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Liang QL, Liu H, Wang T, Lau CH, Wang J, Mo ZY, Zhou ZM, Zhou ZY, Zhu H, Chen G, Tong S. UV radiation enhanced encapsulation of superparamagnetic iron oxide nanoparticles (MNPs) in microparticles derived from tumor repopulating cells. Biochem Biophys Res Commun 2024; 741:151050. [PMID: 39586131 DOI: 10.1016/j.bbrc.2024.151050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 11/06/2024] [Accepted: 11/21/2024] [Indexed: 11/27/2024]
Abstract
Extracellular vesicles (EVs) such as microparticles secreted by the cells can be manipulated and used for delivering therapeutic drugs to target and eradicate cancer cells. However, high encapsulation efficiency and mass production of the microparticles remain difficult to achieve. Efficient and targeted delivery to cancer cells is another hurdle to be addressed. To overcome these issues, we integrated superparamagnetic iron oxide nanoparticles (MNPs) with microparticles. First of all, exposure of highly aggressive tumor-repopulating cells (TRC) to UV radiation dramatically improved microparticle production. These TRC cells were selected from diverse cancer cell lines that are 3D culturing in soft fibrin gel. These microparticles derived from 3D-cultured TRCs have lower membrane stiffness than 2D-cultured cells. Ferrozine assay showed that endocytosis and encapsulation of MNPs during microparticle production were higher in 3D-cultured TRC cells than in 2D cultured cells. Packaging of MNPs into microparticles also enhanced cellular uptake of MNPs without inducing cytotoxicity to treated cells. Compared to the naked MNPs, ex vivo fluorescence imaging shows that mice tail-vein injected with microparticle-encapsulated MNPs displayed continuous increments of intratumoral accumulation of MNPs. Furthermore, MRI images revealed a higher T2 contrast and an uneven distribution of the T2 contrast in the tumor of mice tail-vein injected with microparticle-encapsulated MNPs than naked MNPs. This study provides a new platform for cancer imaging by integrating MNPs and microparticles derived from tumor-repopulating cells.
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Affiliation(s)
- Qing-Le Liang
- Department of Clinical Laboratory Medicine, Chongqing University Jiangjin Hospital, Chongqing, China
| | - He Liu
- Department of Radiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Tao Wang
- Department of Biology, College of Science, Shantou University, Shantou, Guangdong, China
| | - Cia-Hin Lau
- Department of Biology, College of Science, Shantou University, Shantou, Guangdong, China
| | - Jianchao Wang
- Department of Pathology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Zheng-Ying Mo
- Department of Oncology, Tai-He Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Zhang-Ming Zhou
- Department of Neurosurgery, Dujiangyan Medical Center, Chengdu, China
| | - Zhe-Yu Zhou
- Department of Radiology, Tai-He Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Haibao Zhu
- Department of Biology, College of Science, Shantou University, Shantou, Guangdong, China; Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, Guangdong, China; Shantou Key Laboratory of Marine Microbial Resources and Interactions with Environment, Shantou University, Shantou, Guangdong, China.
| | - Gang Chen
- Department of Pathology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China.
| | - Sheng Tong
- Department of Biomedical Engineering, University of Kentucky, USA.
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Li B, Chen H, Hang R. Osseointegration-Related Exosomes for Surface Functionalization of Titanium Implants. Biomater Res 2024; 28:0124. [PMID: 39711824 PMCID: PMC11661649 DOI: 10.34133/bmr.0124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 11/05/2024] [Accepted: 11/27/2024] [Indexed: 12/24/2024] Open
Abstract
Despite that the clinical application of titanium-based implants has achieved great success, patients' own diseases and/or unhealthy lifestyle habits often lead to implant failure. Many studies have been carried out to modify titanium implants to promote osseointegration and implant success. Recent studies showed that exosomes, proactively secreted extracellular vesicles by mammalian cells, could selectively target and modulate the functions of recipient cells such as macrophages, nerve cells, endothelial cells, and bone marrow mesenchymal stem cells that are closely involved in implant osseointegration. Accordingly, using exosomes to functionalize titanium implants has been deemed as a novel and effective way to improve their osseointegration ability. Herein, recent advances pertaining to surface functionalization of titanium implants with exosomes are analyzed and discussed, with focus on the role of exosomes in regulating the functions of osseointegration-related cells, and their immobilization strategies as well as resultant impact on osseointegration ability.
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Affiliation(s)
- Boqiong Li
- Department of Materials Science and Engineering,
Jinzhong University, Jinzhong 030619, China
| | - Huanming Chen
- Shanxi Key Laboratory of Biomedical Metal Materials, College of Materials Science and Engineering,
Taiyuan University of Technology, Taiyuan 030024, China
| | - Ruiqiang Hang
- Shanxi Key Laboratory of Biomedical Metal Materials, College of Materials Science and Engineering,
Taiyuan University of Technology, Taiyuan 030024, China
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Schioppa T, Gaudenzi C, Zucchi G, Piserà A, Vahidi Y, Tiberio L, Sozzani S, Del Prete A, Bosisio D, Salvi V. Extracellular vesicles at the crossroad between cancer progression and immunotherapy: focus on dendritic cells. J Transl Med 2024; 22:691. [PMID: 39075551 PMCID: PMC11288070 DOI: 10.1186/s12967-024-05457-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 06/29/2024] [Indexed: 07/31/2024] Open
Abstract
Extracellular vesicles (EVs) are nanosized heat-stable vesicles released by virtually all cells in the body, including tumor cells and tumor-infiltrating dendritic cells (DCs). By carrying molecules from originating cells, EVs work as cell-to-cell communicators in both homeostasis and cancer but may also represent valuable therapeutic and diagnostic tools. This review focuses on the role of tumor-derived EVs (TEVs) in the modulation of DC functions and on the therapeutic potential of both tumor- and DC-derived EVs in the context of immunotherapy and DC-based vaccine design. TEVs were originally characterized for their capability to transfer tumor antigens to DCs but are currently regarded as mainly immunosuppressive because of the expression of DC-inhibiting molecules such as PD-L1, HLA-G, PGE2 and others. However, TEVs may still represent a privileged system to deliver antigenic material to DCs upon appropriate engineering to reduce their immunosuppressive cargo or increase immunogenicity. DC-derived EVs are more promising than tumor-derived EVs since they expose antigen-loaded MHC, costimulatory molecules and NK cell-activating ligands in the absence of an immunosuppressive cargo. Moreover, DC-derived EVs possess several advantages as compared to cell-based drugs such as a higher antigen/MHC concentration and ease of manipulation and a lower sensitivity to immunosuppressive microenvironments. Preclinical models showed that DC-derived EVs efficiently activate tumor-specific NK and T cell responses either directly or indirectly by transferring antigens to tumor-infiltrating DCs. By contrast, however, phase I and II trials showed a limited clinical efficacy of EV-based anticancer vaccines. We discuss that the future of EV-based therapy depends on our capability to overcome major challenges such as a still incomplete understanding of their biology and pharmacokinetic and the lack of standardized methods for high-throughput isolation and purification. Despite this, EVs remain in the limelight as candidates for cancer immunotherapy which may outmatch cell-based strategies in the fullness of their time.
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Affiliation(s)
- Tiziana Schioppa
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, Brescia, 25123, Italy
- IRCCS Humanitas Research Hospital, Milan, Italy
| | - Carolina Gaudenzi
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, Brescia, 25123, Italy
| | - Giovanni Zucchi
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Institute Pasteur- Italia, Rome, Italy
| | - Arianna Piserà
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Institute Pasteur- Italia, Rome, Italy
| | - Yasmin Vahidi
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, Brescia, 25123, Italy
| | - Laura Tiberio
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, Brescia, 25123, Italy
| | - Silvano Sozzani
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Institute Pasteur- Italia, Rome, Italy
| | - Annalisa Del Prete
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, Brescia, 25123, Italy
- IRCCS Humanitas Research Hospital, Milan, Italy
| | - Daniela Bosisio
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, Brescia, 25123, Italy.
| | - Valentina Salvi
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, Brescia, 25123, Italy
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Sholihah IA, Barlian A. Anti-Inflammatory Potency of Human Wharton's Jelly Mesenchymal Stem Cell-Derived Exosomes on L2 Cell Line Induced by Lipopolysaccharides. Adv Pharm Bull 2024; 14:434-444. [PMID: 39206409 PMCID: PMC11347737 DOI: 10.34172/apb.2024.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 01/05/2024] [Accepted: 01/07/2024] [Indexed: 09/04/2024] Open
Abstract
Purpose At present, therapeutic interventions to treat acute lung injury (ALI) remain largely limited to lung-protective strategies, as no real molecular-driven therapeutic intervention has yet become available. The administration of bacterial lipopolysaccharides (LPS) is known as an inflammatory activator, representing a frequently used model of ALI. This study investigated the biological function of normoxic (21% O2 ) vs. hypoxic conditions (5% O2 ) obtained from human Wharton's Jelly mesenchymal stem cells (hWJ-MSCs) and discovered that exosomes have the ability to suppress inflammatory responses by specifically targeting TNF-α, IL-1β, IL-6. and identify the toll-like receptor 4 (TLR4) NF-κβ gene expression. Methods Primer culture hWJ-MSCs characterization with trilineage differentiation and CD markers was conducted. To obtain exosomes, hWJ-MSCs were stimulated with two different oxygen levels: 21% (nor-exo) and 5% (hypo-exo). Then, the L2 cell line was induced with LPS 1 µg/mL. Inflamed-L2 was treated with nor-exo, hypo-exo, and dexamethasone as a positive control. The RNA extracted from treated L2 cells was utilized to examine the gene expression profiles of TLR4 and NF-κβ, and the medium was used to measure tumor necrosis factor α (TNF-α), interleukin (IL)-1β, and IL-6 levels using ELISA. Lastly, proteomic analysis of the exosome using LC/MS-MS was conducted. Results Nor-exo and hypo-exo can be characterized and can produce higher yields exosomes under hypoxic conditions. The expression of TLR4 and NF-κβ genes and the proinflammatory levels such as IL-6, IL-1β, and TNF-α levels in nor-exo and hypo-exo treatments decreased. Conclusion Nor-exo and hypo-exo derived from hWJ-MSCs were proven to have anti-inflammatory activities.
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Affiliation(s)
- Ika Adhani Sholihah
- School of Life Sciences and Technology, Institut Teknologi Bandung, Jl. Ganesha No.10, Bandung 40132, Indonesia
| | - Anggraini Barlian
- School of Life Sciences and Technology, Institut Teknologi Bandung, Jl. Ganesha No.10, Bandung 40132, Indonesia
- Research Center for Nanosciences and Nanotechnology, Institut Teknologi Bandung, Bandung, West Java 40132, Indonesia
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Palomar-Alonso N, Lee M, Kim M. Exosomes: Membrane-associated proteins, challenges and perspectives. Biochem Biophys Rep 2024; 37:101599. [PMID: 38145105 PMCID: PMC10746368 DOI: 10.1016/j.bbrep.2023.101599] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 11/25/2023] [Accepted: 11/28/2023] [Indexed: 12/26/2023] Open
Abstract
Membrane proteins determine the precise function of each membrane and, therefore, the function of each cell type. These proteins essential roles in cell physiology, participating in the maintenance of the cell metabolism, its homeostasis or promoting proper cell growth. Membrane proteins, as has long been described, are located both in the plasma membrane and in complex subcellular structures. However, they can also be released into the extracellular environment associated with extracellular vesicles (EVs). To date, most of the research have been focused on understanding the role of exosomal RNA in several processes. Recently, there has been increasing interest in studying the function of exosome membrane proteins for exosome-based therapy, but not much research has been done yet on the function of exosome membrane proteins. One of the major limitations of studying exosome membrane proteins and their application to translational research of exosome-based therapeutics is the low yield of exosome isolation. Here, we have introduced a new perspective on exosome membrane protein research by reviewing studies showing the important role of exosome membrane proteins in exosome-based therapies. Furthermore, we have proposed a new strategy to boost the yield of exosome isolation: hybridization of liposomes with exosome-derived membrane. Liposomes have already been reported to affect the cell excitation to increase exosome production in tumor cells. Therefore, increasing cellular uptake of these liposomes would enhance exosome release by increasing cellular excitation. This new perspective could be a breakthrough in exosome-based therapeutic research.
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Affiliation(s)
- Nuria Palomar-Alonso
- Department of Neurology, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea
| | - Mijung Lee
- Department of Neurology, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea
| | - Manho Kim
- Department of Neurology, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea
- Neuroscience Dementia Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- Protein Metabolism Medical Research Center, College of Medicine, Seoul National University Hospital, Seoul, South Korea
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Spasovski V, Romolo A, Zagorc U, Arrigler V, Kisovec M, Bedina Zavec A, Arko M, Molnár A, Schlosser G, Iglič A, Kogej K, Kralj-Iglič V. Characterization of Nanohybridosomes from Lipids and Spruce Homogenate Containing Extracellular Vesicles. Int J Nanomedicine 2024; 19:1709-1721. [PMID: 38410418 PMCID: PMC10896108 DOI: 10.2147/ijn.s432836] [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: 07/28/2023] [Accepted: 12/15/2023] [Indexed: 02/28/2024] Open
Abstract
Introduction Lipid nanovesicles associated with bioactive phytochemicals from spruce needle homogenate (here called nano-sized hybridosomes or nanohybridosomes, NSHs) were considered. Methods We formed NSHs by mixing appropriate amounts of lecithin, glycerol and supernatant of isolation of extracellular vesicles from spruce needle homogenate. We visualized NSHs by light microscopy and cryogenic transmission electron microscopy and assessed them by flow cytometry, dynamic light scattering, ultraviolet-visual spectroscopy, interferometric light microscopy and liquid chromatography-mass spectrometry. Results We found that the particles consisted of a bilayer membrane and a fluid-like interior. Flow cytometry and interferometric light microscopy measurements showed that the majority of the particles were nano-sized. Dynamic light scattering and interferometric light microscopy measurements agreed well on the average hydrodynamic radius of the particles Rh (between 140 and 180 nm), while the concentrations of the particles were in the range between 1013 and 1014/mL indicating that NSHs present a considerable (more than 25%) of the sample which is much more than the yield of natural extracellular vesicles (EVs) from spruce needle homogenate (estimated less than 1%). Spruce specific lipids and proteins were found in hybridosomes. Discussion Simple and low-cost preparation method, non-demanding saving process and efficient formation procedure suggest that large-scale production of NSHs from lipids and spruce needle homogenate is feasible.
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Affiliation(s)
- Vesna Spasovski
- University of Ljubljana, Faculty of Health Sciences, Laboratory of Clinical Biophysics, Ljubljana, Slovenia
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Anna Romolo
- University of Ljubljana, Faculty of Health Sciences, Laboratory of Clinical Biophysics, Ljubljana, Slovenia
- University of Ljubljana, Faculty of Electrical Engineering, Laboratory of Physics, Ljubljana, Slovenia
| | - Urška Zagorc
- University of Ljubljana, Faculty of Chemistry and Chemical Technology, Ljubljana, Slovenia
| | - Vesna Arrigler
- University of Ljubljana, Faculty of Chemistry and Chemical Technology, Ljubljana, Slovenia
| | - Matic Kisovec
- National Institute of Chemistry, Department of Molecular Biology and Nanobiotechnology, Ljubljana, Slovenia
| | - Apolonija Bedina Zavec
- National Institute of Chemistry, Department of Molecular Biology and Nanobiotechnology, Ljubljana, Slovenia
| | - Matevž Arko
- University of Ljubljana, Faculty of Health Sciences, Laboratory of Clinical Biophysics, Ljubljana, Slovenia
| | - Adrienn Molnár
- Hevesy György PhD School of Chemistry, ELTE Eötvös Loránd University, Budapest, Hungary
- MTA-ELTE Lendület Ion Mobility Mass Spectrometry Research Group, Faculty of Science, Institute of Chemistry, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Gitta Schlosser
- MTA-ELTE Lendület Ion Mobility Mass Spectrometry Research Group, Faculty of Science, Institute of Chemistry, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Aleš Iglič
- University of Ljubljana, Faculty of Electrical Engineering, Laboratory of Physics, Ljubljana, Slovenia
- University of Ljubljana, Faculty of Medicine, Laboratory of Clinical Biophysics, Ljubljana, Slovenia
| | - Ksenija Kogej
- University of Ljubljana, Faculty of Chemistry and Chemical Technology, Ljubljana, Slovenia
| | - Veronika Kralj-Iglič
- University of Ljubljana, Faculty of Health Sciences, Laboratory of Clinical Biophysics, Ljubljana, Slovenia
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Yang Q, Li S, Ou H, Zhang Y, Zhu G, Li S, Lei L. Exosome-based delivery strategies for tumor therapy: an update on modification, loading, and clinical application. J Nanobiotechnology 2024; 22:41. [PMID: 38281957 PMCID: PMC10823703 DOI: 10.1186/s12951-024-02298-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 01/02/2024] [Indexed: 01/30/2024] Open
Abstract
Malignancy is a major public health problem and among the leading lethal diseases worldwide. Although the current tumor treatment methods have therapeutic effect to a certain extent, they still have some shortcomings such as poor water solubility, short half-life, local and systemic toxicity. Therefore, how to deliver therapeutic agent so as to realize safe and effective anti-tumor therapy become a problem urgently to be solved in this field. As a medium of information exchange and material transport between cells, exosomes are considered to be a promising drug delivery carrier due to their nano-size, good biocompatibility, natural targeting, and easy modification. In this review, we summarize recent advances in the isolation, identification, drug loading, and modification of exosomes as drug carriers for tumor therapy alongside their application in tumor therapy. Basic knowledge of exosomes, such as their biogenesis, sources, and characterization methods, is also introduced herein. In addition, challenges related to the use of exosomes as drug delivery vehicles are discussed, along with future trends. This review provides a scientific basis for the application of exosome delivery systems in oncological therapy.
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Affiliation(s)
- Qian Yang
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Shisheng Li
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
| | - Haibo Ou
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Yuming Zhang
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Gangcai Zhu
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Shaohong Li
- Department of Otorhinolaryngology Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
| | - Lanjie Lei
- Institute of Translational Medicine, Zhejiang Shuren University, Hangzhou, 310015, Zhejiang, China.
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Chen YS, Harn HJ, Hong ZX, Huang YC, Lin YT, Zheng HX, Chen PY, Yang HH, Chen PR, Tsai HC, Lin SZ, Ho TJ, Chiou TW. Preconditioning of exosomes derived from human olfactory ensheathing cells improved motor coordination and balance in an SCA3/MJD mouse model: A new therapeutic approach. Eur J Pharm Sci 2023; 191:106608. [PMID: 37832855 DOI: 10.1016/j.ejps.2023.106608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 10/10/2023] [Accepted: 10/10/2023] [Indexed: 10/15/2023]
Abstract
Exosome therapy is a novel trend in regeneration medicine. However, identifying a suitable biomarker that can associate the therapeutic efficacy of exosomes with SCA3/MJD is essential. In this study, parental cells were preconditioned with butylidenephthalide (Bdph) for exosome preparation to evaluate the therapeutic effect of SCA3/MJD. The therapeutic agent hsa-miRNA-6780-5p was enriched up to 98-fold in exosomes derived from butylidenephthalide (Bdph)-preconditioned human olfactory ensheathing cells (hOECs) compared with that in naïve hOECs exosomes. The particle sizes of exosomes derived from naïve hOECs and those derived from hOECs preconditioned with Bdph were approximately 113.0 ± 3.5 nm and 128.9 ± 0.7 nm, respectively. A liposome system was used to demonstrate the role of hsa-miRNA-6780-5p, wherein hsa-miRNA-6780-5p was found to enhance autophagy and inhibit the expression of spinocerebellar ataxia type 3 (SCA3) disease proteins with the polyglutamine (polyQ) tract. Exosomes with enriched hsa-miRNA-6780-5p were further applied to HEK-293-84Q cells, leading to decreased expression of polyQ and increased autophagy. The results were reversed when 3MA, an autophagy inhibitor, was added to the cells treated with hsa-miRNA-6780-5p-enriched exosomes, indicating that the decreased polyQ expression was modulated via autophagy. SCA3 mice showed improved motor coordination behavior when they intracranially received exosomes enriched with hsa-miRNA-6780-5p. SCA3 mouse cerebellar tissues treated with hsa-miRNA-6780-5p-enriched exosomes showed decreased expression of polyQ and increased expression of LC3II/I, an autophagy marker. In conclusion, our findings can serve as a basis for developing an alternative therapeutic strategy for SCA3 disease treatment using miRNA-enriched exosomes derived from chemically preconditioned cells.
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Affiliation(s)
- Yu-Shuan Chen
- Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Taiwan, ROC; Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, ROC; Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, Taiwan
| | - Horng-Jyh Harn
- Department of Pathology, Hualien Tzu Chi Hospital, Tzu Chi University, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, ROC
| | - Zhen-Xiang Hong
- Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Taiwan, ROC
| | - Yi-Chen Huang
- Department of Life Science, National Dong Hwa University, No. 1, Sec. 2, Da Hsueh Rd, Shoufeng, Hualien 974301, Taiwan, ROC
| | - Yi-Tung Lin
- Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Taiwan, ROC
| | - Hui-Xuan Zheng
- Department of Life Science, National Dong Hwa University, No. 1, Sec. 2, Da Hsueh Rd, Shoufeng, Hualien 974301, Taiwan, ROC
| | - Pei-Yu Chen
- Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Taiwan, ROC
| | - Hsueh-Hui Yang
- Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, ROC
| | - Peir-Rong Chen
- Department of Otolaryngology, Hualien Tzu Chi Hospital and Tzu Chi University, Hualien, Taiwan, ROC
| | - Hsieh-Chih Tsai
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 106, Taiwan, ROC
| | - Shinn-Zong Lin
- Department of Neurosurgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, ROC
| | - Tsung-Jung Ho
- Department of Chinese Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 707, Sec. 3, Chung-Yang Rd., Hualien, Taiwan, ROC.
| | - Tzyy-Wen Chiou
- Department of Life Science, National Dong Hwa University, No. 1, Sec. 2, Da Hsueh Rd, Shoufeng, Hualien 974301, Taiwan, ROC.
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Chen JW, Liew FF, Tan HW, Misran M, Chung I. Cholesterol-linoleic acid liposomes induced extracellular vesicles secretion from immortalized adipose-derived mesenchymal stem cells for in vitro cell migration. ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY 2023; 51:346-360. [PMID: 37524112 DOI: 10.1080/21691401.2023.2237534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 06/28/2023] [Accepted: 07/12/2023] [Indexed: 08/02/2023]
Abstract
Extracellular vesicles (EVs) are small vesicles that are naturally released by cells and play a crucial role in cell-to-cell communication, tissue repair and regeneration. As naturally secreted EVs are limited, liposomes with different physicochemical properties, such as 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) and linoleic acid (LA) with modifications have been formulated to improve EVs secretion for in vitro wound healing. Various analyses, including dynamic light scattering (DLS) and transmission electron microscopy (TEM) were performed to monitor the successful preparation of different types of liposomes. The results showed that cholesterol-LA liposomes significantly improved the secretion of EVs from immortalized adipose-derived mesenchymal stem cells (AD-MSCs) by 1.5-fold. Based on the cell migration effects obtained from scratch assay, both LA liposomal-induced EVs and cholesterol-LA liposomal-induced EVs significantly enhanced the migration of human keratinocytes (HaCaT) cell line. These findings suggested that LA and cholesterol-LA liposomes that enhance EVs secretion are potentially useful and can be extended for various tissue regeneration applications.
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Affiliation(s)
- Jzit Weii Chen
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Fong Fong Liew
- Department of Oral Biology and Biomedical Science, Faculty of Dentistry, MAHSA University, Selangor, Malaysia
| | - Hsiao Wei Tan
- Institute of Research Management and Services, Research and Innovation Management Complex, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Misni Misran
- Department of Chemistry, Faculty of Science, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Ivy Chung
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
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Shekari F, Alibhai FJ, Baharvand H, Börger V, Bruno S, Davies O, Giebel B, Gimona M, Salekdeh GH, Martin‐Jaular L, Mathivanan S, Nelissen I, Nolte‐’t Hoen E, O'Driscoll L, Perut F, Pluchino S, Pocsfalvi G, Salomon C, Soekmadji C, Staubach S, Torrecilhas AC, Shelke GV, Tertel T, Zhu D, Théry C, Witwer K, Nieuwland R. Cell culture-derived extracellular vesicles: Considerations for reporting cell culturing parameters. JOURNAL OF EXTRACELLULAR BIOLOGY 2023; 2:e115. [PMID: 38939735 PMCID: PMC11080896 DOI: 10.1002/jex2.115] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/18/2023] [Accepted: 09/17/2023] [Indexed: 06/29/2024]
Abstract
Cell culture-conditioned medium (CCM) is a valuable source of extracellular vesicles (EVs) for basic scientific, therapeutic and diagnostic applications. Cell culturing parameters affect the biochemical composition, release and possibly the function of CCM-derived EVs (CCM-EV). The CCM-EV task force of the Rigor and Standardization Subcommittee of the International Society for Extracellular Vesicles aims to identify relevant cell culturing parameters, describe their effects based on current knowledge, recommend reporting parameters and identify outstanding questions. While some recommendations are valid for all cell types, cell-specific recommendations may need to be established for non-mammalian sources, such as bacteria, yeast and plant cells. Current progress towards these goals is summarized in this perspective paper, along with a checklist to facilitate transparent reporting of cell culturing parameters to improve the reproducibility of CCM-EV research.
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Affiliation(s)
- Faezeh Shekari
- Department of Stem Cells and Developmental Biology, Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECRTehranIran
- Advanced Therapy Medicinal Product Technology Development Center (ATMP‐TDC), Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECRTehranIran
| | | | - Hossein Baharvand
- Department of Stem Cells and Developmental Biology, Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECRTehranIran
- Department of Developmental Biology, School of Basic Sciences and Advanced Technologies in BiologyUniversity of Science and CultureTehranIran
| | - Verena Börger
- Institute for Transfusion MedicineUniversity Hospital Essen, University of Duisburg‐EssenEssenGermany
| | - Stefania Bruno
- Department of Medical Sciences and Molecular Biotechnology CenterUniversity of TorinoTurinItaly
| | - Owen Davies
- School of Sport, Exercise and Health SciencesLoughborough UniversityLoughboroughUK
| | - Bernd Giebel
- Institute for Transfusion MedicineUniversity Hospital Essen, University of Duisburg‐EssenEssenGermany
| | - Mario Gimona
- GMP UnitSpinal Cord Injury & Tissue Regeneration Centre Salzburg (SCI‐TReCS) and Research Program “Nanovesicular Therapies” Paracelsus Medical UniversitySalzburgAustria
| | | | - Lorena Martin‐Jaular
- Institut Curie, INSERM U932 and Curie CoreTech Extracellular VesiclesPSL Research UniversityParisFrance
| | - Suresh Mathivanan
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular ScienceLa Trobe UniversityMelbourneVICAustralia
| | - Inge Nelissen
- VITO (Flemish Institute for Technological Research), Health departmentBoeretangBelgium
| | - Esther Nolte‐’t Hoen
- Department of Biomolecular Health Sciences, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Lorraine O'Driscoll
- School of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences InstituteTrinity College DublinDublinIreland
| | - Francesca Perut
- Biomedical Science and Technologies and Nanobiotechnology LabIRCCS Istituto Ortopedico RizzoliBolognaItaly
| | - Stefano Pluchino
- Department of Clinical NeurosciencesUniversity of CambridgeCambridgeUK
| | - Gabriella Pocsfalvi
- Institute of Biosciences and BioResourcesNational Research CouncilNaplesItaly
| | - Carlos Salomon
- Translational Extracellular Vesicles in Obstetrics and Gynae‐Oncology Group, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of MedicineThe University of QueenslandBrisbaneAustralia
| | - Carolina Soekmadji
- School of Biomedical Sciences, Faculty of MedicineUniversity of QueenslandBrisbaneAustralia
| | | | - Ana Claudia Torrecilhas
- Laboratório de Imunologia Celular e Bioquímica de Fungos e Protozoários, Departamento de Ciências FarmacêuticasUniversidade Federal de São Paulo (UNIFESP)SPBrazil
| | - Ganesh Vilas Shelke
- Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaMarylandUSA
| | - Tobias Tertel
- Institute for Transfusion MedicineUniversity Hospital Essen, University of Duisburg‐EssenEssenGermany
| | - Dandan Zhu
- The Ritchie CentreHudson Institute of Medical ResearchClaytonVICAustralia
| | - Clotilde Théry
- Institut Curie, INSERM U932 and Curie CoreTech Extracellular VesiclesPSL Research UniversityParisFrance
| | - Kenneth Witwer
- Departments of Molecular and Comparative Pathobiology and Neurology and Richman Family Precision Medicine Center of Excellence in Alzheimer's DiseaseJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Rienk Nieuwland
- Laboratory of Experimental Clinical Chemistry, Department of Clinical Chemistry, Amsterdam University Medical CentersLocation AMC, University of AmsterdamAmsterdamThe Netherlands
- Amsterdam Vesicle Center, Amsterdam University Medical Centers, location AMCUniversity of AmsterdamAmsterdamThe Netherlands
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11
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Lin SW, Tsai JC, Shyong YJ. Drug delivery of extracellular vesicles: Preparation, delivery strategies and applications. Int J Pharm 2023; 642:123185. [PMID: 37391106 DOI: 10.1016/j.ijpharm.2023.123185] [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: 03/01/2023] [Revised: 06/24/2023] [Accepted: 06/26/2023] [Indexed: 07/02/2023]
Abstract
Extracellular vesicles (EV) are cell-originated vesicles exhibited with characteristics similar to the parent cells. Several studies have suggested the therapeutic potential of EV since they played as an intercellular communicator and modulate disease microenvironment, and thus EV has been widely studied in cancer management and tissue regeneration. However, merely application of EV revealed limited therapeutic outcome in different disease scenario and co-administration of drugs may be necessary to exert proper therapeutic effect. The method of drug loading into EV and efficient delivery of the formulation is therefore important. In this review, the advantages of using EV as drug delivery system compared to traditional synthetic nanoparticles will be emphasized, followed by the method of preparing EV and drug loading. The pharmacokinetic characteristics of EV was discussed, together with the review of reported delivery strategies and related application of EV in different disease management.
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Affiliation(s)
- Shang-Wen Lin
- School of Pharmacy, College of Medicine, National Cheng Kung University, No.1, University Road, Tainan City 701, Taiwan
| | - Jui-Chen Tsai
- School of Pharmacy, College of Medicine, National Cheng Kung University, No.1, University Road, Tainan City 701, Taiwan
| | - Yan-Jye Shyong
- School of Pharmacy, College of Medicine, National Cheng Kung University, No.1, University Road, Tainan City 701, Taiwan.
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12
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Paccosi E, Proietti-De-Santis L. Parkinson's Disease: From Genetics and Epigenetics to Treatment, a miRNA-Based Strategy. Int J Mol Sci 2023; 24:ijms24119547. [PMID: 37298496 DOI: 10.3390/ijms24119547] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/26/2023] [Accepted: 05/29/2023] [Indexed: 06/12/2023] Open
Abstract
Parkinson's disease (PD) is one of the most common neurodegenerative disorders, characterized by an initial and progressive loss of dopaminergic neurons of the substantia nigra pars compacta via a potentially substantial contribution from protein aggregates, the Lewy bodies, mainly composed of α-Synuclein among other factors. Distinguishing symptoms of PD are bradykinesia, muscular rigidity, unstable posture and gait, hypokinetic movement disorder and resting tremor. Currently, there is no cure for PD, and palliative treatments, such as Levodopa administration, are directed to relieve the motor symptoms but induce severe side effects over time. Therefore, there is an urgency for discovering new drugs in order to design more effective therapeutic approaches. The evidence of epigenetic alterations, such as the dysregulation of different miRNAs that may stimulate many aspects of PD pathogenesis, opened a new scenario in the research for a successful treatment. Along this line, a promising strategy for PD treatment comes from the potential exploitation of modified exosomes, which can be loaded with bioactive molecules, such as therapeutic compounds and RNAs, and can allow their delivery to the appropriate location in the brain, overcoming the blood-brain barrier. In this regard, the transfer of miRNAs within Mesenchymal stem cell (MSC)-derived exosomes has yet to demonstrate successful results both in vitro and in vivo. This review, besides providing a systematic overview of both the genetic and epigenetic basis of the disease, aims to explore the exosomes/miRNAs network and its clinical potential for PD treatment.
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Affiliation(s)
- Elena Paccosi
- Unit of Molecular Genetics of Aging, Department of Ecology and Biology (DEB), University of Tuscia, 01100 Viterbo, Italy
| | - Luca Proietti-De-Santis
- Unit of Molecular Genetics of Aging, Department of Ecology and Biology (DEB), University of Tuscia, 01100 Viterbo, Italy
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13
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Brezgin S, Parodi A, Kostyusheva A, Ponomareva N, Lukashev A, Sokolova D, Pokrovsky VS, Slatinskaya O, Maksimov G, Zamyatnin AA, Chulanov V, Kostyushev D. Technological aspects of manufacturing and analytical control of biological nanoparticles. Biotechnol Adv 2023; 64:108122. [PMID: 36813011 DOI: 10.1016/j.biotechadv.2023.108122] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 01/19/2023] [Accepted: 02/09/2023] [Indexed: 02/22/2023]
Abstract
Extracellular vesicles (EVs) are cell-derived biological nanoparticles that gained great interest for drug delivery. EVs have numerous advantages compared to synthetic nanoparticles, such as ideal biocompatibility, safety, ability to cross biological barriers and surface modification via genetic or chemical methods. On the other hand, the translation and the study of these carriers resulted difficult, mostly because of significant issues in up-scaling, synthesis and impractical methods of quality control. However, current manufacturing advances enable EV packaging with any therapeutic cargo, including DNA, RNA (for RNA vaccines and RNA therapeutics), proteins, peptides, RNA-protein complexes (including gene-editing complexes) and small molecules drugs. To date, an array of new and upgraded technologies have been introduced, substantially improving EV production, isolation, characterization and standardization. The used-to-be "gold standards" of EV manufacturing are now outdated, and the state-of-art requires extensive revision. This review re-evaluates the pipeline for EV industrial production and provides a critical overview of the modern technologies required for their synthesis and characterization.
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Affiliation(s)
- Sergey Brezgin
- Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, Sechenov University, Moscow 119048, Russia; Sirius University of Science and Technology, Sochi 354340, Russia
| | | | - Anastasiya Kostyusheva
- Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, Sechenov University, Moscow 119048, Russia
| | - Natalia Ponomareva
- Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, Sechenov University, Moscow 119048, Russia; Sirius University of Science and Technology, Sochi 354340, Russia
| | - Alexander Lukashev
- Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, Sechenov University, Moscow 119048, Russia
| | - Darina Sokolova
- Sirius University of Science and Technology, Sochi 354340, Russia; Blokhin National Medical Research Center of Oncology, Moscow 115478, Russia; People's Friendship University, Moscow 117198, Russia
| | - Vadim S Pokrovsky
- Sirius University of Science and Technology, Sochi 354340, Russia; Blokhin National Medical Research Center of Oncology, Moscow 115478, Russia; People's Friendship University, Moscow 117198, Russia
| | - Olga Slatinskaya
- Lomonosov Moscow State University, Faculty of Biology, Moscow 119991, Russia
| | - Georgy Maksimov
- Lomonosov Moscow State University, Faculty of Biology, Moscow 119991, Russia
| | - Andrey A Zamyatnin
- Sirius University of Science and Technology, Sochi 354340, Russia; Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russia; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia; Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7X, UK
| | - Vladimir Chulanov
- Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, Sechenov University, Moscow 119048, Russia; Sirius University of Science and Technology, Sochi 354340, Russia; Department of Infectious Diseases, Sechenov University, Moscow 119048, Russia; National Medical Research Center for Tuberculosis and Infectious Diseases, Moscow 127994, Russia
| | - Dmitry Kostyushev
- Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, Sechenov University, Moscow 119048, Russia; Sirius University of Science and Technology, Sochi 354340, Russia.
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14
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Richards T, Patel H, Patel K, Schanne F. Endogenous Lipid Carriers-Bench-to-Bedside Roadblocks in Production and Drug Loading of Exosomes. Pharmaceuticals (Basel) 2023; 16:421. [PMID: 36986523 PMCID: PMC10058361 DOI: 10.3390/ph16030421] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/04/2023] [Accepted: 03/07/2023] [Indexed: 03/16/2023] Open
Abstract
Exosomes are cell-derived, nano-sized extracellular vesicles comprising a lipid bilayer membrane that encapsulates several biological components, such as nucleic acids, lipids, and proteins. The role of exosomes in cell-cell communication and cargo transport has made them promising candidates in drug delivery for an array of diseases. Despite several research and review papers describing the salient features of exosomes as nanocarriers for drug delivery, there are no FDA-approved commercial therapeutics based on exosomes. Several fundamental challenges, such as the large-scale production and reproducibility of batches, have hindered the bench-to-bedside translation of exosomes. In fact, compatibility and poor drug loading sabotage the possibility of delivering several drug molecules. This review provides an overview of the challenges and summarizes the potential solutions/approaches to facilitate the clinical development of exosomal nanocarriers.
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Affiliation(s)
| | | | | | - Frank Schanne
- College of Pharmacy & Health Sciences, St. John’s University, Queens, NY 11439, USA
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15
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Zheng Y, Xu P, Pan C, Wang Y, Liu Z, Chen Y, Chen C, Fu S, Xue K, Zhou Q, Liu K. Production and Biological Effects of Extracellular Vesicles from Adipose-Derived Stem Cells Were Markedly Increased by Low-Intensity Ultrasound Stimulation for Promoting Diabetic Wound Healing. Stem Cell Rev Rep 2022; 19:784-806. [PMID: 36562958 DOI: 10.1007/s12015-022-10487-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/03/2022] [Indexed: 12/24/2022]
Abstract
Diabetic wound treatment has posed a significant challenge in clinical practice. As a kind of cell-derived nanoparticles, extracellular vesicles produced by adipose-derived stem cells (ADSC-EVs) have been reported to be potential agents for diabetic wound treatment. However, ADSC-EV yield is insufficient to meet the demands of clinical therapy. In this study, a novel method involving the use of low-intensity ultrasound stimulation on ADSCs is developed to promote EV secretion for clinical use. A proper low-intensity ultrasound stimulation parameter which significantly increases ADSC-EV quantity has been found. In addition, EVs secreted by ADSCs following low-intensity ultrasound stimulation (US-EVs) are enriched in wound healing-related miRNAs. Moreover, US-EVs promote the biological functions of fibroblasts, keratinocytes, and endothelial cells in vitro, and promote diabetic wound healing in db/db mice in vivo through re-epithelialization, collagen production, cell proliferation, keratinocyte differentiation and migration, and angiogenesis. This study proposes low-intensity ultrasound stimulation as a new method for promoting significant EV secretion by ADSCs and for improving the diabetic wound-healing potential of EVs, which will meet the clinical needs for these nanoparticles. The production of extracellular vesicles of adipose-derived stem cells is obviously promoted by a low-intensity ultrasound stimulation method, and the biological effects of promoting diabetic wound healing were markedly increased in vitro and in vivo.
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Affiliation(s)
- Yi Zheng
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, 200011, Shanghai, China
| | - Peng Xu
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, 200011, Shanghai, China.
| | - Chuqiao Pan
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, 200011, Shanghai, China
| | - Yikai Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, 200011, Shanghai, China
| | - Zibo Liu
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, 200011, Shanghai, China
| | - Yahong Chen
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, 200011, Shanghai, China
| | - Chuhsin Chen
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, 200011, Shanghai, China
| | - Shibo Fu
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, 200011, Shanghai, China
| | - Ke Xue
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, 200011, Shanghai, China
| | - Qimin Zhou
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, 200011, Shanghai, China
| | - Kai Liu
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, 200011, Shanghai, China.
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16
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Almeria C, Kreß S, Weber V, Egger D, Kasper C. Heterogeneity of mesenchymal stem cell-derived extracellular vesicles is highly impacted by the tissue/cell source and culture conditions. Cell Biosci 2022; 12:51. [PMID: 35501833 PMCID: PMC9063275 DOI: 10.1186/s13578-022-00786-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 04/10/2022] [Indexed: 12/19/2022] Open
Abstract
AbstractExtracellular vesicles (EVs) are cell-derived membrane structures exerting major effects in physiological as well as pathological processes by functioning as vehicles for the delivery of biomolecules to their target cells. An increasing number of effects previously attributed to cell-based therapies have been recognized to be actually mediated by EVs derived from the respective cells, suggesting the administration of purified EVs instead of living cells for cell-based therapies. In this review, we focus on the heterogeneity of EVs derived from mesenchymal stem/stromal cells (MSC) and summarize upstream process parameters that crucially affect the resulting therapeutic properties and biological functions. Hereby, we discuss the effects of the cell source, medium composition, 3D culture, bioreactor culture and hypoxia. Furthermore, aspects of the isolation and storage strategies influences EVs are described. Conclusively, optimization of upstream process parameters should focus on controlling MSC-derived EV heterogeneity for specific therapeutic applications.
Graphical Abstract
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17
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Wu Y, Zhang Z, Wei Y, Qian Z, Wei X. Nanovaccines for cancer immunotherapy: Current knowledge and future perspectives. CHINESE CHEM LETT 2022. [DOI: 10.1016/j.cclet.2022.108098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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18
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Gurunathan S, Kim JH. Graphene Oxide Enhances Biogenesis and Release of Exosomes in Human Ovarian Cancer Cells. Int J Nanomedicine 2022; 17:5697-5731. [PMID: 36466784 PMCID: PMC9717435 DOI: 10.2147/ijn.s385113] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 11/04/2022] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND Exosomes, which are nanovesicles secreted by almost all the cells, mediate intercellular communication and are involved in various physiological and pathological processes. We aimed to investigate the effects of graphene oxide (GO) on the biogenesis and release of exosomes in human ovarian cancer (SKOV3) cells. METHODS Exosomes were isolated using ultracentrifugation and ExoQuick and characterized by various analytical techniques. The expression levels of exosome markers were analyzed via quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS Graphene oxide (10-50 μg/mL), cisplatin (2-10 μg/mL), and C6-ceramide (5-25 μM) inhibited the cell viability, proliferation, and cytotoxicity in a dose-dependent manner. We observed that graphene oxide (GO), cisplatin (CIS), and C6-Ceramide (C6-Cer) stimulated acetylcholine esterase and neutral sphingomyelinase activity, total exosome protein concentration, and exosome counts associated with increased level of apoptosis, oxidative stress and endoplasmic reticulum stress. In contrast, GW4869 treatment inhibits biogenesis and release of exosomes. We observed that the human ovarian cancer cells secreted exosomes with typical cup-shaped morphology and surface protein biomarkers. The expression levels of TSG101, CD9, CD63, and CD81 were significantly higher in GO-treated cells than in control cells. Further, cytokine and chemokine levels were significantly higher in exosomes isolated from GO-treated SKOV3 cells than in those isolated from control cells. SKOV3 cells pre-treated with N-acetylcysteine or GW4869 displayed a significant reduction in GO-induced exosome biogenesis and release. Furthermore, endocytic inhibitors decrease exosome biogenesis and release by impairing endocytic pathways. CONCLUSION This study identifies GO as a potential tool for targeting the exosome pathway and stimulating exosome biogenesis and release. We believe that the knowledge acquired in this study can be potentially extended to other exosome-dominated pathologies and model systems. Furthermore, these nanoparticles can provide a promising means to enhance exosome production in SKOV3 cells.
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Affiliation(s)
- Sangiliyandi Gurunathan
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, 05029, Korea
| | - Jin Hoi Kim
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, 05029, Korea
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19
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Hussen BM, Faraj GSH, Rasul MF, Hidayat HJ, Salihi A, Baniahmad A, Taheri M, Ghafouri-Frad S. Strategies to overcome the main challenges of the use of exosomes as drug carrier for cancer therapy. Cancer Cell Int 2022; 22:323. [PMID: 36258195 PMCID: PMC9580186 DOI: 10.1186/s12935-022-02743-3] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 10/05/2022] [Indexed: 11/10/2022] Open
Abstract
Exosomes are naturally occurring nanosized particles that aid intercellular communication by transmitting biological information between cells. Exosomes have therapeutic efficacy that can transfer their contents between cells as natural carriers. In addition, the exosomal contents delivered to the recipient pathological cells significantly inhibit cancer progression. However, exosome-based tumor treatments are inadequately precise or successful, and various challenges should be adequately overcome. Here, we discuss the significant challenges that exosomes face as drug carriers used for therapeutic targets and strategies for overcoming these challenges in order to promote this new incoming drug carrier further and improve future clinical outcomes. We also present techniques for overcoming these challenges.
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Affiliation(s)
- Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region, Iraq.,Center of Research and Strategic Studies, Lebanese French University, Erbil, Iraq
| | - Goran Sedeeq Hama Faraj
- College of Medicine, Department of Medical Laboratory Sciences, Komar University of Science and Technology, Sulaymaniyah, Iraq
| | - Mohammad Fatih Rasul
- Department of Pharmaceutical Basic Science, Faculty of Pharmacy, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Hazha Jamal Hidayat
- Department of Biology, College of Education, Salahaddin University, Erbil, Kurdistan Region, Iraq
| | - Abbas Salihi
- Department of Biology, College of Science, Salahaddin University, Erbil, Kurdistan Region, Iraq
| | - Aria Baniahmad
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospital, Jena, Germany. .,Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Soudeh Ghafouri-Frad
- Department of Medical Genetics,, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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20
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Debbi L, Guo S, Safina D, Levenberg S. Boosting extracellular vesicle secretion. Biotechnol Adv 2022; 59:107983. [PMID: 35588952 PMCID: PMC9420194 DOI: 10.1016/j.biotechadv.2022.107983] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 04/14/2022] [Accepted: 05/12/2022] [Indexed: 02/05/2023]
Abstract
In recent years, extracellular vesicles (EVs), specifically exosomes, have emerged as a promising strategy for treating a wide spectrum of pathologies, such as cancer and COVID-19, as well as promoting tissue regeneration in various conditions, including cardiomyopathies and spinal cord injuries. Despite the great potential of EV-based therapies, poor yield and unscalable production of EVs remain big challenges to overcome to translate these types of treatment to clinical practices. Here, we review different strategies for enhancing EV yield by physical, biological or chemical means. Some of these novel approaches can lead to about 100-fold increase in EV production yield, thus bringing closer the clinical translation with regard to scalability and efficiency.
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Affiliation(s)
- Lior Debbi
- Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa, Israel
| | - Shaowei Guo
- The First Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Dina Safina
- Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa, Israel
| | - Shulamit Levenberg
- Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa, Israel.
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21
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Wong CW, Han HW, Hsu SH. Changes of cell membrane fluidity for mesenchymal stem cell spheroids on biomaterial surfaces. World J Stem Cells 2022; 14:616-632. [PMID: 36157913 PMCID: PMC9453270 DOI: 10.4252/wjsc.v14.i8.616] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 05/02/2022] [Accepted: 07/11/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The therapeutic potential of mesenchymal stem cells (MSCs) in the form of three-dimensional spheroids has been extensively demonstrated. The underlying mechanisms for the altered cellular behavior of spheroids have also been investigated. Cell membrane fluidity is a critically important physical property for the regulation of cell behavior, but it has not been studied for the spheroid-forming cells to date.
AIM To explore the association between cell membrane fluidity and the morphological changes of MSC spheroids on the surface of biomaterials to elucidate the role of membrane fluidity during the spheroid-forming process of MSCs.
METHODS We generated three-dimensional (3D) MSC spheroids on the surface of various culture substrates including chitosan (CS), CS-hyaluronan (CS-HA), and polyvinyl alcohol (PVA) substrates. The cell membrane fluidity and cell morphological change were examined by a time-lapse recording system as well as a high-resolution 3D cellular image explorer. MSCs and normal/cancer cells were pre-stained with fluorescent dyes and co-cultured on the biomaterials to investigate the exchange of cell membrane during the formation of heterogeneous cellular spheroids.
RESULTS We discovered that vesicle-like bubbles randomly appeared on the outer layer of MSC spheroids cultured on different biomaterial surfaces. The average diameter of the vesicle-like bubbles of MSC spheroids on CS-HA at 37 °C was approximately 10 μm, smaller than that on PVA substrates (approximately 27 μm). Based on time-lapse images, these unique bubbles originated from the dynamic movement of the cell membrane during spheroid formation, which indicated an increment of membrane fluidity for MSCs cultured on these substrates. Moreover, the membrane interaction in two different types of cells with similar membrane fluidity may further induce a higher level of membrane translocation during the formation of heterogeneous spheroids.
CONCLUSION Changes in cell membrane fluidity may be a novel path to elucidate the complicated physiological alterations in 3D spheroid-forming cells.
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Affiliation(s)
- Chui-Wei Wong
- National Taiwan University, Institute of Polymer Science and Engineering, Taipei 10617, Taiwan
| | - Hao-Wei Han
- National Taiwan University, Institute of Polymer Science and Engineering, Taipei 10617, Taiwan
| | - Shan-hui Hsu
- National Taiwan University, Institute of Polymer Science and Engineering, Taipei 10617, Taiwan
- National Health Research Institutes, Institute of Cellular and System Medicine, Miaoli 350, Taiwan
- National Taiwan University, Research and Development Center for Medical Devices, Taipei 10617, Taiwan
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22
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Xia J, Miao Y, Wang X, Huang X, Dai J. Recent progress of dendritic cell-derived exosomes (Dex) as an anti-cancer nanovaccine. Biomed Pharmacother 2022; 152:113250. [PMID: 35700679 DOI: 10.1016/j.biopha.2022.113250] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/27/2022] [Accepted: 06/02/2022] [Indexed: 11/02/2022] Open
Abstract
Although cancer vaccines such as dendritic cell (DC) vaccines and peptide vaccines have become appealing and attractive anticancer immunotherapy options in recent decades, some obstacles have hindered their successful application in the clinical setting. The difficulties associated with the high cost of DC preparation, storage of DC vaccines, tumor-mediated immunosuppressive environment, identification of specific tumor antigens, and high degradation of antigen peptides in vivo limit the clinical application and affect the outcomes of these cancer vaccines. Recently, nanocarriers have been considered as a new approach for vaccine delivery. As biogenic nanocarriers, exosomes are small membrane vesicles secreted by cells that carry various proteins, RNAs, and lipids. More importantly, DC-derived exosomes (Dex) express tumor antigens, MHC molecules, and co-stimulatory molecules on their surface, which trigger the release of antigen-specific CD4+ and CD8+ T cells. With their membrane structure, Dex can avoid high degradation while ensuring favorable biocompatibility and biosafety in vivo. In addition, Dex can be stored in vitro for a longer period, which facilitates a significant reduction in production costs. Furthermore, they have shown better antitumor efficacy in preclinical studies compared with DC vaccines owing to their higher immunogenicity and stronger resistance to immunosuppressive effects. However, the clinical efficacy of Dex vaccines remains limited. In this review, we aimed to evaluate the efficacy of Dex as an anticancer nanovaccine.
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Affiliation(s)
- Jingyi Xia
- Department of Hematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Qingyang District, Chengdu 610000, China.
| | - Yangbao Miao
- Department of Hematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Qingyang District, Chengdu 610000, China.
| | - Xi Wang
- Department of Hematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Qingyang District, Chengdu 610000, China.
| | - Xiaobing Huang
- Department of Hematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Qingyang District, Chengdu 610000, China.
| | - Jingying Dai
- Department of Hematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Qingyang District, Chengdu 610000, China.
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23
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Škufca D, Božič D, Hočevar M, Jeran M, Bedina Zavec A, Kisovec M, Podobnik M, Matos T, Tomazin R, Iglič A, Griessler Bulc T, Heath E, Kralj-Iglič V. Interaction between Microalgae P. tricornutum and Bacteria Thalassospira sp. for Removal of Bisphenols from Conditioned Media. Int J Mol Sci 2022; 23:ijms23158447. [PMID: 35955586 PMCID: PMC9369128 DOI: 10.3390/ijms23158447] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/26/2022] [Accepted: 07/27/2022] [Indexed: 02/01/2023] Open
Abstract
We studied the efficiency of three culture series of the microalgae Phaeodactylum tricornutum (P. tricornutum) and bacteria Thalassospira sp. (axenic microalgae, bacterial culture and co-culture of the two) in removing bisphenols (BPs) from their growth medium. Bacteria were identified by 16S ribosomal RNA polymerase chain reaction (16S rRNA PCR). The microorganism growth rate was determined by flow cytometry. Cultures and isolates of their small cellular particles (SCPs) were imaged by scanning electron microscopy (SEM) and cryogenic transmission electron microscopy (Cryo-TEM). BPs were analyzed by gas chromatography coupled with tandem mass spectrometry (GC-MS/MS). Our results indicate that some organisms may have the ability to remove a specific pollutant with high efficiency. P. tricornutum in axenic culture and in mixed culture removed almost all (more than 99%) of BPC2. Notable differences in the removal of 8 out of 18 BPs between the axenic, mixed and bacterial cultures were found. The overall removals of BPs in axenic P. tricornutum, mixed and bacterial cultures were 11%, 18% and 10%, respectively. Finding the respective organisms and creating microbe societies seems to be key for the improvement of wastewater treatment. As a possible mediating factor, numerous small cellular particles from all three cultures were detected by electron microscopy. Further research on the mechanisms of interspecies communication is needed to advance the understanding of microbial communities at the nano-level.
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Affiliation(s)
- David Škufca
- University of Ljubljana, Faculty of Health Sciences, Biomedical Research Group, Zdravstvena 5, SI-1000 Ljubljana, Slovenia; (D.Š.); (D.B.); (M.J.); (T.G.B.)
| | - Darja Božič
- University of Ljubljana, Faculty of Health Sciences, Biomedical Research Group, Zdravstvena 5, SI-1000 Ljubljana, Slovenia; (D.Š.); (D.B.); (M.J.); (T.G.B.)
- University of Ljubljana, Faculty of Electrical Engineering, Laboratory of Physics, Tržaška 25, SI-1000 Ljubljana, Slovenia;
| | - Matej Hočevar
- Department of Physics and Chemistry of Materials, Institute of Metals and Technology, Lepi Pot 11, SI-1000 Ljubljana, Slovenia;
| | - Marko Jeran
- University of Ljubljana, Faculty of Health Sciences, Biomedical Research Group, Zdravstvena 5, SI-1000 Ljubljana, Slovenia; (D.Š.); (D.B.); (M.J.); (T.G.B.)
- University of Ljubljana, Faculty of Electrical Engineering, Laboratory of Physics, Tržaška 25, SI-1000 Ljubljana, Slovenia;
| | - Apolonija Bedina Zavec
- Department of Molecular Biology and Nanobiotechnology, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia; (A.B.Z.); (M.K.); (M.P.)
| | - Matic Kisovec
- Department of Molecular Biology and Nanobiotechnology, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia; (A.B.Z.); (M.K.); (M.P.)
| | - Marjetka Podobnik
- Department of Molecular Biology and Nanobiotechnology, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia; (A.B.Z.); (M.K.); (M.P.)
| | - Tadeja Matos
- University of Ljubljana, Faculty of Medicine, Institute of Microbiology and Immunology, Zaloška 4, SI-1000 Ljubljana, Slovenia; (T.M.); (R.T.)
| | - Rok Tomazin
- University of Ljubljana, Faculty of Medicine, Institute of Microbiology and Immunology, Zaloška 4, SI-1000 Ljubljana, Slovenia; (T.M.); (R.T.)
| | - Aleš Iglič
- University of Ljubljana, Faculty of Electrical Engineering, Laboratory of Physics, Tržaška 25, SI-1000 Ljubljana, Slovenia;
| | - Tjaša Griessler Bulc
- University of Ljubljana, Faculty of Health Sciences, Biomedical Research Group, Zdravstvena 5, SI-1000 Ljubljana, Slovenia; (D.Š.); (D.B.); (M.J.); (T.G.B.)
| | - Ester Heath
- Department of Environmental Sciences, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia;
- Jožef Stefan International Postgraduate School, Jamova 39, SI-1000 Ljubljana, Slovenia
| | - Veronika Kralj-Iglič
- University of Ljubljana, Faculty of Health Sciences, Biomedical Research Group, Zdravstvena 5, SI-1000 Ljubljana, Slovenia; (D.Š.); (D.B.); (M.J.); (T.G.B.)
- Correspondence:
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24
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Ng CY, Kee LT, Al-Masawa ME, Lee QH, Subramaniam T, Kok D, Ng MH, Law JX. Scalable Production of Extracellular Vesicles and Its Therapeutic Values: A Review. Int J Mol Sci 2022; 23:7986. [PMID: 35887332 PMCID: PMC9315612 DOI: 10.3390/ijms23147986] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/14/2022] [Accepted: 07/15/2022] [Indexed: 02/07/2023] Open
Abstract
Extracellular vesicles (EVs) are minute vesicles with lipid bilayer membranes. EVs are secreted by cells for intercellular communication. Recently, EVs have received much attention, as they are rich in biological components such as nucleic acids, lipids, and proteins that play essential roles in tissue regeneration and disease modification. In addition, EVs can be developed as vaccines against cancer and infectious diseases, as the vesicle membrane has an abundance of antigenic determinants and virulent factors. EVs for therapeutic applications are typically collected from conditioned media of cultured cells. However, the number of EVs secreted by the cells is limited. Thus, it is critical to devise new strategies for the large-scale production of EVs. Here, we discussed the strategies utilized by researchers for the scalable production of EVs. Techniques such as bioreactors, mechanical stimulation, electrical stimulation, thermal stimulation, magnetic field stimulation, topographic clue, hypoxia, serum deprivation, pH modification, exposure to small molecules, exposure to nanoparticles, increasing the intracellular calcium concentration, and genetic modification have been used to improve the secretion of EVs by cultured cells. In addition, nitrogen cavitation, porous membrane extrusion, and sonication have been utilized to prepare EV-mimetic nanovesicles that share many characteristics with naturally secreted EVs. Apart from inducing EV production, these upscaling interventions have also been reported to modify the EVs' cargo and thus their functionality and therapeutic potential. In summary, it is imperative to identify a reliable upscaling technique that can produce large quantities of EVs consistently. Ideally, the produced EVs should also possess cargo with improved therapeutic potential.
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Affiliation(s)
- Chiew Yong Ng
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, University Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Kuala Lumpur 56000, Malaysia; (C.Y.N.); (L.T.K.); (M.E.A.-M.); (Q.H.L.); (T.S.); (D.K.); (M.H.N.)
| | - Li Ting Kee
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, University Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Kuala Lumpur 56000, Malaysia; (C.Y.N.); (L.T.K.); (M.E.A.-M.); (Q.H.L.); (T.S.); (D.K.); (M.H.N.)
| | - Maimonah Eissa Al-Masawa
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, University Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Kuala Lumpur 56000, Malaysia; (C.Y.N.); (L.T.K.); (M.E.A.-M.); (Q.H.L.); (T.S.); (D.K.); (M.H.N.)
| | - Qian Hui Lee
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, University Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Kuala Lumpur 56000, Malaysia; (C.Y.N.); (L.T.K.); (M.E.A.-M.); (Q.H.L.); (T.S.); (D.K.); (M.H.N.)
| | - Thayaalini Subramaniam
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, University Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Kuala Lumpur 56000, Malaysia; (C.Y.N.); (L.T.K.); (M.E.A.-M.); (Q.H.L.); (T.S.); (D.K.); (M.H.N.)
| | - David Kok
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, University Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Kuala Lumpur 56000, Malaysia; (C.Y.N.); (L.T.K.); (M.E.A.-M.); (Q.H.L.); (T.S.); (D.K.); (M.H.N.)
- Faculty of Applied Sciences, UCSI University, Jalan Menara Gading No. 1, Kuala Lumpur 56000, Malaysia
| | - Min Hwei Ng
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, University Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Kuala Lumpur 56000, Malaysia; (C.Y.N.); (L.T.K.); (M.E.A.-M.); (Q.H.L.); (T.S.); (D.K.); (M.H.N.)
| | - Jia Xian Law
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, University Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Kuala Lumpur 56000, Malaysia; (C.Y.N.); (L.T.K.); (M.E.A.-M.); (Q.H.L.); (T.S.); (D.K.); (M.H.N.)
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25
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Loch-Neckel G, Matos AT, Vaz AR, Brites D. Challenges in the Development of Drug Delivery Systems Based on Small Extracellular Vesicles for Therapy of Brain Diseases. Front Pharmacol 2022; 13:839790. [PMID: 35422699 PMCID: PMC9002061 DOI: 10.3389/fphar.2022.839790] [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: 12/20/2021] [Accepted: 02/21/2022] [Indexed: 12/12/2022] Open
Abstract
Small extracellular vesicles (sEVs) have ∼30–200 nm diameter size and may act as carriers of different cargoes, depending on the cell of origin or on the physiological/pathological condition. As endogenous nanovesicles, sEVs are important in intercellular communication and have many of the desirable features of an ideal drug delivery system. sEVs are naturally biocompatible, with superior targeting capability, safety profile, nanometric size, and can be loaded with both lipophilic and hydrophilic agents. Because of their biochemical and physical properties, sEVs are considered a promising strategy over other delivery vehicles in the central nervous system (CNS) since they freely cross the blood-brain barrier and they can be directed to specific nerve cells, potentiating a more precise targeting of their cargo. In addition, sEVs remain stable in the peripheral circulation, making them attractive nanocarrier systems to promote neuroregeneration. This review focuses on the recent progress in methods for manufacturing, isolating, and engineering sEVs that can be used as a therapeutic strategy to overcome neurodegeneration associated with pathologies of the CNS, with particular emphasis on Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis diseases, as well as on brain tumors.
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Affiliation(s)
- Gecioni Loch-Neckel
- Neuroinflammation, Signaling and Neuroregeneration Lab, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Ana Teresa Matos
- Neuroinflammation, Signaling and Neuroregeneration Lab, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Ana Rita Vaz
- Neuroinflammation, Signaling and Neuroregeneration Lab, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.,Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Dora Brites
- Neuroinflammation, Signaling and Neuroregeneration Lab, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.,Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
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26
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Busatto S, Yang Y, Iannotta D, Davidovich I, Talmon Y, Wolfram J. Considerations for extracellular vesicle and lipoprotein interactions in cell culture assays. J Extracell Vesicles 2022; 11:e12202. [PMID: 35362268 PMCID: PMC8971175 DOI: 10.1002/jev2.12202] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 02/25/2022] [Indexed: 12/11/2022] Open
Abstract
With an exponential increase in extracellular vesicle (EV) studies in the past decade, focus has been placed on standardization of experimental design to ensure inter‐study comparisons and validity of conclusions. In the case of in vitro assays, the composition of cell culture media is important to consider for EV studies. In particular, levels of lipoproteins, which are critical components of the interstitial fluid, should be taken into consideration. Results from this study reveal that lipoprotein levels in cell culture medium impact the effects that EVs have on recipient cells. Additionally, evidence of EV binding and fusion to lipoprotein‐like structures in plasma is provided. However, it is unclear whether the impact of lipoproteins in cell culture is due to direct interactions with EVs, indirect effects, or a combination of both mechanisms. Taken together, cell culture studies performed in the absence of physiological levels of lipoproteins are unlikely to reflect interactions that occur between EVs and recipient cells in an in vivo environment.
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Affiliation(s)
- Sara Busatto
- Vascular Biology Program, Boston Children's Hospital, Boston, Massachusetts, USA.,Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA
| | - Yubo Yang
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Dalila Iannotta
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, Florida, USA.,Department of Pharmacy, University of Chieti-Pescara "G. d'Annunzio", Chieti, Italy
| | - Irina Davidovich
- Department of Chemical Engineering and the Russell Berrie Nanotechnology Institute, Technion-Israel Institute of Technology, Haifa, Israel
| | - Yeshayahu Talmon
- Department of Chemical Engineering and the Russell Berrie Nanotechnology Institute, Technion-Israel Institute of Technology, Haifa, Israel
| | - Joy Wolfram
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, Florida, USA.,Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, Australia.,School of Chemical Engineering, University of Queensland, Brisbane, QLD, Australia
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27
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Karami Fath M, Azargoonjahromi A, Jafari N, Mehdi M, Alavi F, Daraei M, Mohammadkhani N, Mueller AL, Brockmueller A, Shakibaei M, Payandeh Z. Exosome application in tumorigenesis: diagnosis and treatment of melanoma. Med Oncol 2022; 39:19. [PMID: 34982284 DOI: 10.1007/s12032-021-01621-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 11/28/2021] [Indexed: 12/12/2022]
Abstract
Melanoma is the most aggressive of skin cancer derived from genetic mutations in the melanocytes. Current therapeutic approaches include surgical resection, chemotherapy, photodynamic therapy, immunotherapy, biochemotherapy, and targeted therapy. However, the efficiency of these strategies may be decreased due to the development of diverse resistance mechanisms. Here, it has been proven that therapeutic monoclonal antibodies (mAbs) can improve the efficiency of melanoma therapies and also, cancer vaccines are another approach for the treatment of melanoma that has already improved clinical outcomes in these patients. The use of antibodies and gene vaccines provides a new perspective in melanoma treatment. Since the tumor microenvironment is another important factor for cancer progression and metastasis, in recent times, a mechanism has been identified to provide an opportunity for melanoma cells to communicate with remote cells. This mechanism is involved by a novel molecular structure, named extracellular vesicles (EVs). Depending on the functional status of origin cells, exosomes contain various cargos and different compositions. In this review, we presented recent progress of exosome applications in the treatment of melanoma. Different aspects of exosome therapy and ongoing efforts in this field will be discussed too.
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Affiliation(s)
- Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Ali Azargoonjahromi
- Department of Nursing, School of Nursing and Midwifery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nafiseh Jafari
- Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maryam Mehdi
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Fatemeh Alavi
- Department of Pathobiology, Faculty of Specialized Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mona Daraei
- Pharmacy School, Ahvaz Jundishapour University of Medical Sciences, Ahvaz, Iran
| | - Niloufar Mohammadkhani
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, 1985717443, Tehran, Iran
| | - Anna-Lena Mueller
- Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Faculty of Medicine, Institute of Anatomy, Ludwig-Maximilian-University Munich, 80336, Munich, Germany
| | - Aranka Brockmueller
- Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Faculty of Medicine, Institute of Anatomy, Ludwig-Maximilian-University Munich, 80336, Munich, Germany
| | - Mehdi Shakibaei
- Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Faculty of Medicine, Institute of Anatomy, Ludwig-Maximilian-University Munich, 80336, Munich, Germany.
| | - Zahra Payandeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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28
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Grangier A, Branchu J, Volatron J, Piffoux M, Gazeau F, Wilhelm C, Silva AKA. Technological advances towards extracellular vesicles mass production. Adv Drug Deliv Rev 2021; 176:113843. [PMID: 34147532 DOI: 10.1016/j.addr.2021.113843] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/29/2021] [Accepted: 06/15/2021] [Indexed: 12/13/2022]
Abstract
Extracellular vesicles (EVs) are becoming essential actors in bio-therapeutics, as much for their regenerative or immunomodulatory properties as for their potential as cargo delivery vehicles. To enable the democratization of these EV-based therapies, many challenges remain such as large-scale production which is necessary to reduce costs of treatment. Herein, we review some advanced works on high-yield EV manufacturing. One approach consists in developing large-scale cell culture platforms, while others focus on cell stimulation to increase particle yield per cell. This can be done by moderate physico-chemical stresses or by disrupting cell membrane towards autoassembled vesicle-like particles. We critically compare these different techniques, keeping in mind that the field still lacks shared characterization standards, underline the importance of therapeutic potency assessment and discuss mass production strategies that have been identified in current clinical trials.
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Affiliation(s)
- Alice Grangier
- Laboratoire MSC Matière et Systèmes Complexes, CNRS UMR 7057, Université de Paris, 75013 and 75006 Paris, France
| | | | | | - Max Piffoux
- Laboratoire MSC Matière et Systèmes Complexes, CNRS UMR 7057, Université de Paris, 75013 and 75006 Paris, France; Everzom, 75006 Paris, France; Department of Medical Oncology, Centre Léon Bérard, Lyon, France
| | - Florence Gazeau
- Laboratoire MSC Matière et Systèmes Complexes, CNRS UMR 7057, Université de Paris, 75013 and 75006 Paris, France
| | - Claire Wilhelm
- Laboratoire MSC Matière et Systèmes Complexes, CNRS UMR 7057, Université de Paris, 75013 and 75006 Paris, France; Laboratoire PhysicoChimie Curie, Institut Curie, PSL Research University - Sorbonne Université - CNRS, 75005 Paris, France.
| | - Amanda K A Silva
- Laboratoire MSC Matière et Systèmes Complexes, CNRS UMR 7057, Université de Paris, 75013 and 75006 Paris, France.
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29
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Panda B, Sharma Y, Gupta S, Mohanty S. Mesenchymal Stem Cell-Derived Exosomes as an Emerging Paradigm for Regenerative Therapy and Nano-Medicine: A Comprehensive Review. Life (Basel) 2021; 11:life11080784. [PMID: 34440528 PMCID: PMC8399916 DOI: 10.3390/life11080784] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 01/08/2023] Open
Abstract
Mesenchymal Stem Cells are potent therapeutic candidates in the field of regenerative medicine, owing to their immunomodulatory and differentiation potential. However, several complications come with their translational application like viability, duration, and degree of expansion, long-term storage, and high maintenance cost. Therefore, drawbacks of cell-based therapy can be overcome by a novel therapeutic modality emerging in translational research and application, i.e., exosomes. These small vesicles derived from mesenchymal stem cells are emerging as new avenues in the field of nano-medicine. These nano-vesicles have caught the attention of researchers with their potency as regenerative medicine both in nanotherapeutics and drug delivery systems. In this review, we discuss the current knowledge in the biology and handling of exosomes, with their limitations and future applications. Additionally, we highlight current perspectives that primarily focus on their effect on various diseases and their potential as a drug delivery vehicle.
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30
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Patel N, Chin DD, Chung EJ. Exosomes in Atherosclerosis, a Double-Edged Sword: Their Role in Disease Pathogenesis and Their Potential as Novel Therapeutics. AAPS JOURNAL 2021; 23:95. [PMID: 34312734 DOI: 10.1208/s12248-021-00621-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 06/29/2021] [Indexed: 12/23/2022]
Abstract
Cardiovascular disease (CAD) due to atherosclerosis is a major cause of death worldwide. The development of atherosclerosis involves intercellular communication facilitated by exosomes secreted from vascular endothelial cells (VECs), vascular smooth muscle cells (VSMCs), immune cells, and platelets. In this review, we summarize the current understanding of exosome biogenesis and uptake, and discuss atherogenic and atheroprotective functions of exosomes secreted from these cell types. In addition, we examine the potential of enhancing the therapeutic and targeting ability of exosomes exhibiting atheroprotective function by drug loading and surface modification with targeting ligands. We conclude with current challenges associated with exosome engineering for therapeutic use.
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Affiliation(s)
- Neil Patel
- Department of Biomedical Engineering, University of Southern California, 1042 Downey Way, DRB 140, California, Los Angeles, 90089, USA
| | - Deborah D Chin
- Department of Biomedical Engineering, University of Southern California, 1042 Downey Way, DRB 140, California, Los Angeles, 90089, USA
| | - Eun Ji Chung
- Department of Biomedical Engineering, University of Southern California, 1042 Downey Way, DRB 140, California, Los Angeles, 90089, USA. .,Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Keck School of Medicine, University of Southern California, California, Los Angeles, 90033, USA. .,Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, California, Los Angeles, 90089, USA. .,Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, California, Los Angeles, 90033, USA.
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31
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Mishra A, Singh P, Qayoom I, Prasad A, Kumar A. Current strategies in tailoring methods for engineered exosomes and future avenues in biomedical applications. J Mater Chem B 2021; 9:6281-6309. [PMID: 34286815 DOI: 10.1039/d1tb01088c] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Exosomes are naturally occurring nanovesicles of endosomal origin, responsible for cellular communication. Depending on the cell type, exosomes display disparity in the cargo and are involved in up/down regulation of different biological pathways. Naturally secreted exosomes, owing to their inherent delivery potential, non-immunogenic nature and limited structural resemblance to the cells have emerged as ideal candidates for various drug delivery and therapeutic applications. Moreover, the structural versatility of exosomes provides greater flexibility for surface modifications to be made in the native configuration, by different methods, like genetic-engineering, chemical procedures, physical methods and microfluidic-technology, to enhance the cargo quality for expanded biomedical applications. Post isolation and prior to engineering exosomes for various applications, the internal and external structural compositions of exosomes are studied via different techniques. Efficiency and scalability of the exosome modification methods are pivotal in determining the scope of the technique for clinical applications. This review majorly focuses on different methods employed for engineering exosomes, and advantages/disadvantages associated with different tailoring approaches, along with the efficacy of engineered exosomes in biomedical applications. Further, the review highlights the importance of a relatively recent avenue for delivery of exosomes via scaffold-based delivery of naïve/engineered exosomes for regenerative medicine and tissue engineering. This review is based on the recent knowledge generated in this field and our comprehension in this domain.
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Affiliation(s)
- Ankita Mishra
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur-208016, UP, India.
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32
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Zhu D, Fang H, Kusuma GD, Schwab R, Barabadi M, Chan ST, McDonald H, Leong CM, Wallace EM, Greening DW, Lim R. Impact of chemically defined culture media formulations on extracellular vesicle production by amniotic epithelial cells. Proteomics 2021; 21:e2000080. [PMID: 34081834 DOI: 10.1002/pmic.202000080] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 05/27/2021] [Accepted: 05/28/2021] [Indexed: 02/06/2023]
Abstract
The therapeutic properties of cell derived extracellular vesicles (EVs) make them promising cell-free alternative to regenerative medicine. However, clinical translation of this technology relies on the ability to manufacture EVs in a scalable, reproducible, and cGMP-compliant manner. To generate EVs in sufficient quantity, a critical step is the selection and development of culture media, where differences in formulation may influence the EV manufacturing process. In this study, we used human amniotic epithelial cells (hAECs) as a model system to explore the effect of different formulations of chemically defined, commercially sourced media on EV production. Here, we determined that cell viability and proliferation rate are not reliable quality indicators for EV manufacturing. The levels of tetraspanins and epitope makers of EVs were significantly impacted by culture media formulations. Mass spectrometry-based proteomic profiling revealed proteome composition of hAEC-EVs and the influence of media formulations on composition of EV proteome. This study has revealed critical aspects including cell viability and proliferation rate, EV yield, and tetraspanins, surface epitopes and proteome composition of EVs influenced by media formulations, and further insight into standardised EV production culture media that should be considered in clinical-grade scalable EV manufacture for generation of therapeutic EVs.
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Affiliation(s)
- Dandan Zhu
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
| | - Haoyun Fang
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Gina D Kusuma
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
| | - Renate Schwab
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
| | - Mehri Barabadi
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
| | - Siow Teng Chan
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
| | - Hannah McDonald
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
| | - Cheng Mee Leong
- Thermo Fisher Scientific Australia Pty Ltd, Scoresby, Victoria, Australia
| | - Euan M Wallace
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
| | - David W Greening
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.,Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia.,Central Clinical School, Monash University, Clayton, Victoria, Australia.,Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Victoria, Australia
| | - Rebecca Lim
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
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33
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Park DJ, Seo YJ. Engineering of Extracellular Vesicles Based on Payload Changes for Tissue Regeneration. Tissue Eng Regen Med 2021; 18:485-497. [PMID: 34050888 DOI: 10.1007/s13770-021-00349-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/14/2021] [Accepted: 04/19/2021] [Indexed: 12/20/2022] Open
Abstract
In the field of tissue regeneration and tissue engineering, many years ago, various nano to macroscopic-sized materials have been used to reduce inflammation and restore damaged tissue. Whether it is safe to study the regeneration of all tissues based on the biological mechanisms of an organism composed of cells is still debated, and studies using extracellular vesicles derived from cells have become popular in the past decade. It has been reported that exosomes with a size of 100 nm or less, which plays an important role in cell-cell communication, contain various factors, such as proliferation, anti-inflammatory, and growth factors. In addition, the payload of exosomes varies depending on the parent cell and the recipient cell, and a technology to differentiate the selective payload must treat specific diseases. In this review, we examined the current trends in research using exosomes derived from cells or tissues and analyzed various research reports on factors that can affect tissue regeneration.
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Affiliation(s)
- Dong Jun Park
- Department of Surgery, University of California San Diego, 212 Dickinson Street, MC 8236, San Diego, CA, 92103, USA.,Department of Otorhinolaryngology, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do, 26426, South Korea.,Research Institute of Hearing Enhancement, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do, 26426, South Korea
| | - Young Joon Seo
- Department of Otorhinolaryngology, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do, 26426, South Korea. .,Research Institute of Hearing Enhancement, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do, 26426, South Korea. .,School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, WA, Australia.
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34
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Gurunathan S, Kang MH, Qasim M, Khan K, Kim JH. Biogenesis, Membrane Trafficking, Functions, and Next Generation Nanotherapeutics Medicine of Extracellular Vesicles. Int J Nanomedicine 2021; 16:3357-3383. [PMID: 34040369 PMCID: PMC8140893 DOI: 10.2147/ijn.s310357] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 04/25/2021] [Indexed: 12/15/2022] Open
Abstract
Extracellular vesicles (EVs) are a heterogeneous group of membrane-limited vesicles and multi-signal messengers loaded with biomolecules. Exosomes and ectosomes are two different types of EVs generated by all cell types. Their formation depends on local microdomains assembled in endocytic membranes for exosomes and in the plasma membrane for ectosomes. Further, EV release is a fundamental process required for intercellular communication in both normal physiology and pathological conditions to transmit/exchange bioactive molecules to recipient cells and the extracellular environment. The unique structure and composition of EVs enable them to serve as natural nanocarriers, and their physicochemical properties and biological functions can be used to develop next-generation nano and precision medicine. Knowledge of the cellular processes that govern EVs biology and membrane trafficking is essential for their clinical applications. However, in this rapidly expanding field, much remains unknown regarding EV origin, biogenesis, cargo sorting, and secretion, as well as EV-based theranostic platform generation. Hence, we present a comprehensive overview of the recent advances in biogenesis, membrane trafficking, and functions of EVs, highlighting the impact of nanoparticles and oxidative stress on EVs biogenesis and release and finally emphasizing the role of EVs as nanotherapeutic agents.
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Affiliation(s)
- Sangiliyandi Gurunathan
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, 05029, Korea
| | - Min-Hee Kang
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, 05029, Korea
| | - Muhammad Qasim
- Center of Bioengineering and Nanomedicine, Department of Food Science, University of Otago, Dunedin, 9054, New Zealand
| | - Khalid Khan
- Science and Technology KPK, Peshawar, Pakistan
| | - Jin-Hoi Kim
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, 05029, Korea
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35
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Emam SE, Elsadek NE, Abu Lila AS, Takata H, Kawaguchi Y, Shimizu T, Ando H, Ishima Y, Ishida T. Anti-PEG IgM production and accelerated blood clearance phenomenon after the administration of PEGylated exosomes in mice. J Control Release 2021; 334:327-334. [PMID: 33957196 DOI: 10.1016/j.jconrel.2021.05.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 04/30/2021] [Accepted: 05/02/2021] [Indexed: 12/18/2022]
Abstract
Recently, there is an increasing interest in exosomes or extracellular vesicles as potential candidates for delivering RNAs, proteins, genes, and anticancer agents. Engineering of exosome properties is rapidly evolving as a means of expanding exosome applications. PEGylation of exosomes is a technique used to improve their in vivo stability, circulation half-lives, and sometimes to allow the binding targeting ligands to the exosome exterior. According to FDA guidelines for the development of PEGylated proteins, immunological responses to PEGylated molecules and particles should be examined. In this study, we prepared PEGylated exosomes and investigated the production of anti-PEG IgM antibodies after single i.v. injections in mice. In addition, we monitored blood concentrations and tumor accumulation of a second dose of PEGylated exosomes administered after the initial dose. Single injections of PEGylated exosomes in mice induced anti-PEG IgM production in a T cell-dependent manner. The anti-PEG IgM production decreased when the injection dose of PEGylated exosomes was further increased. Anti-PEG IgM induced by injection of PEGylated exosomes decreased blood concentrations of a second dose of PEGylated exosomes and suppressed their tumor accumulation in a C26 murine colorectal cancer model. Initial injection doses of either PEGylated liposomes or PEGylated ovalbumin (PEG-OVA), both of them induced anti-PEG IgM production, also decreased the blood concentration of PEGylated exosomes. Interestingly, anti-PEG IgM induced by injection of PEGylated exosomes did not affect the blood concentration of PEG-OVA. These results imply the importance of monitoring anti-PEG IgM when repeat PEGylated exosome doses are required and/or when PEGylated exosomes are used together with other PEGylated therapeutics.
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Affiliation(s)
- Sherif E Emam
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima 770-8505, Japan; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
| | - Nehal E Elsadek
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
| | - Amr S Abu Lila
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; Department of Pharmaceutics, College of Pharmacy, Hail University, Hail 81442, Saudi Arabia
| | - Haruka Takata
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
| | - Yoshino Kawaguchi
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
| | - Taro Shimizu
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
| | - Hidenori Ando
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
| | - Yu Ishima
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
| | - Tatsuhiro Ishida
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima 770-8505, Japan.
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36
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Gurunathan S, Kang MH, Jeyaraj M, Kim JH. Palladium Nanoparticle-Induced Oxidative Stress, Endoplasmic Reticulum Stress, Apoptosis, and Immunomodulation Enhance the Biogenesis and Release of Exosome in Human Leukemia Monocytic Cells (THP-1). Int J Nanomedicine 2021; 16:2849-2877. [PMID: 33883895 PMCID: PMC8055296 DOI: 10.2147/ijn.s305269] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 03/11/2021] [Indexed: 12/23/2022] Open
Abstract
Background Exosomes are endosome-derived nano-sized vesicles that have emerged as important mediators of intercellular communication and play significant roles in various diseases. However, their applications are rigorously restricted by the limited secretion competence of cells. Therefore, strategies to enhance the production and functions of exosomes are warranted. Studies have shown that nanomaterials can significantly enhance the effects of cells and exosomes in intercellular communication; however, how palladium nanoparticles (PdNPs) enhance exosome release in human leukemia monocytic cells (THP-1) remains unclear. Therefore, this study aimed to address the effect of PdNPs on exosome biogenesis and release in THP-1 cells. Methods Exosomes were isolated by ultracentrifugation and ExoQuickTM and characterized by dynamic light scattering, nanoparticle tracking analysis system, scanning electron microscopy, transmission electron microscopy, EXOCETTM assay, and fluorescence polarization. The expression levels of exosome markers were analyzed via quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Results PdNP treatment enhanced the biogenesis and release of exosomes by inducing oxidative stress, endoplasmic reticulum stress, apoptosis, and immunomodulation. The exosomes were spherical in shape and had an average diameter of 50–80 nm. Exosome production was confirmed via total protein concentration, exosome counts, acetylcholinesterase activity, and neutral sphingomyelinase activity. The expression levels of TSG101, CD9, CD63, and CD81 were significantly higher in PdNP-treated cells than in control cells. Further, cytokine and chemokine levels were significantly higher in exosomes isolated from PdNP-treated THP-1 cells than in those isolated from control cells. THP-1 cells pre-treated with N-acetylcysteine or GW4869 showed significant decreases in PdNP-induced exosome biogenesis and release. Conclusion To our knowledge, this is the first study showing that PdNPs stimulate exosome biogenesis and release and simultaneously increase the levels of cytokines and chemokines by modulating various physiological processes. Our findings suggest a reasonable approach to improve the production of exosomes for various therapeutic applications.
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Affiliation(s)
| | - Min-Hee Kang
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, Korea
| | - Muniyandi Jeyaraj
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, Korea
| | - Jin-Hoi Kim
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, Korea
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37
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Ou YH, Zou S, Goh WJ, Wang JW, Wacker M, Czarny B, Pastorin G. Cell-Derived Nanovesicles as Exosome-Mimetics for Drug Delivery Purposes: Uses and Recommendations. Methods Mol Biol 2021; 2211:147-170. [PMID: 33336276 DOI: 10.1007/978-1-0716-0943-9_11] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2023]
Abstract
Cell-derived Drug Delivery Systems (DDSs), particularly exosomes, have grown in popularity and have been increasingly explored as novel DDSs, due to their intrinsic targeting capabilities. However, clinical translation of exosomes is impeded by the tedious isolation procedures and poor yield. Cell-derived nanovesicles (CDNs) have recently been produced and proposed as exosome-mimetics. Various methods for producing exosome-mimetics have been developed. In this chapter, we present a simple, efficient, and cost-effective CDNs production method that uses common laboratory equipment (microcentrifuge) and spin cups. Through a series of extrusion and size exclusion steps, CDNs are produced from in vitro cell culture and are found to highly resemble the endogenous exosomes. Thus, we envision that this strategy holds great potential as a viable alternative to exosomes in the development of ideal DDS.
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Affiliation(s)
- Yi-Hsuan Ou
- Department of Pharmacy, National University of Singapore, Singapore, Singapore
| | - Shui Zou
- Department of Pharmacy, National University of Singapore, Singapore, Singapore
| | - Wei Jiang Goh
- Department of Pharmacy, National University of Singapore, Singapore, Singapore
- NUS Graduate School for Integrative Sciences and Engineering, Centre for Life Sciences (CeLS), Singapore, Singapore
| | - Jiong-Wei Wang
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cardiovascular Research Institute, National University Heart Centre, Singapore, Singapore
| | - Matthias Wacker
- Department of Pharmacy, National University of Singapore, Singapore, Singapore
| | - Bertrand Czarny
- School of Materials Science and Engineering, Nanyang Technological University, Singapore, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Giorgia Pastorin
- Department of Pharmacy, National University of Singapore, Singapore, Singapore.
- NUS Graduate School for Integrative Sciences and Engineering, Centre for Life Sciences (CeLS), Singapore, Singapore.
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38
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Gaurav I, Thakur A, Iyaswamy A, Wang X, Chen X, Yang Z. Factors Affecting Extracellular Vesicles Based Drug Delivery Systems. Molecules 2021; 26:molecules26061544. [PMID: 33799765 PMCID: PMC7999478 DOI: 10.3390/molecules26061544] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 02/18/2021] [Accepted: 02/19/2021] [Indexed: 02/07/2023] Open
Abstract
Extracellular vesicles (EVs) play major roles in intracellular communication and participate in several biological functions in both normal and pathological conditions. Surface modification of EVs via various ligands, such as proteins, peptides, or aptamers, offers great potential as a means to achieve targeted delivery of therapeutic cargo, i.e., in drug delivery systems (DDS). This review summarizes recent studies pertaining to the development of EV-based DDS and its advantages compared to conventional nano drug delivery systems (NDDS). First, we compare liposomes and exosomes in terms of their distinct benefits in DDS. Second, we analyze what to consider for achieving better isolation, yield, and characterization of EVs for DDS. Third, we summarize different methods for the modification of surface of EVs, followed by discussion about different origins of EVs and their role in developing DDS. Next, several major methods for encapsulating therapeutic cargos in EVs have been summarized. Finally, we discuss key challenges and pose important open questions which warrant further investigation to develop more effective EV-based DDS.
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Affiliation(s)
- Isha Gaurav
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; (I.G.); (A.I.); (X.W.); (X.C.)
| | - Abhimanyu Thakur
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation-CAS Limited, Hong Kong, China;
| | - Ashok Iyaswamy
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; (I.G.); (A.I.); (X.W.); (X.C.)
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson’s Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Xuehan Wang
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; (I.G.); (A.I.); (X.W.); (X.C.)
| | - Xiaoyu Chen
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; (I.G.); (A.I.); (X.W.); (X.C.)
| | - Zhijun Yang
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; (I.G.); (A.I.); (X.W.); (X.C.)
- Changshu Research Institute, Hong Kong Baptist University, Changshu Economic and Technological Development (CETD) Zone, Changshu 215500, Jiangsu Province, China
- Correspondence: ; Tel.: +852-3411-2961
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39
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Lee JH, Yoon JY, Lee JH, Lee HH, Knowles JC, Kim HW. Emerging biogenesis technologies of extracellular vesicles for tissue regenerative therapeutics. J Tissue Eng 2021; 12:20417314211019015. [PMID: 34104388 PMCID: PMC8155774 DOI: 10.1177/20417314211019015] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 05/02/2021] [Indexed: 12/14/2022] Open
Abstract
Extracellular vesicles (EVs), including exosomes, carry the genetic packages of RNA, DNA, and proteins and are heavily involved in cell-cell communications and intracellular signalings. Therefore, EVs are spotlighted as therapeutic mediators for the treatment of injured and dysfunctional tissues as well as biomarkers for the detection of disease status and progress. Several key issues in EVs, including payload content and bioactivity, targeting and bio-imaging ability, and mass-production, need to be improved to enable effective therapeutics and clinical translation. For this, significant efforts have been made recently, including genetic modification, biomolecular and chemical treatment, application of physical/mechanical cues, and 3D cultures. Here we communicate those recent technological advances made mainly in the biogenesis process of EVs or at post-collection stages, which ultimately aimed to improve the therapeutic efficacy in tissue healing and disease curing and the possibility of clinical translation. This communication will help tissue engineers and biomaterial scientists design and produce EVs optimally for tissue regenerative therapeutics.
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Affiliation(s)
- Jung-Hwan Lee
- Institute of Tissue Regeneration
Engineering (ITREN), Dankook University, Chungcheongnam-do, Cheonan, Republic of
Korea
- Department of Nanobiomedical Science
& BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook
University, Chungcheongnam-do, Cheonan, Republic of Korea
- Department of Biomaterials Science,
College of Dentistry, Dankook University, Chungcheongnam-do, Cheonan, Republic of
Korea
- Department of Regenerative Dental
Medicine, College of Dentistry, Dankook University, Chungcheongnam-do, Cheonan,
Republic of Korea
- Cell & Matter Institute, Dankook
University, Chungcheongnam-do, Cheonan, South Korea
- UCL Eastman-Korea Dental Medicine
Innovation Centre, Dankook University, Chungcheongnam-do, Cheonan, Republic of
Korea
| | - Ji-Young Yoon
- Institute of Tissue Regeneration
Engineering (ITREN), Dankook University, Chungcheongnam-do, Cheonan, Republic of
Korea
- Department of Nanobiomedical Science
& BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook
University, Chungcheongnam-do, Cheonan, Republic of Korea
| | - Jun Hee Lee
- Institute of Tissue Regeneration
Engineering (ITREN), Dankook University, Chungcheongnam-do, Cheonan, Republic of
Korea
- Department of Nanobiomedical Science
& BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook
University, Chungcheongnam-do, Cheonan, Republic of Korea
- Department of Regenerative Dental
Medicine, College of Dentistry, Dankook University, Chungcheongnam-do, Cheonan,
Republic of Korea
- Cell & Matter Institute, Dankook
University, Chungcheongnam-do, Cheonan, South Korea
- UCL Eastman-Korea Dental Medicine
Innovation Centre, Dankook University, Chungcheongnam-do, Cheonan, Republic of
Korea
| | - Hae-Hyoung Lee
- Institute of Tissue Regeneration
Engineering (ITREN), Dankook University, Chungcheongnam-do, Cheonan, Republic of
Korea
- Department of Biomaterials Science,
College of Dentistry, Dankook University, Chungcheongnam-do, Cheonan, Republic of
Korea
- UCL Eastman-Korea Dental Medicine
Innovation Centre, Dankook University, Chungcheongnam-do, Cheonan, Republic of
Korea
| | - Jonathan C Knowles
- UCL Eastman-Korea Dental Medicine
Innovation Centre, Dankook University, Chungcheongnam-do, Cheonan, Republic of
Korea
- Division of Biomaterials and Tissue
Engineering, Eastman Dental Institute, University College London, Royal Free
Hospital, London, UK
- The Discoveries Centre for Regenerative
and Precision Medicine, Eastman Dental Institute, University College London, London,
UK
| | - Hae-Won Kim
- Institute of Tissue Regeneration
Engineering (ITREN), Dankook University, Chungcheongnam-do, Cheonan, Republic of
Korea
- Department of Nanobiomedical Science
& BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook
University, Chungcheongnam-do, Cheonan, Republic of Korea
- Department of Biomaterials Science,
College of Dentistry, Dankook University, Chungcheongnam-do, Cheonan, Republic of
Korea
- Department of Regenerative Dental
Medicine, College of Dentistry, Dankook University, Chungcheongnam-do, Cheonan,
Republic of Korea
- Cell & Matter Institute, Dankook
University, Chungcheongnam-do, Cheonan, South Korea
- UCL Eastman-Korea Dental Medicine
Innovation Centre, Dankook University, Chungcheongnam-do, Cheonan, Republic of
Korea
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40
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Du Y, Du S, Liu L, Gan F, Jiang X, Wangrao K, Lyu P, Gong P, Yao Y. Radiation-Induced Bystander Effect can be Transmitted Through Exosomes Using miRNAs as Effector Molecules. Radiat Res 2020; 194:89-100. [PMID: 32343639 DOI: 10.1667/rade-20-00019.1] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 03/27/2020] [Indexed: 02/05/2023]
Abstract
The radiation-induced bystander effect (RIBE) is a destructive reaction in nonirradiated cells and is one primary factor in determining the efficacy and success of radiation therapy in the field of cancer treatment. Previously reported studies have shown that the RIBE can be mediated by exosomes that carry miRNA components within. Exosomes, which are one type of cell-derived vesicle, exist in different biological conditions and serve as an important additional pathway for signal exchange between cells. In addition, exosome-derived miRNAs are confirmed to play an important role in RIBE, activating the bystander effect and genomic instability after radiotherapy. After investigating the field of RIBE, it is important to understand the mechanisms and consequences of biological effects as well as the role of exosomes and exosomal miRNAs therein, from different sources and under different circumstances, respectively. More discoveries could help to establish early interventions against RIBE while improving the efficacy of radiotherapy. Meanwhile, measures that would alleviate or even inhibit RIBE to some extent may exist in the near future.
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Affiliation(s)
- Yu Du
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Shufang Du
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Liu Liu
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Operative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Feihong Gan
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xiaoge Jiang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Kaijuan Wangrao
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ping Lyu
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ping Gong
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yang Yao
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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41
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Klyachko NL, Arzt CJ, Li SM, Gololobova OA, Batrakova EV. Extracellular Vesicle-Based Therapeutics: Preclinical and Clinical Investigations. Pharmaceutics 2020; 12:E1171. [PMID: 33271883 PMCID: PMC7760239 DOI: 10.3390/pharmaceutics12121171] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 11/24/2020] [Accepted: 11/29/2020] [Indexed: 12/11/2022] Open
Abstract
Drug nanoformulations hold remarkable promise for the efficient delivery of therapeutics to a disease site. Unfortunately, artificial nanocarriers, mostly liposomes and polymeric nanoparticles, show limited applications due to the unfavorable pharmacokinetics and rapid clearance from the blood circulation by the reticuloendothelial system (RES). Besides, many of them have high cytotoxicity, low biodegradability, and the inability to cross biological barriers, including the blood brain barrier. Extracellular vesicles (EVs) are novel candidates for drug delivery systems with high bioavailability, exceptional biocompatibility, and low immunogenicity. They provide a means for intercellular communication and the transmission of bioactive compounds to targeted tissues, cells, and organs. These features have made them increasingly attractive as a therapeutic platform in recent years. However, there are many obstacles to designing EV-based therapeutics. In this review, we will outline the main hurdles and limitations for therapeutic and clinical applications of drug loaded EV formulations and describe various attempts to solve these problems.
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Affiliation(s)
- Natalia L. Klyachko
- Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (N.L.K.); (O.A.G.)
- Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (C.J.A.); (S.M.L.)
| | - Camryn J. Arzt
- Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (C.J.A.); (S.M.L.)
| | - Samuel M. Li
- Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (C.J.A.); (S.M.L.)
| | - Olesia A. Gololobova
- Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (N.L.K.); (O.A.G.)
- Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (C.J.A.); (S.M.L.)
| | - Elena V. Batrakova
- Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (N.L.K.); (O.A.G.)
- Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (C.J.A.); (S.M.L.)
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42
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Xu Z, Zeng S, Gong Z, Yan Y. Exosome-based immunotherapy: a promising approach for cancer treatment. Mol Cancer 2020; 19:160. [PMID: 33183286 PMCID: PMC7661275 DOI: 10.1186/s12943-020-01278-3] [Citation(s) in RCA: 314] [Impact Index Per Article: 62.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 11/03/2020] [Indexed: 02/08/2023] Open
Abstract
In the era of the rapid development of cancer immunotherapy, there is a high level of interest in the application of cell-released small vesicles that stimulate the immune system. As cell-derived nanovesicles, exosomes show great promise in cancer immunotherapy because of their immunogenicity and molecular transfer function. The cargoes carried on exosomes have been recently identified with improved technological advances and play functional roles in the regulation of immune responses. In particular, exosomes derived from tumor cells and immune cells exhibit unique composition profiles that are directly involved in anticancer immunotherapy. More importantly, exosomes can deliver their cargoes to targeted cells and thus influence the phenotype and immune-regulation functions of targeted cells. Accumulating evidence over the last decade has further revealed that exosomes can participate in multiple cellular processes contributing to cancer development and therapeutic effects, showing the dual characteristics of promoting and suppressing cancer. The potential of exosomes in the field of cancer immunotherapy is huge, and exosomes may become the most effective cancer vaccines, as well as targeted antigen/drug carriers. Understanding how exosomes can be utilized in immune therapy is important for controlling cancer progression; additionally, exosomes have implications for diagnostics and the development of novel therapeutic strategies. This review discusses the role of exosomes in immunotherapy as carriers to stimulate an anti-cancer immune response and as predictive markers for immune activation; furthermore, it summarizes the mechanism and clinical application prospects of exosome-based immunotherapy in human cancer.
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Affiliation(s)
- Zhijie Xu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Shuangshuang Zeng
- Department of Pharmacy, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China
| | - Zhicheng Gong
- Department of Pharmacy, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Yuanliang Yan
- Department of Pharmacy, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.
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43
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Ambattu LA, Ramesan S, Dekiwadia C, Hanssen E, Li H, Yeo LY. High frequency acoustic cell stimulation promotes exosome generation regulated by a calcium-dependent mechanism. Commun Biol 2020; 3:553. [PMID: 33020585 PMCID: PMC7536404 DOI: 10.1038/s42003-020-01277-6] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 09/07/2020] [Indexed: 02/07/2023] Open
Abstract
Exosomes are promising disease diagnostic markers and drug delivery vehicles, although their use in practice is limited by insufficient homogeneous quantities that can be produced. We reveal that exposing cells to high frequency acoustic irradiation stimulates their generation without detriment to cell viability by exploiting their innate membrane repair mechanism, wherein the enhanced recruitment of calcium ions from the extracellular milieu into the cells triggers an ESCRT pathway known to orchestrate exosomal production. Given the high post-irradiation cell viabilities (≈95%), we are able to recycle the cells through iterative irradiation and post-excitation incubation steps, which facilitate high throughput production of a homogeneous population of exosomes-a particular challenge for translating exosome therapy into clinical practice. In particular, we show that approximately eight- to ten-fold enrichment in the number of exosomes produced can be achieved with just 7 cycles over 280 mins, equivalent to a yield of around 1.7-2.1-fold/h.
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Affiliation(s)
- Lizebona August Ambattu
- Micro/Nanophysics Research Laboratory, School of Engineering, RMIT University, Melbourne, VIC, 3000, Australia
| | - Shwathy Ramesan
- Micro/Nanophysics Research Laboratory, School of Engineering, RMIT University, Melbourne, VIC, 3000, Australia
| | - Chaitali Dekiwadia
- RMIT Microscopy and Microanalysis Facility, RMIT University, Melbourne, VIC, 3000, Australia
| | - Eric Hanssen
- Advanced Microscopy Facility, Bio21 Molecular Science & Biotechnology Institute, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - Haiyan Li
- School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - Leslie Y Yeo
- Micro/Nanophysics Research Laboratory, School of Engineering, RMIT University, Melbourne, VIC, 3000, Australia.
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Jafari D, Malih S, Eini M, Jafari R, Gholipourmalekabadi M, Sadeghizadeh M, Samadikuchaksaraei A. Improvement, scaling-up, and downstream analysis of exosome production. Crit Rev Biotechnol 2020; 40:1098-1112. [PMID: 32772758 DOI: 10.1080/07388551.2020.1805406] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Exosomes are the most researched extracellular vesicles. In many biological, physiological, and pathological studies, they have been identified as suitable candidates for treatment and diagnosis of diseases by acting as the carriers of both drugs and genes. Considerable success has been achieved regarding the use of exosomes for tissue regeneration, cancer diagnosis, and targeted drug/gene delivery to specific tissues. While major progress has been made in exosome extraction and purification, extraction of large quantities of exosomes is still a major challenge. This issue limits the scope of both exosome-based research and therapeutic development. In this review, we have aimed to summarize experimental studies focused at increasing the number of exosomes. Biotechnological studies aimed at identifying the pathways of exosome biogenesis to manipulate some genes in order to increase the production of exosomes. Generally, two major strategies are employed to increase the production of exosomes. First, oogenesis pathways are genetically manipulated to overexpress activator genes of exosome biogenesis and downregulate the genes involved in exosome recycling pathways. Second, manipulation of the cell culture medium, treatment with specific drugs, and limiting certain conditions can force the cell to produce more exosomes. In this study, we have reviewed and categorized these strategies. It is hoped that the information presented in this review will provide a better understanding for expanding biotechnological approaches in exosome-based therapeutic development.
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Affiliation(s)
- Davod Jafari
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran.,Student Research Committee, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Sara Malih
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Maryam Eini
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Rasool Jafari
- Department of Medical Parasitology and Mycology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Mazaher Gholipourmalekabadi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.,Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Majid Sadeghizadeh
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ali Samadikuchaksaraei
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran.,Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.,Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
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45
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Srivastava A, Amreddy N, Pareek V, Chinnappan M, Ahmed R, Mehta M, Razaq M, Munshi A, Ramesh R. Progress in extracellular vesicle biology and their application in cancer medicine. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2020; 12:e1621. [PMID: 32131140 PMCID: PMC7317410 DOI: 10.1002/wnan.1621] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 01/15/2020] [Accepted: 01/29/2020] [Indexed: 12/11/2022]
Abstract
Under the broader category of extracellular vesicles (EVs), exosomes are now well recognized for their contribution and potential for biomedical research. During the last ten years, numerous technologies for purification and characterization of EVs have been developed. This enhanced knowledge has resulted in the development of novel applications of EVs. This review is an attempt to capture the exponential growth observed in EV science in the last decade and discuss the future potential to improve our understanding of EVs, develop technologies to overcome current limitations, and advance their utility for human benefit, especially in cancer medicine. This article is categorized under:
Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
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Affiliation(s)
- Akhil Srivastava
- Department of Pathology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Narsireddy Amreddy
- Department of Pathology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Vipul Pareek
- Department of Hematology and Oncology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Mahendran Chinnappan
- Department of Pathology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Rebaz Ahmed
- Department of Pathology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Meghna Mehta
- Department of Radiation Oncology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Mohammad Razaq
- Department of Hematology and Oncology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Anupama Munshi
- Department of Radiation Oncology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Rajagopal Ramesh
- Department of Pathology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
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46
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Abstract
As a nanoscale subset of extracellular vehicles, exosomes represent a new pathway of intercellular communication by delivering cargos such as proteins and nucleic acids to recipient cells. Importantly, it has been well documented that exosome-mediated delivery of such cargo is involved in many pathological processes such as tumor progression, cancer metastasis, and development of drug resistance. Innately biocompatible and possessing ideal structural properties, exosomes offer distinct advantages for drug delivery over artificial nanoscale drug carriers. In this review, we summarize recent progress in methods for engineering exosomes including isolation techniques and exogenous cargo encapsulation, with a focus on applications of engineered exosomes to target cancer metastasis.
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Affiliation(s)
- Zhenjiang Zhang
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37212 USA
| | - Jenna A. Dombroski
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37212 USA
| | - Michael R. King
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37212 USA
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47
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Emam SE, Abu Lila AS, Elsadek NE, Ando H, Shimizu T, Okuhira K, Ishima Y, Mahdy MA, Ghazy FES, Ishida T. Cancer cell-type tropism is one of crucial determinants for the efficient systemic delivery of cancer cell-derived exosomes to tumor tissues. Eur J Pharm Biopharm 2019; 145:27-34. [DOI: 10.1016/j.ejpb.2019.10.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 10/03/2019] [Accepted: 10/16/2019] [Indexed: 01/02/2023]
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48
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Fukuta T, Nishikawa A, Kogure K. Low level electricity increases the secretion of extracellular vesicles from cultured cells. Biochem Biophys Rep 2019; 21:100713. [PMID: 31828227 PMCID: PMC6889636 DOI: 10.1016/j.bbrep.2019.100713] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 10/31/2019] [Accepted: 11/22/2019] [Indexed: 01/01/2023] Open
Abstract
Exosomes, a type of extracellular vesicles, can be collected from the conditioned medium of cultured cells, and are expected to be used in disease therapy and drug delivery systems. However, since the yield of exosomes from conditioned medium is generally low, investigations to develop new methods to increase exosome secretion and to elucidate the secretion mechanism have been performed. Our previous studies demonstrated that activation of intracellular signaling including Rho GTPase and subsequent endocytosis of extraneous molecules in cells could be induced by low level electricity (0.3–0.5 mA/cm2). Since exosomes are produced in the process of endocytosis and secreted by exocytosis via certain signaling pathways, we hypothesized that low level electric treatment (ET) would increase exosome secretion from cultured cells via intracellular signaling activation. In the present study, the influence of ET (0.34 mA/cm2) on extracellular vesicle (EV) secretion from cultured cells was examined by using murine melanoma and murine fibroblast cells. The results showed that the number of EV particles collected by ultracentrifugation was remarkably increased by ET in both cell lines without cellular toxicity or changes in the particle distribution. Also, protein amounts of the collected EVs were significantly increased in both cells by ET without alteration of expression of representative exosome marker proteins. Moreover, in both cells, the ratio of particle numbers to protein amount was not significantly changed by ET. Rho GTPase inhibition significantly suppressed ET-mediated increase of EV secretion in murine melanoma, indicating that Rho GTPase activation could be involved in ET-mediated EV secretion in the cell. Additionally, there were almost no differences in uptake of each EV into each donor cell regardless of whether the cells had been exposed to ET for EV collection. Taken together, these results suggest that ET could increase EV secretion from both cancer and normal cells without apparent changes in EV quality.
Low level electric treatment (ET; 0.34 mA/cm2) increased exosome yield from cells. The number of exosome particles was increased by ET without distribution changes. ET increased protein amounts of the collected exosomes from conditioned media. ET did not induce cellular toxicity and change in exosomal marker protein expression. ET-mediated increase of exosome secretion occurred in both cancer and normal cells.
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Affiliation(s)
- Tatsuya Fukuta
- Department of Pharmaceutical Health Chemistry, Graduate School of Biomedical Sciences, Tokushima University, Shomachi 1, Tokushima, 770-8505, Japan
| | - Akina Nishikawa
- Department of Pharmaceutical Health Chemistry, Graduate School of Biomedical Sciences, Tokushima University, Shomachi 1, Tokushima, 770-8505, Japan
| | - Kentaro Kogure
- Department of Pharmaceutical Health Chemistry, Graduate School of Biomedical Sciences, Tokushima University, Shomachi 1, Tokushima, 770-8505, Japan
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49
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Woith E, Fuhrmann G, Melzig MF. Extracellular Vesicles-Connecting Kingdoms. Int J Mol Sci 2019; 20:E5695. [PMID: 31739393 PMCID: PMC6888613 DOI: 10.3390/ijms20225695] [Citation(s) in RCA: 175] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 11/09/2019] [Accepted: 11/12/2019] [Indexed: 12/11/2022] Open
Abstract
It is known that extracellular vesicles (EVs) are shed from cells of almost every type of cell or organism, showing their ubiquity in all empires of life. EVs are defined as naturally released particles from cells, delimited by a lipid bilayer, and cannot replicate. These nano- to micrometer scaled spheres shuttle a set of bioactive molecules. EVs are of great interest as vehicles for drug targeting and in fundamental biological research, but in vitro culture of animal cells usually achieves only small yields. The exploration of other biological kingdoms promises comprehensive knowledge on EVs broadening the opportunities for basic understanding and therapeutic use. Thus, plants might be sustainable biofactories producing nontoxic and highly specific nanovectors, whereas bacterial and fungal EVs are promising vaccines for the prevention of infectious diseases. Importantly, EVs from different eukaryotic and prokaryotic kingdoms are involved in many processes including host-pathogen interactions, spreading of resistances, and plant diseases. More extensive knowledge of inter-species and interkingdom regulation could provide advantages for preventing and treating pests and pathogens. In this review, we present a comprehensive overview of EVs derived from eukaryota and prokaryota and we discuss how better understanding of their intercommunication role provides opportunities for both fundamental and applied biology.
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Affiliation(s)
- Eric Woith
- Institute of Pharmacy, Pharmaceutical Biology, Dahlem Center of Plant Sciences, Freie Universität Berlin, Königin-Luise-Str. 2+4, D-14195 Berlin, Germany;
| | - Gregor Fuhrmann
- Helmholtz Centre for Infection Research (HZI), Biogenic Nanotherapeutics Group (BION), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus E8.1, 66123 Saarbrücken, Germany
- Department of Pharmacy, Saarland University, Campus E8.1, 66123 Saarbrücken, Germany
| | - Matthias F. Melzig
- Institute of Pharmacy, Pharmaceutical Biology, Dahlem Center of Plant Sciences, Freie Universität Berlin, Königin-Luise-Str. 2+4, D-14195 Berlin, Germany;
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50
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Mohammadi S, Yousefi F, Shabaninejad Z, Movahedpour A, Mahjoubin Tehran M, Shafiee A, Moradizarmehri S, Hajighadimi S, Savardashtaki A, Mirzaei H. Exosomes and cancer: From oncogenic roles to therapeutic applications. IUBMB Life 2019; 72:724-748. [PMID: 31618516 DOI: 10.1002/iub.2182] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 09/23/2019] [Indexed: 12/11/2022]
Abstract
Exosomes belong to extracellular vehicles that were produced and secreted from most eukaryotic cells and are involved in cell-to-cell communications. They are an effective delivery system for biological compounds such as mRNAs, microRNAs (miRNAs), proteins, lipids, saccharides, and other physiological compounds to target cells. In this way, they could influence on cellular pathways and mediate their physiological behaviors including cell proliferation, tumorigenesis, differentiation, and so on. Many research studies focused on their role in cancers and also on potentially therapeutic and biomarker applications. In the current study, we reviewed the exosomes' effects on cancer progression based on their cargoes including miRNAs, long noncoding RNAs, circular RNAs, DNAs, mRNAs, proteins, and lipids. Moreover, their therapeutic roles in cancer were considered. In this regard, we have given a brief overview of challenges and obstacles in using exosomes as therapeutic agents.
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Affiliation(s)
- Soheila Mohammadi
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fatemeh Yousefi
- Department of Biological Sciences, Faculty of Genetics, Tarbiat Modares University, Tehran, Iran
| | - Zahra Shabaninejad
- Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.,Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ahmad Movahedpour
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.,Student Research Committee, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maryam Mahjoubin Tehran
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alimohammad Shafiee
- Division of General Internal Medicine, Toronto General Hospital, Toronto, Canada
| | - Sanaz Moradizarmehri
- Division of General Internal Medicine, Toronto General Hospital, Toronto, Canada
| | - Sarah Hajighadimi
- Division of General Internal Medicine, Toronto General Hospital, Toronto, Canada
| | - Amir Savardashtaki
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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