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Begh MZA, Zehravi M, Bhuiyan MAK, Molla MR, Raman K, Emran TB, Ullah MH, Ahmad I, Osman H, Khandaker MU. Recent advances in stem cell approaches to neurodegeneration: A comprehensive review with mechanistic insight. Pathol Res Pract 2025; 271:156013. [PMID: 40381433 DOI: 10.1016/j.prp.2025.156013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2025] [Revised: 05/10/2025] [Accepted: 05/12/2025] [Indexed: 05/20/2025]
Abstract
The progressive nature of neurodegenerative diseases (NDs), such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, presents substantial problems because current treatments are still obscure. Stem cell-based treatments are emerging as a viable solution to address the significant gaps in treating these severe diseases. This study provides a comprehensive analysis of the latest advancements in stem cell research, focusing on the treatment of NDs. Various types of stem cells, such as adult, induced pluripotent, and embryonic stem cells, and their potential applications in immunomodulation, neurotrophic factor release, and neuronal development are also discussed. Recent clinical studies reveal outcomes, challenges, and solutions, with advancements in disease-specific neural cell production, gene editing, and improved stem cell transplantation transport strategies. The review discussed future perspectives on developing more effective stem cell-based interventions. Biomaterials are being used for cell distribution and personalized medicine techniques to improve treatment outcomes, while exploring stem cell treatments for NDs and identifying areas for further research.
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Affiliation(s)
- Md Zamshed Alam Begh
- Department of Pharmacy, Faculty of Health and Life Sciences, Daffodil International University, Dhaka 1216, Bangladesh.
| | - Mehrukh Zehravi
- Department of Clinical Pharmacy, College of Dentistry & Pharmacy, Buraydah Private Colleges, Buraydah 51418, Saudi Arabia.
| | | | - M Raju Molla
- Department of Pharmacy, Atish Dipankar University of Science and Technology, Dhaka 1230, Bangladesh
| | - Kannan Raman
- Department of Pharmacology, St. John's College of Pharmaceutical Sciences & Research, Kattappana, Idukki, Kerala, India
| | - Talha Bin Emran
- Department of Pharmacy, Faculty of Health and Life Sciences, Daffodil International University, Dhaka 1216, Bangladesh
| | - Md Habib Ullah
- Department of Physics, American International University-Bangladesh (AIUB), 408/1, Kuratoli, Khilkhet, Dhaka 1229, Bangladesh
| | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Hamid Osman
- Department of Radiological Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia
| | - Mayeen Uddin Khandaker
- Applied Physics and Radiation Technologies Group, CCDCU, Faculty of Engineering and Technology, Sunway University, Bandar Sunway, 47500 Selangor, Malaysia; Department of Physics, College of Science, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea
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2
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Lee WJ, Cho KJ, Kim GW. Mitigation of Atherosclerotic Vascular Damage and Cognitive Improvement Through Mesenchymal Stem Cells in an Alzheimer's Disease Mouse Model. Int J Mol Sci 2024; 25:13210. [PMID: 39684920 DOI: 10.3390/ijms252313210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 12/05/2024] [Accepted: 12/05/2024] [Indexed: 12/18/2024] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive memory loss and other cognitive disturbances. Patients with AD can be vulnerable to vascular damage, and damaged vessels can lead to cognitive impairment. Mesenchymal stem cell (MSC) treatment has shown potential in ameliorating AD pathogenesis, but its effect on vascular function remains unclear. This study aimed to improve cognitive function by alleviating atherosclerosis-induced vessel damage using MSCs in mice with a genetic AD background. In this study, a 5xFAD mouse model of AD was used, and atherosclerotic vessel damage was induced by high-fat diets (HFDs). MSCs were injected into the tail vein along with mannitol in 5xFAD mice on an HFD. MSCs were detected in the brain, and vascular damage was improved following MSC treatment. Behavioral tests showed that MSCs enhanced cognitive function, as measured by the Y-maze and passive avoidance tests. Additionally, muscle strength measured by the rotarod test was also increased by MSCs in AD mice with vessel damage induced by HFDs. Overall, our results suggest that stem cells can alleviate vascular damage caused by metabolic diseases, including HFDs, and vascular disease in individuals carrying the AD gene. Consequently, this alleviates cognitive decline related to vascular dementia symptoms.
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Affiliation(s)
- Woong Jin Lee
- Department of Neurology, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea
| | - Kyoung Joo Cho
- Department of Life Science, Kyonggi University, Suwon 16227, Republic of Korea
| | - Gyung Whan Kim
- Department of Neurology, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea
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Ou CM, Xue WW, Liu D, Ma L, Xie HT, Ning K. Stem cell therapy in Alzheimer's disease: current status and perspectives. Front Neurosci 2024; 18:1440334. [PMID: 39640295 PMCID: PMC11618239 DOI: 10.3389/fnins.2024.1440334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 10/09/2024] [Indexed: 12/07/2024] Open
Abstract
An incurable neurogenerative illness, Alzheimer's disease, is the cause of most global health, medical, and social disasters. The two main symptoms are cognitive impairment and neuronal loss. Current medications that target tau protein tangles and Aβ plaques are not very effective because they only slow the symptoms of AD and do not repair damaged cells. Stem cell-based treatments, however, present an alternative strategy in the treatment of AD. They have the capacity to divide into specialized adult cells, have self-renewal abilities, and multiplication. Stem cells can now be employed as a donor source for cell therapy due to developments in stem cell technology. This review covers preclinical and clinical updates on studies based on targeting the tau protein tangles and Aβ plaque, as well as four types of stem cells employed in AD treatment. The review also outlines the two basic pathologic aspects, tau protein tangles and Aβ plaques, of AD.
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Affiliation(s)
- Chu-Min Ou
- Guangdong Celconta Biotechnology Co., Ltd., Dongguan, Guangdong, China
| | - Wei-Wei Xue
- Guangdong Celconta Biotechnology Co., Ltd., Dongguan, Guangdong, China
- School of Biological Engineering, Dalian Polytechnic University, Dalian, China
| | - Dong Liu
- Guangdong Celconta Biotechnology Co., Ltd., Dongguan, Guangdong, China
| | - Liya Ma
- Guangdong Celconta Biotechnology Co., Ltd., Dongguan, Guangdong, China
| | - Hai-Tao Xie
- Guangdong Celconta Biotechnology Co., Ltd., Dongguan, Guangdong, China
| | - Ke Ning
- Guangdong Celconta Biotechnology Co., Ltd., Dongguan, Guangdong, China
- Sheffield Institute of Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom
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Zhidu S, Ying T, Rui J, Chao Z. Translational potential of mesenchymal stem cells in regenerative therapies for human diseases: challenges and opportunities. Stem Cell Res Ther 2024; 15:266. [PMID: 39183341 PMCID: PMC11346273 DOI: 10.1186/s13287-024-03885-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 08/14/2024] [Indexed: 08/27/2024] Open
Abstract
Advances in stem cell technology offer new possibilities for patients with untreated diseases and disorders. Stem cell-based therapy, which includes multipotent mesenchymal stem cells (MSCs), has recently become important in regenerative therapies. MSCs are multipotent progenitor cells that possess the ability to undergo in vitro self-renewal and differentiate into various mesenchymal lineages. MSCs have demonstrated promise in several areas, such as tissue regeneration, immunological modulation, anti-inflammatory qualities, and wound healing. Additionally, the development of specific guidelines and quality control methods that ultimately result in the therapeutic application of MSCs has been made easier by recent advancements in the study of MSC biology. This review discusses the latest clinical uses of MSCs obtained from the umbilical cord (UC), bone marrow (BM), or adipose tissue (AT) in treating various human diseases such as pulmonary dysfunctions, neurological disorders, endocrine/metabolic diseases, skin burns, cardiovascular conditions, and reproductive disorders. Additionally, this review offers comprehensive information regarding the clinical application of targeted therapies utilizing MSCs. It also presents and examines the concept of MSC tissue origin and its potential impact on the function of MSCs in downstream applications. The ultimate aim of this research is to facilitate translational research into clinical applications in regenerative therapies.
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Affiliation(s)
- Song Zhidu
- Department of Ophthalmology, the Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun City, Jilin Province, China
| | - Tao Ying
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jiang Rui
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Zhang Chao
- Department of Ophthalmology, the Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun City, Jilin Province, China.
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Ham HJ, Lee YS, Koo JK, Yun J, Son DJ, Han SB, Hong JT. Inhibition of Amyloid-β (Aβ)-Induced Cognitive Impairment and Neuroinflammation in CHI3L1 Knockout Mice through Downregulation of ERK-PTX3 Pathway. Int J Mol Sci 2024; 25:5550. [PMID: 38791588 PMCID: PMC11122210 DOI: 10.3390/ijms25105550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 05/15/2024] [Accepted: 05/17/2024] [Indexed: 05/26/2024] Open
Abstract
Several clinical studies reported that the elevated expression of Chitinase-3-like 1 (CHI3L1) was observed in patients suffering from a wide range of diseases: cancer, metabolic, and neurological diseases. However, the role of CHI3L1 in AD is still unclear. Our previous study demonstrated that 2-({3-[2-(1-Cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}culfanyl)-N-(4-ethylphenyl)butanamide, a CHI3L1 inhibiting compound, alleviates memory and cognitive impairment and inhibits neuroinflammation in AD mouse models. In this study, we studied the detailed correlation of CHI3L1 and AD using serum from AD patients and using CHI3L1 knockout (KO) mice with Aβ infusion (300 pmol/day, 14 days). Serum levels of CHI3L1 were significantly elevated in patients with AD compared to normal subjects, and receiver operating characteristic (ROC) analysis data based on serum analysis suggested that CHI3L1 could be a significant diagnostic reference for AD. To reveal the role of CHI3L1 in AD, we investigated the CHI3L1 deficiency effect on memory impairment in Aβ-infused mice and microglial BV-2 cells. In CHI3L1 KO mice, Aβ infusion resulted in lower levels of memory dysfunction and neuroinflammation compared to that of WT mice. CHI3L1 deficiency selectively inhibited phosphorylation of ERK and IκB as well as inhibition of neuroinflammation-related factors in vivo and in vitro. On the other hand, treatment with recombinant CHI3L1 increased neuroinflammation-related factors and promoted phosphorylation of IκB except for ERK in vitro. Web-based gene network analysis and our results showed that CHI3L1 is closely correlated with PTX3. Moreover, in AD patients, we found that serum levels of PTX3 were correlated with serum levels of CHI3L1 by Spearman correlation analysis. These results suggest that CHI3L1 deficiency could inhibit AD development by blocking the ERK-dependent PTX3 pathway.
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Affiliation(s)
| | | | | | | | | | | | - Jin Tae Hong
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju 28160, Republic of Korea
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Virk MS, Virk MA, He Y, Tufail T, Gul M, Qayum A, Rehman A, Rashid A, Ekumah JN, Han X, Wang J, Ren X. The Anti-Inflammatory and Curative Exponent of Probiotics: A Comprehensive and Authentic Ingredient for the Sustained Functioning of Major Human Organs. Nutrients 2024; 16:546. [PMID: 38398870 PMCID: PMC10893534 DOI: 10.3390/nu16040546] [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: 01/27/2024] [Revised: 02/10/2024] [Accepted: 02/14/2024] [Indexed: 02/25/2024] Open
Abstract
Several billion microorganisms reside in the gastrointestinal lumen, including viruses, bacteria, fungi, and yeast. Among them, probiotics were primarily used to cure digestive disorders such as intestinal infections and diarrhea; however, with a paradigm shift towards alleviating health through food, their importance is large. Moreover, recent studies have changed the perspective that probiotics prevent numerous ailments in the major organs. Probiotics primarily produce biologically active compounds targeting discommodious pathogens. This review demonstrates the implications of using probiotics from different genres to prevent and alleviate ailments in the primary human organs. The findings reveal that probiotics immediately activate anti-inflammatory mechanisms by producing anti-inflammatory cytokines such as interleukin (IL)-4, IL-10, IL-11, and IL-13, and hindering pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α by involving regulatory T cells (Tregs) and T helper cells (Th cells). Several strains of Lactobacillus plantarum, Lactobacillus rhamnosus, Lactobacillus casei, Lactobacillus reuteri, Bifidobacterium longum, and Bifidobacterium breve have been listed among the probiotics that are excellent in alleviating various simple to complex ailments. Therefore, the importance of probiotics necessitates robust research to unveil the implications of probiotics, including the potency of strains, the optimal dosages, the combination of probiotics, their habitat in the host, the host response, and other pertinent factors.
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Affiliation(s)
- Muhammad Safiullah Virk
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; (M.S.V.)
| | | | - Yufeng He
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; (M.S.V.)
| | - Tabussam Tufail
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; (M.S.V.)
- University Institute of Diet and Nutritional Sciences, The University of Lahore, Lahore 54000, Pakistan
| | - Mehak Gul
- Department of Internal Medicine, Sheikh Zayed Hospital, Lahore 54000, Pakistan
| | - Abdul Qayum
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; (M.S.V.)
| | - Abdur Rehman
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; (M.S.V.)
| | - Arif Rashid
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; (M.S.V.)
| | - John-Nelson Ekumah
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; (M.S.V.)
| | - Xu Han
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; (M.S.V.)
| | - Junxia Wang
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; (M.S.V.)
| | - Xiaofeng Ren
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China; (M.S.V.)
- Institute of Food Physical Processing, Jiangsu University, Zhenjiang 212013, China
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7
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Jeyaraman M, Rajendran RL, Muthu S, Jeyaraman N, Sharma S, Jha SK, Muthukanagaraj P, Hong CM, Furtado da Fonseca L, Santos Duarte Lana JF, Ahn BC, Gangadaran P. An update on stem cell and stem cell-derived extracellular vesicle-based therapy in the management of Alzheimer's disease. Heliyon 2023; 9:e17808. [PMID: 37449130 PMCID: PMC10336689 DOI: 10.1016/j.heliyon.2023.e17808] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 05/10/2023] [Accepted: 06/28/2023] [Indexed: 07/18/2023] Open
Abstract
Globally, neurological diseases pose a major burden to healthcare professionals in terms of the management and prevention of the disorder. Among neurological diseases, Alzheimer's disease (AD) accounts for 50%-70% of dementia and is the fifth leading cause of mortality worldwide. AD is a progressive, degenerative neurological disease, with the loss of neurons and synapses in the cerebral cortex and subcortical regions. The management of AD remains a debate among physicians as no standard and specific "disease-modifying" modality is available. The concept of 'Regenerative Medicine' is aimed at regenerating the degenerated neural tissues to reverse the pathology in AD. Genetically modified engineered stem cells modify the course of AD after transplantation into the brain. Extracellular vesicles (EVs) are an emerging new approach in cell communication that involves the transfer of cellular materials from parental cells to recipient cells, resulting in changes at the molecular and signaling levels in the recipient cells. EVs are a type of vesicle that can be transported between cells. Many have proposed that EVs produced from mesenchymal stem cells (MSCs) may have therapeutic promise in the treatment of AD. The biology of AD, as well as the potential applications of stem cells and their derived EVs-based therapy, were explored in this paper.
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Affiliation(s)
- Madhan Jeyaraman
- Department of Orthopaedics, ACS Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai, Tamil Nadu, 600056, India
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, 226010, India
| | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea
| | - Sathish Muthu
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, 226010, India
- Department of Orthopedics, Government Dindigul Medical College and Hospital, Dindigul, Tamil Nadu, 624001, India
| | - Naveen Jeyaraman
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, 226010, India
- Department of Orthopedics, Shri Sathya Sai Medical College and Research Institute, Sri Balaji Vidyapeeth, Chengalpet, Tamil Nadu, 603108, India
| | - Shilpa Sharma
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, 226010, India
- Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
| | - Purushothaman Muthukanagaraj
- Department of Internal Medicine & Psychiatry, SUNY-Upstate Binghamton Clinical Campus, Binghamton, NY, 13904, USA
| | - Chae Moon Hong
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea
| | - Lucas Furtado da Fonseca
- Department of Orthopedics, The Federal University of São Paulo, São Paulo, 04023-062, SP, Brazil
| | | | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea
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Gaber A, Ahmed OM, Khadrawy YA, Zoheir KMA, Abo-ELeneen RE, Alblihed MA, Elbakry AM. Mesenchymal Stem Cells and Begacestat Mitigate Amyloid-β 25-35-Induced Cognitive Decline in Rat Dams and Hippocampal Deteriorations in Offspring. BIOLOGY 2023; 12:905. [PMID: 37508337 PMCID: PMC10376406 DOI: 10.3390/biology12070905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/11/2023] [Accepted: 06/21/2023] [Indexed: 07/30/2023]
Abstract
Alzheimer's disease (AD) is the most common cause of age-related neurodegeneration and cognitive decline. AD more commonly occurs in females than in males, so it is necessary to consider new treatments specifically targeting this population. The present study investigated the protective effects of Begacestat (γ-secretase inhibitor-953, GSI-953) and bone marrow-derived mesenchymal stem cells (BM-MSCs) during pregnancy on cognitive impairment in rat dams and neurodegeneration in offspring caused by the intracerebroventricular injection of Aβ 25-35 before pregnancy. The performances of dams injected with amyloid-β 25-35 (Aβ 25-35) during behavioral tests were significantly impaired. The offspring of Aβ 25-35-injected dams treated with BM-MSCs or GSI-953 showed a dramatically reduced number and size of activated microglial cells, enhancement in the processes length, and a decrease in the proinflammatory cytokine levels. Additionally, BM-MSC or GSI-953 therapy reduced Aβ 25-35-induced increases in tau phosphorylation and amyloid precursor protein levels in the neonates' hippocampus and elevated the lower levels of glycogen synthase kinase-3 and brain-derived neurotrophic factor; moreover, reversed Aβ 25-35-induced alterations in gene expression in the neonatal hippocampus. Finally, the treatments with BM-MSC or GSI-953 are globally beneficial against Aβ 25-35-induced brain alterations, particularly by suppressing neural inflammation, inhibiting microglial cell activation, restoring developmental plasticity, and increasing neurotrophic signaling.
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Affiliation(s)
- Asmaa Gaber
- Comparative Anatomy and Embryology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni-Suef P.O. Box 62521, Egypt
| | - Osama M. Ahmed
- Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni-Suef P.O. Box 62521, Egypt
| | - Yasser A. Khadrawy
- Medical Physiology Department, National Research Center, Giza P.O. Box 12622, Egypt
| | - Khairy M. A. Zoheir
- Cell Biology Department, National Research Center, Giza P.O. Box 12622, Egypt
| | - Rasha E. Abo-ELeneen
- Comparative Anatomy and Embryology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni-Suef P.O. Box 62521, Egypt
| | - Mohamed A. Alblihed
- Department of Medical Microbiology, college of medicine, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Ahlam M. Elbakry
- Comparative Anatomy and Embryology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni-Suef P.O. Box 62521, Egypt
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9
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Gaber A, Elbakry AM, Aljarari RM, Jaber FA, Khadrawy YA, Sabry D, Abo-ELeneen RE, Ahmed OM. Bone Marrow-Derived Mesenchymal Stem Cells and γ-Secretase Inhibitor Treatments Suppress Amyloid- β25-35-Induced Cognitive Impairment in Rat Dams and Cortical Degeneration in Offspring. Stem Cells Int 2023; 2023:2690949. [PMID: 37274020 PMCID: PMC10234728 DOI: 10.1155/2023/2690949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 04/02/2023] [Accepted: 05/02/2023] [Indexed: 06/06/2023] Open
Abstract
Alzheimer's disease (AD) is the most frequent cause of age-related neurodegeneration and ensuing cognitive impairment. Progressive deposition of extracellular amyloid beta (Aβ) aggregates (plaques) and intracellular hyperphosphorylated Tau protein (p-Tau) are the core pathological markers of AD but may precede clinical symptoms by many years, presenting a therapeutic window of opportunity. Females are more frequently afflicted by AD than males, necessitating evaluation of novel treatments for the female population. The current study examined the protective efficacies of intravenous bone marrow-derived mesenchymal stem cells (BM-MSCs) and oral gamma-secretase inhibitor-953 (GSI-953) during pregnancy on cognitive impairment in rat dams and neurodegeneration in offspring induced by intracerebroventricular injection of Aβ25-35 prior to pregnancy. The Aβ25-35 (AD) group exhibited significant (P < 0.001) impairments in the Y-maze and novel object recognition test performance prior to conception. Histological analysis of the offspring cortex revealed substantial dendritic shrinkage and activation of microglial cells, while neurochemical analysis demonstrated significant increases in the proinflammatory cytokine interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). In contrast, BM-MSC or GSI-953 treatment of dams following Aβ25-35 injection significantly (P < 0.001) reduced the number and size of activated microglial cells, markedly increased dendrite length, and reversed proinflammatory cytokine elevations in offspring. Moreover, BM-MSC or GSI-953 treatment reversed the Aβ25-35-induced amyloid precursor protein and p-Tau elevations in the offspring brain; these changes were accompanied by upregulation of the brain-derived neurotrophic factor and downregulation of glycogen synthase kinase-3β in the serum and brain. Treatment with BM-MSCs or GSI-953 also reversed Aβ25-35-induced elevations in different gene expressions in the neonatal cortex. Finally, treatment of dams with BM-MSCs or GSI-953 prevented the Aβ25-35-induced disruption of newborn brain development. Thus, BM-MSC and GSI-953 treatments have broad-spectrum effects against Aβ25-35-induced brain pathology, including the suppression of neural inflammation, restoration of developmental plasticity, and promotion of neurotrophic signaling.
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Affiliation(s)
- Asmaa Gaber
- Comparative Anatomy and Embryology Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni Suef, Egypt
| | - Ahlam M. Elbakry
- Comparative Anatomy and Embryology Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni Suef, Egypt
| | - Rabab M. Aljarari
- Department of Biology, College of Science, University of Jeddah, Jeddah 21589, Saudi Arabia
| | - Fatima A. Jaber
- Department of Biology, College of Science, University of Jeddah, Jeddah 21589, Saudi Arabia
| | - Yasser A. Khadrawy
- Medical Physiology Department, Medical Branch Department, National Research Center, Giza, Egypt
| | - Dina Sabry
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Badr University in Cairo, Cairo 11829, Egypt
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo 11562, Egypt
| | - Rasha E. Abo-ELeneen
- Comparative Anatomy and Embryology Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni Suef, Egypt
| | - Osama M. Ahmed
- Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni Suef, Egypt
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Zhang K, Du X, Gao Y, Liu S, Xu Y. Mesenchymal Stem Cells for Treating Alzheimer's Disease: Cell Therapy and Chemical Reagent Pretreatment. J Alzheimers Dis 2023:JAD221253. [PMID: 37125553 DOI: 10.3233/jad-221253] [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: 05/02/2023]
Abstract
As the size of the population aged 65 and older continues to grow, the incidence and mortality rates of Alzheimer's disease (AD) are increasing annually. Unfortunately, current treatments only treat symptoms temporarily and do not alter the patients' life expectancy or course of AD. Mesenchymal stem cells (MSCs) have shown a certain therapeutic potential in neurodegenerative diseases including AD due to their neuroinflammatory regulation and neuroprotective effects. However, the low survival and homing rates of MSCs after transplantation seriously affect their therapeutic effectiveness. Therefore, appropriate in vitro preconditioning is necessary to increase the survival and homing rates of MSCs to improve their effectiveness in treating AD. Here we summarize the therapeutic mechanisms of MSCs in AD and the chemical reagents used for the pretreatment of MSCs.
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Affiliation(s)
- Kexin Zhang
- Department of Psychiatry, First Hospital/FirstClinical Medical College of Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Xinzhe Du
- Department of Psychiatry, First Hospital/FirstClinical Medical College of Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Yao Gao
- Department of Psychiatry, First Hospital/FirstClinical Medical College of Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Sha Liu
- Department of Psychiatry, First Hospital/FirstClinical Medical College of Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Yong Xu
- Department of Psychiatry, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China
- Department of Mental Health, Shanxi Medical University, Taiyuan, China
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11
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Duan Y, Lyu L, Zhan S. Stem Cell Therapy for Alzheimer's Disease: A Scoping Review for 2017-2022. Biomedicines 2023; 11:120. [PMID: 36672626 PMCID: PMC9855936 DOI: 10.3390/biomedicines11010120] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 12/28/2022] [Accepted: 12/28/2022] [Indexed: 01/05/2023] Open
Abstract
Alzheimer's disease (AD) has been a major causal factor for mortality among elders around the world. The treatments for AD, however, are still in the stage of development. Stem cell therapy, compared to drug therapies and many other therapeutic options, has many advantages and is very promising in the future. There are four major types of stem cells used in AD therapy: neural stem cells, mesenchymal stem cells, embryonic stem cells, and induced pluripotent stem cells. All of them have applications in the treatments, either at the (1) cellular level, in an (2) animal model, or at the (3) clinical level. In general, many more types of stem cells were studied on the cellular level and animal model, than the clinical level. We suggest for future studies to increase research on various types of stem cells and include cross-disciplinary research with other diseases. In the future, there could also be improvements in the timeliness of research and individualization for stem cell therapies for AD.
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Affiliation(s)
- Yunxiao Duan
- Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510, USA
| | - Linshuoshuo Lyu
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT 06510, USA
| | - Siyan Zhan
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
- Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing 100191, China
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12
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Choudhary S, Shanu K, Devi S. Psychobiotics as an Emerging Category of Probiotic Products. PROBIOTICS, PREBIOTICS, SYNBIOTICS, AND POSTBIOTICS 2023:361-391. [DOI: 10.1007/978-981-99-1463-0_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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13
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Hay AJD, Murphy TJ, Popichak KA, Zabel MD, Moreno JA. Adipose-derived mesenchymal stromal cells decrease prion-induced glial inflammation in vitro. Sci Rep 2022; 12:22567. [PMID: 36581683 PMCID: PMC9800558 DOI: 10.1038/s41598-022-26628-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 12/16/2022] [Indexed: 12/30/2022] Open
Abstract
Prion diseases are characterized by the cellular prion protein, PrPC, misfolding and aggregating into the infectious prion protein, PrPSc, which leads to neurodegeneration and death. An early sign of disease is inflammation in the brain and the shift of resting glial cells to reactive astrocytes and activated microglia. Few therapeutics target this stage of disease. Mesenchymal stromal cells produce anti-inflammatory molecules when exposed to inflammatory signals and damaged tissue. Here, we show that adipose-derived mesenchymal stromal cells (AdMSCs) migrate toward prion-infected brain homogenate and produce the anti-inflammatory molecules transforming growth factor β (TGFβ) and tumor necrosis factor-stimulated gene 6 (TSG-6). In an in vitro model of prion exposure of both primary mixed glia and BV2 microglial cell line, co-culturing with AdMSCs led to a significant decrease in inflammatory cytokine mRNA and markers of reactive astrocytes and activated microglia. This protection against in vitro prion-associated inflammatory responses is independent of PrPSc replication. These data support a role for AdMSCs as a beneficial therapeutic for decreasing the early onset of glial inflammation and reprogramming glial cells to a protective phenotype.
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Affiliation(s)
- Arielle J. D. Hay
- grid.47894.360000 0004 1936 8083Prion Research Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA ,grid.47894.360000 0004 1936 8083Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA
| | - Tanner J. Murphy
- grid.47894.360000 0004 1936 8083Prion Research Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA ,grid.47894.360000 0004 1936 8083Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA ,grid.47894.360000 0004 1936 8083Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA
| | - Katriana A. Popichak
- grid.47894.360000 0004 1936 8083Prion Research Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA ,grid.47894.360000 0004 1936 8083Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA ,grid.47894.360000 0004 1936 8083Present Address: Center for Healthy Aging, Colorado State University, Fort Collins, CO 80523 USA
| | - Mark D. Zabel
- grid.47894.360000 0004 1936 8083Prion Research Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA ,grid.47894.360000 0004 1936 8083Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA ,grid.47894.360000 0004 1936 8083Present Address: Center for Healthy Aging, Colorado State University, Fort Collins, CO 80523 USA
| | - Julie A. Moreno
- grid.47894.360000 0004 1936 8083Prion Research Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA ,grid.47894.360000 0004 1936 8083Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523 USA ,grid.47894.360000 0004 1936 8083Present Address: Center for Healthy Aging, Colorado State University, Fort Collins, CO 80523 USA
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14
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Bone Tissue and the Nervous System: What Do They Have in Common? Cells 2022; 12:cells12010051. [PMID: 36611845 PMCID: PMC9818711 DOI: 10.3390/cells12010051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 12/12/2022] [Accepted: 12/16/2022] [Indexed: 12/25/2022] Open
Abstract
Degenerative diseases affecting bone tissues and the brain represent important problems with high socio-economic impact. Certain bone diseases, such as osteoporosis, are considered risk factors for the progression of neurological disorders. Often, patients with neurodegenerative diseases have bone fractures or reduced mobility linked to osteoarthritis. The bone is a dynamic tissue involved not only in movement but also in the maintenance of mineral metabolism. Bone is also associated with the generation of both hematopoietic stem cells (HSCs), and thus the generation of the immune system, and mesenchymal stem cells (MSCs). Bone marrow is a lymphoid organ and contains MSCs and HSCs, both of which are involved in brain health via the production of cytokines with endocrine functions. Hence, it seems clear that bone is involved in the regulation of the neuronal system and vice versa. This review summarizes the recent knowledge on the interactions between the nervous system and bone and highlights the importance of the interaction between nerve and bone cells. In addition, experimental models that study the interaction between nerve and skeletal cells are discussed, and innovative models are suggested to better evaluate the molecular interactions between these two cell types.
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15
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Srivastava R, Li A, Datta T, Jha NK, Talukder S, Jha SK, Chen ZS. Advances in stromal cell therapy for management of Alzheimer’s disease. Front Pharmacol 2022; 13:955401. [PMID: 36267273 PMCID: PMC9576849 DOI: 10.3389/fphar.2022.955401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 09/08/2022] [Indexed: 11/13/2022] Open
Abstract
Deposition of misfolded proteins and synaptic failure affects the brain in Alzheimer’s disease (AD). Its progression results in amnesia and cognitive impairment. Absence of treatment is due to excessive loss of neurons in the patients and the delayed effects of drugs. The enhanced pluripotency, proliferation, differentiation, and recombination characteristics of stromal cells into nerve cells and glial cells present them as a potential treatment for AD. Successful evidence of action in animal models along with positive results in preclinical studies further encourage its utilization for AD treatment. With regard to humans, cell replacement therapy involving mesenchymal stromal cells, induced-pluripotent stromal cells, human embryonic stromal cells, and neural stems show promising results in clinical trials. However, further research is required prior to its use as stromal cell therapy in AD related disorders. The current review deals with the mechanism of development of anomalies such as Alzheimer’s and the prospective applications of stromal cells for treatment.
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Affiliation(s)
- Rashi Srivastava
- Chemical and Biochemical Engineering, Indian Institute of Technology, Patna, India
| | - Aidong Li
- Department of Rehabilitation, The Second People’s Hospital of Shenzhen, Shenzhen, China
| | - Tirtharaj Datta
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
| | - Salehikram Talukder
- Institute for Biotechnology, St. John’s University, New York City, NY, United States
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
- Department of Biotechnology, School of Applied and Life Sciences, Uttaranchal University, Dehradun, India
- Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, India
- *Correspondence: Saurabh Kumar Jha, ; Zhe-Sheng Chen,
| | - Zhe-Sheng Chen
- Institute for Biotechnology, St. John’s University, New York City, NY, United States
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, New York City, NY, United States
- *Correspondence: Saurabh Kumar Jha, ; Zhe-Sheng Chen,
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16
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López-Ornelas A, Jiménez A, Pérez-Sánchez G, Rodríguez-Pérez CE, Corzo-Cruz A, Velasco I, Estudillo E. The Impairment of Blood-Brain Barrier in Alzheimer's Disease: Challenges and Opportunities with Stem Cells. Int J Mol Sci 2022; 23:ijms231710136. [PMID: 36077533 PMCID: PMC9456198 DOI: 10.3390/ijms231710136] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/28/2022] [Accepted: 09/01/2022] [Indexed: 11/17/2022] Open
Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and its prevalence is increasing. Nowadays, very few drugs effectively reduce AD symptoms and thus, a better understanding of its pathophysiology is vital to design new effective schemes. Presymptomatic neuronal damage caused by the accumulation of Amyloid β peptide and Tau protein abnormalities remains a challenge, despite recent efforts in drug development. Importantly, therapeutic targets, biomarkers, and diagnostic techniques have emerged to detect and treat AD. Of note, the compromised blood-brain barrier (BBB) and peripheral inflammation in AD are becoming more evident, being harmful factors that contribute to the development of the disease. Perspectives from different pre-clinical and clinical studies link peripheral inflammation with the onset and progression of AD. This review aims to analyze the main factors and the contribution of impaired BBB in AD development. Additionally, we describe the potential therapeutic strategies using stem cells for AD treatment.
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Affiliation(s)
- Adolfo López-Ornelas
- División de Investigación, Hospital Juárez de México, Mexico City 07760, Mexico
- Hospital Nacional Homeopático, Hospitales Federales de Referencia, Mexico City 06800, Mexico
| | - Adriana Jiménez
- División de Investigación, Hospital Juárez de México, Mexico City 07760, Mexico
| | - Gilberto Pérez-Sánchez
- Laboratorio de Psicoinmunología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, Ciudad de México 14370, Mexico
| | - Citlali Ekaterina Rodríguez-Pérez
- Laboratorio de Neurofarmacología Molecular y Nanotecnología, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico
| | - Alejandro Corzo-Cruz
- Laboratorio Traslacional, Escuela Militar de Graduados de Sanidad, Secretaría de la Defensa Nacional, Batalla de Celaya 202, Lomas de Sotelo, Miguel Hidalgo, Ciudad de México 11200, Mexico
| | - Iván Velasco
- Instituto de Fisiología Celular—Neurociencias, Universidad Nacional Autónoma de Mexico, Mexico City 04510, Mexico
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico
| | - Enrique Estudillo
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico
- Correspondence:
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17
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Pradhan AU, Uwishema O, Onyeaka H, Adanur I, Dost B. A review of stem cell therapy: An emerging treatment for dementia in Alzheimer's and Parkinson's disease. Brain Behav 2022; 12:e2740. [PMID: 35971625 PMCID: PMC9480940 DOI: 10.1002/brb3.2740] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 07/27/2022] [Indexed: 02/06/2023] Open
Abstract
AIM This article aims to study the benefits and disadvantages of stem cell therapy, especially for patients who have dementia. METHODS The databases PubMed, Google Scholar, and the National Library of Medicine were searched for literature. All papers on Alzheimer's disease, Lewy body dementia, Parkinson's disease, stem cell therapy, and its effect on dementia treatment were considered. RESULTS Stem cell treatment has demonstrated promising outcomes in animal studies by positively modifying the degenerative alterations in dementia. However, it is not without drawbacks, such as ethical concerns while using embryonic stem cells and the danger of developing cancer if the cells undergo uncontrolled differentiation. CONCLUSION Although stem cell therapy has its risks, it has the potential to be a viable therapeutic option for patients with dementia if developed appropriately. Hence, more research and clinical trials are needed to establish its efficacy in this context.
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Affiliation(s)
| | - Olivier Uwishema
- Oli Health Magazine Organization, Research and Education, Kigali, Rwanda.,Department of Research and Project, Clinton Global Initiative University, New York, New York.,Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Helen Onyeaka
- School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham, UK
| | - Irem Adanur
- Oli Health Magazine Organization, Research and Education, Kigali, Rwanda.,Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Burhan Dost
- Department of Anesthesiology, School of Medicine, Ondokuz Mayis University, Kurupelit, Samsun, Turkey
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18
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Li Y, Wu H, Jiang X, Dong Y, Zheng J, Gao J. New idea to promote the clinical applications of stem cells or their extracellular vesicles in central nervous system disorders: combining with intranasal delivery. Acta Pharm Sin B 2022; 12:3215-3232. [PMID: 35967290 PMCID: PMC9366301 DOI: 10.1016/j.apsb.2022.04.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 01/27/2022] [Accepted: 02/14/2022] [Indexed: 12/25/2022] Open
Abstract
The clinical translation of stem cells and their extracellular vesicles (EVs)-based therapy for central nervous system (CNS) diseases is booming. Nevertheless, the insufficient CNS delivery and retention together with the invasiveness of current administration routes prevent stem cells or EVs from fully exerting their clinical therapeutic potential. Intranasal (IN) delivery is a possible strategy to solve problems as IN route could circumvent the brain‒blood barrier non-invasively and fit repeated dosage regimens. Herein, we gave an overview of studies and clinical trials involved with IN route and discussed the possibility of employing IN delivery to solve problems in stem cells or EVs-based therapy. We reviewed relevant researches that combining stem cells or EVs-based therapy with IN administration and analyzed benefits brought by IN route. Finally, we proposed possible suggestions to facilitate the development of IN delivery of stem cells or EVs.
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Affiliation(s)
- Yaosheng Li
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Honghui Wu
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xinchi Jiang
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou 310058, China
| | - Yunfei Dong
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Juanjuan Zheng
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Jianqing Gao
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou 310058, China
- Hangzhou Institute of Innovative Medicine, Zhejiang University, Hangzhou 310058, China
- Corresponding author. Tel.: +86 571 88208436.
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19
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Chiang MH, Ho SM, Wu HY, Lin YC, Tsai WH, Wu T, Lai CH, Wu CL. Drosophila Model for Studying Gut Microbiota in Behaviors and Neurodegenerative Diseases. Biomedicines 2022; 10:596. [PMID: 35327401 PMCID: PMC8945323 DOI: 10.3390/biomedicines10030596] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/01/2022] [Accepted: 03/01/2022] [Indexed: 01/14/2023] Open
Abstract
Mounting evidence indicates that the gut microbiota is linked to several physiological processes and disease development in mammals; however, the underlying mechanisms remained unexplored mostly due to the complexity of the mammalian gut microbiome. The fruit fly, Drosophila melanogaster, is a valuable animal model for studying host-gut microbiota interactions in translational aspects. The availability of powerful genetic tools and resources in Drosophila allowed the scientists to unravel the mechanisms by which the gut microbes affect fitness, health, and behavior of their hosts. Drosophila models have been extensively used not only to study animal behaviors (i.e., courtship, aggression, sleep, and learning & memory), but also some human related neurodegenerative diseases (i.e., Alzheimer's disease and Parkinson's disease) in the past. This review comprehensively summarizes the current understanding of the gut microbiota of Drosophila and its impact on fly behavior, physiology, and neurodegenerative diseases.
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Affiliation(s)
- Meng-Hsuan Chiang
- Graduate Institute of Biomedical Sciences, Department of Biochemistry, Department of Microbiology, Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (M.-H.C.); (S.-M.H.); (H.-Y.W.); (Y.-C.L.)
| | - Shuk-Man Ho
- Graduate Institute of Biomedical Sciences, Department of Biochemistry, Department of Microbiology, Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (M.-H.C.); (S.-M.H.); (H.-Y.W.); (Y.-C.L.)
| | - Hui-Yu Wu
- Graduate Institute of Biomedical Sciences, Department of Biochemistry, Department of Microbiology, Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (M.-H.C.); (S.-M.H.); (H.-Y.W.); (Y.-C.L.)
| | - Yu-Chun Lin
- Graduate Institute of Biomedical Sciences, Department of Biochemistry, Department of Microbiology, Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (M.-H.C.); (S.-M.H.); (H.-Y.W.); (Y.-C.L.)
| | - Wan-Hua Tsai
- Research and Development Department, GenMont Biotech Incorporation, Tainan 74144, Taiwan;
| | - Tony Wu
- Department of Neurology, Molecular Infectious Disease Research Center, Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan;
- Department of Neurology, New Taipei Municipal Tucheng Hospital, Tucheng 23652, Taiwan
- Department of Neurology, Xiamen Chang Gung Hospital, Xiamen 361028, China
| | - Chih-Ho Lai
- Graduate Institute of Biomedical Sciences, Department of Biochemistry, Department of Microbiology, Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (M.-H.C.); (S.-M.H.); (H.-Y.W.); (Y.-C.L.)
- Department of Neurology, Molecular Infectious Disease Research Center, Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan;
- Department of Medical Research, Graduate Institute of Biomedical Sciences, China Medical University and Hospital, Taichung 40402, Taiwan
- Department of Nursing, Asia University, Taichung 41354, Taiwan
| | - Chia-Lin Wu
- Graduate Institute of Biomedical Sciences, Department of Biochemistry, Department of Microbiology, Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (M.-H.C.); (S.-M.H.); (H.-Y.W.); (Y.-C.L.)
- Department of Neurology, Molecular Infectious Disease Research Center, Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan;
- Brain Research Center, National Tsing Hua University, Hsinchu 30013, Taiwan
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20
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The functional mechanism of bone marrow-derived mesenchymal stem cells in the treatment of animal models with Alzheimer's disease: crosstalk between autophagy and apoptosis. Stem Cell Res Ther 2022; 13:90. [PMID: 35241159 PMCID: PMC8895531 DOI: 10.1186/s13287-022-02765-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 11/24/2021] [Indexed: 12/25/2022] 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 mechanism remains undefined. Based on meta-analysis and comprehensive review, high-profile studies support the theory that transplanted BMMSCs activate autophagy, as evidenced by the expression levels of signal molecules such as Beclin-1, Atg5, LC3-II, and mTOR. Functional autophagy mitigates neuronal apoptosis, which is reflected by the alterations of IAPs, Bcl-2, caspase-3, and so forth. Moreover, the transplantation of BMMSCs can decrease aberrant amyloid-beta peptides as well as tau aggregates, inhibit neuroinflammation, and stimulate synaptogenesis. There is a signal crosstalk between autophagy and apoptosis, which may be regulated to produce synergistic effect on the preconditioning of stem cells. Forasmuch, the therapeutic effect of transplanted BMMSCs can be enhanced by autophagy and/or apoptosis modulators.
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21
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Karvelas N, Bennett S, Politis G, Kouris NI, Kole C. Advances in stem cell therapy in Alzheimer's disease: a comprehensive clinical trial review. Stem Cell Investig 2022; 9:2. [PMID: 35280344 PMCID: PMC8898169 DOI: 10.21037/sci-2021-063] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 01/27/2022] [Indexed: 07/30/2023]
Abstract
Alzheimer's disease (AD) is the most common type of dementia responsible for more than 121,499 deaths from AD in 2019 making AD the sixth-leading cause in the United States. AD is a progressive neurodegenerative disorder characterized by decline of memory, behavioral impairments that affects a person's ability to function independently ultimately leading to death. The current pressing need for a treatment for (AD) and advances in the field of cell therapy, has rendered stem cell therapeutics a promising field of research. Despite advancements in stem cell technology, confirmed by encouraging pre-clinical utilization of stem cells in AD animal models, the number of clinical trials evaluating the efficacy of stem cell therapy is limited, with the results of many ongoing clinical trials on cell therapy for AD still pending. Mesenchymal stem cells (MSCs) have been the main focus in these studies, reporting encouraging results concerning safety profile, however their efficacy remains unproven. In the current article we review the latest advances regarding different sources of stem cell therapy and present a comprehensive list of every available clinical trial in national and international registries. Finally, we discuss drawbacks arising from AD pathology and technical limitations that hinder the transition of stem cell technology from bench to bedside. Our findings emphasize the need to increase clinical trials towards uncovering the mode of action and the underlying therapeutic mechanisms of transplanted cells as well as the molecular mechanisms controlling regeneration and neuronal microenvironment.
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Affiliation(s)
- Nikolaos Karvelas
- Faculty of Medicine, National and Kapodistrian University of Athens, Athina, Greece
| | | | - Georgios Politis
- Faculty of Medicine, National and Kapodistrian University of Athens, Athina, Greece
| | | | - Christo Kole
- Faculty of Medicine, National and Kapodistrian University of Athens, Athina, Greece
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22
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Schirò G, Balistreri CR. The close link between brain vascular pathological conditions and neurodegenerative diseases: Focus on some examples and potential treatments. Vascul Pharmacol 2021; 142:106951. [PMID: 34942382 DOI: 10.1016/j.vph.2021.106951] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 12/16/2021] [Indexed: 12/13/2022]
Abstract
A close relationship is emerging among the age-related neurodegenerative decline, and the age-related typical alterations, dysfunctions, and related diseases of the cerobro-and/or cardiovascular system, which contributes in a significative manner to the triggering and progressing of neurodegenerative diseases (NeuroDegD). Specifically, macroinfarcts, microinfarcts, micro-hemorrhages (and particularly their number), atherosclerosis, arteriolosclerosis and cerebral amyloid angiopathy have been documented to be significantly associated with the onset of the cognitive impairment. In addition, vascular alterations and dysfunctions resulting in a reduced cerebral blood flow, and anomalies in the brain blood barrier (BBB), have been also demonstrated to contribute to NeuroDegD pathophysiologic processes. At the same time, such vascular alterations are also observed in cognitively unimpaired subjects. Here, some of these aspects are described with a particular focus on some NeuroDegD, as well as potential strategies for delaying or stopping their onset and progression.
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Affiliation(s)
- Giuseppe Schirò
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90134 Palermo, Italy
| | - Carmela Rita Balistreri
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90134 Palermo, Italy.
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Chen P, Chen F, Lei J, Wang G, Zhou B. The Gut Microbiota Metabolite Urolithin B Improves Cognitive Deficits by Inhibiting Cyt C-Mediated Apoptosis and Promoting the Survival of Neurons Through the PI3K Pathway in Aging Mice. Front Pharmacol 2021; 12:768097. [PMID: 34867396 PMCID: PMC8634731 DOI: 10.3389/fphar.2021.768097] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 10/22/2021] [Indexed: 12/15/2022] Open
Abstract
Background: Despite considerable advances in pharmacotherapy, more effective therapeutic interventions for aging-related neurodegenerative disorders (NDs), such as Alzheimer’s disease (AD), remain limited. Urolithin B (UB), one of the major subcategories of urolithins (microbiota metabolites) found in various tissues after ellagitannin consumption, has been shown to possess antioxidant, anti-inflammatory, and antiapoptotic effects. However, the neuroprotective effect of UB on brain aging in mice and its potential mechanisms were still unknown. Methods: In the current research, we first assessed the ameliorative effects of UB on oxidative injury and apoptosis induced by H2O2 in neuro-2a cells. Then a subcutaneous injection of D-galactose in mice for 8 weeks was used to establish the aging model to evaluate the protective effects of UB. The capacity of memory and learning, alterations of hippocampus histology and corresponding molecular mechanisms were all evaluated. Results: The D-gal-induced accelerated aging model in vivo demonstrated that UB could significantly ameliorate deficits in learning and memory by inhibiting the accumulation of advanced glycation end products (AGEs) and elevating the expression and activity of Cu, Zn-SOD and CAT. Furthermore, UB downregulated the c-Jun N-terminal kinase (JNK) signaling pathway and prevented cytochrome c release from isolated mitochondria, thereby inhibiting neuronal apoptosis during the aging process. More importantly, UB stimulation of aging mice activated ERK and phosphoinositide 3-kinase (PI3K), leading to neuronal survival along with Akt and p44/42 mitogen-activated protein kinase (MAPK) phosphorylation and activation. Conclusion: In summary, UB effectively alleviated cognitive deficits and ameliorated brain aging-related conditions and could be considered a healthcare product to prevent aging-associated NDs such as AD.
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Affiliation(s)
- Peng Chen
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, China
| | - Fuchao Chen
- Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan, China.,Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Shiyan, China
| | - Jiexin Lei
- Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Gaohua Wang
- Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, China
| | - Benhong Zhou
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, China.,Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, China
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24
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Aneesh A, Liu A, Moss HE, Feinstein D, Ravindran S, Mathew B, Roth S. Emerging concepts in the treatment of optic neuritis: mesenchymal stem cell-derived extracellular vesicles. Stem Cell Res Ther 2021; 12:594. [PMID: 34863294 PMCID: PMC8642862 DOI: 10.1186/s13287-021-02645-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/31/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Optic neuritis (ON) is frequently encountered in multiple sclerosis, neuromyelitis optica spectrum disorder, anti-myelin oligodendrocyte glycoprotein associated disease, and other systemic autoimmune disorders. The hallmarks are an abnormal optic nerve and inflammatory demyelination; episodes of optic neuritis tend to be recurrent, and particularly for neuromyelitis optica spectrum disorder, may result in permanent vision loss. MAIN BODY Mesenchymal stem cell (MSC) therapy is a promising approach that results in remyelination, neuroprotection of axons, and has demonstrated success in clinical studies in other neuro-degenerative diseases and in animal models of ON. However, cell transplantation has significant disadvantages and complications. Cell-free approaches utilizing extracellular vesicles (EVs) produced by MSCs exhibit anti-inflammatory and neuroprotective effects in multiple animal models of neuro-degenerative diseases and in rodent models of multiple sclerosis (MS). EVs have potential to be an effective cell-free therapy in optic neuritis because of their anti-inflammatory and remyelination stimulating properties, ability to cross the blood brain barrier, and ability to be safely administered without immunosuppression. CONCLUSION We review the potential application of MSC EVs as an emerging treatment strategy for optic neuritis by reviewing studies in multiple sclerosis and related disorders, and in neurodegeneration, and discuss the challenges and potential rewards of clinical translation of EVs including cell targeting, carrying of therapeutic microRNAs, and prolonging delivery for treatment of optic neuritis.
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Affiliation(s)
- Anagha Aneesh
- Department of Anesthesiology, College of Medicine, University of Illinois, 835 South Wolcott Avenue, Room E714, Chicago, IL, 60612, USA
| | - Alice Liu
- Department of Anesthesiology, College of Medicine, University of Illinois, 835 South Wolcott Avenue, Room E714, Chicago, IL, 60612, USA
| | - Heather E Moss
- Departments of Ophthalmology and Neurology & Neurological Sciences, Stanford University, Palo Alto, CA, USA
| | - Douglas Feinstein
- Department of Anesthesiology, College of Medicine, University of Illinois, 835 South Wolcott Avenue, Room E714, Chicago, IL, 60612, USA
| | - Sriram Ravindran
- Department of Oral Biology, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA
| | - Biji Mathew
- Department of Anesthesiology, College of Medicine, University of Illinois, 835 South Wolcott Avenue, Room E714, Chicago, IL, 60612, USA.
| | - Steven Roth
- Department of Anesthesiology, College of Medicine, University of Illinois, 835 South Wolcott Avenue, Room E714, Chicago, IL, 60612, USA.
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25
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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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26
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Lee DY, Lee SE, Kwon DH, Nithiyanandam S, Lee MH, Hwang JS, Basith S, Ahn JH, Shin TH, Lee G. Strategies to Improve the Quality and Freshness of Human Bone Marrow-Derived Mesenchymal Stem Cells for Neurological Diseases. Stem Cells Int 2021; 2021:8444599. [PMID: 34539792 PMCID: PMC8445711 DOI: 10.1155/2021/8444599] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 08/26/2021] [Indexed: 12/14/2022] Open
Abstract
Human bone marrow-derived mesenchymal stem cells (hBM-MSCs) have been studied for their application to manage various neurological diseases, owing to their anti-inflammatory, immunomodulatory, paracrine, and antiapoptotic ability, as well as their homing capacity to specific regions of brain injury. Among mesenchymal stem cells, such as BM-MSCs, adipose-derived MSCs, and umbilical cord MSCs, BM-MSCs have many merits as cell therapeutic agents based on their widespread availability and relatively easy attainability and in vitro handling. For stem cell-based therapy with BM-MSCs, it is essential to perform ex vivo expansion as low numbers of MSCs are obtained in bone marrow aspirates. Depending on timing, before hBM-MSC transplantation into patients, after detaching them from the culture dish, cell viability, deformability, cell size, and membrane fluidity are decreased, whereas reactive oxygen species generation, lipid peroxidation, and cytosolic vacuoles are increased. Thus, the quality and freshness of hBM-MSCs decrease over time after detachment from the culture dish. Especially, for neurological disease cell therapy, the deformability of BM-MSCs is particularly important in the brain for the development of microvessels. As studies on the traditional characteristics of hBM-MSCs before transplantation into the brain are very limited, omics and machine learning approaches are needed to evaluate cell conditions with indepth and comprehensive analyses. Here, we provide an overview of hBM-MSCs, the application of these cells to various neurological diseases, and improvements in their quality and freshness based on integrated omics after detachment from the culture dish for successful cell therapy.
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Affiliation(s)
- Da Yeon Lee
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Sung Eun Lee
- Department of Emergency Medicine, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Do Hyeon Kwon
- Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea
| | | | - Mi Ha Lee
- Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea
| | - Ji Su Hwang
- Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea
| | - Shaherin Basith
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Jung Hwan Ahn
- Department of Emergency Medicine, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Tae Hwan Shin
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Gwang Lee
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea
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27
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Neves AF, Camargo C, Premer C, Hare JM, Baumel BS, Pinto M. Intravenous administration of mesenchymal stem cells reduces Tau phosphorylation and inflammation in the 3xTg-AD mouse model of Alzheimer's disease. Exp Neurol 2021; 341:113706. [PMID: 33757765 DOI: 10.1016/j.expneurol.2021.113706] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 03/11/2021] [Accepted: 03/17/2021] [Indexed: 12/15/2022]
Abstract
Mesenchymal stem cell (MSC) administration is a novel and promising therapeutic approach for Alzheimer's disease (AD). Focusing on an intervention easily translatable into clinical practice, we administered allogeneic bone marrow-derived MSCs intravenously in a mouse model of AD (3xTg-AD). We systematically evaluated the effects of a single-dose and multiple-doses of MSCs in young and old mice (5 or 10 months old), comparing the short-term and long-term effects after 1, 2, or 7 months of treatment. A single dose of MSCs in young mice attenuated neuroinflammation 1 and 7 months after injection, whereas multiple-doses did not show any effect. Multiple-doses of MSCs (administered at 5 to 12 mo, or 10 to 12 mo) reduced the β-secretase cleavage of the amyloid precursor protein, although levels of Aβ-42 did not change. Most interestingly, multiple doses of MSCs affected tau hyperphosphorylation. MSCs administered in young mice for 7 months decreased the pathological tau phosphorylation at T205, S214, and T231. MSCs administered in old mice for 2 months decreased tau phosphorylation at S396. Our findings show how different timing and frequency of MSC injections can affect and modulate several aspects of the AD-like neuropathology in the 3xTg-AD mouse model, strengthening the concept of fine-tuning MSC therapy for Alzheimer's disease.
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Affiliation(s)
- Amanda Ferreira Neves
- University of Miami Miller School of Medicine, Department of Neurology, 1420 NW 9th Avenue, Miami, FL 33136, United States of America.
| | - Christian Camargo
- University of Miami Miller School of Medicine, Department of Neurology, 1150 Northwest 14th Street, Miami, FL 33136, United States of America.
| | - Courtney Premer
- Interdisciplinary Stem Cell Institute, Biomedical Research Building, 1501 NW 10th Avenue, Suite 909, Miami, FL 33136, United States of America.
| | - Joshua M Hare
- Interdisciplinary Stem Cell Institute, Biomedical Research Building, 1501 NW 10th Avenue, Suite 909, Miami, FL 33136, United States of America.
| | - Bernard S Baumel
- University of Miami Miller School of Medicine, Department of Neurology, 1150 Northwest 14th Street, Miami, FL 33136, United States of America.
| | - Milena Pinto
- University of Miami Miller School of Medicine, Department of Neurology, 1420 NW 9th Avenue, Miami, FL 33136, United States of America.
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28
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Andrzejewska A, Dabrowska S, Lukomska B, Janowski M. Mesenchymal Stem Cells for Neurological Disorders. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2002944. [PMID: 33854883 PMCID: PMC8024997 DOI: 10.1002/advs.202002944] [Citation(s) in RCA: 187] [Impact Index Per Article: 46.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 11/23/2020] [Indexed: 05/13/2023]
Abstract
Neurological disorders are becoming a growing burden as society ages, and there is a compelling need to address this spiraling problem. Stem cell-based regenerative medicine is becoming an increasingly attractive approach to designing therapies for such disorders. The unique characteristics of mesenchymal stem cells (MSCs) make them among the most sought after cell sources. Researchers have extensively studied the modulatory properties of MSCs and their engineering, labeling, and delivery methods to the brain. The first part of this review provides an overview of studies on the application of MSCs to various neurological diseases, including stroke, traumatic brain injury, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, and other less frequently studied clinical entities. In the second part, stem cell delivery to the brain is focused. This fundamental but still understudied problem needs to be overcome to apply stem cells to brain diseases successfully. Here the value of cell engineering is also emphasized to facilitate MSC diapedesis, migration, and homing to brain areas affected by the disease to implement precision medicine paradigms into stem cell-based therapies.
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Affiliation(s)
- Anna Andrzejewska
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
| | - Sylwia Dabrowska
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
| | - Barbara Lukomska
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
| | - Miroslaw Janowski
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
- Center for Advanced Imaging ResearchDepartment of Diagnostic Radiology and Nuclear MedicineUniversity of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer CenterUniversity of MarylandBaltimoreMD21201‐1595USA
- Tumor Immunology and Immunotherapy ProgramUniversity of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer CenterUniversity of MarylandBaltimoreMD21201‐1595USA
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29
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Zhang YT, He KJ, Zhang JB, Ma QH, Wang F, Liu CF. Advances in intranasal application of stem cells in the treatment of central nervous system diseases. Stem Cell Res Ther 2021; 12:210. [PMID: 33762014 PMCID: PMC7992869 DOI: 10.1186/s13287-021-02274-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 03/08/2021] [Indexed: 02/06/2023] Open
Abstract
Stem cells are characterized by their self-renewal and multipotency and have great potential in the therapy of various disorders. However, the blood-brain barrier (BBB) limits the application of stem cells in the therapy of neurological disorders, especially in a noninvasive way. It has been shown that small molecular substances, macromolecular proteins, and even stem cells can bypass the BBB and reach the brain parenchyma following intranasal administration. Here, we review the possible brain-entry routes of transnasal treatment, the cell types, and diseases involved in intranasal stem cell therapy, and discuss its advantages and disadvantages in the treatment of central nervous system diseases, to provide a reference for the application of intranasal stem cell therapy.
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Affiliation(s)
- Yu-Ting Zhang
- Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.,Institute of Neuroscience, Soochow University, Suzhou, 215123, China
| | - Kai-Jie He
- Institute of Neuroscience, Soochow University, Suzhou, 215123, China
| | - Jin-Bao Zhang
- Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.,Institute of Neuroscience, Soochow University, Suzhou, 215123, China
| | - Quan-Hong Ma
- Institute of Neuroscience, Soochow University, Suzhou, 215123, China
| | - Fen Wang
- Institute of Neuroscience, Soochow University, Suzhou, 215123, China.
| | - Chun-Feng Liu
- Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China. .,Institute of Neuroscience, Soochow University, Suzhou, 215123, China.
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30
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Sharma R, Gupta D, Mehrotra R, Mago P. Psychobiotics: The Next-Generation Probiotics for the Brain. Curr Microbiol 2021; 78:449-463. [PMID: 33394083 DOI: 10.1007/s00284-020-02289-5] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 11/07/2020] [Indexed: 12/13/2022]
Abstract
Psychobiotics are a special class of probiotics, which deliver mental health benefits to individuals. They differ from conventional probiotics in their ability to produce or stimulate the production of neurotransmitters, short-chain fatty acids, enteroendocrine hormones and anti-inflammatory cytokines. Owing to this potential, psychobiotics have a broad spectrum of applications ranging from mood and stress alleviation to being an adjuvant in therapeutic treatment for various neurodevelopment and neurodegenerative disorders. The common psychobiotic bacteria belong to the family Lactobacilli, Streptococci, Bifidobacteria, Escherichia and Enterococci. The two-way crosstalk between the brain and the gastrointestinal system is influenced by these bacteria. The neurons present in the enteric nervous system interact directly with the neurochemicals produced by microbiota of the gut, thereby influencing the signaling to central nervous system. The present review highlights the scope and advancements made in the field, enlisting numerous commercial psychobiotic products that have flooded the market. In the latter part we discuss the potential concerns with respect to psychobiotics, such as the effects due to withdrawal, compatibility with immunocompromised patients, and the relatively unregulated probiotic market.
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Affiliation(s)
- Richa Sharma
- Department of Microbiology, Shaheed Rajguru College of Applied Sciences for Women, University of Delhi, New Delhi, 110096, India.
| | - Deesha Gupta
- Department of Microbiology, Shaheed Rajguru College of Applied Sciences for Women, University of Delhi, New Delhi, 110096, India
| | - Rekha Mehrotra
- Department of Microbiology, Shaheed Rajguru College of Applied Sciences for Women, University of Delhi, New Delhi, 110096, India
| | - Payal Mago
- Shaheed Rajguru College of Applied Sciences for Women, University of Delhi, New Delhi, India
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31
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Yu Z, Ling Z, Lu L, Zhao J, Chen X, Xu P, Zou X. Regulatory Roles of Bone in Neurodegenerative Diseases. Front Aging Neurosci 2020; 12:610581. [PMID: 33408628 PMCID: PMC7779400 DOI: 10.3389/fnagi.2020.610581] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 11/24/2020] [Indexed: 12/18/2022] Open
Abstract
Osteoporosis and neurodegenerative diseases are two kinds of common disorders of the elderly, which often co-occur. Previous studies have shown the skeletal and central nervous systems are closely related to pathophysiology. As the main structural scaffold of the body, the bone is also a reservoir for stem cells, a primary lymphoid organ, and an important endocrine organ. It can interact with the brain through various bone-derived cells, mostly the mesenchymal and hematopoietic stem cells (HSCs). The bone marrow is also a place for generating immune cells, which could greatly influence brain functions. Finally, the proteins secreted by bones (osteokines) also play important roles in the growth and function of the brain. This article reviews the latest research studying the impact of bone-derived cells, bone-controlled immune system, and bone-secreted proteins on the brain, and evaluates how these factors are implicated in the progress of neurodegenerative diseases and their potential use in the diagnosis and treatment of these diseases.
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Affiliation(s)
- Zhengran Yu
- Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute/Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zemin Ling
- Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute/Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Lin Lu
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jin Zhao
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiang Chen
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Pingyi Xu
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xuenong Zou
- Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute/Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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32
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Culibrk RA, Hahn MS. The Role of Chronic Inflammatory Bone and Joint Disorders in the Pathogenesis and Progression of Alzheimer's Disease. Front Aging Neurosci 2020; 12:583884. [PMID: 33364931 PMCID: PMC7750365 DOI: 10.3389/fnagi.2020.583884] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 11/06/2020] [Indexed: 12/12/2022] Open
Abstract
Late-onset Alzheimer's Disease (LOAD) is a devastating neurodegenerative disorder that causes significant cognitive debilitation in tens of millions of patients worldwide. Throughout disease progression, abnormal secretase activity results in the aberrant cleavage and subsequent aggregation of neurotoxic Aβ plaques in the cerebral extracellular space and hyperphosphorylation and destabilization of structural tau proteins surrounding neuronal microtubules. Both pathologies ultimately incite the propagation of a disease-associated subset of microglia-the principle immune cells of the brain-characterized by preferentially pro-inflammatory cytokine secretion and inhibited AD substrate uptake capacity, which further contribute to neuronal degeneration. For decades, chronic neuroinflammation has been identified as one of the cardinal pathophysiological driving features of AD; however, despite a number of works postulating the underlying mechanisms of inflammation-mediated neurodegeneration, its pathogenesis and relation to the inception of cognitive impairment remain obscure. Moreover, the limited clinical success of treatments targeting specific pathological features in the central nervous system (CNS) illustrates the need to investigate alternative, more holistic approaches for ameliorating AD outcomes. Accumulating evidence suggests significant interplay between peripheral immune activity and blood-brain barrier permeability, microglial activation and proliferation, and AD-related cognitive decline. In this work, we review a narrow but significant subset of chronic peripheral inflammatory conditions, describe how these pathologies are associated with the preponderance of neuroinflammation, and posit that we may exploit peripheral immune processes to design interventional, preventative therapies for LOAD. We then provide a comprehensive overview of notable treatment paradigms that have demonstrated considerable merit toward treating these disorders.
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Affiliation(s)
| | - Mariah S. Hahn
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, United States
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33
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Watanabe C, Imaizumi T, Kawai H, Suda K, Honma Y, Ichihashi M, Ema M, Mizutani KI. Aging of the Vascular System and Neural Diseases. Front Aging Neurosci 2020; 12:557384. [PMID: 33132896 PMCID: PMC7550630 DOI: 10.3389/fnagi.2020.557384] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 09/01/2020] [Indexed: 12/14/2022] Open
Abstract
Vertebrates have acquired complex high-order functions facilitated by the dispersion of vascular and neural networks to every corner of the body. Blood vessels deliver oxygen and nutrients to all cells and provide essential transport systems for removing waste products. For these functions, tissue vascularization must be spatiotemporally appropriate. Recent studies revealed that blood vessels create a tissue-specific niche, thus attracting attention as biologically active sites for tissue development. Each capillary network is critical for maintaining proper brain function because age-related and disease-related impairment of cognitive function is associated with the loss or diminishment of brain capillaries. This review article highlights how structural and functional alterations in the brain vessels may change with age and neurogenerative diseases. Capillaries are also responsible for filtering toxic byproducts, providing an appropriate vascular environment for neuronal function. Accumulation of amyloid β is a key event in Alzheimer’s disease pathogenesis. Recent studies have focused on associations reported between Alzheimer’s disease and vascular aging. Furthermore, the glymphatic system and meningeal lymphatic systems contribute to a functional unit for clearance of amyloid β from the brain from the central nervous system into the cervical lymph nodes. This review article will also focus on recent advances in stem cell therapies that aim at repopulation or regeneration of a degenerating vascular system for neural diseases.
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Affiliation(s)
- Chisato Watanabe
- Laboratory of Stem Cell Biology, Graduate School of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan.,Department of Stem Cells and Human Disease Models, Research Center for Animal Life Science, Shiga University of Medical Science, Shiga, Japan
| | - Tsutomu Imaizumi
- Basic Research Development Division, Rohto Pharmaceutical Co., Ltd., Osaka, Japan
| | - Hiromi Kawai
- Basic Research Development Division, Rohto Pharmaceutical Co., Ltd., Osaka, Japan
| | - Kazuma Suda
- Basic Research Development Division, Rohto Pharmaceutical Co., Ltd., Osaka, Japan
| | - Yoichi Honma
- Basic Research Development Division, Rohto Pharmaceutical Co., Ltd., Osaka, Japan
| | - Masamitsu Ichihashi
- Laboratory of Stem Cell Biology, Graduate School of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan
| | - Masatsugu Ema
- Department of Stem Cells and Human Disease Models, Research Center for Animal Life Science, Shiga University of Medical Science, Shiga, Japan.,Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University Institute for Advanced Study, Kyoto, Japan
| | - Ken-Ichi Mizutani
- Laboratory of Stem Cell Biology, Graduate School of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan
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34
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Qin C, Lu Y, Wang K, Bai L, Shi G, Huang Y, Li Y. Transplantation of bone marrow mesenchymal stem cells improves cognitive deficits and alleviates neuropathology in animal models of Alzheimer's disease: a meta-analytic review on potential mechanisms. Transl Neurodegener 2020; 9:20. [PMID: 32460886 PMCID: PMC7251864 DOI: 10.1186/s40035-020-00199-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 05/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Alzheimer's disease is a neurodegenerative disorder. Therapeutically, a transplantation of bone marrow mesenchymal stem cells (BMMSCs) can play a beneficial role in animal models of Alzheimer's disease. However, the relevant mechanism remains to be fully elucidated. MAIN BODY Subsequent to the transplantation of BMMSCs, memory loss and cognitive impairment were significantly improved in animal models with Alzheimer's disease (AD). Potential mechanisms involved neurogenesis, apoptosis, angiogenesis, inflammation, immunomodulation, etc. The above mechanisms might play different roles at certain stages. It was revealed that the transplantation of BMMSCs could alter some gene levels. Moreover, the differential expression of representative genes was responsible for neuropathological phenotypes in Alzheimer's disease, which could be used to construct gene-specific patterns. CONCLUSIONS Multiple signal pathways involve therapeutic mechanisms by which the transplantation of BMMSCs improves cognitive and behavioral deficits in AD models. Gene expression profile can be utilized to establish statistical regression model for the evaluation of therapeutic effect. The transplantation of autologous BMMSCs maybe a prospective therapy for patients with 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 Engineering Research Center for Experimental Animal Models of Human Critical Diseases, 5 Panjiayuan Nanli St, Beijing, 100021, China.
| | - Yalan Lu
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, 5 Panjiayuan Nanli St, Beijing, 100021, China
| | - Kewei Wang
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, 5 Panjiayuan Nanli St, Beijing, 100021, China
| | - Lin Bai
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, 5 Panjiayuan Nanli St, Beijing, 100021, China
| | - Guiying Shi
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, 5 Panjiayuan Nanli St, Beijing, 100021, China
| | - Yiying Huang
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, 5 Panjiayuan Nanli St, Beijing, 100021, 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, Shuaifuyuan 1, Dong Cheng District, Beijing, 100730, China
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35
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Pascale A, Marchesi N, Govoni S, Barbieri A. Targeting the microbiota in pharmacology of psychiatric disorders. Pharmacol Res 2020; 157:104856. [PMID: 32389857 DOI: 10.1016/j.phrs.2020.104856] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 04/18/2020] [Accepted: 04/20/2020] [Indexed: 02/07/2023]
Abstract
There is increasing interest in the role of the gut microbiota in health and disease. In particular, gut microbiota influences the Central Nervous System (CNS) development and homeostasis through neural pathways or routes involving the immune and circulatory systems. The CNS, in turn, shapes the intestinal flora through endocrine or stress-mediated responses. These overall bidirectional interactions, known as gut microbiota-brain axis, profoundly affect some brain functions, such as neurogenesis and the production of neurotransmitters, up to influence behavioral aspects of healthy subjects. Consequently, a dysfunction within this axis, as observed in case of dysbiosis, can have an impact on the behavior of a given individual (e.g. anxiety and depression) or on the development of pathologies affecting the CNS, such as autism spectrum disorders and neurodegenerative diseases (e.g. Alzheimer's disease and Parkinson's disease). It should be considered that the whole microbiota has a significant role not only on aspects concerning human physiology, such as harvesting of nutrients and energy from the ingested food or production of a wide range of bioactive compounds, but also has positive effects on the gastrointestinal barrier function and actively contributes to the pharmacokinetics of several compounds including neuropsychiatric drugs. Indeed, the microbiota is able to affect drug absorption and metabolism up to have an impact on drug activity and/or toxicity. On the other hand, drugs are able to shape the human gut microbiota itself, where these changes may contribute to their pharmacologic profile. Therefore, the emerging picture on the complex drug-microbiota bidirectional interplay will have considerable implications in the future not only in terms of clinical practice but also, upstream, on drug development.
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Affiliation(s)
- Alessia Pascale
- Department of Drug Sciences, Pharmacology Section, University of Pavia, Viale Taramelli 14, 27100 Pavia, Italy.
| | - Nicoletta Marchesi
- Department of Drug Sciences, Pharmacology Section, University of Pavia, Viale Taramelli 14, 27100 Pavia, Italy
| | - Stefano Govoni
- Department of Drug Sciences, Pharmacology Section, University of Pavia, Viale Taramelli 14, 27100 Pavia, Italy
| | - Annalisa Barbieri
- Department of Drug Sciences, Pharmacology Section, University of Pavia, Viale Taramelli 14, 27100 Pavia, Italy
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Karaivazoglou K, Konstantakis C, Assimakopoulos SF, Triantos C. Neonate gut colonization: The rise of a social brain. Neurogastroenterol Motil 2020; 32:e13767. [PMID: 31788958 DOI: 10.1111/nmo.13767] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 10/07/2019] [Accepted: 10/30/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND The human gut microbiota constitutes an integral part of human physiology, playing an important role in maintaining health, and compositional or functional changes in intestinal microbiota may be associated with the emergence of several chronic diseases. Animal and human studies have shown that there is a dynamic cross-talk between intestinal microorganisms and brain networks which has an impact on neurodevelopment and may be extremely critical in shaping human social behavior. PURPOSE The aim of the current review is to appraise and present in a concise manner all findings linking the evolution of neonate and infant gut colonization with early social development and to formulate scientifically informed hypotheses which could guide future research on this field.
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Affiliation(s)
- Katerina Karaivazoglou
- Department of Psychiatry, University Hospital of Patras, Rio, Greece.,Centre for Children with Developmental Disorders, EPSYPEA, Mesolongi, Greece
| | - Christos Konstantakis
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Rio, Greece
| | | | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Rio, Greece
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37
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Li A, Zhao J, Fan C, Zhu L, Huang C, Li Q, Gan D, Wen C, Chen M, Lu D. Delivery of exogenous proteins by mesenchymal stem cells attenuates early memory deficits in a murine model of Alzheimer's disease. Neurobiol Aging 2019; 86:81-91. [PMID: 31837910 DOI: 10.1016/j.neurobiolaging.2019.10.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 10/18/2019] [Accepted: 10/20/2019] [Indexed: 01/04/2023]
Abstract
A promising intervention for Alzheimer's disease (AD) would ideally target key pathological factors that are involved in AD pathogenesis. Soluble factors produced by engrafted mesenchymal stem cells (MSCs) mediate potential therapeutic effects in AD. However, these therapeutic benefits are largely hampered by the limited paracrine capacity of MSCs. In this study, we used adenovirus-mediated gene transduction of bone marrow MSCs to deliver exogenous proteins into the brain of APPswe/PSEN1dE9 (APP/PS1) mice in the early stage of impairment. We observed that engrafted MSCs carrying exogenous (C-X3-C motif) ligand 1 (CX3CL1) alone reduced the production of the inflammatory cytokine TNF-ɑ and improved synapse-related protein expression but not cognitive function. Transplantation of MSCs carrying CX3CL1 and Wnt3a (CX3CL1-Wnt3a-MSC) significantly attenuated the learning and memory impairment when compared with a control group. The improvement of neurobehavioral functions in APP/PS1 mice treated with CX3CL1-Wnt3a-MSC was related to the inhibition of microglial neurotoxicity and promotion of hippocampal neurogenesis. Transplantation of CX3CL1-Wnt3a-MSC also regulated phosphoinositide 3-kinase/activated protein kinase B (PI3K/AKT) signaling to inhibit the activity of glycogen synthase kinase 3 beta (GSK3β). Taken together, these results indicate that the delivery of exogenous proteins via MSCs can modulate microglial function and enhance neurogenesis, thereby providing new insights into AD intervention.
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Affiliation(s)
- An Li
- Department of Pathophysiology, School of Basic Medical Sciences, Jinan University, Guangzhou, Guangdong, China
| | - Jiayi Zhao
- Department of Pathophysiology, School of Basic Medical Sciences, Jinan University, Guangzhou, Guangdong, China
| | - Chongzhu Fan
- Department of Pathophysiology, School of Basic Medical Sciences, Jinan University, Guangzhou, Guangdong, China
| | - Lihong Zhu
- Department of Pathophysiology, School of Basic Medical Sciences, Jinan University, Guangzhou, Guangdong, China
| | - Cuiqin Huang
- Department of Pathophysiology, School of Basic Medical Sciences, Jinan University, Guangzhou, Guangdong, China
| | - Qin Li
- Department of Pathophysiology, School of Basic Medical Sciences, Jinan University, Guangzhou, Guangdong, China
| | - Danhui Gan
- Department of Pathophysiology, School of Basic Medical Sciences, Jinan University, Guangzhou, Guangdong, China
| | - Caiyan Wen
- Department of Pathophysiology, School of Basic Medical Sciences, Jinan University, Guangzhou, Guangdong, China
| | - Mengfei Chen
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Daxiang Lu
- Department of Pathophysiology, School of Basic Medical Sciences, Jinan University, Guangzhou, Guangdong, China.
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38
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Bodart-Santos V, de Carvalho LRP, de Godoy MA, Batista AF, Saraiva LM, Lima LG, Abreu CA, De Felice FG, Galina A, Mendez-Otero R, Ferreira ST. Extracellular vesicles derived from human Wharton's jelly mesenchymal stem cells protect hippocampal neurons from oxidative stress and synapse damage induced by amyloid-β oligomers. Stem Cell Res Ther 2019; 10:332. [PMID: 31747944 PMCID: PMC6864996 DOI: 10.1186/s13287-019-1432-5] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 08/26/2019] [Accepted: 09/30/2019] [Indexed: 12/14/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) have been explored as promising tools for treatment of several neurological and neurodegenerative diseases. MSCs release abundant extracellular vesicles (EVs) containing a variety of biomolecules, including mRNAs, miRNAs, and proteins. We hypothesized that EVs derived from human Wharton’s jelly would act as mediators of the communication between hMSCs and neurons and could protect hippocampal neurons from damage induced by Alzheimer’s disease-linked amyloid beta oligomers (AβOs). Methods We isolated and characterized EVs released by human Wharton’s jelly mesenchymal stem cells (hMSC-EVs). The neuroprotective action of hMSC-EVs was investigated in primary hippocampal cultures exposed to AβOs. Results hMSC-EVs were internalized by hippocampal cells in culture, and this was enhanced in the presence of AβOs in the medium. hMSC-EVs protected hippocampal neurons from oxidative stress and synapse damage induced by AβOs. Neuroprotection by hMSC-EVs was mediated by catalase and was abolished in the presence of the catalase inhibitor, aminotriazole. Conclusions hMSC-EVs protected hippocampal neurons from damage induced by AβOs, and this was related to the transfer of enzymatically active catalase contained in EVs. Results suggest that hMSC-EVs should be further explored as a cell-free therapeutic approach to prevent neuronal damage in Alzheimer’s disease.
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Affiliation(s)
- Victor Bodart-Santos
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.,Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.,Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil
| | - Luiza R P de Carvalho
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil
| | - Mariana A de Godoy
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.,Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil
| | - André F Batista
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil
| | - Leonardo M Saraiva
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil
| | - Luize G Lima
- National Cancer Institute, Rio de Janeiro, RJ, 20230-240, Brazil
| | - Carla Andreia Abreu
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil
| | - Fernanda G De Felice
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.,Centre for Neuroscience Studies and Department of Psychiatry, Queen's University, Kingston, Ontario, K7L 3N6, Canada
| | - Antonio Galina
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil
| | - Rosalia Mendez-Otero
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil. .,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, RJ, 21941-590, Brazil.
| | - Sergio T Ferreira
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil. .,Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.
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Boese AC, Hamblin MH, Lee JP. Neural stem cell therapy for neurovascular injury in Alzheimer's disease. Exp Neurol 2019; 324:113112. [PMID: 31730762 DOI: 10.1016/j.expneurol.2019.113112] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 11/02/2019] [Accepted: 11/11/2019] [Indexed: 02/07/2023]
Abstract
Alzheimer's disease (AD), the most common form of dementia, is characterized by progressive neurodegeneration leading to severe cognitive decline and eventual death. AD pathophysiology is complex, but neurotoxic accumulation of amyloid-β (Aβ) and hyperphosphorylation of Tau are believed to be main drivers of neurodegeneration in AD. The formation and deposition of Aβ plaques occurs in the brain parenchyma as well as in the cerebral vasculature. Thus, proper blood-brain barrier (BBB) and cerebrovascular functioning are crucial for clearance of Aβ from the brain, and neurovascular dysfunction may be a critical component of AD development. Further, neuroinflammation and dysfunction of angiogenesis, neurogenesis, and neurorestorative capabilities play a role in AD pathophysiology. Currently, there is no effective treatment to prevent or restore loss of brain tissue and cognitive decline in patients with AD. Based on multifactorial and complex pathophysiological cascades in multiple Alzheimer's disease stages, effective AD therapies need to focus on targeting early AD pathology and preserving cerebrovascular function. Neural stem cells (NSCs) participate extensively in mammalian brain homeostasis and repair and exhibit pleiotropic intrinsic properties that likely make them attractive candidates for the treatment of AD. In the review, we summarize the current advances in knowledge regarding neurovascular aspects of AD-related neurodegeneration and discuss multiple actions of NSCs from preclinical studies of AD to evaluate their potential for future clinical treatment of AD.
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Affiliation(s)
- Austin C Boese
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Milton H Hamblin
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Jean-Pyo Lee
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Brain Institute, Tulane University, New Orleans, LA 70112, USA.
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Ham HJ, Han SB, Yun J, Yeo IJ, Ham YW, Kim SH, Park PH, Choi DY, Hong JT. Bee venom phospholipase A2 ameliorates amyloidogenesis and neuroinflammation through inhibition of signal transducer and activator of transcription-3 pathway in Tg2576 mice. Transl Neurodegener 2019; 8:26. [PMID: 31592103 PMCID: PMC6774221 DOI: 10.1186/s40035-019-0167-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Accepted: 08/12/2019] [Indexed: 12/21/2022] Open
Abstract
Background Neuroinflammation and accumulation of β-amyloid (Aβ) play a significant role in the onset and progression of Alzheimer’s disease (AD). Our previous study demonstrated that signal transducer and activator of transcription-3 (STAT3) plays a major role in neuroinflammation and amyloidogenesis. Methods In the present study, we investigated the inhibitory effect of bee venom phospholipase A2 (bvPLA2) on memory deficiency in Tg2576 mice, which demonstrate genetic characteristics of AD and the mechanism of its action at the cellular and animal level. For in vivo study, we examined the effect of bvPLA2 on improving memory by conducting several behavioral tests with the administration of bvPLA2 (1 mg/kg) to Tg2576 mice. For in vitro study, we examined the effect of bvPLA2 on amyloidogenesis and neuroinflammation by treating bvPLA2 on LPS-activated BV2 cells. Results We found that bvPLA2 alleviated memory impairment in Tg2576 mice, as demonstrated in the behavioral tests assessing memory. In the bvPLA2-treated group, Aβ, amyloid precursor protein (APP), and β-secretase 1 (BACE1) levels and β-secretase activity were significantly decreased. Expression of pro-inflammatory cytokines and inflammation-related proteins decreased in the brain of bvPLA2-treated group, whereas anti-inflammatory cytokines increased. In addition, bvPLA2 reduced STAT3 phosphorylation in the brains of the bvPLA2-treated group. At the cellular level, bvPLA2 inhibits production of nitric oxide, pro-inflammatory cytokines, and inflammation-related proteins including p-STAT3. Additionally, bvPLA2 inhibits the production of Aβ in cultured BV-2 cells. Results from the docking experiment, pull-down assay, and the luciferase assay show that bvPLA2 directly binds STAT3 and, thus, regulates gene expression levels. Moreover, when the STAT3 inhibitor and bvPLA2 were administered together, the anti-amyloidogenic and anti-inflammatory effects were further enhanced than when they were administered alone. Conclusion These results suggest that bvPLA2 could restore memory by inhibiting the accumulation of Aβ and inflammatory responses via blockage of STAT3 activity. Electronic supplementary material The online version of this article (10.1186/s40035-019-0167-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Hyeon Joo Ham
- 1College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 28160 Republic of Korea
| | - Sang-Bae Han
- 1College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 28160 Republic of Korea
| | - Jaesuk Yun
- 1College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 28160 Republic of Korea
| | - In Jun Yeo
- 1College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 28160 Republic of Korea
| | - Young Wan Ham
- 2Department of Chemistry, Utah Valley University, 800 W University Pkwy, Orem, UT 84058 USA
| | - Se Hyun Kim
- INISTst Co., LTD, 767, Sinsu-ro, Suji-gu, Yongin-si, 16827 Gyeonggi-do Republic of Korea
| | - Pil-Hoon Park
- 4College of Pharmacy, Yeungnam University, 280 Daehak Road, Gyeonsan, Gyeongbuk, 38541 Republic of Korea
| | - Dong-Young Choi
- 4College of Pharmacy, Yeungnam University, 280 Daehak Road, Gyeonsan, Gyeongbuk, 38541 Republic of Korea
| | - Jin Tae Hong
- 1College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 28160 Republic of Korea
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Chen P, Chen F, Lei J, Li Q, Zhou B. Activation of the miR-34a-Mediated SIRT1/mTOR Signaling Pathway by Urolithin A Attenuates D-Galactose-Induced Brain Aging in Mice. Neurotherapeutics 2019; 16:1269-1282. [PMID: 31420820 PMCID: PMC6985387 DOI: 10.1007/s13311-019-00753-0] [Citation(s) in RCA: 139] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Despite tremendous advances in modern medicine, effective prevention or therapeutic strategies for age-related neurodegenerative diseases such as Alzheimer's disease (AD) remain limited. Currently, accumulating evidence has demonstrated that microRNAs (miRNAs) are increasingly associated with age-related diseases and are emerging as promising therapeutic targets. Urolithin A, a metabolite compound resulting from the transformation of ellagitannins by gut bacteria, has been reported to have anti-oxidant, anti-inflammatory, and anti-apoptotic properties. The present study primarily focused on the ameliorative effect of urolithin A on aging mice and on the exploration of the potential mechanisms of such an ameliorative effect on cognitive impairment and brain aging. In this study, we first tested the neuroprotective effect of urolithin A using an in vitro H2O2-induced PC12 cell oxidative damage model. The in vivoD-gal-induced brain aging model showed that urolithin A significantly suppressed the upregulation of miR-34a induced by D-gal. Moreover, target genes associated with miR-34a were also examined. Urolithin A supplementation ameliorated apoptosis induced by D-gal and rescued miR-34a overexpression-induced impaired autophagy in brain aging mice after a 2-month administration. Furthermore, urolithin A activated autophagy by upregulating the SIRT1 signaling pathway and downregulating the mTOR signaling pathway. In conclusion, urolithin A may exert neuroprotective effects and may aid in preventing D-gal-induced brain aging through activation of the miR-34a-mediated SIRT1/mTOR signaling pathway.
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Affiliation(s)
- Peng Chen
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
| | - Fuchao Chen
- Department of Pharmacy, Dongfeng Hospital, Hubei University of Medicine, Shiyan, 442008, Hubei, People's Republic of China
| | - Jiexin Lei
- Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
| | - Qiaoling Li
- School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, Hubei, People's Republic of China
| | - Benhong Zhou
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, People's Republic of China.
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Levy ML, Crawford JR, Dib N, Verkh L, Tankovich N, Cramer SC. Phase I/II Study of Safety and Preliminary Efficacy of Intravenous Allogeneic Mesenchymal Stem Cells in Chronic Stroke. Stroke 2019; 50:2835-2841. [PMID: 31495331 DOI: 10.1161/strokeaha.119.026318] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background and Purpose- Stroke is a leading cause of long-term disability. Limited treatment options exist for patients with chronic stroke and substantial functional deficits. The current study examined safety and preliminary efficacy estimates of intravenous allogeneic mesenchymal stem cells in this population. Methods- Entry criteria included ischemic stroke >6 months prior and substantial impairment (National Institutes of Health Stroke Scale score ≥6) and disability. Enrollees received a single intravenous dose of allogeneic ischemia-tolerant mesenchymal stem cells. Phase 1 used a dose-escalation design (3 tiers, n=5 each). Phase 2 was an expanded safety cohort. The primary end point was safety over 1-year. Secondary end points examined behavioral change. Results- In phase 1 (n=15), each dose (0.5, 1.0, and 1.5 million cells/kg body weight) was found safe, so phase 2 subjects (n=21) received 1.5 million cells/kg. At baseline, subjects (n=36) averaged 4.2±4.6 years poststroke, age 61.1±10.8 years, National Institutes of Health Stroke Scale score 8 (6.5-10), and Barthel Index 65±29. Two were lost to follow-up, one was withdrawn and 2 died (unrelated to study treatment). Of 15 serious adverse events, none was possibly or probably related to study treatment. Two mild adverse events were possibly related to study treatment, a urinary tract infection and intravenous site irritation. Treatment was safe based on serial exams, electrocardiograms, laboratory tests, and computed tomography scans of chest/abdomen/pelvis. All behavioral end points showed significant gains over the 12-months of follow-up. For example, Barthel Index scores increased by 6.8±11.4 points (mean±SD) at 6-months (P=0.002) and by 10.8±15.5 points at 12-months (P<0.001) post-infusion; the proportion of patients achieving excellent functional outcome (Barthel score ≥95) increased from 11.4% at baseline to 27.3% at 6-months and to 35.5% at 12-months. Conclusions- Intravenous transfusion of allogeneic ischemia-tolerant mesenchymal stem cell in patients with chronic stroke and substantial functional deficits was safe and suggested behavioral gains. These data support proceeding to a randomized, placebo-controlled study of this therapy in this population. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01297413.
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Affiliation(s)
- Michael L Levy
- From the University of California, San Diego, La Jolla, CA (M.L.L., J.R.C.)
| | - John R Crawford
- From the University of California, San Diego, La Jolla, CA (M.L.L., J.R.C.)
| | - Nabil Dib
- Mercy Gilbert Medical Center and Chandler Regional Medical Center, Chandler, AZ (N.D.)
| | - Lev Verkh
- Stemedica Cell Technologies Inc, San Diego, CA (L.V., N.T.)
| | | | - Steven C Cramer
- Department of Neurology and the Sue & Bill Gross Stem Cell Research Center (S.C.C.), University of California, Irvine
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Human intracerebroventricular (ICV) injection of autologous, non-engineered, adipose-derived stromal vascular fraction (ADSVF) for neurodegenerative disorders: results of a 3-year phase 1 study of 113 injections in 31 patients. Mol Biol Rep 2019; 46:5257-5272. [PMID: 31327120 DOI: 10.1007/s11033-019-04983-5] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Accepted: 07/15/2019] [Indexed: 12/12/2022]
Abstract
We have chosen to test the safety of human intracerebroventricular (ICV) brain injections of autologous non-genetically-modified adipose-derived stromal vascular fraction (ADSVF). In this IRB-approved trial, 24 patients received ICV ADSVF via an implanted reservoir between 5/22/14 and 5/22/17. Seven others were injected via their ventriculo-peritoneal shunts. Ten patients had Alzheimer's disease (AD), 6 had amyotrophic lateral sclerosis (ALS), 6 had progressive multiple sclerosis (MS-P), 6 had Parkinson's "Plus" (PD+), 1 had spinal cord injury, 1 had traumatic brain injury, and 1 had stroke. Median age was 74 (range 41-83). Injections were planned every 2-3 months. Thirty-one patients had 113 injections. Patients received SVF injection volumes of 3.5-20 cc (median:4 cc) containing 4.05 × 105 to 6.2 × 107 cells/cc, which contained an average of 8% hematopoietic and 7.5% adipose stem cells. Follow-up ranged from 0 to 36 months (median: 9.2 months). MRIs post injection(s) were unchanged, except for one AD patient whose hippocampal volume increased from < 5th percentile to 48th percentile (NeuroQuant® volumetric MRI). Of the 10 AD patients, 8 were stable or improved in tests of cognition. Two showed improvement in P-tau and ß-amyloid levels. Of the 6 MS-P patients all are stable or improved. Four of 6 ALS patients died of disease progression. Twelve of 111 injections (11%) led to 1-4 days of transient meningismus, and mild temperature elevation, which resolved with acetaminophen and/or dexamethasone. Two (1.8% of injections) required hospitalization for these symptoms. One patient (0.9% of injections) had his reservoir removed and later replaced for presumed infection. In this Phase 1 safety trial, ADSVF was safely injected into the human brain ventricular system in patients with no other treatment options. Secondary endpoints of clinical improvement or stability were particularly promising in the AD and MS-P groups. These results will be submitted for a Phase 2 FDA-approved trial.
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Urrutia DN, Caviedes P, Mardones R, Minguell JJ, Vega-Letter AM, Jofre CM. Comparative study of the neural differentiation capacity of mesenchymal stromal cells from different tissue sources: An approach for their use in neural regeneration therapies. PLoS One 2019; 14:e0213032. [PMID: 30856179 PMCID: PMC6437714 DOI: 10.1371/journal.pone.0213032] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 02/13/2019] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) can trans/differentiate to neural precursors and/or
mature neurons and promote neuroprotection and neurogenesis. The above could
greatly benefit neurodegenerative disorders as well as in the treatment of
post-traumatic and hereditary diseases of the central nervous system (CNS). In
order to attain an ideal source of adult MSCs for the treatment of CNS diseases,
adipose tissue, bone marrow, skin and umbilical cord derived MSCs were isolated
and studied to explore differences with regard to neural differentiation
capacity. In this study, we demonstrated that MSCs from several tissues can
differentiate into neuron-like cells and differentially express progenitors and
mature neural markers. Adipose tissue MSCs exhibited significantly higher
expression of neural markers and had a faster proliferation rate. Our results
suggest that adipose tissue MSCs are the best candidates for the use in
neurological diseases.
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Affiliation(s)
| | - Pablo Caviedes
- Program of Molecular & Clinical Pharmacology, ICBM, Faculty of
Medicine, Universidad de Chile, Santiago, Chile
- Centro de Biotecnología y Bioingeniería (CeBiB), Departamento de
Ingeniería Química, Biotecnología y Materiales, Facultad de Ciencias Físicas y
Matemáticas, Universidad de Chile, Santiago, Chile
| | - Rodrigo Mardones
- Regenerative Cell Therapy Center, Clinica Las Condes, Santiago,
Chile
- Orthopedic Department, Clinica Las Condes, Santiago,
Chile
| | - José J. Minguell
- Regenerative Cell Therapy Center, Clinica Las Condes, Santiago,
Chile
| | - Ana Maria Vega-Letter
- Program of Traslational Immunology ICIM, Faculty of Medicine, Clinica
Alemana Universidad del Desarrollo, Santiago, Chile
| | - Claudio M. Jofre
- Regenerative Cell Therapy Center, Clinica Las Condes, Santiago,
Chile
- * E-mail:
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Wang S, Colonna M. Microglia in Alzheimer's disease: A target for immunotherapy. J Leukoc Biol 2019; 106:219-227. [PMID: 30725482 DOI: 10.1002/jlb.mr0818-319r] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 01/11/2018] [Accepted: 01/14/2019] [Indexed: 12/29/2022] Open
Abstract
Microglia are resident Mϕs of the CNS that play pleiotropic functions in brain development and homeostasis. Impaired microglial functions are thought to be involved in the onset and progression of various neurodevelopmental and neurodegenerative diseases. Thus, understanding microglia in these settings may indicate new approaches for therapeutic intervention. Here, we review recent evidence implicating microglia in Alzheimer's disease and discuss potential therapeutic strategies targeting microglia and their receptors in this disease.
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Affiliation(s)
- Shoutang Wang
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri, USA
| | - Marco Colonna
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri, USA
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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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Off-label mesenchymal stromal cell treatment in two infants with severe bronchopulmonary dysplasia: clinical course and biomarkers profile. Cytotherapy 2018; 20:1337-1344. [PMID: 30327248 DOI: 10.1016/j.jcyt.2018.09.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 09/12/2018] [Accepted: 09/13/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND Bronchopulmonary dysplasia (BPD) is the most prevalent sequelae of premature birth, for which therapeutic options are currently limited. Mesenchymal stromal cells (MSCs) are a potential therapy for prevention or reversal of BPD. SERIES OF CASES We report on two infants with severe BPD in whom off-label treatment with repeated intravenous doses of allogeneic bone marrow-derived MSCs were administered. We analyzed the temporal profile of serum and tracheal cytokines and growth factors as well as safety, tolerability and clinical response. The administration of repeated intravenous doses of MSCs in two human babies with severe and advanced BPD was feasible and safe and was associated with a decrease of pro-inflammatory molecules and lung injury biomarkers. Both patients were at very advanced stages of BPD with very severe lung fibrosis and did not survive the disease. CONCLUSIONS MSCs are a promising therapy for BPD, but they should be administered in early stages of the disease.
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Ullah I, Chung K, Oh J, Beloor J, Bae S, Lee SC, Lee M, Kumar P, Lee SK. Intranasal delivery of a Fas-blocking peptide attenuates Fas-mediated apoptosis in brain ischemia. Sci Rep 2018; 8:15041. [PMID: 30301943 PMCID: PMC6178348 DOI: 10.1038/s41598-018-33296-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 09/25/2018] [Indexed: 12/22/2022] Open
Abstract
Ischemic stroke-induced neuronal cell death results in the permanent disabling of brain function. Apoptotic mechanisms are thought to play a prominent role in neuronal injury and ample evidence implicates Fas signaling in mediating cell death. In this study, we describe the neuroprotective effects of a Fas-blocking peptide (FBP) that by obstructing Fas signaling in cerebral ischemia inhibits apoptosis. Using an intranasal administration route in a rat model of focal cerebral ischemia, we demonstrate that nose-to-brain delivery of FBP after middle cerebral artery occlusion (MCAO) surgery results in the delivery and retention of FBP in Fas-expressing ischemic areas of the brain. A single intranasal administration of 2 mg/kg FBP resulted in significantly reduced neuronal cell death by inhibiting Fas-mediated apoptosis leading to decreased infarct volumes, reduced neurologic deficit scores and recovery from cerebral ischemia. Intranasally delivered FBP might be a promising strategy for the treatment of cerebral ischemic stroke.
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Affiliation(s)
- Irfan Ullah
- Department of Bioengineering and Institute of Nanoscience and Technology, Hanyang University, Seoul, Korea
- Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - Kunho Chung
- Department of Bioengineering and Institute of Nanoscience and Technology, Hanyang University, Seoul, Korea
- Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - Jungju Oh
- Department of Bioengineering and Institute of Nanoscience and Technology, Hanyang University, Seoul, Korea
| | - Jagadish Beloor
- Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - Sumin Bae
- Department of Bioengineering and Institute of Nanoscience and Technology, Hanyang University, Seoul, Korea
| | - Sangah Clara Lee
- Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, USA
- Department of Behavioral and Social Sciences, Brown University, Providence, RI, USA
| | - Minhyung Lee
- Department of Bioengineering and Institute of Nanoscience and Technology, Hanyang University, Seoul, Korea
| | - Priti Kumar
- Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, USA.
| | - Sang-Kyung Lee
- Department of Bioengineering and Institute of Nanoscience and Technology, Hanyang University, Seoul, Korea.
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Zhang Y, Wang P. Age-Related Increase of Insulin-Degrading Enzyme Is Inversely Correlated with Cognitive Function in APPswe/PS1dE9 Mice. Med Sci Monit 2018; 24:2446-2455. [PMID: 29680859 PMCID: PMC5935016 DOI: 10.12659/msm.909596] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Insulin-degrading enzyme (IDE) is an important regulator for Aβ clearance and diabetes. Although it is indispensable in removing plaques related to onset Alzheimer’s disease (AD) and in degrading insulin related to diabetes, there have been few studies on the dynamic level of IDE in different stages of AD. Material/Methods The present study explored the level IDE protein in different stages of APPswe/PS1dE9 mice and their correlations with cognitive decline. The 4-month-old, 10-month-old, and 18-month-old mice were used as the different age stages of mice. Cognitive function was evaluated using the Morris water maze test. We also observed the level of Aβ plaques in brain regions of different stages. Results The data revealed that the expression of IDE was dramatically higher than in age-matched wild mice at the age of 10 months and 18 months. In terms of distribution, Aβ plaques were deposited mostly in the cortex and hippocampus, especially in 10-month-old and 18-month-old APPswe/PS1dE9 mice. The cognitive function of 4-month-old APPswe/PS1dE9 mice was not significantly differ in spatial learning. However, the cognitive function, both spatial learning and spatial memory, was dramatically lower in 10-month-old and 18-month-old groups. Conclusions There was a positive correlation between the expression of IDE and spatial memory in 10-month-old and 18-month-old APPswe/PS1dE9 mice. The study of this protein may provide reference values for the further study of IDE in Alzheimer’s disease.
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Affiliation(s)
- Yi Zhang
- Department of Clinical Laboratory, Xuanwu Hospital, Capital Medical University, Beijing, China (mainland)
| | - Peichang Wang
- Department of Clinical Laboratory, Xuanwu Hospital, Capital Medical University, Beijing, China (mainland)
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Cenit MC, Sanz Y, Codoñer-Franch P. Influence of gut microbiota on neuropsychiatric disorders. World J Gastroenterol 2017; 23:5486-5498. [PMID: 28852308 PMCID: PMC5558112 DOI: 10.3748/wjg.v23.i30.5486] [Citation(s) in RCA: 256] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 05/08/2017] [Accepted: 07/04/2017] [Indexed: 02/06/2023] Open
Abstract
The last decade has witnessed a growing appreciation of the fundamental role played by an early assembly of a diverse and balanced gut microbiota and its subsequent maintenance for future health of the host. Gut microbiota is currently viewed as a key regulator of a fluent bidirectional dialogue between the gut and the brain (gut-brain axis). A number of preclinical studies have suggested that the microbiota and its genome (microbiome) may play a key role in neurodevelopmental and neurodegenerative disorders. Furthermore, alterations in the gut microbiota composition in humans have also been linked to a variety of neuropsychiatric conditions, including depression, autism and Parkinson's disease. However, it is not yet clear whether these changes in the microbiome are causally related to such diseases or are secondary effects thereof. In this respect, recent studies in animals have indicated that gut microbiota transplantation can transfer a behavioral phenotype, suggesting that the gut microbiota may be a modifiable factor modulating the development or pathogenesis of neuropsychiatric conditions. Further studies are warranted to establish whether or not the findings of preclinical animal experiments can be generalized to humans. Moreover, although different communication routes between the microbiota and brain have been identified, further studies must elucidate all the underlying mechanisms involved. Such research is expected to contribute to the design of strategies to modulate the gut microbiota and its functions with a view to improving mental health, and thus provide opportunities to improve the management of psychiatric diseases. Here, we review the evidence supporting a role of the gut microbiota in neuropsychiatric disorders and the state of the art regarding the mechanisms underlying its contribution to mental illness and health. We also consider the stages of life where the gut microbiota is more susceptible to the effects of environmental stressors, and the possible microbiota-targeted intervention strategies that could improve health status and prevent psychiatric disorders in the near future.
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