|
1
|
Yang X, Gao X, Jiang X, Yue K, Luo P. Targeting capabilities of engineered extracellular vesicles for the treatment of neurological diseases. Neural Regen Res 2025; 20:3076-3094. [PMID: 39435635 PMCID: PMC11881733 DOI: 10.4103/nrr.nrr-d-24-00462] [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: 04/23/2024] [Revised: 07/15/2024] [Accepted: 09/07/2024] [Indexed: 10/23/2024] Open
Abstract
Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases. Owing to their therapeutic properties and ability to cross the blood-brain barrier, extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions, including ischemic stroke, traumatic brain injury, neurodegenerative diseases, glioma, and psychosis. However, the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body. To address these limitations, multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles, thereby enabling the delivery of therapeutic contents to specific tissues or cells. Therefore, this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles, exploring their applications in treating traumatic brain injury, ischemic stroke, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, glioma, and psychosis. Additionally, we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases. This review offers new insights for developing highly targeted therapies in this field.
Collapse
Affiliation(s)
- Xinyu Yang
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, China
| | - Xiangyu Gao
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, China
| | - Xiaofan Jiang
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, China
| | - Kangyi Yue
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, China
| | - Peng Luo
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, China
| |
Collapse
|
|
2
|
Yin W, Ma H, Qu Y, Ren J, Sun Y, Guo ZN, Yang Y. Exosomes: the next-generation therapeutic platform for ischemic stroke. Neural Regen Res 2025; 20:1221-1235. [PMID: 39075892 PMCID: PMC11624871 DOI: 10.4103/nrr.nrr-d-23-02051] [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: 12/19/2023] [Revised: 02/05/2024] [Accepted: 03/19/2024] [Indexed: 07/31/2024] Open
Abstract
Current therapeutic strategies for ischemic stroke fall short of the desired objective of neurological functional recovery. Therefore, there is an urgent need to develop new methods for the treatment of this condition. Exosomes are natural cell-derived vesicles that mediate signal transduction between cells under physiological and pathological conditions. They have low immunogenicity, good stability, high delivery efficiency, and the ability to cross the blood-brain barrier. These physiological properties of exosomes have the potential to lead to new breakthroughs in the treatment of ischemic stroke. The rapid development of nanotechnology has advanced the application of engineered exosomes, which can effectively improve targeting ability, enhance therapeutic efficacy, and minimize the dosages needed. Advances in technology have also driven clinical translational research on exosomes. In this review, we describe the therapeutic effects of exosomes and their positive roles in current treatment strategies for ischemic stroke, including their anti-inflammation, anti-apoptosis, autophagy-regulation, angiogenesis, neurogenesis, and glial scar formation reduction effects. However, it is worth noting that, despite their significant therapeutic potential, there remains a dearth of standardized characterization methods and efficient isolation techniques capable of producing highly purified exosomes. Future optimization strategies should prioritize the exploration of suitable isolation techniques and the establishment of unified workflows to effectively harness exosomes for diagnostic or therapeutic applications in ischemic stroke. Ultimately, our review aims to summarize our understanding of exosome-based treatment prospects in ischemic stroke and foster innovative ideas for the development of exosome-based therapies.
Collapse
Affiliation(s)
- Wenjing Yin
- Stroke Center, Department of Neurology, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Hongyin Ma
- Stroke Center, Department of Neurology, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Yang Qu
- Stroke Center, Department of Neurology, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Jiaxin Ren
- Stroke Center, Department of Neurology, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Yingying Sun
- Stroke Center, Department of Neurology, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Zhen-Ni Guo
- Stroke Center, Department of Neurology, First Hospital of Jilin University, Changchun, Jilin Province, China
- Neuroscience Research Center, Department of Neurology, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Yi Yang
- Stroke Center, Department of Neurology, First Hospital of Jilin University, Changchun, Jilin Province, China
| |
Collapse
|
|
3
|
Yang YP, Nicol CJB, Chiang MC. A Review of the Neuroprotective Properties of Exosomes Derived from Stem Cells and Exosome-Coated Nanoparticles for Treating Neurodegenerative Diseases and Stroke. Int J Mol Sci 2025; 26:3915. [PMID: 40332773 PMCID: PMC12028030 DOI: 10.3390/ijms26083915] [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: 02/18/2025] [Revised: 04/15/2025] [Accepted: 04/16/2025] [Indexed: 05/08/2025] Open
Abstract
Neurological diseases, including neurodegenerative disorders and stroke, represent significant medical challenges due to their complexity and the limitations of current treatment approaches. This review explores the potential of stem cell (SC)-derived exosomes (Exos) as a transformative therapeutic strategy for these diseases. Exos, especially those derived from SCs, exhibit natural targeting ability, biocompatibility, and the capacity to cross the blood-brain barrier (BBB), making them ideal vehicles for drug delivery. This review provides an in-depth discussion of the properties and advantages of SC-Exos. It highlights their potential synergistic benefits in therapeutic approaches to treat neurological diseases. This article discusses the mechanisms of action of SC-Exos, highlighting their ability to target specific cells, modulate disease pathways, and provide controlled release of therapeutic agents. Applications in specific neurological disorders have been investigated, demonstrating the potential to improve outcomes in conditions such as Alzheimer's Disease (AD), Parkinson's Disease (PD), and stroke. Moreover, Exos-coated nanoparticles (NPs) combine the natural properties of Exos with the multifunctionality of NPs. This integration takes advantage of exosome membrane biocompatibility and targeting capabilities while preserving NPs' beneficial features, such as drug loading and controlled release. As a result, Exos-coated NPs may enhance the precision, efficacy, and safety of therapeutic interventions. In conclusion, SC-Exos represent a promising and innovative approach to treating neurological diseases.
Collapse
Affiliation(s)
- Yu-Ping Yang
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Christopher J. B. Nicol
- Departments of Pathology & Molecular Medicine and Biomedical & Molecular Sciences, and Cancer Biology and Genetics Division, Sinclair Cancer Research Institute, Queen’s University, Kingston, ON K7L 3N6, Canada;
| | - Ming-Chang Chiang
- Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City 242, Taiwan
| |
Collapse
|
|
4
|
Madhan S, Dhar R, Devi A. Clinical Impact of Exosome Chemistry in Cancer. ACS APPLIED BIO MATERIALS 2025; 8:1862-1876. [PMID: 39936581 DOI: 10.1021/acsabm.4c01920] [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] [Indexed: 02/13/2025]
Abstract
As we progress into the 21st century, cancer stands as one of the most dreaded diseases. With approximately one in every four individuals facing a lifetime risk of developing cancer, cancer remains one of the most serious health challenges worldwide. Its multifaceted nature makes it an arduous and tricky problem to diagnose and treat. Over the years, researchers have explored plenty of approaches and avenues to improve cancer management. One notable strategy includes the study of extracellular vesicles (EVs) as potential biomarkers and therapeutics. Among these EVs, exosomes have emerged as particularly promising candidates due to their unique characteristic properties and functions. They are small membrane-bound vesicles secreted by cells carrying a cargo of biomolecules such as proteins, nucleic acids, and lipids. These vesicles play crucial roles in intercellular communication, facilitating the transfer of biological information between cell-to-cell communication. Exosomes transport cargoes such as DNA, RNA, proteins, and lipids involved in cellular reprogramming and promoting cancer. In this review, we explore the molecular composition of exosomes, significance of exosomes chemistry in cancer development, and its theranostic application as well as exosomes research complications and solutions.
Collapse
Affiliation(s)
- Shrishti Madhan
- Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu District, Tamil Nadu-603203, India
| | - Rajib Dhar
- Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu District, Tamil Nadu-603203, India
| | - Arikketh Devi
- Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu District, Tamil Nadu-603203, India
| |
Collapse
|
|
5
|
Greșiță A, Hermann DM, Boboc IKS, Doeppner TR, Petcu E, Semida GF, Popa-Wagner A. Glial Cell Reprogramming in Ischemic Stroke: A Review of Recent Advancements and Translational Challenges. Transl Stroke Res 2025:10.1007/s12975-025-01331-7. [PMID: 39904845 DOI: 10.1007/s12975-025-01331-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 01/16/2025] [Accepted: 01/18/2025] [Indexed: 02/06/2025]
Abstract
Ischemic stroke, the second leading cause of death worldwide and the leading cause of long-term disabilities, presents a significant global health challenge, particularly in aging populations where the risk and severity of cerebrovascular events are significantly increased. The aftermath of stroke involves neuronal loss in the infarct core and reactive astrocyte proliferation, disrupting the neurovascular unit, especially in aged brains. Restoring the balance between neurons and non-neuronal cells within the perilesional area is crucial for post-stroke recovery. The aged post-stroke brain mounts a fulminant proliferative astroglial response, leading to gliotic scarring that prevents neural regeneration. While countless therapeutic techniques have been attempted for decades with limited success, alternative strategies aim to transform inhibitory gliotic tissue into an environment conducive to neuronal regeneration and axonal growth through genetic conversion of astrocytes into neurons. This concept gained momentum following discoveries that in vivo direct lineage reprogramming in the adult mammalian brain is a feasible strategy for reprogramming non-neuronal cells into neurons, circumventing the need for cell transplantation. Recent advancements in glial cell reprogramming, including transcription factor-based methods with factors like NeuroD1, Ascl1, and Neurogenin2, as well as small molecule-induced reprogramming and chemical induction, show promise in converting glial cells into functional neurons. These approaches leverage the brain's intrinsic plasticity for neuronal replacement and circuit restoration. However, applying these genetic conversion therapies in the aged, post-stroke brain faces significant challenges, such as the hostile inflammatory environment and compromised regenerative capacity. There is a critical need for safe and efficient delivery methods, including viral and non-viral vectors, to ensure targeted and sustained expression of reprogramming factors. Moreover, addressing the translational gap between preclinical successes and clinical applications is essential, emphasizing the necessity for robust stroke models that replicate human pathophysiology. Ethical considerations and biosafety concerns are critically evaluated, particularly regarding the long-term effects and potential risks of genetic reprogramming. By integrating recent research findings, this comprehensive review provides an in-depth understanding of the current landscape and future prospects of genetic conversion therapy for ischemic stroke rehabilitation, highlighting the potential to enhance personalized stroke management and regenerative strategies through innovative approaches.
Collapse
Affiliation(s)
- Andrei Greșiță
- Experimental Research Center for Normal and Pathological Aging, University of Medicine and Pharmacy Craiova, 200349, Craiova, Romania
- Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY, 11568, USA
| | - Dirk M Hermann
- Chair of Vascular Neurology and Dementia, Department of Neurology, University Hospital Essen, 45147, Essen, Germany
- Experimental Research Center for Normal and Pathological Aging, University of Medicine and Pharmacy Craiova, 200349, Craiova, Romania
| | - Ianis Kevyn Stefan Boboc
- Experimental Research Center for Normal and Pathological Aging, University of Medicine and Pharmacy Craiova, 200349, Craiova, Romania
| | - Thorsten R Doeppner
- Department of Neurology, University Medical Center Göttingen, 37075, Göttingen, Germany
- Department of Neurology, University of Giessen Medical School, 35392, Giessen, Germany
| | - Eugen Petcu
- Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY, 11568, USA
- Department of Biological & Chemical Sciences, New York Institute of Technology, Old Westbury, NY, 11568, USA
| | - Ghinea Flavia Semida
- Experimental Research Center for Normal and Pathological Aging, University of Medicine and Pharmacy Craiova, 200349, Craiova, Romania.
| | - Aurel Popa-Wagner
- Chair of Vascular Neurology and Dementia, Department of Neurology, University Hospital Essen, 45147, Essen, Germany.
- Experimental Research Center for Normal and Pathological Aging, University of Medicine and Pharmacy Craiova, 200349, Craiova, Romania.
| |
Collapse
|
|
6
|
Wang L, Zhang Y, Mao C, Li X. Enhancing Exosomal Delivery to Abdominal Aortic Aneurysms using Magnetically Responsive Chemotactic Nanomotors for Elastic Matrix Regenerative Repair. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2405085. [PMID: 39429209 PMCID: PMC11633499 DOI: 10.1002/advs.202405085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 09/13/2024] [Indexed: 10/22/2024]
Abstract
Abdominal aortic aneurysms (AAAs) involve localized dilation of the abdominal aorta, with the reversal of this condition being significantly limited by the inherently poor and abnormal regenerative repair of the aortic elastic matrix. Mesenchymal stem cell exosomes (MSCEs) are promising regenerative tools; however, achieving precise targeting of AAA with MSCEs is challenging owing to the high blood flow in the arterial system. In this study, an engineered exosomal nanomotor is developed for magnetic and chemical propulsion. The results demonstrate that this nanomotor effectively enhances the delivery of MSCEs to the AAA through magnetic field navigation and catalase-induced chemotaxis. The nanomotor significantly enhances the elastic matrix repair, reduces oxidative stress, and activates the PI3K/Akt pathway, leading to aneurysm shrinkage and reversal. In addition, the nanomotor possesses magnetic resonance imaging capabilities. The use of this nanomotor offers a novel, targeted drug delivery system in a rat model of AAA and holds promise as a potential therapeutic option for this condition.
Collapse
Affiliation(s)
- Lulu Wang
- Department of Vascular SurgeryNanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjingJiangsu210008China
| | - Yao Zhang
- National and Local Joint Engineering Research Center of Biomedical Functional MaterialsSchool of Chemistry and Materials ScienceNanjing Normal UniversityNanjingJiangsu210023China
| | - Chun Mao
- Department of Vascular SurgeryNanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjingJiangsu210008China
- National and Local Joint Engineering Research Center of Biomedical Functional MaterialsSchool of Chemistry and Materials ScienceNanjing Normal UniversityNanjingJiangsu210023China
| | - Xiaoqiang Li
- Department of Vascular SurgeryNanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjingJiangsu210008China
| |
Collapse
|
|
7
|
Lee J, Geum D, Park DH, Kim JH. Molecular Targeting of Ischemic Stroke: The Promise of Naïve and Engineered Extracellular Vesicles. Pharmaceutics 2024; 16:1492. [PMID: 39771472 PMCID: PMC11678501 DOI: 10.3390/pharmaceutics16121492] [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: 11/01/2024] [Revised: 11/18/2024] [Accepted: 11/19/2024] [Indexed: 01/04/2025] Open
Abstract
Ischemic stroke (IS) remains a leading cause of mortality and long-term disability worldwide, with limited therapeutic options available. Despite the success of early interventions, such as tissue-type plasminogen activator administration and mechanical thrombectomy, many patients continue to experience persistent neurological deficits. The pathophysiology of IS is multifaceted, encompassing excitotoxicity, oxidative and nitrosative stress, inflammation, and blood-brain barrier disruption, all of which contribute to neural cell death, further complicating the treatment of IS. Recently, extracellular vesicles (EVs) secreted naturally by various cell types have emerged as promising therapeutic agents because of their ability to facilitate selective cell-to-cell communication, neuroprotection, and tissue regeneration. Furthermore, engineered EVs, designed to enhance targeted delivery and therapeutic cargo, hold the potential to improve their therapeutic benefits by mitigating neuronal damage and promoting neurogenesis and angiogenesis. This review summarizes the characteristics of EVs, the molecular mechanisms underlying IS pathophysiology, and the emerging role of EVs in IS treatment at the molecular level. This review also explores the recent advancements in EV engineering, including the incorporation of specific proteins, RNAs, or pharmacological agents into EVs to enhance their therapeutic efficacy.
Collapse
Affiliation(s)
- Jihun Lee
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea;
| | - Dongho Geum
- Department of Medical Science, College of Medicine, Korea University, Seoul 02841, Republic of Korea;
| | - Dong-Hyuk Park
- Department of Neurosurgery, Anam Hospital, College of Medicine, Korea University, Seoul 02841, Republic of Korea;
| | - Jong-Hoon Kim
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea;
| |
Collapse
|
|
8
|
Cheng T, Mao M, Liu Y, Xie L, Shi F, Liu H, Li X. The potential therapeutic effect of human umbilical cord mesenchymal stem cell-derived exosomes in bronchopulmonary dysplasia. Life Sci 2024; 357:123047. [PMID: 39260518 DOI: 10.1016/j.lfs.2024.123047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 08/25/2024] [Accepted: 09/07/2024] [Indexed: 09/13/2024]
Abstract
Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm infants, with its incidence rising due to improved survival rates of these infants. BPD results from a combination of prenatal and postnatal factors, such as mechanical ventilation, oxygen toxicity, and infections, all of which significantly impact the prognosis and growth of affected infants. Current treatment options for BPD are largely supportive and do not address the underlying pathology. Exosomes are cell-derived bilayer-enclosed membrane structures enclosing proteins, lipids, RNAs, growth factors, cytokines and metabolites. They have become recognized as crucial regulators of intercellular communication in various physiological and pathological processes. Previous studies have revealed the therapeutic potential of human umbilical cord mesenchymal stem cells-derived exosomes (HUCMSCs-Exos) in promoting tissue repair and regeneration. Therefore, HUCMSCs-Exos maybe a promising and effective therapeutic modality for BPD. In this review, we firstly provide a comprehensive overview of BPD, including its etiology and the mechanisms of lung injury. Then we detail the isolation, characterization, and contents of HUCMSCs-Exos, and discuss their potential mechanisms of HUCMSCs-Exos in BPD treatment. Additionally, we summarize current clinical trials and discuss the challenges in translating these findings from bench to bedside. This review aims to lay the groundwork for future clinical applications of HUCMSCs-Exos in treating BPD.
Collapse
Affiliation(s)
- Tianyu Cheng
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Min Mao
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yang Liu
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Liang Xie
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Fang Shi
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Hanmin Liu
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China.
| | - Xin Li
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China.
| |
Collapse
|
|
9
|
Zhang X, Guo J, Liu J, Liu J, Li Z, Chen J, Jiang J, Zhang K, Zhou B. Exosomal Src from hypoxic vascular smooth muscle cells exacerbates ischemic brain injury by promoting M1 microglial polarization. Neurochem Int 2024; 179:105819. [PMID: 39084350 DOI: 10.1016/j.neuint.2024.105819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 07/14/2024] [Accepted: 07/28/2024] [Indexed: 08/02/2024]
Abstract
Inflammatory response mediated by M1 microglia is a crucial factor leading to the exacerbation of brain injury after ischemic stroke (IS). Under the stimulation of IS, vascular smooth muscle cells (VSMCs) switch to the synthetic phenotype characterized by exosome secretion. Previous studies have shown that exosomes play an important role in the regulation of microglial polarization. We reported that exosomes derived from primary human brain VSMCs under hypoxia (HExos), but not those under normoxia (Exos), significantly promoted primary human microglia (HM1900) shift to M1 phenotype. Proteomic analysis showed that the Src protein enriched in HExos was a potential pro-inflammatory mediator. In vitro experiments showed that the expression of Src and M1 markers were upregulated in HM1900 co-incubated with HExos. However, the Src inhibitor dasatinib (DAS) significantly promoted the transformation of HM1900 phenotype from M1 to M2. In vivo experiments of pMCAO mice also revealed that DAS could effectively inhibit the activation of M1 microglia/macrophages, protect neurons from apoptosis, and improve neuronal function. These data suggested that hypoxic-VSMCs-derived exosomes were involved in post-IS inflammation by promoting M1 microglial polarization through Src transmission. Targeting inhibition of Src potentially acts as an effective strategy for treating brain injury after IS.
Collapse
MESH Headings
- Animals
- Exosomes/metabolism
- Microglia/metabolism
- Microglia/drug effects
- Humans
- Mice
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/pathology
- Male
- src-Family Kinases/metabolism
- src-Family Kinases/antagonists & inhibitors
- Mice, Inbred C57BL
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/drug effects
- Brain Ischemia/metabolism
- Brain Ischemia/pathology
- Cell Hypoxia/physiology
- Cell Hypoxia/drug effects
- Cell Polarity/physiology
- Cell Polarity/drug effects
- Cells, Cultured
Collapse
Affiliation(s)
- Xiaoting Zhang
- Center of Interventional Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China; Center of Cerebrovascular Disease, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China
| | - Jingpei Guo
- Center of Interventional Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China; Center of Cerebrovascular Disease, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China
| | - Junbin Liu
- Center of Interventional Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China; Center of Cerebrovascular Disease, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China
| | - Junfeng Liu
- Center of Interventional Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China; Center of Cerebrovascular Disease, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China
| | - Zhaozhu Li
- Department of Medical Ultrasonics, The Fourth People's Hospital of Nanhai District of Foshan City, Foshan, Guangdong Province, 528211, China
| | - Jiayao Chen
- Center of Interventional Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China; Center of Cerebrovascular Disease, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China
| | - Jiawei Jiang
- College of Education, Jinan University, Zhuhai, Guangdong Province, 519000, China
| | - Ke Zhang
- Center of Interventional Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China; Center of Cerebrovascular Disease, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China.
| | - Bin Zhou
- Center of Interventional Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China; Center of Cerebrovascular Disease, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China.
| |
Collapse
|
|
10
|
Dhyani N, Tian C, Gao L, Rudebush TL, Zucker IH. Nrf2-Keap1 in Cardiovascular Disease: Which Is the Cart and Which the Horse? Physiology (Bethesda) 2024; 39:0. [PMID: 38687468 PMCID: PMC11460534 DOI: 10.1152/physiol.00015.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 04/23/2024] [Accepted: 04/24/2024] [Indexed: 05/02/2024] Open
Abstract
High levels of oxidant stress in the form of reactive oxidant species are prevalent in the circulation and tissues in various types of cardiovascular disease including heart failure, hypertension, peripheral arterial disease, and stroke. Here we review the role of nuclear factor erythroid 2-related factor 2 (Nrf2), an important and widespread antioxidant and anti-inflammatory transcription factor that may contribute to the pathogenesis and maintenance of cardiovascular diseases. We review studies showing that downregulation of Nrf2 exacerbates heart failure, hypertension, and autonomic function. Finally, we discuss the potential for using Nrf2 modulation as a therapeutic strategy for cardiovascular diseases and autonomic dysfunction.
Collapse
Affiliation(s)
- Neha Dhyani
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska, United States
| | - Changhai Tian
- Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, Kentucky, United States
| | - Lie Gao
- Department of Anesthesiology, University of Nebraska Medical Center, Omaha, Nebraska, United States
| | - Tara L Rudebush
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska, United States
| | - Irving H Zucker
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska, United States
| |
Collapse
|
|
11
|
Brooks B, D'Egidio F, Borlongan MC, Borlongan MC, Lee JY. Stem cell grafts enhance endogenous extracellular vesicle expression in the stroke brain. Brain Res Bull 2024; 214:110999. [PMID: 38851436 DOI: 10.1016/j.brainresbull.2024.110999] [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: 02/19/2024] [Revised: 06/04/2024] [Accepted: 06/05/2024] [Indexed: 06/10/2024]
Abstract
Endogenous brain repair occurs following an ischemic stroke but is transient, thus unable to fully mount a neuroprotective response against the evolving secondary cell death. Finding a treatment strategy that may render robust and long-lasting therapeutic effects stands as a clinically relevant therapy for stroke. Extracellular vesicles appear to be upregulated after stroke, which may represent a candidate target for neuroprotection. In this study, we probed whether transplanted stem cells could enhance the expression of extracellular vesicles to afford stable tissue remodeling in the ischemic stroke brain. Aged rats were initially exposed to the established ischemic stroke model of middle cerebral artery occlusion then received intravenous delivery of either bone marrow-derived mesenchymal stem cell transplantation or vehicle. A year later, the animals were assayed for brain damage, inflammation, and extracellular vesicle expression. Our findings revealed that while core infarction was not reduced, the stroke animals transplanted with stem cells displayed a significant reduction in peri-infarct cell loss that coincided with downregulated Iba1-labeled inflammatory cells and upregulated CD63-positive extracellular vesicles that appeared to be co-localized with GFAP-positive astrocytes. Interestingly, grafted stem cells were not detected at one year post-transplantation period, suggesting that the extracellular vesicles likely originated within the host brain. That long-lasting functional benefits persisted in the absence of surviving transplanted stem cells, but with upregulation of endogenous extracellular vesicles, advances the concept that transplantation of stem cells acutely after stroke propels host extracellular vesicles to the ischemic brain, altogether promoting chronic brain remodeling.
Collapse
Affiliation(s)
- Beverly Brooks
- Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, United States
| | - Francesco D'Egidio
- Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, United States
| | - Maximillian C Borlongan
- Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, United States
| | - Mia C Borlongan
- Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, United States
| | - Jea-Young Lee
- Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, United States.
| |
Collapse
|
|
12
|
Qadri S, Sohail MU, Akhtar N, Pir GJ, Yousif G, Pananchikkal SV, Al-Noubi M, Choi S, Shuaib A, Haik Y, Parray A, Schmidt F. Mass spectrometry-based proteomic profiling of extracellular vesicle proteins in diabetic and non-diabetic ischemic stroke patients: a case-control study. Front Mol Biosci 2024; 11:1387859. [PMID: 38948080 PMCID: PMC11211575 DOI: 10.3389/fmolb.2024.1387859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Accepted: 05/23/2024] [Indexed: 07/02/2024] Open
Abstract
Acute ischemic stroke is the most common cause of neurologic dysfunction caused by focal brain ischemia and tissue injury. Diabetes is a major risk factor of stroke, exacerbating disease management and prognosis. Therefore, discovering new diagnostic markers and therapeutic targets is critical for stroke prevention and treatment. Extracellular vesicles (EVs), with their distinctive properties, have emerged as promising candidates for biomarker discovery and therapeutic application. This case-control study utilized mass spectrometry-based proteomics to compare EVs from non-diabetic stroke (nDS = 14), diabetic stroke (DS = 13), and healthy control (HC = 12) subjects. Among 1288 identified proteins, 387 were statistically compared. Statistical comparisons using a general linear model (log2 foldchange ≥0.58 and FDR-p≤0.05) were performed for nDS vs HC, DS vs HC, and DS vs nDS. DS vs HC and DS vs nDS comparisons produced 123 and 149 differentially expressed proteins, respectively. Fibrinogen gamma chain (FIBG), Fibrinogen beta chain (FIBB), Tetratricopeptide repeat protein 16 (TTC16), Proline rich 14-like (PR14L), Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKE), Biorientation of chromosomes in cell division protein 1-like 1 (BD1L1), and protein PR14L exhibited significant differences in the DS group. The pathway analysis revealed that the complement system pathways were activated, and blood coagulation and neuroprotection were inhibited in the DS group (z-score ≥2; p ≤ 0.05). These findings underscore the potential of EVs proteomics in identifying biomarkers for stroke management and prevention, warranting further clinical investigation.
Collapse
Affiliation(s)
- Shahnaz Qadri
- Department of Pharmaceutical Sciences, Irma Lerma Rangel School of Pharmacy, Texas A&M University, Kingsville, TX, United States
- Sustainability Division, College of Science and Engineering, Hamad Bin Khalifa University, Doha, Qatar
| | | | - Naveed Akhtar
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Ghulam Jeelani Pir
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Ghada Yousif
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | | | - Muna Al-Noubi
- Proteomics Core, Weill Cornell Medicine, Doha, Qatar
| | - Sunkyu Choi
- Proteomics Core, Weill Cornell Medicine, Doha, Qatar
| | - Ashfaq Shuaib
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Yousef Haik
- Department of Mechanical and Nuclear Engineering, University of Sharjah, Sharjah, United Arab Emirates
| | - Aijaz Parray
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Frank Schmidt
- Proteomics Core, Weill Cornell Medicine, Doha, Qatar
| |
Collapse
|
|
13
|
Xing L, Wang Z, Feng Y, Luo H, Dai G, Sang L, Zhang C, Qian J. The biological roles of CD47 in ovarian cancer progression. Cancer Immunol Immunother 2024; 73:145. [PMID: 38832992 PMCID: PMC11150368 DOI: 10.1007/s00262-024-03708-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 04/19/2024] [Indexed: 06/06/2024]
Abstract
Ovarian cancer is one of the most lethal malignant tumors, characterized by high incidence and poor prognosis. Patients relapse occurred in 65-80% after initial treatment. To date, no effective treatment has been established for these patients. Recently, CD47 has been considered as a promising immunotherapy target. In this paper, we reviewed the biological roles of CD47 in ovarian cancer and summarized the related mechanisms. For most types of cancers, the CD47/Sirpα immune checkpoint has attracted the most attention in immunotherapy. Notably, CD47 monoclonal antibodies and related molecules are promising in the immunotherapy of ovarian cancer, and further research is needed. In the future, new immunotherapy regimens targeting CD47 can be applied to the clinical treatment of ovarian cancer patients.
Collapse
Affiliation(s)
- Linan Xing
- Department of Gynecology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, People's Republic of China
| | - Zhao Wang
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, People's Republic of China
| | - Yue Feng
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, People's Republic of China
| | - Haixia Luo
- Department of Gynecology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, People's Republic of China
| | - Guijiang Dai
- Department of Comprehensive Office, The Second Affiliated Hospital of MuDanjiang Medical University, Mudanjiang, 157009, People's Republic of China
| | - Lin Sang
- Department of Obstetrics and Gynecology, People's Hospital of Anji, Huzhou, 310022, People's Republic of China
| | - Chunlong Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, People's Republic of China.
| | - Jianhua Qian
- Department of Gynecology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, People's Republic of China.
| |
Collapse
|
|
14
|
Yavuz B, Mutlu EC, Ahmed Z, Ben-Nissan B, Stamboulis A. Applications of Stem Cell-Derived Extracellular Vesicles in Nerve Regeneration. Int J Mol Sci 2024; 25:5863. [PMID: 38892052 PMCID: PMC11172915 DOI: 10.3390/ijms25115863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 05/15/2024] [Accepted: 05/23/2024] [Indexed: 06/21/2024] Open
Abstract
Extracellular vesicles (EVs), including exosomes, microvesicles, and other lipid vesicles derived from cells, play a pivotal role in intercellular communication by transferring information between cells. EVs secreted by progenitor and stem cells have been associated with the therapeutic effects observed in cell-based therapies, and they also contribute to tissue regeneration following injury, such as in orthopaedic surgery cases. This review explores the involvement of EVs in nerve regeneration, their potential as drug carriers, and their significance in stem cell research and cell-free therapies. It underscores the importance of bioengineers comprehending and manipulating EV activity to optimize the efficacy of tissue engineering and regenerative therapies.
Collapse
Affiliation(s)
- Burcak Yavuz
- Vocational School of Health Services, Altinbas University, 34147 Istanbul, Turkey;
| | - Esra Cansever Mutlu
- Biomaterials Research Group, School of Metallurgy and Materials, College of Engineering and Physical Science, University of Birmingham, Birmingham B15 2TT, UK;
| | - Zubair Ahmed
- Neuroscience & Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Edgbaston B15 2TT, UK
| | - Besim Ben-Nissan
- Translational Biomaterials and Medicine Group, School of Life Sciences, University of Technology Sydney, P.O. Box 123, Broadway, NSW 2007, Australia;
| | - Artemis Stamboulis
- Biomaterials Research Group, School of Metallurgy and Materials, College of Engineering and Physical Science, University of Birmingham, Birmingham B15 2TT, UK;
| |
Collapse
|
|
15
|
Wang X, Li A, Fan H, Li Y, Yang N, Tang Y. Astrocyte-Derived Extracellular Vesicles for Ischemic Stroke: Therapeutic Potential and Prospective. Aging Dis 2024; 15:1227-1254. [PMID: 37728588 PMCID: PMC11081164 DOI: 10.14336/ad.2023.0823-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 08/23/2023] [Indexed: 09/21/2023] Open
Abstract
Stroke is a leading cause of death and disability in the world. Astrocytes are special glial cells within the central nervous system and play important roles in mediating neuroprotection and repair processes during stroke. Extracellular vesicles (EVs) are lipid bilayer particles released from cells that facilitate intercellular communication in stroke by delivering proteins, lipids, and RNA to target cells. Recently, accumulating evidence suggested that astrocyte-derived EVs (ADEVs) are actively involved in mediating numerous biological processes including neuroprotection and neurorepair in stroke and they are realized as an excellent therapeutic approach for treating stroke. In this review we systematically summarize the up-to-date research on ADEVs in stroke, and prospects for its potential as a novel therapeutic target for stroke. We also provide an overview of the effects and functions of ADEVs on stroke recovery, which may lead to developing clinically relevant therapies for stroke.
Collapse
Affiliation(s)
- Xianghui Wang
- School of Bioscience and Technology, Weifang Medical University, Weifang, Shandong, China.
- School of Biomedical Engineering and Affiliated Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, China.
| | - Aihua Li
- Department of rehabilitation medicine, Jinan Hospital, Jinan, China
| | - Huaju Fan
- School of Bioscience and Technology, Weifang Medical University, Weifang, Shandong, China.
| | - Yanyan Li
- School of Bioscience and Technology, Weifang Medical University, Weifang, Shandong, China.
| | - Nana Yang
- School of Bioscience and Technology, Weifang Medical University, Weifang, Shandong, China.
- School of Biomedical Engineering and Affiliated Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, China.
| | - Yaohui Tang
- School of Biomedical Engineering and Affiliated Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, China.
| |
Collapse
|
|
16
|
Haroon K, Zheng H, Wu S, Liu Z, Tang Y, Yang GY, Liu Y, Zhang Z. Engineered exosomes mediated targeted delivery of neuroprotective peptide NR2B9c for the treatment of traumatic brain injury. Int J Pharm 2024; 649:123656. [PMID: 38040392 DOI: 10.1016/j.ijpharm.2023.123656] [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: 09/12/2023] [Revised: 11/19/2023] [Accepted: 11/28/2023] [Indexed: 12/03/2023]
Abstract
Neuroprotection is one of the core treatment strategies for brain injuries including traumatic brain injury (TBI). NR2B9c is a promising neuroprotective peptide but its clinical translation is limited because of poor brain penetrability. Exosomes are naturally occurring nanovesicles having therapeutic potential for TBI as well as an efficient drug delivery carrier to the brain. Here, we engineered exosomes with neuron targeting peptide rabies virus glycoprotein (RVG29) via bio-orthogonal click chemistry technique and loaded it with NR2B9c, developing RVG-ExoNR2B9c. RVG29 conjugated exosome had higher neuron targeting efficiency compared to naïve exosomes both in vivo and in vitro. RVG-ExoNR2B9c had great cytoprotective effect against oxygen glucose deprived Neuro2a cells. Intravenous administration of RVG-ExoNR2B9c significantly improved behavioral outcomes and reduced the lesion volume after TBI injury in a mice controlled cortical impact model. Due to their multifunctionality and significant efficacy, we anticipate that RVG-ExoNR2B9c have the potential to be translated both as therapeutic agent as well as cargo delivery system to the brain for the treatment of TBI.
Collapse
Affiliation(s)
- Khan Haroon
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Haoran Zheng
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Shengju Wu
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Ze Liu
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Yaohui Tang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Guo-Yuan Yang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
| | - Yingli Liu
- Department of Nephrology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, 639 Zhizaoju Road, Shanghai 200025, China.
| | - Zhijun Zhang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
| |
Collapse
|
|
17
|
Han D, Wang M, Dong N, Zhang J, Li D, Ma X, Ma Y, Wang S, Zhu Y, Wang C. Selective homing of brain-derived reconstituted lipid nanoparticles to cerebral ischemic area enables improved ischemic stroke treatment. J Control Release 2024; 365:957-968. [PMID: 38104776 DOI: 10.1016/j.jconrel.2023.12.020] [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: 08/24/2023] [Revised: 12/11/2023] [Accepted: 12/13/2023] [Indexed: 12/19/2023]
Abstract
Lipid nanoparticles (LNPs) hold great promise as carriers for developing drug delivery systems (DDSs) aimed at managing ischemic stroke (IS). Previous research has highlighted the vital role played by the lipid composition and biophysical characteristics of LNPs, influencing their interactions with cells and tissues. This understanding presents an opportunity to engineer LNPs tailored specifically for enhanced IS treatment. We previously introduced the innovative concept of reconstituted lipid nanoparticles (rLNPs), which not only retain the advantages of conventional LNPs but also incorporate lipids from the originating cell or tissue. Brain-derived rLNPs (B-rLNPs) exhibit significantly superior accumulation within the cerebral ischemic region when compared to liver-derived rLNPs (L-rLNPs). The homing effect of B-rLNPs was then employed to construct 3-n-butylphthalide (NBP) loaded DDS (B-rLNPs/NBP) for the treatment of IS. Our results demonstrated that compared with free NBP, B-rLNPs/NBP can significantly reduce infarct volume, neurological deficits, blood-brain barrier (BBB) leakage rate, brain water content, neutrophil infiltration, alleviate pathological structures, and improve the motor function in MCAO/R model. We also proved that B-rLNPs/NBP showed further reinforced protective effects on the same model than free NBP through the regulation of TLR4/MyD88/NF-κB (anti-inflammation) and Bax/Bcl-2 (anti-apoptosis) pathways. This study offers a promising tool towards improved IS treatment.
Collapse
Affiliation(s)
- Dan Han
- Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China; Nanjing Medical Center for Clinical Pharmacy, Nanjing, Jiangsu, China
| | - Meihua Wang
- Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China; Nanjing Medical Center for Clinical Pharmacy, Nanjing, Jiangsu, China
| | - Ningyu Dong
- Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Jiaxing Zhang
- School of Pharmacy, Changzhou University, Changzhou, Jiangsu, China
| | - Dingran Li
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Xiaoling Ma
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Ying Ma
- Jiangsu Institute for Food and Drug Control, Nanjing, Jiangsu, China
| | - Siliang Wang
- Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
| | - Yun Zhu
- Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
| | - Cheng Wang
- School of Pharmacy, Changzhou University, Changzhou, Jiangsu, China.
| |
Collapse
|
|
18
|
Ahmed W, Huang S, Chen L. Engineered exosomes derived from stem cells: a new brain-targeted strategy. Expert Opin Drug Deliv 2024; 21:91-110. [PMID: 38258509 DOI: 10.1080/17425247.2024.2306877] [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: 09/27/2023] [Accepted: 01/15/2024] [Indexed: 01/24/2024]
Abstract
INTRODUCTION Using engineered exosomes produced from stem cells is an experimental therapeutic approach for treating brain diseases. According to reports, preclinical research has demonstrated notable neurogenesis and angiogenesis effects using modified stem cell-derived exosomes. These biological nanoparticles have a variety of anti-apoptotic, anti-inflammatory, and antioxidant properties that make them very promising for treating nervous system disorders. AREAS COVERED This review examines different ways to enhance the delivery of modified stem cell-derived exosomes, how they infiltrate the blood-brain barrier (BBB), and how they facilitate their access to the brain. We would also like to determine whether these nanoparticles have the most significant transmission rates through BBB when targeting brain lesions. EXPERT OPINION Using engineered stem cell-derived exosomes for treating brain disorders has generated considerable attention toward clinical research and application. However, stem cell-derived exosomes lack consistency, and their mechanisms of action are uncertain. Therefore, upcoming research needs to prioritize examining the underlying mechanisms and strategies via which these nanoparticles combat neurological disorders.
Collapse
Affiliation(s)
- Waqas Ahmed
- Department of Neurosurgery, Integrated Traditional Chinese and Western Medicine Hospital, Southern Medical University, Guangzhou, Guangdong, China
- School of Medicine, Southeast University, Nanjing, Jiangsu, China
| | - Songze Huang
- Department of Neurosurgery, Integrated Traditional Chinese and Western Medicine Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Lukui Chen
- Department of Neurosurgery, Integrated Traditional Chinese and Western Medicine Hospital, Southern Medical University, Guangzhou, Guangdong, China
| |
Collapse
|
|
19
|
Wang X, Bai R. Advances in smart delivery of magnetic field-targeted drugs in cardiovascular diseases. Drug Deliv 2023; 30:2256495. [PMID: 37702067 PMCID: PMC10501169 DOI: 10.1080/10717544.2023.2256495] [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: 06/06/2023] [Revised: 08/11/2023] [Accepted: 08/26/2023] [Indexed: 09/14/2023] Open
Abstract
Magnetic Drug Targeting (MDT) is of particular interest to researchers because of its good loading efficiency, targeting accuracy, and versatile use in vivo. Cardiovascular Disease (CVD) is a global chronic disease with a high mortality rate, and the development of more precise and effective treatments is imminent. A growing number of studies have begun to explore the feasibility of MDT in CVD, but an up-to-date systematic summary is still lacking. This review discusses the current research status of MDT from guiding magnetic fields, magnetic nanocarriers, delivery channels, drug release control, and safety assessment. The current application status of MDT in CVD is also critically introduced. On this basis, new insights into the existing problems and future optimization directions of MDT are further highlighted.
Collapse
Affiliation(s)
- Xinyu Wang
- Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Ruru Bai
- Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| |
Collapse
|
|
20
|
Wu P, Wu W, Zhang S, Han J, Liu C, Yu H, Chen X, Chen X. Therapeutic potential and pharmacological significance of extracellular vesicles derived from traditional medicinal plants. Front Pharmacol 2023; 14:1272241. [PMID: 38108066 PMCID: PMC10725203 DOI: 10.3389/fphar.2023.1272241] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 11/20/2023] [Indexed: 12/19/2023] Open
Abstract
Medicinal plants are the primary sources for the discovery of novel medicines and the basis of ethnopharmacological research. While existing studies mainly focus on the chemical compounds, there is little research about the functions of other contents in medicinal plants. Extracellular vesicles (EVs) are functionally active, nanoscale, membrane-bound vesicles secreted by almost all eukaryotic cells. Intriguingly, plant-derived extracellular vesicles (PDEVs) also have been implicated to play an important role in therapeutic application. PDEVs were reported to have physical and chemical properties similar to mammalian EVs, which are rich in lipids, proteins, nucleic acids, and pharmacologically active compounds. Besides these properties, PDEVs also exhibit unique advantages, especially intrinsic bioactivity, high stability, and easy absorption. PDEVs were found to be transferred into recipient cells and significantly affect their biological process involved in many diseases, such as inflammation and tumors. PDEVs also could offer unique morphological and compositional characteristics as natural nanocarriers by innately shuttling bioactive lipids, RNA, proteins, and other pharmacologically active substances. In addition, PDEVs could effectively encapsulate hydrophobic and hydrophilic chemicals, remain stable, and cross stringent biological barriers. Thus, this study focuses on the pharmacological action and mechanisms of PDEVs in therapeutic applications. We also systemically deal with facets of PDEVs, ranging from their isolation to composition, biological functions, and biotherapeutic roles. Efforts are also made to elucidate recent advances in re-engineering PDEVs applied as stable, effective, and non-immunogenic therapeutic applications to meet the ever-stringent demands. Considering its unique advantages, these studies not only provide relevant scientific evidence on therapeutic applications but could also replenish and inherit precious cultural heritage.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Xiping Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaofeng Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| |
Collapse
|
|
21
|
Huang L, Wu E, Liao J, Wei Z, Wang J, Chen Z. Research Advances of Engineered Exosomes as Drug Delivery Carrier. ACS OMEGA 2023; 8:43374-43387. [PMID: 38027310 PMCID: PMC10666244 DOI: 10.1021/acsomega.3c04479] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 09/05/2023] [Accepted: 10/27/2023] [Indexed: 12/01/2023]
Abstract
Exosomes are nanoscale vesicles secreted by living cells that have similar membrane composition to parental cells and carry a variety of proteins, lipids, and nucleic acids. Therefore, exosomes have certain biological activities and play an important role in intercellular communication. On the basis of its potential as a carrier for drug delivery systems, exosomes have been engineered to compensate for the shortage of natural exosomes through various engineering strategies for improving drug delivery efficiency, enhancing targeting to tissues and organs, and extending the circulating half-life of exosomes. This review focuses on the engineered exosomes loading drugs through different strategies, discussions on exosome surface modification strategies, and summarizes the advantages and disadvantages of different strategies. In addition, this review provides an overview of the recent applications of engineered exosomes in a number of refractory and relapsable diseases. This review has the potential to provide a reference for further research and development of engineered exosomes.
Collapse
Affiliation(s)
- Lianghui Huang
- Jiangxi Province Key Laboratory of
Drug Design and Evaluation, School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang 330013, P. R. China
| | - Enguang Wu
- Jiangxi Province Key Laboratory of
Drug Design and Evaluation, School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang 330013, P. R. China
| | - Jiawei Liao
- Jiangxi Province Key Laboratory of
Drug Design and Evaluation, School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang 330013, P. R. China
| | - Zongyi Wei
- Jiangxi Province Key Laboratory of
Drug Design and Evaluation, School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang 330013, P. R. China
| | - Jin Wang
- Jiangxi Province Key Laboratory of
Drug Design and Evaluation, School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang 330013, P. R. China
| | - Zhenhua Chen
- Jiangxi Province Key Laboratory of
Drug Design and Evaluation, School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang 330013, P. R. China
| |
Collapse
|
|
22
|
Haupt M, Gerner ST, Huttner HB, Doeppner TR. Preconditioning Concepts for the Therapeutic Use of Extracellular Vesicles Against Stroke. Stem Cells Transl Med 2023; 12:707-713. [PMID: 37696005 PMCID: PMC10630075 DOI: 10.1093/stcltm/szad055] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 08/02/2023] [Indexed: 09/13/2023] Open
Abstract
Various preclinical stroke models have demonstrated the neuroprotective effects of extracellular vesicles (EVs) obtained from several types of cells, including neurons, astrocytes, microglia, neuronal progenitor cells, bone marrow stem cells, and mesenchymal stem cells. EVs interfere with key mechanisms in stroke pathophysiology such as cell death, neuroinflammation, autophagy, and angiogenesis. The mode of action and efficacy depend on the specific EV content, including miRNAs, proteins, and lipids, which can be modified through (I) bioengineering methods, (II) choice of source cells, and (III) modification of the source cell environment. Indeed, modifying the environment by preconditioning the EV-secreting cells with oxygen-glucose deprivation or medium modification revealed superior neuroprotective effects in stroke models. Although the concept of preconditioned EVs is relatively novel, it holds promise for the future treatment of ischemic stroke. Here, we give a brief overview about the main mechanisms of EV-induced neuroprotection and discuss the current status of preconditioning concepts for EV-treatment of ischemic stroke.
Collapse
Affiliation(s)
- Matteo Haupt
- Deparment of Neurology, University of Göttingen Medical School, Göttingen, Lower Saxony, Germany
| | - Stefan T Gerner
- Deparment of Neurology, University Hospital Giessen, Giessen, Hesse, Germany
- Center for Mind, Brain and Behavior (CMBB), University of Marburg and Justus Liebig University Giessen, Marburg, Hesse, Germany
| | - Hagen B Huttner
- Deparment of Neurology, University Hospital Giessen, Giessen, Hesse, Germany
- Center for Mind, Brain and Behavior (CMBB), University of Marburg and Justus Liebig University Giessen, Marburg, Hesse, Germany
| | - Thorsten R Doeppner
- Deparment of Neurology, University of Göttingen Medical School, Göttingen, Lower Saxony, Germany
- Deparment of Neurology, University Hospital Giessen, Giessen, Hesse, Germany
- Center for Mind, Brain and Behavior (CMBB), University of Marburg and Justus Liebig University Giessen, Marburg, Hesse, Germany
- Department of Anatomy and Cell Biology, Medical University of Varna, Varna, Bulgaria
- Medipol University Istanbul, Research Institute for Health Sciences and Technologies (SABITA), Istanbul, Turkey
| |
Collapse
|
|
23
|
Haroon K, Ruan H, Zheng H, Wu S, Liu Z, Shi X, Tang Y, Yang GY, Zhang Z. Bio-clickable, small extracellular vesicles-COCKTAIL therapy for ischemic stroke. J Control Release 2023; 363:585-596. [PMID: 37793483 DOI: 10.1016/j.jconrel.2023.10.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 09/29/2023] [Accepted: 10/01/2023] [Indexed: 10/06/2023]
Abstract
Delivering large therapeutic molecules via the blood-brain barrier to treat ischemic stroke remains challenging. NR2B9c is a potent neuroprotective peptide but it's safe and targeted delivery to the brain requires an efficient, natural, and non-immunogenic delivery technique. Small extracellular vesicles (sEVs) have shown great potential as a non-immunogenic, natural cargo delivery system; however, tailoring of its inefficient brain targeting is desired. Here, we coupled rabies virus glycoprotein 29 with sEVs surface via bio-orthogonal click chemistry reactions, followed by loading of NR2B9c, ultimately generating stroke-specific therapeutic COCKTAIL (sEVs-COCKTAIL). Primary neurons and Neuro-2a cells were cultured for in vitro and transient middle cerebral artery occlusion model was used for in vivo studies to evaluate neuron targeting and anti-ischemic stroke potential of the sEVs-COCKTAIL. Bio-clickable sEVs were selectively taken up by neurons but not glial cells. In the in vitro ischemic stroke model of oxygen-glucose deprivation, the sEVs-COCKTAIL exhibited remarkable potential against reactive oxygen species and cellular apoptosis. In vivo studies further demonstrated the brain targeting and increased half-life of bio-clickable sEVs, delivering NR2B9c to the ischemic brain and reducing stroke injury. Treatment with the sEVs-COCKTAIL significantly increased behavioral recovery and reduced neuronal apoptosis after transient middle cerebral artery occlusion. NR2B9c was delivered to neurons binding to post-synaptic density protein-95, inhibiting N-methyl-d-Aspartate receptor-mediated over production of oxidative stress and mitigating protein B-cell lymphoma 2 and P38 proteins expression. Our results provide an efficient and biocompatible approach to a targeted delivery system, which is a promising modality for stroke therapy.
Collapse
Affiliation(s)
- Khan Haroon
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Huitong Ruan
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Haoran Zheng
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Shengju Wu
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Ze Liu
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Xiaojing Shi
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Yaohui Tang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Guo-Yuan Yang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
| | - Zhijun Zhang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
| |
Collapse
|
|
24
|
Li P, Yin R, Chen Y, Chang J, Yang L, Liu X, Xu H, Zhang X, Wang S, Han Q, Wei J. Engineered extracellular vesicles for ischemic stroke: a systematic review and meta-analysis of preclinical studies. J Nanobiotechnology 2023; 21:396. [PMID: 37904204 PMCID: PMC10617166 DOI: 10.1186/s12951-023-02114-8] [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: 06/21/2023] [Accepted: 09/15/2023] [Indexed: 11/01/2023] Open
Abstract
BACKGROUND This systematic review and meta-analysis aimed to evaluate the efficacy of engineered extracellular vesicles (EEVs) in the treatment of ischemic stroke (IS) in preclinical studies and to compare them with natural extracellular vesicles (EVs). The systematic review provides an up-to-date overview of the current state of the literature on the use of EEVs for IS and informs future research in this area. METHODS We searched PubMed, EMBASE, Web of Science, Cochrane Library, and Scopus databases for peer-reviewed preclinical studies on the therapeutic effect of EEVs on IS.Databases ranged from the inception to August 1, 2023. The outcome measures included infarct volumes, neurological scores, behavioral scores, apoptosis rates, numbers of neurons, and levels of IL-1β, IL-6, and TNF-α. The CAMARADES checklist was used to assess the quality and bias risks of the studies. All statistical analyses were performed using RevMan 5.4 software. RESULTS A total of 28 studies involving 1760 animals met the inclusion criteria. The results of the meta-analysis showed that compared to natural EVs, EEVs reduced infarct volume (percentage: SMD = -2.33, 95% CI: -2.92, -1.73; size: SMD = -2.36, 95% CI: -4.09, -0.63), improved neurological scores (mNSS: SMD = -1.78, 95% CI: -2.39, -1.17; Zea Longa: SMD = -2.75, 95% CI: -3.79, -1.71), promoted behavioral recovery (rotarod test: SMD = 2.50, 95% CI: 1.81, 3.18; grid-walking test: SMD = -3.45, 95% CI: -5.15, -1.75; adhesive removal test: SMD = -2.60, 95% CI: -4.27, -0.93; morris water maze test: SMD = -3.91, 95% CI: -7.03, -0.79), and reduced the release of proinflammatory factors (IL-1β: SMD = -2.02, 95% CI: -2.77, -1.27; IL-6: SMD = -3.01, 95% CI: -4.47, -1.55; TNF-α: SMD = -2.72, 95% CI: -4.30, -1.13), increasing the number of neurons (apoptosis rate: SMD = -2.24, 95% CI: -3.32, -1.16; the number of neurons: SMD = 3.70, 95% CI: 2.44, 4.96). The funnel plots for the two main outcome measures were asymmetric, indicating publication bias. The median score on the CAMARADES checklist was 7 points (IQR: 6-9). CONCLUSIONS This meta-analysis shows that EEVs are superior to natural EVs for the treatment of IS. However, research in this field is still at an early stage, and more research is needed to fully understand the potential therapeutic mechanism of EEVs and their potential use in the treatment of IS. PROSPERO REGISTRATION NUMBER CRD42022368744.
Collapse
Affiliation(s)
- Pengtao Li
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Rui Yin
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Yihao Chen
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Jianbo Chang
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Lang Yang
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaoyu Liu
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Houshi Xu
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiao Zhang
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Shihua Wang
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Qin Han
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
| | - Junji Wei
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
| |
Collapse
|
|
25
|
Ahmed W, Kuniyan MS, Jawed AM, Chen L. Engineered Extracellular Vesicles for Drug Delivery in Therapy of Stroke. Pharmaceutics 2023; 15:2173. [PMID: 37765144 PMCID: PMC10537154 DOI: 10.3390/pharmaceutics15092173] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/10/2023] [Accepted: 08/17/2023] [Indexed: 09/29/2023] Open
Abstract
Extracellular vesicles (EVs) are promising therapeutic modalities for treating neurological conditions. EVs facilitate intercellular communication among brain cells under normal and abnormal physiological conditions. The potential capability of EVs to pass through the blood-brain barrier (BBB) makes them highly promising as nanocarrier contenders for managing stroke. EVs possess several potential advantages compared to existing drug-delivery vehicles. These advantages include their capacity to surpass natural barriers, target specific cells, and stability within the circulatory system. This review explores the trafficking and cellular uptake of EVs and evaluates recent findings in the field of EVs research. Additionally, an overview is provided of the techniques researchers utilize to bioengineer EVs for stroke therapy, new results on EV-BBB interactions, and the limitations and prospects of clinically using EVs for brain therapies. The primary objective of this study is to provide a comprehensive analysis of the advantages and challenges related to engineered EVs drug delivery, specifically focusing on their application in the treatment of stroke.
Collapse
Affiliation(s)
- Waqas Ahmed
- Department of Neurosurgery, Neuroscience Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, China;
- School of Medicine, Southeast University, Nanjing 210009, China; (M.S.K.); (A.M.J.)
| | | | - Aqil Mohammad Jawed
- School of Medicine, Southeast University, Nanjing 210009, China; (M.S.K.); (A.M.J.)
| | - Lukui Chen
- Department of Neurosurgery, Neuroscience Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, China;
| |
Collapse
|
|
26
|
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: 46] [Impact Index Per Article: 23.0] [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.
Collapse
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
| |
Collapse
|
|
27
|
Ren X, Kang C, Garcia-Contreras L, Kim D. Understanding of Ovarian Cancer Cell-Derived Exosome Tropism for Future Therapeutic Applications. Int J Mol Sci 2023; 24:8166. [PMID: 37175872 PMCID: PMC10179437 DOI: 10.3390/ijms24098166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/18/2023] [Accepted: 04/30/2023] [Indexed: 05/15/2023] Open
Abstract
Exosomes, a subtype of extracellular vesicles, ranging from 50 to 200 nm in diameter, and mediate cell-to-cell communication in normal biological and pathological processes. Exosomes derived from tumors have multiple functions in cancer progression, resistance, and metastasis through cancer exosome-derived tropism. However, there is no quantitative information on cancer exosome-derived tropism. Such data would be highly beneficial to guide cancer therapy by inhibiting exosome release and/or uptake. Using two fluorescent protein (mKate2) transfected ovarian cancer cell lines (OVCA4 and OVCA8), cancer exosome tropism was quantified by measuring the released exosome from ovarian cancer cells and determining the uptake of exosomes into parental ovarian cancer cells, 3D spheroids, and tumors in tumor-bearing mice. The OVCA4 cells release 50 to 200 exosomes per cell, and the OVCA8 cells do 300 to 560 per cell. The uptake of exosomes by parental ovarian cancer cells is many-fold higher than by non-parental cells. In tumor-bearing mice, most exosomes are homing to the parent cancer rather than other tissues. We successfully quantified exosome release and uptake by the parent cancer cells, further proving the tropism of cancer cell-derived exosomes. The results implied that cancer exosome tropism could provide useful information for future cancer therapeutic applications.
Collapse
Affiliation(s)
- Xiaoyu Ren
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA; (X.R.); (C.K.); (L.G.-C.)
| | - Changsun Kang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA; (X.R.); (C.K.); (L.G.-C.)
| | - Lucila Garcia-Contreras
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA; (X.R.); (C.K.); (L.G.-C.)
| | - Dongin Kim
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA; (X.R.); (C.K.); (L.G.-C.)
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| |
Collapse
|
|
28
|
Liang Y, Iqbal Z, Lu J, Wang J, Zhang H, Chen X, Duan L, Xia J. Cell-derived nanovesicle-mediated drug delivery to the brain: Principles and strategies for vesicle engineering. Mol Ther 2023; 31:1207-1224. [PMID: 36245129 PMCID: PMC10188644 DOI: 10.1016/j.ymthe.2022.10.008] [Citation(s) in RCA: 64] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 09/27/2022] [Accepted: 10/14/2022] [Indexed: 11/06/2022] Open
Abstract
Developing strategies toward safe and effective drug delivery into the central nervous system (CNS) with improved targeting abilities and reduced off-target effects is crucial. CNS-targeted drug carriers made of synthetic molecules raise concerns about their biodegradation, clearance, immune responses, and neurotoxicity. Cell-derived nanovesicles (CDNs) have recently been applied in CNS-targeted drug delivery, because of their intrinsic stability, biocompatibility, inherent homing capability, and the ability to penetrate through biological barriers, including the blood-brain barrier. Among these CDNs, extracellular vesicles and exosomes are the most studied because their surface can be engineered and modified to cater to brain targeting. In this review, we focus on the application of CDNs in brain-targeted drug delivery to treat neurological diseases. We cover recently developed methods of exosome derivation and engineering, including exosome-like particles, hybrid exosomes, exosome-associated adeno-associated viruses, and envelope protein nanocages. Finally, we discuss the limitations and project the future development of the CDN-based brain-targeted delivery systems, and conclude that engineered CDNs hold great potential in the treatment of neurological diseases.
Collapse
Affiliation(s)
- Yujie Liang
- Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, Guangdong 518020, China; Department of Orthopedics, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, China
| | - Zoya Iqbal
- Department of Orthopedics, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, China
| | - Jianping Lu
- Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, Guangdong 518020, China
| | - Jianhong Wang
- Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, Guangdong 518020, China
| | - Hao Zhang
- State Key Laboratory of Bioelectronics, National Demonstration Center for Experimental Biomedical Engineering Education, Southeast University, Nanjing, Jiangsu 210096, China; EVLiXiR Biotech Inc., Nanjing, Jiangsu 210032, China
| | - Xi Chen
- Department of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Li Duan
- Department of Orthopedics, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, China.
| | - Jiang Xia
- Department of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
| |
Collapse
|
|
29
|
Liu Y, Li YP, Xiao LM, Chen LK, Zheng SY, Zeng EM, Xu CH. Extracellular Vesicles Derived from Bone Mesenchymal Stem Cells Carrying circ_0000075 Relieves Cerebral Ischemic Injury by Competitively Inhibiting miR-218-5p and Up-regulating E3 Ubiquitin Ligase SMURF2. Mol Neurobiol 2023; 60:2801-2818. [PMID: 36732429 DOI: 10.1007/s12035-022-03192-9] [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: 08/17/2022] [Accepted: 12/23/2022] [Indexed: 02/04/2023]
Abstract
Extracellular vesicle (EV)-encapsulated circRNAs have the potential role in affecting brain disorders. However, the role of circ_0000075 in cerebral ischemic injury remains unclear. Here, we tried to investigate the mechanism of bone marrow mesenchymal stem cell (BMSC)-derived EVs carrying circ_0000075 in the control of cerebral ischemic injury. Initially, a mouse model with cerebral ischemic injury was induced by middle cerebral artery occlusion (MCAO), followed by the determination of circ_0000075 expression. Then, neurons were isolated and subjected to oxygen-glucose deprivation/reperfusion. BMSCs were isolated for extraction of EVs. The correlation among circ_0000075, microRNA (miR)-218-5p, and Smad ubiquitination regulatory factor 2 (SMURF2) was detected with their roles in cerebral ischemic injury analyzed in vivo and in vitro. circ_0000075 was down-regulated in MCAO mice and engineered RVG-EVs were internalized by neurons to up-regulate circ_0000075 expression. Treatment of RVG-circ_0000075-EVs reduced brain tissue damage, increased neuronal count, and significantly curtailed apoptosis rate, suppressing cerebral ischemic injury in vitro and in vivo. miR-218-5p was targeted by circ_0000075 in neurons, which promoted SMURF2 expression. A negative correlation between SMURF2 and transcriptional regulator Yin Yang 1 (YY1) was identified. In vitro experiments further proved that circ_ 00,000 75 could down-regulate the expression of YY1 through SMURF2, and finally relieving cerebral ischemic injury. Collectively, engineered EVs delivered circ_0000075 into brain tissues and increased circ_0000075 expression, which down-regulated miR-218-5p and up-regulated SMURF2, thus alleviating cerebral ischemic injury.
Collapse
Affiliation(s)
- Yue Liu
- Department of Neurosurgery, Jiangxi Province, The First Affiliated Hospital of Nanchang University, No. 17, Yongwaizheng Street, Nanchang, 330006, People's Republic of China
| | - You-Ping Li
- Department of Neurosurgery, Jiangxi Province, The First Affiliated Hospital of Nanchang University, No. 17, Yongwaizheng Street, Nanchang, 330006, People's Republic of China
| | - Li-Min Xiao
- Department of Neurosurgery, Jiangxi Province, The First Affiliated Hospital of Nanchang University, No. 17, Yongwaizheng Street, Nanchang, 330006, People's Republic of China
| | - Li-Ke Chen
- Department of Neurosurgery, Jiangxi Province, The First Affiliated Hospital of Nanchang University, No. 17, Yongwaizheng Street, Nanchang, 330006, People's Republic of China
| | - Su-Yue Zheng
- Department of Neurosurgery, Jiangxi Province, The First Affiliated Hospital of Nanchang University, No. 17, Yongwaizheng Street, Nanchang, 330006, People's Republic of China
| | - Er-Ming Zeng
- Department of Neurosurgery, Jiangxi Province, The First Affiliated Hospital of Nanchang University, No. 17, Yongwaizheng Street, Nanchang, 330006, People's Republic of China
| | - Chun-Hua Xu
- Department of Neurosurgery, Jiangxi Province, The First Affiliated Hospital of Nanchang University, No. 17, Yongwaizheng Street, Nanchang, 330006, People's Republic of China.
| |
Collapse
|
|
30
|
Mardi N, Salahpour-Anarjan F, Nemati M, Shahsavari Baher N, Rahbarghazi R, Zarebkohan A. Exosomes; multifaceted nanoplatform for targeting brain cancers. Cancer Lett 2023; 557:216077. [PMID: 36731592 DOI: 10.1016/j.canlet.2023.216077] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/25/2023] [Accepted: 01/26/2023] [Indexed: 01/31/2023]
Abstract
At the moment, anaplastic changes within the brain are challenging due to the complexity of neural tissue, leading to the inefficiency of therapeutic protocols. The existence of a cellular interface, namely the blood-brain barrier (BBB), restricts the entry of several macromolecules and therapeutic agents into the brain. To date, several nano-based platforms have been used in laboratory settings and in vivo conditions to overcome the barrier properties of BBB. Exosomes (Exos) are one-of-a-kind of extracellular vesicles with specific cargo to modulate cell bioactivities in a paracrine manner. Regarding unique physicochemical properties and easy access to various biofluids, Exos provide a favorable platform for drug delivery and therapeutic purposes. Emerging data have indicated that Exos enable brain penetration of selective cargos such as bioactive factors and chemotherapeutic compounds. Along with these statements, the application of smart delivery approaches can increase delivery efficiency and thus therapeutic outcomes. Here, we highlighted the recent advances in the application of Exos in the context of brain tumors.
Collapse
Affiliation(s)
- Narges Mardi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Salahpour-Anarjan
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdieh Nemati
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasim Shahsavari Baher
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Amir Zarebkohan
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
31
|
Khalil S, Kanapathipillai M. Exosome-Coated tPA/Catalase Nanoformulation for Thrombolytic Therapy. Bioengineering (Basel) 2023; 10:bioengineering10020177. [PMID: 36829671 PMCID: PMC9952084 DOI: 10.3390/bioengineering10020177] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/19/2023] [Accepted: 01/21/2023] [Indexed: 02/01/2023] Open
Abstract
Current tissue plasminogen-based therapeutic strategies for stroke suffer from systemic side effects and poor efficacy. Hence, novel drug delivery methods are needed to overcome these shortcomings. Exosome-based drug formulations have been shown to have superior therapeutic outcomes compared to conventional systemic drug delivery approaches. In this paper, we report exosome surface-coated tissue plasminogen activator (tPA)/catalase nanoformulations with improved thrombolytic efficacy compared to free tPA, which also reduce side effects. The results showed that the tPA exosome formulations retained tPA activity, improved tPA stability, exhibited significant fibrinolysis, and showed no significant toxicity effects. Further, when combined with antioxidant enzyme catalase, the formulation was able to inhibit hydrogen peroxide-mediated oxidative stress and toxicity. Hence, exosome-based tPA/catalase nanoformulations could have the potential to offer a safer and effective thrombolytic therapy.
Collapse
|
|
32
|
Liu Y, Zheng Y, Yang Y, Liu K, Wu J, Gao P, Zhang C. Exosomes in liver fibrosis: The role of modulating hepatic stellate cells and immune cells, and prospects for clinical applications. Front Immunol 2023; 14:1133297. [PMID: 37020547 PMCID: PMC10067730 DOI: 10.3389/fimmu.2023.1133297] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 03/01/2023] [Indexed: 04/07/2023] Open
Abstract
Liver fibrosis is a global health problem caused by chronic liver injury resulting from various factors. Hepatic stellate cells (HSCs) have been found to play a major role in liver fibrosis, and pathological stimuli lead to their transdifferentiation into myofibroblasts. Complex multidirectional interactions between HSCs, immune cells, and cytokines are also critical for the progression of liver fibrosis. Despite the advances in treatments for liver fibrosis, they do not meet the current medical needs. Exosomes are extracellular vesicles of 30-150 nm in diameter and are capable of intercellular transport of molecules such as lipids, proteins and nucleic acids. As an essential mediator of intercellular communication, exosomes are involved in the physiological and pathological processes of many diseases. In liver fibrosis, exosomes are involved in the pathogenesis mainly by regulating the activation of HSCs and the interaction between HSCs and immune cells. Serum-derived exosomes are promising biomarkers of liver fibrosis. Exosomes also have promising therapeutic potential in liver fibrosis. Exosomes derived from mesenchymal stem cells and other cells exhibit anti-liver fibrosis effects. Moreover, exosomes may serve as potential therapeutic targets for liver fibrosis and hold promise in becoming drug carriers for liver fibrosis treatment.
Collapse
Affiliation(s)
- Yufei Liu
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuhong Zheng
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yang Yang
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ke Liu
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jianying Wu
- Department of Digestive Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Peiyang Gao
- Department of Critical Care Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Chuantao Zhang, ; Peiyang Gao,
| | - Chuantao Zhang
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Chuantao Zhang, ; Peiyang Gao,
| |
Collapse
|
|
33
|
Exosomes in Cerebral Ischemia-Reperfusion Injury: Current Perspectives and Future Challenges. Brain Sci 2022; 12:brainsci12121657. [PMID: 36552117 PMCID: PMC9776031 DOI: 10.3390/brainsci12121657] [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: 09/23/2022] [Revised: 11/18/2022] [Accepted: 11/25/2022] [Indexed: 12/12/2022] Open
Abstract
Cerebral ischemia impedes the functional or metabolic demands of the central nervous system (CNS), which subsequently leads to irreversible brain damage. While recanalization of blocked vessels recovers cerebral blood flow, it can also aggravate brain injury, termed as ischemia/reperfusion (I/R) injury. Exosomes, nanometric membrane vesicles, attracted wide attention as carriers of biological macromolecules. In the brain, exosomes can be secreted by almost all types of cells, and their contents can be altered during the pathological and clinical processes of cerebral I/R injury. Herein, we will review the current literature on the possible role of cargos derived from exosomes and exosomes-mediated intercellular communication in cerebral I/R injury. The PubMed and Web of Science databases were searched through January 2015. The studies published in English were identified using search terms including "exosomes", "cerebral ischemia-reperfusion injury", "brain ischemia-reperfusion injury", and "stroke". We will also focus on the potential therapeutic effects of stem cell-derived exosomes and underlying mechanisms in cerebral I/R injury. Meanwhile, with the advantages of low immunogenicity and cytotoxicity, high bioavailability, and the capacity to pass through the blood-brain barrier, exosomes also attract more attention as therapeutic modalities for the treatment of cerebral I/R injury.
Collapse
|
|
34
|
Pauwels MJ, Xie J, Ceroi A, Balusu S, Castelein J, Van Wonterghem E, Van Imschoot G, Ward A, Menheniott TR, Gustafsson O, Combes F, El Andaloussi S, Sanders NN, Mäger I, Van Hoecke L, Vandenbroucke RE. Choroid plexus-derived extracellular vesicles exhibit brain targeting characteristics. Biomaterials 2022; 290:121830. [PMID: 36302306 DOI: 10.1016/j.biomaterials.2022.121830] [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: 05/11/2022] [Revised: 09/16/2022] [Accepted: 09/25/2022] [Indexed: 11/17/2022]
Abstract
The brain is protected against invading organisms and other unwanted substances by tightly regulated barriers. However, these central nervous system (CNS) barriers impede the delivery of drugs into the brain via the blood circulation and are therefore considered major hurdles in the treatment of neurological disorders. Consequently, there is a high need for efficient delivery systems that are able to cross these strict barriers. While most research focuses on the blood-brain barrier (BBB), the design of drug delivery platforms that are able to cross the blood-cerebrospinal fluid (CSF) barrier, formed by a single layer of choroid plexus epithelial cells, remains a largely unexplored domain. The discovery that extracellular vesicles (EVs) make up a natural mechanism for information transfer between cells and across cell layers, has stimulated interest in their potential use as drug delivery platform. Here, we report that choroid plexus epithelial cell-derived EVs exhibit the capacity to home to the brain after peripheral administration. Moreover, these vesicles are able to functionally deliver cargo into the brain. Our findings underline the therapeutic potential of choroid plexus-derived EVs as a brain drug delivery vehicle via targeting of the blood-CSF interface.
Collapse
Affiliation(s)
- Marie J Pauwels
- VIB Center for Inflammation Research, VIB, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium
| | - Junhua Xie
- VIB Center for Inflammation Research, VIB, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium
| | - Adam Ceroi
- VIB Center for Inflammation Research, VIB, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium
| | - Sriram Balusu
- VIB Center for the Biology of Disease, VIB, Herestraat 49, 3000, Leuven, Belgium
| | - Jonas Castelein
- VIB Center for Inflammation Research, VIB, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium
| | - Elien Van Wonterghem
- VIB Center for Inflammation Research, VIB, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium
| | - Griet Van Imschoot
- VIB Center for Inflammation Research, VIB, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium
| | - Andrew Ward
- Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK
| | - Trevelyan R Menheniott
- Murdoch Children's Research Institute, Flemington Rd. Parkville, Melbourne, Victoria, Australia; Department of Paediatrics, University of Melbourne, Flemington Rd. Parkville, Melbourne, Victoria, Australia
| | - Oskar Gustafsson
- Department of Laboratory Medicine, Karolinska Institutet, 141 86 Stockholm, Sweden
| | - Francis Combes
- Department of Biotechnology and Nanomedicine, SINTEF AS, Sem Sælands V. 2A, N-7034 Trondheim, Norway
| | - Samir El Andaloussi
- Department of Laboratory Medicine, Karolinska Institutet, 141 86 Stockholm, Sweden
| | - Niek N Sanders
- Laboratory of Gene Therapy, Department of Nutrition, Genetics and Ethology, Faculty of Veterinary Medicine, Ghent University, Heidestraat 19, 9820 Merelbeke, Belgium; Cancer Research Institute Ghent (CRIG), 9000, Ghent, Belgium
| | - Imre Mäger
- Institute of Technology, University of Tartu, 50 411, Tartu, Estonia; Department of Paediatrics, University of Oxford, Oxford, OX3 9DU, UK
| | - Lien Van Hoecke
- VIB Center for Inflammation Research, VIB, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium
| | - Roosmarijn E Vandenbroucke
- VIB Center for Inflammation Research, VIB, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium.
| |
Collapse
|
|
35
|
Jiang XH, Li HF, Chen ML, Zhang YX, Chen HB, Chen RH, Xiao YC, Liu N. Treadmill exercise exerts a synergistic effect with bone marrow mesenchymal stem cell-derived exosomes on neuronal apoptosis and synaptic-axonal remodeling. Neural Regen Res 2022; 18:1293-1299. [PMID: 36453414 PMCID: PMC9838147 DOI: 10.4103/1673-5374.357900] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Treadmill exercise and mesenchymal stem cell transplantation are both practical and effective methods for the treatment of cerebral ischemia. However, whether there is a synergistic effect between the two remains unclear. In this study, we established rat models of ischemia/reperfusion injury by occlusion of the middle cerebral artery for 2 hours and reperfusion for 24 hours. Rat models were perfused with bone marrow mesenchymal stem cell-derived exosomes (MSC-exos) via the tail vein and underwent 14 successive days of treadmill exercise. Neurological assessment, histopathology, and immunohistochemistry results revealed decreased neuronal apoptosis and cerebral infarct volume, evident synaptic formation and axonal regeneration, and remarkably recovered neurological function in rats subjected to treadmill exercise and MSC-exos treatment. These effects were superior to those in rats subjected to treadmill exercise or MSC-exos treatment alone. Mechanistically, further investigation revealed that the activation of JNK1/c-Jun signaling pathways regulated neuronal apoptosis and synaptic-axonal remodeling. These findings suggest that treadmill exercise may exhibit a synergistic effect with MSC-exos treatment, which may be related to activation of the JNK1/c-Jun signaling pathway. This study provides novel theoretical evidence for the clinical application of treadmill exercise combined with MSC-exos treatment for ischemic cerebrovascular disease.
Collapse
Affiliation(s)
- Xin-Hong Jiang
- Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China,Fujian Institute of Cerebrovascular Disease, Fuzhou, Fujian Province, China,Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Hang-Feng Li
- Department of Neurology, Longyan First Hospital of Fujian Medical University, Longyan, Fujian Province, China
| | - Man-Li Chen
- Fujian Institute of Cerebrovascular Disease, Fuzhou, Fujian Province, China,Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China,Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Yi-Xian Zhang
- Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China,Fujian Institute of Cerebrovascular Disease, Fuzhou, Fujian Province, China,Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Hong-Bin Chen
- Fujian Institute of Cerebrovascular Disease, Fuzhou, Fujian Province, China,Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China,Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Rong-Hua Chen
- Fujian Institute of Cerebrovascular Disease, Fuzhou, Fujian Province, China,Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China,Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Ying-Chun Xiao
- Fujian Institute of Cerebrovascular Disease, Fuzhou, Fujian Province, China,Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China,Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Nan Liu
- Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China,Fujian Institute of Cerebrovascular Disease, Fuzhou, Fujian Province, China,Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian Province, China,Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China,Correspondence to: Nan Liu, .
| |
Collapse
|
|
36
|
Xiao R, Wang Q, Peng J, Yu Z, Zhang J, Xia Y. BMSC-Derived Exosomal Egr2 Ameliorates Ischemic Stroke by Directly Upregulating SIRT6 to Suppress Notch Signaling. Mol Neurobiol 2022; 60:1-17. [PMID: 36208355 DOI: 10.1007/s12035-022-03037-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 09/19/2022] [Indexed: 11/25/2022]
Abstract
Exosomes generated by BMSCs contribute to functional recovery in ischemic stroke. However, the regulatory mechanism is largely unknown. Exosomes were isolated from BMSCs. Tube formation, MTT, TUNEL, and flow cytometry assays were applied to examine cell angiogenesis, viability, and apoptosis. Protein and DNA interaction was evaluated by ChIP and luciferase assays. LDH release into the culture medium was examined. Infarction area was evaluated by TTC staining. Immunofluorescence staining was applied to examine CD31 expression. A mouse model of MCAO/R was established. BMSC-derived exosomes attenuated neuronal cell damage and facilitated angiogenesis of brain endothelial cells in response to OGD/R, but these effects were abolished by the knockdown of Egr2. Egr2 directly bound to the promoter of SIRT6 to promote its expression. The incompetency of Egr2-silencing exosomes was reversed by overexpression of SIRT6. Furthermore, SIRT6 inhibited Notch signaling via suppressing Notch1. Overexpression of SIRT6 and inhibition of Notch signaling improved cell injury and angiogenesis in OGD/R-treated cells. BMSC-derived exosomal Egr2 ameliorated MCAO/R-induced brain damage via upregulating SIRT6 to suppress Notch signaling in mice. BMSC-derived exosomes ameliorate OGD/R-induced injury and MCAO/R-caused cerebral damage in mice by delivering Egr2 to promote SIRT6 expression and subsequently suppress Notch signaling. Our study provides a potential exosome-based therapy for ischemic stroke.
Collapse
Affiliation(s)
- Rongjun Xiao
- Department of Neurosurgery, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, 570208, Hainan Province, People's Republic of China
| | - Qingsong Wang
- Department of Neurosurgery, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, 570208, Hainan Province, People's Republic of China
| | - Jun Peng
- Department of Neurosurgery, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, 570208, Hainan Province, People's Republic of China
| | - Zhengtao Yu
- Department of Neurosurgery, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, 570208, Hainan Province, People's Republic of China
| | - Jikun Zhang
- Department of Neurosurgery, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, 570208, Hainan Province, People's Republic of China
| | - Ying Xia
- Department of Neurosurgery, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, 570208, Hainan Province, People's Republic of China.
| |
Collapse
|
|
37
|
Yang H, Chen J. Bone marrow mesenchymal stem cell-derived exosomes carrying long noncoding RNA ZFAS1 alleviate oxidative stress and inflammation in ischemic stroke by inhibiting microRNA-15a-5p. Metab Brain Dis 2022; 37:2545-2557. [PMID: 35907132 DOI: 10.1007/s11011-022-00997-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 04/27/2022] [Indexed: 10/16/2022]
Abstract
BACKGROUND/AIM Bone marrow mesenchymal stem cell (BMSC)-derived exosomes can prevent oxidative stress and inflammation in cerebral ischemia-reperfusion injury. This study intended to assess influences of BMSC-released exosomes on oxidative stress and inflammation following ischemic stroke. METHODS In vitro and in vivo models were developed using oxygen-glucose deprivation/reperfusion (OGD/R) and middle cerebral artery occlusion (MCAO), respectively. After exosome isolation, co-culture experiments of BMSCs or BMSC-derived exosomes and OGD/R-treated BV-2 cells were implemented to evaluate the impacts of BMSCs or BMSC-secreted exosomes on proliferation, inflammation, oxidative stress, and apoptosis. The gain-of-function experiments of ZFAS1 or microRNA (miR)-15a-5p were conducted to investigate the associated mechanisms. Besides, MCAO mice were injected with exosomes from BMSCs overexpressing ZFAS1 for in vivo verification. The binding of ZFAS1 to miR-15a-5p was assessed through dual-luciferase reporter gene assay. RESULTS Co-culture with BMSCs accelerated proliferation and downregulated IL-1β, IL-6, and TNF-α in OGD/R-exposed BV-2 cells, accompanied by increased SOD level and decreased MDA level and apoptosis, all of which were nullified by inhibiting exosome secretion. Mechanistically, ZFAS1 bound to miR-15a-5p to negatively orchestrate its expression. In addition, BMSC-released exosomes or BMSC-secreted exosomal ZFAS1 augmented proliferation but reduced oxidative stress, apoptosis, and inflammation in OGD/R-exposed BV-2 cells, whereas these impacts of BMSC-released exosomal ZFAS1 were nullified by overexpressing miR-15a-5p. Moreover, BMSC-derived exosomal ZFAS1 diminished MCAO-induced oxidative stress, cerebral infarction, and inflammation in mice. CONCLUSIONS Conclusively, BMSC-released exosomes might carry long noncoding RNA ZFAS1 to curb oxidative stress and inflammation related to ischemic stroke, which was possibly realized through miR-15a-5p inhibition.
Collapse
Affiliation(s)
- Huaitao Yang
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan University, No. 169, Donghu Road, Wuchang District, 430071, Wuhan, Hubei, P.R. China
| | - Jincao Chen
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan University, No. 169, Donghu Road, Wuchang District, 430071, Wuhan, Hubei, P.R. China.
| |
Collapse
|
|
38
|
Toghiani R, Abolmaali SS, Najafi H, Tamaddon AM. Bioengineering exosomes for treatment of organ ischemia-reperfusion injury. Life Sci 2022; 302:120654. [PMID: 35597547 DOI: 10.1016/j.lfs.2022.120654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 05/11/2022] [Accepted: 05/16/2022] [Indexed: 11/30/2022]
Abstract
Ischemia-reperfusion (I/R) injury is a leading cause of death worldwide. It arises from blood reflowing after tissue hypoxia induced by ischemia that causes severe damages due to the accumulation of reactive oxygen species and the activation of inflammatory responses. Exosomes are the smallest members of the extracellular vesicles' family, which originate from nearly all eukaryotic cells. Exosomes have a great potential in the treatment of I/R injury either in native or modified forms. Native exosomes are secreted by different cell types, such as stem cells, and contain components such as specific miRNA molecules with tissue protective properties. On the other hand, exosome bioengineering has recently received increased attention in context of current advances in the purification, manipulation, biological characterization, and pharmacological applications. There are various pre-isolation and post-isolation manipulation approaches that can be utilized to increase the circulation half-life of exosomes or the availability of their bioactive cargos in the target site. In this review, the various therapeutic actions of native exosomes in different I/R injury will be discussed first. Exosome bioengineering approaches will then be explained, including pre- and post-isolation manipulation methods, applicability for delivery of bioactive agents to injured tissue, clinical translation issues, and future perspectives.
Collapse
Affiliation(s)
- Reyhaneh Toghiani
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Samira Sadat Abolmaali
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Haniyeh Najafi
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Mohammad Tamaddon
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran.
| |
Collapse
|
|
39
|
Cornelison C, Fadel S. Clickable Biomaterials for Modulating Neuroinflammation. Int J Mol Sci 2022; 23:8496. [PMID: 35955631 PMCID: PMC9369181 DOI: 10.3390/ijms23158496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/27/2022] [Accepted: 07/27/2022] [Indexed: 02/04/2023] Open
Abstract
Crosstalk between the nervous and immune systems in the context of trauma or disease can lead to a state of neuroinflammation or excessive recruitment and activation of peripheral and central immune cells. Neuroinflammation is an underlying and contributing factor to myriad neuropathologies including neurodegenerative diseases like Alzheimer's disease and Parkinson's disease; autoimmune diseases like multiple sclerosis; peripheral and central nervous system infections; and ischemic and traumatic neural injuries. Therapeutic modulation of immune cell function is an emerging strategy to quell neuroinflammation and promote tissue homeostasis and/or repair. One such branch of 'immunomodulation' leverages the versatility of biomaterials to regulate immune cell phenotypes through direct cell-material interactions or targeted release of therapeutic payloads. In this regard, a growing trend in biomaterial science is the functionalization of materials using chemistries that do not interfere with biological processes, so-called 'click' or bioorthogonal reactions. Bioorthogonal chemistries such as Michael-type additions, thiol-ene reactions, and Diels-Alder reactions are highly specific and can be used in the presence of live cells for material crosslinking, decoration, protein or cell targeting, and spatiotemporal modification. Hence, click-based biomaterials can be highly bioactive and instruct a variety of cellular functions, even within the context of neuroinflammation. This manuscript will review recent advances in the application of click-based biomaterials for treating neuroinflammation and promoting neural tissue repair.
Collapse
Affiliation(s)
- Chase Cornelison
- Department of Biomedical Engineering, University of Massachusetts Amherst, Amherst, MA 01003, USA;
| | | |
Collapse
|
|
40
|
Liao J, Li Y, Luo Y, Meng S, Zhang C, Xiong L, Wang T, Lu Y. Recent Advances in Targeted Nanotherapies for Ischemic Stroke. Mol Pharm 2022; 19:3026-3041. [PMID: 35905397 DOI: 10.1021/acs.molpharmaceut.2c00383] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Ischemic stroke (IS) is a severe neurological disease caused by the narrowing or occlusion of cerebral blood vessels and is known for high morbidity, disability, and mortality rates. Clinically available treatments of stroke include the surgical removal of the thrombus and thrombolysis with tissue fibrinogen activator. Pharmaceuticals targeting IS are uncommon, and the development of new therapies is hindered by the low bioavailability and stability of many drugs. Nanomedicine provides new opportunities for the development of novel neuroprotective and thrombolytic strategies for the diagnosis and treatment of IS. Numerous nanotherapeutics with different physicochemical properties are currently being developed to facilitate drug delivery by accumulation and controlled release and to improve their restorative properties. In this review, we discuss recent developments in IS therapy, including assisted drug delivery and targeting, neuroprotection through regulation of the neuron environment, and sources of endogenous biomimetic specific targeting. In addition, we discuss the role and neurotoxic effects of inorganic metal nanoparticles in IS therapy. This study provides a theoretical basis for the utilization of nano-IS therapies that may contribute to the development of new strategies for a range of embolic diseases.
Collapse
Affiliation(s)
- Jun Liao
- School of Medicine, Shanghai University, Shanghai 200444, China
| | - Yi Li
- School of Medicine, Shanghai University, Shanghai 200444, China
| | - Yunchun Luo
- School of Medicine, Shanghai University, Shanghai 200444, China
| | - Sha Meng
- School of Medicine, Shanghai University, Shanghai 200444, China
| | - Chuan Zhang
- School of Medicine, Shanghai University, Shanghai 200444, China
| | - Liyan Xiong
- School of Medicine, Shanghai University, Shanghai 200444, China
| | - Tingfang Wang
- School of Medicine, Shanghai University, Shanghai 200444, China
| | - Ying Lu
- School of Pharmacy, Naval Medical University, Shanghai 200433, China
| |
Collapse
|
|
41
|
Wang Q, Chen Y, Meng L, Yin J, Wang L, Gong T. A Novel Perspective on Ischemic Stroke: A Review of Exosome and Noncoding RNA Studies. Brain Sci 2022; 12:1000. [PMID: 36009062 PMCID: PMC9406049 DOI: 10.3390/brainsci12081000] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/27/2022] [Accepted: 07/18/2022] [Indexed: 02/01/2023] Open
Abstract
Ischemic stroke is a life-threatening condition that also frequently results in long-term disability. Currently, intravenous thrombolysis with tissue plasminogen activator and mechanical thrombectomy is the most popular treatment. However, the narrow time window and related complications limit the treatment benefits. Exosomes have recently emerged as ideal therapeutic candidates for ischemic stroke with the ability to pass through the blood_brain barrier and mediate intercellular communication, in addition, exosomes and their contents can be bioengineered to implement targeted delivery. In the last two decades, exosomes and exosomal noncoding RNAs have been found to be involved in the pathophysiological progression of ischemic stroke, including atherosclerosis, apoptosis, inflammation, oxidative stress, and neurovascular remodeling. In this review, we describe the latest progress regarding the role of exosomal long noncoding RNAs and circular RNAs in the occurrence, progression, and recovery of ischemic stroke. Exploration of exosomal noncoding RNAs and their correlated effects in ischemic stroke may facilitate accurate diagnosis, and they may serve as new therapeutic targets for the disease.
Collapse
Affiliation(s)
- Qianwen Wang
- Department of Neurology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing 100730, China; (Q.W.); (Y.C.); (J.Y.); (L.W.)
- Graduate School, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdansantiao, Dongcheng District, Beijing 100730, China;
| | - Yuhui Chen
- Department of Neurology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing 100730, China; (Q.W.); (Y.C.); (J.Y.); (L.W.)
| | - Lingbing Meng
- Graduate School, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdansantiao, Dongcheng District, Beijing 100730, China;
- Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing 100730, China
| | - Jiawen Yin
- Department of Neurology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing 100730, China; (Q.W.); (Y.C.); (J.Y.); (L.W.)
- Graduate School, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdansantiao, Dongcheng District, Beijing 100730, China;
| | - Li Wang
- Department of Neurology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing 100730, China; (Q.W.); (Y.C.); (J.Y.); (L.W.)
| | - Tao Gong
- Department of Neurology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing 100730, China; (Q.W.); (Y.C.); (J.Y.); (L.W.)
- Graduate School, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdansantiao, Dongcheng District, Beijing 100730, China;
| |
Collapse
|
|
42
|
Lee EC, Ha TW, Lee DH, Hong DY, Park SW, Lee JY, Lee MR, Oh JS. Utility of Exosomes in Ischemic and Hemorrhagic Stroke Diagnosis and Treatment. Int J Mol Sci 2022; 23:ijms23158367. [PMID: 35955498 PMCID: PMC9368737 DOI: 10.3390/ijms23158367] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 07/23/2022] [Accepted: 07/26/2022] [Indexed: 11/23/2022] Open
Abstract
Stroke is the leading cause of death and neurological disorders worldwide. However, diagnostic techniques and treatments for stroke patients are still limited for certain types of stroke. Intensive research has been conducted so far to find suitable diagnostic techniques and treatments, but so far there has been no success. In recent years, various studies have drawn much attention to the clinical value of utilizing the mechanism of exosomes, low toxicity, biodegradability, and the ability to cross the blood–brain barrier. Recent studies have been reported on the use of biomarkers and protective and recovery effects of exosomes derived from stem cells or various cells in the diagnostic stage after stroke. This review focuses on publications describing changes in diagnostic biomarkers of exosomes following various strokes and processes for various potential applications as therapeutics.
Collapse
Affiliation(s)
- Eun Chae Lee
- Department of Neurosurgery, College of Medicine, Cheonan Hospital, Soonchunhyang University, Cheonan 31151, Korea; (E.C.L.); (D.-H.L.); (D.-Y.H.); (S.-W.P.); (J.Y.L.)
- Soonchunhyang Institute of Medi-Bio Science (SIMS), Soon Chun Hyang University, Cheonan 31151, Korea;
| | - Tae Won Ha
- Soonchunhyang Institute of Medi-Bio Science (SIMS), Soon Chun Hyang University, Cheonan 31151, Korea;
| | - Dong-Hun Lee
- Department of Neurosurgery, College of Medicine, Cheonan Hospital, Soonchunhyang University, Cheonan 31151, Korea; (E.C.L.); (D.-H.L.); (D.-Y.H.); (S.-W.P.); (J.Y.L.)
- Soonchunhyang Institute of Medi-Bio Science (SIMS), Soon Chun Hyang University, Cheonan 31151, Korea;
| | - Dong-Yong Hong
- Department of Neurosurgery, College of Medicine, Cheonan Hospital, Soonchunhyang University, Cheonan 31151, Korea; (E.C.L.); (D.-H.L.); (D.-Y.H.); (S.-W.P.); (J.Y.L.)
- Soonchunhyang Institute of Medi-Bio Science (SIMS), Soon Chun Hyang University, Cheonan 31151, Korea;
| | - Sang-Won Park
- Department of Neurosurgery, College of Medicine, Cheonan Hospital, Soonchunhyang University, Cheonan 31151, Korea; (E.C.L.); (D.-H.L.); (D.-Y.H.); (S.-W.P.); (J.Y.L.)
- Soonchunhyang Institute of Medi-Bio Science (SIMS), Soon Chun Hyang University, Cheonan 31151, Korea;
| | - Ji Young Lee
- Department of Neurosurgery, College of Medicine, Cheonan Hospital, Soonchunhyang University, Cheonan 31151, Korea; (E.C.L.); (D.-H.L.); (D.-Y.H.); (S.-W.P.); (J.Y.L.)
| | - Man Ryul Lee
- Soonchunhyang Institute of Medi-Bio Science (SIMS), Soon Chun Hyang University, Cheonan 31151, Korea;
- Correspondence: (M.R.L.); (J.S.O.)
| | - Jae Sang Oh
- Department of Neurosurgery, College of Medicine, Cheonan Hospital, Soonchunhyang University, Cheonan 31151, Korea; (E.C.L.); (D.-H.L.); (D.-Y.H.); (S.-W.P.); (J.Y.L.)
- Correspondence: (M.R.L.); (J.S.O.)
| |
Collapse
|
|
43
|
Bauzá-Martinez J, Armony G, Pronker MF, Wu W. Characterization of protein complexes in extracellular vesicles by intact extracellular vesicle crosslinking mass spectrometry (iEVXL). J Extracell Vesicles 2022; 11:e12245. [PMID: 35918900 PMCID: PMC9346492 DOI: 10.1002/jev2.12245] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 06/05/2022] [Accepted: 06/25/2022] [Indexed: 11/15/2022] Open
Abstract
Extracellular vesicles (EVs) are blood‐borne messengers that coordinate signalling between different tissues and organs in the body. The specificity of such crosstalk is determined by preferential EV docking to target sites, as mediated through protein‐protein interactions. As such, the need to structurally characterize the EV surface precedes further understanding of docking selectivity and recipient‐cell uptake mechanisms. Here, we describe an intact extracellular vesicle crosslinking mass spectrometry (iEVXL) method that can be applied for structural characterization of protein complexes in EVs. By using a partially membrane‐permeable disuccinimidyl suberate crosslinker, proteins on the EV outer‐surface and inside EVs can be immobilized together with their interacting partners. This not only provides covalent stabilization of protein complexes before extraction from the membrane‐enclosed environment, but also generates a set of crosslinking distance restraints that can be used for structural modelling and comparative screening of changes in EV protein assemblies. Here we demonstrate iEVXL as a powerful approach to reveal high‐resolution information, about protein determinants that govern EV docking and signalling, and as a crucial aid in modelling docking interactions.
Collapse
Affiliation(s)
- Julia Bauzá-Martinez
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.,Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Gad Armony
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.,Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Matti F Pronker
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.,Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Wei Wu
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.,Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.,Department of Pharmacy, National University of Singapore, Singapore, Singapore
| |
Collapse
|
|
44
|
Yakovlev AA. Neuroprotective Effects of Astrocyte Extracellular Vesicles in Stroke. NEUROCHEM J+ 2022. [DOI: 10.1134/s1819712422020143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
|
|
45
|
Wan T, Huang Y, Gao X, Wu W, Guo W. Microglia Polarization: A Novel Target of Exosome for Stroke Treatment. Front Cell Dev Biol 2022; 10:842320. [PMID: 35356292 PMCID: PMC8959940 DOI: 10.3389/fcell.2022.842320] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/14/2022] [Indexed: 12/14/2022] Open
Abstract
The vast majority of cells in the human body are capable of secreting exosomes. Exosomes have become an important vehicle for signaling between cells. Exosomes secreted by different cells have some of the structural and functional properties of that cell and thus have different regulatory functions. A large number of recent experimental studies have shown that exosomes from different sources have different regulatory effects on stroke, and the mechanisms still need to be elucidated. Microglia are core members of central intrinsic immune regulatory cells, which play an important regulatory role in the pathogenesis and progression of stroke. M1 microglia cause neuroinflammation and induce neurotoxic effects, while M2 microglia inhibit neuroinflammation and promote neurogenesis, thus exerting a series of neuroprotective effects. It was found that there is a close link between exosomes and microglia polarization, and that exosome inclusions such as microRNAs play a regulatory role in the M1/M2 polarization of microglia. This research reviews the role of exosomes in the regulation of microglia polarization and reveals their potential value in stroke treatment.
Collapse
Affiliation(s)
- Teng Wan
- Hengyang Medical College, University of South China, Hengyang, China.,Sports Medicine Department, Huazhong University of Science and Technology Union Shenzhen Hospital, The 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
| | - Yunling Huang
- Hengyang Medical College, University of South China, Hengyang, China
| | - Xiaoyu Gao
- Hengyang Medical College, University of South China, Hengyang, China
| | - Wanpeng Wu
- Shenzhen Futian District Maternity & Child Healthcare Hospital, Shenzhen, China
| | - Weiming Guo
- Sports Medicine Department, Huazhong University of Science and Technology Union Shenzhen Hospital, The 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
| |
Collapse
|
|
46
|
Yang Y, Yin N, Gu Z, Zhao Y, Liu C, Zhou T, Zhang K, Zhang Z, Liu J, Shi J. Engineered biomimetic drug-delivery systems for ischemic stroke therapy. MEDICINE IN DRUG DISCOVERY 2022. [DOI: 10.1016/j.medidd.2022.100129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
|
|
47
|
Choi H, Choi K, Kim DH, Oh BK, Yim H, Jo S, Choi C. Strategies for Targeted Delivery of Exosomes to the Brain: Advantages and Challenges. Pharmaceutics 2022; 14:672. [PMID: 35336049 PMCID: PMC8948948 DOI: 10.3390/pharmaceutics14030672] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 03/10/2022] [Accepted: 03/16/2022] [Indexed: 02/08/2023] Open
Abstract
Delivering therapeutics to the central nervous system (CNS) is difficult because of the blood-brain barrier (BBB). Therapeutic delivery across the tight junctions of the BBB can be achieved through various endogenous transportation mechanisms. Receptor-mediated transcytosis (RMT) is one of the most widely investigated and used methods. Drugs can hijack RMT by expressing specific ligands that bind to receptors mediating transcytosis, such as the transferrin receptor (TfR), low-density lipoprotein receptor (LDLR), and insulin receptor (INSR). Cell-penetrating peptides and viral components originating from neurotropic viruses can also be utilized for the efficient BBB crossing of therapeutics. Exosomes, or small extracellular vesicles, have gained attention as natural nanoparticles for treating CNS diseases, owing to their potential for natural BBB crossing and broad surface engineering capability. RMT-mediated transport of exosomes expressing ligands such as LDLR-targeting apolipoprotein B has shown promising results. Although surface-modified exosomes possessing brain targetability have shown enhanced CNS delivery in preclinical studies, the successful development of clinically approved exosome therapeutics for CNS diseases requires the establishment of quantitative and qualitative methods for monitoring exosomal delivery to the brain parenchyma in vivo as well as elucidation of the mechanisms underlying the BBB crossing of surface-modified exosomes.
Collapse
Affiliation(s)
- Hojun Choi
- ILIAS Biologics Inc., Daejeon 34014, Korea; (H.C.); (K.C.); (D.-H.K.); (B.-K.O.); (H.Y.); (S.J.)
| | - Kyungsun Choi
- ILIAS Biologics Inc., Daejeon 34014, Korea; (H.C.); (K.C.); (D.-H.K.); (B.-K.O.); (H.Y.); (S.J.)
| | - Dae-Hwan Kim
- ILIAS Biologics Inc., Daejeon 34014, Korea; (H.C.); (K.C.); (D.-H.K.); (B.-K.O.); (H.Y.); (S.J.)
| | - Byung-Koo Oh
- ILIAS Biologics Inc., Daejeon 34014, Korea; (H.C.); (K.C.); (D.-H.K.); (B.-K.O.); (H.Y.); (S.J.)
| | - Hwayoung Yim
- ILIAS Biologics Inc., Daejeon 34014, Korea; (H.C.); (K.C.); (D.-H.K.); (B.-K.O.); (H.Y.); (S.J.)
| | - Soojin Jo
- ILIAS Biologics Inc., Daejeon 34014, Korea; (H.C.); (K.C.); (D.-H.K.); (B.-K.O.); (H.Y.); (S.J.)
| | - Chulhee Choi
- ILIAS Biologics Inc., Daejeon 34014, Korea; (H.C.); (K.C.); (D.-H.K.); (B.-K.O.); (H.Y.); (S.J.)
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
| |
Collapse
|
|
48
|
Bang OY, Kim JE. Stem cell-derived extracellular vesicle therapy for acute brain insults and neurodegenerative diseases. BMB Rep 2022. [PMID: 35000673 PMCID: PMC8810548 DOI: 10.5483/bmbrep.2022.55.1.162] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Stem cell-based therapy is a promising approach for treating a variety of disorders, including acute brain insults and neurodegenerative diseases. Stem cells such as mesenchymal stem cells (MSCs) secrete extracellular vesicles (EVs), circular membrane fragments (30 nm−1 μm) that are shed from the cell surface, carrying several therapeutic molecules such as proteins and microRNAs. Because EV-based therapy is superior to cell therapy in terms of scalable production, biodistribution, and safety profiles, it can be used to treat brain diseases as an alternative to stem cell therapy. This review presents evidences evaluating the role of stem cell-derived EVs in stroke, traumatic brain injury, and degenerative brain diseases, such as Alzheimer’s disease and Parkinson’ disease. In addition, stem cell-derived EVs have better profiles in biocompatibility, immunogenicity, and safety than those of small chemical and macromolecules. The advantages and disadvantages of EVs compared with other strategies are discussed. Even though EVs obtained from native stem cells have potential in the treatment of brain diseases, the successful clinical application is limited by the short half-life, limited targeting, rapid clearance after application, and insufficient payload. We discuss the strategies to enhance the efficacy of EV therapeutics. Finally, EV therapies have yet to be approved by the regulatory authorities. Major issues are discussed together with relevant advances in the clinical application of EV therapeutics.
Collapse
Affiliation(s)
- Oh Young Bang
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
- S&E bio, Inc, Seoul 06351, Korea
- Translational and Stem Cell Research Laboratory on Stroke, Samsung Medical Center, Seoul 06351, Korea
- Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Seoul 06351, Korea
| | - Ji-Eun Kim
- Translational and Stem Cell Research Laboratory on Stroke, Samsung Medical Center, Seoul 06351, Korea
- Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Seoul 06351, Korea
| |
Collapse
|
|
49
|
Jankovic M, Petrovic B, Novakovic I, Brankovic S, Radosavljevic N, Nikolic D. The Genetic Basis of Strokes in Pediatric Populations and Insight into New Therapeutic Options. Int J Mol Sci 2022; 23:ijms23031601. [PMID: 35163523 PMCID: PMC8835808 DOI: 10.3390/ijms23031601] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 01/27/2022] [Accepted: 01/28/2022] [Indexed: 02/04/2023] Open
Abstract
Strokes within pediatric populations are considered to be the 10th leading cause of death in the United States of America, with over half of such events occurring in children younger than one year of life. The multifactorial etiopathology that has an influence on stroke development and occurrence signify the importance of the timely recognition of both modifiable and non-modifiable factors for adequate diagnostic and treatment approaches. The early recognition of a stroke and stroke risk in children has the potential to advance the application of neuroprotective, thrombolytic, and antithrombotic interventions and rehabilitation strategies to the earliest possible timepoints after the onset of a stroke, improving the outcomes and quality of life for affected children and their families. The recent development of molecular genetic methods has greatly facilitated the analysis and diagnosis of single-gene disorders. In this review, the most significant single gene disorders associated with pediatric stroke are presented, along with specific therapeutic options whenever they exist. Besides monogenic disorders that may present with stroke as a first symptom, genetic polymorphisms may contribute to the risk of pediatric and perinatal stroke. The most frequently studied genetic risk factors are several common polymorphisms in genes associated with thrombophilia; these genes code for proteins that are part of the coagulation cascade, fibrolysis, homocystein metabolism, lipid metabolism, or platelets. Single polymorphism frequencies may not be sufficient to completely explain the stroke causality and an analysis of several genotype combinations is a more promising approach. The recent steps forward in our understanding of the disorders underlying strokes has given us a next generation of therapeutics and therapeutic targets by which to improve stroke survival, protect or rebuild neuronal connections in the brain, and enhance neural function. Advances in DNA sequencing and the development of new tools to correct human gene mutations have brought genetic analysis and gene therapy into the focus of investigations for new therapeutic options for stroke patients.
Collapse
Affiliation(s)
- Milena Jankovic
- Neurology Clinic, Clinical Center of Serbia, 11000 Belgrade, Serbia;
| | - Bojana Petrovic
- Clinic of Gynecology and Obstetrics, Clinical Center of Serbia, 11000 Belgrade, Serbia;
| | - Ivana Novakovic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Slavko Brankovic
- Faculty of Sciences and Mathematics, University of Priština in Kosovska Mitrovica, 38220 Kosovska Mitrovica, Serbia;
| | - Natasa Radosavljevic
- Department of Physical Medicine and Rehabilitation, King Abdulaziz Specialist Hospital, Taif 26521, Saudi Arabia;
| | - Dejan Nikolic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
- Physical Medicine and Rehabilitation Department, University Children’s Hospital, 11000 Belgrade, Serbia
- Correspondence:
| |
Collapse
|
|
50
|
Jiang L, Chen W, Ye J, Wang Y. Potential Role of Exosomes in Ischemic Stroke Treatment. Biomolecules 2022; 12:115. [PMID: 35053263 PMCID: PMC8773818 DOI: 10.3390/biom12010115] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/01/2022] [Accepted: 01/07/2022] [Indexed: 12/15/2022] Open
Abstract
Ischemic stroke is a life-threatening cerebral vascular disease and accounts for high disability and mortality worldwide. Currently, no efficient therapeutic strategies are available for promoting neurological recovery in clinical practice, except rehabilitation. The majority of neuroprotective drugs showed positive impact in pre-clinical studies but failed in clinical trials. Therefore, there is an urgent demand for new promising therapeutic approaches for ischemic stroke treatment. Emerging evidence suggests that exosomes mediate communication between cells in both physiological and pathological conditions. Exosomes have received extensive attention for therapy following a stroke, because of their unique characteristics, such as the ability to cross the blood brain-barrier, low immunogenicity, and low toxicity. An increasing number of studies have demonstrated positively neurorestorative effects of exosome-based therapy, which are largely mediated by the microRNA cargo. Herein, we review the current knowledge of exosomes, the relationships between exosomes and stroke, and the therapeutic effects of exosome-based treatments in neurovascular remodeling processes after stroke. Exosomes provide a viable and prospective treatment strategy for ischemic stroke patients.
Collapse
Affiliation(s)
- Lingling Jiang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; (L.J.); (W.C.); (J.Y.)
- Chinese Institute for Brain Research, Beijing 102206, China
- China National Clinical Research Center for Neurological Diseases, Beijing 100070, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100070, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing 100070, China
| | - Weiqi Chen
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; (L.J.); (W.C.); (J.Y.)
- Chinese Institute for Brain Research, Beijing 102206, China
- China National Clinical Research Center for Neurological Diseases, Beijing 100070, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100070, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing 100070, China
| | - Jinyi Ye
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; (L.J.); (W.C.); (J.Y.)
- Chinese Institute for Brain Research, Beijing 102206, China
- China National Clinical Research Center for Neurological Diseases, Beijing 100070, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100070, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing 100070, China
| | - Yilong Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; (L.J.); (W.C.); (J.Y.)
- Chinese Institute for Brain Research, Beijing 102206, China
- China National Clinical Research Center for Neurological Diseases, Beijing 100070, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100070, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing 100070, China
| |
Collapse
|