|
1
|
Li Y, Quan X, Hu J, Han Y, Chen J, Zhou M, Zhang F, Yang Y, Liao M, Wang B, Zhao Y. BMSCs-derived small extracellular vesicles antagonize cerebral endothelial Caveolin-1 driven autophagic degradation of tight-junction proteins to protect blood-brain barrier post-stroke. Int J Biol Sci 2025; 21:842-859. [PMID: 39781452 PMCID: PMC11705626 DOI: 10.7150/ijbs.101937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 12/22/2024] [Indexed: 01/12/2025] Open
Abstract
Bone marrow mesenchymal stem cells (BMSCs) -derived extracellular vesicles (EVs), especially small EVs (sEVs), were vastly reported to enable multiple restorative effects on ischemic stroke, yet the protective mechanism of blood-brain barrier (BBB) has not been fully illustrated. In the present study, we investigated the therapeutic effects and mechanism of BMSCs-derived sEVs on BBB injury after ischemic stroke. In-vivo, administering sEVs to transient middle cerebral artery occlusion (tMCAo) mice mitigated the brain infarct volume, BBB permeability and neural apoptosis, and improved the cerebral blood flow perfusion and neurological function. Simultaneously, cerebral vascular endothelial overexpressed Caveolin-1 (Cav-1) together with its strong co-localization with autophagosome protein LC3B were suppressed, and ZO-1 and Occludin expressions were enhanced, whose results were consistent with those of oxygen-glucose-deprivation/reperfusion (OGD/R)-insulted brain endothelial cells (BECs) in vitro. Furthermore, by employing Cav-1 siRNA and pcDNA3.1 transfection, Co-immunoprecipitation, cycloheximide assay, and molecular docking, it proved that brain endothelial Cav-1 was an essential upstream of autophagy activation, contributing to tight-junction proteins delegation via the autophagy-lysosomal pathway. Altogether, our study demonstrates the novel mechanism of Cav-1-dependent tight-junction proteins autophagic disruption on BBB integrity after ischemic stroke, and BMSC-sEVs treatment can reverse such hazard cascades.
Collapse
Affiliation(s)
- Yiyang Li
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macau SAR, China
| | - Xingping Quan
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macau SAR, China
| | - Jiacheng Hu
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macau SAR, China
| | - Yan Han
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macau SAR, China
| | - Jinfen Chen
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macau SAR, China
| | - Manfei Zhou
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macau SAR, China
| | - Fan Zhang
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macau SAR, China
| | - Yayue Yang
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macau SAR, China
- Guangdong Institute of Intelligence Science and Technology, Zhuhai, Guangdong, China
| | - Mingchun Liao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macau SAR, China
- Guangdong Institute of Intelligence Science and Technology, Zhuhai, Guangdong, China
| | - Bin Wang
- Guangdong Institute of Intelligence Science and Technology, Zhuhai, Guangdong, China
| | - Yonghua Zhao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macau SAR, China
- Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
| |
Collapse
|
|
2
|
Elsherbiny NM, Abdel-Maksoud MS, Prabahar K, Mohammedsaleh ZM, Badr OAM, Dessouky AA, Salem HA, Refadah OA, Farid AS, Shamaa AA, Ebrahim N. MSCs-derived EVs protect against chemotherapy-induced ovarian toxicity: role of PI3K/AKT/mTOR axis. J Ovarian Res 2024; 17:222. [PMID: 39529187 PMCID: PMC11552115 DOI: 10.1186/s13048-024-01545-7] [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: 08/07/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024] Open
Abstract
Chemotherapy detrimentally impacts fertility via depletion of follicular reserves in the ovaries leading to ovarian failure (OF) and development of estrogen deficiency-related complications. The currently proposed options to preserve fertility such as Oocyte or ovarian cortex cryopreservation are faced with many technical obstacles that limit their effective implementation. Therefore, developing new modalities to protect ovarian function remains a pending target. Exosomes are nano-sized cell-derived extracellular vesicles (EVs) with documented efficacy in the field of regenerative medicine. The current study sought to determine the potential beneficial effects of mesenchymal stem cells (MSCs)-derived EVs in experimentally induced OF. Female albino rats were randomly allocated to four groups: control, OF group, OF + MSCs-EVs group, OF + Rapamycin (mTOR inhibitor) group, and OF + Quercetin (PI3K/AKT inhibitor) group. Follicular development was assessed via histopathological and immunohistochemical examination, and ovarian function was evaluated by hormonal assay. PI3K/Akt/mTOR signaling pathway as a key modulator of ovarian follicular activation was also assessed. MSCs-EVs administration to OF rats resulted in restored serum hormonal levels, preserved primordial follicles and oocytes, suppressed ovarian PI3K/AKT axis and downstream effectors (mTOR and FOXO3), modulated miRNA that target this axis, decreased expression of ovarian apoptotic markers (BAX, BCl2) and increased expression of proliferation marker Ki67. The present study validated the effectiveness of MSCs-EVs therapy in preventing ovarian insufficiency induced by chemotherapy. Concomitant MSCs-EVs treatment during chemotherapy could significantly preserve ovarian function and fertility by suppressing the PI3K/Akt axis, preventing follicular overactivation, maintaining normal ovarian cellular proliferation, and inhibiting granulosa cell apoptosis.
Collapse
Affiliation(s)
- Nehal M Elsherbiny
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia.
| | - Mohamed S Abdel-Maksoud
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Kousalya Prabahar
- Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Zuhair M Mohammedsaleh
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, 71491, Saudi Arabia
| | - Omnia A M Badr
- Department of Genetics and Genetic Engineering, Faculty of Agriculture, Benha University, Benha, Egypt
| | - Arigue A Dessouky
- Department of Medical Histology and Cell Biology, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt
| | - Hoda A Salem
- Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Omnia A Refadah
- PharmD Program, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Ayman Samir Farid
- Department of Clinical Pathology, Faculty of Veterinary Medicine, Benha University, Moshtohor, Toukh, Qalyubia, 13736, Egypt
| | - Ashraf A Shamaa
- Surgery, Anesthesiology and Radiology Department, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt
| | - Nesrine Ebrahim
- Department of Medical Histology and Cell Biology Faculty of Medicine, Benha University, Benha, Egypt.
- Stem Cell Unit, Faculty of Medicine, Benha University, Benha, Egypt.
- Faculty of Medicine, Benha National University, Al Obour City, Egypt.
- Cell and Tissue Engineering, School of Pharmacy and Bioengineering, Keele University, Keele, UK.
| |
Collapse
|
|
3
|
Kijima C, Inaba T, Hira K, Miyamoto N, Yamashiro K, Urabe T, Hattori N, Ueno Y. Astrocytic Extracellular Vesicles Regulated by Microglial Inflammatory Responses Improve Stroke Recovery. Mol Neurobiol 2024; 61:1002-1021. [PMID: 37676390 PMCID: PMC10861643 DOI: 10.1007/s12035-023-03629-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 08/30/2023] [Indexed: 09/08/2023]
Abstract
There are no effective treatments for post-stroke glial scar formation, which inhibits axonal outgrowth and functional recovery after stroke. We investigated whether astrocytic extracellular vesicles (AEVs) regulated by microglia modulate glial scars and improve stroke recovery. We found that peri-infarct glial scars comprised reactive astrocytes with proliferating C3d and decreased S100A10 expression in chronic stroke. In cultured astrocytes, microglia-conditioned media and treatment with P2Y1 receptor antagonists increased and reduced the area of S100A10- and C3d-expressing reactive astrocytes, respectively, by suppressing mitogen-activated protein kinase/nuclear factor-κβ (NF-κB)/tumor necrosis factor-α (TNF-α)/interleukin-1β signaling after oxygen-glucose deprivation. Intracerebral administrations of AEVs enriched miR-146a-5p, downregulated NF-κB, and suppressed TNF-α expressions, by transforming reactive astrocytes to those with S100A10 preponderance, causing functional recovery in rats subjected to middle cerebral artery occlusion. Modulating neuroinflammation in post-stroke glial scars could permit axonal outgrowth, thus providing a basis for stroke recovery with neuroprotective AEVs.
Collapse
Affiliation(s)
- Chikage Kijima
- Department of Neurology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Toshiki Inaba
- Department of Neurology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Kenichiro Hira
- Department of Neurology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Nobukazu Miyamoto
- Department of Neurology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Kazuo Yamashiro
- Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan
| | - Takao Urabe
- Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan
| | - Nobutaka Hattori
- Department of Neurology, Juntendo University Faculty of Medicine, Tokyo, Japan
- Neurodegenerative Disorders Collaborative Laboratory, RIKEN Center for Brain Science, Saitama, Japan
| | - Yuji Ueno
- Department of Neurology, Juntendo University Faculty of Medicine, Tokyo, Japan.
| |
Collapse
|
|
4
|
Hladkykh FV. MESENCHYMAL STEM CELLS: EXOSOMES AND CONDITIONED MEDIA AS INNOVATIVE STRATEGIES IN THE TREATMENT OF PATIENTS WITH AUTOIMMUNE DISEASES. CLINICAL AND PREVENTIVE MEDICINE 2023:121-130. [DOI: 10.31612/2616-4868.6.2023.15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Introduction. Autoimmune diseases are a class of immunopathological conditions heterogeneous in clinical manifestations, characterized by immune disorders that cause the loss of the body's autoimmune tolerance and, as a result, abnormal reactivity of B-cells and T-cells, which leads to damage to own tissues. Today, about 10% of the population suffers from diseases of this class, which are clinically manifested in the form of more than 80 forms of autoimmune diseases.
The aim of the study. Summarize current ideas about the therapeutic potential of conditioned media and exosomes of MSCs in the treatment of patients with autoimmune diseases based on data from open sources of information.
Materials and methods. Publications were selected based on PubMed, Clinical Key Elsevier, Cochrane Library, eBook Business Collection and Google Scholar databases, which covered information on the use of conditioned media and MSC exosomes in the treatment of diseases of premature newborns using the
Keywords:
mesenchymal stem cells, conditioned media, secretion, autoimmune diseases.
Results. The technical complexity and high costs associated with the production and regulatory approval procedures of MSC therapy create barriers to their clinical use. Studies have shown that the cell-free secretome of MSCs, which consists of a wide range of growth factors, cytokines, chemokines and extracellular vesicles, exhibits a pluripotent effect. Today, extracellular vesicles are classified according to their diameter into apoptotic bodies (>1000 nm), microvesicles (100–1000 nm) and exosomes (30–150 nm). Exosome activity can be easily manipulated by preconditioning MSCs, by simply adding cytokines or chemicals to the culture medium, by introducing gene modifications, or by using hypoxic culture conditions. A number of studies have demonstrated the comparable effectiveness of conditioned media and MSC exosomes in the treatment of patients with autoimmune diseases.
Conclusions. Exosomes and conditioned media with MSCs have the potential to replace cell therapy or serve as a comparable clinical strategy to biological therapy in neonatology. MSC preconditioning will allow modulating the therapeutic effects of exosomes and will become the basis for establishing recommendations and standards for effective and safe cell-free therapy.
Collapse
|
|
5
|
Markowska A, Koziorowski D, Szlufik S. Microglia and Stem Cells for Ischemic Stroke Treatment-Mechanisms, Current Status, and Therapeutic Challenges. FRONT BIOSCI-LANDMRK 2023; 28:269. [PMID: 37919085 DOI: 10.31083/j.fbl2810269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/07/2023] [Accepted: 09/12/2023] [Indexed: 11/04/2023]
Abstract
Ischemic stroke is one of the major causes of death and disability. Since the currently used treatment option of reperfusion therapy has several limitations, ongoing research is focusing on the neuroprotective effects of microglia and stem cells. By exerting the bystander effect, secreting exosomes and forming biobridges, mesenchymal stem cells (MSCs), neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), and multilineage-differentiating stress-enduring cells (Muse cells) have been shown to stimulate neurogenesis, angiogenesis, cell migration, and reduce neuroinflammation. Exosome-based therapy is now being extensively researched due to its many advantageous properties over cell therapy, such as lower immunogenicity, no risk of blood vessel occlusion, and ease of storage and modification. However, although preclinical studies have shown promising therapeutic outcomes, clinical trials have been associated with several translational challenges. This review explores the therapeutic effects of preconditioned microglia as well as various factors secreted in stem cell-derived extracellular vesicles with their mechanisms of action explained. Furthermore, an overview of preclinical and clinical studies is presented, explaining the main challenges of microglia and stem cell therapies, and providing potential solutions. In particular, a highlight is the use of novel stem cell therapy of Muse cells, which bypasses many of the conventional stem cell limitations. The paper concludes with suggestions for directions in future neuroprotective research.
Collapse
Affiliation(s)
- Aleksandra Markowska
- Department of Neurology, Faculty of Health Sciences, Medical University of Warsaw, 03-242 Warsaw, Poland
| | - Dariusz Koziorowski
- Department of Neurology, Faculty of Health Sciences, Medical University of Warsaw, 03-242 Warsaw, Poland
| | - Stanisław Szlufik
- Department of Neurology, Faculty of Health Sciences, Medical University of Warsaw, 03-242 Warsaw, Poland
| |
Collapse
|
|
6
|
Chen N, Wang YL, Sun HF, Wang ZY, Zhang Q, Fan FY, Ma YC, Liu FX, Zhang YK. Potential regulatory effects of stem cell exosomes on inflammatory response in ischemic stroke treatment. World J Stem Cells 2023; 15:561-575. [PMID: 37424949 PMCID: PMC10324506 DOI: 10.4252/wjsc.v15.i6.561] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 04/22/2023] [Accepted: 05/16/2023] [Indexed: 06/26/2023] Open
Abstract
The high incidence and disability rates of stroke pose a heavy burden on society. Inflammation is a significant pathological reaction that occurs after an ischemic stroke. Currently, therapeutic methods, except for intravenous thrombolysis and vascular thrombectomy, have limited time windows. Mesenchymal stem cells (MSCs) can migrate, differentiate, and inhibit inflammatory immune responses. Exosomes (Exos), which are secretory vesicles, have the characteristics of the cells from which they are derived, making them attractive targets for research in recent years. MSC-derived exosomes can attenuate the inflammatory response caused by cerebral stroke by modulating damage-associated molecular patterns. In this review, research on the inflammatory response mechanisms associated with Exos therapy after an ischemic injury is discussed to provide a new approach to clinical treatment.
Collapse
Affiliation(s)
- Na Chen
- First School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Yan-Lin Wang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Hui-Fang Sun
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zhuo-Ya Wang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Qi Zhang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Fei-Yan Fan
- First School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Yu-Cheng Ma
- First School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Fei-Xiang Liu
- Department of Neurology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Yun-Ke Zhang
- Department of Neurology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, Henan Province, China
- School of Rehabilitation Medicine, Henan University of Chinese Medicine, Zhengzhou 450008, Henan Province, China
| |
Collapse
|
|
7
|
Li Y, Liu B, Zhao T, Quan X, Han Y, Cheng Y, Chen Y, Shen X, Zheng Y, Zhao Y. Comparative study of extracellular vesicles derived from mesenchymal stem cells and brain endothelial cells attenuating blood-brain barrier permeability via regulating Caveolin-1-dependent ZO-1 and Claudin-5 endocytosis in acute ischemic stroke. J Nanobiotechnology 2023; 21:70. [PMID: 36855156 PMCID: PMC9976550 DOI: 10.1186/s12951-023-01828-z] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 02/22/2023] [Indexed: 03/02/2023] Open
Abstract
BACKGROUND Blood-brain barrier (BBB) disruption is a major adverse event after ischemic stroke (IS). Caveolin-1 (Cav-1), a scaffolding protein, played multiple roles in BBB permeability after IS, while the pros and cons of Cav-1 on BBB permeability remain controversial. Numerous studies revealed that extracellular vesicles (EVs), especially stem cells derived EVs, exerted therapeutic efficacy on IS; however, the mechanisms of BBB permeability needed to be clearly illustrated. Herein, we compared the protective efficacy on BBB integrity between bone marrow mesenchymal stem cells derived extracellular vesicles (BMSC-EVs) and EVs from brain endothelial cells (BEC-EVs) after acute IS and investigated whether the mechanism was associated with EVs antagonizing Cav-1-dependent tight junction proteins endocytosis. METHODS BMSC-EVs and BEC-EVs were isolated and characterized by nanoparticle tracking analysis, western blotting, and transmission electron microscope. Oxygen and glucose deprivation (OGD) treated b. End3 cells were utilized to evaluate brain endothelial cell leakage. CCK-8 and TRITC-dextran leakage assays were used to measure cell viability and transwell monolayer permeability. Permanent middle cerebral artery occlusion (pMCAo) model was established, and EVs were intravenously administered in rats. Animal neurological function tests were applied, and microvessels were isolated from the ischemic cortex. BBB leakage and tight junction proteins were analyzed by Evans Blue (EB) staining and western blotting, respectively. Co-IP assay and Cav-1 siRNA/pcDNA 3.1 vector transfection were employed to verify the endocytosis efficacy of Cav-1 on tight junction proteins. RESULTS Both kinds of EVs exerted similar efficacies in reducing the cerebral infarction volume and BBB leakage and enhancing the expressions of ZO-1 and Claudin-5 after 24 h pMCAo in rats. At the same time, BMSC-EVs were outstanding in ameliorating neurological function. Simultaneously, both EVs treatments suppressed the highly expressed Cav-1 in OGD-exposed b. End3 cells and ischemic cerebral microvessels, and this efficacy was more prominent after BMSC-EVs administration. Cav-1 knockdown reduced OGD-treated b. End3 cells monolayer permeability and recovered ZO-1 and Claudin-5 expressions, whereas Cav-1 overexpression aggravated permeability and enhanced the colocalization of Cav-1 with ZO-1 and Claudin-5. Furthermore, Cav-1 overexpression partly reversed the lower cell leakage by BMSC-EVs and BEC-EVs administrations in OGD-treated b. End3 cells. CONCLUSIONS Our results demonstrated that Cav-1 aggravated BBB permeability in acute ischemic stroke, and BMSC-EVs exerted similar antagonistic efficacy to BEC-EVs on Cav-1-dependent ZO-1 and Claudin-5 endocytosis. BMSC-EVs treatment was superior in Cav-1 suppression and neurological function amelioration.
Collapse
Affiliation(s)
- Yiyang Li
- grid.437123.00000 0004 1794 8068Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macau SAR China
| | - Bowen Liu
- grid.268505.c0000 0000 8744 8924Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Tingting Zhao
- grid.259384.10000 0000 8945 4455Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR China
| | - Xingping Quan
- grid.437123.00000 0004 1794 8068Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macau SAR China
| | - Yan Han
- grid.437123.00000 0004 1794 8068Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macau SAR China
| | - Yaxin Cheng
- grid.437123.00000 0004 1794 8068Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macau SAR China
| | - Yanling Chen
- grid.417409.f0000 0001 0240 6969Department of Pathophysiology, Zhuhai Campus of Zunyi Medical University, Zhuhai, Guangdong China
| | - Xu Shen
- grid.410745.30000 0004 1765 1045Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica and State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ying Zheng
- grid.437123.00000 0004 1794 8068Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macau SAR China ,grid.437123.00000 0004 1794 8068Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR China
| | - Yonghua Zhao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Taipa, Macau SAR, China. .,Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China.
| |
Collapse
|
|
8
|
Asgari Taei A, Khodabakhsh P, Nasoohi S, Farahmandfar M, Dargahi L. Paracrine Effects of Mesenchymal Stem Cells in Ischemic Stroke: Opportunities and Challenges. Mol Neurobiol 2022; 59:6281-6306. [PMID: 35922728 DOI: 10.1007/s12035-022-02967-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 07/17/2022] [Indexed: 10/16/2022]
Abstract
It is well acknowledged that neuroprotective effects of transplanted mesenchymal stem cells (MSCs) in ischemic stroke are attributed to their paracrine-mediated actions or bystander effects rather than to cell replacement in infarcted areas. This therapeutic plasticity is due to MSCs' ability to secrete a broad range of bioactive molecules including growth factors, trophic factors, cytokines, chemokines, and extracellular vesicles, overall known as the secretome. The secretome derivatives, such as conditioned medium (CM) or purified extracellular vesicles (EVs), exert remarkable advantages over MSC transplantation in stroke treating. Here, in this review, we used published information to provide an overview on the secretome composition of MSCs, underlying mechanisms of therapeutic effects of MSCs, and preclinical studies on MSC-derived products application in stroke. Furthermore, we discussed current advantages and challenges for successful bench-to-bedside translation.
Collapse
Affiliation(s)
- Afsaneh Asgari Taei
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pariya Khodabakhsh
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sanaz Nasoohi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Farahmandfar
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Leila Dargahi
- Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
9
|
Lu Y, Wang L, Zhang M, Chen Z. Mesenchymal Stem Cell-Derived Small Extracellular Vesicles: A Novel Approach for Kidney Disease Treatment. Int J Nanomedicine 2022; 17:3603-3618. [PMID: 35990308 PMCID: PMC9386173 DOI: 10.2147/ijn.s372254] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 08/04/2022] [Indexed: 12/24/2022] Open
Abstract
Globally, kidney disease has become a serious health challenge, with approximately 10% of adults suffering with the disease, and increasing incidence and mortality rates every year. Small extracellular vesicles (sEVs) are 30 nm-100 nm sized nanovesicles released by cells into the extracellular matrix (ECM), which serve as mediators of intercellular communication. Depending on the cell origin, sEVs have different roles which depend on internal cargoes including, nucleic acids, proteins, and lipids. Mesenchymal stem cell (MSCs) exert anti-inflammatory, anti-aging, and wound healing functions mainly via sEVs in a stable and safe manner. MSC-derived sEVs (MSC-sEVs) exert roles in several kidney diseases by transporting renoprotective cargoes to reduce oxidative stress, inhibit renal cell apoptosis, suppress inflammation, and mediate anti-fibrosis mechanisms. Additionally, because MSC-sEVs efficiently target damaged kidneys, they have the potential to become the next generation cell-free therapies for kidney disease. Herein, we review recent research data on how MSC-sEVs could be used to treat kidney disease.
Collapse
Affiliation(s)
- Yukang Lu
- First Clinical Medical College, Gannan Medical University, Ganzhou, People's Republic of China.,Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, People's Republic of China
| | - Lanfeng Wang
- Department of Nephrology, First Affiliated Hospital of Gannan Medical University, Ganzhou, People's Republic of China
| | - Mengting Zhang
- First Clinical Medical College, Gannan Medical University, Ganzhou, People's Republic of China.,Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, People's Republic of China
| | - Zhiping Chen
- Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, People's Republic of China
| |
Collapse
|
|
10
|
Karn V, Ahmed S, Tsai LW, Dubey R, Ojha S, Singh HN, Kumar M, Gupta PK, Sadhu S, Jha NK, Kumar A, Pandit S, Kumar S. Extracellular Vesicle-Based Therapy for COVID-19: Promises, Challenges and Future Prospects. Biomedicines 2021; 9:biomedicines9101373. [PMID: 34680490 PMCID: PMC8533559 DOI: 10.3390/biomedicines9101373] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/19/2021] [Accepted: 09/25/2021] [Indexed: 12/11/2022] Open
Abstract
The COVID-19 pandemic has become a serious concern and has negatively impacted public health and the economy. It primarily targets the lungs, causing acute respiratory distress syndrome (ARDS); however, it may also lead to multiple organ failure (MOF) and enhanced mortality rates. Hence, there is an urgent need to develop potential effective therapeutic strategies for COVID-19 patients. Extracellular vesicles (EVs) are released from various types of cells that participate in intercellular communication to maintain physiological and pathological processes. EVs derived from various cellular origins have revealed suppressive effects on the cytokine storm during systemic hyper-inflammatory states of severe COVID-19, leading to enhanced alveolar fluid clearance, promoted epithelial and endothelial recovery, and cell proliferation. Being the smallest subclass of EVs, exosomes offer striking characteristics such as cell targeting, being nano-carriers for drug delivery, high biocompatibility, safety, and low-immunogenicity, thus rendering them a potential cell-free therapeutic candidate against the pathogeneses of various diseases. Due to these properties, numerous studies and clinical trials have been performed to assess their safety and therapeutic efficacy against COVID-19. Hence, in this review, we have comprehensively described current updates on progress and challenges for EVs as a potential therapeutic agent for the management of COVID-19.
Collapse
Affiliation(s)
- Vamika Karn
- Department of Biotechnology, Amity University, Mumbai 410221, India;
| | - Shaista Ahmed
- Faculty of Medical and Paramedical Sciences, Aix-Marseille University, 13005 Marseille, France;
| | - Lung-Wen Tsai
- Department of Medicine Research, Taipei Medical University Hospital, Taipei 11031, Taiwan; (L.-W.T.); (R.D.)
- Department of Information Technology Office, Taipei Medical University Hospital, Taipei 11031, Taiwan
| | - Rajni Dubey
- Department of Medicine Research, Taipei Medical University Hospital, Taipei 11031, Taiwan; (L.-W.T.); (R.D.)
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, UAE University, Al Ain, Abu Dhabi P.O. Box 17666, United Arab Emirates;
| | - Himanshu Naryan Singh
- Department of System Biology, Columbia University Irving Medical Center, New York, NY 10032, USA;
| | - Mukesh Kumar
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110029, India;
| | - Piyush Kumar Gupta
- Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida 201310, India; (P.K.G.); (S.S.); (S.P.)
| | - Soumi Sadhu
- Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida 201310, India; (P.K.G.); (S.S.); (S.P.)
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, Greater Noida 201310, India;
| | - Ashutosh Kumar
- Department of Anatomy, All India Institute of Medical Sciences, Patna 801507, India;
| | - Soumya Pandit
- Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida 201310, India; (P.K.G.); (S.S.); (S.P.)
| | - Sanjay Kumar
- Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida 201310, India; (P.K.G.); (S.S.); (S.P.)
- Correspondence: or ; Tel.: +91-120-4570-000
| |
Collapse
|
|
11
|
Gualerzi A, Picciolini S, Rodà F, Bedoni M. Extracellular Vesicles in Regeneration and Rehabilitation Recovery after Stroke. BIOLOGY 2021; 10:843. [PMID: 34571720 PMCID: PMC8465790 DOI: 10.3390/biology10090843] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/24/2021] [Accepted: 08/25/2021] [Indexed: 12/15/2022]
Abstract
Patients that survive after a stroke event may present disabilities that can persist for a long time or permanently after it. If stroke prevention fails, the prompt and combinatorial intervention with pharmacological and rehabilitation therapy is pivotal for the optimal recovery of patients and the reduction of disabilities. In the present review, we summarize some key features of the complex events that occur in the brain during and after the stroke event, with a special focus on extracellular vesicles (EVs) and their role as both carriers of biomarkers and potential therapeutics. EVs have already demonstrated their ability to be used for diagnostic purposes for multiple brain disorders and could represent valuable tools to track the regenerative and inflammatory processes occurring in the injured brain after stroke. Last, but not least, the use of artificial or stem cell-derived EVs were proved to be effective in stimulating brain remodeling and ameliorating recovery after stroke. Still, effective biomarkers of recovery are needed to design robust trials for the validation of innovative therapeutic strategies, such as regenerative rehabilitation approaches.
Collapse
Affiliation(s)
- Alice Gualerzi
- IRCCS Fondazione Don Carlo Gnocchi Onlus, 20148 Milan, Italy; (S.P.); (F.R.); (M.B.)
| | | | | | | |
Collapse
|
|
12
|
Dupuis V, Oltra E. Methods to produce induced pluripotent stem cell-derived mesenchymal stem cells: Mesenchymal stem cells from induced pluripotent stem cells. World J Stem Cells 2021; 13:1094-1111. [PMID: 34567428 PMCID: PMC8422924 DOI: 10.4252/wjsc.v13.i8.1094] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/03/2021] [Accepted: 07/14/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have received significant attention in recent years due to their large potential for cell therapy. Indeed, they secrete a wide variety of immunomodulatory factors of interest for the treatment of immune-related disorders and inflammatory diseases. MSCs can be extracted from multiple tissues of the human body. However, several factors may restrict their use for clinical applications: the requirement of invasive procedures for their isolation, their limited numbers, and their heterogeneity according to the tissue of origin or donor. In addition, MSCs often present early signs of replicative senescence limiting their expansion in vitro, and their therapeutic capacity in vivo. Due to the clinical potential of MSCs, a considerable number of methods to differentiate induced pluripotent stem cells (iPSCs) into MSCs have emerged. iPSCs represent a new reliable, unlimited source to generate MSCs (MSCs derived from iPSC, iMSCs) from homogeneous and well-characterized cell lines, which would relieve many of the above mentioned technical and biological limitations. Additionally, the use of iPSCs prevents some of the ethical concerns surrounding the use of human embryonic stem cells. In this review, we analyze the main current protocols used to differentiate human iPSCs into MSCs, which we classify into five different categories: MSC Switch, Embryoid Body Formation, Specific Differentiation, Pathway Inhibitor, and Platelet Lysate. We also evaluate common and method-specific culture components and provide a list of positive and negative markers for MSC characterization. Further guidance on material requirements to produce iMSCs with these methods and on the phenotypic features of the iMSCs obtained is added. The information may help researchers identify protocol options to design and/or refine standardized procedures for large-scale production of iMSCs fitting clinical demands.
Collapse
Affiliation(s)
- Victoria Dupuis
- Faculté des Sciences et d’Ingénierie, Sorbonne Université, Paris 75252, France
| | - Elisa Oltra
- Department of Pathology, Universidad Católica de Valencia San Vicente Mártir, Valencia 46001, Spain
- Centro de Investigación Traslacional San Alberto Magno, Universidad Católica de Valencia San Vicente Mártir, Valencia 46001, Spain.
| |
Collapse
|
|
13
|
Xu M, Feng T, Liu B, Qiu F, Xu Y, Zhao Y, Zheng Y. Engineered exosomes: desirable target-tracking characteristics for cerebrovascular and neurodegenerative disease therapies. Theranostics 2021; 11:8926-8944. [PMID: 34522219 PMCID: PMC8419041 DOI: 10.7150/thno.62330] [Citation(s) in RCA: 142] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 07/22/2021] [Indexed: 12/12/2022] Open
Abstract
As extracellular vesicles secreted by cells, exosomes are intercellular signalosomes for cell communication and pharmacological effectors. Because of their special properties, including low toxicity and immunogenicity, biodegradability, ability to encapsulate endogenous biologically active molecules and cross the blood-brain barrier (BBB), exosomes have great therapeutic potential in cerebrovascular and neurodegenerative diseases. However, the poor targeting ability of natural exosomes greatly reduces the therapeutic effect. Using engineering technology, exosomes can obtain active targeting ability to accumulate in specific cell types and tissues by attaching targeting units to the membrane surface or loading them into cavities. In this review, we outline the improved targeting functions of bioengineered exosomes, tracing and imaging techniques, administration methods, internalization in the BBB, and therapeutic effects of exosomes in cerebrovascular and neurodegenerative diseases and further evaluate the clinical opportunities and challenges in this research field.
Collapse
Affiliation(s)
- Meng Xu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
| | - Tao Feng
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
| | - Bowen Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
| | - Fen Qiu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
| | - Youhua Xu
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, China
| | - Yonghua Zhao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
| | - Ying Zheng
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
| |
Collapse
|
|
14
|
Merimi M, El-Majzoub R, Lagneaux L, Moussa Agha D, Bouhtit F, Meuleman N, Fahmi H, Lewalle P, Fayyad-Kazan M, Najar M. The Therapeutic Potential of Mesenchymal Stromal Cells for Regenerative Medicine: Current Knowledge and Future Understandings. Front Cell Dev Biol 2021; 9:661532. [PMID: 34490235 PMCID: PMC8416483 DOI: 10.3389/fcell.2021.661532] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 05/28/2021] [Indexed: 12/11/2022] Open
Abstract
In recent decades, research on the therapeutic potential of progenitor cells has advanced considerably. Among progenitor cells, mesenchymal stromal cells (MSCs) have attracted significant interest and have proven to be a promising tool for regenerative medicine. MSCs are isolated from various anatomical sites, including bone marrow, adipose tissue, and umbilical cord. Advances in separation, culture, and expansion techniques for MSCs have enabled their large-scale therapeutic application. This progress accompanied by the rapid improvement of transplantation practices has enhanced the utilization of MSCs in regenerative medicine. During tissue healing, MSCs may exhibit several therapeutic functions to support the repair and regeneration of injured tissue. The process underlying these effects likely involves the migration and homing of MSCs, as well as their immunotropic functions. The direct differentiation of MSCs as a cell replacement therapeutic mechanism is discussed. The fate and behavior of MSCs are further regulated by their microenvironment, which may consequently influence their repair potential. A paracrine pathway based on the release of different messengers, including regulatory factors, chemokines, cytokines, growth factors, and nucleic acids that can be secreted or packaged into extracellular vesicles, is also implicated in the therapeutic properties of MSCs. In this review, we will discuss relevant outcomes regarding the properties and roles of MSCs during tissue repair and regeneration. We will critically examine the influence of the local microenvironment, especially immunological and inflammatory signals, as well as the mechanisms underlying these therapeutic effects. Importantly, we will describe the interactions of local progenitor and immune cells with MSCs and their modulation during tissue injury. We will also highlight the crucial role of paracrine pathways, including the role of extracellular vesicles, in this healing process. Moreover, we will discuss the therapeutic potential of MSCs and MSC-derived extracellular vesicles in the treatment of COVID-19 (coronavirus disease 2019) patients. Overall, this review will provide a better understanding of MSC-based therapies as a novel immunoregenerative strategy.
Collapse
Affiliation(s)
- Makram Merimi
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
- LBBES Laboratory, Genetics and Immune-Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Rania El-Majzoub
- Department of Biomedical Sciences, School of Pharmacy, Lebanese International University, Beirut, Lebanon
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon
| | - Laurence Lagneaux
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Douâa Moussa Agha
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Fatima Bouhtit
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
- LBBES Laboratory, Genetics and Immune-Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Nathalie Meuleman
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Hassan Fahmi
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
| | - Philippe Lewalle
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Mohammad Fayyad-Kazan
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut, Lebanon
| | - Mehdi Najar
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
| |
Collapse
|
|
15
|
Chen Y, Wang X, Guan L, Wang Y. Role of White Matter Hyperintensities and Related Risk Factors in Vascular Cognitive Impairment: A Review. Biomolecules 2021; 11:biom11081102. [PMID: 34439769 PMCID: PMC8391787 DOI: 10.3390/biom11081102] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 07/24/2021] [Accepted: 07/25/2021] [Indexed: 02/06/2023] Open
Abstract
White matter hyperintensities (WMHs) of presumed vascular origin are one of the imaging markers of cerebral small-vessel disease, which is prevalent in older individuals and closely associated with the occurrence and development of cognitive impairment. The heterogeneous nature of the imaging manifestations of WMHs creates difficulties for early detection and diagnosis of vascular cognitive impairment (VCI) associated with WMHs. Because the underlying pathological processes and biomarkers of WMHs and their development in cognitive impairment remain uncertain, progress in prevention and treatment is lagging. For this reason, this paper reviews the status of research on the features of WMHs related to VCI, as well as mediators associated with both WMHs and VCI, and summarizes potential treatment strategies for the prevention and intervention in WMHs associated with VCI.
Collapse
Affiliation(s)
- Yiyi Chen
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; (Y.C.); (X.W.)
- 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
| | - Xing Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; (Y.C.); (X.W.)
- 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
- Department of Neurology, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing 400000, China
| | - Ling Guan
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; (Y.C.); (X.W.)
- 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
- Correspondence: (L.G.); (Y.W.)
| | - Yilong Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; (Y.C.); (X.W.)
- 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
- Correspondence: (L.G.); (Y.W.)
| |
Collapse
|
|
16
|
Seifali E, Hassanzadeh G, Mahdavipour M, Mortezaee K, Moini A, Satarian L, Shekari F, Nazari A, Movassaghi S, Akbari M. Extracellular Vesicles Derived from Human Umbilical Cord Perivascular Cells Improve Functional Recovery in Brain Ischemic Rat via the Inhibition of Apoptosis. IRANIAN BIOMEDICAL JOURNAL 2021; 24:347-60. [PMID: 32872749 PMCID: PMC7601540 DOI: 10.29252/ibj.24.6.342] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background: Ischemic stroke, as a health problem caused by the reduced blood supply to the brain, can lead to the neuronal death. The number of reliable therapies for stroke is limited. MSCs exhibit therapeutic achievement. A major limitation of MSC application in cell therapy is the short survival span. MSCs affect target tissues through the secretion of many paracrine agents including EVs. This study aimed to investigate the effect of HUCPVCs-derived EVs on apoptosis, functional recovery, and neuroprotection. Methods: Ischemia was induced by MCAO in male Wistar rats. Animals were classified into sham, MCAO, MCAO + HUCPVC, and MCAO + EV groups. Treatments began at two hours after ischemia. Expressions of apoptotic-related proteins (BAX/BCl-2 and caspase-3 and -9), the amount of TUNEL-positive cells, neuronal density (MAP2), and dead neurons (Nissl staining) were assessed on day seven post MCAO. Results: Administration of EVs improved the sensorimotor function (p < 0.001) and reduced the apoptotic rate of Bax/Bcl-2 ratio (p < 0.001), as well as caspases and TUNEL-positive cells (p < 0.001) in comparison to the MCAO group. EV treatment also reduced the number of dead neurons and increased the number of MAP2+ cells in the IBZ (p < 0.001), as compared to the MCAO group. Conclusion: Our findings showed that HUCPVCs-derived EVs are more effective than their mother’s cells in improving neural function, possibly via the regulation of apoptosis in the ischemic rats. The strategy of cell-free extracts is, thus, helpful in removing the predicaments surrounding cell therapy in targeting brain diseases.
Collapse
Affiliation(s)
- Elham Seifali
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Gholamreza Hassanzadeh
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Marzieh Mahdavipour
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Keywan Mortezaee
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Ashraf Moini
- Department of Gynecology and Obstetrics, School of Medicine, Tehran University of Medical Science, Tehran, Iran.,Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.,Breast Disease Research Center (BDRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Leila Satarian
- Department of Brain and Cognitive Science, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Faezeh Shekari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Abdoreza Nazari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Shabnam Movassaghi
- Department of Anatomy and cognitive neuroscience, School of Medicine, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Mohammad Akbari
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
17
|
Zhang M, Wang L, Huang S, He X. Exosomes with high level of miR-181c from bone marrow-derived mesenchymal stem cells inhibit inflammation and apoptosis to alleviate spinal cord injury. J Mol Histol 2021; 52:301-311. [PMID: 33548000 DOI: 10.1007/s10735-020-09950-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 12/26/2020] [Indexed: 12/21/2022]
Abstract
Stem cell transplantation is a promising method in the treatment of spinal cord injury (SCI). Researches have shown that stem cell-derived exosomes as well as its contents such as microRNAs contribute to the protective effects of stem cell against SCI. However, the effects of exosomes derived from bone marrow stem cells on SCI and the underlying mechanisms remain unknown. In this study, we collected bone marrow stem cells derived exosomes (BMSCs-exo) to deal with SCI rats and LPS induced microglia to explore the possible mechanisms. We found that BMSCs-exo showed significant effects on decreasing pro-inflammatory cytokines as well as increasing Basso-Beattie-Bresnahan score after acute SCI. MicroRNA-181c levels in tissue were elevated with the use of BMSCs-exo. Then we verified the effect in vitro and found that in LPS induced microglia, the administration of BMSCs-exo could inhibit the expression of pro-inflammatory cytokines, and the phosphorylation of NF-κB signal was also suppressed. During which, the expression of microRNA-181c in microglia was elevated. When LPS induced microglia were treated with BMSCs-exo over-expressing microRNA-181c, the levels of pro-inflammatory cytokines decreased. Then bioinformatics techniques were used to detect the possible target gene of microRNA-181c and then PTEN was found as a candidate. Further experiments showed that the protection effects of BMSCs-exo over-expressing microRNA-181c could be antagonized by the elevation of PTEN expression both in vitro and in vivo. In conclusion, we verified that BMSCs-exo could protect against SCI through its content microRNA-181c which suppressed the inflammation in microglia and spinal cord. It was related to the inhibition of PTEN and the suppression of NF-κB signal, and finally decreasing inflammation and apoptosis in spinal cord and improved SCI.
Collapse
Affiliation(s)
- Meng Zhang
- Department of Orthopaedics, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi Province, China.,Department of Orthopaedics, Ankang Central Hospital of Shaanxi, No.85 Jinzhou South Road, AnKang, 725000, Shaanxi Province, China
| | - Lin Wang
- Department of Orthopaedics, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi Province, China
| | - Sihua Huang
- Department of Orthopaedics, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi Province, China
| | - Xijing He
- Department of Orthopaedics, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi Province, China.
| |
Collapse
|
|
18
|
Liquid Biomarkers for Pediatric Brain Tumors: Biological Features, Advantages and Perspectives. J Pers Med 2020; 10:jpm10040254. [PMID: 33260839 PMCID: PMC7711550 DOI: 10.3390/jpm10040254] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 11/16/2020] [Accepted: 11/24/2020] [Indexed: 12/14/2022] Open
Abstract
Tumors of the central nervous system are the most frequent solid tumor type and the major cause for cancer-related mortality in children and adolescents. These tumors are biologically highly heterogeneous and comprise various different entities. Molecular diagnostics are already well-established for pediatric brain tumors and have facilitated a more accurate patient stratification. The availability of targeted, biomarker-driven therapies has increased the necessity of longitudinal monitoring of molecular alterations within tumors for precision medicine-guided therapy. Nevertheless, diagnosis is still primarily based on analyses of the primary tumor and follow-up is usually performed by imaging techniques which lack important information on tumor biology possibly changing the course of the disease. To overcome this shortage of longitudinal information, liquid biopsy has emerged as a promising diagnostic tool representing a less-invasive source of biomarkers for tumor monitoring and therapeutic decision making. Novel ultrasensitive methods for detection of allele variants, genetic alterations with low abundance, have been developed and are promising tools for establishing and integrating liquid biopsy techniques into clinical routine. Pediatric brain tumors harbor multiple molecular alterations with the potential to be used as liquid biomarkers. Consequently, studies have already investigated different types of biomarker in diverse entities of pediatric brain tumors. However, there are still certain pitfalls until liquid biomarkers can be unleashed and implemented into routine clinical care. Within this review, we summarize current knowledge on liquid biopsy markers and technologies in pediatric brain tumors, their advantages and drawbacks, as well as future potential biomarkers and perspectives with respect to clinical implementation in patient care.
Collapse
|
|
19
|
Xu R, Bai Y, Min S, Xu X, Tang T, Ju S. In vivo Monitoring and Assessment of Exogenous Mesenchymal Stem Cell-Derived Exosomes in Mice with Ischemic Stroke by Molecular Imaging. Int J Nanomedicine 2020; 15:9011-9023. [PMID: 33235449 PMCID: PMC7680167 DOI: 10.2147/ijn.s271519] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 09/29/2020] [Indexed: 12/13/2022] Open
Abstract
Purpose Mesenchymal stem cell-derived exosomes (MSC-exos) are considered an important restorative treatment for ischemic stroke. However, the migration ability and survival of exogenous MSC-exos remain unclear. Here, we investigated whether MSC-exos migrate into the ischemic brain and play a protective role against ischemic stroke. Methods MSC-exos labeled with DiR were injected intravenously into mice with ischemic stroke. Near-infrared fluorescence (NIRF) images were obtained on days 0, 1, 3, 5, 7, 10, and 14, and magnetic resonance (MR) images were obtained on days 1, 7 and 14. On day 14, the functional outcomes, angiogenesis, neurogenesis, and white matter remodeling were assessed, and Western blot assays were performed. Results Fluorescence signals from the MSC-exos appeared in the injured brain from day 1 and peaked on day 3. The immunofluorescence staining of the brain samples revealed that the MSC-exos were localized in neurons. The behavioral scores and T2-weighted imaging indicated that the MSC-exos improved neurological functional recovery after stroke. In addition, the in vivo MR-diffusion tensor imaging (DTI) indicated that the exogenous MSC-exos increased the fractional anisotropy (FA) value, fiber length, and fiber number ratio. Furthermore, in the mice with ischemic stroke treated with MSC-exos, angiogenesis and neurogenesis were significantly improved, and the expression of IL-1β was reduced. Conclusion MSC-exos can migrate into the brains of mice with ischemic stroke and exert therapeutic effects against ischemic stroke; therefore, MSC-exos may have broad clinical applications in the future.
Collapse
Affiliation(s)
- Rong Xu
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, People's Republic of China
| | - Yingying Bai
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, People's Republic of China
| | - Shudan Min
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, People's Republic of China
| | - Xiaoxuan Xu
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, People's Republic of China
| | - Tianyu Tang
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, People's Republic of China
| | - Shenghong Ju
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, People's Republic of China
| |
Collapse
|
|
20
|
Ueno Y, Hira K, Miyamoto N, Kijima C, Inaba T, Hattori N. Pleiotropic Effects of Exosomes as a Therapy for Stroke Recovery. Int J Mol Sci 2020; 21:ijms21186894. [PMID: 32962207 PMCID: PMC7555640 DOI: 10.3390/ijms21186894] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 09/16/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Stroke is the leading cause of disability, and stroke survivors suffer from long-term sequelae even after receiving recombinant tissue plasminogen activator therapy and endovascular intracranial thrombectomy. Increasing evidence suggests that exosomes, nano-sized extracellular membrane vesicles, enhance neurogenesis, angiogenesis, and axonal outgrowth, all the while suppressing inflammatory reactions, thereby enhancing functional recovery after stroke. A systematic literature review to study the association of stroke recovery with exosome therapy was carried out, analyzing species, stroke model, source of exosomes, behavioral analyses, and outcome data, as well as molecular mechanisms. Thirteen studies were included in the present systematic review. In the majority of studies, exosomes derived from mesenchymal stromal cells or stem cells were administered intravenously within 24 h after transient middle cerebral artery occlusion, showing a significant improvement of neurological severity and motor functions. Specific microRNAs and molecules were identified by mechanistic investigations, and their amplification was shown to further enhance therapeutic effects, including neurogenesis, angiogenesis, axonal outgrowth, and synaptogenesis. Overall, this review addresses the current advances in exosome therapy for stroke recovery in preclinical studies, which can hopefully be preparatory steps for the future development of clinical trials involving stroke survivors to improve functional outcomes.
Collapse
Affiliation(s)
- Yuji Ueno
- Correspondence: ; Tel.: +81-3-3813-3111; Fax: +81-3-5800-0547
| | | | | | | | | | | |
Collapse
|
|
21
|
Intranasal administration of Cytoglobin modifies human umbilical cord‑derived mesenchymal stem cells and improves hypoxic‑ischemia brain damage in neonatal rats by modulating p38 MAPK signaling‑mediated apoptosis. Mol Med Rep 2020; 22:3493-3503. [PMID: 32945464 PMCID: PMC7453519 DOI: 10.3892/mmr.2020.11436] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 07/17/2020] [Indexed: 12/21/2022] Open
Abstract
Neonatal hypoxic‑ischemic brain damage (HIBD) is a common clinical syndrome in newborns. Hypothermia is the only approved therapy for the clinical treatment; however, the therapeutic window of hypothermia is confined to 6 h after birth and even then, >40% of the infants either die or survive with various impairments, including cerebral palsy, seizure disorder and intellectual disability following hypothermic treatment. The aim of the present study was to determine whether nasal transplantation of Cytoglobin (CYGB) genetically modified human umbilical cord‑derived mesenchymal stem cells (CYGB‑HuMSCs) exhibited protective effects in neonatal rats with HIBD compared with those treated without genetically modified CYGB. A total of 120 neonatal Sprague‑Dawley rats (postnatal day 7) were assigned to either a Sham, HIBD, HuMSCs or CYGB‑HuMSCs group (n = 30 rats/group). For HIBD modeling, rats underwent left carotid artery ligation and were exposed to 8% oxygen for 2.5 h. A total of 30 min after HI, HuMSCs (or CYGB‑HuMSCs) labeled with enhanced‑green fluorescent protein (eGFP) were intranasally administered. After modeling for 3, 14 and 29 days, five randomly selected rats were sacrificed in each group, and the expression levels of CYGB, ERK, JNK and p38 in brain tissues were determined. Nissl staining of the cortex and hippocampal Cornu Ammonis 1 area of rats in each group were compared after 3 days of modeling. TUNEL assay and immunofluorescence were performed 3 days after modeling. Long term memory in rats was assessed using a Morris‑water maze 29 days after modeling. The HIBD group demonstrated significant deficiencies compared with the Sham group based on Nissl staining, TUNEL assay and the Morris‑water maze test. HuMSC treated rats exhibited improvement on in all the tests, and CYGB‑HuMSCs treatment resulted in further improvements. PCR and western blotting results indicated that the CYGB mRNA and protein levels were increased from day 3 to day 29 after transplantation of CYGB‑HuMSCs. Furthermore, it was identified that CYGB‑HuMSC transplantation suppressed p38 signaling at all experimental time points. Immunofluorescence indicated the scattered presence of HuMSCs or CYGB‑HuMSCs in damaged brain tissue. No eGFP and glial fibrillary acidic protein or eGFP and neuron‑specific enolase double‑stained positive cells were found in the brain tissues. Therefore, CYGB‑HuMSCs may serve as a gene transporter, as well as exert a neuroprotective and antiapoptotic effect in HIBD, potentially via the p38 mitogen‑activated protein kinase signaling pathway.
Collapse
|
|
22
|
Gomzikova MO, Aimaletdinov AM, Bondar OV, Starostina IG, Gorshkova NV, Neustroeva OA, Kletukhina SK, Kurbangaleeva SV, Vorobev VV, Garanina EE, Persson JL, Jeyapalan J, Mongan NP, Khaiboullina SF, Rizvanov AA. Immunosuppressive properties of cytochalasin B-induced membrane vesicles of mesenchymal stem cells: comparing with extracellular vesicles derived from mesenchymal stem cells. Sci Rep 2020; 10:10740. [PMID: 32612100 PMCID: PMC7330035 DOI: 10.1038/s41598-020-67563-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 06/05/2020] [Indexed: 12/13/2022] Open
Abstract
Extracellular vesicles derived from mesenchymal stem cells (MSCs) represent a novel approach for regenerative and immunosuppressive therapy. Recently, cytochalasin B-induced microvesicles (CIMVs) were shown to be effective drug delivery mediators. However, little is known about their immunological properties. We propose that the immunophenotype and molecular composition of these vesicles could contribute to the therapeutic efficacy of CIMVs. To address this issue, CIMVs were generated from murine MSC (CIMVs-MSCs) and their cytokine content and surface marker expression determined. For the first time, we show that CIMVs-MSCs retain parental MSCs phenotype (Sca-1+, CD49e+, CD44+, CD45−). Also, CIMVs-MSCs contained a cytokine repertoire reflective of the parental MSCs, including IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12(p40), IL-13, IL-17, CCL2, CCL3, CCL4, CCL5, CCL11, G-CSF, GM-CSF and TNF-α. Next, we evaluated the immune-modulating properties of CIMVs-MSCs in vivo using standard preclinical tests. MSCs and CIMVs-MSCs reduced serum levels of anti-sheep red blood cell antibody and have limited effects on neutrophil and peritoneal macrophage activity. We compared the immunomodulatory effect of MSCs, CIMVs and EVs. We observed no immunosuppression in mice pretreated with natural EVs, whereas MSCs and CIMVs-MSCs suppressed antibody production in vivo. Additionally, we have investigated the biodistribution of CIMVs-MSCs in vivo and demonstrated that CIMVs-MSCs localized in liver, lung, brain, heart, spleen and kidneys 48 h after intravenous injection and can be detected 14 days after subcutaneous and intramuscular injection. Collectively our data demonstrates immunomodulatory efficacy of CIMVs and supports their further preclinical testing as an effective therapeutic delivery modality.
Collapse
Affiliation(s)
- M O Gomzikova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008. .,M.M. Shemyakin-Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia, 117997.
| | - A M Aimaletdinov
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008
| | - O V Bondar
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008
| | - I G Starostina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008
| | - N V Gorshkova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008
| | - O A Neustroeva
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008
| | - S K Kletukhina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008
| | - S V Kurbangaleeva
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008
| | - V V Vorobev
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008
| | - E E Garanina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008
| | - J L Persson
- Department of Translational Medicine, Lund University, 205 02, Malmö, Sweden.,Department of Molecular Biology, Umeå University, Umeå, 901 87, USA
| | - J Jeyapalan
- Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Science, University of Nottingham, Nottingham, LE12 5RD, UK
| | - N P Mongan
- Department of Translational Medicine, Lund University, 205 02, Malmö, Sweden.,Department of Pharmacology, Weill Cornell Medicine, 1300 York Ave., New York, NY, 10065, USA
| | - S F Khaiboullina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008.,Department of Microbiology and Immunology, Reno School of Medicine, University of Nevada, Reno, NV, USA
| | - A A Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia, 420008. .,M.M. Shemyakin-Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia, 117997.
| |
Collapse
|
|
23
|
Fan XL, Zhang Y, Li X, Fu QL. Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy. Cell Mol Life Sci 2020; 77:2771-2794. [PMID: 31965214 PMCID: PMC7223321 DOI: 10.1007/s00018-020-03454-6] [Citation(s) in RCA: 332] [Impact Index Per Article: 66.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 01/02/2020] [Accepted: 01/03/2020] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSCs) have been extensively investigated for the treatment of various diseases. The therapeutic potential of MSCs is attributed to complex cellular and molecular mechanisms of action including differentiation into multiple cell lineages and regulation of immune responses via immunomodulation. The plasticity of MSCs in immunomodulation allow these cells to exert different immune effects depending on different diseases. Understanding the biology of MSCs and their role in treatment is critical to determine their potential for various therapeutic applications and for the development of MSC-based regenerative medicine. This review summarizes the recent progress of particular mechanisms underlying the tissue regenerative properties and immunomodulatory effects of MSCs. We focused on discussing the functional roles of paracrine activities, direct cell-cell contact, mitochondrial transfer, and extracellular vesicles related to MSC-mediated effects on immune cell responses, cell survival, and regeneration. This will provide an overview of the current research on the rapid development of MSC-based therapies.
Collapse
Affiliation(s)
- Xing-Liang Fan
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road II, Guangzhou, 510080, People's Republic of China
| | - Yuelin Zhang
- Department of Emergency, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Road II, Guangzhou, 510080, People's Republic of China
| | - Xin Li
- Department of Emergency, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Road II, Guangzhou, 510080, People's Republic of China
| | - Qing-Ling Fu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road II, Guangzhou, 510080, People's Republic of China.
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.
| |
Collapse
|
|
24
|
Rostom DM, Attia N, Khalifa HM, Abou Nazel MW, El Sabaawy EA. The Therapeutic Potential of Extracellular Vesicles Versus Mesenchymal Stem Cells in Liver Damage. Tissue Eng Regen Med 2020; 17:537-552. [PMID: 32506351 DOI: 10.1007/s13770-020-00267-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 04/05/2020] [Accepted: 04/15/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The extracellular vesicles (EVs) secreted by bone marrow-derived mesenchymal stem cells (MSCs) hold significant potential as a novel alternative to whole-cell therapy. We herein compare the therapeutic potential of BM-MSCs versus their EVs (MSC-EVs) in an experimental Carbon tetrachloride (CCl4)-induced liver damage rat model. METHODS Rats with liver damage received a single IV injection of MSC-EVs, 1 million MSCs, or 3 million MSCs. The therapeutic efficacy of each treatment was assessed using liver histopathology, liver function tests and immunohistochemistry for liver fibrosis and hepatocellular injury. RESULTS Animals that received an injection of either MSCs-EVs or 3 million MSCs depicted significant regression of collagen deposition in the liver tissue and marked attenuation of hepatocellular damage, both structurally and functionally. CONCLUSION Similar to high doses of MSC-based therapy (3 million MSCs), MSC-EVs mitigated the fibrogenesis and hepatocellular injury in a rat model of CCl4-induced liver fibrosis. The anti-fibrinogenic effect was induced by attenuating hepatic stellate cell activation. Therefore, the administration of MSC-EVs could be considered as a candidate cell-free therapeutic strategy for liver fibrosis and hepatocellular damage.
Collapse
Affiliation(s)
- Dina M Rostom
- Department of Medical Histology and Cell Biology, Faculty of Medicine, University of Alexandria, Dr. Fahmi Abdelmeguid St., Mowassah Campus, Alexandria, 21561, Egypt
| | - Noha Attia
- Department of Medical Histology and Cell Biology, Faculty of Medicine, University of Alexandria, Dr. Fahmi Abdelmeguid St., Mowassah Campus, Alexandria, 21561, Egypt. .,Department of Basic Sciences, The American University of Antigua - College of Medicine, University Park, Jabberwock Beach Road, P.O. Box 1451, Coolidge, Antigua and Barbuda.
| | - Hoda M Khalifa
- Department of Medical Histology and Cell Biology, Faculty of Medicine, University of Alexandria, Dr. Fahmi Abdelmeguid St., Mowassah Campus, Alexandria, 21561, Egypt
| | - Maha W Abou Nazel
- Department of Medical Histology and Cell Biology, Faculty of Medicine, University of Alexandria, Dr. Fahmi Abdelmeguid St., Mowassah Campus, Alexandria, 21561, Egypt
| | - Eshrak A El Sabaawy
- Department of Medical Histology and Cell Biology, Faculty of Medicine, University of Alexandria, Dr. Fahmi Abdelmeguid St., Mowassah Campus, Alexandria, 21561, Egypt
| |
Collapse
|
|
25
|
Extracellular Vesicle Isolation and Characterization from Periprosthetic Joint Synovial Fluid in Revision Total Joint Arthroplasty. J Clin Med 2020; 9:jcm9020516. [PMID: 32075029 PMCID: PMC7074102 DOI: 10.3390/jcm9020516] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 02/07/2020] [Accepted: 02/11/2020] [Indexed: 01/08/2023] Open
Abstract
Extracellular vesicles (EVs) comprise an as yet insufficiently investigated intercellular communication pathway in the field of revision total joint arthroplasty (RTJA). This study examined whether periprosthetic joint synovial fluid contains EVs, developed a protocol for their isolation and characterized them with respect to quantity, size, surface markers as well as documented their differences between aseptic implant failure (AIF) and periprosthetic joint infection (PJI). EV isolation was accomplished using ultracentrifugation, electron microscopy (EM) and nanoparticle tracking analysis evaluated EV presence as well as particle size and quantity. EV surface markers were studied by a bead-based multiplex analysis. Using our protocol, EM confirmed the presence of EVs in periprosthetic joint synovial fluid. Higher EV particle concentrations and decreased particle sizes were apparent for PJI. Multiplex analysis confirmed EV-typical surface epitopes and revealed upregulated CD44 and HLA-DR/DP/DQ for AIF, as well as increased CD40 and CD105. Our protocol achieved isolation of EVs from periprosthetic joint synovial fluid, confirmed by EM and multiplex analysis. Characterization was documented with respect to size, concentration and epitope surface signature. Our results indicate various differences between PJI and AIF EVs. This pilot study enables new research approaches and rising diagnostic opportunities in the field of RTJA.
Collapse
|
|
26
|
Munshi A, Mehic J, Creskey M, Gobin J, Gao J, Rigg E, Muradia G, Luebbert CC, Westwood C, Stalker A, Allan DS, Johnston MJW, Cyr T, Rosu-Myles M, Lavoie JR. A comprehensive proteomics profiling identifies NRP1 as a novel identity marker of human bone marrow mesenchymal stromal cell-derived small extracellular vesicles. Stem Cell Res Ther 2019; 10:401. [PMID: 31852509 PMCID: PMC6921509 DOI: 10.1186/s13287-019-1516-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 11/05/2019] [Accepted: 11/28/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Clinical applications have shown extracellular vesicles (EVs) to be a major paracrine effector in therapeutic responses produced by human mesenchymal stromal/stem cells (hMSCs). As the regenerative capacity of EVs is mainly ascribed to the transfer of proteins and RNA composing its cargo, and to the activity attributed by the protein surface markers, we sought to profile the protein composition of small EVs released from hMSCs to identify hMSC-EV biomarkers with potential clinical relevance. METHODS Small EVs were produced and qualified from five human bone marrow MSC donors at low passage following a 48-h culture in exosome-depleted medium further processed by steps of centrifugation, filtration, and precipitation. Quantitative proteomic analysis comparing the protein profile of the EVs released from hMSCs and their parental cell was conducted using tandem mass tag labeling combined to mass spectrometry (LC-MS/MS) to identify enriched EV protein markers. RESULTS Nanoparticle tracking analysis showed no differences in the EV concentration and size among the five hMSC donors (1.83 × 1010 ± 3.23 × 109/mL), with the mode particle size measuring at 109.3 ± 5.7 nm. Transmission electron microscopy confirmed the presence of nanovesicles with bilayer membranes. Flow cytometric analysis identified commonly found exosomal (CD63/CD81) and hMSC (CD105/CD44/CD146) markers from released EVs in addition to surface mediators of migration (CD29 and MCSP). Quantitative proteomic identified 270 proteins significantly enriched by at least twofold in EVs released from hMSCs as compared to parental hMSCs, where neuropilin 1 (NRP1) was identified among 21 membrane-bound proteins regulating the migration and invasion of cells, as well as chemotaxis and vasculogenesis. Validation by western blot of multiple batches of EVs confirmed consistent enrichment of NRP1 in the nanovesicles released from all five hMSC donors. CONCLUSION The identification and verification of NRP1 as a novel enriched surface marker from multiple batches of EVs derived from multiple hMSC donors may serve as a biomarker for the assessment and measurement of EVs for therapeutic uses.
Collapse
Affiliation(s)
- Afnan Munshi
- Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada
- University of Ottawa, Ottawa, Ontario, Canada
| | - Jelica Mehic
- Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada
| | - Marybeth Creskey
- Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada
| | - Jonathan Gobin
- Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada
- University of Ottawa, Ottawa, Ontario, Canada
| | - Jun Gao
- Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada
| | - Emma Rigg
- Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada
- University of Ottawa, Ottawa, Ontario, Canada
| | - Gauri Muradia
- Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada
| | - Christian C Luebbert
- Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada
| | - Carole Westwood
- Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada
| | - Andrew Stalker
- Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada
| | - David S Allan
- Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada
- University of Ottawa, Ottawa, Ontario, Canada
| | - Michael J W Johnston
- Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada
- University of Carleton, Ottawa, Ontario, Canada
| | - Terry Cyr
- Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada
| | - Michael Rosu-Myles
- Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada
- University of Ottawa, Ottawa, Ontario, Canada
| | - Jessie R Lavoie
- Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada.
| |
Collapse
|
|
27
|
Goodarzi P, Alavi-Moghadam S, Payab M, Larijani B, Rahim F, Gilany K, Bana N, Tayanloo-Beik A, Foroughi Heravani N, Hadavandkhani M, Arjmand B. Metabolomics Analysis of Mesenchymal Stem Cells. INTERNATIONAL JOURNAL OF MOLECULAR AND CELLULAR MEDICINE 2019; 8:30-40. [PMID: 32351907 PMCID: PMC7175611 DOI: 10.22088/ijmcm.bums.8.2.30] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 05/20/2019] [Indexed: 12/12/2022]
Abstract
Various mesenchymal stem cells as easily accessible and multipotent cells can share different essential signaling pathways related to their stemness ability. Understanding the mechanism of stemness ability can be useful for controlling the stem cells for regenerative medicine targets. In this context, OMICs studies can analyze the mechanism of different stem cell properties or stemness ability via a broad range of current high-throughput techniques. This field is fundamentally directed toward the analysis of whole genome (genomics), mRNAs (transcriptomics), proteins (proteomics) and metabolites (metabolomics) in biological samples. According to several studies, metabolomics is more effective than other OMICs ّfor various system biology concerns. Metabolomics can elucidate the biological mechanisms of various mesenchymal stem cell function by measuring their metabolites such as their secretome components. Analyzing the metabolic alteration of mesenchymal stem cells can be useful to promote their regenerative medicine application.
Collapse
Affiliation(s)
- Parisa Goodarzi
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Alavi-Moghadam
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Moloud Payab
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical sciences, Tehran, Iran
| | - Fakher Rahim
- Health Research Institute, Thalassemia and Hemoglobinopathies Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Kambiz Gilany
- Integrative Oncology Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran .,Department of Biomedical Sciences, University of Antwerp, Belgium
| | - Nikoo Bana
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular- Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Akram Tayanloo-Beik
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Najmeh Foroughi Heravani
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahdieh Hadavandkhani
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran .,Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular- Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
28
|
Yin H, Chen CY, Liu YW, Tan YJ, Deng ZL, Yang F, Huang FY, Wen C, Rao SS, Luo MJ, Hu XK, Liu ZZ, Wang ZX, Cao J, Liu HM, Liu JH, Yue T, Tang SY, Xie H. Synechococcus elongatus PCC7942 secretes extracellular vesicles to accelerate cutaneous wound healing by promoting angiogenesis. Am J Cancer Res 2019; 9:2678-2693. [PMID: 31131061 PMCID: PMC6525994 DOI: 10.7150/thno.31884] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Accepted: 02/17/2019] [Indexed: 01/08/2023] Open
Abstract
Poor wound healing affects millions of people worldwide each year and needs better therapeutic strategies. Synechococcus elongatus PCC 7942 is a naturally occurring photoautotrophic cyanobacterium that can be easily obtained and large-scale expanded. Here, we investigated the therapeutic efficacy of this cyanobacterium in a mouse model of acute burn injury and whether the secretion of extracellular vesicles (EVs), important mediators of cell paracrine activity, is a key mechanism of the cyanobacterium-induced regulation of wound healing. Methods: The effects of Synechococcus elongatus PCC 7942 on burn wound healing in mice under light or dark conditions were evaluated by measuring wound closure rates, histological and immunofluorescence analyses. A series of assays in vivo and in vitro were conducted to assess the impact of the cyanobacterium on angiogenesis. GW4869 was used to interfere with the secretion of EVs by the cyanobacterium and the abilities of the GW4869-pretreated and untreated Synechococcus elongatus PCC 7942 to regulate endothelial angiogenesis were compared. The direct effects of the cyanobacterium-derived EVs (S. elongatus-EVs) on angiogenesis, wound healing and expressions of a class of pro-inflammatory factors that have regulatory roles in wound healing were also examined. Results: Synechococcus elongatus PCC 7942 treatment under light and dark conditions both significantly promoted angiogenesis and burn wound repair in mice. In vitro, the cyanobacterium enhanced angiogenic activities of endothelial cells, but the effects were markedly blocked by GW4869 pretreatment. S. elongatus-EVs were capable of augmenting endothelial angiogenesis in vitro, and stimulating new blood vessel formation and burn wound healing in mice. The expression of interleukin 6 (IL-6), which has an essential role in angiogenesis during skin wound repair, was induced in wound tissues and wound healing-related cells by S. elongatus-EVs and Synechococcus elongatus PCC 7942. Conclusion: Synechococcus elongatus PCC 7942 has the potential as a promising strategy for therapeutic angiogenesis and wound healing primarily by the delivery of functional EVs, not by its photosynthetic activity. The promotion of IL-6 expression may be a mechanism of the cyanobacterium and its EVs-induced pro-angiogenic and -wound healing effects.
Collapse
|
|
29
|
Hwang DW. Perspective in Nuclear Theranostics Using Exosome for the Brain. Nucl Med Mol Imaging 2019; 53:108-114. [PMID: 31057682 PMCID: PMC6473017 DOI: 10.1007/s13139-018-00567-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 12/22/2018] [Accepted: 12/26/2018] [Indexed: 12/11/2022] Open
Abstract
Owing to its highly biocompatible property as naturally produced nanoscale particle and drug carrying ability, exosome has attracted much interest in the biomedical area. Versatile functions of exosome in biological system play an important role in elucidating mysterious and unknown biological processes and pathological disease progression. For usage of exosome as brain disease therapeutics, even though the ability of exosomes crossing blood brain barrier (BBB) is not well clearly proven, the small size and their own characteristics possessing cell-derived molecular contents may provide great and beneficial tools for brain delivery and brain-associated disease therapy. A variety of trials related to bioapplications using stem cell-derived exosome in regenerative therapy or autologous exosome shuttling inhibitor targeting brain disease-associated protein marker enhance possibility of exosome toward clinical application. The radionuclide PET or SPECT imaging of radiolabeled exosome will be clearly able to provide accurate clues for analyzing their whole body distribution, targeting efficacy, and the degree of non-specific tissue uptake. In this perspective, the practical information on thranostics of exosome for brain delivery and therapy is offered and radionuclide-based exosome applicability will be dealt with.
Collapse
Affiliation(s)
- Do Won Hwang
- Department of Nuclear Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 28 Yongon-Dong, Jongno-Gu, Seoul, 110-744 South Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Seoul, South Korea
| |
Collapse
|
|
30
|
Abstract
Stroke is the result of blockage or rupture of blood vessels in the brain and is the leading cause of death and disability in the world. Currently only a very limited number of therapeutic approaches are available for treatment of stroke patients, and the vast majority of neuroprotective agents that tested positively in pre-clinical studies failed in clinical trials. In recent years, the clinical value of the use of exosomes for stroke treatment has received widespread attention due their unique characteristics such as low immunogenicity, low toxicity and biodegradability, ability to cross the blood–brain barrier (BBB), and their important role in communication between cells. More and more evidence suggests that the secretion of exosomes is the mechanism underlying the protection induced by mesenchymal stromal cells (MSCs) after stroke. Exosomes are thought to support brain restoration and induce repairing effects, including neurovascular remodeling, and anti-apoptosis and anti-inflammatory effects. Recent reports have focused on the clinical application of exosomes as a potential drug delivery approach. This review focuses on the ability of exosomes to interrupt the stroke-induced pathologic processes of stroke, and on publications describing how to achieve more effective treatment of stroke with exosomes.
Collapse
Affiliation(s)
- Shi-Bin Hong
- 1 Department of Anatomy, Histology and Embryology, Discipline of Neuroscience, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,* These authors contributed equally to this work
| | - Hua Yang
- 2 Department of Neurosurgery, Binhai People's Hospital, Jiangsu province, China.,* These authors contributed equally to this work
| | - Anatol Manaenko
- 3 Departments of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Jianfei Lu
- 1 Department of Anatomy, Histology and Embryology, Discipline of Neuroscience, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiyong Mei
- 4 Department of Neurosurgery, Changzheng Hospital, the Second Military Medical University, Shanghai, China
| | - Qin Hu
- 1 Department of Anatomy, Histology and Embryology, Discipline of Neuroscience, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
31
|
Zhu LP, Tian T, Wang JY, He JN, Chen T, Pan M, Xu L, Zhang HX, Qiu XT, Li CC, Wang KK, Shen H, Zhang GG, Bai YP. Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction. Am J Cancer Res 2018; 8:6163-6177. [PMID: 30613290 PMCID: PMC6299684 DOI: 10.7150/thno.28021] [Citation(s) in RCA: 389] [Impact Index Per Article: 55.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 10/29/2018] [Indexed: 12/13/2022] Open
Abstract
Exosomes (Exo) secreted from hypoxia-conditioned bone marrow mesenchymal stem cells (BM-MSCs) were found to be protective for ischemic disease. However, the role of exosomal miRNA in the protective effect of hypoxia-conditioned BM-MSCs-derived Exo (Hypo-Exo) remains largely uncharacterized and the poor specificity of tissue targeting of Exo limits their clinical applications. Therefore, the objective of this study was to examine the effect of miRNA in Hypo-Exo on the repair of ischemic myocardium and its underlying mechanisms. We further developed modified Hypo-Exo with high specificity to the myocardium and evaluate its therapeutic effects. Methods: Murine BM-MSCs were subjected to hypoxia or normoxia culture and Exo were subsequently collected. Hypo-Exo or normoxia-conditioned BM-MSC-derived Exo (Nor-Exo) were administered to mice with permanent condition of myocardial infarction (MI). After 28 days, to evaluate the therapeutic effects of Hypo-Exo, infarction area and cardio output in Hypo-Exo and Nor-Exo treated MI mice were compared through Masson's trichrome staining and echocardiography respectively. We utilized the miRNA array to identify the significantly differentially expressed miRNAs between Nor-Exo and Hypo-Exo. One of the most enriched miRNA in Hypo-Exo was knockdown by applying antimiR in Hypoxia-conditioned BM-MSCs. Then we performed intramyocardial injection of candidate miRNA-knockdown-Hypo-Exo in a murine MI model, changes in the candidate miRNA's targets expression of cardiomyocytes and the cardiac function were characterized. We conjugated Hypo-Exo with an ischemic myocardium-targeted (IMT) peptide by bio-orthogonal chemistry, and tested its targeting specificity and therapeutic efficiency via systemic administration in the MI mice. Results: The miRNA array revealed significant enrichment of miR-125b-5p in Hypo-Exo compared with Nor-Exo. Administration of miR-125b knockdown Hypo-Exo significantly increased the infarction area and suppressed cardiomyocyte survival post-MI. Mechanistically, miR-125b knockdown Hypo-Exo lost the capability to suppress the expression of the proapoptotic genes p53 and BAK1 in cardiomyocytes. Intravenous administration of IMT-conjugated Hypo-Exo (IMT-Exo) showed specific targeting to the ischemic lesions in the injured heart and exerted a marked cardioprotective function post-MI. Conclusion: Our results illustrate a new mechanism by which Hypo-Exo-derived miR125b-5p facilitates ischemic cardiac repair by ameliorating cardiomyocyte apoptosis. Furthermore, our IMT- Exo may serve as a novel drug carrier that enhances the specificity of drug delivery for ischemic disease.
Collapse
|
|
32
|
Zagrean AM, Hermann DM, Opris I, Zagrean L, Popa-Wagner A. Multicellular Crosstalk Between Exosomes and the Neurovascular Unit After Cerebral Ischemia. Therapeutic Implications. Front Neurosci 2018; 12:811. [PMID: 30459547 PMCID: PMC6232510 DOI: 10.3389/fnins.2018.00811] [Citation(s) in RCA: 120] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 10/17/2018] [Indexed: 12/14/2022] Open
Abstract
Restorative strategies after stroke are focused on the remodeling of cerebral endothelial cells and brain parenchymal cells. The latter, i.e., neurons, neural precursor cells and glial cells, synergistically interact with endothelial cells in the ischemic brain, providing a neurovascular unit (NVU) remodeling that can be used as target for stroke therapies. Intercellular communication and signaling within the NVU, the multicellular brain-vessel-blood interface, including its highly selective blood-brain barrier, are fundamental to the central nervous system homeostasis and function. Emerging research designates cell-derived extracellular vesicles and especially the nano-sized exosomes, as a complex mean of cell-to-cell communication, with potential use for clinical applications. Through their richness in active molecules and biological information (e.g., proteins, lipids, genetic material), exosomes contribute to intercellular signaling, a condition particularly required in the central nervous system. Cerebral endothelial cells, perivascular astrocytes, pericytes, microglia and neurons, all part of the NVU, have been shown to release and uptake exosomes. Also, exosomes cross the blood-brain and blood-cerebrospinal fluid barriers, allowing communication between periphery and brain, in normal and disease conditions. As such exosomes might be a powerful diagnostic tool and a promising therapeutic shuttle of natural nanoparticles, but also a means of disease spreading (e.g., immune system modulation, pro-inflammatory action, propagation of neurodegenerative factors). This review highlights the importance of exosomes in mediating the intercellular crosstalk within the NVU and reveals the restorative therapeutic potential of exosomes harvested from multipotent mesenchymal stem cells in ischemic stroke, a frequent neurologic condition lacking an efficient therapy.
Collapse
Affiliation(s)
- Ana-Maria Zagrean
- Division of Physiology and Neuroscience, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Dirk M Hermann
- Department of Neurology, Chair of Vascular Neurology, Dementia and Ageing Research, University Hospital Essen, Essen, Germany.,Center of Clinical and Experimental Medicine, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - Ioan Opris
- Department of Neurological Surgery, University of Miami, Miami, FL, United States
| | - Leon Zagrean
- Division of Physiology and Neuroscience, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Aurel Popa-Wagner
- Department of Neurology, Chair of Vascular Neurology, Dementia and Ageing Research, University Hospital Essen, Essen, Germany.,Center of Clinical and Experimental Medicine, University of Medicine and Pharmacy of Craiova, Craiova, Romania.,School of Medicine, Griffith University, Gold Coast, QLD, Australia
| |
Collapse
|
|
33
|
Moon GJ, Sung JH, Kim DH, Kim EH, Cho YH, Son JP, Cha JM, Bang OY. Application of Mesenchymal Stem Cell-Derived Extracellular Vesicles for Stroke: Biodistribution and MicroRNA Study. Transl Stroke Res 2018; 10:509-521. [PMID: 30341718 DOI: 10.1007/s12975-018-0668-1] [Citation(s) in RCA: 98] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 09/23/2018] [Accepted: 10/02/2018] [Indexed: 12/13/2022]
Abstract
Mesenchymal stem cells (MSCs) exert their therapeutic capability through a variety of bioactive substances, including trophic factors, microRNAs, and extracellular vesicles (EVs) in infarcted tissues. We therefore hypothesized that MSC-derived EVs (MSC-EVs) possess therapeutic molecules similar to MSCs. Moreover, given their nature as nanosized and lipid-shielded particles, the intravenous infusion of MSC-EVs would be advantageous over MSCs as a safer therapeutic approach. In this study, we investigated the biodistribution, therapeutic efficacy, and mode of action of MSC-EVs in a rat stroke model. MSC-EVs successfully stimulated neurogenesis and angiogenesis in vivo. When compared to the MSC-treated group, rats treated with MSC-EVs exhibited greater behavioral improvements than the control group (p < 0.05). Our biodistribution study using fluorescence-labeled MSC-EVs and MSCs demonstrated that the amounts of MSC-EVs in the infarcted hemisphere increased in a dose-dependent manner, and were rarely found in the lung and liver. In addition, MSC-EVs were highly inclusive of various proteins and microRNAs (miRNAs) associated with neurogenesis and/or angiogenesis compared to fibro-EVs. We further analyzed those miRNAs and found that miRNA-184 and miRNA-210 were essential for promoting neurogenesis and angiogenesis of MSC-EVs, respectively. MSC-EVs represent an ideal alternative to MSCs for stroke treatment, with similar medicinal capacity but an improved safety profile that overcomes cell-associated limitations in stem cell therapy.
Collapse
Affiliation(s)
- Gyeong Joon Moon
- Translational and Stem Cell Research Laboratory on Stroke, School of Medicine, Sungkyunkwan University, Seoul, 06351, South Korea.,School of Life Sciences, BK21 plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, 41566, South Korea
| | - Ji Hee Sung
- Translational and Stem Cell Research Laboratory on Stroke, School of Medicine, Sungkyunkwan University, Seoul, 06351, South Korea.,Stem Cell & Regenerative Medicine Institute for Future Medicine, Samsung Medical Center, Seoul, 06351, South Korea
| | - Dong Hee Kim
- Translational and Stem Cell Research Laboratory on Stroke, School of Medicine, Sungkyunkwan University, Seoul, 06351, South Korea.,Stem Cell & Regenerative Medicine Institute for Future Medicine, Samsung Medical Center, Seoul, 06351, South Korea.,Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, 06351, South Korea
| | - Eun Hee Kim
- Translational and Stem Cell Research Laboratory on Stroke, School of Medicine, Sungkyunkwan University, Seoul, 06351, South Korea.,Stem Cell & Regenerative Medicine Institute for Future Medicine, Samsung Medical Center, Seoul, 06351, South Korea
| | - Yeon Hee Cho
- Translational and Stem Cell Research Laboratory on Stroke, School of Medicine, Sungkyunkwan University, Seoul, 06351, South Korea.,Stem Cell & Regenerative Medicine Institute for Future Medicine, Samsung Medical Center, Seoul, 06351, South Korea
| | - Jeong Pyo Son
- Translational and Stem Cell Research Laboratory on Stroke, School of Medicine, Sungkyunkwan University, Seoul, 06351, South Korea.,Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, 06351, South Korea
| | - Jae Min Cha
- 3D Stem Cell Bioprocessing Laboratory, Department of Mechatronics, Incheon National University, Incheon, 22012, Republic of Korea
| | - Oh Young Bang
- Translational and Stem Cell Research Laboratory on Stroke, School of Medicine, Sungkyunkwan University, Seoul, 06351, South Korea. .,Stem Cell & Regenerative Medicine Institute for Future Medicine, Samsung Medical Center, Seoul, 06351, South Korea. .,Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, 06351, South Korea. .,Department of Neurology, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, 06351, South Korea.
| |
Collapse
|
|
34
|
Izadpanah M, Seddigh A, Ebrahimi Barough S, Fazeli SAS, Ai J. Potential of Extracellular Vesicles in Neurodegenerative Diseases: Diagnostic and Therapeutic Indications. J Mol Neurosci 2018; 66:172-179. [PMID: 30140997 DOI: 10.1007/s12031-018-1135-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 07/20/2018] [Indexed: 01/09/2023]
Abstract
Extracellular vesicles (EVs) are membrane-bound vesicles, including exosomes and microvesicles. EVs are nanometer sized, found in physiological fluids such as urine, blood, cerebro-spinal fluid (CSF), with a capacity of transferring various biological materials such as microRNAs, proteins, and lipids among cells without direct cell-to-cell contact. Many cells in the nervous system have been shown to release EVs. These vesicles are involved in intercellular communication and a variety of biological processes such as modulation of immune response, signal transduction, and transport of genetic materials with low immunogenicity; therefore, they have also been recently investigated for the delivery of therapeutic molecules such as siRNAs and drugs in the treatment of diseases. In addition, since EV components reflect the physiological status of the cells and tissues producing them, they can be utilized as biomarkers for early detection of various diseases. In this review, we summarize EV application, in diagnosis as biomarker sources and as a carrier tool for drug delivery in EV-based therapies in neurodegenerative diseases.
Collapse
Affiliation(s)
- Mehrnaz Izadpanah
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, P. O. Box: 1417755469, Tehran, Iran.,Human and Animal Cell Bank, Iranian Biological Resource Center (IBRC), ACECR, Tehran, Iran
| | - Arshia Seddigh
- Department of Neurology, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Trust, London, UK
| | - Somayeh Ebrahimi Barough
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, P. O. Box: 1417755469, Tehran, Iran
| | - Seyed Abolhassan Shahzadeh Fazeli
- Human and Animal Cell Bank, Iranian Biological Resource Center (IBRC), ACECR, Tehran, Iran.,Department of Molecular and Cellular Biology, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran
| | - Jafar Ai
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, P. O. Box: 1417755469, Tehran, Iran.
| |
Collapse
|