrated motor and objective sensory improvement (P = 0.05), two other patients reported subjective sensory improvement, and the fourth one remained without any improvement (P = 0.1). None of these patients demonstrated any sign of deterioration or complication either on the surgery or on implanting of the SCs. MRI clearly proved that the inserted biological scaffold remained in place of reconstruction. Conclusion: SCs may play a role in restoring spinal cord functions. However, the unsolved problems of the use of SCs and related ethical issues should be addressed.
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Affiliation(s)
- Ahmed Sabry Ammar
- Department of Neurosurgery, King Fahd University Hospital, Faculty of Medicine, University of Dammam, Al Khobar, Kingdom of Saudi Arabia
| | - Yasser Osman
- Department of Heamatology, King Fahd University Hospital, Faculty of Medicine, University of Dammam, Al Khobar, Kingdom of Saudi Arabia
| | - Ahmed Taher Hendam
- Department of Neurosurgery, King Fahd University Hospital, Faculty of Medicine, University of Dammam, Al Khobar, Kingdom of Saudi Arabia
| | - Mohammed Ahmed Hasen
- Department of Neurosurgery, King Fahd University Hospital, Faculty of Medicine, University of Dammam, Al Khobar, Kingdom of Saudi Arabia
| | - Fatma Abdullah Al Rubaish
- Department of Internal Medicine, King Fahd University Hospital, Faculty of Medicine, University of Dammam, Al Khobar, Kingdom of Saudi Arabia
| | - Danya Yaagoub Al Nujaidi
- Department of Internal Medicine, King Fahd University Hospital, Faculty of Medicine, University of Dammam, Al Khobar, Kingdom of Saudi Arabia
| | - Faisal Mishal Al Abbas
- Department of Neurosurgery, King Fahd University Hospital, Faculty of Medicine, University of Dammam, Al Khobar, Kingdom of Saudi Arabia
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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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30
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Salem H, Rocha NP, Colpo GD, Teixeira AL. Moving from the Dish to the Clinical Practice: A Decade of Lessons and Perspectives from the Pre-Clinical and Clinical Stem Cell Studies for Alzheimer’s Disease. J Alzheimers Dis 2016; 53:1209-30. [DOI: 10.3233/jad-160250] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Haitham Salem
- Department of Psychiatry and Behavioral Sciences, Neuropsychiatry Program, McGovern Medical School, The University of Texas Health Science Center, Houston, TX, USA
- Regenerative Medicine Program, University of Lübeck, Schleswig-Holstein, Germany
| | - Natalia Pessoa Rocha
- Department of Psychiatry and Behavioral Sciences, Neuropsychiatry Program, McGovern Medical School, The University of Texas Health Science Center, Houston, TX, USA
| | - Gabriela Delevati Colpo
- Department of Psychiatry and Behavioral Sciences, Neuropsychiatry Program, McGovern Medical School, The University of Texas Health Science Center, Houston, TX, USA
| | - Antonio Lucio Teixeira
- Department of Psychiatry and Behavioral Sciences, Neuropsychiatry Program, McGovern Medical School, The University of Texas Health Science Center, Houston, TX, USA
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31
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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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32
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Yang JW, Ma W, Luo T, Wang DY, Lu JJ, Li XT, Wang TT, Cheng JR, Ru J, Gao Y, Liu J, Liang Z, Yang ZY, Dai P, He YS, Guo XB, Guo JH, Li LY. BDNF promotes human neural stem cell growth via GSK-3β-mediated crosstalk with the wnt/β-catenin signaling pathway. Growth Factors 2016; 34:19-32. [PMID: 27144323 DOI: 10.3109/08977194.2016.1157791] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Brain-derived neurotrophic factor (BDNF) plays important roles in neural stem cell (NSC) growth. In this study, we investigated whether BDNF exerts its neurotrophic effects through the Wnt/β-catenin signaling pathway in human embryonic spinal cord NSCs (hESC-NSCs) in vitro. We found an increase in hESC-NSC growth by BDNF overexpression. Furthermore, expression of Wnt1, Frizzled1 and Dsh was upregulated, whereas GSK-3β expression was downregulated. In contrast, hESC-NSC growth was decreased by BDNF RNA interference. BDNF, Wnt1 and β-catenin components were all downregulated, whereas GSK-3β was upregulated. Next, we treated hESC-NSCs with 6-bromoindirubin-3'-oxime (BIO), a small molecule inhibitor of GSK-3β. BIO reduced the effects of BDNF upregulation/downregulation on the cell number, soma size and differentiation, and suppressed the effect of BDNF modulation on the Wnt signaling pathway. Our findings suggest that BDNF promotes hESC-NSC growth in vitro through crosstalk with the Wnt/β-catenin signaling pathway, and that this interaction may be mediated by GSK-3β.
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Affiliation(s)
- Jin-Wei Yang
- a Institue of Neuroscience, Kunming Medical University , Yunnan Kunming , China
- b Second Department of General Surgery, First People's Hospital of Yunnan Province , Yunnan Kunming , China
| | - Wei Ma
- a Institue of Neuroscience, Kunming Medical University , Yunnan Kunming , China
| | - Tao Luo
- a Institue of Neuroscience, Kunming Medical University , Yunnan Kunming , China
| | - Dong-Yan Wang
- a Institue of Neuroscience, Kunming Medical University , Yunnan Kunming , China
| | - Jian-Jun Lu
- c Department of Anatomy and Biomedical Sciences , Monash University , Melbourne , Australia
| | - Xing-Tong Li
- a Institue of Neuroscience, Kunming Medical University , Yunnan Kunming , China
| | - Tong-Tong Wang
- a Institue of Neuroscience, Kunming Medical University , Yunnan Kunming , China
| | - Jing-Ru Cheng
- b Second Department of General Surgery, First People's Hospital of Yunnan Province , Yunnan Kunming , China
| | - Jin Ru
- a Institue of Neuroscience, Kunming Medical University , Yunnan Kunming , China
- b Second Department of General Surgery, First People's Hospital of Yunnan Province , Yunnan Kunming , China
| | - Yan Gao
- d Department of Pathology , Children's Hospital of Kunming City , Yunnan Kunming , China , and
| | - Jia Liu
- b Second Department of General Surgery, First People's Hospital of Yunnan Province , Yunnan Kunming , China
| | - Zhang Liang
- a Institue of Neuroscience, Kunming Medical University , Yunnan Kunming , China
| | - Zhi-Yong Yang
- e Department of Neurosurgery , First Affiliated Hospital of Kunming Medical University , Yunnan Kunming , China
| | - Ping Dai
- a Institue of Neuroscience, Kunming Medical University , Yunnan Kunming , China
| | - Yong-Sheng He
- a Institue of Neuroscience, Kunming Medical University , Yunnan Kunming , China
| | - Xiao-Bing Guo
- a Institue of Neuroscience, Kunming Medical University , Yunnan Kunming , China
| | - Jian-Hui Guo
- b Second Department of General Surgery, First People's Hospital of Yunnan Province , Yunnan Kunming , China
| | - Li-Yan Li
- a Institue of Neuroscience, Kunming Medical University , Yunnan Kunming , China
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Abud EM, Blurton-Jones M. Could Stem Cells Be Used to Treat or Model Alzheimer’s Disease? Transl Neurosci 2016. [DOI: 10.1007/978-1-4899-7654-3_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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Kim JA, Ha S, Shin KY, Kim S, Lee KJ, Chong YH, Chang KA, Suh YH. Neural stem cell transplantation at critical period improves learning and memory through restoring synaptic impairment in Alzheimer's disease mouse model. Cell Death Dis 2015; 6:e1789. [PMID: 26086962 PMCID: PMC4669825 DOI: 10.1038/cddis.2015.138] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Revised: 04/05/2015] [Accepted: 04/22/2015] [Indexed: 12/20/2022]
Abstract
Alzheimer's disease (AD) is characterized by neuronal loss in several regions of the brain. Recent studies have suggested that stem cell transplantation could serve as a potential therapeutic strategy to halt or ameliorate the inexorable disease progression. However, the optimal stage of the disease for stem cell transplantation to have a therapeutic effect has yet to be determined. Here, we demonstrated that transplantation of neural stem cells into 12-month-old Tg2576 brains markedly improved both cognitive impairments and neuropathological features by reducing β-amyloid processing and upregulating clearance of β-amyloid, secretion of anti-inflammatory cytokines, endogenous neurogenesis, as well as synapse formation. In contrast, the stem cell transplantation did not recover cognitive dysfunction and β-amyloid neuropathology in Tg2576 mice aged 15 months when the memory loss is manifest. Overall, this study underscores that stem cell therapy at optimal time frame is crucial to obtain maximal therapeutic effects that can restore functional deficits or stop the progression of AD.
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Affiliation(s)
- J A Kim
- Department of Pharmacology, College of Medicine, Neuroscience Research Institute, MRC, Seoul National University, Seoul, 110-799, Korea
| | - S Ha
- Department of Pharmacology, College of Medicine, Neuroscience Research Institute, Gachon University, Incheon, 405-760, Korea
| | - K Y Shin
- Department of Pharmacology, College of Medicine, Neuroscience Research Institute, MRC, Seoul National University, Seoul, 110-799, Korea
| | - S Kim
- Department of Pharmacology, College of Medicine, Neuroscience Research Institute, Gachon University, Incheon, 405-760, Korea
| | - K J Lee
- Synaptic Circuit Plasticity Laboratory, Department of Structure & Function of Neural Network, Korea Brain Research Institute, 61 Cheomdan-ro, Dong-gu, Daegu 701-300, Korea
| | - Y H Chong
- Division of Molecular Biology and Neuroscience, Department of Microbiology, School of Medicine, Ewha Medical Research Institute, Ewha Womans University, Seoul, 158-710, Korea
| | - K-A Chang
- Department of Pharmacology, College of Medicine, Neuroscience Research Institute, Gachon University, Incheon, 405-760, Korea
| | - Y-H Suh
- 1] Department of Pharmacology, College of Medicine, Neuroscience Research Institute, MRC, Seoul National University, Seoul, 110-799, Korea [2] Synaptic Circuit Plasticity Laboratory, Department of Structure & Function of Neural Network, Korea Brain Research Institute, 61 Cheomdan-ro, Dong-gu, Daegu 701-300, Korea
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35
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Marei HES, Lashen S, Farag A, Althani A, Afifi N, A AE, Rezk S, Pallini R, Casalbore P, Cenciarelli C. Human olfactory bulb neural stem cells mitigate movement disorders in a rat model of Parkinson's disease. J Cell Physiol 2015; 230:1614-29. [PMID: 25536543 DOI: 10.1002/jcp.24909] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2014] [Accepted: 12/18/2014] [Indexed: 12/14/2022]
Abstract
Parkinson's disease (PD) is a neurological disorder characterized by the loss of midbrain dopaminergic (DA) neurons. Neural stem cells (NSCs) are multipotent stem cells that are capable of differentiating into different neuronal and glial elements. The production of DA neurons from NSCs could potentially alleviate behavioral deficits in Parkinsonian patients; timely intervention with NSCs might provide a therapeutic strategy for PD. We have isolated and generated highly enriched cultures of neural stem/progenitor cells from the human olfactory bulb (OB). If NSCs can be obtained from OB, it would alleviate ethical concerns associated with the use of embryonic tissue, and provide an easily accessible cell source that would preclude the need for invasive brain surgery. Following isolation and culture, olfactory bulb neural stem cells (OBNSCs) were genetically engineered to express hNGF and GFP. The hNFG-GFP-OBNSCs were transplanted into the striatum of 6-hydroxydopamin (6-OHDA) Parkinsonian rats. The grafted cells survived in the lesion environment for more than eight weeks after implantation with no tumor formation. The grafted cells differentiated in vivo into oligodendrocyte-like (25 ± 2.88%), neuron-like (52.63 ± 4.16%), and astrocyte -like (22.36 ± 1.56%) lineages, which we differentiated based on morphological and immunohistochemical criteria. Transplanted rats exhibited a significant partial correction in stepping and placing in non-pharmacological behavioral tests, pole and rotarod tests. Taken together, our data encourage further investigations of the possible use of OBNSCs as a promising cell-based therapeutic strategy for Parkinson's disease.
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Affiliation(s)
- Hany E S Marei
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
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Lai S, Zhang M, Xu D, Zhang Y, Qiu L, Tian C, Zheng JC. Direct reprogramming of induced neural progenitors: a new promising strategy for AD treatment. Transl Neurodegener 2015; 4:7. [PMID: 25949812 PMCID: PMC4422611 DOI: 10.1186/s40035-015-0028-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2014] [Accepted: 04/03/2015] [Indexed: 12/23/2022] Open
Abstract
Alzheimer's disease (AD) is a prominent form of dementia, characterized by aggregation of the amyloid β-peptide (Aβ) plaques and neurofibrillary tangles, loss of synapses and neurons, and degeneration of cognitive functions. Currently, although a variety of medications can relieve some of the symptoms, there is no cure for AD. Recent breakthroughs in the stem cell field provide promising strategies for AD treatment. Stem cells including embryonic stem cells (ESCs), neural stem cells (NSCs), mesenchymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs) are potentials for AD treatment. However, the limitation of cell sources, safety issues, and ethical issues restrict their applications in AD. Recently, the direct reprogramming of induced neural progenitor cells (iNPCs) has shed light on the treatment of AD. In this review, we will discuss the latest progress, challenges, and potential applications of direct reprogramming in AD treatment.
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Affiliation(s)
- Siqiang Lai
- />Tenth People’s Hospital affiliated to Tongji University School of Medicine, Shanghai, 200072 China
| | - Min Zhang
- />Tenth People’s Hospital affiliated to Tongji University School of Medicine, Shanghai, 200072 China
| | - Dongsheng Xu
- />Tenth People’s Hospital affiliated to Tongji University School of Medicine, Shanghai, 200072 China
- />University of Nebraska Medical Center, Omaha, NE 68198-5930 USA
| | - Yiying Zhang
- />Tenth People’s Hospital affiliated to Tongji University School of Medicine, Shanghai, 200072 China
| | - Lisha Qiu
- />Tenth People’s Hospital affiliated to Tongji University School of Medicine, Shanghai, 200072 China
| | - Changhai Tian
- />Tenth People’s Hospital affiliated to Tongji University School of Medicine, Shanghai, 200072 China
- />University of Nebraska Medical Center, Omaha, NE 68198-5930 USA
| | - Jialin Charlie Zheng
- />Tenth People’s Hospital affiliated to Tongji University School of Medicine, Shanghai, 200072 China
- />University of Nebraska Medical Center, Omaha, NE 68198-5930 USA
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Tong LM, Fong H, Huang Y. Stem cell therapy for Alzheimer's disease and related disorders: current status and future perspectives. Exp Mol Med 2015; 47:e151. [PMID: 25766620 PMCID: PMC4351411 DOI: 10.1038/emm.2014.124] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Accepted: 11/19/2014] [Indexed: 12/31/2022] Open
Abstract
Underlying cognitive declines in Alzheimer's disease (AD) are the result of neuron and neuronal process losses due to a wide range of factors. To date, all efforts to develop therapies that target specific AD-related pathways have failed in late-stage human trials. As a result, an emerging consensus in the field is that treatment of AD patients with currently available drug candidates might come too late, likely as a result of significant neuronal loss in the brain. In this regard, cell-replacement therapies, such as human embryonic stem cell- or induced pluripotent stem cell-derived neural cells, hold potential for treating AD patients. With the advent of stem cell technologies and the ability to transform these cells into different types of central nervous system neurons and glial cells, some success in stem cell therapy has been reported in animal models of AD. However, many more steps remain before stem cell therapies will be clinically feasible for AD and related disorders in humans. In this review, we will discuss current research advances in AD pathogenesis and stem cell technologies; additionally, the potential challenges and strategies for using cell-based therapies for AD and related disorders will be discussed.
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Affiliation(s)
- Leslie M Tong
- Gladstone Institute of Neurological Disease, University of California, San Francisco, CA, USA
- Biomedical Sciences Graduate Program, University of California, San Francisco, CA, USA
| | - Helen Fong
- Gladstone Institute of Neurological Disease, University of California, San Francisco, CA, USA
- Department of Neurology, University of California, San Francisco, CA, USA
| | - Yadong Huang
- Gladstone Institute of Neurological Disease, University of California, San Francisco, CA, USA
- Biomedical Sciences Graduate Program, University of California, San Francisco, CA, USA
- Department of Neurology, University of California, San Francisco, CA, USA
- Department of Pathology, University of California, San Francisco, CA, USA
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Gu G, Zhang W, Li M, Ni J, Wang P. Transplantation of NSC-derived cholinergic neuron-like cells improves cognitive function in APP/PS1 transgenic mice. Neuroscience 2015; 291:81-92. [PMID: 25681520 DOI: 10.1016/j.neuroscience.2015.01.073] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Revised: 01/30/2015] [Accepted: 01/30/2015] [Indexed: 01/10/2023]
Abstract
The ability to selectively control the differentiation of neural stem cells (NSCs) into cholinergic neurons in vivo would be an important step toward cell replacement therapy. First, green fluorescent protein (GFP)-NSCs were induced to differentiate into cholinergic neuron-like cells (CNLs) with retinoic acid (RA) pre-induction followed by nerve growth factor (NGF) induction. Then, these CNLs were transplanted into bilateral hippocampus of APP/PS1 transgenic mice. Behavioral parameters showed by Morris water maze (MWM) tests and the percentages of GFP-labeled cholinergic neurons of CNL transplanted mice were compared with those of controls. Brain levels of choline acetyltransferase (ChAT) mRNA and proteins were analyzed by quantitative real-time PCR and Western blotting, ChAT activity and acetylcholine (ACh) concentration were also evaluated by ChAT activity and ACh concentration assay kits. Immunofluorescence analysis showed that 80.3±1.5% NSCs differentiated into CNLs after RA pre-induction followed by NGF induction in vitro. Three months after transplantation, 82.4±6.3% CNLs differentiated into cholinergic neurons in vivo. APP/PS1 mice transplanted with CNLs showed a significant improvement in learning and memory ability compared with control groups at different time points. Furthermore, CNLs transplantation dramatically increased in the expressions of ChAT mRNA and protein, as well ChAT activity and ACh concentration in APP/PS1 mice. Our findings support the prospect of using NSC-derived CNLs in developing therapies for Alzheimer's disease (AD).
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Affiliation(s)
- G Gu
- Department of Medical Imaging, Tongji Hospital, Medical School of Tongji University, Shanghai 200065, China
| | - W Zhang
- Department of Medical Imaging, Tongji Hospital, Medical School of Tongji University, Shanghai 200065, China
| | - M Li
- Department of Medical Imaging, Tongji Hospital, Medical School of Tongji University, Shanghai 200065, China
| | - J Ni
- Department of Medical Imaging, Tongji Hospital, Medical School of Tongji University, Shanghai 200065, China
| | - P Wang
- Department of Medical Imaging, Tongji Hospital, Medical School of Tongji University, Shanghai 200065, China.
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39
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Intranasal delivery of stem cells as therapy for central nervous system disease. Exp Mol Pathol 2015; 98:145-51. [PMID: 25645932 DOI: 10.1016/j.yexmp.2015.01.016] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Accepted: 01/29/2015] [Indexed: 12/13/2022]
Abstract
Stem cells, upon entering the CNS, can preferentially migrate into disease foci, where they exert therapeutic effects that compensate for lost tissue, reconstructing damaged neuronal circuitry and establishing in the brain a new microenvironment suitable for cell survival. However, the route of stem cell delivery into the CNS remains a challenge: with systemic administration (e.g., intravenous injection), a fraction of cells may be trapped in other organs than the CNS, while direct CNS injections, e.g., intracerebroventricular or transcranial, are invasive. Intranasal (i.n.) delivery of stem cells, in contrast, can effectively bypass the blood-brain barrier, rapidly enter the CNS, and minimize systemic distribution. I.n. delivery of stem cells may therefore be a safe and non-invasive way of targeting the CNS and would thus be a promising therapeutic option for CNS disease. In this review we discuss the i.n. route for stem cell delivery into the CNS, and the perspectives of i.n. stem cell-based therapy in CNS disease.
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40
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Marei HES, Farag A, Althani A, Afifi N, Abd-Elmaksoud A, Lashen S, Rezk S, Pallini R, Casalbore P, Cenciarelli C. Human olfactory bulb neural stem cells expressing hNGF restore cognitive deficit in Alzheimer's disease rat model. J Cell Physiol 2015; 230:116-30. [PMID: 24911171 DOI: 10.1002/jcp.24688] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2014] [Accepted: 05/22/2014] [Indexed: 12/14/2022]
Abstract
In this study, we aim to demonstrate the fate of allogenic adult human olfactory bulb neural stem/progenitor cells (OBNSC/NPCs) transplanted into the rat hippocampus treated with ibotenic acid (IBO), a neurotoxicant specific to hippocampal cholinergic neurons that are lost in Alzheimer's disease. We assessed their possible ability to survive, integrate, proliferate, and differentiate into different neuronal and glial elements: we also evaluate their possible therapeutic potential, and the mechanism(s) relevant to neuroprotection following their engraftment into the CNS milieu. OBNSC/NPCs were isolated from adult human olfactory bulb patients, genetically engineered to express GFP and human nerve growth factor (hNGF) by lentivirus-mediated infection, and stereotaxically transplanted into the hippocampus of IBO-treated animals and controls. Stereological analysis of engrafted OBNSCs eight weeks post transplantation revealed a 1.89 fold increase with respect to the initial cell population, indicating a marked ability for survival and proliferation. In addition, 54.71 ± 11.38%, 30.18 ± 6.00%, and 15.09 ± 5.38% of engrafted OBNSCs were identified by morphological criteria suggestive of mature neurons, oligodendrocytes and astrocytes respectively. Taken together, this work demonstrated that human OBNSCs expressing NGF ameliorate the cognitive deficiencies associated with IBO-induced lesions in AD model rats, and the improvement can probably be attributed primarily to neuronal and glial cell replacement as well as the trophic influence exerted by the secreted NGF.
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Affiliation(s)
- Hany E S Marei
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
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Chen SQ, Cai Q, Shen YY, Wang PY, Li MH, Teng GY. Neural stem cell transplantation improves spatial learning and memory via neuronal regeneration in amyloid-β precursor protein/presenilin 1/tau triple transgenic mice. Am J Alzheimers Dis Other Demen 2014; 29:142-9. [PMID: 24265106 PMCID: PMC10852951 DOI: 10.1177/1533317513506776] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Neural stem cell (NSC) transplantation has recently become a main research target for Alzheimer's disease (AD) treatment. In the present study, we transplanted NSCs from C57BL/6 mice into the hippocampus in the 12-month-old triple transgenic model of AD (3 × Tg) and determined whether NSC transplantation can alleviate impairments in spatial learning and memory via neuronal regeneration in AD mice. Two months after transplantation, Morris water maze tests suggested that spatial learning and memory in the 3 × Tg mice receiving NSCs was significantly improved compared to 3 × Tg mice not receiving NSCs. Furthermore, quantification of Nissl staining revealed that the number of neurons in the hippocampus of 3 × Tg mice receiving NSCs was significantly greater than that in 3 × Tg mice not receiving NSCs, indicating that new neurons were generated. These results may demonstrate that NSC transplantation can improve spatial learning and memory via neuronal regeneration in amyloid-β precursor protein/presenilin 1/tau 3 × Tg mice.
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Affiliation(s)
- Shuang-Qing Chen
- Neuroimaging Research Center, the Affiliated Suzhou Hospital, Nanjing Medical University, Suzhou, China
| | - Qing Cai
- Neuroimaging Research Center, the Affiliated Suzhou Hospital, Nanjing Medical University, Suzhou, China
| | - Yu-Ying Shen
- Neuroimaging Research Center, the Affiliated Suzhou Hospital, Nanjing Medical University, Suzhou, China
| | - Pei-Yun Wang
- Department of Radiology, the Affiliated Tongji Hospital, Tongji University, Shanghai, China
| | - Ming-Hua Li
- Department of Radiology, the Affiliated Tongji Hospital, Tongji University, Shanghai, China
| | - Gao-Yun Teng
- Key Laboratory of Molecular Imaging, Southeast University, Nanjing 210009, China
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Fan X, Sun D, Tang X, Cai Y, Yin ZQ, Xu H. Stem-cell challenges in the treatment of Alzheimer's disease: a long way from bench to bedside. Med Res Rev 2014; 34:957-78. [PMID: 24500883 DOI: 10.1002/med.21309] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Alzheimer's disease (AD) is the most prevalent type of dementia, and its neuropathology is characterized by deposition of insoluble β-amyloid peptides, intracellular neurofibrillary tangles, and the loss of diverse neurons. Current pharmacological treatments for AD relieve symptoms without affecting the major pathological characteristics of the disease. Therefore, it is essential to develop new and effective therapies. Stem-cell types include tissue-specific stem cells, such as neural stem cells and mesenchymal stem cells, embryonic stem cells derived from blastocysts, and induced pluripotent stem cells (iPSCs) reprogrammed from somatic cells. Recent preclinical evidence suggests that stem cells can be used to treat or model AD. The mechanisms of stem cell based therapies for AD include stem cell mediated neuroprotection and trophic actions, antiamyloidogenesis, beneficial immune modulation, and the replacement of the lost neurons. iPSCs have been recently used to model AD, investigate sporadic and familial AD pathogenesis, and screen for anti-AD drugs. Although considerable progress has been achieved, a series of challenges must be overcome before stem cell based cell therapies are used clinically for AD patients. This review highlights the recent experimental and preclinical progress of stem-cell therapies for AD, and discusses the translational challenges of their clinical application.
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Affiliation(s)
- Xiaotang Fan
- Department of Histology and Embryology, Third Military Medical University, Chongqing, 400038, P.R. China
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Dai G, Liu X, Zhang Z, Wang X, Li M, Cheng H, Hua R, Shi J, Wang R, Qin C, Gao J, An Y. Comparative analysis of curative effect of CT-guided stem cell transplantation and open surgical transplantation for sequelae of spinal cord injury. J Transl Med 2013; 11:315. [PMID: 24355001 PMCID: PMC3878170 DOI: 10.1186/1479-5876-11-315] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2013] [Accepted: 12/16/2013] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND This study compared the clinical efficacies, advantages and disadvantages of two transplantation approaches for treating spinal cord injury: open surgical exploration combined with local stem cell transplantation (referred to as open surgical transplantation) and local stem cell transplantation by CT-guided puncture (referred to as CT-guided transplantation). METHODS The patients were divided into the following three groups to perform a retrospective controlled study: Group A included nine patients who underwent open surgical transplantation, Group B included nine patients who underwent CT-guided transplantation, and Group C included nine patients who did not receive stem cell transplantation. The Abbreviated Injury Scale (AIS), the American Spinal Injury Association (ASIA) score and the motor evoked potentials (MEP) examination were utilized to compare the differences in the clinical efficacies. The advantages and disadvantages of the two transplantation approaches were also compared, including the surgical risks, the possibility of repeating the operation, the interval between surgery and rehabilitation exercises and the scope of conditions suitable for the operation. RESULTS Whether evaluated by the AIS grading scale, the ASIA score or the MEP results, there were significant differences in the clinical efficacy among the three patient groups. Group B exhibited the best clinical outcome, followed by Group A, and Group C fared the worst. The CT-guided transplantation had the advantages of lower surgical risk, the potential to repeat the operations within a short time-frame and a short interval between surgery and rehabilitation exercise compared with the open surgical transplantation. The conditions that are suitable for CT-guided transplantation versus the conditions suitable for open surgical transplantation are not identical. The application scopes for the two approaches had their respective strengths. CONCLUSIONS CT-guided stem cell transplantation was confirmed as a safe and effective approach to treat sequelae of spinal cord injury with the advantages of simpler operation, minimal invasion, less adverse reaction and quicker recovery. TRIAL REGISTRATION CLINICAL TRIALS REGISTRATION NUMBER ChiCTR-TNRC-12002477.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Yihua An
- Department of Cell Transplantation, General Hospital of Chinese people's Armed Police Forces, Yongding Road, No, 69, Hai Dian District, Beijing 100039, China.
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Transplantation of autologous bone marrow mesenchymal stem cells in the treatment of complete and chronic cervical spinal cord injury. Brain Res 2013; 1533:73-9. [PMID: 23948102 DOI: 10.1016/j.brainres.2013.08.016] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Revised: 07/29/2013] [Accepted: 08/07/2013] [Indexed: 12/15/2022]
Abstract
Neuronal injuries have been a challenging problem for treatment, especially in the case of complete and chronic cervical spinal cord injury (SCI). Recently, particular attention is paid to the potential of stem cell in treating SCI, but there are only few clinical studies and insufficient data. This study explored the efficacy of autologous bone marrow mesenchymal stem cells (BMMSCs) transplantation in the treatment of SCI. Forty patients with complete and chronic cervical SCI were selected and randomly assigned to one of the two experimental groups, treatment group and control group. The treatment group received BMMSCs transplantation to the area surrounding injury, while the control group was not treated with any cell transplantation. Both the transplant recipients and the control group were followed up to 6 months, postoperatively. Preoperative and postoperative neurological functions were evaluated with AIS grading, ASIA score, residual urine volume and neurophysiological examination. Results showed that in the treatment group 10 patients had a significant clinical improvement in terms of motor, light touch, pin prick sensory and residual urine volume, while nine patients showed changes in AIS grade. Neurophysiological examination was consistent with clinical observations. No sign of tumor was evident until 6 months postoperatively. In the control group, no improvement was observed in any of the neurological functions specified above. BMMSCs transplantation improves neurological function in patients with complete and chronic cervical SCI, providing valuable information on applications of BMMSCs for the treatment of SCI.
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45
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Park D, Yang YH, Bae DK, Lee SH, Yang G, Kyung J, Kim D, Choi EK, Lee SW, Kim GH, Hong JT, Choi KC, Lee HJ, Kim SU, Kim YB. Improvement of cognitive function and physical activity of aging mice by human neural stem cells over-expressing choline acetyltransferase. Neurobiol Aging 2013; 34:2639-46. [PMID: 23731954 DOI: 10.1016/j.neurobiolaging.2013.04.026] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2012] [Revised: 04/18/2013] [Accepted: 04/28/2013] [Indexed: 12/16/2022]
Abstract
Aging is characterized by progressive loss of cognitive and memory functions as well as decrease in physical activities. In the present study, a human neural stem cell line (F3 NSC) over-expressing choline acetyltransferase (F3.ChAT), an enzyme responsible for acetylcholine synthesis, was generated and transplanted in the brain of 18-month-old male ICR mice. Four weeks post-transplantation, neurobehavioral functions, expression of ChAT enzyme, production of acetylcholine and neurotrophic factors, and expression of cholinergic nervous system markers in transplanted animals were investigated. F3.ChAT NSCs markedly improved both the cognitive function and physical activity of aging animals, in parallel with the elevation of brain acetylcholine level. Transplanted F3 and F3.ChAT cells were found to differentiate into neurons and astrocytes, and to produce ChAT proteins. Transplantation of the stem cells increased brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), enhanced expression of Trk B, and restored host microtubule-associated protein 2 and cholinergic nervous system. The results demonstrate that human NSCs over-expressing ChAT improve cognitive function and physical activity of aging mice, not only by producing ACh directly but also by restoring cholinergic neuronal integrity, which might be mediated by neurotrophins BDNF and NGF.
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Affiliation(s)
- Dongsun Park
- College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
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Zhang W, Wang PJ, Li MH, Gao XL, Gu GJ, Shao ZH. 1H-MRS can monitor metabolites changes of lateral intraventricular BDNF infusion into a mouse model of Alzheimer's disease in vivo. Neuroscience 2013; 245:40-9. [PMID: 23608100 DOI: 10.1016/j.neuroscience.2013.04.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Revised: 04/02/2013] [Accepted: 04/03/2013] [Indexed: 11/16/2022]
Abstract
Proton magnetic resonance spectroscopy (1H-MRS) can provide noninvasive detection of brain metabolite changes in vivo in Alzheimer's disease (AD). AD is a prevalent neurodegenerative disorder characterized by deposition of β-amyloid peptides (Aβ) in multiple brain regions. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor whose level has been shown to be decreased in AD. BDNF supplementation can offer improvement in AD. However, the means of evaluation are still relatively limited. In the present study, 1H-MRS was applied to evaluate the therapeutic effects of bilateral intraventricular BDNF infusion into APP+PS1 (amyloid precursor protein+presenilin 1) transgenic mice. For comparison to the 1H-MRS changes in the prefrontal cortex, Morris water maze (MWM) test, Fluoro-Jade B staining and immunofluorescence for Aβ, glial fibrillary acidic protein and tropomyosin-related kinase B (TrkB) were also performed. Our results showed that N-acetylaspartate (NAA) levels increased and myo-inositol levels decreased in Tg-BDNF mice compared with Tg-PBS mice. But NAA level in Tg-BDNF mice was still lower than that in wild-type mice at 6weeks after infusion. These changes correlated with increased immunoreactivity of TrkB, reduced compact Aβ peptide and FJB+ neurons in Tg-BDNF mice compared to Tg-PBS mice. However, Tg-BDNF mice did not present obvious changes in behavior in the MWM. Taken together, we suggest that 1H-MRS may be a sensitive means of evaluating metabolic changes in response to therapeutic strategies in AD. Moreover, BDNF, may be a viable means of offering trophic support during disease.
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Affiliation(s)
- W Zhang
- Department of Radiology, Tongji Hospital, Medical School of Tongji University, Shanghai, China
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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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Park D, Yang G, Bae DK, Lee SH, Yang YH, Kyung J, Kim D, Choi EK, Choi KC, Kim SU, Kang SK, Ra JC, Kim YB. Human adipose tissue-derived mesenchymal stem cells improve cognitive function and physical activity in ageing mice. J Neurosci Res 2013; 91:660-70. [PMID: 23404260 DOI: 10.1002/jnr.23182] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2012] [Revised: 10/19/2012] [Accepted: 10/31/2012] [Indexed: 12/12/2022]
Abstract
Brain ageing leads to atrophy and degeneration of the cholinergic nervous system, resulting in profound neurobehavioral and cognitive dysfunction from decreased acetylcholine biosynthesis and reduced secretion of growth and neurotrophic factors. Human adipose tissue-derived mesenchymal stem cells (ADMSCs) were intravenously (1 × 10(6) cells) or intracerebroventricularly (4 × 10(5) cells) transplanted into the brains of 18-month-old mice once or four times at 2-week intervals. Transplantation of ADMSCs improved both locomotor activity and cognitive function in the aged animals, in parallel with recovery of acetylcholine levels in brain tissues. Transplanted cells differentiated into neurons and, in part, into astrocytes and produced choline acetyltransferase proteins. Transplantation of ADMSCs restored microtubule-associated protein 2 in brain tissue and enhanced Trk B expression and the concentrations of brain-derived neurotrophic factor and nerve growth factor. These results indicate that human ADMSCs differentiate into neural cells in the brain microenvironment and can restore physical and cognitive functions of aged mice not only by increasing acetylcholine synthesis but also by restoring neuronal integrity that may be mediated by growth/neurotrophic factors. © 2013 Wiley Periodicals, Inc.
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Affiliation(s)
- Dongsun Park
- College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
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1H-MRS assessment of the therapeutic effect of bilateral intraventricular BDNF infusion into APP/PS1 double transgenic mice. J Mol Neurosci 2013; 50:434-42. [PMID: 23315172 DOI: 10.1007/s12031-013-9951-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Accepted: 01/02/2013] [Indexed: 01/26/2023]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular accumulation of amyloid deposits. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor whose levels have been shown to be decreased in AD brains. BDNF supplementation can offer improvement in the course of AD. However, the means of assessment are still relatively limited. In the present study, 1H-MRS was used to evaluate the therapeutic effects of bilateral intraventricular BDNF infusion into Alzheimer's disease APP/PS1 double transgenic mice. For comparison to the 1H-MRS observations, Fluoro-Jade B staining and immunofluorescence for beta amyloid peptides (Aβ), glial fibrillary acidic protein, and tropomyosin-related kinase B (TrkB) were also performed. Our results showed that N-acetylaspartate (NAA) levels increased and myoinositol levels decreased in the BDNF group compared with the PBS group. However, the BDNF group NAA level was still lower than the control group at 6 weeks after infusion. These changes correlated with increased immunoreactivity for TrkB, decreased compact Aβ peptide containing plaques, and decreased Fluoro-Jade B-positive cells in the BDNF-infused mice compared to vehicle controls. These findings demonstrate that 1H-MRS may be a promising means of evaluating the therapeutic effects of BDNF on AD.
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50
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Karussis D, Petrou P, Kassis I. Clinical experience with stem cells and other cell therapies in neurological diseases. J Neurol Sci 2012; 324:1-9. [PMID: 23107343 DOI: 10.1016/j.jns.2012.09.031] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2012] [Revised: 09/26/2012] [Accepted: 09/27/2012] [Indexed: 12/13/2022]
Abstract
To overcome the limited capacity of the CNS for regeneration, the theoretical alternative would be to use stem cells for more effective management of chronic degenerative and inflammatory neurological conditions, and also of acute neuronal damage from injuries or cerebrovascular diseases. Although the adult brain contains small numbers of stem cells in restricted areas, this intrinsic stem cell repertoire is small and does not measurably contribute to functional recovery. Embryonic cells carrying pluripotent and self-renewal properties represent the stem cell prototype, but there are additional somatic stem cells that may be harvested and expanded from various tissues during adult life. Stem cell transplantation is based on the assumption that such cells may have the potential to regenerate or support the survival of the existing, partially damaged cells. This review summarizes the state-of-the-art and the clinical worldwide experience with the use of various types of stem cells in neurological diseases.
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Affiliation(s)
- Dimitrios Karussis
- Department of Neurology, MS Center and Laboratory of Neuroimmunology, Agnes-Ginges Center for Neurogenetics, Hadassah University Hospital, Ein Kerem, Jerusalem, Israel.
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