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Li J, Gao K, Wang L, Wang J, Qin M, Wang X, Lian K, Li C, Gao S, Sun C. Astrocytes: Therapeutic targets for stroke. Neural Regen Res 2026; 21:1074-1088. [PMID: 40183353 DOI: 10.4103/nrr.nrr-d-24-01062] [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: 09/09/2024] [Accepted: 12/13/2024] [Indexed: 04/05/2025] Open
Abstract
Stroke is the leading cause of mortality globally, ultimately leading to severe, lifelong neurological impairments. Patients often suffer from a secondary cascade of damage, including neuroinflammation, cytotoxicity, oxidative stress, and mitochondrial dysfunction. Regrettably, there is a paucity of clinically available therapeutics to address these issues. Emerging evidence underscores the pivotal roles of astrocytes, the most abundant glial cells in the brain, throughout the various stages of ischemic stroke. In this comprehensive review, we initially provide an overview of the fundamental physiological functions of astrocytes in the brain, emphasizing their critical role in modulating neuronal homeostasis, synaptic activity, and blood-brain barrier integrity. We then delve into the growing body of evidence that highlights the functional diversity and heterogeneity of astrocytes in the context of ischemic stroke. Their well-established contributions to energy provision, metabolic regulation, and neurotransmitter homeostasis, as well as their emerging roles in mitochondrial recovery, neuroinflammation regulation, and oxidative stress modulation following ischemic injury, are discussed in detail. We also explore the cellular and molecular mechanisms underpinning these functions, with particular emphasis on recently identified targets within astrocytes that offer promising prospects for therapeutic intervention. In the final section of this review, we offer a detailed overview of the current therapeutic strategies targeting astrocytes in the treatment of ischemic stroke. These astrocyte-targeting strategies are categorized into traditional small-molecule drugs, microRNAs (miRNAs), stem cell-based therapies, cellular reprogramming, hydrogels, and extracellular vesicles. By summarizing the current understanding of astrocyte functions and therapeutic targeting approaches, we aim to highlight the critical roles of astrocytes during and after stroke, particularly in the pathophysiological development in ischemic stroke. We also emphasize promising avenues for novel, astrocyte-targeted therapeutics that could become clinically available options, ultimately improving outcomes for patients with stroke.
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Affiliation(s)
- Jingxiu Li
- School of Life Science and Technology, Shandong Second Medical University, Weifang, Shandong Province, China
| | - Keyuan Gao
- School of Life Science and Technology, Shandong Second Medical University, Weifang, Shandong Province, China
| | - Lili Wang
- Department of Operating Room, Affiliated Hospital of Shandong Second Medical University, Shandong Second Medical University, Weifang, Shandong Province, China
| | - Jiayue Wang
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- NeuroRe Medical Technology Limited Company, Shanghai, China
| | - Mian Qin
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- NeuroRe Medical Technology Limited Company, Shanghai, China
| | - Xinrui Wang
- School of Life Science and Technology, Shandong Second Medical University, Weifang, Shandong Province, China
| | - Kai Lian
- School of Life Science and Technology, Shandong Second Medical University, Weifang, Shandong Province, China
| | - Chao Li
- Hepatobiliary and Pancreatic Medicine Center, Weifang People's Hospital, Shandong Second Medical University, Weifang, Shandong Province, China
| | - Shan'e Gao
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Chenxi Sun
- School of Life Science and Technology, Shandong Second Medical University, Weifang, Shandong Province, China
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2
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Ray D, Bose P, Mukherjee S, Roy S, Kaity S. Recent drug delivery systems targeting the gut-brain-microbiome axis for the management of chronic diseases. Int J Pharm 2025; 680:125776. [PMID: 40425058 DOI: 10.1016/j.ijpharm.2025.125776] [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: 02/25/2025] [Revised: 05/14/2025] [Accepted: 05/24/2025] [Indexed: 05/29/2025]
Abstract
In recent years, the study of microorganisms and the brain has become increasingly connected. The gut-brain-microbiome axis (GBMA), a bi-directional communication system, is the key part of how the body's bacteria and the brain interact. This system can influence the brain and behaviour. Changes in this relationship have been linked to various mental and physical health conditions. The immune system, tryptophan metabolism, the vagus nerve, and the enteric nervous system all facilitate connections between the gut and brain. Microbes produce Peptidoglycans, branched-chain amino acids, and short-chain fatty acids, which are involved in this communication. Studies suggest the gut microbiome may be involved in conditions like autism, anxiety, obesity, schizophrenia, Parkinson's disease, and Alzheimer's disease. Researchers are exploring the gut-brain connection to cure a variety of disorders, such as neurological disorders, cancers, metabolic problems, and liver diseases. Developing novel drug delivery systems is a key focus in GBMA for therapeutic targeting at various disease pathways. Notable platforms attracting significant interest include silica nanoparticle-based delivery systems for probiotic spores, composite hydrogels formulated from protein isolates and citrus pectin, and biomimetic nanosystems designed for targeted therapeutic delivery. This review summarizes different methods of delivering drugs and using dietary interventions to target the GBMA and treat these conditions in a less invasive way. By understanding how the gut and brain communicate, scientists aim to develop new and more effective therapies for these complex chronic diseases.
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Affiliation(s)
- Debjani Ray
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, West Bengal, India
| | - Piyas Bose
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, West Bengal, India
| | - Saptarshi Mukherjee
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, West Bengal, India
| | - Subhadeep Roy
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, West Bengal, India; Division of Pharmacology, Department of Pharmaceutical Sciences and Technology, BIT, Mesra, Ranchi, India
| | - Santanu Kaity
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, West Bengal, India.
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Zheng F, Lei J, He Z, Ning T, Sun S, Cai Y, Zhao Q, Ma S, Zhang W, Qu J, Liu GH, Wang S. FOXO3-engineered human mesenchymal stem cells efficiently enhance post-ischemic stroke functional rehabilitation. Protein Cell 2025; 16:365-373. [PMID: 39820392 PMCID: PMC12120242 DOI: 10.1093/procel/pwaf004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Accepted: 11/24/2024] [Indexed: 01/19/2025] Open
Affiliation(s)
- Fangshuo Zheng
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Department of Neurology, The Fifth People’s Hospital of Chongqing, Chongqing 400062, China
| | - Jinghui Lei
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Aging Translational Medicine Center, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Zan He
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Aging Translational Medicine Center, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Taixin Ning
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Aging Translational Medicine Center, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Shuhui Sun
- Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Yusheng Cai
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Qian Zhao
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Aging Translational Medicine Center, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Shuai Ma
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- Aging Biomarker Consortium, Beijing 100101, China
| | - Weiqi Zhang
- Aging Biomarker Consortium, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- China National Center for Bioinformation, Beijing 100101, China
- Sino-Danish College, University of Chinese Academy of Sciences, Beijing 101408, China
- Sino-Danish Center for Education and Research, Beijing 101408, China
| | - Jing Qu
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- Aging Biomarker Consortium, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Guang-Hui Liu
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- Aging Biomarker Consortium, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Si Wang
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Aging Translational Medicine Center, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Aging Biomarker Consortium, Beijing 100101, China
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Ke X, Wu Q, Cai S, Wang C, Lu T, Sun Z, Tian X, Wu X, Wang B, Sun B. Dl-3-n-Butylphthalide enhances the survival of rat bone marrow stem cells via a reactive oxygen species mediated Erk1/2 signaling pathway. Brain Res 2025; 1855:149551. [PMID: 40086743 DOI: 10.1016/j.brainres.2025.149551] [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: 12/30/2024] [Revised: 02/23/2025] [Accepted: 03/04/2025] [Indexed: 03/16/2025]
Abstract
Survival of bone marrow stem cells (BMSCs) is crucial for successful bone marrow transplantation. However, the underlying molecular mechanisms remain inadequately understood. Our previous research has demonstrated that dl-3-n-butylphthalide (NBP) can protect rat BMSCs (rBMSCs) from cell death via its antioxidative properties and by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. The findings suggest that the PI3K/Akt pathway may be one of the primary targets through which NBP exert its protective effects. In this study, we explored an additional signaling pathway to further elucidate the molecular mechanisms involved in NBP-mediated protection against oxidative stress injury in rBMSCs. Oxidative stress was induced in rBMSCs using hydrogen peroxide (H2O2), imitating the cerebral ischemia microenvironment surrounding transplanted cells in vitro. The protective effects of NBP on rBMSCs against apoptosis were observed, achieving by decreasing the level of reduce reactive oxygen species (ROS) and malondialdehyde (MDA) while simultaneously increasing the concentration of superoxide dismutase (SOD). Notably, these protective effects were partially inhibited by U0126, an extracellular signal-regulated kinase1/2 (Erk1/2) inhibitor, which enhanced the suppression of NBP's antiapoptotic effects. Our results indicated that NBP could protect rBMSCs from apoptosis through modulation of ROS/Erk pathways. Further investigations are warranted to clarify the unknown mechanisms.
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Affiliation(s)
- Xianjin Ke
- Department of Neurology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, PR China
| | - Qianqian Wu
- Department of Electrophysiology Laboratory, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, PR China
| | - Shikun Cai
- Department of Neurology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, PR China
| | - Chengyun Wang
- Department of Neurology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, PR China
| | - Ting Lu
- Department of Neurology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, PR China
| | - Zhenjie Sun
- Department of Neurology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, PR China
| | - Xiangyang Tian
- Department of Neurology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, PR China
| | - Xian Wu
- Department of Stomatology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, PR China
| | - Bingjian Wang
- Department of Cardiology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, PR China.
| | - Bo Sun
- Department of Neurology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, PR China; Department of Neurology, The Huaian Clinical College of Xuzhou Medical University, Huai'an, Jiangsu 223300, PR China.
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Rinald JH, Troy CM. A review of cell death pathways in hemorrhagic stroke. Front Cell Dev Biol 2025; 13:1570569. [PMID: 40356598 PMCID: PMC12066518 DOI: 10.3389/fcell.2025.1570569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Accepted: 04/15/2025] [Indexed: 05/15/2025] Open
Abstract
Hemorrhagic stroke is a debilitating neurological disease, affecting millions worldwide. Characterized by bleeding in the brain, it is caused by a breakdown of the blood-brain barrier (BBB) and causes damage through the presence of iron in the brain, immune activation and increased intracranial pressure. The goal of this mini-review is to explore the signaling pathways that lead to cell death that are a part of disease progression in hemorrhagic stroke. This mini-review will highlight clinical observations and data, while also incorporating findings using preclinical disease models. There are important roles for apoptosis, necroptosis, necrosis, autophagy, ferroptosis, and pyroptosis in hemorrhagic stroke. Recent work has highlighted the interplay between these phenomena, providing key regulators as potential therapeutic targets, including reactive oxygen species, iron metabolism, and caspases. Therapeutic strategies that can delay or counteract the cytotoxic effects of hemorrhage can improve clinical outcomes in hemorrhagic stroke patients.
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Affiliation(s)
- John H. Rinald
- Neurobiology and Behavior PhD Program, Columbia University, New York, NY, United States
| | - Carol M. Troy
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
- Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
- The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
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6
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Levinson S, Pulli B, Heit JJ. Neuroinflammation and acute ischemic stroke: impact on translational research and clinical care. Front Surg 2025; 12:1501359. [PMID: 40356948 PMCID: PMC12066521 DOI: 10.3389/fsurg.2025.1501359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 04/07/2025] [Indexed: 05/15/2025] Open
Abstract
Background Stroke, encompassing both ischemic and hemorrhagic subtypes, is a leading cause of mortality and disability globally and current treatments remain limited. Neuroinflammation plays a crucial role in the pathophysiology of stroke, influencing both acute injury and long-term recovery. Objective This review aims to provide a comprehensive overview of neuroinflammation in stroke, detailing the mechanisms, clinical implications, and potential therapeutic strategies. Methods A detailed literature review was conducted, focusing on recent advancements in understanding the neuroinflammatory processes in stroke, including the roles of thromboinflammation, blood-brain barrier (BBB) disruption, and the immune response. Results The initial ischemic insult triggers an inflammatory cascade involving both innate and adaptive immune responses. BBB disruption allows peripheral immune cells and neurotoxic substances to infiltrate the brain, exacerbating neuronal damage and increasing the risk of infections such as pneumonia and urinary tract infections. Thromboinflammation, characterized by platelet activation and immune cell interactions, further complicates the ischemic environment. Proteomic studies have identified key biomarkers that offer insights into neuroinflammatory mechanisms and potential therapeutic targets. Advances in imaging techniques, such as PET and MRI, enable real-time monitoring of neuroinflammation, facilitating personalized treatment approaches. Conclusion Neuroinflammation significantly impacts stroke outcomes, presenting both challenges and opportunities for treatment. Current immunologic therapeutic strategies are limited. Future research should aim to further elucidate the complex immune interactions in stroke, refine imaging biomarkers for clinical use, and develop effective interventions to mitigate neuroinflammation.
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Affiliation(s)
- Simon Levinson
- Department of Neurosurgery, School of Medicine, Stanford University, Stanford, CA, United States
| | - Benjamin Pulli
- Department of Radiology, School of Medicine, Stanford University, Stanford, CA, United States
| | - Jeremy J. Heit
- Department of Radiology, School of Medicine, Stanford University, Stanford, CA, United States
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Yang Y, Duan Y, Yue J, Yin Y, Ma Y, Wan X, Shao J. Exosomes: an innovative therapeutic target for cerebral ischemia-reperfusion injury. Front Pharmacol 2025; 16:1552500. [PMID: 40206077 PMCID: PMC11979243 DOI: 10.3389/fphar.2025.1552500] [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: 12/28/2024] [Accepted: 03/17/2025] [Indexed: 04/11/2025] Open
Abstract
Ischemic stroke is caused by artery stenosis or occlusion, which reduces blood flow and may cause brain damage. Treatment includes restoring blood supply; however, ischemia-reperfusion can still aggravate tissue injury. Reperfusion injury can increase levels of reactive oxygen species, exacerbate mitochondrial dysfunction, create excessive autophagy and ferroptosis, and cause inflammation during microglial infiltration. Cerebral ischemia-reperfusion injury (CIRI) is a key challenge in the treatment of ischemic stroke. Currently, thrombolysis (e.g., rt-PA therapy) and mechanical thrombectomy are the primary treatments, but their application is restricted by narrow therapeutic windows (<4.5 h) and risks of hemorrhagic complications. Exosomes reduce CIRI by regulating oxidative stress, mitochondrial autophagy, inflammatory responses, and glial cell polarization. In addition, their noncellular characteristics provide a safer alternative to stem cell therapy. This article reviews the research progress of exosomes in CIRI in recent years.
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Affiliation(s)
- Yuan Yang
- Department of Critical Care Medicine, The Second Affiliated Hospital, Kunming Medical University, Kunming, China
- Department of Anesthesiology, The First Affiliated Hospital, Kunming Medical University, Kunming, China
| | - Yushan Duan
- Department of Critical Care Medicine, The Second Affiliated Hospital, Kunming Medical University, Kunming, China
| | - Jinxi Yue
- Department of Critical Care Medicine, The Second Affiliated Hospital, Kunming Medical University, Kunming, China
| | - Yue Yin
- Department of Critical Care Medicine, The Second Affiliated Hospital, Kunming Medical University, Kunming, China
| | - Yiming Ma
- Department of Critical Care Medicine, The Second Affiliated Hospital, Kunming Medical University, Kunming, China
| | - Xiaohong Wan
- Department of Critical Care Medicine, The Second Affiliated Hospital, Kunming Medical University, Kunming, China
| | - Jianlin Shao
- Department of Anesthesiology, The First Affiliated Hospital, Kunming Medical University, Kunming, China
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Naftaly S, Pery T, Mhajne R, Ashkar A, Davidovich-Pinhas M, Zinger A. Harnessing the Potential of Human Breast Milk to Boost Intestinal Permeability for Nanoparticles and Macromolecules. J Control Release 2025; 379:768-785. [PMID: 39842727 DOI: 10.1016/j.jconrel.2025.01.049] [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: 06/25/2024] [Revised: 01/17/2025] [Accepted: 01/18/2025] [Indexed: 01/24/2025]
Abstract
The intricate interplay between human breast milk, nanoparticles, and macromolecules holds promise for innovative nutritional delivery strategies. Compared to bovine milk and infant formula, this study explores human breast milk's role in modulating intestinal permeability and its impact on nanoparticle and macromolecule transport. Comparative analysis with bovine milk and infant formula reveals significant elevations in permeability with human breast milk, accompanied by a decrease in transepithelial electrical resistance, suggesting enhanced paracellular transport. Mechanistically, human breast milk reduces Zonula occludens-1 levels, suggesting a regulatory role in intestinal barrier function. Through in vitro and ex vivo evaluations, we aim to understand better the mechanisms behind enhanced permeability and how human breast milk affects nanoparticle physicochemical properties, potentially modulating their behavior. Specifically, human breast milk improves the intestinal permeability of liposomes in a porcine intestinal model, with associated changes in the composition of milk proteins corona related to liposome charge. These findings underscore the unexploited potential of human breast milk in facilitating transport across the intestinal barrier, offering novel avenues for human nutritional delivery and therapeutic interventions.
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Affiliation(s)
- Si Naftaly
- Laboratory for Bioinspired Nano Engineering and Translational Therapeutics, Department of Chemical Engineering, Technion-Israel Institute of Technology, Haifa 3200003, Israel
| | - Topaz Pery
- Laboratory for Bioinspired Nano Engineering and Translational Therapeutics, Department of Chemical Engineering, Technion-Israel Institute of Technology, Haifa 3200003, Israel
| | - Rawan Mhajne
- Laboratory for Bioinspired Nano Engineering and Translational Therapeutics, Department of Chemical Engineering, Technion-Israel Institute of Technology, Haifa 3200003, Israel
| | - Areen Ashkar
- Faculty of Biotechnology and Food Engineering, Technion, Israel
| | - Maya Davidovich-Pinhas
- Faculty of Biotechnology and Food Engineering, Technion, Israel; Russell-Berrie Nanotechnology Institute, Technion - Israel Institute of Technology, Haifa 3200003, Israel
| | - Assaf Zinger
- Laboratory for Bioinspired Nano Engineering and Translational Therapeutics, Department of Chemical Engineering, Technion-Israel Institute of Technology, Haifa 3200003, Israel; Russell-Berrie Nanotechnology Institute, Technion - Israel Institute of Technology, Haifa 3200003, Israel; Cardiovascular Sciences Department, Houston Methodist Academic Institute, Houston, TX 77030, United States; Neurosurgery Department, Houston Methodist Academic Institute, Houston, TX 77030, United States; Resnick Sustainability Center of Catalysis, Technion-Israel Institute of Technology, Haifa 3200003, Israel; Bruce and Ruth Rappaport Cancer Research Center, Technion-Israel Institute of Technology, Haifa 3200003, Israel.
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9
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Diane A, Mu-U-Min RBA, Al-Siddiqi HH. Epigenetic memory as crucial contributing factor in directing the differentiation of human iPSC into pancreatic β-cells in vitro. Cell Tissue Res 2025; 399:267-276. [PMID: 39883142 PMCID: PMC11870940 DOI: 10.1007/s00441-025-03952-8] [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: 10/16/2024] [Accepted: 01/20/2025] [Indexed: 01/31/2025]
Abstract
Impaired insulin secretion contributes to the pathogenesis of type 1 diabetes mellitus through autoimmune destruction of pancreatic β-cells and the pathogenesis of severe forms of type 2 diabetes mellitus through β-cell dedifferentiation and other mechanisms. Replenishment of malfunctioning β-cells via islet transplantation has the potential to induce long-term glycemic control in the body. However, this treatment option cannot widely be implemented in clinical due to healthy islet donor shortage. Emerging β-cell replacement with human-induced pluripotent stem cell (iPSC) provides high remedial therapy hopes. Thus, tremendous progress has been made in developing β-cell differentiation protocols in vitro; however, most of the differentiated iPSC-derived β-cells showed immature phenotypes associated with low efficiency depending on the iPSC lines used, creating a crucial barrier for their clinical implementation. Multiple mechanisms including differences in genetic, cell cycle patterns, and mitochondrial dysfunction underlie the defective differentiation propensity of iPSC into insulin-producing β-cells. Accumulating evidence recently indicated that, following the reprogramming, epigenetic memory inherited from parental cells substantially affects the differentiation capacity of many iPSC lines. Therefore, differences in epigenetic signature are likely to be essential contributing factors influencing the propensity of iPSC differentiation. In this review, we will document the impact of the epigenome on the reprogramming efficacy and differentiation potential of iPSCs and how targeting the epigenetic residual memory could be an additional strategy to improve the differentiation efficiency of existing protocols to generate fully functional hPSC-derived pancreatic β-cells for diabetes therapy and drug screening.
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Affiliation(s)
- Abdoulaye Diane
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Qatar Foundation (QF), Hamad Bin Khalifa University (HBKU), Doha, Qatar.
| | - Razik Bin Abdul Mu-U-Min
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Qatar Foundation (QF), Hamad Bin Khalifa University (HBKU), Doha, Qatar
| | - Heba Hussain Al-Siddiqi
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Qatar Foundation (QF), Hamad Bin Khalifa University (HBKU), Doha, Qatar
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10
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Habib P, Steinberg GK. Clinical state and future directions of stem cell therapy in stroke rehabilitation. Exp Neurol 2025; 385:115132. [PMID: 39743037 DOI: 10.1016/j.expneurol.2024.115132] [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: 11/05/2024] [Revised: 12/20/2024] [Accepted: 12/24/2024] [Indexed: 01/04/2025]
Abstract
Despite substantial advances in the acute management of stroke, it remains a leading cause of adult disability and mortality worldwide. Currently, the reperfusion modalities thrombolysis and thrombectomy benefit only a fraction of patients in the hyperacute phase of ischemic stroke. Thus, with the exception of vagal nerve stimulation combined with intensive physical therapy, there are no approved neuroprotective/neurorestorative therapies for stroke survivors. Stem cell therapy is a promising treatment for stroke patients and has been the focus of an increasing number of clinical trials over the past two decades. We provide a comprehensive overview of stem cell therapies available to stroke patients, focusing on the different types and doses of stem cells, timing and route of administration, patient selection, clinical outcomes, translational challenges, and future directions for the field. Information on ongoing and completed studies was retrieved from ClinicalTrials.gov, PubMed, Google Scholar, ICTRP, and Scopus. Autologous bone marrow-derived mononuclear cells (BMMNCs) are the most used, followed by autologous bone marrow stromal cells. IV therapy is typically applied in acute to subacute phases, while IT or IC routes are utilized in chronic phases. Although early-phase trials (Phase I/II) indicate strong safety and tolerability, definitive clinical effectiveness has yet to be unequivocally proven. Cochrane meta-analyses show NIH Stroke Scale improvements, though studies often have high bias and small sample sizes. Larger randomized, double-blind, placebo-controlled trials are ongoing to refine stem cell transplantation protocols, addressing cell type and source, dosage, timing, patient selection, the potential for combination therapies, and clinical efficacy.
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Affiliation(s)
- Pardes Habib
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA; Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA, USA.
| | - Gary K Steinberg
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA; Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA, USA.
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11
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Kuang L, Wu L, Li Y. Extracellular vesicles in tumor immunity: mechanisms and novel insights. Mol Cancer 2025; 24:45. [PMID: 39953480 PMCID: PMC11829561 DOI: 10.1186/s12943-025-02233-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 01/14/2025] [Indexed: 02/17/2025] Open
Abstract
Extracellular vesicles (EVs), nanoscale vesicles secreted by cells, have attracted considerable attention in recent years due to their role in tumor immunomodulation. These vesicles facilitate intercellular communication by transporting proteins, nucleic acids, and other biologically active substances, and they exhibit a dual role in tumor development and immune evasion mechanisms. Specifically, EVs can assist tumor cells in evading immune surveillance and attack by impairing immune cell function or modulating immunosuppressive pathways, thereby promoting tumor progression and metastasis. Conversely, they can also transport and release immunomodulatory factors that stimulate the activation and regulation of the immune system, enhancing the body's capacity to combat malignant diseases. This dual functionality of EVs presents promising avenues and targets for tumor immunotherapy. By examining the biological characteristics of EVs and their influence on tumor immunity, novel therapeutic strategies can be developed to improve the efficacy and relevance of cancer treatment. This review delineates the complex role of EVs in tumor immunomodulation and explores their potential implications for cancer therapeutic approaches, aiming to establish a theoretical foundation and provide practical insights for the advancement of future EVs-based cancer immunotherapy strategies.
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Affiliation(s)
- Liwen Kuang
- School of Medicine, Chongqing University, Chongqing, China
| | - Lei Wu
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Yongsheng Li
- School of Medicine, Chongqing University, Chongqing, China.
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China.
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12
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Udagatti VD, Kumar RD, Rao AG, Sowmya S. Pathological Sequelae of Chronic Vestibular Migraine and Cerebrovascular Insufficiency Leading to Cognitive Decline and Dementia. Indian J Otolaryngol Head Neck Surg 2025; 77:975-982. [PMID: 40070764 PMCID: PMC11890893 DOI: 10.1007/s12070-024-05200-x] [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: 09/28/2024] [Accepted: 11/05/2024] [Indexed: 03/14/2025] Open
Abstract
Chronic vestibular migraine (CVM) and cerebrovascular insufficiency are recognized contributors to cognitive impairment. Vestibular dysfunction affects spatial orientation and balance, while compromised cerebral perfusion impacts neuronal health. This study explores the combined pathological effects of these conditions and their role in cognitive decline and dementia. To evaluate the association between chronic vestibular migraine, cerebrovascular insufficiency, and their potential role in accelerating cognitive decline and the onset of dementia. A patient was evaluated from the ages of 48 to 74 years, initially diagnosed with chronic vestibular migraine and later developing cerebrovascular insufficiency. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) over a 5-year follow-up. Neuroimaging, including MRI and CT angiography, was employed to assess cerebral perfusion and white matter changes. The incidence of dementia was evaluated based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria. The patient with coexisting CVM and cerebrovascular insufficiency demonstrated rapid cognitive decline, with MMSE scores decreasing by an average of 5 points over the follow-up period. Neuroimaging revealed microvascular ischemic changes and white matter lesions. Frequent vestibular migraines were associated with the progression to dementia over years of regular assessment and follow-up. Chronic vestibular migraine and cerebrovascular insufficiency are significantly associated with accelerated cognitive decline and an increased risk of dementia. The presence of white matter lesions and ischemic changes appears to exacerbate neurodegeneration. Early diagnosis and management of vestibular dysfunction and cerebrovascular risk factors may help mitigate cognitive decline and reduce the incidence of dementia in affected patients.
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Affiliation(s)
| | - Rajendran Dinesh Kumar
- Dr.M.G.R. Educational and Research Institute, Rajarajeswari Medical College and Hospital, Department of ENT and Head-Neck Surgery, Bengaluru, Karnataka 560074 India
| | - Ashish Gurudutt Rao
- Dr.M.G.R. Educational and Research Institute, Rajarajeswari Medical College and Hospital, Department of ENT and Head-Neck Surgery, Bengaluru, Karnataka 560074 India
| | - S. Sowmya
- Dr.M.G.R. Educational and Research Institute, Rajarajeswari Medical College and Hospital, Department of ENT and Head-Neck Surgery, Bengaluru, Karnataka 560074 India
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13
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Zhu P, Tan H, Gao H, Wang J, Liu Y, Yang D, Wu T. Potential Mechanism and Perspectives of Mesenchymal Stem Cell Therapy for Ischemic Stroke: A Review. Glob Med Genet 2024; 11:278-284. [PMID: 39224463 PMCID: PMC11368559 DOI: 10.1055/s-0044-1790231] [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: 09/04/2024] Open
Abstract
Mesenchymal stem cells (MSCs), as a stem cell type with multiple differentiation potentials and immune regulatory abilities, have shown broad prospects in the treatment of ischemic stroke in recent years. The main characteristics of MSCs include their self-renewal ability, differentiation potential for different types of cells, and the ability to secrete various bioactive factors such as cytokines, chemokines, and growth factors, which play a key role in tissue repair and regeneration. In the treatment of ischemic stroke, MSCs exert therapeutic effects through various mechanisms, including promoting vascular regeneration of damaged brain tissue, reducing inflammatory responses, and protecting neurons from damage caused by apoptosis. Research have shown that MSCs can promote the repair of ischemic areas by releasing neurotrophic factors and angiogenic factors, while inhibiting immune responses triggered by ischemia, thereby improving neurological function. With the in-depth study of its biological mechanism, MSCs have gradually shown good safety and effectiveness in clinical applications. Therefore, fully exploring and utilizing the potential of MSCs in the treatment of ischemic stroke may provide new ideas and solutions for future neural repair and regenerative medicine.
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Affiliation(s)
- Pengcheng Zhu
- Department of Intervention, Encephalopathy Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China
| | - Hongtu Tan
- Department of Intervention, Encephalopathy Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China
| | - Haobo Gao
- Department of Intervention, Encephalopathy Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China
| | - Jiabin Wang
- Department of Intervention, Encephalopathy Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China
| | - Yangyang Liu
- Department of Intervention, Encephalopathy Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China
| | - Dongyi Yang
- Department of Intervention, Encephalopathy Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China
| | - Tao Wu
- Department of Intervention, Encephalopathy Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, People's Republic of China
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14
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Li Z, Xu P, Deng Y, Duan R, Peng Q, Wang S, Xu Z, Hong Y, Zhang Y. M1 Microglia-Derived Exosomes Promote A1 Astrocyte Activation and Aggravate Ischemic Injury via circSTRN3/miR-331-5p/MAVS/NF-κB Pathway. J Inflamm Res 2024; 17:9285-9305. [PMID: 39588134 PMCID: PMC11587797 DOI: 10.2147/jir.s485252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 11/06/2024] [Indexed: 11/27/2024] Open
Abstract
Background After ischemic stroke (IS), microglia and astrocytes undergo polarization, transforming into a pro-inflammatory phenotype (M1 or A1). According to previous studies, exosomes might play an important role in the interplay between M1 microglia and A1 astrocytes after IS. Methods We used the microglial oxygen-glucose deprivation/reperfusion (OGD/R) model and ultracentrifugation to extract M1 microglial exosomes (M1-exos). Subsequently, we identified circSTRN3 enriched in exosomes through RNA sequencing and detected the role of circSTRN3 in astrocyte activation based on bioinformatics analysis, immunofluorescence, Western blotting, and polymerase chain reaction analysis. We validated these findings in the middle cerebral artery occlusion/reperfusion (MCAO/R) model of adult male C57BL/6J mice. Finally, we confirmed the correlation among circSTRN3, miR-331-5p, and stroke severity score in exosomes isolated from peripheral blood of IS patients. Results Our findings revealed that M1-exos promoted A1 astrocyte activation. CircSTRN3 was abundant in M1-exos, which could sponge miR-331-5p to affect mitochondrial antiviral signaling protein (MAVS), activate NF-κB pathway, and participate in A1 astrocyte activation. In addition, overexpressed circSTRN3 augmented the infarct size and neurological dysfunction in MCAO/R models, while miR-331-5p mimics reversed the effect. Furthermore, circSTRN3 in IS patients was positively correlated with stroke severity score (R 2 = 0.83, P < 0.001), while miR-331-5p demonstrated a negative correlation with the same score (R 2 = 0.81, P < 0.001). Conclusion Taken together, our research indicated that circSTRN3 from M1-exos could promote A1 astrocyte activation and exacerbate ischemic brain injury via miR331-5p/MAVS/NF-κB axis.
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Affiliation(s)
- Zhongyuan Li
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210000, People’s Republic of China
| | - Pengfei Xu
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People’s Republic of China
| | - Yang Deng
- Department of Neurology, Nanjing First Hospital, China Pharmaceutical University, Nanjing, 210006, People’s Republic of China
| | - Rui Duan
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210000, People’s Republic of China
| | - Qiang Peng
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210000, People’s Republic of China
| | - Shiyao Wang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210000, People’s Republic of China
| | - Zhaohan Xu
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210000, People’s Republic of China
| | - Ye Hong
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210000, People’s Republic of China
| | - Yingdong Zhang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210000, People’s Republic of China
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15
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Wang S, He Q, Qu Y, Yin W, Zhao R, Wang X, Yang Y, Guo ZN. Emerging strategies for nerve repair and regeneration in ischemic stroke: neural stem cell therapy. Neural Regen Res 2024; 19:2430-2443. [PMID: 38526280 PMCID: PMC11090435 DOI: 10.4103/1673-5374.391313] [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: 07/19/2023] [Revised: 09/26/2023] [Accepted: 11/10/2023] [Indexed: 03/26/2024] Open
Abstract
Ischemic stroke is a major cause of mortality and disability worldwide, with limited treatment options available in clinical practice. The emergence of stem cell therapy has provided new hope to the field of stroke treatment via the restoration of brain neuron function. Exogenous neural stem cells are beneficial not only in cell replacement but also through the bystander effect. Neural stem cells regulate multiple physiological responses, including nerve repair, endogenous regeneration, immune function, and blood-brain barrier permeability, through the secretion of bioactive substances, including extracellular vesicles/exosomes. However, due to the complex microenvironment of ischemic cerebrovascular events and the low survival rate of neural stem cells following transplantation, limitations in the treatment effect remain unresolved. In this paper, we provide a detailed summary of the potential mechanisms of neural stem cell therapy for the treatment of ischemic stroke, review current neural stem cell therapeutic strategies and clinical trial results, and summarize the latest advancements in neural stem cell engineering to improve the survival rate of neural stem cells. We hope that this review could help provide insight into the therapeutic potential of neural stem cells and guide future scientific endeavors on neural stem cells.
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Affiliation(s)
- Siji Wang
- Stroke Center, Department of Neurology, the First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Qianyan He
- Stroke Center, Department of Neurology, the First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Yang Qu
- Stroke Center, Department of Neurology, the First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Wenjing Yin
- Stroke Center, Department of Neurology, the First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Ruoyu Zhao
- Stroke Center, Department of Neurology, the First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Xuyutian Wang
- Department of Breast Surgery, General Surgery Center, the First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Yi Yang
- Stroke Center, Department of Neurology, the First Hospital of Jilin University, Changchun, Jilin Province, China
- Neuroscience Research Center, Department of Neurology, the First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Zhen-Ni Guo
- Stroke Center, Department of Neurology, the First Hospital of Jilin University, Changchun, Jilin Province, China
- Neuroscience Research Center, Department of Neurology, the First Hospital of Jilin University, Changchun, Jilin Province, China
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16
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Gong S, Cai X, Wang Y, Wang J, Xiao H, Bai L, Zhu J, Li X. Botch improves cognitive impairment after cerebral ischemia associated with microglia-induced A1-type astrocyte activation. Neurobiol Dis 2024; 201:106684. [PMID: 39341511 DOI: 10.1016/j.nbd.2024.106684] [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: 06/25/2024] [Revised: 09/24/2024] [Accepted: 09/26/2024] [Indexed: 10/01/2024] Open
Abstract
Vascular cognitive impairment (VCI) is a clinical syndrome that arises from cerebrovascular issues and associated risk factors, resulting in difficulties in at least one area of cognitive function. VCI has emerged as the second most prevalent type of dementia following Alzheimer's disease, yet there is no effective clinical treatment. Botch, an endogenous Notch1 antagonist, demonstrates neuroprotective effects by inhibiting neuroinflammatory responses mediated through the Notch pathway. While its role in stroke-induced neuroinflammation is well-established, its involvement in VCI remains largely unexplored. This study investigates the role and potential mechanisms of Botch in a rat model of cognitive impairment caused by bilateral common carotid artery occlusion (BCCAO). Firstly, we observed that Botch levels were down-regulated in BCCAO rats, which correlated with increased release of inflammatory cytokines and neuronal damage. Microglia in BCCAO rats released interleukin-1α (IL-1α), tumor necrosis factor-α (TNF-α), and complement component 1q (C1q), leading to the activation of neurotoxic C3+ A1 reactive astrocytes. Then, the down-regulation of Botch exacerbated microglia-mediated inflammation, activated C3+ A1 astrocytes, worsened neuronal damage, and led to a decline in cognitive function. Conversely, the re-expression of Botch alleviated C3+ astrocyte activation, inhibited neuronal damage, and improved mental function. In conclusion, Botch plays a crucial role in inhibiting neuroinflammation induced by type A1 reactive astrocytes. It achieves this by blocking the activation of microglia triggered by the Notch pathway. Ultimately, it inhibits neuronal damage to play a neuroprotective role. These findings suggest that Botch may represent a novel potential target for treating VCI.
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Affiliation(s)
- Siqi Gong
- Department of Neurology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu Province, China
| | - Xiuying Cai
- Department of Neurology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu Province, China
| | - Yue Wang
- Department of Neurology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu Province, China
| | - Jiaxing Wang
- Department of Neurology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu Province, China
| | - Haixing Xiao
- Department of Neurology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu Province, China
| | - Lei Bai
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu Province, China; Institute of Stroke Research, Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu Province, China
| | - Juehua Zhu
- Department of Neurology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu Province, China; Institute of Stroke Research, Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu Province, China.
| | - Xiang Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu Province, China; Institute of Stroke Research, Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu Province, China.
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17
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Gordon J, Borlongan CV. An update on stem cell therapy for stroke patients: Where are we now? J Cereb Blood Flow Metab 2024; 44:1469-1479. [PMID: 38639015 PMCID: PMC11418600 DOI: 10.1177/0271678x241227022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/17/2023] [Accepted: 11/29/2023] [Indexed: 04/20/2024]
Abstract
With a foundation built upon initial work from the 1980s demonstrating graft viability in cerebral ischemia, stem cell transplantation has shown immense promise in promoting survival, enhancing neuroprotection and inducing neuroregeneration, while mitigating both histological and behavioral deficits that frequently accompany ischemic stroke. These findings have led to a number of clinical trials that have thoroughly supported a strong safety profile for stem cell therapy in patients but have generated variable efficacy. As preclinical evidence continues to expand through the investigation of new cell lines and optimization of stem cell delivery, it remains critical for translational models to adhere to the protocols established through basic scientific research. With the recent shift in approach towards utilization of stem cells as a conjunctive therapy alongside standard thrombolytic treatments, key issues including timing, route of administration, and stem cell type must each be appropriately translated from the laboratory in order to resolve the question of stem cell efficacy for cerebral ischemia that ultimately will enhance therapeutics for stroke patients towards improving quality of life.
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Affiliation(s)
- Jonah Gordon
- Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Cesar V Borlongan
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
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18
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Chen X, Qian W, Zhang Y, Zhao P, Lin X, Yang S, Zhuge Q, Ni H. Ginsenoside CK cooperates with bone mesenchymal stem cells to enhance angiogenesis post-stroke via GLUT1 and HIF-1α/VEGF pathway. Phytother Res 2024. [PMID: 38990183 DOI: 10.1002/ptr.8235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 04/08/2024] [Accepted: 04/23/2024] [Indexed: 07/12/2024]
Abstract
The transplantation of bone marrow mesenchymal stem cells (MSCs) in stroke is hindered by the restricted rates of survival and differentiation. Ginsenoside compound K (CK), is reported to have a neuroprotective effect and regulate energy metabolism. We applied CK to investigate if CK could promote the survival of MSCs and differentiation into brain microvascular endothelial-like cells (BMECs), thereby alleviating stroke symptoms. Therefore, transwell and middle cerebral artery occlusion (MCAO) models were used to mimic oxygen and glucose deprivation (OGD) in vitro and in vivo, respectively. Our results demonstrated that CK had a good affinity for GLUT1, which increased the expression of GLUT1 and the production of ATP, facilitated the proliferation and migration of MSCs, and activated the HIF-1α/VEGF signaling pathway to promote MSC differentiation. Moreover, CK cooperated with MSCs to protect BMECs, promote angiogenesis and vascular density, enhance neuronal and astrocytic proliferation, thereby reducing infarct volume and consequently improving neurobehavioral outcomes. These results suggest that the synergistic effects of CK and MSCs could potentially be a promising strategy for stroke.
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Affiliation(s)
- Xijun Chen
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-US Joint Laboratory for Aging and Neurological Disease Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wenqi Qian
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-US Joint Laboratory for Aging and Neurological Disease Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ying Zhang
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-US Joint Laboratory for Aging and Neurological Disease Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Peiqi Zhao
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-US Joint Laboratory for Aging and Neurological Disease Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiangxiang Lin
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-US Joint Laboratory for Aging and Neurological Disease Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Su Yang
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-US Joint Laboratory for Aging and Neurological Disease Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qichuan Zhuge
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-US Joint Laboratory for Aging and Neurological Disease Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Haoqi Ni
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang-US Joint Laboratory for Aging and Neurological Disease Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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19
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Cha Z, Qiao Y, Lu Q, Wang Q, Lu X, Zhou H, Li T. Research progress and challenges of stem cell therapy for ischemic stroke. Front Cell Dev Biol 2024; 12:1410732. [PMID: 39040041 PMCID: PMC11260720 DOI: 10.3389/fcell.2024.1410732] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 06/17/2024] [Indexed: 07/24/2024] Open
Abstract
Ischemic stroke is a significant global cause of death and disability. Currently, treatment options for acute ischemic stroke are limited to intravenous thrombolysis and mechanical recanalization. Therefore, novel neuroprotective strategies are imperative. Stem cell transplantation possesses the capabilities of differentiation, proliferation, neuronal replacement, nerve pathway reconstruction, secretion of nerve growth factors, and enhancement of the microenvironment; thus, it is a potential therapeutic approach for ischemic stroke. In addition, the immunomodulatory function of stem cells and the combined treatment of stem cells and exosomes exhibit a favorable protective effect on brain injury and neurological dysfunction following stroke. Meanwhile, the theory of microbiota-gut-brain axis provides us with a novel perspective for comprehending and managing neurological diseases. Lastly, stem cell transplantation has demonstrated promising outcomes not only in treating ischemic stroke but also in dealing with other neurological disorders, such as brain tumors. Furthermore, challenges related to the tissue source, delivery method, immune response, and timing of transplantation still need to be addressed to optimize the treatment.
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Affiliation(s)
- Zaihong Cha
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Yisheng Qiao
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Qixiong Lu
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Qiyang Wang
- Department of Orthopedics, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Xiaoyang Lu
- Department of Neurosurgery, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Hu Zhou
- Department of Neurosurgery, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Tao Li
- Research Center for Clinical Medicine, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
- Institute of Neurosurgery and Neuroscience, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
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20
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Ruscu M, Glavan D, Surugiu R, Doeppner TR, Hermann DM, Gresita A, Capitanescu B, Popa-Wagner A. Pharmacological and stem cell therapy of stroke in animal models: Do they accurately reflect the response of humans? Exp Neurol 2024; 376:114753. [PMID: 38490317 DOI: 10.1016/j.expneurol.2024.114753] [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: 11/19/2023] [Revised: 02/22/2024] [Accepted: 03/10/2024] [Indexed: 03/17/2024]
Abstract
Cerebrovascular diseases are the second leading cause of death worldwide. Despite significant research investment, the only available therapeutic options are mechanical thrombectomy and tissue plasminogen activator thrombolysis. None of the more than a thousand drugs tested on animal models have proven successful in human clinical trials. Several factors contribute to this poor translation of data from stroke-related animal models to human stroke patients. Firstly, our understanding of the molecular and cellular processes involved in recovering from an ischemic stroke is severely limited. Secondly, although the risk of stroke is particularly high among older patients with comorbidities, most drugs are tested on young, healthy animals in controlled laboratory conditions. Furthermore, in animal models, the tracking of post-stroke recovery typically spans only 3 to 28 days, with occasional extensions to 60 days, whereas human stroke recovery is a more extended and complex process. Thirdly, young animal models often exhibit a considerably higher rate of spontaneous recovery compared to humans following a stroke. Fourth, only a very limited number of animals are utilized for each condition, including control groups. Another contributing factor to the much smaller beneficial effects in humans is that positive outcomes from numerous animal studies are more readily accepted than results reported in human trials that do not show a clear benefit to the patient. Useful recommendations for conducting experiments in animal models, with increased chances of translatability to humans, have been issued by both the STEPS investigative team and the STAIR committee. However, largely, due to economic factors, these recommendations are largely ignored. Furthermore, one might attribute the overall failures in predicting and subsequently developing effective acute stroke therapies beyond thrombolysis to potential design deficiencies in clinical trials.
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Affiliation(s)
- Mihai Ruscu
- Department of Neurology, University Hospital Essen, Essen 45147, Germany; Department of Psychiatry, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania; Department of Neurology, University of Giessen Medical School, 35392 Giessen, Germany
| | - Daniela Glavan
- Department of Psychiatry, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania
| | - Roxana Surugiu
- Department of Psychiatry, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania; Department of Neurology, University Medical Center Göttingen, Göttingen 37075, Germany
| | - Thorsten R Doeppner
- Department of Neurology, University Medical Center Göttingen, Göttingen 37075, Germany; Department of Neurology, University of Giessen Medical School, 35392 Giessen, Germany
| | - Dirk M Hermann
- Department of Neurology, University Hospital Essen, Essen 45147, Germany
| | - Andrei Gresita
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, NY 115680-8000, USA
| | - Bogdan Capitanescu
- Department of Psychiatry, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania; Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, NY 115680-8000, USA.
| | - Aurel Popa-Wagner
- Department of Psychiatry, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania; Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, NY 115680-8000, USA.
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21
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Chen M, Qin Y, Peng Y, Mai R, Teng H, Qi Z, Mo J. Advancing stroke therapy: the potential of MOF-based nanozymes in biomedical applications. Front Bioeng Biotechnol 2024; 12:1363227. [PMID: 38798955 PMCID: PMC11119330 DOI: 10.3389/fbioe.2024.1363227] [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: 12/30/2023] [Accepted: 04/12/2024] [Indexed: 05/29/2024] Open
Abstract
In this study, we explored the growing use of metal-organic framework (MOF)-based Nanozymes in biomedical research, with a specific emphasis on their applications in stroke therapy. We have discussed the complex nature of stroke pathophysiology, highlighting the crucial role of reactive oxygen species (ROS), and acknowledging the limitations of natural enzymes in addressing these challenges. We have also discussed the role of nanozymes, particularly those based on MOFs, their structural similarities to natural enzymes, and their potential to improve reactivity in various biomedical applications. The categorization of MOF nanozymes based on enzyme-mimicking activities is discussed, and their applications in stroke therapy are explored. We have reported the potential of MOF in treating stroke by regulating ROS levels, alleviation inflammation, and reducing neuron apoptosis. Additionally, we have addressed the challenges in developing efficient antioxidant nanozyme systems for stroke treatment. The review concludes with the promise of addressing these challenges and highlights the promising future of MOF nanozymes in diverse medical applications, particularly in the field of stroke treatment.
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Affiliation(s)
- Meirong Chen
- The Guangxi Clinical Research Center for Neurological Diseases, The Affiliated Hospital of Guilin Medical University, Guilin, China
- Medical College of Guangxi University, Nanning, China
| | - Yang Qin
- Department of Graduate and Postgraduate Education Management, The Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Yongmei Peng
- School of Clinical Medicine, Guilin Medical University, Guilin, China
| | - Ruyu Mai
- School of Clinical Medicine, Guilin Medical University, Guilin, China
| | - Huanyao Teng
- School of Clinical Medicine, Guilin Medical University, Guilin, China
| | - Zhongquan Qi
- Medical College of Guangxi University, Nanning, China
| | - Jingxin Mo
- The Guangxi Clinical Research Center for Neurological Diseases, The Affiliated Hospital of Guilin Medical University, Guilin, China
- Lab of Neurology, The Affiliated Hospital of Guilin Medical University, Guilin, China
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22
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Qi L, Wang F, Sun X, Li H, Zhang K, Li J. Recent advances in tissue repair of the blood-brain barrier after stroke. J Tissue Eng 2024; 15:20417314241226551. [PMID: 38304736 PMCID: PMC10832427 DOI: 10.1177/20417314241226551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 12/31/2023] [Indexed: 02/03/2024] Open
Abstract
The selective permeability of the blood-brain barrier (BBB) enables the necessary exchange of substances between the brain parenchyma and circulating blood and is important for the normal functioning of the central nervous system. Ischemic stroke inflicts damage upon the BBB, triggering adverse stroke outcomes such as cerebral edema, hemorrhagic transformation, and aggravated neuroinflammation. Therefore, effective repair of the damaged BBB after stroke and neovascularization that allows for the unique selective transfer of substances from the BBB after stroke is necessary and important for the recovery of brain function. This review focuses on four important therapies that have effects of BBB tissue repair after stroke in the last seven years. Most of these new therapies show increased expression of BBB tight-junction proteins, and some show beneficial results in terms of enhanced pericyte coverage at the injured vessels. This review also briefly outlines three effective classes of approaches and their mechanisms for promoting neoangiogenesis following a stroke.
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Affiliation(s)
- Liujie Qi
- School of Material Science and Engineering & Henan Key Laboratory of Advanced Magnesium Alloy & Key Laboratory of Materials Processing and Mold (Ministry of Education), Zhengzhou University, Zhengzhou, PR China
| | - Fei Wang
- School of Material Science and Engineering & Henan Key Laboratory of Advanced Magnesium Alloy & Key Laboratory of Materials Processing and Mold (Ministry of Education), Zhengzhou University, Zhengzhou, PR China
| | - Xiaojing Sun
- School of Material Science and Engineering & Henan Key Laboratory of Advanced Magnesium Alloy & Key Laboratory of Materials Processing and Mold (Ministry of Education), Zhengzhou University, Zhengzhou, PR China
| | - Hang Li
- School of Material Science and Engineering & Henan Key Laboratory of Advanced Magnesium Alloy & Key Laboratory of Materials Processing and Mold (Ministry of Education), Zhengzhou University, Zhengzhou, PR China
| | - Kun Zhang
- School of Life Science, Zhengzhou University, Zhengzhou, PR China
| | - Jingan Li
- School of Material Science and Engineering & Henan Key Laboratory of Advanced Magnesium Alloy & Key Laboratory of Materials Processing and Mold (Ministry of Education), Zhengzhou University, Zhengzhou, PR China
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23
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Gu C, Li Y, Liu J, Liu S, Long J, Zhang Q, Duan W, Feng T, Huang J, Qiu Y, Ahmed W, Cai H, Hu Y, Wu Y, Chen L. Neural stem cell-derived exosomes-loaded adhesive hydrogel controlled-release promotes cerebral angiogenesis and neurological function in ischemic stroke. Exp Neurol 2023; 370:114547. [PMID: 37743000 DOI: 10.1016/j.expneurol.2023.114547] [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: 04/21/2023] [Revised: 08/31/2023] [Accepted: 09/21/2023] [Indexed: 09/26/2023]
Abstract
OBJECTIVE Ischemic stroke has become one of the leading diseases for international death, which brings burden to the economy and society. Exosomes (Exos) derived following neural stem cells (NSCs) stimulation promote neurogenesis and migration of NSCs. However, Exos themselves are easily to be removed in vivo. Our study is to investigate whether adhesive hyaluronic acid (HAD) hydrogel loading NSCs-derived-Exo (HAD-Exo) would promote the recovery of ischemic stroke. METHODS A mouse model of middle cerebral artery occlusion (MCAO) was established. PBS, Exo, HAD, and HAD-Exo groups were independently stereotactically injected in mice, respectively. The modified neurological severity score scale and behaviour tests were used to evaluate neurological improvement. Neuroimagings were used to observe the improvement of cerebral infarct volume and vessels. Immunofluorescence staining was used to verify the expression of vascular and cell proliferation-related proteins. RESULTS The structural and mechanical property of HAD and HAD-Exo were detected. Behavioral results showed that HAD-Exo significantly improved neurological functions, especially motor function. Neuroimagings showed that HAD-Exo significantly promoted infarct volume and angiogenesis. Immunofluorescence staining showed that HAD-Exo significantly promoted the cerebral angiogenesis and anti-inflammation. CONCLUSION NSCs derived exosomes-loaded adhesive HAD hydrogel controlled-release could promote cerebral angiogenesis and neurological function for ischemic stroke.
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Affiliation(s)
- Chenyang Gu
- Department of Neurosurgery, Neuroscience Centre, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, PR China; Department of Neurology, Affiliated Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, PR China
| | - Yajing Li
- The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Dongguan 523059, PR China
| | - Jiale Liu
- Department of Neurosurgery, Neuroscience Centre, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, PR China
| | - Sitian Liu
- Guangdong Engineering Research Centre for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Medical Biomechanics, Department of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, PR China
| | - Jun Long
- Department of Neurosurgery, Neuroscience Centre, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, PR China
| | - Qiankun Zhang
- Department of Neurosurgery, Neuroscience Centre, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, PR China
| | - Wenjie Duan
- Department of Neurosurgery, Neuroscience Centre, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, PR China
| | - Tingle Feng
- Department of Neurosurgery, Neuroscience Centre, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, PR China
| | - Jiajun Huang
- Department of Neurosurgery, Neuroscience Centre, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, PR China
| | - Yunhui Qiu
- Department of Pathology, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, PR China
| | - Waqas Ahmed
- Department of Neurology, Affiliated Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, PR China
| | - Hengsen Cai
- Department of Neurosurgery, The Second People's Hospital of Pingnan, Pingnan 537300, PR China
| | - Yong Hu
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Hongkong 999077, PR China
| | - Yaobin Wu
- Guangdong Engineering Research Centre for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Medical Biomechanics, Department of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, PR China.
| | - Lukui Chen
- Department of Neurosurgery, Neuroscience Centre, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, PR China.
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24
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Waseem A, Saudamini, Haque R, Janowski M, Raza SS. Mesenchymal stem cell-derived exosomes: Shaping the next era of stroke treatment. NEUROPROTECTION 2023; 1:99-116. [PMID: 38283953 PMCID: PMC10811806 DOI: 10.1002/nep3.30] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 10/05/2023] [Accepted: 11/10/2023] [Indexed: 01/30/2024]
Abstract
Exosome-based treatments are gaining traction as a viable approach to addressing the various issues faced by an ischemic stroke. These extracellular vesicles, mainly produced by Mesenchymal Stem Cells (MSCs), exhibit many properties with substantial therapeutic potential. Exosomes are particularly appealing for stroke therapy because of their low immunogenicity, effective cargo transport, and ability to cross the blood-brain barrier. Their diverse effects include neuroprotection, angiogenesis stimulation, inflammatory response modulation, and cell death pathway attenuation, synergistically promoting neuronal survival, tissue regeneration, and functional recovery. Exosomes also show potential as diagnostic indicators for early stroke identification and customized treatment options. Despite these promising qualities, current exosome-based therapeutics have some limitations. The heterogeneity of exosome release among cell types, difficulty in standardization and isolation techniques, and complications linked to dosage and targeted administration necessitates extensive investigation. It is critical to thoroughly understand exosomal processes and their complicated interactions within the cellular milieu. To improve the practicality and efficacy of exosome-based medicines, research efforts must focus on improving production processes, developing robust evaluation criteria, and developing large-scale isolation techniques. Altogether, exosomes' multifunctional properties offer a new route for transforming stroke treatment and significantly improving patient outcomes.
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Affiliation(s)
- Arshi Waseem
- Laboratory for Stem Cell & Restorative Neurology, Department of Biotechnology, Era's Lucknow Medical College HospitalEra University, SarfarazganjLucknowIndia
| | - Saudamini
- Laboratory for Stem Cell & Restorative Neurology, Department of Biotechnology, Era's Lucknow Medical College HospitalEra University, SarfarazganjLucknowIndia
- Department of BiotechnologyCentral University of South BiharGayaIndia
| | - Rizwanul Haque
- Department of BiotechnologyCentral University of South BiharGayaIndia
| | - Miroslaw Janowski
- Center for Advanced Imaging Research, Department of Diagnostic Radiology and Nuclear MedicineUniversity of MarylandBaltimoreMarylandUSA
| | - Syed S. Raza
- Laboratory for Stem Cell & Restorative Neurology, Department of Biotechnology, Era's Lucknow Medical College HospitalEra University, SarfarazganjLucknowIndia
- Department of Stem Cell Biology and Regenerative Medicine, Era's Lucknow Medical College HospitalEra University, SarfarazganjLucknowIndia
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25
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Sarma S, Deka DJ, Rajak P, Laloo D, Das T, Chetia P, Saha D, Bharali A, Deka B. Potential injectable hydrogels as biomaterials for central nervous system injury: A narrative review. IBRAIN 2023; 9:402-420. [PMID: 38680508 PMCID: PMC11045191 DOI: 10.1002/ibra.12137] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 10/20/2023] [Accepted: 10/27/2023] [Indexed: 05/01/2024]
Abstract
Numerous modalities exist through which the central nervous system (CNS) may sustain injury or impairment, encompassing traumatic incidents, stroke occurrences, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Presently available pharmacological and therapeutic interventions are incapable of restoring or regenerating damaged CNS tissue, leading to substantial unmet clinical needs among patients with CNS ailments or injuries. To address and facilitate the recovery of the impaired CNS, cell-based repair strategies encompass multiple mechanisms, such as neuronal replacement, therapeutic factor secretion, and the promotion of host brain plasticity. Despite the progression of cell-based CNS reparation as a therapeutic strategy throughout the years, substantial barriers have impeded its widespread implementation in clinical settings. The integration of cell technologies with advancements in regenerative medicine utilizing biomaterials and tissue engineering has recently facilitated the surmounting of several of these impediments. This comprehensive review presents an overview of distinct CNS conditions necessitating cell reparation, in addition to exploring potential biomaterial methodologies that enhance the efficacy of treating brain injuries.
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Affiliation(s)
- Santa Sarma
- Girijananda Chowdhury Institute of Pharmaceutical ScienceAssam Science and Technology UniversityGuwahatiAssamIndia
| | - Dhruva J. Deka
- Girijananda Chowdhury Institute of Pharmaceutical ScienceAssam Science and Technology UniversityGuwahatiAssamIndia
| | - Prakash Rajak
- Department of Pharmaceutical SciencesDibrugarh UniversityDibrugarhAssamIndia
| | - Damiki Laloo
- School of Pharmaceutical SciencesGirijananda Chowdhury UniversityGuwahatiAssamIndia
| | - Trishna Das
- School of Pharmaceutical SciencesGirijananda Chowdhury UniversityGuwahatiAssamIndia
| | - Purbajit Chetia
- Department of PharmacologyNETES Institute of Pharmaceutical Science, Nemcare Group of Institutes, MirzaGuwahatiAssamIndia
| | - Dipankar Saha
- School of Pharmaceutical SciencesGirijananda Chowdhury UniversityGuwahatiAssamIndia
| | - Alakesh Bharali
- Department of Pharmaceutical SciencesDibrugarh UniversityDibrugarhAssamIndia
- School of Pharmaceutical SciencesGirijananda Chowdhury UniversityGuwahatiAssamIndia
| | - Bhargab Deka
- School of Pharmaceutical SciencesGirijananda Chowdhury UniversityGuwahatiAssamIndia
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26
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Alvarez MM, Salazar FE, Rodriguez T, D’Egidio F, Borlongan CV, Lee JY. Endogenous Extracellular Vesicles Participate in Brain Remodeling after Ischemic Stroke. Int J Mol Sci 2023; 24:16857. [PMID: 38069179 PMCID: PMC10706116 DOI: 10.3390/ijms242316857] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/21/2023] [Accepted: 11/26/2023] [Indexed: 12/18/2023] Open
Abstract
Brain remodeling after an ischemic stroke represents a promising avenue for exploring the cellular mechanisms of endogenous brain repair. A deeper understanding of these mechanisms is crucial for optimizing the safety and efficacy of neuroprotective treatments for stroke patients. Here, we interrogated the role of extracellular vesicles, particularly exosomes, as potential mediators of endogenous repair within the neurovascular unit (NVU). We hypothesized that these extracellular vesicles may play a role in achieving transient stroke neuroprotection. Using the established ischemic stroke model of middle cerebral artery occlusion in adult rats, we detected a surged in the extracellular vesicle marker CD63 in the peri-infarct area that either juxtaposed or co-localized with GFAP-positive glial cells, MAP2-labeled young neurons, and VEGF-marked angiogenic cells. This novel observation that CD63 exosomes spatially and temporally approximated glial activation, neurogenesis, and angiogenesis suggests that extracellular vesicles, especially exosomes, contribute to the endogenous repair of the NVU, warranting exploration of extracellular vesicle-based stroke therapeutics.
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Affiliation(s)
| | | | | | | | - Cesar V. Borlongan
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA; (M.M.A.); (F.E.S.); (T.R.); (F.D.); (J.-Y.L.)
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27
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Khamis T, Abdelkhalek A, Abdellatif H, Dwidar N, Said A, Ahmed R, Wagdy K, Elgarhy R, Eltahan R, Mohamed H, Said Amer E, Hanna M, Ragab T, Kishk A, Wael J, Sarhan E, Saweres L, Reda M, Elkomy S, Mohamed A, Samy A, Khafaga A, Shaker Y, Yehia H, Alanazi A, Alassiri M, Tîrziu E, Bucur IM, Arisha AH. BM-MSCs alleviate diabetic nephropathy in male rats by regulating ER stress, oxidative stress, inflammation, and apoptotic pathways. Front Pharmacol 2023; 14:1265230. [PMID: 38044936 PMCID: PMC10690373 DOI: 10.3389/fphar.2023.1265230] [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: 07/22/2023] [Accepted: 10/12/2023] [Indexed: 12/05/2023] Open
Abstract
Introduction: Diabetic nephropathy (DN), a chronic kidney disease, is a major cause of end-stage kidney disease worldwide. Mesenchymal stem cells (MSCs) have become a promising option to mitigate several diabetic complications. Methods: In this study, we evaluated the therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) in a rat model of STZ-induced DN. After the confirmation of diabetes, rats were treated with BM-MSCs and sacrificed at week 12 after treatment. Results: Our results showed that STZ-induced DN rats had extensive histopathological changes, significant upregulation in mRNA expression of renal apoptotic markers, ER stress markers, inflammatory markers, fibronectin, and intermediate filament proteins, and reduction of positive immunostaining of PCNA and elevated P53 in kidney tissue compared to the control group. BM-MSC therapy significantly improved renal histopathological changes, reduced renal apoptosis, ER stress, inflammation, and intermediate filament proteins, as well as increased positive immunostaining of PCNA and reduced P53 in renal tissue compared to the STZ-induced DN group. Conclusion: In conclusion, our study indicates that BM-MSCs may have therapeutic potential for the treatment of DN and provide important insights into their potential use as a novel therapeutic approach for DN.
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Affiliation(s)
- Tarek Khamis
- Department of Pharmacology and Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Adel Abdelkhalek
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Hussein Abdellatif
- Department of Human and Clinical Anatomy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
- Anatomy and Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Nourelden Dwidar
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Ahmed Said
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Rama Ahmed
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Kerolos Wagdy
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Rowina Elgarhy
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Rawan Eltahan
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Hisham Mohamed
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Eman Said Amer
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Maria Hanna
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Tarek Ragab
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Abdallah Kishk
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Judy Wael
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Eyad Sarhan
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Linda Saweres
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Mohamed Reda
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Sara Elkomy
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Abdalah Mohamed
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Abdullah Samy
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Ateya Khafaga
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Youliana Shaker
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Hamdy Yehia
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Asma Alanazi
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Mohammed Alassiri
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- Department of Basic Sciences, College of Science and Health Professions, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia
- Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City (KAMC), Ministry of the National Guard—Health Affairs, Riyadh, Saudi Arabia
| | - Emil Tîrziu
- Department of Animal Production and Veterinary Public Health, Faculty of Veterinary Medicine, University of Life Sciences, “King Mihai I” from Timisoara [ULST], Timisoara, Romania
| | - Iulia Maria Bucur
- Department of Animal Production and Veterinary Public Health, Faculty of Veterinary Medicine, University of Life Sciences, “King Mihai I” from Timisoara [ULST], Timisoara, Romania
| | - Ahmed Hamed Arisha
- Department of Animal Physiology and Biochemistry, Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
- Department of Physiology, Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
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28
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Kaur H, Sarmah D, Datta A, Borah A, Yavagal DR, Bhattacharya P. Stem cells alleviate OGD/R mediated stress response in PC12 cells following a co-culture: modulation of the apoptotic cascade through BDNF-TrkB signaling. Cell Stress Chaperones 2023; 28:1041-1051. [PMID: 36622548 PMCID: PMC10746664 DOI: 10.1007/s12192-022-01319-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 12/02/2022] [Accepted: 12/17/2022] [Indexed: 01/10/2023] Open
Abstract
Apoptosis mediated by endoplasmic reticulum (ER) stress plays a crucial role in several neurovascular disorders, including ischemia/reperfusion injury (I/R injury). Previous in vitro and in vivo studies have suggested that following I/R injury, ER stress is vital for mediating CCAT-enhancer-binding protein homologous protein (CHOP) and caspase-12-dependent apoptosis. However, its modulation in the presence of stem cells and the underlying mechanism of cytoprotection remains elusive. In vivo studies from our lab have reported that post-stroke endovascular administration of stem cells renders neuroprotection and regulates apoptosis mediated by ER stress. In the current study, a more robust in vitro validation has been undertaken to decipher the mechanism of stem cell-mediated cytoprotection. Results from our study have shown that oxygen-glucose deprivation/reoxygenation (OGD/R) potentiated ER stress and apoptosis in the pheochromocytoma 12 (PC12) cell line as evident by the increase of protein kinase R (PKR)-like ER kinase (p-PERK), p-Eukaryotic initiation factor 2α subunit (EIF2α), activation transcription factor 4 (ATF4), CHOP, and caspase 12 expressions. Following the co-culture of PC12 cells with MSCs, ER stress was significantly reduced, possibly via modulating the brain-derived neurotrophic factor (BDNF) signaling. Furthermore, inhibition of BDNF by inhibitor K252a abolished the protective effects of BDNF secreted by MSCs following OGD/R. Our study suggests that inhibition of ER stress-associated apoptotic pathway with MSCs co-culture following OGD/R may help to alleviate cellular injury and further substantiate the use of stem cells as a therapeutic modality toward neuroprotection following hypoxic injury or stroke in clinical settings.
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Affiliation(s)
- Harpreet Kaur
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, 382355, India
| | - Deepaneeta Sarmah
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, 382355, India
| | - Aishika Datta
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, 382355, India
| | - Anupom Borah
- Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, 788011, Assam, India
| | - Dileep R Yavagal
- Department of Neurology and Neurosurgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Pallab Bhattacharya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, 382355, India.
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29
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Zou X, Xie Y, Zhang Z, Feng Z, Han J, Ouyang Q, Hua S, Huang S, Li C, Liu Z, Cai Y, Zou Y, Tang Y, Chen H, Jiang X. MCPIP-1 knockdown enhances endothelial colony-forming cell angiogenesis via the TFRC/AKT/mTOR signaling pathway in the ischemic penumbra of MCAO mice. Exp Neurol 2023; 369:114532. [PMID: 37689231 DOI: 10.1016/j.expneurol.2023.114532] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 08/10/2023] [Accepted: 08/30/2023] [Indexed: 09/11/2023]
Abstract
Cerebral ischemia is a serious disease characterized by brain tissue ischemia and hypoxic necrosis caused by the blockage of blood vessels within the central nervous system. Although stem cell therapy is a promising approach for treating ischemic stroke, the inflammatory, oxidative, and hypoxic environment generated by cerebral ischemia greatly reduces the survival and therapeutic effects of transplanted stem cells. Endothelial colony-forming cells (ECFCs) are a class of precursor cells with strong proliferative potential that can migrate and differentiate directly into mature vascular endothelial cells. Consequently, ECFCs can exert significant therapeutic and reparative effects in diseases associated with vascular injury. Monocyte chemoattractant protein-induced protein 1 (MCPIP-1) exerts multiple biological effects; however, no studies have yet reported its role in the angiogenic function of ECFCs. In this study, we performed Proteome Profiler™ Human Angiogenesis Antibody arrays and tandem mass tag protein profiling to investigate the effect of MCPIP-1 on ECFCs. We demonstrated that MCPIP-1 knockdown enhanced the proliferation, migration, and in vivo and in vitro angiogenic capacity of ECFCs by upregulating the transferrin receptor-activated AKT/m-TOR signaling pathway to promote cellular trophic factor secretion. Furthermore, we found that the lateral ventricular transplantation of ECFCs with lentiviral MCPIP-1 knockdown into mice with middle cerebral artery occlusion increased serum vacular endothelial growth factor(VEGF), angiopoietin-1, and HIF-1a levels, enhanced neovascularization and neurogenesis in the ischemic penumbra, reduced the size of cerebral infarcts, and promoted neurological recovery. Together, these findings suggest new avenues for enhancing the therapeutic efficacy of ECFCs.
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Affiliation(s)
- Xiaoxiong Zou
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Yu Xie
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Zhongfei Zhang
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Zhiming Feng
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Jianbang Han
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Qian Ouyang
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Shiting Hua
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Sixian Huang
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Cong Li
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Zhizheng Liu
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Yingqian Cai
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Yuxi Zou
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Yanping Tang
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Haijia Chen
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Xiaodan Jiang
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
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Markowska A, Koziorowski D, Szlufik S. Microglia and Stem Cells for Ischemic Stroke Treatment-Mechanisms, Current Status, and Therapeutic Challenges. FRONT BIOSCI-LANDMRK 2023; 28:269. [PMID: 37919085 DOI: 10.31083/j.fbl2810269] [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: 07/28/2023] [Revised: 09/07/2023] [Accepted: 09/12/2023] [Indexed: 11/04/2023]
Abstract
Ischemic stroke is one of the major causes of death and disability. Since the currently used treatment option of reperfusion therapy has several limitations, ongoing research is focusing on the neuroprotective effects of microglia and stem cells. By exerting the bystander effect, secreting exosomes and forming biobridges, mesenchymal stem cells (MSCs), neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), and multilineage-differentiating stress-enduring cells (Muse cells) have been shown to stimulate neurogenesis, angiogenesis, cell migration, and reduce neuroinflammation. Exosome-based therapy is now being extensively researched due to its many advantageous properties over cell therapy, such as lower immunogenicity, no risk of blood vessel occlusion, and ease of storage and modification. However, although preclinical studies have shown promising therapeutic outcomes, clinical trials have been associated with several translational challenges. This review explores the therapeutic effects of preconditioned microglia as well as various factors secreted in stem cell-derived extracellular vesicles with their mechanisms of action explained. Furthermore, an overview of preclinical and clinical studies is presented, explaining the main challenges of microglia and stem cell therapies, and providing potential solutions. In particular, a highlight is the use of novel stem cell therapy of Muse cells, which bypasses many of the conventional stem cell limitations. The paper concludes with suggestions for directions in future neuroprotective research.
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Affiliation(s)
- Aleksandra Markowska
- Department of Neurology, Faculty of Health Sciences, Medical University of Warsaw, 03-242 Warsaw, Poland
| | - Dariusz Koziorowski
- Department of Neurology, Faculty of Health Sciences, Medical University of Warsaw, 03-242 Warsaw, Poland
| | - Stanisław Szlufik
- Department of Neurology, Faculty of Health Sciences, Medical University of Warsaw, 03-242 Warsaw, Poland
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31
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Tan R, Hu X, Wang X, Sun M, Cai Z, Zhang Z, Fu Y, Chen X, An J, Lu H. Leptin Promotes the Proliferation and Neuronal Differentiation of Neural Stem Cells through the Cooperative Action of MAPK/ERK1/2, JAK2/STAT3 and PI3K/AKT Signaling Pathways. Int J Mol Sci 2023; 24:15151. [PMID: 37894835 PMCID: PMC10606644 DOI: 10.3390/ijms242015151] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/08/2023] [Accepted: 10/09/2023] [Indexed: 10/29/2023] Open
Abstract
The potential of neural stem cells (NSCs) for neurological disorders the treatment has relied in large part upon identifying the NSCs fate decision. The hormone leptin has been reported to be a crucial regulator of brain development, able to influence the glial and neural development, yet, the underlying mechanism of leptin acting on NSCs' biological characteristics is still poorly understood. This study aims to investigate the role of leptin in the biological properties of NSCs. In this study, we investigate the possibility that leptin may regulate the NSCs' fate decision, which may promote the proliferation and neuronal differentiation of NSCs and thus act positively in neurological disorders. NSCs from the embryonic cerebral cortex were used in this study. We used CCK-8 assay, ki67 immunostaining, and FACS analysis to confirm that 25-100 ng/mL leptin promotes the proliferation of NSCs in a concentration-dependent pattern. This change was accompanied by the upregulation of p-AKT and p-ERK1/2, which are the classical downstream signaling pathways of leptin receptors b (LepRb). Inhibition of PI3K/AKT or MAPK/ERK signaling pathways both abolished the effect of leptin-induced proliferation. Moreover, leptin also enhanced the directed neuronal differentiation of NSCs. A blockade of the PI3K/AKT pathway reversed leptin-stimulated neurogenesis, while a blockade of JAK2/STAT3 had no effect on it. Taken together, our results support a role for leptin in regulating the fate of NSCs differentiation and promoting NSCs proliferation, which could be a promising approach for brain repair via regulating the biological characteristics of NSCs.
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Affiliation(s)
- Ruolan Tan
- Department of Neurobiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an 710061, China; (R.T.); (X.H.); (X.W.); (M.S.); (Z.C.); (Z.Z.); (Y.F.); (X.C.)
- Department of Human Anatomy and Histo-Embryology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an 710061, China
| | - Xiaoxuan Hu
- Department of Neurobiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an 710061, China; (R.T.); (X.H.); (X.W.); (M.S.); (Z.C.); (Z.Z.); (Y.F.); (X.C.)
- Department of Human Anatomy and Histo-Embryology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an 710061, China
| | - Xinyi Wang
- Department of Neurobiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an 710061, China; (R.T.); (X.H.); (X.W.); (M.S.); (Z.C.); (Z.Z.); (Y.F.); (X.C.)
- Department of Human Anatomy and Histo-Embryology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an 710061, China
| | - Meiqi Sun
- Department of Neurobiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an 710061, China; (R.T.); (X.H.); (X.W.); (M.S.); (Z.C.); (Z.Z.); (Y.F.); (X.C.)
| | - Zhenlu Cai
- Department of Neurobiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an 710061, China; (R.T.); (X.H.); (X.W.); (M.S.); (Z.C.); (Z.Z.); (Y.F.); (X.C.)
| | - Zixuan Zhang
- Department of Neurobiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an 710061, China; (R.T.); (X.H.); (X.W.); (M.S.); (Z.C.); (Z.Z.); (Y.F.); (X.C.)
- Department of Human Anatomy and Histo-Embryology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an 710061, China
| | - Yali Fu
- Department of Neurobiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an 710061, China; (R.T.); (X.H.); (X.W.); (M.S.); (Z.C.); (Z.Z.); (Y.F.); (X.C.)
- Department of Human Anatomy and Histo-Embryology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an 710061, China
| | - Xinlin Chen
- Department of Neurobiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an 710061, China; (R.T.); (X.H.); (X.W.); (M.S.); (Z.C.); (Z.Z.); (Y.F.); (X.C.)
| | - Jing An
- Department of Neurobiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an 710061, China; (R.T.); (X.H.); (X.W.); (M.S.); (Z.C.); (Z.Z.); (Y.F.); (X.C.)
| | - Haixia Lu
- Department of Neurobiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an 710061, China; (R.T.); (X.H.); (X.W.); (M.S.); (Z.C.); (Z.Z.); (Y.F.); (X.C.)
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32
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Nguyen QT, Thanh LN, Hoang VT, Phan TTK, Heke M, Hoang DM. Bone Marrow-Derived Mononuclear Cells in the Treatment of Neurological Diseases: Knowns and Unknowns. Cell Mol Neurobiol 2023; 43:3211-3250. [PMID: 37356043 PMCID: PMC11410020 DOI: 10.1007/s10571-023-01377-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 06/14/2023] [Indexed: 06/27/2023]
Abstract
Bone marrow-derived mononuclear cells (BMMNCs) have been used for decades in preclinical and clinical studies to treat various neurological diseases. However, there is still a knowledge gap in the understanding of the underlying mechanisms of BMMNCs in the treatment of neurological diseases. In addition, prerequisite factors for the efficacy of BMMNC administration, such as the optimal route, dose, and number of administrations, remain unclear. In this review, we discuss known and unknown aspects of BMMNCs, including the cell harvesting, administration route and dose; mechanisms of action; and their applications in neurological diseases, including stroke, cerebral palsy, spinal cord injury, traumatic brain injury, amyotrophic lateral sclerosis, autism spectrum disorder, and epilepsy. Furthermore, recommendations on indications for BMMNC administration and the advantages and limitations of BMMNC applications for neurological diseases are discussed. BMMNCs in the treatment of neurological diseases. BMMNCs have been applied in several neurological diseases. Proposed mechanisms for the action of BMMNCs include homing, differentiation and paracrine effects (angiogenesis, neuroprotection, and anti-inflammation). Further studies should be performed to determine the optimal cell dose and administration route, the roles of BMMNC subtypes, and the indications for the use of BMMNCs in neurological conditions with and without genetic abnormalities.
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Affiliation(s)
- Quyen Thi Nguyen
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hai Ba Trung, Hanoi, 11622, Vietnam
| | - Liem Nguyen Thanh
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hai Ba Trung, Hanoi, 11622, Vietnam.
- College of Health Science, Vin University, Vinhomes Ocean Park, Gia Lam District, Hanoi, 12400, Vietnam.
- Vinmec International Hospital-Times City, Vinmec Healthcare System, 458 Minh Khai, Hanoi, 11622, Vietnam.
| | - Van T Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hai Ba Trung, Hanoi, 11622, Vietnam
| | - Trang T K Phan
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hai Ba Trung, Hanoi, 11622, Vietnam
| | - Michael Heke
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Duc M Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hai Ba Trung, Hanoi, 11622, Vietnam
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Li Z, Chen Z, Peng J. Neural stem cell-derived exosomal FTO protects neuron from microglial inflammatory injury by inhibiting microglia NRF2 mRNA m6A modification. J Neurogenet 2023; 37:103-114. [PMID: 37812019 DOI: 10.1080/01677063.2023.2259995] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 09/13/2023] [Indexed: 10/10/2023]
Abstract
Ischemic stroke (IS) can cause neuronal cell loss and function defects. Exosomes derived from neural stem cells (NSC-Exos) improve neural plasticity and promote neural function repair following IS. However, the potential mechanism remains unclear. In this study, NSC-Exos were characterized and co-cultured with microglia. We found that NSC-Exos increased NRF2 expression in oxygen-glucose deprivation/reoxygenation and LPS-induced microglia and converted microglia from M1 pro-inflammatory phenotype to M2 anti-inflammatory phenotype. NSC-Exos reduced m6A methylation modification of nuclear factor erythroid 2-related factor 2 (NRF2) mRNA via obesity-associated gene (FTO). Furthermore, NSC-Exos reduced the damage to neurons caused by microglia's inflammatory response. Finally, the changes in microglia polarization and neuron damage caused by FTO knockdown in NSE-Exos were attenuated by NRF2 overexpression in microglia. These findings revealed that NSC-Exos promotes NRF2 expression and M2 polarization of microglial via transferring FTO, thereby resulting in neuroprotective effects.
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Affiliation(s)
- Zhiyong Li
- Medical Quality Management Department, The First Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China
| | - Zhenggang Chen
- Neurosurgery Department, The First Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China
| | - Jun Peng
- Neurosurgery Department, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, Hainan, China
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Ibrahim AA, Abdel Mageed SS, Safar MM, El-Yamany MF, Oraby MA. MitoQ alleviates hippocampal damage after cerebral ischemia: The potential role of SIRT6 in regulating mitochondrial dysfunction and neuroinflammation. Life Sci 2023; 328:121895. [PMID: 37385372 DOI: 10.1016/j.lfs.2023.121895] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 06/19/2023] [Accepted: 06/26/2023] [Indexed: 07/01/2023]
Abstract
AIMS Mitochondrial perturbations are the major culprit of the inflammatory response during the initial phase of cerebral ischemia. The present study explored the neuroprotective effect of the mitochondrial-targeted antioxidant, Mitoquinol (MitoQ), against hippocampal neuronal loss in an experimental model of brain ischemia/reperfusion (I/R) injury. MAIN METHODS Rats were subjected to common carotid artery occlusion for 45 min, followed by reperfusion for 24 h. MitoQ (2 mg/kg; i.p daily) was administered for 7 successive days prior to the induction of brain ischemia. KEY FINDINGS I/R rats exhibited hippocampal damage evidenced by aggravated mitochondrial oxidative stress, thereby enhancing mtROS and oxidized mtDNA, together with inhibiting mtGSH. Mitochondrial biogenesis and function were also affected, as reflected by the reduction of PGC-1α, TFAM, and NRF-1 levels, as well as loss of mitochondrial membrane potential (△Ψm (. These changes were associated with neuroinflammation, apoptosis, impairment of cognitive function as well as hippocampal neurodegenerative changes in histopathological examination. Notably, SIRT6 was suppressed. Pretreatment with MitoQ markedly potentiated SIRT6, modulated mitochondrial oxidative status and restored mitochondrial biogenesis and function. In addition, MitoQ alleviated the inflammatory mediators, TNF-α, IL-18, and IL-1β and dampened GFAB immunoexpression along with downregulation of cleaved caspase-3 expression. Reversal of hippocampal function by MitoQ was accompanied by improved cognitive function and hippocampal morphological aberrations. SIGNIFICANCE This study suggests that MitoQ preserved rats' hippocampi from I/R insults via maintenance of mitochondrial redox status, biogenesis, and activity along with mitigation of neuroinflammation and apoptosis, thereby regulating SIRT6.
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Affiliation(s)
- Ayman A Ibrahim
- Drug Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority, Cairo, Egypt
| | - Sherif S Abdel Mageed
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt.
| | - Marwa M Safar
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Mohammed F El-Yamany
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Mamdouh A Oraby
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Badr University in Cairo, 11829 Cairo, Egypt.
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Palanisamy CP, Pei J, Alugoju P, Anthikapalli NVA, Jayaraman S, Veeraraghavan VP, Gopathy S, Roy JR, Janaki CS, Thalamati D, Mironescu M, Luo Q, Miao Y, Chai Y, Long Q. New strategies of neurodegenerative disease treatment with extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs). Theranostics 2023; 13:4138-4165. [PMID: 37554286 PMCID: PMC10405853 DOI: 10.7150/thno.83066] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 07/08/2023] [Indexed: 08/10/2023] Open
Abstract
Neurodegenerative diseases are characterized by the progressive loss of neurons and intricate interactions between different cell types within the affected regions. Reliable biomarkers that can accurately reflect disease activity, diagnose, and monitor the progression of neurodegenerative diseases are crucial for the development of effective therapies. However, identifying suitable biomarkers has been challenging due to the heterogeneous nature of these diseases, affecting specific subsets of neurons in different brain regions. One promising approach for promoting brain regeneration and recovery involves the transplantation of mesenchymal stem cells (MSCs). MSCs have demonstrated the ability to modulate the immune system, promote neurite outgrowth, stimulate angiogenesis, and repair damaged tissues, partially through the release of their extracellular vesicles (EVs). MSC-derived EVs retain some of the therapeutic characteristics of their parent MSCs, including their ability to regulate neurite outgrowth, promote angiogenesis, and facilitate tissue repair. This review aims to explore the potential of MSC-derived EVs as an emerging therapeutic strategy for neurodegenerative diseases, highlighting their role in modulating disease progression and promoting neuronal recovery. By elucidating the mechanisms by which MSC-derived EVs exert their therapeutic effects, we can advance our understanding and leverage their potential for the development of novel treatment approaches in the field of neurodegenerative diseases.
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Affiliation(s)
- Chella Perumal Palanisamy
- Mini-invasive Neurosurgery and Translational Medical Center, Xi'an Central Hospital, Xi'an Jiaotong University, No. 161, West 5th Road, Xincheng District, Xi'an, 710003, PR China
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospital, Saveetha Institute of Medical & Technical Sciences, Saveetha University, Chennai 600077, India
| | - JinJin Pei
- Qinba State Key Laboratory of Biological Resources and Ecological Environment, 2011 QinLing-Bashan Mountains Bioresources Comprehensive Development C. I. C, Shaanxi Province Key Laboratory of Bio-Resources, College of Bioscience and Bioengineering, Shaanxi University of Technology, Hanzhong 723001, China
| | - Phaniendra Alugoju
- Department of Clinical Chemistry, Chulalongkorn University, Bangkok 10330, Thailand
| | | | - Selvaraj Jayaraman
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospital, Saveetha Institute of Medical & Technical Sciences, Saveetha University, Chennai 600077, India
| | - Vishnu Priya Veeraraghavan
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospital, Saveetha Institute of Medical & Technical Sciences, Saveetha University, Chennai 600077, India
| | - Sridevi Gopathy
- Department of Physiology, SRM Dental College, Ramapuram campus, Chennai, Tamil Nadu 600089, India
| | - Jeane Rebecca Roy
- Department of Anatomy, Bhaarath Medical College and hospital, Bharath Institute of Higher Education and Research (BIHER), Chennai, Tamil Nadu 600073, India
| | - Coimbatore Sadagopan Janaki
- Department of Anatomy, Bhaarath Medical College and hospital, Bharath Institute of Higher Education and Research (BIHER), Chennai, Tamil Nadu 600073, India
| | | | - Monica Mironescu
- Faculty of Agricultural Sciences Food Industry and Environmental Protection, Lucian Blaga University of Sibiu, Bv. Victoriei 10, 550024 Sibiu, Romania
| | - Qiang Luo
- Mini-invasive Neurosurgery and Translational Medical Center, Xi'an Central Hospital, Xi'an Jiaotong University, No. 161, West 5th Road, Xincheng District, Xi'an, 710003, PR China
| | - Yu Miao
- Mini-invasive Neurosurgery and Translational Medical Center, Xi'an Central Hospital, Xi'an Jiaotong University, No. 161, West 5th Road, Xincheng District, Xi'an, 710003, PR China
| | - Yuan Chai
- Mini-invasive Neurosurgery and Translational Medical Center, Xi'an Central Hospital, Xi'an Jiaotong University, No. 161, West 5th Road, Xincheng District, Xi'an, 710003, PR China
| | - Qianfa Long
- Mini-invasive Neurosurgery and Translational Medical Center, Xi'an Central Hospital, Xi'an Jiaotong University, No. 161, West 5th Road, Xincheng District, Xi'an, 710003, PR China
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Chen N, Wang YL, Sun HF, Wang ZY, Zhang Q, Fan FY, Ma YC, Liu FX, Zhang YK. Potential regulatory effects of stem cell exosomes on inflammatory response in ischemic stroke treatment. World J Stem Cells 2023; 15:561-575. [PMID: 37424949 PMCID: PMC10324506 DOI: 10.4252/wjsc.v15.i6.561] [Citation(s) in RCA: 8] [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: 01/07/2023] [Revised: 04/22/2023] [Accepted: 05/16/2023] [Indexed: 06/26/2023] Open
Abstract
The high incidence and disability rates of stroke pose a heavy burden on society. Inflammation is a significant pathological reaction that occurs after an ischemic stroke. Currently, therapeutic methods, except for intravenous thrombolysis and vascular thrombectomy, have limited time windows. Mesenchymal stem cells (MSCs) can migrate, differentiate, and inhibit inflammatory immune responses. Exosomes (Exos), which are secretory vesicles, have the characteristics of the cells from which they are derived, making them attractive targets for research in recent years. MSC-derived exosomes can attenuate the inflammatory response caused by cerebral stroke by modulating damage-associated molecular patterns. In this review, research on the inflammatory response mechanisms associated with Exos therapy after an ischemic injury is discussed to provide a new approach to clinical treatment.
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Affiliation(s)
- Na Chen
- First School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Yan-Lin Wang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Hui-Fang Sun
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zhuo-Ya Wang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Qi Zhang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Fei-Yan Fan
- First School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Yu-Cheng Ma
- First School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Fei-Xiang Liu
- Department of Neurology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Yun-Ke Zhang
- Department of Neurology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, Henan Province, China
- School of Rehabilitation Medicine, Henan University of Chinese Medicine, Zhengzhou 450008, Henan Province, China
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37
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Muallah D, Matschke J, Kappler M, Kroschwald LM, Lauer G, Eckert AW. Dental Pulp Stem Cells for Salivary Gland Regeneration-Where Are We Today? Int J Mol Sci 2023; 24:ijms24108664. [PMID: 37240009 DOI: 10.3390/ijms24108664] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 05/02/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
Xerostomia is the phenomenon of dry mouth and is mostly caused by hypofunction of the salivary glands. This hypofunction can be caused by tumors, head and neck irradiation, hormonal changes, inflammation or autoimmune disease such as Sjögren's syndrome. It is associated with a tremendous decrease in health-related quality of life due to impairment of articulation, ingestion and oral immune defenses. Current treatment concepts mainly consist of saliva substitutes and parasympathomimetic drugs, but the outcome of these therapies is deficient. Regenerative medicine is a promising approach for the treatment of compromised tissue. For this purpose, stem cells can be utilized due to their ability to differentiate into various cell types. Dental pulp stem cells are adult stem cells that can be easily harvested from extracted teeth. They can form tissues of all three germ layers and are therefore becoming more and more popular for tissue engineering. Another potential benefit of these cells is their immunomodulatory effect. They suppress proinflammatory pathways of lymphocytes and could therefore probably be used for the treatment of chronic inflammation and autoimmune disease. These attributes make dental pulp stem cells an interesting tool for the regeneration of salivary glands and the treatment of xerostomia. Nevertheless, clinical studies are still missing. This review will highlight the current strategies for using dental pulp stem cells in the regeneration of salivary gland tissue.
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Affiliation(s)
- David Muallah
- Department of Oral and Maxillofacial Surgery, University Hospital Hamburg-Eppendorf, Martinistraße 52, 20251 Hamburg, Germany
| | - Jan Matschke
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine "Carl Gustav Carus", Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany
| | - Matthias Kappler
- Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany
| | - Lysann Michaela Kroschwald
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine "Carl Gustav Carus", Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany
- Center for Translational Bone, Joint and Soft Tissue Research, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany
| | - Günter Lauer
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine "Carl Gustav Carus", Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany
| | - Alexander W Eckert
- Department of Cranio Maxillofacial Surgery, Paracelsus Medical University, Breslauer Straße 201, 90471 Nuremberg, Germany
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Fauzi AA, Thamrin AMH, Permana AT, Ranuh IGMAR, Hidayati HB, Hamdan M, Wahyuhadi J, Suroto NS, Lestari P, Chandra PS. Comparison of the Administration Route of Stem Cell Therapy for Ischemic Stroke: A Systematic Review and Meta-Analysis of the Clinical Outcomes and Safety. J Clin Med 2023; 12:jcm12072735. [PMID: 37048818 PMCID: PMC10094955 DOI: 10.3390/jcm12072735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/06/2023] [Accepted: 04/04/2023] [Indexed: 04/09/2023] Open
Abstract
Stem cell treatment is emerging as an appealing alternative for stroke patients, but there still needs to be an agreement on the protocols in place, including the route of administration. This systematic review aimed to assess the efficacy and safety of the administration routes of stem cell treatment for ischemic stroke. A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. A comprehensive literature search was undertaken using the PubMed, Scopus, and Cochrane databases. A total of 21 publications on stem cell therapy for ischemic stroke were included. Efficacy outcomes were measured using the National Institutes of Health Stroke Scale (NIHSS), the modified Rankin Scale (mRS), and the Barthel index (BI). Intracerebral administration showed a better outcome than other routes, but a greater number of adverse events followed due to its invasiveness. Adverse events were shown to be related to the natural history of stroke not to the treatment. However, further investigation is required, since studies have yet to compare the different administration methods directly.
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Affiliation(s)
- Asra Al Fauzi
- Department of Neurosurgery, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya 60286, Indonesia
| | - Ahmad Muslim Hidayat Thamrin
- Department of Neurosurgery, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya 60286, Indonesia
| | - Andhika Tomy Permana
- Department of Neurosurgery, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya 60286, Indonesia
| | - I. G. M. Aswin R. Ranuh
- Department of Neurosurgery, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya 60286, Indonesia
| | - Hanik Badriyah Hidayati
- Department of Neurology, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya 60286, Indonesia
| | - Muhammad Hamdan
- Department of Neurology, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya 60286, Indonesia
| | - Joni Wahyuhadi
- Department of Neurosurgery, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya 60286, Indonesia
| | - Nur Setiawan Suroto
- Department of Neurosurgery, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya 60286, Indonesia
| | - Pudji Lestari
- Department of Public Health and Preventive Medicine, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya 60286, Indonesia
| | - Poodipedi Sarat Chandra
- Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi 110608, India
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Wang QS, Xiao RJ, Peng J, Yu ZT, Fu JQ, Xia Y. Bone Marrow Mesenchymal Stem Cell-Derived Exosomal KLF4 Alleviated Ischemic Stroke Through Inhibiting N6-Methyladenosine Modification Level of Drp1 by Targeting lncRNA-ZFAS1. Mol Neurobiol 2023; 60:3945-3962. [DOI: 10.1007/s12035-023-03301-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 03/06/2023] [Indexed: 04/03/2023]
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40
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Wang Y, Niu H, Li L, Han J, Liu Z, Chu M, Sha X, Zhao J. Anti-CHAC1 exosomes for nose-to-brain delivery of miR-760-3p in cerebral ischemia/reperfusion injury mice inhibiting neuron ferroptosis. J Nanobiotechnology 2023; 21:109. [PMID: 36967397 PMCID: PMC10041751 DOI: 10.1186/s12951-023-01862-x] [Citation(s) in RCA: 73] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 03/16/2023] [Indexed: 03/28/2023] Open
Abstract
Ferroptosis plays a critical role in ischemic stroke, and anti-ferroptosis strategies were regarded as potentially effective measures. Based on ferroptosis-related mechanisms, this study aims to design and prepare anti-ferroptosis exosomes from adipose-derived mesenchymal stem cells (ADSC-Exo) for treating ischemic brain injury via intranasal (IN) administration. According to the bioinformatic analysis, CHAC1 was a key gene in the progress of ferroptosis in ischemic stroke. miR-760-3p can inhibit the expression of CHAC1 and may be abundant in ADSC-Exo. Therefore, ADSC-Exo were successfully isolated and the immunofluorescence showed that they can be efficiently delivered to the brain via IN administration. Additionally, IN administration of ADSC-Exo can effectively improve the neurobehavior function of mice after I/R, and improve the ferroptosis-related outcomes. As the immunofluorescence showed the co-localization of NeuN with CHAC1 obviously, we further evaluated the systematic effect of ADSC-Exo in an oxygen-glucose deprivation (OGD) mouse neuroblastoma cell line N2a model. The results showed that miR-760-3p in ADSC-Exo contributed to their function in inhibiting ferroptosis by targeting CHAC1 in neurons. Collectively, the present study successfully designed and prepared anti-CHAC1 ADSC-Exo and suggested a promising exosome-based strategy for anti-ferroptosis therapy in cerebral ischemia/reperfusion injury.
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Affiliation(s)
- Yong Wang
- grid.8547.e0000 0001 0125 2443Department of Neurology, Minhang Hospital, Fudan University, Floor 16th, # 170 Xinsong Road, Shanghai, 201199 China
| | - Huicong Niu
- grid.8547.e0000 0001 0125 2443Department of Neurology, Minhang Hospital, Fudan University, Floor 16th, # 170 Xinsong Road, Shanghai, 201199 China
| | - Luyu Li
- grid.16821.3c0000 0004 0368 8293Department of Dermatology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jing Han
- grid.8547.e0000 0001 0125 2443State Key Laboratory of Medical Neurobiology, Department of Integrative Medicine and Neurobiology, Brain Science Collaborative Innovation Center, School of Basic Medical Sciences, Institutes of Brain Science, Fudan Institutes of Integrative Medicine, Fudan University, Shanghai, China
| | - Zhuohang Liu
- grid.8547.e0000 0001 0125 2443Department of Neurology, Minhang Hospital, Fudan University, Floor 16th, # 170 Xinsong Road, Shanghai, 201199 China
| | - Min Chu
- grid.8547.e0000 0001 0125 2443Department of Neurology, Minhang Hospital, Fudan University, Floor 16th, # 170 Xinsong Road, Shanghai, 201199 China
| | - Xianyi Sha
- grid.8547.e0000 0001 0125 2443Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, 201203 China
- grid.8547.e0000 0001 0125 2443The Institutes of Integrative Medicine, Fudan University, 120 Urumqi Middle Road, Shanghai, 200040 China
| | - Jing Zhao
- grid.8547.e0000 0001 0125 2443Department of Neurology, Minhang Hospital, Fudan University, Floor 16th, # 170 Xinsong Road, Shanghai, 201199 China
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Tang H, Zhang X, Hao X, Dou H, Zou C, Zhou Y, Li B, Yue H, Wang D, Wang Y, Yang C, Fu J. Hepatocyte growth factor-modified hair follicle stem cells ameliorate cerebral ischemia/reperfusion injury in rats. Stem Cell Res Ther 2023; 14:25. [PMID: 36782269 PMCID: PMC9926795 DOI: 10.1186/s13287-023-03251-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 08/22/2022] [Indexed: 02/15/2023] Open
Abstract
BACKGROUND Hair follicle stem cells (HFSCs) are considered as a promising cell type in the stem cell transplantation treatment of neurological diseases because of their rich sources, easy access, and the same ectoderm source as the nervous system. Hepatocyte growth factor (HGF) is a pleiotropic cytokine that shows neuroprotective function in ischemic stroke. Here we assessed the therapeutic effects of HFSCs on ischemic stroke injury and the synthetic effect of HGF along with HFSCs. METHODS Rat HFSCs were intravenously transplanted into a middle cerebral artery ischemia/reperfusion (I/R) rat model. Neurological scoring and TTC staining were performed to assess the benefits of HFSC transplantation. Inflammatory cytokines, blood-brain barrier integrity and angiogenesis within penumbra were estimated by Western blot and immunohistochemistry. The differentiation of HFSCs was detected by immunofluorescence method 2 weeks after transplantation. RESULTS HFSC transplantation could significantly inhibit the activation of microglia, improve the integrity of blood-brain barrier and reduce brain edema. Moreover, the number of surviving neurons and microvessels density in the penumbra were upregulated by HFSC transplantation, leading to better neurological score. The combination of HFSCs and HGF could significantly improve the therapeutic benefit. CONCLUSION Our results indicate for the first time that HGF modified HFSCs can reduce I/R injury and promote the neurological recovery by inhibiting inflammatory response, protecting blood-brain barrier and promoting angiogenesis.
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Affiliation(s)
- Hao Tang
- grid.412463.60000 0004 1762 6325Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086 Heilongjiang China
| | - Xuemei Zhang
- grid.412463.60000 0004 1762 6325Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086 Heilongjiang China
| | - Xiaojun Hao
- grid.412463.60000 0004 1762 6325Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086 Heilongjiang China
| | - Haitong Dou
- grid.412463.60000 0004 1762 6325Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086 Heilongjiang China
| | - Chendan Zou
- grid.410736.70000 0001 2204 9268Department of Biochemistry and Molecular Biology, Harbin Medical University, No.157 Baojian Road, Nangang District, Harbin, 150086 Heilongjiang China
| | - Yinglian Zhou
- grid.412463.60000 0004 1762 6325Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086 Heilongjiang China
| | - Bing Li
- grid.412463.60000 0004 1762 6325Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086 Heilongjiang China
| | - Hui Yue
- grid.412463.60000 0004 1762 6325Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086 Heilongjiang China
| | - Duo Wang
- grid.412463.60000 0004 1762 6325Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086 Heilongjiang China
| | - Yifei Wang
- grid.412463.60000 0004 1762 6325Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086 Heilongjiang China
| | - Chunxiao Yang
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, China.
| | - Jin Fu
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, China.
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Zhang Q, Shi S, Tang Y, Qu C, Wen S, Pan Y. Manf Enhances the Pyroptosis Inhibition of Bone Marrow-derived Mesenchymal Stem Cells to Relieve Cerebral Infarction Injury. Neuroscience 2023; 510:109-128. [PMID: 36529294 DOI: 10.1016/j.neuroscience.2022.11.002] [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: 04/06/2022] [Revised: 10/30/2022] [Accepted: 11/04/2022] [Indexed: 12/17/2022]
Abstract
Cerebral infarction is a common disease characterized by high mortality, a narrow therapeutic window, and limited therapeutic options. Recently, cell therapy based on gene modification has brought a glimmer of hope to the treatment of cerebral infarction although the explicit underlying mechanism is beyond being well dissected. In the present study, we constructed an animal model of middle cerebral artery occlusion (MCAO), compared differentially expressed genes (DEGs) between the sham and MCAO groups by single-cell RNA sequencing (scRNA-seq) to explore the potential cell death-related pathways involved in cerebral infarction, and transfected Manf into BMSCs by lentivirus. Subsequently, we injected BMSCs (bone marrow-derived mesenchymal stem cells), Manf-modified BMSCs, or lentivirus encoding Manf into the brain. Their effects on MANF content, apoptosis, pyroptosis, infarct volume in the brain, and neurological function were evaluated after MCAO. We found that the DEGs upregulated in four major cell clusters after MCAO and were enriched with not only apoptosis, ferroptosis, and necroptosis but also with pyroptosis-related pathways. In addition, transfection of Manf into BMSCs significantly increased the expression and secretion of MANF in BMSCs; BMSCs, Manf-modified BMSCs, and Manf treatment all resulted in an increase in Manf content in the brain, a decrease in the expression of apoptosis- and pyroptosis-related molecules, a reduction in infarct volume, and an improvement in neurological function after MCAO. Moreover, Manf-modified BMSCs have the strongest therapeutic effect. Collectively, Manf-modified BMSCs ameliorate ischemic injury after cerebral infarction by repressing apoptosis- and pyroptosis-related molecules, which represents a new cell therapy strategy for cerebral infarction.
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Affiliation(s)
- Qi Zhang
- Department of Neurology, the First Clinical College of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin 150001, Heilongjiang Province, China
| | - Shanshan Shi
- Department of Neurology, the First Clinical College of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin 150001, Heilongjiang Province, China
| | - Yushi Tang
- Department of Neurology, the First Clinical College of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin 150001, Heilongjiang Province, China
| | - Changda Qu
- Department of Neurology, the First Clinical College of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin 150001, Heilongjiang Province, China
| | - Shirong Wen
- Department of Neurology, the First Clinical College of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin 150001, Heilongjiang Province, China
| | - Yujun Pan
- Department of Neurology, the First Clinical College of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin 150001, Heilongjiang Province, China.
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43
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Yu Q, Jian Z, Yang D, Zhu T. Perspective insights into hydrogels and nanomaterials for ischemic stroke. Front Cell Neurosci 2023; 16:1058753. [PMID: 36761147 PMCID: PMC9902513 DOI: 10.3389/fncel.2022.1058753] [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: 09/30/2022] [Accepted: 12/30/2022] [Indexed: 01/26/2023] Open
Abstract
Ischemic stroke (IS) is a neurological disorder prevalent worldwide with a high disability and mortality rate. In the clinic setting, tissue plasminogen activator (tPA) and thrombectomy could restore blood flow of the occlusion region and improve the outcomes of IS patients; however, these therapies are restricted by a narrow time window. Although several preclinical trials have revealed the molecular and cellular mechanisms underlying infarct lesions, the translatability of most findings is unsatisfactory, which contributes to the emergence of new biomaterials, such as hydrogels and nanomaterials, for the treatment of IS. Biomaterials function as structural scaffolds or are combined with other compounds to release therapeutic drugs. Biomaterial-mediated drug delivery approaches could optimize the therapeutic effects based on their brain-targeting property, biocompatibility, and functionality. This review summarizes the advances in biomaterials in the last several years, aiming to discuss the therapeutic potential of new biomaterials from the bench to bedside. The promising prospects of new biomaterials indicate the possibility of an organic combination between materialogy and medicine, which is a novel field under exploration.
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Affiliation(s)
- Qingbo Yu
- Laboratory of Anesthesia & Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital of Sichuan University, Chengdu, China,Department of Anesthesiology, North Sichuan Medical College, Nanchong, China
| | - Zhang Jian
- Sichuan Provincial Maternity and Child Health Care Hospital, Women’s and Children’s Hospital Affiliated of Chengdu Medical College, Chengdu, China
| | - Dan Yang
- Department of Anesthesiology, North Sichuan Medical College, Nanchong, China
| | - Tao Zhu
- Laboratory of Anesthesia & Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital of Sichuan University, Chengdu, China,*Correspondence: Tao Zhu,
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Yoshida Y, Takeda Y, Yamahara K, Yamamoto H, Takagi T, Kuramoto Y, Nakano-Doi A, Nakagomi T, Soma T, Matsuyama T, Doe N, Yoshimura S. Enhanced angiogenic properties of umbilical cord blood primed by OP9 stromal cells ameliorates neurological deficits in cerebral infarction mouse model. Sci Rep 2023; 13:262. [PMID: 36609640 PMCID: PMC9822952 DOI: 10.1038/s41598-023-27424-7] [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: 09/15/2022] [Accepted: 12/29/2022] [Indexed: 01/09/2023] Open
Abstract
Umbilical cord blood (UCB) transplantation shows proangiogenic effects and contributes to symptom amelioration in animal models of cerebral infarction. However, the effect of specific cell types within a heterogeneous UCB population are still controversial. OP9 is a stromal cell line used as feeder cells to promote the hematoendothelial differentiation of embryonic stem cells. Hence, we investigated the changes in angiogenic properties, underlying mechanisms, and impact on behavioral deficiencies caused by cerebral infarction in UCB co-cultured with OP9 for up to 24 h. In the network formation assay, only OP9 pre-conditioned UCB formed network structures. Single-cell RNA sequencing and flow cytometry analysis showed a prominent phenotypic shift toward M2 in the monocytic fraction of OP9 pre-conditioned UCB. Further, OP9 pre-conditioned UCB transplantation in mice models of cerebral infarction facilitated angiogenesis in the peri-infarct lesions and ameliorated the associated symptoms. In this study, we developed a strong, fast, and feasible method to augment the M2, tissue-protecting, pro-angiogenic features of UCB using OP9. The ameliorative effect of OP9-pre-conditioned UCB in vivo could be partly due to promotion of innate angiogenesis in peri-infarct lesions.
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Affiliation(s)
- Yasunori Yoshida
- grid.272264.70000 0000 9142 153XDepartment of Neurosurgery, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Yuki Takeda
- grid.272264.70000 0000 9142 153XDepartment of Neurosurgery, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Kenichi Yamahara
- Laboratory of Molecular and Cellular Therapy, Institute for Advanced Medical Sciences, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan.
| | - Hanae Yamamoto
- grid.272264.70000 0000 9142 153XLaboratory of Molecular and Cellular Therapy, Institute for Advanced Medical Sciences, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Toshinori Takagi
- grid.272264.70000 0000 9142 153XDepartment of Neurosurgery, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Yoji Kuramoto
- grid.272264.70000 0000 9142 153XDepartment of Neurosurgery, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Akiko Nakano-Doi
- Laboratory of Neurogenesis and CNS Repair, Institute for Advanced Medical Sciences, Hyogo Medial University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Takayuki Nakagomi
- Laboratory of Neurogenesis and CNS Repair, Institute for Advanced Medical Sciences, Hyogo Medial University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Toshihiro Soma
- grid.272264.70000 0000 9142 153XDepartment of Hematology, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Tomohiro Matsuyama
- grid.272264.70000 0000 9142 153XDepartment of Therapeutic Progress in Brain Diseases, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Nobutaka Doe
- Laboratory of Neurogenesis and CNS Repair, Institute for Advanced Medical Sciences, Hyogo Medial University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan ,grid.272264.70000 0000 9142 153XDepartment of Occupational Therapy, School of Rehabilitation, Hyogo Medical University, 1-3-6 Minatojima, Chuo-Ku, Kobe, Hyogo 650-8530 Japan
| | - Shinichi Yoshimura
- grid.272264.70000 0000 9142 153XDepartment of Neurosurgery, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
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Monsour M, Croci DM, Agazzi S, Borlongan CV. Contemplating IL-6, a double-edged sword cytokine: Which side to use for stroke pathology? CNS Neurosci Ther 2022; 29:493-497. [PMID: 36478506 PMCID: PMC9873516 DOI: 10.1111/cns.14041] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 11/02/2022] [Accepted: 11/09/2022] [Indexed: 12/12/2022] Open
Abstract
Interleukin (IL)-6 is a unique cytokine due to its dual signaling, with one pathway being pro-inflammatory (trans) and the other homeostatic (classical). Both of these pathways have been implicated in neuroinflammation following stroke, with initial inflammatory mechanisms being protective and later anti-inflammatory signaling promoting ischemic tissue recovery. IL-6 plays a major role in stroke pathology. However, given these distinctive IL-6 signaling consequences, IL-6 is a difficult cytokine to target for stroke therapies. Recent research suggests that the ratio between the pro-inflammatory binary IL6:sIL6R complex and the inactive ternary IL6:sIL6R:sgp130 complex may be a novel way to measure IL-6 signaling at different time points following ischemic injury. This ratio may approximate functional consequences on individualized stroke therapies, allowing clinicians to determine whether IL-6 agonists or antagonists should be used at specific time points.
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Affiliation(s)
- Molly Monsour
- University of South Florida Morsani College of MedicineTampaFloridaUSA
| | - Davide M. Croci
- Department of Neurosurgery and Brain RepairUniversity of South Florida, Morsani College of MedicineTampaFloridaUSA
| | - Siviero Agazzi
- Department of Neurosurgery and Brain RepairUniversity of South Florida, Morsani College of MedicineTampaFloridaUSA
| | - Cesar V. Borlongan
- Center of Excellence for Aging and Brain RepairUniversity of South Florida Morsani College of MedicineTampaFloridaUSA
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Calderazzo S, Covert M, Alba DD, Bowley BE, Pessina MA, Rosene DL, Buller B, Medalla M, Moore TL. Neural recovery after cortical injury: Effects of MSC derived extracellular vesicles on motor circuit remodeling in rhesus monkeys. IBRO Neurosci Rep 2022; 13:243-254. [PMID: 36590089 PMCID: PMC9795302 DOI: 10.1016/j.ibneur.2022.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 07/01/2022] [Accepted: 08/07/2022] [Indexed: 01/04/2023] Open
Abstract
Reorganization of motor circuits in the cortex and corticospinal tract are thought to underlie functional recovery after cortical injury, but the mechanisms of neural plasticity that could be therapeutic targets remain unclear. Recent work from our group have shown that systemic treatment with mesenchymal stem cell derived (MSCd) extracellular vesicles (EVs) administered after cortical damage to the primary motor cortex (M1) of rhesus monkeys resulted in a robust recovery of fine motor function and reduced chronic inflammation. Here, we used immunohistochemistry for cfos, an activity-dependent intermediate early gene, to label task-related neurons in the surviving primary motor and premotor cortices, and markers of axonal and synaptic plasticity in the spinal cord. Compared to vehicle, EV treatment was associated with a greater density of cfos+ pyramidal neurons in the deep layers of M1, greater density of cfos+ inhibitory interneurons in premotor areas, and lower density of synapses on MAP2+ lower motor neurons in the cervical spinal cord. These data suggest that the anti-inflammatory effects of EVs may reduce injury-related upper motor neuron damage and hyperexcitability, as well as aberrant compensatory re-organization in the cervical spinal cord to improve motor function.
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Key Words
- CB, Calbindin
- CR, Calretinin
- CSC, Cervical Spinal Cord
- Circuit Remodeling
- Cortical Injury
- DH, Dorsal Horn
- EVs, Extracellular Vesicles
- Extracellular Vesicles
- Ischemia
- LCST, Lateral Corticospinal Tract
- M1, Primary Motor Cortex
- MAP2, Microtubule Associated Protein 2
- MSCd, Mesenchymal Stem Cell derived
- Motor Cortex
- NHP, Non-Human Primate
- PV, Parvalbumin
- Plasticity
- ROS, Reactive Oxygen Species
- SYN, Synaptophysin
- Stem Cell-Based Treatments
- VH, Ventral Horn
- dPMC, dorsal Premotor Cortex
- miRNA, Micro RNA
- periM1, Perilesional Primary Motor Cortex
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Affiliation(s)
| | | | | | | | | | - Douglas L. Rosene
- Anatomy and Neurobiology Dept, BUSM, USA
- Center for Systems Neuroscience, BU, USA
| | | | - Maria Medalla
- Anatomy and Neurobiology Dept, BUSM, USA
- Center for Systems Neuroscience, BU, USA
| | - Tara L. Moore
- Anatomy and Neurobiology Dept, BUSM, USA
- Center for Systems Neuroscience, BU, USA
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47
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Nistor-Cseppentö DC, Jurcău MC, Jurcău A, Andronie-Cioară FL, Marcu F. Stem Cell- and Cell-Based Therapies for Ischemic Stroke. Bioengineering (Basel) 2022; 9:717. [PMID: 36421118 PMCID: PMC9687728 DOI: 10.3390/bioengineering9110717] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/14/2022] [Accepted: 11/18/2022] [Indexed: 09/12/2023] Open
Abstract
Stroke is the second cause of disability worldwide as it is expected to increase its incidence and prevalence. Despite efforts to increase the number of patients eligible for recanalization therapies, a significant proportion of stroke survivors remain permanently disabled. This outcome boosted the search for efficient neurorestorative methods. Stem cells act through multiple pathways: cell replacement, the secretion of growth factors, promoting endogenous reparative pathways, angiogenesis, and the modulation of neuroinflammation. Although neural stem cells are difficult to obtain, pose a series of ethical issues, and require intracerebral delivery, mesenchymal stem cells are less immunogenic, are easy to obtain, and can be transplanted via intravenous, intra-arterial, or intranasal routes. Extracellular vesicles and exosomes have similar actions and are easier to obtain, also allowing for engineering to deliver specific molecules or RNAs and to promote the desired effects. Appropriate timing, dosing, and delivery protocols must be established, and the possibility of tumorigenesis must be settled. Nonetheless, stem cell- and cell-based therapies for stroke have already entered clinical trials. Although safe, the evidence for efficacy is less impressive so far. Hopefully, the STEP guidelines and the SPAN program will improve the success rate. As such, stem cell- and cell-based therapy for ischemic stroke holds great promise.
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Affiliation(s)
- Delia Carmen Nistor-Cseppentö
- Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
| | | | - Anamaria Jurcău
- Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
| | - Felicia Liana Andronie-Cioară
- Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
| | - Florin Marcu
- Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
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48
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Zhou L, Wang J, Huang J, Song X, Wu Y, Chen X, Tan Y, Yang Q. The role of mesenchymal stem cell transplantation for ischemic stroke and recent research developments. Front Neurol 2022; 13:1000777. [PMID: 36468067 PMCID: PMC9708730 DOI: 10.3389/fneur.2022.1000777] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 10/03/2022] [Indexed: 09/08/2023] Open
Abstract
Ischemic stroke is a common cerebrovascular disease that seriously affects human health. However, most patients do not practice self-care and cannot rely on the current clinical treatment for guaranteed functional recovery. Stem cell transplantation is an emerging treatment studied in various central nervous system diseases. More importantly, animal studies show that transplantation of mesenchymal stem cells (MSCs) can alleviate neurological deficits and bring hope to patients suffering from ischemic stroke. This paper reviews the biological characteristics of MSCs and discusses the mechanism and progression of MSC transplantation to provide new therapeutic directions for ischemic stroke.
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Affiliation(s)
| | | | | | | | | | | | | | - Qin Yang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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49
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Monsour M, Gordon J, Lockard G, Alayli A, Elsayed B, Connolly J, Borlongan CV. Minor Changes for a Major Impact: A Review of Epigenetic Modifications in Cell-Based Therapies for Stroke. Int J Mol Sci 2022; 23:13106. [PMID: 36361891 PMCID: PMC9656972 DOI: 10.3390/ijms232113106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 10/25/2022] [Accepted: 10/26/2022] [Indexed: 08/16/2024] Open
Abstract
Epigenetic changes in stroke may revolutionize cell-based therapies aimed at reducing ischemic stroke risk and damage. Epigenetic changes are a novel therapeutic target due to their specificity and potential for reversal. Possible targets for epigenetic modification include DNA methylation and demethylation, post-translational histone modification, and the actions of non-coding RNAs such as microRNAs. Many of these epigenetic modifications have been reported to modulate atherosclerosis development and progression, ultimately contributing to stroke pathogenesis. Furthermore, epigenetics may play a major role in inflammatory responses following stroke. Stem cells for stroke have demonstrated safety in clinical trials for stroke and show therapeutic benefit in pre-clinical studies. The efficacy of these cell-based interventions may be amplified with adjunctive epigenetic modifications. This review advances the role of epigenetics in atherosclerosis and inflammation in the context of stroke, followed by a discussion on current stem cell studies modulating epigenetics to ameliorate stroke damage.
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Affiliation(s)
- Molly Monsour
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Jonah Gordon
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Gavin Lockard
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Adam Alayli
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Bassel Elsayed
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Jacob Connolly
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Cesar V. Borlongan
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA
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50
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Monsour M, Croci DM, Agazzi S, Borlongan CV. Getting the guts to expand stroke treatment: The potential for microbiome targeted therapies. CNS Neurosci Ther 2022. [PMID: 36217699 DOI: 10.1111/cns.13988] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/07/2022] [Accepted: 08/11/2022] [Indexed: 11/28/2022] Open
Abstract
AIMS This review focuses on the recent literature regarding the role of the gut-brain axis (GBA) following ischemic stroke. DISCUSSION Stroke is the 5th leading cause of death and disability in the United States; however, few therapies have been developed to improve prognoses. There is a plethora of evidence suggesting peripheral inflammatory responses play a large role in the pathogenesis of stroke. Additionally, hyperglycemic conditions may play a significant role in worsening stroke outcomes due to microbiome dysbiosis. CONCLUSION Recent research has illuminated the vital role of the GBA in propagating poor clinical outcomes, such as hemorrhagic transformation, following ischemic stroke. Considering this detrimental consequence of stroke, and the apparent role of the GBA role, future therapeutics should aim to mitigate this peripheral contribution to stroke complications.
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Affiliation(s)
- Molly Monsour
- University of South Florida Morsani College of Medicine, Tampa, Florida, USA
| | - Davide M Croci
- Department of Neurosurgery and Brain Repair, University of South Florida, Morsani College of Medicine, Tampa, Florida, USA
| | - Siviero Agazzi
- Department of Neurosurgery and Brain Repair, University of South Florida, Morsani College of Medicine, Tampa, Florida, USA
| | - Cesario V Borlongan
- Center of Excellence for Aging and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, Florida, USA
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