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Calvo B, Schembri-Wismayer P, Durán-Alonso MB. Age-Related Neurodegenerative Diseases: A Stem Cell's Perspective. Cells 2025; 14:347. [PMID: 40072076 PMCID: PMC11898746 DOI: 10.3390/cells14050347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 02/22/2025] [Accepted: 02/24/2025] [Indexed: 03/15/2025] Open
Abstract
Neurodegenerative diseases encompass a number of very heterogeneous disorders, primarily characterized by neuronal loss and a concomitant decline in neurological function. Examples of this type of clinical condition are Alzheimer's Disease, Parkinson's Disease, Huntington's Disease and Amyotrophic Lateral Sclerosis. Age has been identified as a major risk in the etiology of these disorders, which explains their increased incidence in developed countries. Unfortunately, despite continued and intensive efforts, no cure has yet been found for any of these diseases; reliable markers that allow for an early diagnosis of the disease and the identification of key molecular events leading to disease onset and progression are lacking. Altered adult neurogenesis appears to precede the appearance of severe symptoms. Given the scarcity of human samples and the considerable differences with model species, increasingly complex human stem-cell-based models are being developed. These are shedding light on the molecular alterations that contribute to disease development, facilitating the identification of new clinical targets and providing a screening platform for the testing of candidate drugs. Moreover, the secretome and other promising features of these cell types are being explored, to use them as replacement cells of high plasticity or as co-adjuvant therapy in combinatorial treatments.
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Affiliation(s)
- Belén Calvo
- Faculty of Health Sciences, Catholic University of Ávila, 05005 Ávila, Spain;
| | - Pierre Schembri-Wismayer
- Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, MSD 2080 Msida, Malta;
| | - María Beatriz Durán-Alonso
- Department of Biochemistry and Molecular Biology and Physiology, Faculty of Medicine, University of Valladolid, 47005 Valladolid, Spain
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Chang Z, Wang QY, Li LH, Jiang B, Zhou XM, Zhu H, Sun YP, Pan X, Tu XX, Wang W, Liu CY, Kuang HX. Potential Plausible Role of Stem Cell for Treating Depressive Disorder: a Retrospective Review. Mol Neurobiol 2024; 61:4454-4472. [PMID: 38097915 DOI: 10.1007/s12035-023-03843-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 11/29/2023] [Indexed: 07/11/2024]
Abstract
Depression poses a significant threat to global physical and mental health, impacting around 3.8% of the population with a rising incidence. Current treatment options primarily involve medication and psychological support, yet their effectiveness remains limited, contributing to high relapse rates. There is an urgent need for innovative and more efficacious treatment modalities. Stem cell therapy, a promising avenue in regenerative medicine for a spectrum of neurodegenerative conditions, has recently garnered attention for its potential application in depression. While much of this work remains preclinical, it has demonstrated considerable promise. Identified mechanisms underlying the antidepressant effects of stem cell therapy encompass the stimulation of neurotrophic factors, immune function modulation, and augmented monoamine levels. Nonetheless, these pathways and other undiscovered mechanisms necessitate further investigation. Depression fundamentally manifests as a neurodegenerative disorder. Given stem cell therapy's success in addressing a range of neurodegenerative pathologies, it opens the door to explore its application in depression treatment. This exploration may include repairing damaged nerves directly or indirectly and inhibiting neurotoxicity. Nevertheless, significant challenges must be overcome before stem cell therapies can be applied clinically. Successful resolution of these issues will ultimately determine the feasibility of incorporating stem cell therapies into the clinical landscape. This narrative review provides insights into the progress of research, potential avenues for exploration, and the prevailing challenges in the implementation of stem cell therapy for treatment of depression.
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Affiliation(s)
- Zhuo Chang
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Qing-Yi Wang
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Lu-Hao Li
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Bei Jiang
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Xue-Ming Zhou
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Hui Zhu
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Yan-Ping Sun
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Xue Pan
- Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xu-Xu Tu
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China
| | - Wei Wang
- First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
| | - Chen-Yue Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Hai-Xue Kuang
- Heilongjiang University of Chinese Medicine, Heping Road 26, Harbin, Heilongjiang, 150040, China.
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Song XY, Fan CX, Atta-ur-Rahman FRS, Choudhary MI, Wang XP. Neuro-regeneration or Repair: Cell Therapy of Neurological Disorders as A Way Forward. Curr Neuropharmacol 2024; 22:2272-2283. [PMID: 38939990 PMCID: PMC11451317 DOI: 10.2174/1570159x22666240509092903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 04/28/2024] [Accepted: 05/02/2024] [Indexed: 06/29/2024] Open
Abstract
The human central nervous system (CNS) has a limited capacity for regeneration and repair, as many other organs do. Partly as a result, neurological diseases are the leading cause of medical burden globally. Most neurological disorders cannot be cured, and primary treatments focus on managing their symptoms and slowing down their progression. Cell therapy for neurological disorders offers several therapeutic potentials and provides hope for many patients. Here we provide a general overview of cell therapy in neurological disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Wilson's disease (WD), stroke and traumatic brain injury (TBI), involving many forms of stem cells, including embryonic stem cells and induced pluripotent stem cells. We also address the current concerns and perspectives for the future. Most studies for cell therapy in neurological diseases are in the pre-clinical stage, and there is still a great need for further research to translate neural replacement and regenerative therapies into clinical settings.
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Affiliation(s)
- Xiao-Yan Song
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Cun-Xiu Fan
- Department of Neurology, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Atta-ur-Rahman FRS
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Muhammad Iqbal Choudhary
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Xiao-Ping Wang
- Department of Neurology, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
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Ancheta LR, Shramm PA, Bouajram R, Higgins D, Lappi DA. Streptavidin-Saporin: Converting Biotinylated Materials into Targeted Toxins. Toxins (Basel) 2023; 15:toxins15030181. [PMID: 36977072 PMCID: PMC10059012 DOI: 10.3390/toxins15030181] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/12/2023] [Accepted: 02/19/2023] [Indexed: 03/02/2023] Open
Abstract
Streptavidin-Saporin can be considered a type of ‘secondary’ targeted toxin. The scientific community has taken advantage of this conjugate in clever and fruitful ways using many kinds of biotinylated targeting agents to send saporin into a cell selected for elimination. Saporin is a ribosome-inactivating protein that causes inhibition of protein synthesis and cell death when delivered inside a cell. Streptavidin-Saporin, mixed with biotinylated molecules to cell surface markers, results in powerful conjugates that are used both in vitro and in vivo for behavior and disease research. Streptavidin-Saporin harnesses the ‘Molecular Surgery’ capability of saporin, creating a modular arsenal of targeted toxins used in applications ranging from the screening of potential therapeutics to behavioral studies and animal models. The reagent has become a well-published and validated resource in academia and industry. The ease of use and diverse functionality of Streptavidin-Saporin continues to have a significant impact on the life science industry.
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Zhou Z, Shi B, Xu Y, Zhang J, liu X, Zhou X, Feng B, Ma J, Cui H. Neural stem/progenitor cell therapy for Alzheimer disease in preclinical rodent models: a systematic review and meta-analysis. Stem Cell Res Ther 2023; 14:3. [PMID: 36600321 PMCID: PMC9814315 DOI: 10.1186/s13287-022-03231-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 12/25/2022] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is a common progressive neurodegenerative disease characterized by memory impairments, and there is no effective therapy. Neural stem/progenitor cell (NSPC) has emerged as potential novel therapy for AD, and we aim to explore whether neural stem/progenitor cell therapy was effective for rodent models of AD. METHODS We searched PubMed, Embase, Cochrane Library and Web of Science up to December 6, 2022. The outcomes included cognitive function, pathological features and BDNF. The GetData Graph Digitizer software (version 2.26) was applied to extract numerical values, and RevMan 5.3 and Stata 16 were used to analyze data. The SYRCLE risk of bias tool was used to assess study quality. RESULTS We evaluated 22 mice studies and 8 rat studies. Compared to control groups, cognitive function of NSPC groups of both mice studies (SMD = - 1.96, 95% CI - 2.47 to - 1.45, I2 = 75%, P < 0.00001) and rat studies (SMD = - 1.35, 95% CI - 2.11 to - 0.59, I2 = 77%, P = 0.0005) was apparently improved. In mice studies, NSPC group has lower Aβ deposition (SMD = - 0.96, 95% CI - 1.40 to - 0.52, P < 0.0001) and p-tau level (SMD = - 4.94, 95% CI - 7.29 to - 2.95, P < 0.0001), higher synaptic density (SMD = 2.02, 95% CI 0.50-3.55, P = 0.009) and BDNF (SMD = 1.69, 95% CI 0.61-2.77, P = 0.002). Combined with nanoformulation (SMD = - 1.29, 95% CI - 2.26 to - 0.32, I2 = 65%, P = 0.009) and genetically modified (SMD = - 1.29, 95% CI - 1.92 to - 0.66, I2 = 60%, P < 0.0001) could improve the effect of NSPC. In addition, both xenogeneic and allogeneic transplant of NSPC could reverse the cognitive impairment of AD animal models. CONCLUSIONS Our results suggested that NSPC therapy could improve the cognitive function and slow down the progression of AD. Due to the limitations of models, more animal trials and clinical trials are needed.
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Affiliation(s)
- Zijing Zhou
- grid.256883.20000 0004 1760 8442Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, 050017 Hebei Province China ,grid.256883.20000 0004 1760 8442Hebei Research Center for Stem Cell Medical Translational Engineering, Hebei Medical University, Shijiazhuang, 050017 Hebei Province China
| | - Ben Shi
- grid.256883.20000 0004 1760 8442Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, 050017 Hebei Province China ,grid.256883.20000 0004 1760 8442Hebei Research Center for Stem Cell Medical Translational Engineering, Hebei Medical University, Shijiazhuang, 050017 Hebei Province China
| | - Yaxing Xu
- grid.256883.20000 0004 1760 8442Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, 050017 Hebei Province China ,grid.256883.20000 0004 1760 8442Hebei Research Center for Stem Cell Medical Translational Engineering, Hebei Medical University, Shijiazhuang, 050017 Hebei Province China
| | - Jinyu Zhang
- grid.256883.20000 0004 1760 8442Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, 050017 Hebei Province China ,grid.256883.20000 0004 1760 8442Hebei Research Center for Stem Cell Medical Translational Engineering, Hebei Medical University, Shijiazhuang, 050017 Hebei Province China
| | - Xin liu
- grid.256883.20000 0004 1760 8442Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, 050017 Hebei Province China ,grid.256883.20000 0004 1760 8442Hebei Research Center for Stem Cell Medical Translational Engineering, Hebei Medical University, Shijiazhuang, 050017 Hebei Province China
| | - Xinghong Zhou
- grid.256883.20000 0004 1760 8442Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, 050017 Hebei Province China ,grid.256883.20000 0004 1760 8442Hebei Research Center for Stem Cell Medical Translational Engineering, Hebei Medical University, Shijiazhuang, 050017 Hebei Province China
| | - Baofeng Feng
- grid.256883.20000 0004 1760 8442Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, 050017 Hebei Province China ,grid.256883.20000 0004 1760 8442Hebei Research Center for Stem Cell Medical Translational Engineering, Hebei Medical University, Shijiazhuang, 050017 Hebei Province China ,grid.256883.20000 0004 1760 8442Human Anatomy Department, Hebei Medical University, Shijiazhuang, 050017 Hebei Province China
| | - Jun Ma
- Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, 050017, Hebei Province, China. .,Hebei Research Center for Stem Cell Medical Translational Engineering, Hebei Medical University, Shijiazhuang, 050017, Hebei Province, China. .,Human Anatomy Department, Hebei Medical University, Shijiazhuang, 050017, Hebei Province, China.
| | - Huixian Cui
- grid.256883.20000 0004 1760 8442Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, 050017 Hebei Province China ,grid.256883.20000 0004 1760 8442Hebei Research Center for Stem Cell Medical Translational Engineering, Hebei Medical University, Shijiazhuang, 050017 Hebei Province China ,grid.256883.20000 0004 1760 8442Human Anatomy Department, Hebei Medical University, Shijiazhuang, 050017 Hebei Province China
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Zayed MA, Sultan S, Alsaab HO, Yousof SM, Alrefaei GI, Alsubhi NH, Alkarim S, Al Ghamdi KS, Bagabir SA, Jana A, Alghamdi BS, Atta HM, Ashraf GM. Stem-Cell-Based Therapy: The Celestial Weapon against Neurological Disorders. Cells 2022; 11:3476. [PMID: 36359871 PMCID: PMC9655836 DOI: 10.3390/cells11213476] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 10/15/2022] [Accepted: 10/24/2022] [Indexed: 09/01/2023] Open
Abstract
Stem cells are a versatile source for cell therapy. Their use is particularly significant for the treatment of neurological disorders for which no definitive conventional medical treatment is available. Neurological disorders are of diverse etiology and pathogenesis. Alzheimer's disease (AD) is caused by abnormal protein deposits, leading to progressive dementia. Parkinson's disease (PD) is due to the specific degeneration of the dopaminergic neurons causing motor and sensory impairment. Huntington's disease (HD) includes a transmittable gene mutation, and any treatment should involve gene modulation of the transplanted cells. Multiple sclerosis (MS) is an autoimmune disorder affecting multiple neurons sporadically but induces progressive neuronal dysfunction. Amyotrophic lateral sclerosis (ALS) impacts upper and lower motor neurons, leading to progressive muscle degeneration. This shows the need to try to tailor different types of cells to repair the specific defect characteristic of each disease. In recent years, several types of stem cells were used in different animal models, including transgenic animals of various neurologic disorders. Based on some of the successful animal studies, some clinical trials were designed and approved. Some studies were successful, others were terminated and, still, a few are ongoing. In this manuscript, we aim to review the current information on both the experimental and clinical trials of stem cell therapy in neurological disorders of various disease mechanisms. The different types of cells used, their mode of transplantation and the molecular and physiologic effects are discussed. Recommendations for future use and hopes are highlighted.
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Affiliation(s)
- Mohamed A. Zayed
- Physiology Department, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Physiology Department, Faculty of Medicine, Menoufia University, Menoufia 32511, Egypt
| | - Samar Sultan
- Medical Laboratory Technology Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Regenerative Medicine Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Hashem O. Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taif University, Taif 21944, Saudi Arabia
| | - Shimaa Mohammad Yousof
- Physiology Department, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Medical Physiology Department, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Ghadeer I. Alrefaei
- Department of Biology, College of Science, University of Jeddah, Jeddah 21589, Saudi Arabia
| | - Nouf H. Alsubhi
- Department of Biological Sciences, College of Science & Arts, King Abdulaziz University, Rabigh 21911, Saudi Arabia
| | - Saleh Alkarim
- Embryonic and Cancer Stem Cell Research Group, King Fahad Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Biology Department, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Embryonic Stem Cells Research Unit, Biology Department, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Kholoud S. Al Ghamdi
- Department of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
| | - Sali Abubaker Bagabir
- Genetic Unit, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Jazan University, Jazan 45142, Saudi Arabia
| | - Ankit Jana
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT) Deemed to be University, Campus-11, Patia, Bhubaneswar 751024, Odisha, India
| | - Badrah S. Alghamdi
- Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Hazem M. Atta
- Clinical Biochemistry Department, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo 11562, Egypt
| | - Ghulam Md Ashraf
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, University City, Sharjah 27272, United Arab Emirates
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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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Advances in polysaccharides of natural source of the anti-Alzheimer's disease effect and mechanism. Carbohydr Polym 2022; 296:119961. [DOI: 10.1016/j.carbpol.2022.119961] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/19/2022] [Accepted: 08/03/2022] [Indexed: 12/13/2022]
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Roberton VH, Phillips JB. Considerations for the use of biomaterials to support cell therapy in neurodegenerative disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2022; 166:191-205. [DOI: 10.1016/bs.irn.2022.09.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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10
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Soleimani Asl S, Amiri I, Samzadeh-Kermani A, Abbasalipourkabir R, Gholamigeravand B, Shahidi S. Chitosan-coated Selenium nanoparticles enhance the efficiency of stem cells in the neuroprotection of streptozotocin-induced neurotoxicity in male rats. Int J Biochem Cell Biol 2021; 141:106089. [PMID: 34601090 DOI: 10.1016/j.biocel.2021.106089] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 09/23/2021] [Accepted: 09/25/2021] [Indexed: 12/27/2022]
Abstract
Alzheimer's disease (AD) is one of the common neurodegenerative diseases characterized by memory impairment. The protective effects of stem cell-based therapy have been reported in AD. In this study, it was assumed that Chitosan-coated Selenium nanoparticles (ChSeNPs) increase the efficiency of stem cells in the attenuation of neurotoxicity in the rat AD model. The AD model was induced using Streptozotocin (STZ) and treated by the adipose-derived mesenchymal stem cells (AMSCs) and SeNPs/ChSeNPs (0.4 mg/kg). Passive avoidance learning and recognition memory were assessed using shuttle box and novel object recognition tasks. The amyloid-beta deposition, the injected cells' homing and survival, antioxidant capacity, and BDNF concentration were evaluated using the histological, biochemical, and ELISA methods. The results showed that the combined administration of ChSeNPs and AMSCs is more effective in increasing the step-through latency and discrimination index than administering SeNPs and stem cells. Combined therapy caused a significant increase in antioxidant capacity that ChSeNPs was more effective than SeNPs, while AMSCs beside SeNPs had a greater effect on BDNF levels compared to conventional treatment of nanoparticles or AMSCs alone. Ultimately, the homing and survival of the transplanted AMSCs were greater in the group that received both stem cells and ChSeNPs. Taken together, it seems that the administration of ChSeNPs enhances the efficiency of transplanted stem cells in decreasing the neurotoxicity induced by STZ through an increase in the antioxidant capacity.
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Affiliation(s)
- Sara Soleimani Asl
- Endometrium and Endometriosis Research Centre, Hamadan University of Medical Sciences, Hamadan, Iran; Department of Anatomy, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Iraj Amiri
- Endometrium and Endometriosis Research Centre, Hamadan University of Medical Sciences, Hamadan, Iran; Department of Anatomy, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | | | - Roghayeh Abbasalipourkabir
- Department of Clinical Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Bahareh Gholamigeravand
- Department of Anatomy, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Siamak Shahidi
- Department of Physiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
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11
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Novel Balance Mechanism Participates in Stem Cell Therapy to Alleviate Neuropathology and Cognitive Impairment in Animal Models with Alzheimer's Disease. Cells 2021; 10:cells10102757. [PMID: 34685737 PMCID: PMC8534506 DOI: 10.3390/cells10102757] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 08/23/2021] [Accepted: 08/27/2021] [Indexed: 12/12/2022] Open
Abstract
Stem cell therapy improves memory loss and cognitive deficits in animal models with Alzheimer's disease. The underlying mechanism remains to be determined, but it may involve the interaction of stem cells with hippocampal cells. The transplantation of stem cells alters the pathological state and establishes a novel balance based on multiple signaling pathways. The new balance mechanism is regulated by various autocrine and paracrine cytokines, including signal molecules that target (a) cell growth and death. Stem cell treatment stimulates neurogenesis and inhibits apoptosis, which is regulated by the crosstalk between apoptosis and autophagy-(b) Aβ and tau pathology. Aberrant Aβ plaques and neurofibrillary tau tangles are mitigated subsequent to stem cell intervention-(c) inflammation. Neuroinflammation in the lesion is relieved, which may be related to the microglial M1/M2 polarization-(d) immunoregulation. The transplanted stem cells modulate immune cells and shape the pathophysiological roles of immune-related genes such as TREM2, CR1, and CD33-(e) synaptogenesis. The functional reconstruction of synaptic connections can be promoted by stem cell therapy through multi-level signaling, such as autophagy, microglial activity, and remyelination. The regulation of new balance mechanism provides perspective and challenge for the treatment of Alzheimer's disease.
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12
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Engrafted stem cell therapy for Alzheimer's disease: A promising treatment strategy with clinical outcome. J Control Release 2021; 338:837-857. [PMID: 34509587 DOI: 10.1016/j.jconrel.2021.09.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 09/06/2021] [Accepted: 09/07/2021] [Indexed: 12/27/2022]
Abstract
To date, although the microscopic alterations present in Alzheimer's disease (AD) have been well known for over a century only a handful of symptomatic treatments have been developed which are a far cry from a full cure providing volatile benefits. In this context, the intervention of stem cell therapy (SCT) has been proposed as an auxiliary treatment for AD as suggested by the rising number of pre-clinical studies that stem cell engraftment could provide an exciting future treatment regimen against neurodegeneration. Although, most of the primary enthusiasm about this approach was based on replacing deteriorating neurons, the latest studies have implied that the positive modulations fostered by stem cells are fuelled by bystander effects. Present review provides a detailed update on stem cell therapy for AD along with meticulous discussion regarding challenges in developing different stem cells from an aspect of experiment to clinical research and their potential in the milieu of AD hallmarks. Specifically, we focus and provide in depth view on recent advancements in the discipline of SCT aiming to repopulate or regenerate the degenerating neuronal circuitry in AD using stem-cell-on-a-chip and 3D bioprinting techniques. The focus is specifically on the successful restoration of cognitive functions upon engraftment of stem cells on in vivo models for the benefit of the current researchers and their understanding about the status of SCT in AD and finally summarizing on what future holds for SCT in the treatment of AD.
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Qin C, Li Y, Wang K. Functional Mechanism of Bone Marrow-Derived Mesenchymal Stem Cells in the Treatment of Animal Models with Alzheimer's Disease: Inhibition of Neuroinflammation. J Inflamm Res 2021; 14:4761-4775. [PMID: 34566422 PMCID: PMC8456430 DOI: 10.2147/jir.s327538] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 08/18/2021] [Indexed: 12/27/2022] Open
Abstract
The transplantation of bone marrow-derived mesenchymal stem cells (BMMSCs) alleviates neuropathology and improves cognitive deficits in animal models with Alzheimer’s disease. However, the underlying mechanisms remain to be determined. Available data demonstrate transplanted BMMSCs can inhibit neuroinflammation, which may be related to microglial M1/M2 polarization and is regulated by the secretion of autocrine and paracrine cytokines. BMMSCs also mitigate Aβ plaques and Tau tangles in the brain, which may be associated with the recruitment of peripheral blood monocytes and the subsequent comprehensive effects. The therapeutic effects of stem cells involve potential mechanisms such as immunomodulation, apoptosis, and proliferation. BMMSC-mediated functional reconstruction through dynamic remodeling develops a novel balance. Herein, present review recapitulates the molecular basis of BMMSC-assisted biological processes and summarizes the possible mechanisms related to the interaction between BMMSCs and microglia. The transplanted BMMSCs can suppress neuroinflammation that plays a key role in the pathogenesis of Alzheimer’s disease.
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Affiliation(s)
- Chuan Qin
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, Beijing, 100021, People's Republic of China
| | - Yongning Li
- Department of International Medical Service & Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Kewei Wang
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, Beijing, 100021, People's Republic of China
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14
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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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15
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Ahani-Nahayati M, Shariati A, Mahmoodi M, Olegovna Zekiy A, Javidi K, Shamlou S, Mousakhani A, Zamani M, Hassanzadeh A. Stem cell in neurodegenerative disorders; an emerging strategy. Int J Dev Neurosci 2021; 81:291-311. [PMID: 33650716 DOI: 10.1002/jdn.10101] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/13/2021] [Accepted: 02/24/2021] [Indexed: 01/28/2023] Open
Abstract
Neurodegenerative disorders are a diversity of disorders, surrounding Alzheimer's (AD), Parkinson's (PD), Huntington's diseases (HD), and amyotrophic lateral sclerosis (ALS) accompanied by some other less common diseases generally characterized by either developed deterioration of central or peripheral nervous system structurally or functionally. Today, with the viewpoint of an increasingly aging society, the number of patients with neurodegenerative diseases and sociomedical burdens will spread intensely. During the last decade, stem cell technology has attracted great attention for treating neurodegenerative diseases worldwide because of its unique attributes. As acknowledged, there are several categories of stem cells being able to proliferate and differentiate into various cellular lineages, highlighting their significance in the context of regenerative medicine. In preclinical models, stem cell therapy using mesenchymal stem/stromal cells (MSCs), hematopoietic stem cells (HSCs), and neural progenitor or stem cells (NPCs or NSCs) along with pluripotent stem cells (PSCs)-derived neuronal cells could elicit desired therapeutic effects, enabling functional deficit rescue partially. Regardless of the noteworthy progress in our scientific awareness and understanding of stem cell biology, there still exist various challenges to defeat. In the present review, we provide a summary of the therapeutic potential of stem cells and discuss the current status and prospect of stem cell strategy in neurodegenerative diseases, in particular, AD, PD, ALS, and HD.
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Affiliation(s)
- Milad Ahani-Nahayati
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Ali Shariati
- Stem Cell Research Center, Tehran University of Medical Science, Tehran, Iran
| | - Mahnaz Mahmoodi
- Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Angelina Olegovna Zekiy
- Department of Prosthetic Dentistry, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Kamran Javidi
- School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran.,Immunology Research Center (IRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Somayeh Shamlou
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Akbar Mousakhani
- Department of Plant Sciences, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Majid Zamani
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Ali Hassanzadeh
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Neurosciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
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16
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Adipose Tissue-Derived Stem Cells Alleviate Cold Allodynia in a Rat Spinal Nerve Ligation Model of Neuropathic Pain. Stem Cells Int 2020; 2020:8845262. [PMID: 33101421 PMCID: PMC7576351 DOI: 10.1155/2020/8845262] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 09/16/2020] [Accepted: 09/24/2020] [Indexed: 01/22/2023] Open
Abstract
Neuropathic pain caused by lesions or nervous system dysfunction is a neuroimmune disease with limited therapeutic options. Adipose tissue-derived stem cells (ASCs) are multipotent mesenchymal stem cells with potent immunosuppressive properties, and their use as novel cell-based therapeutics have been proposed in many immune diseases. However, the analgesic effect and efficacy of ASCs to treat neuropathic pain remain unclear. This study, thus, investigated whether ASCs or ASC-derived culture medium can relieve neuropathic pain behaviors (i.e., mechanical and cold allodynia) in a rat model with L5 spinal nerve ligation. Intrathecal injection of ASCs significantly reduced cold allodynia, but not mechanical allodynia. Importantly, cold allodynia was completely reversed in rats with repeated injections of ASCs. In contrast, intrathecal injection of ASC-derived culture medium or retro-orbital injection of ASCs had no effect on neuropathic pain behaviors. These results suggest a novel and alternative therapeutic application of ASCs to target specific neuropathic pain behaviors.
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17
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Wu S, Fu J, Liu D, Chen D, Hu H. The Blood-Brain Barrier Cell-Targeted Gene Delivery System to Enhance Nerve Growth Factor Protein Secretion in the Brain. ACS Biomater Sci Eng 2020; 6:6207-6216. [PMID: 33449648 DOI: 10.1021/acsbiomaterials.0c01113] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The enhanced permeability efficiencies still remain a big challenge in crossing the blood-brain barrier (BBB). Herein, a BBB-targeting delivery system based on transferrin (Tf)-poly(ethylene glycol) (PEG) PEGylated-cationic liposome was prepared for delivering the protamine labeled nerve growth factor (NGF) gene. The nanoparticle (TLDP) could preferentially accumulate into the BBB by receptor-mediated transcytosis via the Tf receptor present on cerebral endothelial cells. The polyplex showed good encapsulation of the NGF gene as well as triggered corresponding protein release in the BBB. Surface modification of liposomes with PEG imparts a steric barrier to the NPs that decreases their recognition and clearance by the reticuloendothelial system for increasing the circulation time, and cationic liposomes with protamine are indicated with nuclear localization function to improve the efficiency of nucleus localization and gene expression. The polyplex at a DOTAP/DNA ratio of 3 showed an appropriate diameter, desired serum stability, and much higher encapsulation efficiency. The polyplex had no cytotoxicity against cells. The cell uptake of the TLDP was stronger than other groups without transferrin, which suggested that the TLDP could successfully deliver the NGF gene to the BBB cell and enhanced the expression and secretion of the NGF protein in the brain. In vivo imaging further verified that the TLDP exhibited a higher brain distribution than other groups. Consequently, these findings showed that BBB cells as the "transit station" is a promising method to overcome the BBB and increase the concentration of drug in the brain.
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Affiliation(s)
- Shiyang Wu
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Jia Fu
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Dan Liu
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Dawei Chen
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Haiyang Hu
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
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18
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Carvajal-Flores FN, Díaz A, Flores-Gómez GD, de la Cruz F, Flores G. Phenylbutyrate ameliorates prefrontal cortex, hippocampus, and nucleus accumbens neural atrophy as well as synaptophysin and GFAP stress in aging mice. Synapse 2020; 74:e22177. [PMID: 32531811 DOI: 10.1002/syn.22177] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 06/07/2020] [Accepted: 06/08/2020] [Indexed: 12/26/2022]
Abstract
Recent reports on brain aging suggest that oxidative stress and inflammatory processes contribute to aging. Interestingly, sodium phenylbutyrate (PBA) is an inhibitor of histone deacetylase, which has anti-inflammatory properties. Several reports have suggested the effect of PBA on learning and memory processes, however there are no studies of the effect of this inhibitor of histone deacetylase on aging. Consequently, in the present study, the effect of PBA was studied in 18-month-old mice. The animals were administered PBA for 2 months after locomotor activity treatment and Morris water maze tests were performed. The Golgi-Cox staining technique and immunohistochemistry for glial fibrillary acidic protein (GFAP) and synaptophysin were performed for the morphological procedures. The administration of PBA improves learning and memory according to the Morris water maze test compared to vehicle-treated animals, which had unchanged locomotor activity. Using Golgi-Cox staining, dendritic length and the number of dendritic spines were measured in limbic regions, such as the nucleus accumbens (NAcc), prefrontal cortex (PFC) layer 3, and the CA1 of the dorsal hippocampus. In addition, PBA increased the number of dendritic spines in the PFC, NAcc, and CA1 subregions of the hippocampus with an increase in dendritic length only in the CA1 region. Moreover, PBA reduced the levels of the GFAP and increased the levels of synaptophysin in the studied regions. Thus, PBA can be a useful pharmacological tool to prevent or delay synaptic plasticity damage and cognitive impairment caused by age.
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Affiliation(s)
| | - Alfonso Díaz
- Departamento de Farmacia, Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla (BUAP), Puebla, Mexico
| | - Gabriel D Flores-Gómez
- Departamento de Ciencias de la Salud, Licenciatura en Medicina, Universidad de las Américas Puebla, Cholula, Mexico
| | - Fidel de la Cruz
- Departamento de Fisiología, Escuela Nacional de Ciencias Biológica, Instituto Politécnico Nacional, Ciudad de Mexico, Mexico
| | - Gonzalo Flores
- Laboratorio de Neuropsiquiatría, Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla (BUAP), Puebla, Mexico
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19
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Ding XW, Li R, Geetha T, Tao YX, Babu JR. Nerve growth factor in metabolic complications and Alzheimer's disease: Physiology and therapeutic potential. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165858. [PMID: 32531260 DOI: 10.1016/j.bbadis.2020.165858] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 05/11/2020] [Accepted: 06/02/2020] [Indexed: 02/07/2023]
Abstract
As the population ages, obesity and metabolic complications as well as neurological disorders are becoming more prevalent, with huge economic burdens on both societies and families. New therapeutics are urgently needed. Nerve growth factor (NGF), first discovered in 1950s, is a neurotrophic factor involved in regulating cell proliferation, growth, survival, and apoptosis in both central and peripheral nervous systems. NGF and its precursor, proNGF, bind to TrkA and p75 receptors and initiate protein phosphorylation cascades, resulting in changes of cellular functions, and are associated with obesity, diabetes and its complications, and Alzheimer's disease. In this article, we summarize changes in NGF levels in metabolic and neuronal disorders, the signal transduction initiated by NGF and proNGF, the physiological and pathophysiological relevance, and therapeutic potential in treating chronic metabolic diseases and cognitive decline.
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Affiliation(s)
- Xiao-Wen Ding
- Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL 36849, USA
| | - Rongzi Li
- Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL 36849, USA
| | - Thangiah Geetha
- Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL 36849, USA; Boshell Metabolic Diseases and Diabetes Program, Auburn University, Auburn, AL 36849, USA
| | - Ya-Xiong Tao
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
| | - Jeganathan Ramesh Babu
- Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL 36849, USA; Boshell Metabolic Diseases and Diabetes Program, Auburn University, Auburn, AL 36849, USA.
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20
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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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21
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Zhang FQ, Jiang JL, Zhang JT, Niu H, Fu XQ, Zeng LL. Current status and future prospects of stem cell therapy in Alzheimer's disease. Neural Regen Res 2020; 15:242-250. [PMID: 31552889 PMCID: PMC6905342 DOI: 10.4103/1673-5374.265544] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Accepted: 03/18/2019] [Indexed: 12/15/2022] Open
Abstract
Alzheimer's disease is a common progressive neurodegenerative disorder, pathologically characterized by the presence of β-amyloid plaques and neurofibrillary tangles. Current treatment approaches using drugs only alleviate the symptoms without curing the disease, which is a serious issue and influences the quality of life of the patients and their caregivers. In recent years, stem cell technology has provided new insights into the treatment of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Currently, the main sources of stem cells include neural stem cells, embryonic stem cells, mesenchymal stem cells, and induced pluripotent stem cells. In this review, we discuss the pathophysiology and general treatment of Alzheimer's disease, and the current state of stem cell transplantation in the treatment of Alzheimer's disease. We also assess future challenges in the clinical application and drug development of stem cell transplantation as a treatment for Alzheimer's disease.
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Affiliation(s)
- Fu-Qiang Zhang
- Scientific Research Centre of China-Japan Union Hospital, Jilin University, Changchun, Jilin Province, China
| | - Jin-Lan Jiang
- Scientific Research Centre of China-Japan Union Hospital, Jilin University, Changchun, Jilin Province, China
| | - Jing-Tian Zhang
- School of Life Sciences, Jilin University, Changchun, Jilin Province, China
| | - Han Niu
- School of Life Sciences, Jilin University, Changchun, Jilin Province, China
| | - Xue-Qi Fu
- School of Life Sciences, Jilin University, Changchun, Jilin Province, China
| | - Lin-Lin Zeng
- School of Life Sciences, Jilin University, Changchun, Jilin Province, China
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22
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Zhu Q, Zhang N, Hu N, Jiang R, Lu H, Xuan A, Long D, Chen Y. Neural stem cell transplantation improves learning and memory by protecting cholinergic neurons and restoring synaptic impairment in an amyloid precursor protein/presenilin 1 transgenic mouse model of Alzheimer's disease. Mol Med Rep 2020; 21:1172-1180. [PMID: 31922229 PMCID: PMC7002968 DOI: 10.3892/mmr.2020.10918] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 09/04/2019] [Indexed: 02/06/2023] Open
Abstract
Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder. It is featured by the progressive accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles. This can eventually lead to a decrease of cholinergic neurons in the basal forebrain. Stem cell transplantation is an effective treatment for neurodegenerative diseases. Previous studies have revealed that different types of stem or progenitor cells can mitigate cognition impairment in different Alzheimer's disease mouse models. However, understanding the underlying mechanisms of neural stem cell (NSC) therapies for AD requires further investigation. In the present study, the effects and the underlying mechanisms of the treatment of AD by NSCs are reported. The latter were labelled with the enhanced green fluorescent protein (EGFP) prior to implantation into the bilateral hippocampus of an amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (Tg) mouse model of AD. It was observed that the number of basal forebrain cholinergic neurons was restored and the expression of choline acetyltransferase (ChAT) protein was increased. Moreover, the levels of synaptophysin (SYP), postsynaptic density protein 95 (PSD-95) and microtubule-associated protein (MAP-2) were significantly increased in the hippocampus of NSC-treated AD mice. Notably, spatial learning and memory were both improved after transplantation of NSCs. In conclusion, the present study revealed that NSC transplantation improved learning and memory functions in an AD mouse model. This treatment allowed repairing of basal forebrain cholinergic neurons and increased the expression of the cognition-related proteins SYP, PSD-95 and MAP-2 in the hippocampus.
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Affiliation(s)
- Qing Zhu
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, P.R. China
| | - Nianping Zhang
- The Teaching and Research Section of Surgery, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
| | - Nan Hu
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, P.R. China
| | - Rongrong Jiang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, P.R. China
| | - Huicong Lu
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, P.R. China
| | - Aiguo Xuan
- Department of Human Anatomy, Guangzhou Medical University, Guangzhou, Guangdong 511436, P.R. China
| | - Dahong Long
- Department of Human Anatomy, Guangzhou Medical University, Guangzhou, Guangdong 511436, P.R. China
| | - Yan Chen
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, P.R. China
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23
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Khacho M, Harris R, Slack RS. Mitochondria as central regulators of neural stem cell fate and cognitive function. Nat Rev Neurosci 2019; 20:34-48. [PMID: 30464208 DOI: 10.1038/s41583-018-0091-3] [Citation(s) in RCA: 259] [Impact Index Per Article: 43.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Emerging evidence now indicates that mitochondria are central regulators of neural stem cell (NSC) fate decisions and are crucial for both neurodevelopment and adult neurogenesis, which in turn contribute to cognitive processes in the mature brain. Inherited mutations and accumulated damage to mitochondria over the course of ageing serve as key factors underlying cognitive defects in neurodevelopmental disorders and neurodegenerative diseases, respectively. In this Review, we explore the recent findings that implicate mitochondria as crucial regulators of NSC function and cognition. In this respect, mitochondria may serve as targets for stem-cell-based therapies and interventions for cognitive defects.
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Affiliation(s)
- Mireille Khacho
- Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology (OISB), University of Ottawa, Ottawa, Ontario, Canada
| | - Richard Harris
- Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, Ottawa, Ontario, Canada
| | - Ruth S Slack
- Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, Ottawa, Ontario, Canada.
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24
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Restored presynaptic synaptophysin and cholinergic inputs contribute to the protective effects of physical running on spatial memory in aged mice. Neurobiol Dis 2019; 132:104586. [DOI: 10.1016/j.nbd.2019.104586] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 08/06/2019] [Accepted: 08/23/2019] [Indexed: 01/16/2023] Open
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25
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Samal J, Rebelo AL, Pandit A. A window into the brain: Tools to assess pre-clinical efficacy of biomaterials-based therapies on central nervous system disorders. Adv Drug Deliv Rev 2019; 148:68-145. [PMID: 30710594 DOI: 10.1016/j.addr.2019.01.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 01/04/2019] [Accepted: 01/28/2019] [Indexed: 12/13/2022]
Abstract
Therapeutic conveyance into the brain is a cardinal requirement for treatment of diverse central nervous system (CNS) disorders and associated pathophysiology. Effectual shielding of the brain by the blood-brain barrier (BBB) sieves out major proportion of therapeutics with the exception of small lipophilic molecules. Various nano-delivery systems (NDS) provide an effective solution around this obstacle owing to their small size and targeting properties. To date, these systems have been used for several pre-clinical disease models including glioma, neurodegenerative diseases and psychotic disorders. An efficacy screen for these systems involves a test battery designed to probe into the multiple facets of therapeutic delivery. Despite their wide application in redressing various disease targets, the efficacy evaluation strategies for all can be broadly grouped into four modalities, namely: histological, bio-imaging, molecular and behavioural. This review presents a comprehensive insight into all of these modalities along with their strengths and weaknesses as well as perspectives on an ideal design for a panel of tests to screen brain nano-delivery systems.
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Affiliation(s)
- Juhi Samal
- CÚRAM, Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland
| | - Ana Lucia Rebelo
- CÚRAM, Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland
| | - Abhay Pandit
- CÚRAM, Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland.
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26
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Liaw K, Zhang Z, Kannan S. Neuronanotechnology for brain regeneration. Adv Drug Deliv Rev 2019; 148:3-18. [PMID: 31668648 DOI: 10.1016/j.addr.2019.04.004] [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: 11/14/2018] [Revised: 02/16/2019] [Accepted: 04/15/2019] [Indexed: 12/16/2022]
Abstract
Identifying and harnessing regenerative pathways while suppressing the growth-inhibiting processes of the biological response to injury is the central goal of stimulating neurogenesis after central nervous system (CNS) injury. However, due to the complexity of the mature CNS involving a plethora of cellular pathways and extracellular cues, as well as difficulties in accessibility without highly invasive procedures, clinical successes of regenerative medicine for CNS injuries have been extremely limited. Current interventions primarily focus on stabilization and mitigation of further neuronal death rather than direct stimulation of neurogenesis. In the past few decades, nanotechnology has offered substantial innovations to the field of regenerative medicine. Their nanoscale features allow for the fine tuning of biological interactions for enhancing drug delivery and stimulating cellular processes. This review gives an overview of nanotechnology applications in CNS regeneration organized according to cellular and extracellular targets and discuss future directions for the field.
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27
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Alipour M, Nabavi SM, Arab L, Vosough M, Pakdaman H, Ehsani E, Shahpasand K. Stem cell therapy in Alzheimer's disease: possible benefits and limiting drawbacks. Mol Biol Rep 2018; 46:1425-1446. [PMID: 30565076 DOI: 10.1007/s11033-018-4499-7] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Accepted: 11/13/2018] [Indexed: 02/06/2023]
Abstract
Alzheimer's disease (AD) is the sixth leading cause of death globally and the main reason for dementia in elderly people. AD is a long-term and progressive neurodegenerative disorder that steadily worsens memory and communicating skills eventually leads to a disabled person of performing simple daily tasks. Unfortunately, numerous clinical trials exploring new therapeutic drugs have encountered disappointing outcomes in terms of improved cognitive performance since they are not capable of halting or stimulating the regeneration of already-damaged neural cells, and merely provide symptomatic relief. Therefore, a deeper understanding of the mechanism of action of stem cell may contribute to the development of novel and effective therapies. The revolutionary discovery of stem cells has cast a new hope for the development of disease-modifying treatments for AD, in terms of their potency in the replenishment of lost cells via differentiating towards specific lineages, stimulating in situ neurogenesis, and delivering the therapeutic agents to the brain. Herein, firstly, we explore the pathophysiology of AD. Next, we summarize the most recent preclinical stem cell reports designed for AD treatment, their benefits and outcomes according to cell type. We briefly review relevant clinical trials and their potential clinical applications in order to find a unique solution to effectively relieve the patients' pain.
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Affiliation(s)
- Masoume Alipour
- Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Banihashem Sq., Banihashem St., Resalat highway, P.O. Box 19395-4644, Tehran, Iran
| | - Seyed Massood Nabavi
- Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Banihashem Sq., Banihashem St., Resalat highway, P.O. Box 19395-4644, Tehran, Iran
| | - Leila Arab
- Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Banihashem Sq., Banihashem St., Resalat highway, P.O. Box 19395-4644, Tehran, Iran
| | - Massoud Vosough
- Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Hossein Pakdaman
- Department of Neurology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ehsan Ehsani
- Department of Biology, Roudehen Branch, Islamic Azad University, Roudehen, Iran
| | - Koorosh Shahpasand
- Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Banihashem Sq., Banihashem St., Resalat highway, P.O. Box 19395-4644, Tehran, Iran.
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Zhang F, Chen SQ, Tong MM, Wang PJ, Teng GJ. 7.0 tesla high resolution MRI study on intracerebral migration of magnet-labeled neural stem cells in a mouse model of Alzheimer's disease. Magn Reson Imaging 2018; 54:58-62. [PMID: 30118826 DOI: 10.1016/j.mri.2018.08.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 08/12/2018] [Accepted: 08/14/2018] [Indexed: 01/23/2023]
Abstract
OBJECTIVE To observe the migration characteristics of neural stem cells (NSCs) labeled with the MRI contrast agent superparamagnetic iron oxide (SPIO) in the brain of APP/PS1 transgenic mice with Alzheimer's disease (AD) by 7.0 T high resolution MRI. METHODS C57BL/6 mouse NSCs were cultured, amplified, labeled with Feridex and Poly-l-lysine (FE-PLL) and evaluated by transmission electron microscopy (TEM). Using the random number table method, 24 APP/PS1 transgenic AD mice aged 12 months were equally assigned to two groups: animals in group A were transplanted with FE-PLL labeled NSCs and those in group B were transplanted with non-labeled NSCs in the right hippocampus. Twelve wild-type mice of the same age and born from the same litter were used as the control group (group C) and transplanted with FE-PLL labeled NSCs. Using the 7.0 T high resolution MR scanner, the transplanted NSCs were traced in vivo at 1 day, 1 and 2 weeks after cell transplantation. The MRI findings were compared with the histopathological findings. RESULTS C57BL/6 mouse NSCs were cultured and amplified successfully. TEM showed large amounts of iron-containing particles in the cytoplasm of transplanted cells. MRI in group A showed the presence of spheroid low signals at the injection point of the hippocampus on T2*WI one day after transplantation; one weeks later, the low signals were seen diffusing to the surroundings along the injection point, and covering almost the whole hippocampal area but the intensity of the low signals became weaker gradually; two weeks after transplantation, almost all low signals disappeared. In group B, no significant change in low signals was observed in the transplantation area at all designated time points. Although low signals were also observed in the hippocampus after transplantation of FE-PLL labeled NSCs in group C, their size and location remained almost unchanged. Prussian blue staining showed that migration of the FE-PLL labeled NSCs in the hippocampus of the AD mice was consistent with the MRI findings at all designated time points. CONCLUSION NSCs underwent diffuse and non-directional migration to the surroundings after they were transplanted to the hippocampus of APP/PS1 transgenic AD mice, and this migration pattern could be traced in vivo by MRI when they were labeled with magnet.
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Affiliation(s)
- Fan Zhang
- Department of Radiology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215001, China
| | - Shuang-Qing Chen
- Department of Radiology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215001, China.
| | - Ming-Min Tong
- Department of Radiology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215001, China
| | - Pei-Jun Wang
- Department of Radiology, the Affiliated Tongji Hospital of Tongji University, Shanghai 200065, China
| | - Gao-Jun Teng
- Key Laboratory of Molecular Imaging, Southeast University, Nanjing 210009, China
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Liu XY, Zhou CB, Fang C. Nanomaterial-involved neural stem cell research: Disease treatment, cell labeling, and growth regulation. Biomed Pharmacother 2018; 107:583-597. [PMID: 30114642 DOI: 10.1016/j.biopha.2018.08.029] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 07/19/2018] [Accepted: 08/06/2018] [Indexed: 12/21/2022] Open
Abstract
Neural stem cells (NSCs) have been widely investigated for their potential in the treatment of various diseases and transplantation therapy. However, NSC growth regulation, labeling, and its application to disease diagnosis and treatment are outstanding challenges. Recently, nanomaterials have shown promise for various applications including genetic modification, imaging, and controlled drug release. Here we summarize the recent progress in the use of nanomaterials in combination with NSCs for disease treatment and diagnosis, cell labeling, and NSC growth regulation. The toxicity of nanomaterials to NSCs is also discussed.
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Affiliation(s)
- Xiang-Yu Liu
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 280 South Chongqing Road, Shanghai 200025, China
| | - Cheng-Bin Zhou
- Bio-X Institutes, Key Laboratory for the Genetics of Development and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240 China
| | - Chao Fang
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 280 South Chongqing Road, Shanghai 200025, China.
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30
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Stem Cells as Potential Targets of Polyphenols in Multiple Sclerosis and Alzheimer's Disease. BIOMED RESEARCH INTERNATIONAL 2018; 2018:1483791. [PMID: 30112360 PMCID: PMC6077677 DOI: 10.1155/2018/1483791] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 06/19/2018] [Indexed: 12/16/2022]
Abstract
Alzheimer's disease (AD) and multiple sclerosis are major neurodegenerative diseases, which are characterized by the accumulation of abnormal pathogenic proteins due to oxidative stress, mitochondrial dysfunction, impaired autophagy, and pathogens, leading to neurodegeneration and behavioral deficits. Herein, we reviewed the utility of plant polyphenols in regulating proliferation and differentiation of stem cells for inducing brain self-repair in AD and multiple sclerosis. Firstly, we discussed the genetic, physiological, and environmental factors involved in the pathophysiology of both the disorders. Next, we reviewed various stem cell therapies available and how they have proved useful in animal models of AD and multiple sclerosis. Lastly, we discussed how polyphenols utilize the potential of stem cells, either complementing their therapeutic effects or stimulating endogenous and exogenous neurogenesis, against these diseases. We suggest that polyphenols could be a potential candidate for stem cell therapy against neurodegenerative disorders.
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31
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Sun P, Ortega G, Tan Y, Hua Q, Riederer PF, Deckert J, Schmitt-Böhrer AG. Streptozotocin Impairs Proliferation and Differentiation of Adult Hippocampal Neural Stem Cells in Vitro-Correlation With Alterations in the Expression of Proteins Associated With the Insulin System. Front Aging Neurosci 2018; 10:145. [PMID: 29867451 PMCID: PMC5968103 DOI: 10.3389/fnagi.2018.00145] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 04/30/2018] [Indexed: 12/21/2022] Open
Abstract
Rats intracerebroventricularily (icv) treated with streptozotocin (STZ), shown to generate an insulin resistant brain state, were used as an animal model for the sporadic form of Alzheimer’s disease (sAD). Previously, we showed in an in vivo study that 3 months after STZ icv treatment hippocampal adult neurogenesis (AN) is impaired. In the present study, we examined the effects of STZ on isolated adult hippocampal neural stem cells (NSCs) using an in vitro approach. We revealed that 2.5 mM STZ inhibits the proliferation of NSCs as indicated by reduced number and size of neurospheres as well as by less BrdU-immunoreactive NSCs. Double immunofluorescence stainings of NSCs already being triggered to start with their differentiation showed that STZ primarily impairs the generation of new neurons, but not of astrocytes. For revealing mechanisms possibly involved in mediating STZ effects we analyzed expression levels of insulin/glucose system-related molecules such as the glucose transporter (GLUT) 1 and 3, the insulin receptor (IR) and the insulin-like growth factor (IGF) 1 receptor. Applying quantitative Real time-PCR (qRT-PCR) and immunofluorescence stainings we showed that STZ exerts its strongest effects on GLUT3 expression, as GLUT3 mRNA levels were found to be reduced in NSCs, and less GLUT3-immunoreactive NSCs as well as differentiating cells were detected after STZ treatment. These findings suggest that cultured NSCs are a good model for developing new strategies to treat nerve cell loss in AD and other degenerative disorders.
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Affiliation(s)
- Ping Sun
- Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Science & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.,Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany
| | - Gabriela Ortega
- Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany
| | - Yan Tan
- School of Preclinical Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Qian Hua
- School of Preclinical Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Peter F Riederer
- Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany
| | - Jürgen Deckert
- Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany
| | - Angelika G Schmitt-Böhrer
- Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany
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32
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Corrêa-Velloso JC, Gonçalves MC, Naaldijk Y, Oliveira-Giacomelli Á, Pillat MM, Ulrich H. Pathophysiology in the comorbidity of Bipolar Disorder and Alzheimer's Disease: pharmacological and stem cell approaches. Prog Neuropsychopharmacol Biol Psychiatry 2018; 80:34-53. [PMID: 28476640 DOI: 10.1016/j.pnpbp.2017.04.033] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 04/28/2017] [Indexed: 12/22/2022]
Abstract
Neuropsychiatric disorders involve various pathological mechanisms, resulting in neurodegeneration and brain atrophy. Neurodevelopmental processes have shown to be critical for the progression of those disorders, which are based on genetic and epigenetic mechanisms as well as on extrinsic factors. We review here common mechanisms underlying the comorbidity of Bipolar Disorders and Alzheimer's Disease, such as aberrant neurogenesis and neurotoxicity, reporting current therapeutic approaches. The understanding of these mechanisms precedes stem cell-based strategies as a new therapeutic possibility for treatment and prevention of Bipolar and Alzheimer's Disease progression. Taking into account the difficulty of studying the molecular basis of disease progression directly in patients, we also discuss the importance of stem cells for effective drug screening, modeling and treating psychiatric diseases, once in vitro differentiation of patient-induced pluripotent stem cells provides relevant information about embryonic origins, intracellular pathways and molecular mechanisms.
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Affiliation(s)
- Juliana C Corrêa-Velloso
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, SP 05508-000, Brazil
| | - Maria Cb Gonçalves
- Departamento de Neurologia e Neurociências, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Pedro de Toledo 669, São Paulo, SP 04039-032, Brazil
| | - Yahaira Naaldijk
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, SP 05508-000, Brazil
| | - Ágatha Oliveira-Giacomelli
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, SP 05508-000, Brazil
| | - Micheli M Pillat
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, SP 05508-000, Brazil
| | - Henning Ulrich
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, SP 05508-000, Brazil.
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Tang Y, Yu P, Cheng L. Current progress in the derivation and therapeutic application of neural stem cells. Cell Death Dis 2017; 8:e3108. [PMID: 29022921 PMCID: PMC5682670 DOI: 10.1038/cddis.2017.504] [Citation(s) in RCA: 132] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 08/28/2017] [Accepted: 08/31/2017] [Indexed: 12/13/2022]
Abstract
Neural stem cells (NSCs) have a unique role in neural regeneration. Cell therapy based on NSC transplantation is a promising tool for the treatment of nervous system diseases. However, there are still many issues and controversies associated with the derivation and therapeutic application of these cells. In this review, we summarize the different sources of NSCs and their derivation methods, including direct isolation from primary tissues, differentiation from pluripotent stem cells and transdifferentiation from somatic cells. We also review the current progress in NSC implantation for the treatment of various neural defects and injuries in animal models and clinical trials. Finally, we discuss potential optimization strategies for NSC derivation and propose urgent challenges to the clinical translation of NSC-based therapies in the near future.
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Affiliation(s)
- Yuewen Tang
- National Research Center for Translational Medicine, State Key Laboratory of Medical Genomics, Shanghai Institute of Haematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Pei Yu
- Department of Orthopaedics, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lin Cheng
- National Research Center for Translational Medicine, State Key Laboratory of Medical Genomics, Shanghai Institute of Haematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Shi XY, Hu LY, Liu MJ, Zou LP. Hypercapnia-induced brain acidosis: Effects and putative mechanisms on acute kainate induced seizures. Life Sci 2017; 176:82-87. [DOI: 10.1016/j.lfs.2017.03.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Revised: 03/21/2017] [Accepted: 03/22/2017] [Indexed: 01/16/2023]
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Mayburd A, Baranova A. Knowledge-Based Compact Disease Models: A Rapid Path from High-Throughput Data to Understanding Causative Mechanisms for a Complex Disease. Methods Mol Biol 2017; 1613:425-461. [PMID: 28849571 DOI: 10.1007/978-1-4939-7027-8_17] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
High-throughput profiling of human tissues typically yields the gene lists composed of a variety of more or less relevant molecular entities. These lists are riddle by false positive observations that often obstruct generation of mechanistic hypothesis that may explain complex phenotype. From general probabilistic considerations, the gene lists enriched by the mechanistically relevant targets can be far more useful for subsequent experimental design or data interpretation. Using Alzheimer's disease as example, the candidate gene lists were processed into different tiers of evidence consistency established by enrichment analysis across subdatasets collected within the same experiment and across different experiments and platforms. The cutoffs were established empirically through ontological and semantic enrichment; resultant shortened gene list was reexpanded by Ingenuity Pathway Assistant tool. The resulting subnetworks provided the basis for generating mechanistic hypotheses that were partially validated by mined experimental evidence. This approach differs from previous consistency-based studies in that the cutoff on the Receiver Operating Characteristic of the true-false separation process is optimized by flexible selection of the consistency building procedure. The resultant Compact Disease Models (CDM) composed of the gene list distilled by this analytic technique and its network-based representation allowed us to highlight possible role of the protein traffic vesicles in the pathogenesis of Alzheimer's. Considering the distances and complexity of protein trafficking in neurons, it is plausible to hypothesize that spontaneous protein misfolding along with a shortage of growth stimulation may provide a shortcut to neurodegeneration. Several potentially overlapping scenarios of early-stage Alzheimer pathogenesis are discussed, with an emphasis on the protective effects of Angiotensin receptor 1 (AT-1) mediated antihypertensive response on cytoskeleton remodeling, along with neuronal activation of oncogenes, luteinizing hormone signaling and insulin-related growth regulation, forming a pleiotropic model of its early stages. Compact Disease Model generation is a flexible approach for high-throughput data analysis that allows extraction of meaningful, mechanism-centered gene sets compatible with instant translation of the results into testable hypotheses.
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Affiliation(s)
- Anatoly Mayburd
- The Center of the Study of Chronic Metabolic and Rare Diseases, School of Systems Biology, College of Science, George Mason University, Fairfax, VA, 22030, USA
| | - Ancha Baranova
- The Center of the Study of Chronic Metabolic and Rare Diseases, School of Systems Biology, College of Science, George Mason University, Fairfax, VA, 22030, USA.
- Research Centre for Medical Genetics, RAMS, Moskvorechie 1, Moscow, Russia.
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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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