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Ruan J, Xia Y, Ma Y, Xu X, Luo S, Yi J, Wu B, Chen R, Wang H, Yu H, Yang Q, Wu W, Sun D, Zhong J. Milk-derived exosomes as functional nanocarriers in wound healing: Mechanisms, applications, and future directions. Mater Today Bio 2025; 32:101715. [PMID: 40242483 PMCID: PMC12003018 DOI: 10.1016/j.mtbio.2025.101715] [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: 02/06/2025] [Revised: 03/22/2025] [Accepted: 03/28/2025] [Indexed: 04/18/2025] Open
Abstract
Wound healing presents a significant challenge in healthcare, imposing substantial physiological and economic burdens. While traditional treatments and stem cell therapies have shown benefits, milk-derived exosomes (MDEs) offer distinct advantages as a cell-free therapeutic approach. MDEs, isolated from mammalian milk, are characterized by their biocompatibility, ease of acquisition, and high yield, making them a promising tool for enhancing wound repair. This review provides a comprehensive analysis of the composition, sources, and extraction methods of MDEs, with a focus on their therapeutic role in both acute and diabetic chronic wounds. MDEs facilitate wound healing through the delivery of bioactive molecules, modulating key processes such as inflammation, angiogenesis, and collagen synthesis. Their ability to regulate complex wound-healing pathways underscores their potential for widespread clinical application. This review highlights the importance of MDEs in advancing wound management and proposes strategies to optimize their use in regenerative medicine.
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Affiliation(s)
- Jing Ruan
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Yuping Xia
- Department of Burn and Plastic Surgery, Zigong Fourth People's Hospital, Zigong 643099, China
| | - Yilei Ma
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Xiyao Xu
- Department of Burn and Plastic Surgery, Zigong Fourth People's Hospital, Zigong 643099, China
| | - Shihao Luo
- Department of Burn and Plastic Surgery, Zigong Fourth People's Hospital, Zigong 643099, China
| | - Jia Yi
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Baihui Wu
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Rongbing Chen
- Department of Biomedical Engineering, City University of Hong Kong, 999077, Hong Kong Special Administrative Region of China
| | - Hanbing Wang
- Department of Biotechnology, The University of Hong Kong, 999077, Hong Kong Special Administrative Region of China
| | - Honggang Yu
- Hand and Foot Surgery, The Affiliated Yiwu Hospital of Wenzhou Medical University, Yiwu 322000, China
| | - Qinsi Yang
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, China
| | - Wei Wu
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, Bioengineering College of Chongqing University, Chongqing 400044, China
- Jin Feng Laboratory, Chongqing, 401329, China
| | - Da Sun
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Junbo Zhong
- Department of Burn and Plastic Surgery, Zigong Fourth People's Hospital, Zigong 643099, China
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Cohen MJ, Philippe B, Lipke PN. Endocytic tethers modulate unconventional GAPDH secretion. Cell Surf 2025; 13:100138. [PMID: 39830088 PMCID: PMC11742311 DOI: 10.1016/j.tcsw.2024.100138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 12/16/2024] [Accepted: 12/20/2024] [Indexed: 01/22/2025] Open
Abstract
Yeast cell walls contain both classically-secreted and unconventionally-secreted proteins. The latter class lacks the signal sequence for translocation into the ER, therefore these proteins are transported to the wall by uncharacterized mechanisms. One such protein is the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) which is abundant in the cytosol, but also found in the yeast cell wall where it is enzymatically active. We screened diploid Saccharomyces cerevisiae homozygous gene deletions for changes in cell wall GAPDH activity. Deletions targeting endocytic tethers in the endolysosomal system had the largest effects on GAPDH secretion, including vps21, bro1, vps41, and pep12. The predominant GAPDH isoform Tdh3 was partially localized to endolysosomal compartments, including multivesicular bodies, which are common entry points to unconventional protein secretion pathways. Yeast lacking the endosomal Rab5-GTPase Vps21 had defects in GAPDH secretion as well as delayed entry into to the endolysosomal compartments. Therefore, we conclude that entry into the endolysosomal compartment facilitates non-conventional secretion of GAPDH.
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Affiliation(s)
- Michael J. Cohen
- Biology Department, Brooklyn College of the City University of New York, Brooklyn, NY 11210, USA
- The Graduate Center of the City University of New York, New York, NY 10016, USA
| | - Brianne Philippe
- Biology Department, Brooklyn College of the City University of New York, Brooklyn, NY 11210, USA
| | - Peter N. Lipke
- Biology Department, Brooklyn College of the City University of New York, Brooklyn, NY 11210, USA
- The Graduate Center of the City University of New York, New York, NY 10016, USA
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Nochalabadi A, Khazaei M, Rezakhani L. Exosomes and tissue engineering: A novel therapeutic strategy for nerve regenerative. Tissue Cell 2025; 93:102676. [PMID: 39693896 DOI: 10.1016/j.tice.2024.102676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 11/10/2024] [Accepted: 12/06/2024] [Indexed: 12/20/2024]
Abstract
Damage to nerves negatively impacts quality of life and causes considerable morbidity. Self-regeneration is a special characteristic of the nervous system, yet how successful regeneration is accomplished remains unclear. Research on nerve regeneration is advancing and accelerating successful nerve recovery with potential new approaches. Eukaryote cells release extracellular vesicles (EVs), which control intercellular communication in both health and disease. More and more, EVs such as microvesicles and exosomes (EXOs) are being recognized as viable options for cell-free therapies that address complex tissue regeneration. The present study highlights the functional relevance of EVs in regenerative medicine for nerve-related regeneration. A subclass of EVs, EXOs were first identified as a way for cells to expel undesirable cell products. These nanovesicles have a diameter of 30-150 nm and are secreted by a variety of cells in conditions of both health and illness. Their benefits include the ability to promote endothelial cell growth, inhibit inflammation, encourage cell proliferation, and regulate cell differentiation. They are also known to transport functional proteins, metabolites, and nucleic acids to recipient cells, thus playing a significant role in cellular communication. EXOs impact an extensive array of physiological functions, including immunological responses, tissue regeneration, stem cell conservation, communication within the central nervous system, and pathological processes involving cardiovascular disorders, neurodegeneration, cancer, and inflammation. Their biocompatibility and bi-layered lipid structure (which shields the genetic consignment from deterioration and reduces immunogenicity) make them appealing as therapeutic vectors. They can pass through the blood brain barrier and other major biological membranes because of their small size and membrane composition. The creation of modified EXOs is a dynamic area of research that supports the evaluation of diverse therapeutic freights, improvement of target selectivity, and manufacturing optimization.
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Affiliation(s)
- Azadeh Nochalabadi
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mozafar Khazaei
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran; Department of Tissue Engineering, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Leila Rezakhani
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran; Department of Tissue Engineering, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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Chen X, Liu S, Wang H, Liu Y, Xiao Y, Li K, Ni F, Wu W, Lin H, Qing X, Pu F, Wang B, Shao Z, Peng Y. Extracellular vesicles deliver thioredoxin to rescue stem cells from senescence and intervertebral disc degeneration via a feed-forward circuit of the NRF2/AP-1 composite pathway. Acta Pharm Sin B 2025; 15:1007-1022. [PMID: 40177564 PMCID: PMC11959923 DOI: 10.1016/j.apsb.2024.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 07/01/2024] [Accepted: 07/26/2024] [Indexed: 04/05/2025] Open
Abstract
Intervertebral disc degeneration (IDD) is largely attributed to impaired endogenous repair. Nucleus pulposus-derived stem cells (NPSCs) senescence leads to endogenous repair failure. Small extracellular vesicles/exosomes derived from mesenchymal stem cells (mExo) have shown great therapeutic potential in IDD, while whether mExo could alleviate NPSCs senescence and its mechanisms remained unknown. We established a compression-induced NPSCs senescence model and rat IDD models to evaluate the therapeutic efficiency of mExo and investigate the mechanisms. We found that mExo significantly alleviated NPSCs senescence and promoted disc regeneration while knocking down thioredoxin (TXN) impaired the protective effects of mExo. TXN was bound to various endosomal sorting complex required for transport (ESCRT) proteins. Autocrine motility factor receptor (AMFR) mediated TXN K63 ubiquitination to promote the binding of TXN on ESCRT proteins and sorting of TXN into mExo. Knocking down exosomal TXN inhibited the transcriptional activity of nuclear factor erythroid 2-related factor 2 (NRF2) and activator protein 1 (AP-1). NRF2 and AP-1 inhibition reduced endogenous TXN production that was promoted by exosomal TXN. Inhibition of NRF2 in vivo diminished the anti-senescence and regenerative effects of mExo. Conclusively, AMFR-mediated TXN ubiquitination promoted the sorting of TXN into mExo, allowing exosomal TXN to promote endogenous TXN production in NPSCs via TXN/NRF2/AP-1 feed-forward circuit to alleviate NPSCs senescence and disc degeneration.
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Affiliation(s)
- Xuanzuo Chen
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Sheng Liu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Huiwen Wang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yiran Liu
- The First School of Clinical Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yan Xiao
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Kanglu Li
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Feifei Ni
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Wei Wu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Hui Lin
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiangcheng Qing
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Feifei Pu
- Department of Orthopedics, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Baichuan Wang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zengwu Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yizhong Peng
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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Elashry MI, Speer J, De Marco I, Klymiuk MC, Wenisch S, Arnhold S. Extracellular Vesicles: A Novel Diagnostic Tool and Potential Therapeutic Approach for Equine Osteoarthritis. Curr Issues Mol Biol 2024; 46:13078-13104. [PMID: 39590374 PMCID: PMC11593097 DOI: 10.3390/cimb46110780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 11/12/2024] [Accepted: 11/15/2024] [Indexed: 11/28/2024] Open
Abstract
Osteoarthritis (OA) is a chronic progressive degenerative joint disease that affects a significant portion of the equine population and humans worldwide. Current treatment options for equine OA are limited and incompletely curative. Horses provide an excellent large-animal model for studying human OA. Recent advances in the field of regenerative medicine have led to the exploration of extracellular vesicles (EVs)-cargoes of microRNA, proteins, lipids, and nucleic acids-to evaluate their diagnostic value in terms of disease progression and severity, as well as a potential cell-free therapeutic approach for equine OA. EVs transmit molecular signals that influence various biological processes, including the inflammatory response, apoptosis, proliferation, and cell communication. In the present review, we summarize recent advances in the isolation and identification of EVs, the use of their biologically active components as biomarkers, and the distribution of the gap junction protein connexin 43. Moreover, we highlight the role of mesenchymal stem cell-derived EVs as a potential therapeutic tool for equine musculoskeletal disorders. This review aims to provide a comprehensive overview of the current understanding of the pathogenesis, diagnosis, and treatment strategies for OA. In particular, the roles of EVs as biomarkers in synovial fluid, chondrocytes, and plasma for the early detection of equine OA are discussed.
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Affiliation(s)
- Mohamed I. Elashry
- Institute of Veterinary Anatomy, Histology and Embryology, Justus-Liebig-University of Giessen, 35392 Giessen, Germany; (J.S.); (M.C.K.); (S.A.)
| | - Julia Speer
- Institute of Veterinary Anatomy, Histology and Embryology, Justus-Liebig-University of Giessen, 35392 Giessen, Germany; (J.S.); (M.C.K.); (S.A.)
| | - Isabelle De Marco
- Clinic of Small Animals, c/o Institute of Veterinary Anatomy, Histology and Embryology, Justus-Liebig-University of Giessen, 35392 Giessen, Germany; (I.D.M.); (S.W.)
| | - Michele C. Klymiuk
- Institute of Veterinary Anatomy, Histology and Embryology, Justus-Liebig-University of Giessen, 35392 Giessen, Germany; (J.S.); (M.C.K.); (S.A.)
| | - Sabine Wenisch
- Clinic of Small Animals, c/o Institute of Veterinary Anatomy, Histology and Embryology, Justus-Liebig-University of Giessen, 35392 Giessen, Germany; (I.D.M.); (S.W.)
| | - Stefan Arnhold
- Institute of Veterinary Anatomy, Histology and Embryology, Justus-Liebig-University of Giessen, 35392 Giessen, Germany; (J.S.); (M.C.K.); (S.A.)
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Avalos PN, Wong LL, Forsthoefel DJ. Extracellular vesicles promote proliferation in an animal model of regeneration. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.22.586206. [PMID: 38712279 PMCID: PMC11071309 DOI: 10.1101/2024.03.22.586206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2024]
Abstract
Extracellular vesicles (EVs) are secreted nanoparticles composed of a lipid bilayer that carry lipid, protein, and nucleic acid cargo between cells as a mode of intercellular communication. Although EVs can promote tissue repair in mammals, their roles in animals with greater regenerative capacity are not well understood. Planarian flatworms are capable of whole body regeneration due to pluripotent somatic stem cells called neoblasts that proliferate in response to injury. Here, using transmission electron microscopy, nanoparticle tracking analysis, and protein content examination, we showed that EVs enriched from the tissues of the planarian Schmidtea mediterranea had similar morphology and size as other eukaryotic EVs, and that these EVs carried orthologs of the conserved EV biogenesis regulators ALIX and TSG101. PKH67-labeled EVs were taken up more quickly by S/G2 neoblasts than G1 neoblasts/early progeny and differentiated cells. When injected into living planarians, EVs from regenerating tissue fragments enhanced upregulation of neoblast-associated transcripts. In addition, EV injection increased the number of F-ara-EdU-labelled cells by 49% as compared to buffer injection only. Our findings demonstrate that regenerating planarians produce EVs that promote stem cell proliferation, and suggest the planarian as an amenable in vivo model for the study of EV function during regeneration.
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Affiliation(s)
- Priscilla N. Avalos
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
| | - Lily L. Wong
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
| | - David J. Forsthoefel
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
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Zubkova E, Kalinin A, Bolotskaya A, Beloglazova I, Menshikov M. Autophagy-Dependent Secretion: Crosstalk between Autophagy and Exosome Biogenesis. Curr Issues Mol Biol 2024; 46:2209-2235. [PMID: 38534758 DOI: 10.3390/cimb46030142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/22/2024] [Accepted: 01/23/2024] [Indexed: 03/28/2024] Open
Abstract
The cellular secretome is pivotal in mediating intercellular communication and coordinating responses to stressors. Exosomes, initially recognized for their role in waste disposal, have now emerged as key intercellular messengers with significant therapeutic and diagnostic potential. Similarly, autophagy has transcended its traditional role as a waste removal mechanism, emerging as a regulator of intracellular communication pathways and a contributor to a unique autophagy-dependent secretome. Secretory authophagy, initiated by various stress stimuli, prompts the selective release of proteins implicated in inflammation, including leaderless proteins that bypass the conventional endoplasmic reticulum-Golgi secretory pathway. This reflects the significant impact of stress-induced autophagy on cellular secretion profiles, including the modulation of exosome release. The convergence of exosome biogenesis and autophagy is exemplified by the formation of amphisomes, vesicles that integrate autophagic and endosomal pathways, indicating their synergistic interplay. Regulatory proteins common to both pathways, particularly mTORC1, emerge as potential therapeutic targets to alter cellular secretion profiles involved in various diseases. This review explores the dynamic interplay between autophagy and exosome formation, highlighting the potential to influence the secretome composition. While the modulation of exosome secretion and cytokine preconditioning is well-established in regenerative medicine, the strategic manipulation of autophagy is still underexplored, presenting a promising but uncharted therapeutic landscape.
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Affiliation(s)
- Ekaterina Zubkova
- National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, Russia
| | - Alexander Kalinin
- National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, Russia
- Faculty of Fundamental Medicine, Lomonosov Moscow State University, 119991 Moscow, Russia
| | - Anastasya Bolotskaya
- National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, Russia
- Institute of Clinical Medicine, Sechenov University, 119435 Moscow, Russia
| | - Irina Beloglazova
- National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, Russia
| | - Mikhail Menshikov
- National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, Russia
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Lee D, Lee PCW, Hong JH. UBA6 Inhibition Accelerates Lysosomal TRPML1 Depletion and Exosomal Secretion in Lung Cancer Cells. Int J Mol Sci 2024; 25:2843. [PMID: 38474091 PMCID: PMC10932338 DOI: 10.3390/ijms25052843] [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: 12/14/2023] [Revised: 02/25/2024] [Accepted: 02/28/2024] [Indexed: 03/14/2024] Open
Abstract
Ubiquitin-like modifier-activating enzyme 6 (UBA6) is a member of the E1 enzyme family, which initiates the ubiquitin-proteasome system (UPS). The UPS plays critical roles not only in protein degradation but also in various cellular functions, including neuronal signaling, myocardial remodeling, immune cell differentiation, and cancer development. However, the specific role of UBA6 in cellular functions is not fully elucidated in comparison with the roles of the UPS. It has been known that the E1 enzyme is associated with the motility of cancer cells. In this study, we verified the physiological roles of UBA6 in lung cancer cells through gene-silencing siRNA targeting UBA6 (siUBA6). The siUBA6 treatment attenuated the migration of H1975 cells, along with a decrease in lysosomal Ca2+ release. While autophagosomal proteins remained unchanged, lysosomal proteins, including TRPML1 and TPC2, were decreased in siUBA6-transfected cells. Moreover, siUBA6 induced the production of multivesicular bodies (MVBs), accompanied by an increase in MVB markers in siUBA6-transfected H1975 cells. Additionally, the expression of the exosomal marker CD63 and extracellular vesicles was increased by siUBA6 treatment. Our findings suggest that knock-down of UBA6 induces lysosomal TRPML1 depletion and inhibits endosomal trafficking to lysosome, and subsequently, leads to the accumulation of MVBs and enhanced exosomal secretion in lung cancer cells.
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Affiliation(s)
- Dongun Lee
- Department of Health Sciences and Technology, Lee Gil Ya Cancer and Diabetes Institute, GAIHST, Gachon University, 155 Getbeolro, Yeonsu-gu, Incheon 21999, Republic of Korea;
| | - Peter Chang-Whan Lee
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea;
| | - Jeong Hee Hong
- Department of Health Sciences and Technology, Lee Gil Ya Cancer and Diabetes Institute, GAIHST, Gachon University, 155 Getbeolro, Yeonsu-gu, Incheon 21999, Republic of Korea;
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Yu Z, Yang Y, Chan RB, Shi M, Stewart T, Huang Y, Liu Z, Lan G, Sheng L, Tian C, Yang D, Zhang J. GV-971 attenuates α-Synuclein aggregation and related pathology. CNS Neurosci Ther 2024; 30:e14393. [PMID: 37563872 PMCID: PMC10848097 DOI: 10.1111/cns.14393] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 06/10/2023] [Accepted: 06/24/2023] [Indexed: 08/12/2023] Open
Abstract
RATIONALE Synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), share a distinct pathological feature, that is, a widespread accumulation of α-synuclein (α-syn) in the brain. There is a significant clinical unmet need for disease-modifying treatments for synucleinopathies. Recently, a seaweed-derived mixture of oligosaccharides sodium oligomannate, GV-971, was approved for Phase 2 clinical trials for PD. This study aimed to further evaluate the therapeutic effects of GV-971 on synucleinopathies using cellular and animal models and explore its associated molecular mechanisms. METHODS α-Syn aggregation was assessed, in vitro and ex vivo, by ThT assay. A dopaminergic neuron cell line, Prnp-SNCAA53T mice, and brain slices from PD and DLB patients were used to determine the efficacy of GV-971 in ameliorating α-syn pathology. Measurements of motor functions, including pole, cylinder, and rotarod tests, were conducted on Prnp-SNCAA53T mice 4 weeks after intragastric administration of GV-971 (200 mg day-1 kg-1 ). RESULTS GV-971 effectively prevented α-syn aggregation and even disassembled pre-aggregated α-syn fibrils, in vitro and ex vivo. In addition, GV-971 was able to rescue α-syn-induced neuronal damage and reduced release of extracellular vesicles (EVs), likely via modulating Alix expression. In the Prnp-SNCAA53T mouse model, when treated at the age of 5 months, GV-971 significantly decreased α-syn deposition in the cortex, midbrain, and cerebellum regions, along with ameliorating the motor dysfunctions. CONCLUSIONS Our results indicate that GV-971, when administered at a relatively early stage of the disease process, significantly reduced α-syn accumulation and aggregation in Prnp-SNCAA53T mice. Furthermore, GV-971 corrected α-syn-induced inhibition of EVs release in neurons, contributing to neuronal protection. Future studies are needed to further assess GV-971 as a promising disease-modifying therapy for PD and other synucleinopathies.
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Affiliation(s)
- Zhenwei Yu
- Beijing Neurosurgical InstituteCapital Medical UniversityBeijingChina
| | - Ying Yang
- Department of Pathology, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- National Health and Disease Human Brain Tissue Resource CenterZhejiang UniversityHangzhouChina
| | | | - Min Shi
- Department of PathologyUniversity of Washington School of MedicineSeattleWashingtonUSA
| | - Tessandra Stewart
- Department of PathologyUniversity of Washington School of MedicineSeattleWashingtonUSA
| | - Yang Huang
- Department of PathologyPeking University Health Science Center and Third HospitalBeijingChina
| | - Zongran Liu
- Department of PathologyPeking University Health Science Center and Third HospitalBeijingChina
| | - Guoyu Lan
- Department of PathologyPeking University Health Science Center and Third HospitalBeijingChina
| | - Lifu Sheng
- Department of PathologyUniversity of Washington School of MedicineSeattleWashingtonUSA
| | - Chen Tian
- Department of Pathology, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Dishun Yang
- Department of PathologyUniversity of Washington School of MedicineSeattleWashingtonUSA
| | - Jing Zhang
- Department of Pathology, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- National Health and Disease Human Brain Tissue Resource CenterZhejiang UniversityHangzhouChina
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van de Wakker SI, Bauzá‐Martinez J, Ríos Arceo C, Manjikian H, Snijders Blok CJB, Roefs MT, Willms E, Maas RGC, Pronker MF, de Jong OG, Wu W, Görgens A, El Andaloussi S, Sluijter JPG, Vader P. Size matters: Functional differences of small extracellular vesicle subpopulations in cardiac repair responses. J Extracell Vesicles 2024; 13:e12396. [PMID: 38179654 PMCID: PMC10767609 DOI: 10.1002/jev2.12396] [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: 07/18/2023] [Accepted: 11/22/2023] [Indexed: 01/06/2024] Open
Abstract
Cardiac progenitor cell (CPC)-derived small extracellular vesicles (sEVs) exhibit great potential to stimulate cardiac repair. However, the multifaceted nature of sEV heterogeneity presents a challenge in understanding the distinct mechanisms underlying their regenerative abilities. Here, a dual-step multimodal flowthrough and size-exclusion chromatography method was applied to isolate and separate CPC-derived sEV subpopulations to study the functional differences related to cardiac repair responses. Three distinct sEV subpopulations were identified with unique protein profiles. Functional cell assays for cardiac repair-related processes demonstrated that the middle-sized and smallest-sized sEV subpopulations exhibited the highest pro-angiogenic and anti-fibrotic activities. Proteasome activity was uniquely seen in the smallest-sized subpopulation. The largest-sized subpopulation showed no effect in any of the functional assays. This research uncovers the existence of sEV subpopulations, each characterized by a distinct composition and biological function. Enhancing our understanding of sEV heterogeneity will provide valuable insights into sEV mechanisms of action, ultimately accelerating the translation of sEV therapeutics.
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Affiliation(s)
- Simonides Immanuel van de Wakker
- Department of Experimental Cardiology, Regenerative Medicine Center Utrecht, Circulatory health Research CenterUniversity Utrecht, University Medical Center UtrechtUtrechtThe Netherlands
| | - Julia Bauzá‐Martinez
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
| | - Carla Ríos Arceo
- Department of Experimental Cardiology, Regenerative Medicine Center Utrecht, Circulatory health Research CenterUniversity Utrecht, University Medical Center UtrechtUtrechtThe Netherlands
| | - Herak Manjikian
- Department of Experimental Cardiology, Regenerative Medicine Center Utrecht, Circulatory health Research CenterUniversity Utrecht, University Medical Center UtrechtUtrechtThe Netherlands
| | - Christian Jamie Bernard Snijders Blok
- Department of Experimental Cardiology, Regenerative Medicine Center Utrecht, Circulatory health Research CenterUniversity Utrecht, University Medical Center UtrechtUtrechtThe Netherlands
| | - Marieke Theodora Roefs
- Department of Experimental Cardiology, Regenerative Medicine Center Utrecht, Circulatory health Research CenterUniversity Utrecht, University Medical Center UtrechtUtrechtThe Netherlands
| | - Eduard Willms
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular ScienceLa Trobe UniversityMelbourneAustralia
| | - Renee Goverdina Catharina Maas
- Department of Experimental Cardiology, Regenerative Medicine Center Utrecht, Circulatory health Research CenterUniversity Utrecht, University Medical Center UtrechtUtrechtThe Netherlands
| | - Matti Feije Pronker
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
| | - Olivier Gerrit de Jong
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS)Utrecht UniversityUtrechtThe Netherlands
| | - Wei Wu
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
- Singapore Immunology Network (SIgN), Agency for ScienceTechnology and Research (A*STAR)SingaporeSingapore
- Department of PharmacyNational University of SingaporeSingaporeSingapore
| | - André Görgens
- Department of Laboratory MedicineKarolinska InstituteStockholm, HuddingeSweden
- Institute for Transfusion Medicine, University Hospital EssenUniversity of Duisburg‐EssenEssenGermany
| | - Samir El Andaloussi
- Department of Laboratory MedicineKarolinska InstituteStockholm, HuddingeSweden
| | - Joost Petrus Gerardus Sluijter
- Department of Experimental Cardiology, Regenerative Medicine Center Utrecht, Circulatory health Research CenterUniversity Utrecht, University Medical Center UtrechtUtrechtThe Netherlands
| | - Pieter Vader
- Department of Experimental Cardiology, Regenerative Medicine Center Utrecht, Circulatory health Research CenterUniversity Utrecht, University Medical Center UtrechtUtrechtThe Netherlands
- CDL ResearchUniversity Medical Center UtrechtUtrechtThe Netherlands
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11
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Li R, Ma Z, Zheng W, Xiao Y, Wang Z, Yi J, Wang Y, Chen C. Anaplasma phagocytophilum Ats-1 enhances exosome secretion through Syntenin-1. BMC Microbiol 2023; 23:271. [PMID: 37759206 PMCID: PMC10523776 DOI: 10.1186/s12866-023-03023-4] [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: 04/07/2023] [Accepted: 09/15/2023] [Indexed: 09/29/2023] Open
Abstract
Anaplasma phagocytophilum is an intracellular obligate parasite that causes granulocytic anaplasmosis. Effector Ats-1 is an important virulence factor of A. phagocytophilum. Multiomics screening and validation has been used to determine that Ats-1 regulates host cell apoptosis and energy metabolism through the respiratory chain mPTP axis. In this study, a total of 19 potential binding proteins of Ats-1 in host cells were preliminarily screened using a yeast two-hybrid assay, and the interaction between syntenin-1 (SDCBP) and Ats-1 was identified through immunoprecipitation. Bioinformatics analysis showed that SDCBP interacted with SDC1, SDC2, and SDC4 and participated in the host exosome secretion pathway. Further studies confirmed that Ats-1 induced the expression of SDC1, SDC2, and SDC4 in HEK293T cells through SDCBP and increased the exosome secretion of these cells. This indicated that SDCBP played an important role in Ats-1 regulating the exosome secretion of the host cells. These findings expand our understanding of the intracellular regulatory mechanism of A. phagocytophilum, which may enhance its own infection and proliferation by regulating host exosome pathways.
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Affiliation(s)
- Ruirui Li
- International Research Center for Animal Health Breeding, College of Animal Science and Technology, Shihezi University, Shihezi, China
- Collaborative Innovation Center for Prevention and Control of High Incidence Zoonotic Infectious Diseases in Western China, College of Animal Science and Technology, Shihezi University, Shihezi, China
- Shihezi University, Shihezi City, Xinjiang Uygur Autonomous Region, China
| | - Zhongchen Ma
- International Research Center for Animal Health Breeding, College of Animal Science and Technology, Shihezi University, Shihezi, China
- Collaborative Innovation Center for Prevention and Control of High Incidence Zoonotic Infectious Diseases in Western China, College of Animal Science and Technology, Shihezi University, Shihezi, China
| | - Wei Zheng
- International Research Center for Animal Health Breeding, College of Animal Science and Technology, Shihezi University, Shihezi, China
| | - Yangyang Xiao
- International Research Center for Animal Health Breeding, College of Animal Science and Technology, Shihezi University, Shihezi, China
- Collaborative Innovation Center for Prevention and Control of High Incidence Zoonotic Infectious Diseases in Western China, College of Animal Science and Technology, Shihezi University, Shihezi, China
| | - Zhen Wang
- International Research Center for Animal Health Breeding, College of Animal Science and Technology, Shihezi University, Shihezi, China
- Collaborative Innovation Center for Prevention and Control of High Incidence Zoonotic Infectious Diseases in Western China, College of Animal Science and Technology, Shihezi University, Shihezi, China
| | - Jihai Yi
- International Research Center for Animal Health Breeding, College of Animal Science and Technology, Shihezi University, Shihezi, China
- Collaborative Innovation Center for Prevention and Control of High Incidence Zoonotic Infectious Diseases in Western China, College of Animal Science and Technology, Shihezi University, Shihezi, China
| | - Yong Wang
- International Research Center for Animal Health Breeding, College of Animal Science and Technology, Shihezi University, Shihezi, China.
- Collaborative Innovation Center for Prevention and Control of High Incidence Zoonotic Infectious Diseases in Western China, College of Animal Science and Technology, Shihezi University, Shihezi, China.
| | - Chuangfu Chen
- International Research Center for Animal Health Breeding, College of Animal Science and Technology, Shihezi University, Shihezi, China.
- Collaborative Innovation Center for Prevention and Control of High Incidence Zoonotic Infectious Diseases in Western China, College of Animal Science and Technology, Shihezi University, Shihezi, China.
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12
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Velázquez-Cervantes MA, Benítez-Zeferino YR, Flores-Pliego A, Helguera-Repetto AC, Meza-Sánchez DE, Maravillas-Montero JL, León-Reyes G, Mancilla-Ramírez J, Cerna-Cortés JF, Baeza-Ramírez MI, León-Juaárez M. A Review Study of the Participation of Late Domains in Sorting and Transport of Viral Factors to Exosomes. Life (Basel) 2023; 13:1842. [PMID: 37763246 PMCID: PMC10532540 DOI: 10.3390/life13091842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 08/23/2023] [Accepted: 08/29/2023] [Indexed: 09/29/2023] Open
Abstract
Cellular communication depends heavily on the participation of vesicular systems generated by most cells of an organism. Exosomes play central roles in this process. Today, these vesicles have been characterized, and it has been determined that the cargo they transport is not within a random system. In fact, it depends on various molecular signals and the recruitment of proteins that participate in the biogenesis of exosomes. It has also been shown that multiple viruses can recruit these vesicles to transport viral factors such as genomes or proteins. It has been shown that the late domains present in viral proteins are critical for the exosomal selection and biogenesis systems to recognize these viral proteins and introduce them into the exosomes. In this review, the researchers discuss the evidence related to the characterization of these late domains and their role in exosome recruitment during viral infection.
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Affiliation(s)
- Manuel Adrián Velázquez-Cervantes
- Laboratorio de Virología Perinatal y Diseño Molecular de Antígenos y Biomarcadores, Departamento de Inmunobioquímica, Instituto Nacional de Perinatología, Mexico City 11000, Mexico; (M.A.V.-C.); (Y.R.B.-Z.)
- Laboratorio de Biomembranas, Departamento de Bioquimica, Escueala Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico;
| | - Yazmín Rocío Benítez-Zeferino
- Laboratorio de Virología Perinatal y Diseño Molecular de Antígenos y Biomarcadores, Departamento de Inmunobioquímica, Instituto Nacional de Perinatología, Mexico City 11000, Mexico; (M.A.V.-C.); (Y.R.B.-Z.)
- Laboratorio de Microbiología Molecular, Departamento de Microbiología, Escuela Nacional de Ciencias Biologícas, Instituto Politécnico Nacional, Mexico City 11340, Mexico;
| | - Arturo Flores-Pliego
- Departamento de Inmunobioquimica, Instituto Nacional de Perinatología, Mexico City 11000, Mexico; (A.F.-P.); (A.C.H.-R.)
| | - Addy Cecilia Helguera-Repetto
- Departamento de Inmunobioquimica, Instituto Nacional de Perinatología, Mexico City 11000, Mexico; (A.F.-P.); (A.C.H.-R.)
| | - David Eduardo Meza-Sánchez
- Red de Apoyo a la Investigación, Coordinación de la Investigación Científica, Universidad Nacional Autonóma de México, e Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 04510, Mexico; (D.E.M.-S.); (J.L.M.-M.)
| | - José Luis Maravillas-Montero
- Red de Apoyo a la Investigación, Coordinación de la Investigación Científica, Universidad Nacional Autonóma de México, e Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 04510, Mexico; (D.E.M.-S.); (J.L.M.-M.)
| | - Guadalupe León-Reyes
- Laboratorio de Nutrigenómica y Nutrigenética, Instituto Nacional de Medicina Genómica (INMEGEN), Ciudad de México 14610, Mexico;
| | - Javier Mancilla-Ramírez
- Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 113440, Mexico;
- Hospital de la Mujer, Secretaría de Salud, Mexico City 11340, Mexico
| | - Jorge Francisco Cerna-Cortés
- Laboratorio de Microbiología Molecular, Departamento de Microbiología, Escuela Nacional de Ciencias Biologícas, Instituto Politécnico Nacional, Mexico City 11340, Mexico;
| | - María Isabel Baeza-Ramírez
- Laboratorio de Biomembranas, Departamento de Bioquimica, Escueala Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico;
| | - Moises León-Juaárez
- Laboratorio de Virología Perinatal y Diseño Molecular de Antígenos y Biomarcadores, Departamento de Inmunobioquímica, Instituto Nacional de Perinatología, Mexico City 11000, Mexico; (M.A.V.-C.); (Y.R.B.-Z.)
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13
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Lee ES, Ko H, Kim CH, Kim HC, Choi SK, Jeong SW, Lee SG, Lee SJ, Na HK, Park JH, Shin JM. Disease-microenvironment modulation by bare- or engineered-exosome for rheumatoid arthritis treatment. Biomater Res 2023; 27:81. [PMID: 37635253 PMCID: PMC10464174 DOI: 10.1186/s40824-023-00418-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 08/13/2023] [Indexed: 08/29/2023] Open
Abstract
BACKGROUND Exosomes are extracellular vesicles secreted by eukaryotic cells and have been extensively studied for their surface markers and internal cargo with unique functions. A deeper understanding of exosomes has allowed their application in various research areas, particularly in diagnostics and therapy. MAIN BODY Exosomes have great potential as biomarkers and delivery vehicles for encapsulating therapeutic cargo. However, the limitations of bare exosomes, such as rapid phagocytic clearance and non-specific biodistribution after injection, pose significant challenges to their application as drug delivery systems. This review focuses on exosome-based drug delivery for treating rheumatoid arthritis, emphasizing pre/post-engineering approaches to overcome these challenges. CONCLUSION This review will serve as an essential resource for future studies to develop novel exosome-based therapeutic approaches for rheumatoid arthritis. Overall, the review highlights the potential of exosomes as a promising therapeutic approach for rheumatoid arthritis treatment.
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Affiliation(s)
- Eun Sook Lee
- Safety Measurement Institute, Korea Research Institute of Standards and Science (KRISS), 267 Gajeong-Ro, Yuseong-Gu, Daejeon, 34113, Republic of Korea
| | - Hyewon Ko
- Bionanotechnology Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Yuseong-Gu, Daejeon, 34141, Republic of Korea
| | - Chan Ho Kim
- School of Chemical Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Hyun-Chul Kim
- Division of Biotechnology, Convergence Research Institute, DGIST, 333 Techno Jungang-Daero, Daegu, 42988, Republic of Korea
| | - Seong-Kyoon Choi
- Division of Biotechnology, Convergence Research Institute, DGIST, 333 Techno Jungang-Daero, Daegu, 42988, Republic of Korea
| | - Sang Won Jeong
- Division of Biotechnology, Convergence Research Institute, DGIST, 333 Techno Jungang-Daero, Daegu, 42988, Republic of Korea
| | - Se-Guen Lee
- Division of Biotechnology, Convergence Research Institute, DGIST, 333 Techno Jungang-Daero, Daegu, 42988, Republic of Korea
| | - Sung-Jun Lee
- Division of Biotechnology, Convergence Research Institute, DGIST, 333 Techno Jungang-Daero, Daegu, 42988, Republic of Korea
| | - Hee-Kyung Na
- Safety Measurement Institute, Korea Research Institute of Standards and Science (KRISS), 267 Gajeong-Ro, Yuseong-Gu, Daejeon, 34113, Republic of Korea
| | - Jae Hyung Park
- School of Chemical Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Jung Min Shin
- Division of Biotechnology, Convergence Research Institute, DGIST, 333 Techno Jungang-Daero, Daegu, 42988, Republic of Korea.
- Department of Polymer Science and Engineering, Korea National University of Transportation, Chungju, 27469, Republic of Korea.
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14
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Zhong L, Wang J, Wang P, Liu X, Liu P, Cheng X, Cao L, Wu H, Chen J, Zhou L. Neural stem cell-derived exosomes and regeneration: cell-free therapeutic strategies for traumatic brain injury. Stem Cell Res Ther 2023; 14:198. [PMID: 37553595 PMCID: PMC10408078 DOI: 10.1186/s13287-023-03409-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 07/06/2023] [Indexed: 08/10/2023] Open
Abstract
Regenerative repair of the brain after traumatic brain injury (TBI) remains an extensive clinical challenge, inspiring intensified interest in therapeutic approaches to explore superior repair strategies. Exosome therapy is another research hotspot following stem cell alternative therapy. Prior research verified that exosomes produced by neural stem cells can participate in the physiological and pathological changes associated with TBI and have potential neuroregulatory and repair functions. In comparison with their parental stem cells, exosomes have superior stability and immune tolerance and lower tumorigenic risk. In addition, they can readily penetrate the blood‒brain barrier, which makes their treatment efficiency superior to that of transplanted stem cells. Exosomes secreted by neural stem cells present a promising strategy for the development of novel regenerative therapies. Their tissue regeneration and immunomodulatory potential have made them encouraging candidates for TBI repair. The present review addresses the challenges, applications and potential mechanisms of neural stem cell exosomes in regenerating damaged brains.
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Affiliation(s)
- Lin Zhong
- Department of Hematology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, Sichuan, China
| | - Jingjing Wang
- Tianjin Key Laboratory of Neurotrauma Repair, Institute of Neurotrauma Repair, Characteristic Medical Center of People's Armed Police Forces, Tianjin, 300162, China
| | - Peng Wang
- Department of Health Management, Tianjin Hospital, Tianjin, 300211, China
| | - Xiaoyin Liu
- Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Peng Liu
- Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xu Cheng
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610064, Sichuan, China
| | - Lujia Cao
- Department of Hematology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, Sichuan, China
| | - Hongwei Wu
- Department of Hematology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, Sichuan, China.
| | - Jing Chen
- Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, Sichuan, China.
| | - Liangxue Zhou
- Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, Sichuan, China.
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15
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Greenberg ZF, Graim KS, He M. Towards artificial intelligence-enabled extracellular vesicle precision drug delivery. Adv Drug Deliv Rev 2023:114974. [PMID: 37356623 DOI: 10.1016/j.addr.2023.114974] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 06/21/2023] [Accepted: 06/22/2023] [Indexed: 06/27/2023]
Abstract
Extracellular Vesicles (EVs), particularly exosomes, recently exploded into nanomedicine as an emerging drug delivery approach due to their superior biocompatibility, circulating stability, and bioavailability in vivo. However, EV heterogeneity makes molecular targeting precision a critical challenge. Deciphering key molecular drivers for controlling EV tissue targeting specificity is in great need. Artificial intelligence (AI) brings powerful prediction ability for guiding the rational design of engineered EVs in precision control for drug delivery. This review focuses on cutting-edge nano-delivery via integrating large-scale EV data with AI to develop AI-directed EV therapies and illuminate the clinical translation potential. We briefly review the current status of EVs in drug delivery, including the current frontier, limitations, and considerations to advance the field. Subsequently, we detail the future of AI in drug delivery and its impact on precision EV delivery. Our review discusses the current universal challenge of standardization and critical considerations when using AI combined with EVs for precision drug delivery. Finally, we will conclude this review with a perspective on future clinical translation led by a combined effort of AI and EV research.
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Affiliation(s)
- Zachary F Greenberg
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, 32610, USA
| | - Kiley S Graim
- Department of Computer & Information Science & Engineering, Herbert Wertheim College of Engineering, University of Florida, Gainesville, Florida, 32610, USA
| | - Mei He
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, 32610, USA.
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16
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Vp V, Kannan A, Perumal MK. Role of adipocyte-derived extracellular vesicles during the progression of liver inflammation to hepatocellular carcinoma. J Cell Physiol 2023; 238:1125-1140. [PMID: 36960683 DOI: 10.1002/jcp.31008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 03/03/2023] [Accepted: 03/11/2023] [Indexed: 03/25/2023]
Abstract
Extracellular vesicles are membrane-bound cargos that vary in size and are stably transported through various bodily fluids. Extracellular vesicles communicate information between the cells and organs. Extracellular vesicles from the diseased cells alter cellular responses of the recipient cells contributing to disease progression. In obesity, adipocytes become hypertrophic and the extracellular vesicles from these dysfunctional adipocytes showed altered cargo contents instigating pathophysiological response leading to chronic liver diseases. In this review, the role of adipocyte-derived extracellular vesicles on the progression of liver inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma are extensively discussed. Newer approaches are crucial to take advantage of extracellular vesicles and their content as biomarkers to diagnose initial liver inflammation before reaching to an irreversible liver failure stage.
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Affiliation(s)
- Venkateish Vp
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Anbarasu Kannan
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Madan Kumar Perumal
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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17
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Tian MY, Hao DX, Liu Y, He J, Zhao ZH, Guo TY, Li X, Zhang Y. Milk exosomes: an oral drug delivery system with great application potential. Food Funct 2023; 14:1320-1337. [PMID: 36722924 DOI: 10.1039/d2fo02013k] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Exosomes are extracellular vesicles with the smallest diameter, usually divided into cellular sources and body fluid sources. Due to their special properties different from cell-derived exosomes, the application of milk exosomes as an oral drug delivery system has increased greatly. This article introduces the physical and chemical properties of exosomes, separation technology, dyeing and labeling technology, targeted modification technology, and the application of milk exosomes in drug loading and disease therapies.
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Affiliation(s)
- Meng-Yuan Tian
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education; National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China; College of Life Sciences, Shaanxi Normal University, Xi'an, China.
| | - Dong-Xia Hao
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education; National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China; College of Life Sciences, Shaanxi Normal University, Xi'an, China.
| | - Yang Liu
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education; National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China; College of Life Sciences, Shaanxi Normal University, Xi'an, China.
| | - Jin He
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education; National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China; College of Life Sciences, Shaanxi Normal University, Xi'an, China.
| | - Zhuo-Hua Zhao
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education; National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China; College of Life Sciences, Shaanxi Normal University, Xi'an, China.
| | - Ting-Yu Guo
- The International Department of the High School Affiliated to Shaanxi Normal University, Xi'an, China
| | - Xing Li
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education; National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China; College of Life Sciences, Shaanxi Normal University, Xi'an, China.
| | - Yuan Zhang
- Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education; National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China; College of Life Sciences, Shaanxi Normal University, Xi'an, China.
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18
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The Roles of Exosomes in the Diagnose, Development and Therapeutic Resistance of Oral Squamous Cell Carcinoma. Int J Mol Sci 2023; 24:ijms24031968. [PMID: 36768288 PMCID: PMC9916286 DOI: 10.3390/ijms24031968] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/11/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Oral cancer is one of the most common cancers worldwide, of which more than half of patients are diagnosed at a locally advanced stage with poor prognosis due to recurrence, metastasis and resistant to treatment. Thus, it is imperative to further explore the potential mechanism of development and drug resistance of oral cancer. Exosomes are small endosome-derived lipid nanoparticles that are released by cells. Since the cargoes of exosomes were inherited from their donor cells, the cargo profiles of exosomes can well recapitulate that of their donor cells. This is the theoretical basis of exosome-based liquid biopsy, providing a tool for early diagnosis of oral cancer. As an important intracellular bioactive cargo delivery vector, exosomes play a critical role in the development of oral cancer by transferring their cargoes to receipt cells. More importantly, recent studies have revealed that exosomes could induce therapy-resistance in oral cancer through multiple ways, including exosome-mediated drug efflux. In this review, we summarize and compare the role of exosomes in the diagnosis, development and therapy-resistant of oral cancer. We also highlight the clinical application of exosomes, and discuss the advantages and challenges of exosomes serving as predictive biomarker, therapy target and therapy vector in oral cancer.
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19
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Tan M, Ge Y, Wang X, Wang Y, Liu Y, He F, Teng H. Extracellular Vesicles (EVs) in Tumor Diagnosis and Therapy. Technol Cancer Res Treat 2023; 22:15330338231171463. [PMID: 37122245 PMCID: PMC10134167 DOI: 10.1177/15330338231171463] [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] [Indexed: 05/02/2023] Open
Abstract
In recent years, extracellular vesicles (EVs) have gained significant attention due to their tremendous potential for clinical applications. EVs play a crucial role in various aspects, including tumorigenesis, drug resistance, immune escape, and reconstruction of the tumor microenvironment. Despite the growing interest in EVs, many questions still need to be addressed before they can be practically applied in clinical settings. This paper aims to review EVs' isolation methods, structure research, the roles of EVs in tumorigenesis and their mechanisms in multiple types of tumors, their potential application in drug delivery, and the expectations for their future in clinical research.
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Affiliation(s)
- Mingdian Tan
- School of Medicine, Asian Liver Center, Stanford, CA, USA
| | - Yizhi Ge
- The Affiliated Cancer Hospital of Nanjing Medical University (Jiangsu Cancer Hospital) and Jiangsu Institute of Cancer Research, Nanjing, China
| | - Xiaogang Wang
- The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Yan Wang
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
- Stanford University School of Medicine, Stanford, CA, USA
| | - Yi Liu
- School of Medicine, Asian Liver Center, Stanford, CA, USA
| | - Feng He
- Stanford University School of Medicine, Stanford, CA, USA
| | - Hongqi Teng
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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20
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Pourhadi M, Zali H, Ghasemi R, Vafaei-Nezhad S. Promising Role of Oral Cavity Mesenchymal Stem Cell-Derived Extracellular Vesicles in Neurodegenerative Diseases. Mol Neurobiol 2022; 59:6125-6140. [PMID: 35867205 DOI: 10.1007/s12035-022-02951-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 06/28/2022] [Indexed: 10/17/2022]
Abstract
Mesenchymal stem cells (MSCs) and mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been regarded as the beneficial and available tools to treat various hereditary, multifactorial, acute, and chronic diseases. Mesenchymal stem cells can be extracted from numerous sources for clinical purposes while oral cavity-derived mesenchymal stem cells seem to be more effective in neuroregeneration than other sources due to their similar embryonic origins to neuronal tissues. In various studies and different neurodegenerative diseases (NDs), oral cavity mesenchymal stem cells have been applied to prove their promising capacities in disease improvement. Moreover, oral cavity mesenchymal stem cells' secretion is regarded as a novel and practical approach to neuroregeneration; hence, extracellular vesicles (EVs), especially exosomes, may provide promising results to improve CNS defects. This review article focuses on how oral cavity-derived stem cells and their extracellular vesicles can improve neurodegenerative conditions and tries to show which molecules are involved in the recovery process.
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Affiliation(s)
- Masoumeh Pourhadi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hakimeh Zali
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Rasoul Ghasemi
- Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Vafaei-Nezhad
- Cellular & Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran.,Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
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21
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The Role of Extracellular Vesicles in Melanoma Progression. Cancers (Basel) 2022; 14:cancers14133086. [PMID: 35804857 PMCID: PMC9264817 DOI: 10.3390/cancers14133086] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/18/2022] [Accepted: 06/20/2022] [Indexed: 02/07/2023] Open
Abstract
Cutaneous melanoma arises from a malignant transformation of the melanocytes in the skin. It is the deadliest form of skin cancer owing to its potential to metastasize. While recent advances in immuno-oncology have been successful in melanoma treatment, not all the patients respond to the treatment equally, thus individual pre-screening and personalized combination therapies are essential to stratify and monitor patients. Extracellular vesicles (EVs) have emerged as promising biomarker candidates to tackle these challenges. EVs are ~50-1000-nm-sized, lipid bilayer-enclosed spheres, which are secreted by almost all cell types, including cancer cells. Their cargo, such as nucleic acids, proteins, lipids, amino acids, and metabolites, can be transferred to target cells. Thanks to these properties, EVs can both provide a multiplexed molecular fingerprint of the cell of origin and thus serve as potential biomarkers, or reveal pathways important for cancer progression that can be targeted pharmaceutically. In this review we give a general overview of EVs and focus on their impact on melanoma progression. In particular, we shed light on the role of EVs in shaping the tumor-stroma interactions that facilitate metastasis and summarize the latest findings on molecular profiling of EV-derived miRNAs and proteins that can serve as potential biomarkers for melanoma progression.
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22
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Babaker MA, Aljoud FA, Alkhilaiwi F, Algarni A, Ahmed A, Khan MI, Saadeldin IM, Alzahrani FA. The Therapeutic Potential of Milk Extracellular Vesicles on Colorectal Cancer. Int J Mol Sci 2022; 23:ijms23126812. [PMID: 35743255 PMCID: PMC9224713 DOI: 10.3390/ijms23126812] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/16/2022] [Accepted: 06/16/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer remains one of the leading prevalent cancers in the world and is the fourth most common cause of death from cancer. Unfortunately, the currently utilized chemotherapies fail in selectively targeting cancer cells and cause harm to healthy cells, which results in profound side effects. Researchers are focused on developing anti-cancer targeted medications, which is essential to making them safer, more effective, and more selective and to maximizing their therapeutic benefits. Milk-derived extracellular vesicles (EVs) from camels and cows have attracted much attention as a natural substitute product that effectively suppresses a wide range of tumor cells. This review sheds light on the biogenesis, methods of isolation, characterization, and molecular composition of milk EVs as well as the therapeutic potentials of milk EVs on colorectal cancer.
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Affiliation(s)
- Manal A. Babaker
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
- Department of Chemistry, Faculty of Science, Majmaah University, Al Majmaah 11952, Saudi Arabia
| | - Fadwa A. Aljoud
- Regenerative Medicine Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (F.A.A.); (F.A.)
| | - Faris Alkhilaiwi
- Regenerative Medicine Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (F.A.A.); (F.A.)
- Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Abdulrahman Algarni
- Department of Medical Laboratory Technology, College of Applied Medical Sciences, Northern Border University, Arar 73221, Saudi Arabia;
| | - Asif Ahmed
- MirZyme Therapeutics, Innovation Birmingham Campus, Faraday Wharf, Birmingham B7 4BB, UK;
- School of Health Sciences, University of Southampton, University Road, Southampton SO17 1BJ, UK
| | - Mohammad Imran Khan
- Centre of Artificial Intelligence in Precision Medicines (CAIPM), King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Islam M. Saadeldin
- Research Institute of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea
- Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea
- Correspondence: (I.M.S.); (F.A.A.)
| | - Faisal A. Alzahrani
- MirZyme Therapeutics, Innovation Birmingham Campus, Faraday Wharf, Birmingham B7 4BB, UK;
- Centre of Artificial Intelligence in Precision Medicines (CAIPM), King Abdulaziz University, Jeddah 21589, Saudi Arabia;
- Embryonic Stem Cells Unit, Department of Biochemistry, Faculty of Science, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Correspondence: (I.M.S.); (F.A.A.)
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23
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Extracellular Vesicles as Novel Drug-Delivery Systems through Intracellular Communications. MEMBRANES 2022; 12:membranes12060550. [PMID: 35736256 PMCID: PMC9230693 DOI: 10.3390/membranes12060550] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/17/2022] [Accepted: 05/20/2022] [Indexed: 02/07/2023]
Abstract
Since it has been reported that extracellular vesicles (EVs) carry cargo using cell-to-cell comminication according to various in vivo situations, they are exprected to be applied as new drug-delivery systems (DDSs). In addition, non-coding RNAs, such as microRNAs (miRNAs), have attracted much attention as potential biomarkers in the encapsulated extracellular-vesicle (EV) form. EVs are bilayer-based lipids with heterogeneous populations of varying sizes and compositions. The EV-mediated transport of contents, which includes proteins, lipids, and nucleic acids, has attracted attention as a DDS through intracellular communication. Many reports have been made on the development of methods for introducing molecules into EVs and efficient methods for introducing them into target vesicles. In this review, we outline the possible molecular mechanisms by which miRNAs in exosomes participate in the post-transcriptional regulation of signaling pathways via cell–cell communication as novel DDSs, especially small EVs.
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24
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Mastoridou EM, Goussia AC, Glantzounis GK, Kanavaros P, Charchanti AV. Autophagy and Exosomes: Cross-Regulated Pathways Playing Major Roles in Hepatic Stellate Cells Activation and Liver Fibrosis. Front Physiol 2022; 12:801340. [PMID: 35185602 PMCID: PMC8850693 DOI: 10.3389/fphys.2021.801340] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 12/27/2021] [Indexed: 12/14/2022] Open
Abstract
Chronic liver injury, regardless of the underlying disease, results in gradual alteration of the physiological hepatic architecture and in excessive production of extracellular matrix, eventually leading to cirrhosis Liver cellular architecture consists of different cell populations, among which hepatic stellate cells (HSCs) have been found to play a major role in the fibrotic process. Under normal conditions, HSCs serve as the main storage site for vitamin A, however, pathological stimuli lead to their transdifferentiation into myofibroblast cells, with autophagy being the key regulator of their activation, through lipophagy of their lipid droplets. Nevertheless, the role of autophagy in liver fibrosis is multifaceted, as increased autophagic levels have been associated with alleviation of the fibrotic process. In addition, it has been found that HSCs receive paracrine stimuli from neighboring cells, such as injured hepatocytes, Kupffer cells, sinusoidal endothelial cells, which promote liver fibrosis. These stimuli have been found to be transmitted via exosomes, which are incorporated by HSCs and can either be degraded through lysosomes or be secreted back into the extracellular space via fusion with the plasma membrane. Furthermore, it has been demonstrated that autophagy and exosomes may be concomitantly or reciprocally regulated, depending on the cellular conditions. Given that increased levels of autophagy are required to activate HSCs, it is important to investigate whether autophagy levels decrease at later stages of hepatic stellate cell activation, leading to increased release of exosomes and further propagation of hepatic fibrosis.
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Affiliation(s)
- Eleftheria M. Mastoridou
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Anna C. Goussia
- Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Georgios K. Glantzounis
- Hepato-Pancreatico-Biliary Unit, Department of Surgery, University General Hospital of Ioannina and School of Medicine, University of Ioannina, Ioannina, Greece
| | - Panagiotis Kanavaros
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Antonia V. Charchanti
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
- *Correspondence: Antonia V. Charchanti,
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25
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Babuta M, Szabo G. Extracellular vesicles in inflammation: Focus on the microRNA cargo of EVs in modulation of liver diseases. J Leukoc Biol 2022; 111:75-92. [PMID: 34755380 PMCID: PMC9235439 DOI: 10.1002/jlb.3mir0321-156r] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs) are heterogeneous nanometer-ranged particles that are released by cells under both normal and pathological conditions. EV cargo comprises of DNA, protein, lipids cargo, metabolites, mRNA, and non-coding RNA that can modulate the immune system by altering inflammatory response. EV associated miRNAs contribute to the pathobiology of alcoholic liver disease, non-alcoholic liver disease, viral hepatitis, acetaminophen-induced liver injury, fibrosis, and hepatocellular carcinoma. In context of liver diseases, EVs, via their cargo, alter the inflammatory response by communicating with different cell types within the liver and between liver and other organs. Here, the role of EVs and its associated miRNA in inter-cellular communication in different liver disease and as a potential biomarker and therapeutic target is reviewed.
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Affiliation(s)
- Mrigya Babuta
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Gyongyi Szabo
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
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26
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Zhao S, Sun Y, Mao Q, Zhou C, Chen Y, Xue D. Exosomal miR-4639 and miR-210 in Plasma and Urine as Biomarkers in IgA Nephropathy. Nephron Clin Pract 2022; 146:539-552. [PMID: 35381590 DOI: 10.1159/000523924] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 03/01/2022] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND It has been widely recognized that exosomal miRNAs can participate in the pathogenesis of different renal disorders and serve as disease biomarkers. Although kidney biopsy is still the gold standard for diagnosing and monitoring immunoglobulin A nephropathy (IgAN), it is highly required to identify new and effective noninvasive biomarkers for IgAN, the most frequently detected primary glomerulonephritis worldwide. METHODS Plasma and urinary exosomes were extracted by PEG precipitation. Size and morphological characteristics of plasma and urinary exosomes were observed by transmission electron microscopy and nanoparticle tracking analysis. The levels of plasma and urinary exosomes were revealed by Western blotting. The expressions of target miRNAs were revealed by in situ hybridization and qRT-PCR. RESULTS The levels of plasma and urinary exosomes were remarkably enhanced in IgAN patients compared with healthy controls (HCs). The expressions of miR-4639 and miR-210 in IgAN patients were significantly higher in contrast to the individuals with membranous nephropathy, minimal change nephrosis, diabetic nephropathy, or HC. These also played a valuable role in assessing the kidney function and the level of proteinuria. Furthermore, plasma and urinary exosomal miR-4639 expression was associated with more serious and active histological activity (mesangial hypercellularity, crescent, and C3 complement deposition). With an average follow-up of 8 months, miR-4639 and miR-210 expressions in plasma and urinary exosomes were higher in patients with progressive IgAN. Plasma exosomal miR-4639 and miR-210 were better than proteinuria (g/24 h) to estimate renal outcomes. CONCLUSION Exosomal miR-4639 and miR-210 could be used as valid biomarkers to assist in diagnosis, evaluate severity, and assess disease development of IgAN.
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Affiliation(s)
- Shuchen Zhao
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Yangyang Sun
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Qingyan Mao
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Cuixing Zhou
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Yimeng Chen
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Dong Xue
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
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27
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MicroRNAs and exosomes: Cardiac stem cells in heart diseases. Pathol Res Pract 2021; 229:153701. [PMID: 34872024 DOI: 10.1016/j.prp.2021.153701] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 11/09/2021] [Accepted: 11/18/2021] [Indexed: 12/20/2022]
Abstract
Treating cardiovascular diseases with cardiac stem cells (CSCs) is a valid treatment among various stem cell-based therapies. With supplying the physiological need for cardiovascular cells as their main function, under pathological circumstances, CSCs can also reproduce the myocardial cells. Although studies have identified many of CSCs' functions, our knowledge of molecular pathways that regulate these functions is not complete enough. Either physiological or pathological studies have shown, stem cells proliferation and differentiation could be regulated by microRNAs (miRNAs). How miRNAs regulate CSC behavior is an interesting area of research that can help us study and control the function of these cells in vitro; an achievement that may be beneficial for patients with cardiovascular diseases. The secretome of stem and progenitor cells has been studied and it has been determined that exosomes are the main source of their secretion which are very small vesicles at the nanoscale and originate from endosomes, which are secreted into the extracellular space and act as key signaling organelles in intercellular communication. Mesenchymal stem cells, cardiac-derived progenitor cells, embryonic stem cells, induced pluripotent stem cells (iPSCs), and iPSC-derived cardiomyocytes release exosomes that have been shown to have cardioprotective, immunomodulatory, and reparative effects. Herein, we summarize the regulation roles of miRNAs and exosomes in cardiac stem cells.
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28
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Mechanistic roles of tyrosine phosphorylation in reversible amyloids, autoinhibition, and endosomal membrane association of ALIX. J Biol Chem 2021; 297:101328. [PMID: 34688656 PMCID: PMC8577116 DOI: 10.1016/j.jbc.2021.101328] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 10/05/2021] [Accepted: 10/06/2021] [Indexed: 11/26/2022] Open
Abstract
Human apoptosis-linked gene-2 interacting protein X (ALIX), a versatile adapter protein, regulates essential cellular processes by shuttling between late endosomal membranes and the cytosol, determined by its interactions with Src kinase. Here, we investigate the molecular basis of these transitions and the effects of tyrosine phosphorylation on the interplay between structure, assembly, and intramolecular and intermolecular interactions of ALIX. As evidenced by transmission electron microscopy, fluorescence and circular dichroism spectroscopy, the proline-rich domain of ALIX, which encodes binding epitopes of multiple cellular partners, formed rope-like β-sheet–rich reversible amyloid fibrils that dissolved upon Src-mediated phosphorylation and were restored on protein-tyrosine phosphatase 1B–mediated dephosphorylation of its conserved tyrosine residues. Analyses of the Bro1 domain of ALIX by solution NMR spectroscopy elucidated the conformational changes originating from its phosphorylation by Src and established that Bro1 binds to hyperphosphorylated proline-rich domain and to analogs of late endosomal membranes via its highly basic surface. These results uncover the autoinhibition mechanism that relocates ALIX to the cytosol and the diverse roles played by tyrosine phosphorylation in cellular and membrane functions of ALIX.
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29
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Wang L, Chen X, Wang L, Wang S, Li W, Liu Y, Zhang J. Knockdown of ST6Gal-I expression in human hepatocellular carcinoma cells inhibits their exosome-mediated proliferation- and migration-promoting effects. IUBMB Life 2021; 73:1378-1391. [PMID: 34559939 DOI: 10.1002/iub.2562] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 09/07/2021] [Accepted: 09/16/2021] [Indexed: 01/15/2023]
Abstract
Abnormal sialylation is a distinctive feature of human hepatocellular carcinoma (HCC) and is closely related to its malignant properties. Exosomes have characteristic protein and lipid composition; however, the results concerning glycoprotein composition and glycosylation are scarce. In this study, liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified multiple microvesicle-related sialylated proteins including CD63, a classic marker of exosomes. The silencing of α2,6-sialyltransferase I (ST6Gal-I) significantly reduced the levels of α2,6-sialylated glycoconjugates on CD63 and the surface of HCC-derived exosomes (HCC-exo). And surface glycoconjugates play important roles in exosomes biogenesis and in their interaction with other cells. Compared to exosomes derived from naive HCC cells, α2,6-sialylation degradation abolished both the proliferation-promoting and migration-promoting effects of HCC-exo. Further analysis revealed that the Akt/GSK-3β or JNK1/2 signaling mediates HCC-exo-mediated proliferation in HCC cells, while ST6Gal-I silencing deactivated this pathway. These findings suggest that a loss of α2,6-sialylation decreases HCC progression through the loss of cancer cell-derived exosomes; furthermore, it opens novel perspectives to further explore the functional role of glycans in the biology of exosomes.
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Affiliation(s)
- Liping Wang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Xixi Chen
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Lingyan Wang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Shujing Wang
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, China
| | - Wenli Li
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Yubo Liu
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Jianing Zhang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
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30
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Saad MH, Badierah R, Redwan EM, El-Fakharany EM. A Comprehensive Insight into the Role of Exosomes in Viral Infection: Dual Faces Bearing Different Functions. Pharmaceutics 2021; 13:1405. [PMID: 34575480 PMCID: PMC8466084 DOI: 10.3390/pharmaceutics13091405] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 08/31/2021] [Accepted: 09/02/2021] [Indexed: 12/13/2022] Open
Abstract
Extracellular vesicles (EVs) subtype, exosome is an extracellular nano-vesicle that sheds from cells' surface and originates as intraluminal vesicles during endocytosis. Firstly, it was thought to be a way for the cell to get rid of unwanted materials as it loaded selectively with a variety of cellular molecules, including RNAs, proteins, and lipids. However, it has been found to play a crucial role in several biological processes such as immune modulation, cellular communication, and their role as vehicles to transport biologically active molecules. The latest discoveries have revealed that many viruses export their viral elements within cellular factors using exosomes. Hijacking the exosomal pathway by viruses influences downstream processes such as viral propagation and cellular immunity and modulates the cellular microenvironment. In this manuscript, we reviewed exosomes biogenesis and their role in the immune response to viral infection. In addition, we provided a summary of how some pathogenic viruses hijacked this normal physiological process. Viral components are harbored in exosomes and the role of these exosomes in viral infection is discussed. Understanding the nature of exosomes and their role in viral infections is fundamental for future development for them to be used as a vaccine or as a non-classical therapeutic strategy to control several viral infections.
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Affiliation(s)
- Mabroka H. Saad
- Protein Research Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), The City of Scientific Research and Technological Applications (SRTA-City), New Borg EL Arab, Alexandria 21934, Egypt; (M.H.S.); (E.M.R.)
| | - Raied Badierah
- Biological Science Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
- Medical Laboratory, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Elrashdy M. Redwan
- Protein Research Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), The City of Scientific Research and Technological Applications (SRTA-City), New Borg EL Arab, Alexandria 21934, Egypt; (M.H.S.); (E.M.R.)
- Biological Science Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Esmail M. El-Fakharany
- Protein Research Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), The City of Scientific Research and Technological Applications (SRTA-City), New Borg EL Arab, Alexandria 21934, Egypt; (M.H.S.); (E.M.R.)
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31
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Grieco GE, Fignani D, Formichi C, Nigi L, Licata G, Maccora C, Brusco N, Sebastiani G, Dotta F. Extracellular Vesicles in Immune System Regulation and Type 1 Diabetes: Cell-to-Cell Communication Mediators, Disease Biomarkers, and Promising Therapeutic Tools. Front Immunol 2021; 12:682948. [PMID: 34177928 PMCID: PMC8219977 DOI: 10.3389/fimmu.2021.682948] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/10/2021] [Indexed: 12/16/2022] Open
Abstract
Extracellular vesicles (EVs) are generated by cells of origin through complex molecular mechanisms and released into extracellular environment. Hence, the presence of EVs has been described in multiple biological fluids and in most cases their molecular cargo, which includes non-coding RNAs (ncRNA), messenger RNAs (mRNA), and proteins, has been reported to modulate distinct biological processes. EVs release and their molecular cargo have been demonstrated to be altered in multiple diseases, including autoimmune diseases. Notably, numerous evidence showed a relevant crosstalk between immune system and interacting cells through specific EVs release. The crosstalk between insulin-producing pancreatic β cells and immune system through EVs bidirectional trafficking has yet started to be deciphered, thus uncovering an intricate communication network underlying type 1 diabetes (T1D) pathogenesis. EVs can also be found in blood plasma or serum. Indeed, the assessment of circulating EVs cargo has been shown as a promising advance in the detection of reliable biomarkers of disease progression. Of note, multiple studies showed several specific cargo alterations of EVs collected from plasma/serum of subjects affected by autoimmune diseases, including T1D subjects. In this review, we discuss the recent literature reporting evidence of EVs role in autoimmune diseases, specifically focusing on the bidirectional crosstalk between pancreatic β cells and immune system in T1D and highlight the relevant promising role of circulating EVs as disease biomarkers.
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Affiliation(s)
- Giuseppina Emanuela Grieco
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Daniela Fignani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Caterina Formichi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy.,UOC Diabetologia, Azienda Ospedaliera Universitaria Senese, Siena, Italy
| | - Laura Nigi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy.,UOC Diabetologia, Azienda Ospedaliera Universitaria Senese, Siena, Italy
| | - Giada Licata
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Carla Maccora
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy.,UOC Diabetologia, Azienda Ospedaliera Universitaria Senese, Siena, Italy
| | - Noemi Brusco
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Guido Sebastiani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Francesco Dotta
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy.,UOC Diabetologia, Azienda Ospedaliera Universitaria Senese, Siena, Italy.,Tuscany Centre for Precision Medicine (CReMeP), Siena, Italy
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32
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Di Santo R, Romanò S, Mazzini A, Jovanović S, Nocca G, Campi G, Papi M, De Spirito M, Di Giacinto F, Ciasca G. Recent Advances in the Label-Free Characterization of Exosomes for Cancer Liquid Biopsy: From Scattering and Spectroscopy to Nanoindentation and Nanodevices. NANOMATERIALS (BASEL, SWITZERLAND) 2021; 11:1476. [PMID: 34199576 PMCID: PMC8230295 DOI: 10.3390/nano11061476] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/24/2021] [Accepted: 05/27/2021] [Indexed: 12/26/2022]
Abstract
Exosomes (EXOs) are nano-sized vesicles secreted by most cell types. They are abundant in bio-fluids and harbor specific molecular constituents from their parental cells. Due to these characteristics, EXOs have a great potential in cancer diagnostics for liquid biopsy and personalized medicine. Despite this unique potential, EXOs are not yet widely applied in clinical settings, with two main factors hindering their translational process in diagnostics. Firstly, conventional extraction methods are time-consuming, require large sample volumes and expensive equipment, and often do not provide high-purity samples. Secondly, characterization methods have some limitations, because they are often qualitative, need extensive labeling or complex sampling procedures that can induce artifacts. In this context, novel label-free approaches are rapidly emerging, and are holding potential to revolutionize EXO diagnostics. These methods include the use of nanodevices for EXO purification, and vibrational spectroscopies, scattering, and nanoindentation for characterization. In this progress report, we summarize recent key advances in label-free techniques for EXO purification and characterization. We point out that these methods contribute to reducing costs and processing times, provide complementary information compared to the conventional characterization techniques, and enhance flexibility, thus favoring the discovery of novel and unexplored EXO-based biomarkers. In this process, the impact of nanotechnology is systematically highlighted, showing how the effectiveness of these techniques can be enhanced using nanomaterials, such as plasmonic nanoparticles and nanostructured surfaces, which enable the exploitation of advanced physical phenomena occurring at the nanoscale level.
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Affiliation(s)
- Riccardo Di Santo
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy; (R.D.S.); (S.R.); (A.M.); (G.N.); (M.P.); (F.D.G.)
| | - Sabrina Romanò
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy; (R.D.S.); (S.R.); (A.M.); (G.N.); (M.P.); (F.D.G.)
- Dipartimento di Neuroscienze, Sezione di Fisica, Università Cattolica Del Sacro Cuore, 00168 Roma, Italy
| | - Alberto Mazzini
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy; (R.D.S.); (S.R.); (A.M.); (G.N.); (M.P.); (F.D.G.)
- Dipartimento di Neuroscienze, Sezione di Fisica, Università Cattolica Del Sacro Cuore, 00168 Roma, Italy
| | - Svetlana Jovanović
- “Vinča” Institute of Nuclear Sciences—National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia;
| | - Giuseppina Nocca
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy; (R.D.S.); (S.R.); (A.M.); (G.N.); (M.P.); (F.D.G.)
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Gaetano Campi
- Rome International Centre Materials Science Superstripes RICMASS, via dei Sabelli 119A, 00185 Rome, Italy;
- Institute of Crystallography, CNR, via Salaria Km 29. 300, Monterotondo Stazione, 00016 Roma, Italy
| | - Massimiliano Papi
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy; (R.D.S.); (S.R.); (A.M.); (G.N.); (M.P.); (F.D.G.)
- Dipartimento di Neuroscienze, Sezione di Fisica, Università Cattolica Del Sacro Cuore, 00168 Roma, Italy
| | - Marco De Spirito
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy; (R.D.S.); (S.R.); (A.M.); (G.N.); (M.P.); (F.D.G.)
- Dipartimento di Neuroscienze, Sezione di Fisica, Università Cattolica Del Sacro Cuore, 00168 Roma, Italy
| | - Flavio Di Giacinto
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy; (R.D.S.); (S.R.); (A.M.); (G.N.); (M.P.); (F.D.G.)
- Dipartimento di Neuroscienze, Sezione di Fisica, Università Cattolica Del Sacro Cuore, 00168 Roma, Italy
| | - Gabriele Ciasca
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy; (R.D.S.); (S.R.); (A.M.); (G.N.); (M.P.); (F.D.G.)
- Dipartimento di Neuroscienze, Sezione di Fisica, Università Cattolica Del Sacro Cuore, 00168 Roma, Italy
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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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Samal S, Dash P, Dash M. Drug Delivery to the Bone Microenvironment Mediated by Exosomes: An Axiom or Enigma. Int J Nanomedicine 2021; 16:3509-3540. [PMID: 34045855 PMCID: PMC8149288 DOI: 10.2147/ijn.s307843] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 03/30/2021] [Indexed: 12/12/2022] Open
Abstract
The increasing incidence of bone-related disorders is causing a burden on the clinical scenario. Even though bone is one of the tissues that possess tremendous regenerative potential, certain bone anomalies need therapeutic intervention through appropriate delivery of a drug. Among several nanosystems and biologics that offer the potential to contribute towards bone healing, the exosomes from the class of extracellular vesicles are outstanding. Exosomes are extracellular nanovesicles that, apart from the various advantages, are standing out of the crowd for their ability to conduct cellular communication. The internal cargo of the exosomes is leading to its potential use in therapeutics. Exosomes are being unraveled in terms of the mechanism as well as application in targeting various diseases and tissues. Through this review, we have tried to understand and review all that is already established and the gap areas that still exist in utilizing them as drug delivery vehicles targeting the bone. The review highlights the potential of the exosomes towards their contribution to the drug delivery scenario in the bone microenvironment. A comparison of the pros and cons of exosomes with other prevalent drug delivery systems is also done. A section on the patents that have been generated so far from this field is included.
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Affiliation(s)
- Sasmita Samal
- Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, 751023, India
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT) University, Bhubaneswar, Odisha, 751024, India
| | - Pratigyan Dash
- Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, 751023, India
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT) University, Bhubaneswar, Odisha, 751024, India
| | - Mamoni Dash
- Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, 751023, India
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35
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Yokoi A, Ochiya T. Exosomes and extracellular vesicles: Rethinking the essential values in cancer biology. Semin Cancer Biol 2021; 74:79-91. [PMID: 33798721 DOI: 10.1016/j.semcancer.2021.03.032] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 03/17/2021] [Accepted: 03/28/2021] [Indexed: 02/07/2023]
Abstract
Extracellular vesicles (EVs) such as exosomes are released by all living cells and contain diverse bioactive molecules, including nucleic acids, proteins, lipids, and metabolites. Accumulating evidence of EV-related functions has revealed that these tiny vesicles can mediate specific cell-to-cell communication. Within the tumor microenvironment, diverse cells are actively interacting with their surroundings via EVs facilitating tumor malignancy by regulating malignant cascades including angiogenesis, immune modulation, and metastasis. This review summarizes the recent studies of fundamental understandings of EVs from the aspect of EV heterogeneity and highlights the role of EVs in the various steps from oncogenic to metastatic processes. The recognition of EV subtypes is necessary to identify which pathways can be affected by EVs and which subtypes can be targeted in therapeutic approaches or liquid biopsies.
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Affiliation(s)
- Akira Yokoi
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Institute for Advanced Research, Nagoya University, Nagoya, Japan
| | - Takahiro Ochiya
- Department of Molecular and Cellular Medicine, Tokyo Medical University, Tokyo, Japan.
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36
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Matrix Vesicles: Role in Bone Mineralization and Potential Use as Therapeutics. Pharmaceuticals (Basel) 2021; 14:ph14040289. [PMID: 33805145 PMCID: PMC8064082 DOI: 10.3390/ph14040289] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 03/18/2021] [Accepted: 03/23/2021] [Indexed: 12/14/2022] Open
Abstract
Bone is a complex organ maintained by three main cell types: osteoblasts, osteoclasts, and osteocytes. During bone formation, osteoblasts deposit a mineralized organic matrix. Evidence shows that bone cells release extracellular vesicles (EVs): nano-sized bilayer vesicles, which are involved in intercellular communication by delivering their cargoes through protein–ligand interactions or fusion to the plasma membrane of the recipient cell. Osteoblasts shed a subset of EVs known as matrix vesicles (MtVs), which contain phosphatases, calcium, and inorganic phosphate. These vesicles are believed to have a major role in matrix mineralization, and they feature bone-targeting and osteo-inductive properties. Understanding their contribution in bone formation and mineralization could help to target bone pathologies or bone regeneration using novel approaches such as stimulating MtV secretion in vivo, or the administration of in vitro or biomimetically produced MtVs. This review attempts to discuss the role of MtVs in biomineralization and their potential application for bone pathologies and bone regeneration.
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37
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Zhang L, Zhang X, Hsieh LS, Lin TV, Bordey A. Rab27a-Dependent Paracrine Communication Controls Dendritic Spine Formation and Sensory Responses in the Barrel Cortex. Cells 2021; 10:cells10030622. [PMID: 33799820 PMCID: PMC8000154 DOI: 10.3390/cells10030622] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/04/2021] [Accepted: 03/05/2021] [Indexed: 11/20/2022] Open
Abstract
Rab27a is an evolutionarily conserved small GTPase that regulates vesicle trafficking, and copy number variants of RAB27a are associated with increased risk of autism. However, the function of Rab27a on brain development is unknown. Here, we identified a form of paracrine communication that regulates spine development between distinct populations of developing cortical neurons. In the developing somatosensory cortex of mice, we show that decreasing Rab27a levels in late-born pyramidal neurons destined for layer (L) 2/3 had no cell-autonomous effect on their synaptic integration but increased excitatory synaptic transmission onto L4 neurons that receive somatosensory information. This effect resulted in an increased number of L4 neurons activated by whisker stimulation in juvenile mice. In addition, we found that Rab27a, the level of which decreases as neurons mature, regulates the release of small extracellular vesicles (sEVs) in developing neurons in vitro and decreasing Rab27a levels led to the accumulation of CD63-positive vesicular compartments in L2/3 neurons in vivo. Together, our study reveals that Rab27a-mediated paracrine communication regulates the development of synaptic connectivity, ultimately tuning responses to sensory stimulation, possibly via controlling the release of sEVs.
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Affiliation(s)
- Longbo Zhang
- Departments of Neurosurgery, and Cellular & Molecular Physiology, School of Medicine, Yale University, 333 Cedar Street, New Haven, CT 06520-8082, USA; (L.Z.); (L.S.H.); (T.V.L.)
| | - Xiaobing Zhang
- Department of Psychology, Florida State University, Tallahassee, FL 32306, USA;
| | - Lawrence S. Hsieh
- Departments of Neurosurgery, and Cellular & Molecular Physiology, School of Medicine, Yale University, 333 Cedar Street, New Haven, CT 06520-8082, USA; (L.Z.); (L.S.H.); (T.V.L.)
| | - Tiffany V. Lin
- Departments of Neurosurgery, and Cellular & Molecular Physiology, School of Medicine, Yale University, 333 Cedar Street, New Haven, CT 06520-8082, USA; (L.Z.); (L.S.H.); (T.V.L.)
| | - Angélique Bordey
- Departments of Neurosurgery, and Cellular & Molecular Physiology, School of Medicine, Yale University, 333 Cedar Street, New Haven, CT 06520-8082, USA; (L.Z.); (L.S.H.); (T.V.L.)
- Correspondence: ; Tel.: +1-203-737-2515; Fax: +1-203-737-2159
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Zhang Y, Li Y, Liu P, Gong D, Zhou H, Li W, Zhang H, Zheng W, Xu J, Cheng H, Zhang X, Ke Y. Phosphatase Shp2 regulates biogenesis of small extracellular vesicles by dephosphorylating Syntenin. J Extracell Vesicles 2021; 10:e12078. [PMID: 33732417 PMCID: PMC7944561 DOI: 10.1002/jev2.12078] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 01/22/2021] [Accepted: 02/22/2021] [Indexed: 12/12/2022] Open
Abstract
As novel mediators of cell‐to‐cell signalling, small extracellular vesicles (sEVs) play a critical role in physiological and pathophysiological processes. To date, the molecular mechanisms that support sEV generation are incompletely understood. Many kinases are reported for their roles in sEV generation or composition, whereas the involvement of phosphatases remains largely unexplored. Here we reveal that pharmacological inhibition and shRNA‐mediated down‐regulation of tyrosine phosphatase Shp2 significantly increases the formation of sEVs. By Co‐immunoprecipitation (Co‐IP) and in vitro dephosphorylation assays, we identified that Shp2 negatively controlled sEV biogenesis by directly dephosphorylating tyrosine 46 of Syntenin, which has been reported as a molecular switch in sEV biogenesis. More importantly, Shp2 dysfunction led to enhanced epithelial sEV generation in vitro and in vivo. The increase of epithelial sEVs caused by shRNA‐mediated down‐regulation of Shp2 promoted macrophage activation, resulting in strengthened inflammation. Our findings highlight the role of Shp2 in regulating sEV‐mediated epithelial‐macrophage crosstalk by controlling sEV biogenesis through dephosphorylation of Syntenin Y46. The present study determines the strengthened inflammatory characteristics of alveolar macrophages elicited by epithelial sEVs transferred intercellularly. These findings provide a basis for understanding the mechanism of sEV formation and relevant function in epithelial‐macrophage crosstalk.
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Affiliation(s)
- Yuefei Zhang
- Department of Pathology and Pathophysiology and Department of Respiratory Medicine at Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310058 China.,Zhejiang Laboratory for Systems and Precision Medicine Zhejiang University Medical Center Hangzhou 311121 China
| | - Yiqing Li
- Department of Pathology and Pathophysiology and Department of Respiratory Medicine at Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310058 China
| | - Pan Liu
- Department of Pathology and Pathophysiology and Department of Respiratory Medicine at Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310058 China
| | - Dacheng Gong
- Department of Pathology and Pathophysiology and Department of Respiratory Medicine at Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310058 China
| | - Hui Zhou
- Department of Pathology and Pathophysiology and Department of Respiratory Medicine at Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310058 China
| | - Wenjuan Li
- Department of Obstetrics and Gynecology Women's hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310058 China
| | - Huilun Zhang
- Department of Pathology and Pathophysiology and Department of Respiratory Medicine at Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310058 China
| | - Wenfang Zheng
- Department of Gastroenterology Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310058 China
| | - Jiaqi Xu
- Department of Pathology Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310058 China
| | - Hongqiang Cheng
- Department of Pathology and Pathophysiology and Department of Cardiology at Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310058 China
| | - Xue Zhang
- Department of Pathology and Pathophysiology and Department of Respiratory Medicine at Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310058 China.,Zhejiang Laboratory for Systems and Precision Medicine Zhejiang University Medical Center Hangzhou 311121 China
| | - Yuehai Ke
- Department of Pathology and Pathophysiology and Department of Respiratory Medicine at Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310058 China.,Zhejiang Laboratory for Systems and Precision Medicine Zhejiang University Medical Center Hangzhou 311121 China
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Pradhan AK, Maji S, Das SK, Emdad L, Sarkar D, Fisher PB. MDA-9/Syntenin/SDCBP: new insights into a unique multifunctional scaffold protein. Cancer Metastasis Rev 2021; 39:769-781. [PMID: 32410111 DOI: 10.1007/s10555-020-09886-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Tumor metastasis comprises a series of coordinated events that culminate in dissemination of cancer cells to distant sites within the body representing the greatest challenge impeding effective therapy of cancer and the leading cause of cancer-associated morbidity. Cancer cells exploit multiple genes and pathways to colonize to distant organs. These pathways are integrated and regulated at different levels by cellular- and extracellular-associated factors. Defining the genes and pathways that govern metastasis can provide new targets for therapeutic intervention. Melanoma differentiation associated gene-9 (mda-9) (also known as Syntenin-1 and SDCBP (Syndecan binding protein)) was identified by subtraction hybridization as a novel gene displaying differential temporal expression during differentiation of melanoma. MDA-9/Syntenin is an established Syndecan binding protein that functions as an adaptor protein. Expression of MDA-9/Syntenin is elevated at an RNA and protein level in a wide-range of cancers including melanoma, glioblastoma, neuroblastoma, and prostate, breast and liver cancer. Expression is increased significantly in metastatic cancer cells as compared with non-metastatic cancer cells or normal cells, which make it an attractive target in treating cancer metastasis. In this review, we focus on the role and regulation of mda-9 in cancer progression and metastasis.
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Affiliation(s)
- Anjan K Pradhan
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA
| | - Santanu Maji
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA
| | - Swadesh K Das
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.,VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.,VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Luni Emdad
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.,VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.,VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.,VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.,VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA. .,VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA. .,VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
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40
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Faria-Ramos I, Poças J, Marques C, Santos-Antunes J, Macedo G, Reis CA, Magalhães A. Heparan Sulfate Glycosaminoglycans: (Un)Expected Allies in Cancer Clinical Management. Biomolecules 2021; 11:136. [PMID: 33494442 PMCID: PMC7911160 DOI: 10.3390/biom11020136] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/15/2021] [Accepted: 01/18/2021] [Indexed: 12/12/2022] Open
Abstract
In an era when cancer glycobiology research is exponentially growing, we are witnessing a progressive translation of the major scientific findings to the clinical practice with the overarching aim of improving cancer patients' management. Many mechanistic cell biology studies have demonstrated that heparan sulfate (HS) glycosaminoglycans are key molecules responsible for several molecular and biochemical processes, impacting extracellular matrix properties and cellular functions. HS can interact with a myriad of different ligands, and therefore, hold a pleiotropic role in regulating the activity of important cellular receptors and downstream signalling pathways. The aberrant expression of HS glycan chains in tumours determines main malignant features, such as cancer cell proliferation, angiogenesis, invasion and metastasis. In this review, we devote particular attention to HS biological activities, its expression profile and modulation in cancer. Moreover, we highlight HS clinical potential to improve both diagnosis and prognosis of cancer, either as HS-based biomarkers or as therapeutic targets.
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Affiliation(s)
- Isabel Faria-Ramos
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, 4200-135 Porto, Portugal; (I.F.-R.); (J.P.); (C.M.); (J.S.-A.); (C.A.R.)
- Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), 4200-135 Porto, Portugal
| | - Juliana Poças
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, 4200-135 Porto, Portugal; (I.F.-R.); (J.P.); (C.M.); (J.S.-A.); (C.A.R.)
- Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), 4200-135 Porto, Portugal
- Molecular Biology Department, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
| | - Catarina Marques
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, 4200-135 Porto, Portugal; (I.F.-R.); (J.P.); (C.M.); (J.S.-A.); (C.A.R.)
- Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), 4200-135 Porto, Portugal
- Molecular Biology Department, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
| | - João Santos-Antunes
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, 4200-135 Porto, Portugal; (I.F.-R.); (J.P.); (C.M.); (J.S.-A.); (C.A.R.)
- Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), 4200-135 Porto, Portugal
- Pathology Department, Faculdade de Medicina, University of Porto, 4200-319 Porto, Portugal;
- Gastroenterology Department, Centro Hospitalar S. João, 4200-319 Porto, Portugal
| | - Guilherme Macedo
- Pathology Department, Faculdade de Medicina, University of Porto, 4200-319 Porto, Portugal;
- Gastroenterology Department, Centro Hospitalar S. João, 4200-319 Porto, Portugal
| | - Celso A. Reis
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, 4200-135 Porto, Portugal; (I.F.-R.); (J.P.); (C.M.); (J.S.-A.); (C.A.R.)
- Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), 4200-135 Porto, Portugal
- Molecular Biology Department, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
- Pathology Department, Faculdade de Medicina, University of Porto, 4200-319 Porto, Portugal;
| | - Ana Magalhães
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, 4200-135 Porto, Portugal; (I.F.-R.); (J.P.); (C.M.); (J.S.-A.); (C.A.R.)
- Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), 4200-135 Porto, Portugal
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Yousif G, Qadri S, Haik M, Haik Y, Parray AS, Shuaib A. Circulating Exosomes of Neuronal Origin as Potential Early Biomarkers for Development of Stroke. Mol Diagn Ther 2021; 25:163-180. [DOI: 10.1007/s40291-020-00508-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/10/2020] [Indexed: 12/11/2022]
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Extracellular Vesicles in Viral Pathogenesis: A Case of Dr. Jekyll and Mr. Hyde. Life (Basel) 2021; 11:life11010045. [PMID: 33450847 PMCID: PMC7828316 DOI: 10.3390/life11010045] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 01/04/2021] [Accepted: 01/11/2021] [Indexed: 02/06/2023] Open
Abstract
Secretion of extracellular vesicles (EVs) is a fundamental property of living cells. EVs are known to transfer biological signals between cells and thus regulate the functional state of recipient cells. Such vesicles mediate the intercellular transport of many biologically active molecules (proteins, nucleic acids, specific lipids) and participate in regulation of key physiological processes. In addition, EVs are involved in the pathogenesis of multiple diseases: infectious, neurodegenerative, and oncological. The current EV classification into microvesicles, apoptotic bodies, and exosomes is based on their size, pathways of cellular biogenesis, and molecular composition. This review is focused on analysis of the role of EVs (mainly exosomes) in the pathogenesis of viral infection. We briefly characterize the biogenesis and molecular composition of various EV types. Then, we consider EV-mediated pro- and anti-viral mechanisms. EV secretion by infected cells can be an important factor of virus spread in target cell populations, or a protective factor limiting viral invasion. The data discussed in this review, on the effect of EV secretion by infected cells on processes in neighboring cells and on immune cells, are of high significance in the search for new therapeutic approaches and for design of new generations of vaccines.
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Gao Y, Raj JU. Extracellular Vesicles as Unique Signaling Messengers: Role in Lung Diseases. Compr Physiol 2020; 11:1351-1369. [PMID: 33294981 DOI: 10.1002/cphy.c200006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Extracellular vesicles (EVs) are lipid bilayer-enclosed extracellular particles carrying rich cargo such as proteins, lipids, and microRNAs with distinct characteristics of their parental cells. EVs are emerging as an important form of cellular communication with the ability to selectively deliver a kit of directional instructions to nearby or distant cells to modulate their functions and phenotypes. According to their biogenesis, EVs can be divided into two groups: those of endocytic origin are called exosomes and those derived from outward budding of the plasma membrane are called microvesicles (also known as ectosomes or microparticles). Under physiological conditions, EVs are actively involved in maintenance of pulmonary hemostasis. However, EVs can contribute to the pathogenesis of diseases such as chronic obstructive pulmonary disease, asthma, acute lung injury/acute respiratory distress syndrome, interstitial lung disease, and pulmonary arterial hypertension. EVs, especially those derived from mesenchymal/stromal stem cells, can also be beneficial and can curb the development of lung diseases. Novel technologies are continuously being developed to minimize the undesirable effects of EVs and also to engineer EVs so that they may have beneficial effects and can be used as therapeutic agents in lung diseases. © 2021 American Physiological Society. Compr Physiol 11:1351-1369, 2021.
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Affiliation(s)
- Yuansheng Gao
- Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China
| | - J Usha Raj
- Department of Pediatrics, College of Medicine at Chicago, University of Illinois, Chicago, Illinois, USA
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44
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Chiabotto G, Pasquino C, Camussi G, Bruno S. Molecular Pathways Modulated by Mesenchymal Stromal Cells and Their Extracellular Vesicles in Experimental Models of Liver Fibrosis. Front Cell Dev Biol 2020; 8:594794. [PMID: 33425900 PMCID: PMC7794013 DOI: 10.3389/fcell.2020.594794] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 11/06/2020] [Indexed: 12/18/2022] Open
Abstract
End-stage liver fibrosis is common to all chronic liver diseases. Since liver transplantation has several limitations, including lack of donors, immunological rejection, and high medical costs, therapeutic alternatives are needed. The administration of mesenchymal stromal cells (MSCs) has been proven effective in tissue regeneration after damage. However, the risk of uncontrolled side effects, such as cellular rejection and tumorigenesis, should be taken into consideration. A safer alternative to MSC transplantation is represented by the MSC secretome, which retains the same beneficial effect of the cell of origin, without showing any considerable side effect. The paracrine effect of MSCs is mainly carried out by secreted particles in the nanometer range, known as extracellular vesicles (EVs) that play a fundamental role in intercellular communication. In this review, we discuss the current literature on MSCs and MSC-EVs, focusing on their potential therapeutic action in liver fibrosis and on their molecular content (proteins and RNA), which contributes in reverting fibrosis and prompting tissue regeneration.
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Affiliation(s)
- Giulia Chiabotto
- Department of Medical Sciences, University of Turin, Turin, Italy.,Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Chiara Pasquino
- Department of Medical Sciences, University of Turin, Turin, Italy.,Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Giovanni Camussi
- Department of Medical Sciences, University of Turin, Turin, Italy.,Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Stefania Bruno
- Department of Medical Sciences, University of Turin, Turin, Italy.,Molecular Biotechnology Center, University of Turin, Turin, Italy
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45
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Cohen MJ, Chirico WJ, Lipke PN. Through the back door: Unconventional protein secretion. Cell Surf 2020; 6:100045. [PMID: 33225116 PMCID: PMC7666356 DOI: 10.1016/j.tcsw.2020.100045] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 09/08/2020] [Accepted: 09/08/2020] [Indexed: 12/19/2022] Open
Abstract
Proteins are secreted from eukaryotic cells by several mechanisms besides the well-characterized classical secretory system. Proteins destined to enter the classical secretory system contain a signal peptide for translocation into the endoplasmic reticulum. However, many proteins lacking a signal peptide are secreted nonetheless. Contrary to conventional belief, these proteins are not just released as a result of membrane damage leading to cell leakage, but are actively packaged for secretion in alternative pathways. They are called unconventionally secreted proteins, and the best-characterized are from fungi and mammals. These proteins have extracellular functions including cell signaling, immune modulation, as well as moonlighting activities different from their well-described intracellular functions. Among the pathways for unconventional secretion are direct transfer across the plasma membrane, release within plasma membrane-derived microvesicles, use of elements of autophagy, or secretion from endosomal/multivesicular body-related components. We review the fungal and metazoan unconventional secretory pathways and their regulation, and propose experimental criteria to identify their mode of secretion.
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Affiliation(s)
- Michael J. Cohen
- The Graduate Center of the City University of New York, United States
- Biology Department, Brooklyn College of the City University of New York, United States
| | - William J. Chirico
- Department of Cell Biology, Molecular and Cellular Biology Program, SUNY Downstate Medical Center, United States
| | - Peter N. Lipke
- The Graduate Center of the City University of New York, United States
- Biology Department, Brooklyn College of the City University of New York, United States
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46
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Umbaugh DS, Jaeschke H. Extracellular vesicles: Roles and applications in drug-induced liver injury. Adv Clin Chem 2020; 102:63-125. [PMID: 34044913 DOI: 10.1016/bs.acc.2020.08.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Extracellular vesicles (EV) are defined as nanosized particles, with a lipid bilayer, that are unable to replicate. There has been an exponential increase of research investigating these particles in a wide array of diseases and deleterious states (inflammation, oxidative stress, drug-induced liver injury) in large part due to increasing recognition of the functional capacity of EVs. Cells can package lipids, proteins, miRNAs, DNA, and RNA into EVs and send these discrete packages of molecular information to distant, recipient cells to alter the physiological state of that cell. EVs are innately heterogeneous as a result of the diverse molecular pathways that are used to generate them. However, this innate heterogeneity of EVs is amplified due to the diversity in isolation techniques and lack of standardized nomenclature in the literature making it unclear if one scientist's "exosome" is another scientist's "microvesicle." One goal of this chapter is to provide the contextual understanding of EV origin so one can discern between divergent nomenclature. Further, the chapter will explore the potential protective and harmful roles that EVs play in DILI, and the potential of EVs and their cargo as a biomarker. The use of EVs as a therapeutic as well as a vector for therapeutic delivery will be discussed.
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Affiliation(s)
- David S Umbaugh
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States.
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47
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Atkin-Smith GK, Miles MA, Tixeira R, Lay FT, Duan M, Hawkins CJ, Phan TK, Paone S, Mathivanan S, Hulett MD, Chen W, Poon IKH. Plexin B2 Is a Regulator of Monocyte Apoptotic Cell Disassembly. Cell Rep 2020; 29:1821-1831.e3. [PMID: 31722200 DOI: 10.1016/j.celrep.2019.10.014] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 09/10/2019] [Accepted: 10/03/2019] [Indexed: 12/18/2022] Open
Abstract
Billions of cells undergo apoptosis daily and often fragment into small, membrane-bound extracellular vesicles termed apoptotic bodies (ApoBDs). We demonstrate that apoptotic monocytes undergo a highly coordinated disassembly process and form long, beaded protrusions (coined as beaded apoptopodia), which fragment to release ApoBDs. Here, we find that the protein plexin B2 (PlexB2), a transmembrane receptor that regulates axonal guidance in neurons, is enriched in the ApoBDs of THP1 monocytes and is a caspase 3/7 substrate. To determine whether PlexB2 is involved in the disassembly of apoptotic monocytes, we generate PlexB2-deficient THP1 monocytes and demonstrate that lack of PlexB2 impairs the formation of beaded apoptopodia and ApoBDs. Consequently, the loss of PlexB2 in apoptotic THP1 monocytes impairs their uptake by both professional and non-professional phagocytes. Altogether, these data identify PlexB2 as a positive regulator of apoptotic monocyte disassembly and demonstrate the importance of this process in apoptotic cell clearance.
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Affiliation(s)
- Georgia K Atkin-Smith
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia
| | - Mark A Miles
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia
| | - Rochelle Tixeira
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia
| | - Fung T Lay
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia
| | - Mubing Duan
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia
| | - Christine J Hawkins
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia
| | - Thanh Kha Phan
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia
| | - Stephanie Paone
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia
| | - Suresh Mathivanan
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia
| | - Mark D Hulett
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia
| | - Weisan Chen
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia
| | - Ivan K H Poon
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
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48
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Sedykh S, Kuleshova A, Nevinsky G. Milk Exosomes: Perspective Agents for Anticancer Drug Delivery. Int J Mol Sci 2020; 21:E6646. [PMID: 32932782 PMCID: PMC7555228 DOI: 10.3390/ijms21186646] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/05/2020] [Accepted: 09/09/2020] [Indexed: 12/11/2022] Open
Abstract
Exosomes are biological nanovesicles that participate in intercellular communication by transferring biologically active chemical compounds (proteins, microRNA, mRNA, DNA, and others). Due to their small size (diameter 40-100 nm) and high biological compatibility, exosomes are promising delivery tools in personalized therapy. Because artificial exosome synthesis methods are not developed yet, the urgent task is to develop an effective and safe way to obtain exosomes from natural sources. Milk is the only exosome-containing biological fluid that is commercially available. In this regard, milk exosomes are unique and promising candidates for new therapeutic approaches to treating various diseases, including cancer. The appearance of side effects during the use of cytotoxic and cytostatic agents is among the main problems in cancer chemotherapy. According to this, the targeted delivery of chemotherapeutic agents can be a potential solution to the toxic effect of chemotherapy. The ability of milk exosomes to carry out biologically active substances to the cell makes them promising tools for oral delivery of chemotherapeutic agents. This review is devoted to the methods of milk exosome isolation, their biological components, and prospects for their use in cancer treatment.
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Affiliation(s)
- Sergey Sedykh
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 630090 Novosibirsk, Russia; (A.K.); (G.N.)
- Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia
| | - Anna Kuleshova
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 630090 Novosibirsk, Russia; (A.K.); (G.N.)
- Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia
| | - Georgy Nevinsky
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 630090 Novosibirsk, Russia; (A.K.); (G.N.)
- Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia
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49
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Ma ZJ, Yang JJ, Lu YB, Liu ZY, Wang XX. Mesenchymal stem cell-derived exosomes: Toward cell-free therapeutic strategies in regenerative medicine. World J Stem Cells 2020; 12:814-840. [PMID: 32952861 PMCID: PMC7477653 DOI: 10.4252/wjsc.v12.i8.814] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 04/23/2020] [Accepted: 06/27/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells with marked potential for regenerative medicine because of their strong immunosuppressive and regenerative abilities. The therapeutic effects of MSCs are based in part on their secretion of biologically active factors in extracellular vesicles known as exosomes. Exosomes have a diameter of 30-100 nm and mediate intercellular communication and material exchange. MSC-derived exosomes (MSC-Exos) have potential for cell-free therapy for diseases of, for instance, the kidney, liver, heart, nervous system, and musculoskeletal system. Hence, MSC-Exos are an alternative to MSC-based therapy for regenerative medicine. We review MSC-Exos and their therapeutic potential for a variety of diseases and injuries.
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Affiliation(s)
- Zhan-Jun Ma
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Jing-Jing Yang
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Yu-Bao Lu
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Zhao-Yang Liu
- Department of Medical Imaging, Shanxi Medical University, Jinzhong 030600, Shaanxi Province, China
| | - Xue-Xi Wang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, Gansu Province, China.
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50
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Hassanpour M, Rezabakhsh A, Rezaie J, Nouri M, Rahbarghazi R. Exosomal cargos modulate autophagy in recipient cells via different signaling pathways. Cell Biosci 2020; 10:92. [PMID: 32765827 PMCID: PMC7395405 DOI: 10.1186/s13578-020-00455-7] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 07/25/2020] [Indexed: 02/07/2023] Open
Abstract
Vesicular system of mammalian cells is composed of two intracellular and extracellular vesicles systems, which contributes to the intra/intercellular communication and cellular homeostasis. These systems mediate transferring of biological molecules like proteins, nucleic acids, and lipids inside the cytoplasm, and between the cells. By the present study, authors describe molecular crosslink between exosome biogenesis and autophagy and take a certain focus on the autophagic cargos of exosomes and signaling pathways involved in exosome-induced autophagy in target cells and vice versa. Autophagy the generation of double-phospholipid vesicles, is a process that engulfs damaged proteins and organelles, share molecular similarity and function synergy with exosomes biogenesis for degradation or exocytosis of certain cargo. Exosomes, the smallest subtype of extracellular vesicles, originating from the membrane of the multivesicular body located inside cells demonstrate key roles in the intracellular and intercellular communication. Growing evidence demonstrates the interaction between exosome biogenesis and autophagy both at intertwined molecular pathways and crossbred vesicles known as amphisomes. Crosstalk between exosome biogenesis and autophagy contributes to maintain cellular homeostasis under external and internal stresses. Moreover, these processes can modulate each other via different signaling pathways. Exosomes contain autophagic cargos that induce autophagy via the cascade of molecular events in target cells, which called here exosome-induced autophagy. Taken together, crosstalk between exosome biogenesis and autophagy plays pivotal roles in cell homeostasis. Shedding light on the interaction between endomembrane systems may promote our knowledge about the relation between exosome and autophagy pathways in lysosome-related disorders against treatments; proposing a theoretical approach for therapy.
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Affiliation(s)
- Mehdi Hassanpour
- Stem Cell Research Center, Tabriz University of Medical Sciences, Imam Reza St., Golgasht St., Tabriz, 5166614756 Iran.,Department of Clinical Biochemistry and Laboratory Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aysa Rezabakhsh
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jafar Rezaie
- Solid Tumor Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, P.O. Box: 1138, Shafa St, Ershad Blvd., Urmia, 57147 Iran
| | - Mohammad Nouri
- Stem Cell Research Center, Tabriz University of Medical Sciences, Imam Reza St., Golgasht St., Tabriz, 5166614756 Iran.,Department of Clinical Biochemistry and Laboratory Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Imam Reza St., Golgasht St., Tabriz, 5166614756 Iran.,Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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