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Saeedi P, Nilchiani LS, Zand B, Hajimirghasemi M, Halabian R. An overview of stem cells and cell products involved in trauma injury. Regen Ther 2025; 29:60-76. [PMID: 40143930 PMCID: PMC11938091 DOI: 10.1016/j.reth.2025.02.011] [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: 11/14/2024] [Revised: 02/01/2025] [Accepted: 02/20/2025] [Indexed: 03/28/2025] Open
Abstract
Trauma injuries represent a significant public health burden worldwide, often leading to long-term disability and reduced quality of life. This review provides a comprehensive overview of the therapeutic potential of stem cells and cell products for traumatic injuries. The extraordinary characteristics of stem cells, such as self-renewal and transdifferentiation, make them definitive candidates for tissue regeneration. Mesenchymal stem cells (MSCs), neural stem cells (NSCs), and hematopoietic stem cells (HSCs) have been tested in preclinical studies for treating distinct traumatic injuries. Stem cell mechanisms of action are addressed through paracrine signaling, immunomodulation, differentiation, and neuroprotection. Cell products such as conditioned media, exosomes, and secretomes offer cell-free resources, thereby avoiding the risks of live cell transplantation. Clinical trials have reported many effective outcomes; however, variability exists across trauma types. Some challenges include tumorigenicity, standardized protocols, and regulatory issues. Collaboration and interdisciplinary research are being conducted to harness stem cells and products for trauma treatment. This emerging field is promising for improving patient recovery and quality of life after traumatic injuries.
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Affiliation(s)
- Pardis Saeedi
- Research Center for Health Management in Mass Gathering, Red Crescent Society of the Islamic Republic of Iran, Tehran, Iran
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Leila Sadat Nilchiani
- Department of Molecular and Cell Biology, Faculty of Advanced Sciences and Technology, Islamic Azad University Tehran Medical Sciences, Tehran, Iran
| | - Bita Zand
- Department of Molecular and Cell Biology, Faculty of Advanced Sciences and Technology, Islamic Azad University Tehran Medical Sciences, Tehran, Iran
| | - Maryam Hajimirghasemi
- Department of Internal Medicine, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Raheleh Halabian
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Tozak Yıldız H, Kalkan KT, Baydilli N, Gönen ZB, Cengiz Mat Ö, Köseoğlu E, Önder GÖ, Yay A. Extracellular vesicles therapy alleviates cisplatin-ınduced testicular tissue toxicity in a rat model. PLoS One 2025; 20:e0314093. [PMID: 40315228 PMCID: PMC12047789 DOI: 10.1371/journal.pone.0314093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 11/05/2024] [Indexed: 05/04/2025] Open
Abstract
PURPOSE Cisplatin is a commonly used chemotherapy agent effective against various cancers, however it induces significant gonadotoxicity and infertility due to its adverse effects on testicular function. The underlying mechanisms of cisplatin-induced testicular damage include oxidative stress and dysregulated autophagy. This study investigates the potential of extracellular vesicles (EVs) to mitigate cisplatin-induced testicular damage through their regenerative, antioxidant, and autophagy-modulating properties. METHODS In the testicular toxicity model, thirty-two male rats were randomly divided into four groups (n = 8): control, EVs-only, Cis-only, and Cis + EVs. A single intraperitoneal dose of 7.5mg/kg cisplatin was administered on the first day. On the six day, the EVs treatment group received a single dose of EVs (8x107/100μl) intravenously. Animals were sacrificed on day eight. Testicular histoarchitecture was assessed via hematoxylin and eosin staining. Sperm parameters, including motility and count, were measured using light microscopy. Hormone levels (testosterone and inhibin) were determined via enzyme-linked immunosorbent assay (ELISA). Oxidative stress markers, such as glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), catalase (CAT), and is a metabolite malondialdehyde (MDA), were quantified using colorimetric assays. Autophagy and steroidogenesis were evaluated through immunohistochemical analysis of Beclin-1, p62, LC3-2, SF-1, and StAR. RESULTS Cisplatin exposure caused significant testicular damage, characterized by reduced germinal epithelium and degeneration of seminiferous tubules (p < 0.001). These structural changes led to hormonal imbalances, as evidenced by declines in testosterone (p < 0.005) and inhibin (p < 0.001). Additionally, sperm motility (p < 0.05) and count (p < 0.001) were adversely affected. Immunohistochemical analysis revealed upregulation of autophagy markers (p < 0.001), indicating heightened autophagic activity, alongside downregulation of steroidogenic factors (p < 0.001), which contributed to impaired steroidogenesis. Elevated levels of malondialdehyde (MDA) (p < 0.01) and decreased activities of antioxidant enzymes-GSH-PX, SOD, and CAT (p < 0.001) pointed to increased oxidative stress as a contributing mechanism. In contrast, treatment with extracellular vesicles (EVs) significantly improved testicular histoarchitecture (p < 0.001) and restored hormonal levels toward normal (testosterone p < 0.005, inhibin p < 0.001). Furthermore, EVs reduced the expression of autophagy markers (p < 0.001) and enhanced the levels of steroidogenic factors (p < 0.05). Notably, MDA levels decreased (p < 0.001), while antioxidant activities increased (p < 0.001), suggesting a protective effect of EVs against oxidative stress. CONCLUSION EVs protect against cisplatin-induced reproductive toxicity by modulating oxidative stress and autophagy pathways, preserving testicular function and fertility. These findings suggest that EVs may be a promising therapeutic strategy for mitigating cisplatin's negative effects on reproductive health. Further exploration of dosing regimens and localized applications is recommended for improved efficacy.
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Affiliation(s)
- Halime Tozak Yıldız
- Department of Histology and Embryology, Faculty of Medicine, Kirsehir Ahi Evran University, Kirsehir, Turkey
| | - Kübra Tuğçe Kalkan
- Department of Histology and Embryology, Faculty of Medicine, Kirsehir Ahi Evran University, Kirsehir, Turkey
| | - Numan Baydilli
- Department of Urology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Zeynep Burçin Gönen
- Betül-Ziya Eren Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri, Turkey
| | - Özge Cengiz Mat
- Department of Histology and Embryology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Eda Köseoğlu
- Department of Histology and Embryology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Gözde Özge Önder
- Department of Histology and Embryology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Arzu Yay
- Department of Histology and Embryology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
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An J, Chen B, Zhang R, Tian D, Shi K, Zhang L, Zhang G, Wang J, Yang H. Therapeutic Potential of Mesenchymal Stem Cell-Derived Exosomes in Spinal Cord Injury. Mol Neurobiol 2025; 62:1291-1315. [PMID: 39312070 DOI: 10.1007/s12035-024-04490-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 09/10/2024] [Indexed: 01/04/2025]
Abstract
Spinal cord injury (SCI) can lead to severe motor and sensory dysfunction, with a high rate of disability and mortality. Due to the complicated pathological process of SCI, there is no effective clinical treatment strategy at present. Although mesenchymal stem cells (MSCs) are effective in the treatment of SCI, their application is limited by factors such as low survival rate, cell dedifferentiation, tumorigenesis, blood-brain barrier, and immune rejection. Fortunately, there is growing evidence that most of the biological and therapeutic effects of MSCs may be mediated by the release of paracrine factors, which are extracellular vesicles called exosomes. Exosomes are small endosomal vesicles with bilaminar membranes that have recently been recognized as key mediators for communication between cells and tissues through the transfer of proteins, lipids, nucleic acids, cytokines, and growth factors. Mesenchymal stem cell-derived exosomes (MSC-exos) play a critical role in SCI repair by promoting angiogenesis and axonal growth, regulating inflammation and immune response, inhibiting apoptosis, and maintaining the integrity of the blood-spinal cord barrier. Furthermore, they can be used to transport genetic material or drugs to target cells, and their relatively small size allows them to permeate the blood-brain barrier. Studies have demonstrated that some exosomal miRNAs derived from MSCs play a significant role in the treatment of SCI. In this review, we summarize recent research advances in MSC-exos and exosomal miRNAs in SCI therapy to better understand this emerging cell-free therapeutic strategy and discuss the advantages and challenges of MSC-exos in future clinical applications.
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Affiliation(s)
- Jing An
- Translational Medicine Centre, Honghui Hospital, Xi'an Jiaotong University, Beilin District, 555 East Youyi Road, Xi'an, 710054, Shaanxi, China
| | - Bo Chen
- Translational Medicine Centre, Honghui Hospital, Xi'an Jiaotong University, Beilin District, 555 East Youyi Road, Xi'an, 710054, Shaanxi, China.
| | - Rui Zhang
- Department of Medical Technology, Guiyang Healthcare Vocational University, Guiyang, 550081, Guizhou, China
| | - Ding Tian
- Translational Medicine Centre, Honghui Hospital, Xi'an Jiaotong University, Beilin District, 555 East Youyi Road, Xi'an, 710054, Shaanxi, China
| | - Kuohao Shi
- Translational Medicine Centre, Honghui Hospital, Xi'an Jiaotong University, Beilin District, 555 East Youyi Road, Xi'an, 710054, Shaanxi, China
| | - Lingling Zhang
- Translational Medicine Centre, Honghui Hospital, Xi'an Jiaotong University, Beilin District, 555 East Youyi Road, Xi'an, 710054, Shaanxi, China
| | - Gaorong Zhang
- Translational Medicine Centre, Honghui Hospital, Xi'an Jiaotong University, Beilin District, 555 East Youyi Road, Xi'an, 710054, Shaanxi, China
| | - Jingchao Wang
- Translational Medicine Centre, Honghui Hospital, Xi'an Jiaotong University, Beilin District, 555 East Youyi Road, Xi'an, 710054, Shaanxi, China
| | - Hao Yang
- Translational Medicine Centre, Honghui Hospital, Xi'an Jiaotong University, Beilin District, 555 East Youyi Road, Xi'an, 710054, Shaanxi, China.
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Rufo-Martín C, Infante-García D, Díaz-Álvarez J, Miguélez H, Youssef G. Printable and Tunable Bioresin with Strategically Decorated Molecular Structures. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025; 37:e2412338. [PMID: 39648663 DOI: 10.1002/adma.202412338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 11/07/2024] [Indexed: 12/10/2024]
Abstract
As personalized medicine rapidly evolves, there is a critical demand for advanced biocompatible materials surpassing current additive manufacturing capabilities. This study presents a novel printable bioresin engineered with tunable mechanical, thermal, and biocompatibility properties through strategic molecular modifications. The study introduces a new bioresin comprising methyl methacrylate (MMA), ethylene glycol dimethacrylate (EGDMA), and a photoinitiator, which is further enhanced by incorporating high molecular weight polymethyl methacrylate (PMMA) to improve biostability and mechanical performance. The integration of printable PMMA presents several synthesis and processing challenges, necessitating substantial modifications to the 3D printing process. Additionally, the bioresin is functionalized with antibacterial silver oxide and bone-growth-promoting hydroxyapatite at various weight ratios to extend its application further. The results demonstrate the agile printability of the novel bioresin and its potential for transformative impact in biomedical applications, offering a versatile material platform for additive manufacturing-enabled personalized medicine. This work highlights the adaptability of the novel printable bioresin for real-life applications and its capacity for multiscale structural tailoring, potentially achieving properties comparable to native tissues and extending beyond conventional additive manufacturing techniques.
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Affiliation(s)
- Celia Rufo-Martín
- Experimental Mechanics Laboratory, Mechanical Engineering Department, San Diego State University, 5500 Campanile Drive, San Diego, CA, 92182, USA
- Advanced Manufacturing Hub, San Diego State University, 5500 Campanile Drive, San Diego, CA, 92182, USA
- Department of Mechanical Engineering, Universidad Carlos III de Madrid, Avda. de la Universidad 30, Leganés, 28911, Madrid, Spain
| | - Diego Infante-García
- Institute of Mechanical and Biomechanical Engineering, I2MB, Department of Mechanical Engineering and Materials, Universitat Politècnica de València, Camino de Vera, Valencia, 46022, Spain
| | - José Díaz-Álvarez
- Department of Mechanical Engineering, Universidad Carlos III de Madrid, Avda. de la Universidad 30, Leganés, 28911, Madrid, Spain
| | - Henar Miguélez
- Department of Mechanical Engineering, Universidad Carlos III de Madrid, Avda. de la Universidad 30, Leganés, 28911, Madrid, Spain
| | - George Youssef
- Experimental Mechanics Laboratory, Mechanical Engineering Department, San Diego State University, 5500 Campanile Drive, San Diego, CA, 92182, USA
- Advanced Manufacturing Hub, San Diego State University, 5500 Campanile Drive, San Diego, CA, 92182, USA
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Lu X, Wang Y, Piao C, Li P, Cao L, Liu T, Ma Y, Wang H. Exosomes Derived from Adipose Mesenhymal Stem Cells Ameliorate Lipid Metabolism Disturbances Following Liver Ischemia-Reperfusion Injury in Miniature Swine. Int J Mol Sci 2024; 25:13069. [PMID: 39684778 DOI: 10.3390/ijms252313069] [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: 11/01/2024] [Revised: 12/02/2024] [Accepted: 12/03/2024] [Indexed: 12/18/2024] Open
Abstract
The liver plays a crucial role in regulating lipid metabolism. Our study examined the impact of Exosomes derived from adipose mesenchymal stem cells (ADSCs-Exo) on lipid metabolism following liver ischemia-reperfusion injury (IRI) combined with partial hepatectomy. We developed a miniature swine model for a minimally invasive hemi-hepatectomy combined with liver IRI. In this study, we administered PBS, ADSCs-Exo, and adipose-derived stem cells (ADSCs) individually through the portal vein. Before and after surgery, we evaluated various factors including hepatocyte ultrastructure, lipid accumulation in liver tissue, and expression levels of genes and proteins associated with lipid metabolism. In addition, we measured serum and liver tissue levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), and total cholesterol (CHOL). TEM and oil red O stain indicated a significant reduction in liver steatosis following ADSCs-Exo treatment, which also elevated serum levels of HDL, LDL, TG, and CHOL. Additionally, ADSCs-Exo have been shown to significantly decrease serum concentrations of HDL, LDL, TG, and CHOL in the liver (p < 0.05). Finally, ADSCs-Exo significantly downregulated lipid synthesis-related genes and proteins, including SREBP-1, SREBP-2, ACC1, and FASN (p < 0.05), while upregulating lipid catabolism-related genes and proteins, such as PPAR-α and ACOX1 (p < 0.05). ADSCs-Exo as a cell-free therapy highlights its therapeutic potential in hepatic lipid metabolism abnormalities.
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Affiliation(s)
- Xiangyu Lu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Harbin 150030, China
| | - Yue Wang
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Harbin 150030, China
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China
| | - Chenxi Piao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Harbin 150030, China
| | - Pujun Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Harbin 150030, China
| | - Lei Cao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Harbin 150030, China
| | - Tao Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Harbin 150030, China
| | - Yajun Ma
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Harbin 150030, China
| | - Hongbin Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Harbin 150030, China
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He J, Ao C, Li M, Deng T, Zheng S, Zhang K, Tu C, Ouyang Y, Lang R, Jiang Y, Yang Y, Li C, Wu D. Clusterin-carrying extracellular vesicles derived from human umbilical cord mesenchymal stem cells restore the ovarian function of premature ovarian failure mice through activating the PI3K/AKT pathway. Stem Cell Res Ther 2024; 15:300. [PMID: 39272156 PMCID: PMC11401318 DOI: 10.1186/s13287-024-03926-7] [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: 04/30/2024] [Accepted: 09/05/2024] [Indexed: 09/15/2024] Open
Abstract
BACKGROUND Emerging evidence has highlighted the therapeutic potential of human umbilical cord mesenchymal stem cells (UC-MSCs) in chemotherapy-induced premature ovarian failure (POF). This study was designed to investigate the appropriate timing and molecular mechanism of UC-MSCs treatment for chemotherapy-induced POF. METHODS Ovarian structure and function of mice were assessed every 3 days after injections with cyclophosphamide (CTX) and busulfan (BUS). UC-MSCs and UC-MSCs-derived extracellular vesicles (EVs) were infused into mice via the tail vein, respectively. Ovarian function was analyzed by follicle counts, the serum levels of hormones and ovarian morphology. The apoptosis and proliferation of ovarian granulosa cells were analyzed in vitro and in vivo. Label-free quantitative proteomics was used to detect the differentially expressed proteins in UC-MSC-derived EVs. RESULTS After CTX/BUS injection, we observed that the ovarian function of POF mice was significantly deteriorated on day 9 after CTX/BUS infusion. TUNEL assay indicated that the number of apoptotic cells in the ovaries of POF mice was significantly higher than that in normal mice on day 3 after CTX/BUS injection. Transplantation of UC-MSCs on day 6 after CTX/BUS injection significantly improved ovarian function, enhanced proliferation and inhibited apoptosis of ovarian granulosa cells, whereas the therapeutic effect of UC-MSCs transplantation decreased on day 9, or day 12 after CTX/BUS injection. Moreover, EVs derived from UC-MSCs exerted similar therapeutic effects on POF. UC-MSCs-derived EVs could activate the PI3K/AKT signaling pathway and reduce ovarian granulosa cell apoptosis. Quantitative proteomics analysis revealed that clusterin (CLU) was highly expressed in the EVs of UC-MSCs. The supplementation of CLU proteins prevented ovarian granulosa cells from chemotherapy-induced apoptosis. Further mechanistic analysis showed that CLU-knockdown blocked the PI3K/AKT signaling and reversed the protective effects of UC-MSCs-derived EVs. CONCLUSIONS Administration of UC-MSCs and UC-MSCs-derived EVs on day 6 of CTX/BUS injection could effectively improve the ovarian function of POF mice. UC-MSCs-derived EVs carrying CLU promoted proliferation and inhibited apoptosis of ovarian granulosa cells through activating the PI3K/AKT pathway. This study identifies a previously unrecognized molecular mechanism of UC-MSCs-mediated protective effects on POF, which pave the way for the use of cell-free therapeutic approach for POF.
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Affiliation(s)
- Jing He
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical Sciences, Wuhan, China
| | - Chunchun Ao
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical Sciences, Wuhan, China
| | - Mao Li
- College of Life Sciences, Hubei University, Wuhan, China
| | - Taoran Deng
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuo Zheng
- R&D Center, Wuhan Hamilton Biotechnology Co., Ltd, Wuhan, China
| | - Ke Zhang
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical Sciences, Wuhan, China
| | - Chengshu Tu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yu Ouyang
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical Sciences, Wuhan, China
| | - Ruibo Lang
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical Sciences, Wuhan, China
| | - Yijia Jiang
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical Sciences, Wuhan, China
| | - Yifan Yang
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical Sciences, Wuhan, China
| | - Changyong Li
- Department of Physiology, Wuhan University School of Basic Medical Sciences, Wuhan, China.
- Xianning Medical College, Hubei University of Science and Technology, Xianning, China.
| | - Dongcheng Wu
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical Sciences, Wuhan, China.
- R&D Center, Wuhan Hamilton Biotechnology Co., Ltd, Wuhan, China.
- R&D Center, Guangzhou Hamilton Biotechnology Co., Ltd, Guangzhou, China.
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Gordon J, Borlongan CV. An update on stem cell therapy for stroke patients: Where are we now? J Cereb Blood Flow Metab 2024; 44:1469-1479. [PMID: 38639015 PMCID: PMC11418600 DOI: 10.1177/0271678x241227022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/17/2023] [Accepted: 11/29/2023] [Indexed: 04/20/2024]
Abstract
With a foundation built upon initial work from the 1980s demonstrating graft viability in cerebral ischemia, stem cell transplantation has shown immense promise in promoting survival, enhancing neuroprotection and inducing neuroregeneration, while mitigating both histological and behavioral deficits that frequently accompany ischemic stroke. These findings have led to a number of clinical trials that have thoroughly supported a strong safety profile for stem cell therapy in patients but have generated variable efficacy. As preclinical evidence continues to expand through the investigation of new cell lines and optimization of stem cell delivery, it remains critical for translational models to adhere to the protocols established through basic scientific research. With the recent shift in approach towards utilization of stem cells as a conjunctive therapy alongside standard thrombolytic treatments, key issues including timing, route of administration, and stem cell type must each be appropriately translated from the laboratory in order to resolve the question of stem cell efficacy for cerebral ischemia that ultimately will enhance therapeutics for stroke patients towards improving quality of life.
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Affiliation(s)
- Jonah Gordon
- Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Cesar V Borlongan
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
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Zhang XT, Zhao BW, Zhang YL, Chen S. Human umbilical cord mesenchymal stem cells derived-exosomes on VEGF-A in hypoxic-induced mice retinal astrocytes and mice model of retinopathy of prematurity. Int J Ophthalmol 2024; 17:1238-1247. [PMID: 39026907 PMCID: PMC11246947 DOI: 10.18240/ijo.2024.07.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 04/01/2024] [Indexed: 07/20/2024] Open
Abstract
AIM To observe the effect of human umbilical cord mesenchymal stem cells (hUCMSCs) secretions on the relevant factors in mouse retinal astrocytes, and to investigate the effect of hUCMSCs on the expression of vascular endothelial growth factor-A (VEGF-A) and to observe the therapeutic effect on the mouse model of retinopathy of prematurity (ROP). METHODS Cultured hUCMSCs and extracted exosomes from them and then retinal astrocytes were divided into control group and hypoxia group. MTT assay, flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were used to detect related indicators. Possible mechanisms by which hUCMSCs exosomes affect VEGF-A expression in hypoxia-induced mouse retinal astrocytes were explored. At last, the efficacy of exosomes of UCMSCs in a mouse ROP model was explored. Graphpad6 was used to comprehensively process data information. RESULTS The secretion was successfully extracted from the culture supernatant of hUCMSCs by gradient ultracentrifugation. Reactive oxygen species (ROS) and hypoxia inducible factor-1α (HIF-1α) of mice retinal astrocytes under different hypoxia time and the expression level of VEGF-A protein and VEGF-A mRNA increased, and the ROP cell model was established after 6h of hypoxia. The secretions of medium and high concentrations of hUCMSCs can reduce ROS and HIF-1α, the expression levels of VEGF-A protein and VEGF-A mRNA are statistically significant and concentration dependent. Compared with the ROP cell model group, the expression of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signal pathway related factors in the hUCMSCs exocrine group is significantly decreased. The intravitreal injection of the secretions of medium and high concentrations of hUCMSCs can reduce VEGF-A and HIF-1α in ROP model tissues. HE staining shows that the number of retinal neovascularization in ROP mice decreases with the increase of the dose of hUCMSCs secretion. CONCLUSION In a hypoxia induced mouse retinal astrocyte model, hUCMSCs exosomes are found to effectively reduce the expression of HIF-1α and VEGF-A, which are positively correlated with the concentration of hUCMSCs exosomes. HUCMSCs exosomes can effectively reduce the number of retinal neovascularization and the expression of HIF-1α and VEGF-A proteins in ROP mice, and are positively correlated with drug dosage. Besides, they can reduce the related factors on the PI3K/AKT/mTOR signaling pathway.
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Affiliation(s)
- Xiao-Tian Zhang
- Tianjin Eye Hospital, Tianjin 300020, China
- Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin 300020, China
| | - Bo-Wen Zhao
- Tianjin Eye Hospital, Tianjin 300020, China
- Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin 300020, China
| | - Yuan-Long Zhang
- Tianjin Eye Hospital, Tianjin 300020, China
- Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin 300020, China
| | - Song Chen
- Tianjin Eye Hospital, Tianjin 300020, China
- Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin 300020, China
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Chowdhury R, Eslami S, Pham CV, Rai A, Lin J, Hou Y, Greening DW, Duan W. Role of aptamer technology in extracellular vesicle biology and therapeutic applications. NANOSCALE 2024; 16:11457-11479. [PMID: 38856692 DOI: 10.1039/d4nr00207e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2024]
Abstract
Extracellular vesicles (EVs) are cell-derived nanosized membrane-bound vesicles that are important intercellular signalling regulators in local cell-to-cell and distant cell-to-tissue communication. Their inherent capacity to transverse cell membranes and transfer complex bioactive cargo reflective of their cell source, as well as their ability to be modified through various engineering and modification strategies, have attracted significant therapeutic interest. Molecular bioengineering strategies are providing a new frontier for EV-based therapy, including novel mRNA vaccines, antigen cross-presentation and immunotherapy, organ delivery and repair, and cancer immune surveillance and targeted therapeutics. The revolution of EVs, their diversity as biocarriers and their potential to contribute to intercellular communication, is well understood and appreciated but is ultimately dependent on the development of methods and techniques for their isolation, characterization and enhanced targeting. As single-stranded oligonucleotides, aptamers, also known as chemical antibodies, offer significant biological, chemical, economic, and therapeutic advantages in terms of their size, selectivity, versatility, and multifunctional programming. Their integration into the field of EVs has been contributing to the development of isolation, detection, and analysis pipelines associated with bioengineering strategies for nano-meets-molecular biology, thus translating their use for therapeutic and diagnostic utility.
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Affiliation(s)
- Rocky Chowdhury
- School of Medicine, Deakin University, and IMPACT Strategic Research Centre, Waurn Ponds, VIC, 3216, Australia.
| | - Sadegh Eslami
- Molecular Proteomics Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
| | - Cuong Viet Pham
- Molecular Imaging and Theranostics Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia
| | - Alin Rai
- Molecular Proteomics Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
- Department of Cardiovascular Research, Translation and Implementation, and La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia
| | - Jia Lin
- Department of Biochemistry and Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China
| | - Yingchu Hou
- Laboratory of Tumor Molecular and Cellular Biology College of Life Sciences, Shaanxi Normal University 620 West Chang'an Avenue, Xi'an, Shaanxi, 710119, China
| | - David W Greening
- Molecular Proteomics Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
- Department of Cardiovascular Research, Translation and Implementation, and La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia
| | - Wei Duan
- School of Medicine, Deakin University, and IMPACT Strategic Research Centre, Waurn Ponds, VIC, 3216, Australia.
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Xu K, Zhang Q, Zhu D, Jiang Z. Hydrogels in Gene Delivery Techniques for Regenerative Medicine and Tissue Engineering. Macromol Biosci 2024; 24:e2300577. [PMID: 38265144 DOI: 10.1002/mabi.202300577] [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: 12/16/2023] [Revised: 01/16/2024] [Indexed: 01/25/2024]
Abstract
Hydrogels are 3D networks swollen with water. They are biocompatible, strong, and moldable and are emerging as a promising biomedical material for regenerative medicine and tissue engineering to deliver therapeutic genes. The excellent natural extracellular matrix simulation properties of hydrogels enable them to be co-cultured with cells or enhance the expression of viral or non-viral vectors. Its biocompatibility, high strength, and degradation performance also make the action process of carriers in tissues more ideal, making it an ideal biomedical material. It has been shown that hydrogel-based gene delivery technologies have the potential to play therapy-relevant roles in organs such as bone, cartilage, nerve, skin, reproductive organs, and liver in animal experiments and preclinical trials. This paper reviews recent articles on hydrogels in gene delivery and explains the manufacture, applications, developmental timeline, limitations, and future directions of hydrogel-based gene delivery techniques.
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Affiliation(s)
- Kexing Xu
- Zhejiang University School of Medicine, Hangzhou, China
| | - Qinmeng Zhang
- Zhejiang University School of Medicine, Hangzhou, China
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - Danji Zhu
- Zhejiang University School of Medicine, Hangzhou, China
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - Zhiwei Jiang
- Zhejiang University School of Medicine, Hangzhou, China
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
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11
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Bicer M. Revolutionizing dermatology: harnessing mesenchymal stem/stromal cells and exosomes in 3D platform for skin regeneration. Arch Dermatol Res 2024; 316:242. [PMID: 38795200 PMCID: PMC11127839 DOI: 10.1007/s00403-024-03055-4] [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: 11/28/2023] [Revised: 01/09/2024] [Accepted: 04/26/2024] [Indexed: 05/27/2024]
Abstract
Contemporary trends reveal an escalating interest in regenerative medicine-based interventions for addressing refractory skin defects. Conventional wound healing treatments, characterized by high costs and limited efficacy, necessitate a more efficient therapeutic paradigm to alleviate the economic and psychological burdens associated with chronic wounds. Mesenchymal stem/stromal cells (MSCs) constitute cell-based therapies, whereas cell-free approaches predominantly involve the utilization of MSC-derived extracellular vesicles or exosomes, both purportedly safe and effective. Exploiting the impact of MSCs by paracrine signaling, exosomes have emerged as a novel avenue capable of positively impacting wound healing and skin regeneration. MSC-exosomes confer several advantages, including the facilitation of angiogenesis, augmentation of cell proliferation, elevation of collagen production, and enhancement of tissue regenerative capacity. Despite these merits, challenges persist in clinical applications due to issues such as poor targeting and facile removal of MSC-derived exosomes from skin wounds. Addressing these concerns, a three-dimensional (3D) platform has been implemented to emend exosomes, allowing for elevated levels, and constructing more stable granules possessing distinct therapeutic capabilities. Incorporating biomaterials to encapsulate MSC-exosomes emerges as a favorable approach, concentrating doses, achieving intended therapeutic effectiveness, and ensuring continual release. While the therapeutic potential of MSC-exosomes in skin repair is broadly recognized, their application with 3D biomaterial scenarios remains underexplored. This review synthesizes the therapeutic purposes of MSCs and exosomes in 3D for the skin restoration, underscoring their promising role in diverse dermatological conditions. Further research may establish MSCs and their exosomes in 3D as a viable therapeutic option for various skin conditions.
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Affiliation(s)
- Mesude Bicer
- Department of Bioengineering, Faculty of Life and Natural Sciences, Abdullah Gul University, Kayseri, 38080, Turkey.
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12
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Klymiuk MC, Balz N, Elashry MI, Wenisch S, Arnhold S. Effect of storage conditions on the quality of equine and canine mesenchymal stem cell derived nanoparticles including extracellular vesicles for research and therapy. DISCOVER NANO 2024; 19:80. [PMID: 38700790 PMCID: PMC11068712 DOI: 10.1186/s11671-024-04026-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 04/28/2024] [Indexed: 05/06/2024]
Abstract
Nanoparticles including extracellular vesicles derived from mesenchymal stem cells are of increasing interest for research and clinical use in regenerative medicine. Extracellular vesicles (EVs), including also previously named exosomes, provide a promising cell-free tool for therapeutic applications, which is probably a safer approach to achieve sufficient healing. Storage of EVs may be necessary for clinical applications as well as for further experiments, as the preparation is sometimes laborious and larger quantities tend to be gained. For this purpose, nanoparticles were obtained from mesenchymal stem cells from adipose tissue (AdMSC) of horses and dogs. The EVs were then stored for 7 days under different conditions (- 20 °C, 4 °C, 37 °C) and with the addition of various additives (5 mM EDTA, 25-250 µM trehalose). Afterwards, the size and number of EVs was determined using the nano tracking analyzing method. With our investigations, we were able to show that storage of EVs for up to 7 days at 4 °C does not require the addition of supplements. For the other storage conditions, in particular freezing and storage at room temperature, the addition of EDTA was found to be suitable for preventing aggregation of the particles. Contrary to previous publications, trehalose seems not to be a suitable cryoprotectant for AdMSC-derived EVs. The data are useful for processing and storage of isolated EVs for further experiments or clinical approaches in veterinary medicine.
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Affiliation(s)
- Michele Christian Klymiuk
- Institute of Veterinary-Anatomy, -Histology and -Embryology, Faculty of Veterinary Medicine, Justus-Liebig-University Giessen, Frankfurter Strasse 98, 35392, Giessen, Germany.
| | - Natalie Balz
- Institute of Veterinary-Anatomy, -Histology and -Embryology, Faculty of Veterinary Medicine, Justus-Liebig-University Giessen, Frankfurter Strasse 98, 35392, Giessen, Germany
| | - Mohamed I Elashry
- Institute of Veterinary-Anatomy, -Histology and -Embryology, Faculty of Veterinary Medicine, Justus-Liebig-University Giessen, Frankfurter Strasse 98, 35392, Giessen, Germany
| | - Sabine Wenisch
- Clinic of Small Animals, c/o Institute of Veterinary-Anatomy, -Histology and -Embryology, Faculty of Veterinary Medicine, Justus-Liebig-University Giessen, Frankfurter Strasse 98, 35392, Giessen, Germany
| | - Stefan Arnhold
- Institute of Veterinary-Anatomy, -Histology and -Embryology, Faculty of Veterinary Medicine, Justus-Liebig-University Giessen, Frankfurter Strasse 98, 35392, Giessen, Germany
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13
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Chen G, Tong K, Li S, Huang Z, Liu S, Zhu H, Zhong Y, Zhou Z, Jiao G, Wei F, Chen N. Extracellular vesicles released by transforming growth factor-beta 1-preconditional mesenchymal stem cells promote recovery in mice with spinal cord injury. Bioact Mater 2024; 35:135-149. [PMID: 38312519 PMCID: PMC10837068 DOI: 10.1016/j.bioactmat.2024.01.013] [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: 12/12/2023] [Revised: 01/10/2024] [Accepted: 01/15/2024] [Indexed: 02/06/2024] Open
Abstract
Spinal cord injury (SCI) causes neuroinflammation, neuronal death, and severe axonal connections. Alleviating neuroinflammation, protecting residual cells and promoting neuronal regeneration via endogenous neural stem cells (eNSCs) represent potential strategies for SCI treatment. Extracellular vesicles (EVs) released by mesenchymal stem cells have emerged as pathological mediators and alternatives to cell-based therapies following SCI. In the present study, EVs isolated from untreated (control, C-EVs) and TGF-β1-treated (T-EVs) mesenchymal stem cells were injected into SCI mice to compare the therapeutic effects and explore the underlying mechanisms. Our study demonstrated for the first time that the application of T-EVs markedly enhanced the proliferation and antiapoptotic ability of NSCs in vitro. The infusion of T-EVs into SCI mice increased the shift from the M1 to M2 polarization of reactive microglia, alleviated neuroinflammation, and enhanced the neuroprotection of residual cells during the acute phase. Moreover, T-EVs increased the number of eNSCs around the epicenter. Consequently, T-EVs further promoted neurite outgrowth, increased axonal regrowth and remyelination, and facilitated locomotor recovery in the chronic stage. Furthermore, the use of T-EVs in Rictor-/- SCI mice (conditional knockout of Rictor in NSCs) showed that T-EVs failed to increase the activation of eNSCs and improve neurogenesis sufficiently, which suggested that T-EVs might induce the activation of eNSCs by targeting the mTORC2/Rictor pathway. Taken together, our findings indicate the prominent role of T-EVs in the treatment of SCI, and the therapeutic efficacy of T-EVs for SCI treatment might be optimized by enhancing the activation of eNSCs via the mTORC2/Rictor signaling pathway.
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Affiliation(s)
- Guoliang Chen
- Department of Orthopedic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China
- Dongguan Key Laboratory of Central Nervous System Injury and Repair / Department of Orthopedic Surgery, The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital), Dongguan, 523573, China
- Department of Orthopedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Kuileung Tong
- Department of Orthopedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Shiming Li
- Department of Orthopedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Zerong Huang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China
| | - Shuangjiang Liu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China
- Dongguan Key Laboratory of Central Nervous System Injury and Repair / Department of Orthopedic Surgery, The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital), Dongguan, 523573, China
| | - Haoran Zhu
- Department of Orthopedic Surgery, The Fifth Affiliated Hospital of Jinan University (Heyuan Shenhe People's Hospital), Heyuan, 517400, China
| | - Yanheng Zhong
- Department of Orthopedic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China
| | - Zhisen Zhou
- Dongguan Key Laboratory of Central Nervous System Injury and Repair / Department of Orthopedic Surgery, The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital), Dongguan, 523573, China
| | - Genlong Jiao
- Department of Orthopedic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China
- Dongguan Key Laboratory of Central Nervous System Injury and Repair / Department of Orthopedic Surgery, The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital), Dongguan, 523573, China
| | - Fuxin Wei
- Department of Orthopedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Ningning Chen
- Department of Orthopedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
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14
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Wu S, Chen Z, Wu Y, Shi Q, Yang E, Zhang B, Qian Y, Lian X, Xu J. ADSC-Exos enhance functional recovery after spinal cord injury by inhibiting ferroptosis and promoting the survival and function of endothelial cells through the NRF2/SLC7A11/GPX4 pathway. Biomed Pharmacother 2024; 172:116225. [PMID: 38306845 DOI: 10.1016/j.biopha.2024.116225] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 01/16/2024] [Accepted: 01/29/2024] [Indexed: 02/04/2024] Open
Abstract
BACKGROUND Spinal cord injury (SCI) is a devastating disease that causes major motor, sensory and autonomic dysfunctions. Currently, there is a lack of effective treatment. In this study, we aimed to investigate the potential mechanisms of Exosomes from adipose-derived stem cells (ADSC-Exos) in reducing ferroptosis and promoting angiogenesis after spinal cord injury. METHODS We isolated ADSC-Exos, the characteristics of which were confirmed. In vitro, we tested the potential of ADSC-Exos to promote the survival and function of human brain microvascular endothelial cells (HBMECs) and analyzed the ferroptosis of HBMECs. In vivo, we established rat models of SCI and locally injected ADSC-Exos to verify their efficacy. RESULTS ADSC-Exos can reduce reactive oxygen species (ROS) accumulation and cell damage induced by an excessive inflammatory response in HBMECs. ADSC-Exos inhibit ferroptosis induced by excessive inflammation and upregulate the expression of glutathione peroxidase 4(GPX4) in HBMECs. It can also effectively promote proliferation, migration, and vessel-like structure formation. In vitro, ADSC-Exos improved behavioral function after SCI and increased the number and density of blood vessels around the damaged spinal cord. Moreover, we found that ADSC-Exos could increase nuclear factor erythroid-2-related factor 2(NRF2) expression and nuclear translocation, thereby affecting the expression of solute carrier family 7 member 11(SLC7A11) and GPX4, and the NRF2 inhibitor ML385 could reverse the above changes. CONCLUSION Our results suggest that ADSC-Exos may inhibit ferroptosis and promote the recovery of vascular and neural functions after SCI through the NRF2/SLC7A11/GPX4 pathway. This may be a potential therapeutic mechanism for spinal cord injury.
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Affiliation(s)
- Shengting Wu
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai 200233, China
| | - Zhiheng Chen
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai 200233, China
| | - Yinghao Wu
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai 200233, China
| | - Qiang Shi
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai 200233, China
| | - Erzhu Yang
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai 200233, China
| | - Baokun Zhang
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai 200233, China
| | - Yuxuan Qian
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai 200233, China.
| | - Xiaofeng Lian
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai 200233, China.
| | - Jianguang Xu
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai 200233, China.
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15
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Yang Z, Liang Z, Rao J, Xie H, Zhou M, Xu X, Lin Y, Lin F, Wang C, Chen C. Hypoxic-preconditioned mesenchymal stem cell-derived small extracellular vesicles promote the recovery of spinal cord injury by affecting the phenotype of astrocytes through the miR-21/JAK2/STAT3 pathway. CNS Neurosci Ther 2024; 30:e14428. [PMID: 37641874 PMCID: PMC10915983 DOI: 10.1111/cns.14428] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 07/14/2023] [Accepted: 08/15/2023] [Indexed: 08/31/2023] Open
Abstract
BACKGROUND Secondary injury after spinal cord injury (SCI) is a major obstacle to their neurological recovery. Among them, changes in astrocyte phenotype regulate secondary injury dominated by neuroinflammation. Hypoxia-preconditioned mesenchymal stem cells (MSCs)-derived extracellular vesicle (H-EV) plays a multifaceted role in secondary injury by interacting with cellular components and signaling pathways. They possess anti-inflammatory properties, regulate oxidative stress, and modulate apoptotic pathways, promoting cell survival and reducing neuronal loss. Given the unique aspects of secondary injury, H-EV shows promise as a therapeutic approach to mitigate its devastating consequences. Our study aimed to determine whether H-EV could promote SCI repair by altering the phenotype of astrocytes. METHODS Rat bone marrow MSCs (BMSCs) and EVs secreted by them were extracted and characterized. After the SCI model was successfully constructed, EV and H-EV were administered into the tail vein of the rats, respectively, and then their motor function was evaluated by the Basso-Beattie-Bresnahan (BBB) score, Catwalk footprint analysis, and electrophysiological monitoring. The lesion size of the spinal cord was evaluated by hematoxylin-eosin (HE) staining. The key point was to use glial fibrillary acidic protein (GFAP) as a marker of reactive astrocytes to co-localize with A1-type marker complement C3 and A2-type marker S100A10, respectively, to observe phenotypic changes in astrocytes within tissues. The western blot (WB) of the spinal cord was also used to verify the results. We also compared the efficacy differences in apoptosis and inflammatory responses using terminal deoxynucleotidyl transferase dUTP terminal labeling (TUNEL) assay, WB, and enzyme-linked immunosorbent assay (ELISA). Experiments in vitro were also performed to verify the results. Subsequently, we performed microRNA (miRNA) sequencing analysis of EV and H-EV and carried out a series of knockdown and overexpression experiments to further validate the mechanism by which miRNA in H-EV plays a role in promoting astrocyte phenotypic changes, as well as the regulated signaling pathways, using WB both in vivo and in vitro. RESULTS Our findings suggest that H-EV is more effective than EV in the recovery of motor function, anti-apoptosis, and anti-inflammatory effects after SCI, both in vivo and in vitro. More importantly, H-EV promoted the conversion of A1 astrocytes into A2 astrocytes more than EV. Moreover, miR-21, which was found to be highly expressed in H-EV by miRNA sequencing results, was also demonstrated to influence changes in astrocyte phenotype through a series of knockdown and overexpression experiments. At the same time, we also found that H-EV might affect astrocyte phenotypic alterations by delivering miR-21 targeting the JAK2/STAT3 signaling pathway. CONCLUSION H-EV exerts neuroprotective effects by delivering miR-21 to promote astrocyte transformation from the A1 phenotype to the A2 phenotype, providing new targets and ideas for the treatment of SCI.
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Affiliation(s)
- Zhelun Yang
- Department of NeurosurgeryFujian Medical University Union HospitalFuzhouFujianChina
| | - Zeyan Liang
- Department of NeurosurgeryFujian Medical University Union HospitalFuzhouFujianChina
| | - Jian Rao
- Department of NeurosurgeryFujian Medical University Union HospitalFuzhouFujianChina
| | - Haishu Xie
- Department of NeurosurgeryFujian Medical University Union HospitalFuzhouFujianChina
| | - Maochao Zhou
- Department of NeurosurgeryFujian Medical University Union HospitalFuzhouFujianChina
| | - Xiongjie Xu
- Department of NeurosurgeryFujian Medical University Union HospitalFuzhouFujianChina
| | - Yike Lin
- Department of NeurosurgeryFujian Medical University Union HospitalFuzhouFujianChina
| | - Fabin Lin
- Department of NeurosurgeryFujian Medical University Union HospitalFuzhouFujianChina
| | - Chunhua Wang
- Department of NeurosurgeryFujian Medical University Union HospitalFuzhouFujianChina
| | - Chunmei Chen
- Department of NeurosurgeryFujian Medical University Union HospitalFuzhouFujianChina
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16
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Chen Z, Luo L, Ye T, Zhou J, Niu X, Yuan J, Yuan T, Fu D, Li H, Li Q, Wang Y. Identification of specific markers for human pluripotent stem cell-derived small extracellular vesicles. J Extracell Vesicles 2024; 13:e12409. [PMID: 38321535 PMCID: PMC10847391 DOI: 10.1002/jev2.12409] [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: 07/24/2023] [Revised: 12/17/2023] [Accepted: 01/12/2024] [Indexed: 02/08/2024] Open
Abstract
Pluripotent stem cell-derived small extracellular vesicles (PSC-sEVs) have demonstrated great clinical translational potential in multiple aging-related degenerative diseases. Characterizing the PSC-sEVs is crucial for their clinical applications. However, the specific marker pattern of PSC-sEVs remains unknown. Here, the sEVs derived from two typical types of PSCs including induced pluripotent stem cells (iPSC-sEVs) and embryonic stem cells (ESC-sEVs) were analysed using proteomic analysis by liquid chromatography with tandem mass spectrometry (LC-MS/MS), and surface marker phenotyping analysis by nanoparticle flow cytometry (NanoFCM). A group of pluripotency-related proteins were found to be enriched in PSC-sEVs by LC-MS/MS and then validated by Western Blot analysis. To investigate whether these proteins were specifically expressed in PSC-sEVs, sEVs derived from seven types of non-PSCs (non-PSC-sEVs) were adopted for analysis. The results showed that PODXL, OCT4, Dnmt3a, and LIN28A were specifically enriched in PSC-sEVs but not in non-PSC-sEVs. Then, commonly used surface antigens for PSC identification (SSEA4, Tra-1-60 and Tra-1-81) and PODXL were gauged at single-particle resolution by NanoFCM for surface marker identification. The results showed that the positive rates of PODXL (>50%) and SSEA4 (>70%) in PSC-sEVs were much higher than those in non-PSC-sEVs (<10%). These results were further verified with samples purified by density gradient ultracentrifugation. Taken together, this study for the first time identified a cohort of specific markers for PSC-sEVs, among which PODXL, OCT4, Dnmt3a and LIN28A can be detected with Western Blot analysis, and PODXL and SSEA4 can be detected with NanoFCM analysis. The application of these specific markers for PSC-sEVs identification may advance the clinical translation of PSCs-sEVs.
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Affiliation(s)
- Zhengsheng Chen
- Institute of Microsurgery on Extremities, Department of Orthopedic SurgeryShanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Lei Luo
- Institute of Microsurgery on Extremities, Department of Orthopedic SurgeryShanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- School of Biomedical EngineeringShanghai Jiao Tong UniversityShanghaiChina
| | - Teng Ye
- Institute of Microsurgery on Extremities, Department of Orthopedic SurgeryShanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Jiacheng Zhou
- Institute of Microsurgery on Extremities, Department of Orthopedic SurgeryShanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xin Niu
- Institute of Microsurgery on Extremities, Department of Orthopedic SurgeryShanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Ji Yuan
- Institute of Microsurgery on Extremities, Department of Orthopedic SurgeryShanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Ting Yuan
- Department of Orthopedic SurgeryShanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Dehao Fu
- Department of Orthopedic SurgeryShanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Haiyan Li
- School of Biomedical EngineeringShanghai Jiao Tong UniversityShanghaiChina
- Chemical and Environmental Engineering Department, School of EngineeringRMIT UniversityMelbourneVictoriaAustralia
| | - Qing Li
- Institute of Microsurgery on Extremities, Department of Orthopedic SurgeryShanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yang Wang
- Institute of Microsurgery on Extremities, Department of Orthopedic SurgeryShanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
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17
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Liu Y, Dong J, Zhang Z, Liu Y, Wang Y. Regulatory T cells: A suppressor arm in post-stroke immune homeostasis. Neurobiol Dis 2023; 189:106350. [PMID: 37952680 DOI: 10.1016/j.nbd.2023.106350] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 10/09/2023] [Accepted: 11/09/2023] [Indexed: 11/14/2023] Open
Abstract
The activation of the immune system and the onset of pro- and anti-inflammatory responses play crucial roles in the pathophysiological processes of ischaemic stroke (IS). CD4+ regulatory T (Treg) cells is the main immunosuppressive cell population that is studied in the context of peripheral tolerance, autoimmunity, and the development of chronic inflammatory diseases. In recent years, more studies have focused on immune modulation after IS, and Treg cells have been demonstrated to be essential in the remission of inflammation, nerve regeneration, and behavioural recovery. However, the exact effects of Treg cells in the context of IS remain controversial, with some studies suggesting a negative correlation with stroke outcomes. In this review, we aim to provide a comprehensive overview of the current understanding of Treg cell involvement in post-stroke homeostasis. We summarized the literature focusing on the temporal changes in Treg cell populations after IS, the mechanisms of Treg cell-mediated immunomodulation in the brain, and the potential of Treg cell-based therapies for treatment. The purposes of the current article are to address the importance of Treg cells and inspire more studies to help physicians, as well as scientists, understand the whole map of immune responses during IS.
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Affiliation(s)
- Yiqi Liu
- Department of Neurosurgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Jing Dong
- Department of Medical Engineering, Tsinghua University Yuquan Hospital, Beijing 100049, China
| | - Ziqing Zhang
- Department of Neurosurgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Yunpeng Liu
- Department of Neurosurgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
| | - Yang Wang
- Department of Neurosurgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
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18
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Niu S, Li B, Gu H, Huang Q, Cheng Y, Wang C, Cao G, Yang Q, Zhang D, Cao J. Knowledge mapping of extracellular vesicles in wound healing: A bibliometric analysis (2002-2022). Int Wound J 2023; 20:3221-3240. [PMID: 37183322 PMCID: PMC10502250 DOI: 10.1111/iwj.14202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 04/11/2023] [Accepted: 04/12/2023] [Indexed: 05/16/2023] Open
Abstract
Extracellular vesicles in wound healing have become an active research field with substantial value and potential. Nevertheless, there are few bibliometric studies in this field. We aimed to visualise the research hot spots and trends of extracellular vesicles in wound healing using a bibliometric analysis to help understand the future development of basic and clinical research. The articles and reviews regarding extracellular vesicles in the wound healing were selected from the Web of Science Core Collection. VOSviewers, CiteSpace and R package "bibliometric" were used to conduct this bibliometric analysis. A total of 1225 articles from 56 countries led by China and the United States were included. The number of publications related to extracellular vesicles increased year by year. Shanghai Jiaotong University, Huazhong University of Science and Technology, Sun Yat-sen University and Central South University are the main research institutions. International Journal of Molecular Sciences is the most popular journal in this field, while Stem Cell Research & Therapy is the most frequently cited journal. These papers come from 7546 authors, among which Zhang Wei has published the most papers and Zhang Bin has the most cocited papers. The research on the treatment strategy of extracellular vesicles in the process of wound healing is the main topic in this field. "exosomes", "miRNA", "angiogenesis", "regenerative medicine", "inflammation" and "diabetic wound" are the main key words of emerging research hotspots. This is the first bibliometric study, which comprehensively summarises the research trend and development of extracellular vesicles and exocrine bodies in wound healing. These informations determine the latest research frontiers and hot directions, and provide reference for the study of extracellular vesicles and exosomes.
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Affiliation(s)
- Shao‐hui Niu
- Dongfang HospitalBeijing University of Chinese MedicineBeijingChina
| | - Bei Li
- Shanxi University of Chinese MedicineTaiyuanChina
| | - Han‐cheng Gu
- Dongfang HospitalBeijing University of Chinese MedicineBeijingChina
| | - Qiang Huang
- Dongfang HospitalBeijing University of Chinese MedicineBeijingChina
| | - Ya‐qing Cheng
- Dongfang HospitalBeijing University of Chinese MedicineBeijingChina
| | - Chang Wang
- Dongfang HospitalBeijing University of Chinese MedicineBeijingChina
| | - Gang Cao
- Dongfang HospitalBeijing University of Chinese MedicineBeijingChina
| | - Qiaoli Yang
- Dongfang HospitalBeijing University of Chinese MedicineBeijingChina
| | - Dong‐ping Zhang
- Dongzhimen HospitalBeijing University of Chinese MedicineBeijingChina
| | - Jian‐chun Cao
- Dongfang HospitalBeijing University of Chinese MedicineBeijingChina
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19
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Cui E, Lv L, Chen W, Chen N, Pan R. Mesenchymal stem/stromal cell-based cell-free therapy for the treatment of acute lung injury. J Cell Biochem 2023; 124:1241-1248. [PMID: 37668145 DOI: 10.1002/jcb.30469] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/16/2023] [Accepted: 08/28/2023] [Indexed: 09/06/2023]
Abstract
Acute lung injury (ALI) is a severe medical condition that causes inflammation and fluid buildup in the lung, resulting in respiratory distress. Moreover, ALI often occurs as a complication of other medical conditions or injuries, including the coronavirus disease of 2019. Mesenchymal stem/stromal cells (MSCs) are being studied extensively for their therapeutic potential in various diseases, including ALI. The results of recent studies suggest that the beneficial effects of MSCs may not be primarily due to the replacement of damaged cells but rather the release of extracellular vesicles (EVs) and other soluble factors through a paracrine mechanism. Furthermore, EVs derived from MSCs preserve the therapeutic action of the parent MSCs and this approach avoids the safety issues associated with live cell therapy. Thus, MSC-based cell-free therapy may be the focus of future clinical treatments.
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Affiliation(s)
- Enhai Cui
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, China
| | - Lu Lv
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, China
| | - Wenyan Chen
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, China
| | - Na Chen
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, China
| | - Ruolang Pan
- Key Laboratory of Cell-Based Drug and Applied Technology Development in Zhejiang Province, Institute for Cell-Based Drug Development of Zhejiang Province, S-Evans Biosciences, Hangzhou, China
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20
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Symonds EKC, Black B, Brown A, Meredith I, Currie MJ, Hally KE, Danielson KM. Adipose derived stem cell extracellular vesicles modulate primary human macrophages to an anti-inflammatory phenotype in vitro. JOURNAL OF EXTRACELLULAR BIOLOGY 2023; 2:e104. [PMID: 38939512 PMCID: PMC11080877 DOI: 10.1002/jex2.104] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 06/11/2023] [Accepted: 07/12/2023] [Indexed: 06/29/2024]
Abstract
EVs released by adipose derived stem cells (ADSCs) have shown promise as a therapeutic for tissue repair because of their purported immune-regulatory properties. Extracellular vesicles (EVs) from ADSCs could be beneficial in improving graft retention rates for autologous fat grafting (AFG) post-mastectomy as, currently, grafted tissue rates are variable. Enriching grafted tissue with ADSC-EVs may improve retention rates by modulating macrophages resident within both the breast and lipoaspirate. We aimed to identify key macrophage phenotypes that are modulated by ADSC-EVs in vitro. ADSCs were isolated from lipoaspirates of women undergoing AFG and characterised by flow cytometry and differentiation potential. ADSC-EVs were isolated from culture media and characterised by tuneable resistive pulse sensing, transmission electron microscopy and Western blot. Primary monocyte-derived macrophages were polarized to an M1-like (GM-CSF, IFNγ), M2-like phenotype (M-CSF, IL-4) or maintained (M0-like; M-CSF) and ADSC-EVs were co-cultured with macrophages for 48 h. Flow cytometry and high-dimensional analysis clustered macrophages post co-culture. A manual gating strategy was generated to recapitulate these clusters and was applied to a repeat experimental run. Both runs were analysed to examine the prevalence of each cluster, representing a unique macrophage phenotype, with and without ADSC-EVs. Following the addition of ADSC-EVs, M0-like macrophages demonstrated a reciprocal shift of cell distribution from a cluster with a 'high inflammatory profile' (CD36+++CD206+++CD86+++; 16.5 ± 7.0%; p < 0.0001) to a cluster with a 'lower inflammatory profile' (CD36+CD206+CD86+; 35 ± 21.5%; p < 0.05). M1-like macrophages shifted from a cluster with a 'high inflammatory profile' (CD206++CD11b++CD36++CD163++; 26.1 ± 9.4%; p = 0.0024) to a 'lower inflammatory profile' (CD206+CD11b+CD36+CD163+; 72.8 ± 8.7%; p = 0.0007). There was no shift in M2-like clusters following ADSC-EV treatment. ADSC-EVs are complex regulators of macrophage phenotype that can shift macrophages away from a heightened pro-inflammatory state.
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Affiliation(s)
- Emma K. C. Symonds
- Department of Surgery and AnaesthesiaUniversity of Otago WellingtonWellingtonNew Zealand
| | - Bianca Black
- Department of Surgery and AnaesthesiaUniversity of Otago WellingtonWellingtonNew Zealand
| | - Alexander Brown
- Department of General SurgeryWellington Regional HospitalWellingtonNew Zealand
| | - Ineke Meredith
- Department of General SurgeryWellington Regional HospitalWellingtonNew Zealand
| | - Margaret J. Currie
- Mackenzie Cancer Research GroupUniversity of Otago ChristchurchChristchurchNew Zealand
| | - Kathryn E. Hally
- Department of Surgery and AnaesthesiaUniversity of Otago WellingtonWellingtonNew Zealand
| | - Kirsty M. Danielson
- Department of Surgery and AnaesthesiaUniversity of Otago WellingtonWellingtonNew Zealand
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21
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Hu P, Armato U, Freddi G, Chiarini A, Dal Prà I. Human Keratinocytes and Fibroblasts Co-Cultured on Silk Fibroin Scaffolds Exosomally Overrelease Angiogenic and Growth Factors. Cells 2023; 12:1827. [PMID: 37508492 PMCID: PMC10378127 DOI: 10.3390/cells12141827] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 06/30/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
Objectives: The optimal healing of skin wounds, deep burns, and chronic ulcers is an important clinical problem. Attempts to solve it have been driving the search for skin equivalents based on synthetic or natural polymers. Methods: Consistent with this endeavor, we used regenerated silk fibroin (SF) from Bombyx mori to produce a novel compound scaffold by welding a 3D carded/hydroentangled SF-microfiber-based nonwoven layer (C/H-3D-SFnw; to support dermis engineering) to an electrospun 2D SF nanofiber layer (ESFN; a basal lamina surrogate). Next, we assessed-via scanning electron microscopy, attenuated total reflectance Fourier transform infrared spectroscopy, differential scanning calorimetry, mono- and co-cultures of HaCaT keratinocytes and adult human dermal fibroblasts (HDFs), dsDNA assays, exosome isolation, double-antibody arrays, and angiogenesis assays-whether the C/H-3D-SFnws/ESFNs would allow the reconstitution of a functional human skin analog in vitro. Results: Physical analyses proved that the C/H-3D-SFnws/ESFNs met the requirements for human soft-tissue-like implants. dsDNA assays revealed that co-cultures of HaCaTs (on the 2D ESFN surface) and HDFs (inside the 3D C/H-3D-SFnws) grew more intensely than did the respective monocultures. Double-antibody arrays showed that the CD9+/CD81+ exosomes isolated from the 14-day pooled growth media of HDF and/or HaCaT mono- or co-cultures conveyed 35 distinct angiogenic/growth factors (AGFs). However, versus monocultures' exosomes, HaCaT/HDF co-cultures' exosomes (i) transported larger amounts of 15 AGFs, i.e., PIGF, ANGPT-1, bFGF, Tie-2, Angiogenin, VEGF-A, VEGF-D, TIMP-1/-2, GRO-α/-β/-γ, IL-1β, IL-6, IL-8, MMP-9, and MCP-1, and (ii) significantly more strongly stimulated human dermal microvascular endothelial cells to migrate and assemble tubes/nodes in vitro. Conclusions: Our results showed that both cell-cell and cell-SF interactions boosted the exosomal release of AGFs from HaCaTs/HDFs co-cultured on C/H-3D-SFnws/ESFNs. Hence, such exosomes are an asset for prospective clinical applications as they advance cell growth and neoangiogenesis and consequently graft take and skin healing. Moreover, this new integument analog could be instrumental in preclinical and translational studies on human skin pathophysiology and regeneration.
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Affiliation(s)
- Peng Hu
- Department of Surgery, Dentistry, Pediatrics & Gynecology, University of Verona Medical School, 37134 Verona, Italy
| | - Ubaldo Armato
- Department of Surgery, Dentistry, Pediatrics & Gynecology, University of Verona Medical School, 37134 Verona, Italy
| | | | - Anna Chiarini
- Department of Surgery, Dentistry, Pediatrics & Gynecology, University of Verona Medical School, 37134 Verona, Italy
| | - Ilaria Dal Prà
- Department of Surgery, Dentistry, Pediatrics & Gynecology, University of Verona Medical School, 37134 Verona, Italy
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22
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Panagiotou N, McGuinness D, Jaminon AMG, Mees B, Selman C, Schurgers L, Shiels PG. Microvesicle-Mediated Tissue Regeneration Mitigates the Effects of Cellular Ageing. Cells 2023; 12:1707. [PMID: 37443741 PMCID: PMC10340655 DOI: 10.3390/cells12131707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 06/19/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023] Open
Abstract
Extracellular vesicles (EVs), comprising microvesicles (MVs) and exosomes (Exos), are membranous vesicles secreted by cells which mediate the repair of cellular and tissue damage via paracrine mechanisms. The action of EVs under normative and morbid conditions in the context of ageing remains largely unexplored. We demonstrate that MVs, but not Exos, from Pathfinder cells (PCs), a putative stem cell regulatory cell type, enhance the repair of human dermal fibroblast (HDF) and mesenchymal stem cell (MSC) co-cultures, following both mechanical and genotoxic stress. Critically, this effect was found to be both cellular age and stress specific. Notably, MV treatment was unable to repair mechanical injury in older co-cultures but remained therapeutic following genotoxic stress. These observations were further confirmed in human dermal fibroblast (HDF) and vascular smooth muscle cell (VSMC) co-cultures of increasing cellular age. In a model of comorbidity comprising co-cultures of HDFs and highly senescent abdominal aortic aneurysm (AAA) VSMCs, MV administration appeared to be senotherapeutic, following both mechanical and genotoxic stress. Our data provide insights into EVs and the specific roles they play during tissue repair and ageing. These data will potentiate the development of novel cell-free therapeutic interventions capable of attenuating age-associated morbidities and avoiding undesired effects.
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Affiliation(s)
- Nikolaos Panagiotou
- Davidson Building, School of Molecular Biosciences, University of Glasgow, Glasgow G12 8QQ, UK; (N.P.)
| | - Dagmara McGuinness
- School of Infection & Immunity, University of Glasgow, Glasgow G12 8QQ, UK; (D.M.)
| | - Armand M. G. Jaminon
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University,
Maastricht, 6229 ER Maastricht, NetherlandsThe Netherlands
| | - Barend Mees
- Department of Vascular Surgery, Maastricht University Medical Centre (MUMC),
Maastricht, The Netherlands;
| | - Colin Selman
- Graham Kerr Building, College of Medical, Veterinary & Life Sciences, Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow G12 8QQ, UK;
| | - Leon Schurgers
- School of Infection & Immunity, University of Glasgow, Glasgow G12 8QQ, UK; (D.M.)
- Graham Kerr Building, College of Medical, Veterinary & Life Sciences, Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow G12 8QQ, UK;
| | - Paul G. Shiels
- Davidson Building, School of Molecular Biosciences, University of Glasgow, Glasgow G12 8QQ, UK; (N.P.)
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23
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Yasen A, Feng J, Xie XM, Li K, Cai YH, Liao ZH, Liang RB, Dai TX, Wang GY. Exosomes derived from TGF-β1-pretreated mesenchymal stem cells alleviate biliary ischemia-reperfusion injury through Jagged1/Notch1/SOX9 pathway. Int Immunopharmacol 2023; 119:110253. [PMID: 37156030 DOI: 10.1016/j.intimp.2023.110253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 04/17/2023] [Accepted: 04/26/2023] [Indexed: 05/10/2023]
Abstract
BACKGROUND This study aimed to evaluate the efficacy of exosomes (EXO) derived from TGF-β1-pretreated mesenchymal stem cells (MSCs) on biliary ischemia reperfusion injury (IRI) and further reveal the possible mechanisms. METHODS Bone marrow-derived MSCs were treated with exogenous TGF-β1, Jagged1/Notch1/SOX9 pathway inhibitor LY450139, or their combination. Then, EXO were isolated from the culture supernatants and further characterized. After establishing IRI model of biliary epithelial cells (EpiCs), EXO derived from differently-treated MSCs were applied to detect their protective effects on EpiCs, and LY450139 was applied in EpiCs to detect the possible mechanisms after treatment with MSCs-EXO. EXO derived from differently-treated MSCs were further injected into the hepatic artery immediately after establishment of intrahepatic biliary IRI for animal studies. RESULTS Pretreatment with TGF-β1 significantly enhanced MSCs-EXO production and elevated the levels of massive miRNAs associated with anti-apoptosis and tissue repair, which were evidently decreased after TGF-β1 plus LY450139 cotreatment. Notable improvement was observed in EpiCs after MSCs-EXO treatment, evidenced by reduced cellular apoptosis, increased cellular proliferation and declined oxidative stress, which were more evident in EpiCs that were treated with EXO derived from TGF-β1-pretreated MSCs. However, application of EXO derived from TGF-β1 plus LY450139-cotreated MSCs reversely enhanced cellular apoptosis, decreased cellular proliferation and anti-oxidants production. Interestingly, LY450139 application in EpiCs after treatment with MSCs-EXO also reversed the declined cellular apoptosis and enhanced oxidative stress induced by TGF-β1 pretreatment. In animal studies, administration of EXO derived from TGF-β1-pretreated MSCs more effectively attenuated biliary IRI through reducing oxidative stress, apoptosis, inflammation and enhancing the expression levels of TGF-β1 and Jagged1/Notch1/SOX9 pathway-related markers, which were reversed after administration of EXO derived from TGF-β1 plus LY450139-cotreated MSCs. CONCLUSION Our results provided a vital insight that TGF-β1 pretreatment endowed MSCs-EXO with stronger protective effects to improve biliary IRI via Jagged1/Notch1/SOX9 pathway.
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Affiliation(s)
- Aimaiti Yasen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, Guangdong Province, China.
| | - Jun Feng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, Guangdong Province, China
| | - Xing-Ming Xie
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, Guangdong Province, China.
| | - Kai Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, Guangdong Province, China
| | - Yu-Hong Cai
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, Guangdong Province, China
| | - Zhi-Hong Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, Guangdong Province, China
| | - Run-Bin Liang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, Guangdong Province, China.
| | - Tian-Xing Dai
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, Guangdong Province, China
| | - Guo-Ying Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, Guangdong Province, China.
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24
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Raposo G, Stahl PD. Extracellular vesicles - on the cusp of a new language in the biological sciences. EXTRACELLULAR VESICLES AND CIRCULATING NUCLEIC ACIDS 2023; 4:240-254. [PMID: 38288044 PMCID: PMC10824536 DOI: 10.20517/evcna.2023.18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/31/2024]
Abstract
Extracellular vesicles (EVs) play a key role both in physiological balance and homeostasis and in disease processes through their ability to participate in intercellular signaling and communication. An ever-expanding knowledge pool and a myriad of functional properties ascribed to EVs point to a new language of communication in biological systems that has opened a path for the discovery and implementation of novel diagnostic applications. EVs originate in the endosomal network and via non-random shedding from the plasma membrane by mechanisms that allow the packaging of functional cargoes, including proteins, lipids, and genetic materials. Deciphering the molecular mechanisms that govern packaging, secretion and targeted delivery of extracellular vesicle-borne cargo will be required to establish EVs as important signaling entities, especially when ascribing functional properties to a heterogeneous population of vesicles. Several molecular cascades operate within the endosomal network and at the plasma membrane that recognize and segregate cargos as a prelude to vesicle budding and release. EVs are transferred between cells and operate as vehicles in biological fluids within tissues and within the microenvironment where they are responsible for short- and long-range targeted information. In this review, we focus on the remarkable capacity of EVs to establish a dialogue between cells and within tissues, often operating in parallel to the endocrine system, we highlight selected examples of past and recent studies on the functions of EVs in health and disease.
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Affiliation(s)
- Graca Raposo
- Institut Curie, PSL Research University, CNRS, UMR144, Structure and Membrane Compartments, Paris 75005, France
| | - Philip D Stahl
- Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO 63110, USA
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25
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Wang Y, Liu T, Jiao G, Lv Y, Piao C, Lu X, Ma H, Wang H. Exosomes from adipose-derived mesenchymal stem cells can attenuate liver injury caused by minimally invasive hemihepatectomy combined with ischemia-reperfusion in minipigs by modulating the endoplasmic reticulum stress response. Life Sci 2023; 321:121618. [PMID: 36966916 DOI: 10.1016/j.lfs.2023.121618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/14/2023] [Accepted: 03/20/2023] [Indexed: 03/31/2023]
Abstract
AIMS Hepatic ischemia-reperfusion injury (IRI) impairs postoperative recovery of liver function after liver resection or transplantation. It is crucial to minimize liver injury during surgery in order to improve patient survival and quality of life. The aim of this study was to explore the therapeutic efficacy of exosomes from adipose-derived mesenchymal stem cells (ADSCs-exo) against hepatectomy combined with IRI injury and compare that with the effect of adipose-derived mesenchymal stem cells (ADSCs). MAIN METHOD Minimally invasive hemihepatectomy combined with hepatic IRI was established in minipigs. A single dose of ADSCs-exo, ADSCs or PBS was injected through the portal vein. The histopathological features and function of the liver, and the oxidative stress levels, endoplasmic reticulum (ER) ultrastructure and ER stress (ERS) response were analyzed pre- and postoperatively. KEY FINDINGS ADSCs-exo alleviated the histopathological injuries and ultrastructural changes in the ER, and significantly improved ALP, TP and CAT levels. Furthermore, ADSCs-exo treatment also downregulated ERS-related factors such as GRP78, ATF6, IRE1α/XBP1, PERK/eIF2α/ATF4, JNK and CHOP. The therapeutic effects of ADSCs-exo and ADSCs were similar. SIGNIFICANCE Intravenous administration of a single dose of ADSCs-exo is a novel cell-free therapeutic approach to improve surgery-related liver injury. Our findings provide evidence of the paracrine effect of ADSCs and an experimental basis for treating liver injury with ADSCs-exo instead of ADSCs.
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Affiliation(s)
- Yue Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Tao Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Guangming Jiao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Yingguang Lv
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Chenxi Piao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Xiangyu Lu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Haiyang Ma
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Hongbin Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China.
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26
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Greening DW, Xu R, Ale A, Hagemeyer CE, Chen W. Extracellular vesicles as next generation immunotherapeutics. Semin Cancer Biol 2023; 90:73-100. [PMID: 36773820 DOI: 10.1016/j.semcancer.2023.02.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/01/2023] [Accepted: 02/02/2023] [Indexed: 02/11/2023]
Abstract
Extracellular vesicles (EVs) function as a mode of intercellular communication and molecular transfer to elicit diverse biological/functional response. Accumulating evidence has highlighted that EVs from immune, tumour, stromal cells and even bacteria and parasites mediate the communication of various immune cell types to dynamically regulate host immune response. EVs have an innate capacity to evade recognition, transport and transfer functional components to target cells, with subsequent removal by the immune system, where the immunological activities of EVs impact immunoregulation including modulation of antigen presentation and cross-dressing, immune activation, immune suppression, and immune surveillance, impacting the tumour immune microenvironment. In this review, we outline the recent progress of EVs in immunorecognition and therapeutic intervention in cancer, including vaccine and targeted drug delivery and summarise their utility towards clinical translation. We highlight the strategies where EVs (natural and engineered) are being employed as a therapeutic approach for immunogenicity, tumoricidal function, and vaccine development, termed immuno-EVs. With seminal studies providing significant progress in the sequential development of engineered EVs as therapeutic anti-tumour platforms, we now require direct assessment to tune and improve the efficacy of resulting immune responses - essential in their translation into the clinic. We believe such a review could strengthen our understanding of the progress in EV immunobiology and facilitate advances in engineering EVs for the development of novel EV-based immunotherapeutics as a platform for cancer treatment.
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Affiliation(s)
- David W Greening
- Molecular Proteomics, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, Australia; Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe University, Victoria, Australia; Central Clinical School, Monash University, Victoria, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Victoria, Australia.
| | - Rong Xu
- Central Clinical School, Monash University, Victoria, Australia; Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Anukreity Ale
- Central Clinical School, Monash University, Victoria, Australia; Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Christoph E Hagemeyer
- Central Clinical School, Monash University, Victoria, Australia; Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Weisan Chen
- Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe University, Victoria, Australia
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27
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Ramesh D, Bakkannavar S, Bhat VR, Sharan K. Extracellular vesicles as novel drug delivery systems to target cancer and other diseases: Recent advancements and future perspectives. F1000Res 2023; 12:329. [PMID: 37868300 PMCID: PMC10589634 DOI: 10.12688/f1000research.132186.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/16/2023] [Indexed: 10/24/2023] Open
Abstract
Extracellular vesicles (EVs) are lipid-bound vesicles produced into the extracellular space by cells. Apoptotic bodies (ApoBD), microvesicles (MVs), and exosomes are examples of EVs, which act as essential regulators in cell-cell communication in both normal and diseased conditions. Natural cargo molecules such as miRNA, messenger RNA, and proteins are carried by EVs and transferred to nearby cells or distant cells through the process of circulation. Different signalling cascades are then influenced by these functionally active molecules. The information to be delivered to the target cells depends on the substances within the EVs that also includes synthesis method. EVs have attracted interest as potential delivery vehicles for therapies due to their features such as improved circulation stability, biocompatibility, reduced immunogenicity, and toxicity. Therefore, EVs are being regarded as potent carriers of therapeutics that can be used as a therapeutic agent for diseases like cancer. This review focuses on the exosome-mediated drug delivery to cancer cells and the advantages and challenges of using exosomes as a carrier molecule.
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Affiliation(s)
- Divya Ramesh
- Forensic Medicine and Toxicology, Katsurba Medical College, Manipal, Manipal Academy of Higher Education, MAHE, Manipal, Karnataka, 576104, India
| | - Shankar Bakkannavar
- Forensic Medicine and Toxicology, Katsurba Medical College, Manipal, Manipal Academy of Higher Education, MAHE, Manipal, Karnataka, 576104, India
| | - Vinutha R Bhat
- Biochemistry, Katsurba Medical College, Manipal, Manipal Academy of Higher Education, MAHE, Manipal, Karnataka, 576104, India
| | - Krishna Sharan
- Radiotherapy Oncology, Katsurba Medical College, Manipal, Manipal Academy of Higher Education, MAHE, Manipal, Karnataka, 576104, India
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28
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Schepici G, Silvestro S, Mazzon E. Regenerative Effects of Exosomes-Derived MSCs: An Overview on Spinal Cord Injury Experimental Studies. Biomedicines 2023; 11:biomedicines11010201. [PMID: 36672709 PMCID: PMC9855467 DOI: 10.3390/biomedicines11010201] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 01/15/2023] Open
Abstract
Spinal cord injury (SCI) is a devastating condition usually induced by the initial mechanical insult that can lead to permanent motor and sensory deficits. At present, researchers are investigating potential therapeutic strategies to ameliorate the neuro-inflammatory cascade that occurs post-injury. Although the use of mesenchymal stromal/stem (MSCs) as a potential therapy in application to regenerative medicine promoted anti-inflammatory and neuroprotective effects, several disadvantages limit their use. Therefore, recent studies have reported the effects of exosomes-derived MSCs (MSC-EXOs) as an innovative therapeutic option for SCI patients. It is noteworthy that MSC-EXOs can maintain the integrity of the blood-spinal cord barrier (BSCB), promoting angiogenic, proliferative, and anti-oxidant effects, as well as immunomodulatory, anti-inflammatory, and antiapoptotic properties. Therefore, in this study, we summarized the preclinical studies reported in the literature that have shown the effects of MSC-EXOs as a new molecular target to counteract the devastating effects of SCI.
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29
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Kong H, Liu P, Li H, Zeng X, Xu P, Yao X, Liu S, Cheng CK, Xu J. Mesenchymal Stem Cell-Derived Extracellular Vesicles: The Novel Therapeutic Option for Regenerative Dentistry. Stem Cell Rev Rep 2023; 19:46-58. [PMID: 35132538 DOI: 10.1007/s12015-022-10342-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] [Accepted: 01/23/2022] [Indexed: 01/29/2023]
Abstract
Dental mesenchymal stem cells (MSCs) are characterized by unlimited self-renewal ability and high multidirectional differentiation potential. Since dental MSCs can be easily isolated and exhibit a high capability to differentiate into odontogenic cells, they are considered as attractive therapeutic agents in regenerative dentistry. Recently, MSC-derived extracellular vesicles (MSC-EVs) have attracted widespread attention as carriers for cell-free therapy due to their potential functions. Many studies have shown that MSC-EVs can mediate microenvironment at tissue damage site, and coordinate the regeneration process. Additionally, MSC-EVs can mediate intercellular communication, thus affecting the phenotypes and functions of recipient cells. In this review, we mainly summarized the types of MSCs that could be potentially applied in regenerative dentistry, the possible molecular cargos of MSC-EVs, and the major effects of MSC-EVs on the therapeutic induction of osteogenic differentiation.
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Affiliation(s)
- Haiying Kong
- Department of Dentistry, Longgang E.N.T. Hospital & Shenzhen Key Laboratory of E.N.T, Institute of E.N.T, Shenzhen, Guangdong, China
| | - Peiqi Liu
- Department of Dentistry, Longgang E.N.T. Hospital & Shenzhen Key Laboratory of E.N.T, Institute of E.N.T, Shenzhen, Guangdong, China.,Second School of Clinical Medicine, Guangdong Medical University, Dongguan, Guangdong, China
| | - Hongwen Li
- Department of Dentistry, Longgang E.N.T. Hospital & Shenzhen Key Laboratory of E.N.T, Institute of E.N.T, Shenzhen, Guangdong, China.,Shenzhen Longgang Institute of Stomatology, Shenzhen, Guangdong, China
| | - Xiantao Zeng
- Department of Dentistry, Longgang E.N.T. Hospital & Shenzhen Key Laboratory of E.N.T, Institute of E.N.T, Shenzhen, Guangdong, China
| | - Peiwu Xu
- Department of Dentistry, Longgang E.N.T. Hospital & Shenzhen Key Laboratory of E.N.T, Institute of E.N.T, Shenzhen, Guangdong, China
| | - Xinhui Yao
- Department of Dentistry, Longgang E.N.T. Hospital & Shenzhen Key Laboratory of E.N.T, Institute of E.N.T, Shenzhen, Guangdong, China
| | - Senqing Liu
- Department of Dentistry, Longgang E.N.T. Hospital & Shenzhen Key Laboratory of E.N.T, Institute of E.N.T, Shenzhen, Guangdong, China
| | - Chak Kwong Cheng
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
| | - Jian Xu
- Department of Dentistry, Longgang E.N.T. Hospital & Shenzhen Key Laboratory of E.N.T, Institute of E.N.T, Shenzhen, Guangdong, China. .,Shenzhen Longgang Institute of Stomatology, Shenzhen, Guangdong, China.
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30
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Nistor-Cseppentö DC, Jurcău MC, Jurcău A, Andronie-Cioară FL, Marcu F. Stem Cell- and Cell-Based Therapies for Ischemic Stroke. Bioengineering (Basel) 2022; 9:717. [PMID: 36421118 PMCID: PMC9687728 DOI: 10.3390/bioengineering9110717] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/14/2022] [Accepted: 11/18/2022] [Indexed: 09/12/2023] Open
Abstract
Stroke is the second cause of disability worldwide as it is expected to increase its incidence and prevalence. Despite efforts to increase the number of patients eligible for recanalization therapies, a significant proportion of stroke survivors remain permanently disabled. This outcome boosted the search for efficient neurorestorative methods. Stem cells act through multiple pathways: cell replacement, the secretion of growth factors, promoting endogenous reparative pathways, angiogenesis, and the modulation of neuroinflammation. Although neural stem cells are difficult to obtain, pose a series of ethical issues, and require intracerebral delivery, mesenchymal stem cells are less immunogenic, are easy to obtain, and can be transplanted via intravenous, intra-arterial, or intranasal routes. Extracellular vesicles and exosomes have similar actions and are easier to obtain, also allowing for engineering to deliver specific molecules or RNAs and to promote the desired effects. Appropriate timing, dosing, and delivery protocols must be established, and the possibility of tumorigenesis must be settled. Nonetheless, stem cell- and cell-based therapies for stroke have already entered clinical trials. Although safe, the evidence for efficacy is less impressive so far. Hopefully, the STEP guidelines and the SPAN program will improve the success rate. As such, stem cell- and cell-based therapy for ischemic stroke holds great promise.
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Affiliation(s)
- Delia Carmen Nistor-Cseppentö
- Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
| | | | - Anamaria Jurcău
- Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
| | - Felicia Liana Andronie-Cioară
- Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
| | - Florin Marcu
- Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
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The Experimental Study of Periodontal Ligament Stem Cells Derived Exosomes with Hydrogel Accelerating Bone Regeneration on Alveolar Bone Defect. Pharmaceutics 2022; 14:pharmaceutics14102189. [PMID: 36297624 PMCID: PMC9611133 DOI: 10.3390/pharmaceutics14102189] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/05/2022] [Accepted: 10/09/2022] [Indexed: 12/03/2022] Open
Abstract
INTRODUCTION this study was conducted to investigate the osteogenic ability of periodontal ligament stem cells (PDLSCs) derived exosomes (PDLSCs-Exos) and the effect of PDLSCs-Exos with hydrogel on alveolar bone defect repairment in the rat. METHODS the PDLSCs were obtained through primary cell culture, and PDLSCs-Exos were purified by the ultracentrifugation method. The CCK-8 kit and ALP staining were used to explore the effect of PDLSCs-Exos on promoting the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). In vivo, the alveolar bone defect models were made mesial to the bilateral maxillary first molars of rats. MicroCT, HE staining, and Masson staining were used to analyze the new bone at the bone defect of rats. RESULTS the periodontal ligament stem cells and the periodontal ligament stem cells derived exosomes were successfully extracted. The results of the CCK-8 kit and ALP staining showed PDLSCs-Exos significantly promoted the proliferation osteogenic differentiation of BMSCs. In vivo experiment results revealed that compared with the control group and the hydrogel group, the rats in the hydrogel with exosomes group showed more new bone formation in alveolar bone defects. CONCLUSION Periodontal ligament stem cells and exosomes derived from periodontal ligament stem cells were successfully extracted. The results demonstrated that the hydrogel successfully delivered periodontal ligament stem cells derived exosomes for repairing alveolar bone defects in rats in vivo at the initial stage.
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Gingival epithelial cell-derived microvesicles activate mineralization in gingival fibroblasts. Sci Rep 2022; 12:15779. [PMID: 36138045 PMCID: PMC9500071 DOI: 10.1038/s41598-022-19732-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 09/02/2022] [Indexed: 11/08/2022] Open
Abstract
Soft tissue calcification occurs in many parts of the body, including the gingival tissue. Epithelial cell-derived MVs can control many functions in fibroblasts but their role in regulating mineralization has not been explored. We hypothesized that microvesicles (MVs) derived from gingival epithelial cells could regulate calcification of gingival fibroblast cultures in osteogenic environment. Human gingival fibroblasts (HGFs) were cultured in osteogenic differentiation medium with or without human gingival epithelial cell-derived MV stimulation. Mineralization of the cultures, localization of the MVs and mineral deposits in the HGF cultures were assessed. Gene expression changes associated with MV exposure were analyzed using gene expression profiling and real-time qPCR. Within a week of exposure, epithelial MVs stimulated robust mineralization of HGF cultures that was further enhanced by four weeks. The MVs taken up by the HGF's did not calcify themselves but induced intracellular accumulation of minerals. HGF gene expression profiling after short exposure to MVs demonstrated relative dominance of inflammation-related genes that showed increases in gene expression. In later cultures, OSX, BSP and MMPs were significantly upregulated by the MVs. These results suggest for the first time that epithelial cells maybe associated with the ectopic mineralization process often observed in the soft tissues.
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33
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Xu J, Wang J, Chen Y, Hou Y, Hu J, Wang G. Recent advances of natural and bioengineered extracellular vesicles and their application in vascular regeneration. Regen Biomater 2022; 9:rbac064. [PMID: 36176713 PMCID: PMC9514852 DOI: 10.1093/rb/rbac064] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/13/2022] [Accepted: 08/24/2022] [Indexed: 11/22/2022] Open
Abstract
The progression of cardiovascular diseases such as atherosclerosis and myocardial infarction leads to serious vascular injury, highlighting the urgent need for targeted regenerative therapy. Extracellular vesicles (EVs) composed of a lipid bilayer containing nuclear and cytosolic materials are relevant to the progression of cardiovascular diseases. Moreover, EVs can deliver bioactive cargo in pathological cardiovascular and regulate the biological function of recipient cells, such as inflammation, proliferation, angiogenesis and polarization. However, because the targeting and bioactivity of natural EVs are subject to several limitations, bioengineered EVs have achieved wide advancements in biomedicine. Bioengineered EVs involve three main ways to acquire including (i) modification of the EVs after isolation; (ii) modification of producer cells before EVs’ isolation; (iii) synthesize EVs using natural or modified cell membranes, and encapsulating drugs or bioactive molecules into EVs. In this review, we first summarize the cardiovascular injury-related disease and describe the role of different cells and EVs in vascular regeneration. We also discuss the application of bioengineered EVs from different producer cells to cardiovascular diseases. Finally, we summarize the surface modification on EVs which can specifically target abnormal cells in injured vascular.
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Affiliation(s)
| | | | - Yidan Chen
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering Modern Life Science Experiment Teaching Center of Bioengineering College, Chongqing University, Chongqing 400030, China
| | - Yuanfang Hou
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering Modern Life Science Experiment Teaching Center of Bioengineering College, Chongqing University, Chongqing 400030, China
| | - Jianjun Hu
- Correspondence address. E-mail: (G.W.); (J.H.)
| | - Guixue Wang
- Correspondence address. E-mail: (G.W.); (J.H.)
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Zhang J, Shi W, Qu D, Yu T, Qi C, Fu H. Extracellular vesicle therapy for traumatic central nervous system disorders. Stem Cell Res Ther 2022; 13:442. [PMID: 36056445 PMCID: PMC9438220 DOI: 10.1186/s13287-022-03106-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 07/31/2022] [Indexed: 11/10/2022] Open
Abstract
Traumatic central nervous system (CNS) disorders have catastrophic effects on patients, and, currently, there is no effective clinical treatment. Cell transplantation is a common treatment for traumatic CNS injury in animals. In recent years, an increasing number of studies have reported that the beneficial effect of transplanted cells for CNS repair is mediated primarily through the extracellular vesicles (EVs) secreted by the cells, in which microRNAs play a major role. Accordingly, numerous studies have evaluated the roles and applications of EVs secreted by different cell types in neurological diseases. Furthermore, due to their unique biological features, EVs are used as disease biomarkers and drug delivery systems for disease prevention and treatment. We discuss current knowledge related to EVs, focusing on the mechanism underlying their effects on traumatic CNS diseases, and summarize existing research on the potential clinical utility of EVs as disease biomarkers and drug delivery systems.
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Affiliation(s)
- Jing Zhang
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266071, China.,Medical Department of Qingdao University, Qingdao, China
| | - Weipeng Shi
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266071, China.,Medical Department of Qingdao University, Qingdao, China
| | - Di Qu
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266071, China.,Medical Department of Qingdao University, Qingdao, China
| | - Tengbo Yu
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266071, China
| | - Chao Qi
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266071, China.
| | - Haitao Fu
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266071, China.
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Zhu J, Quan H. Adipose-derived stem cells-derived exosomes facilitate cutaneous wound healing by delivering XIST and restoring discoidin domain receptor 2. Cytokine 2022; 158:155981. [PMID: 35952595 DOI: 10.1016/j.cyto.2022.155981] [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: 05/23/2022] [Revised: 07/22/2022] [Accepted: 07/25/2022] [Indexed: 11/03/2022]
Abstract
BACKGROUND Adipose-derived stem cells (ADSCs) and their derived exosomes (ADSC-Exos) have shown potential functions in tissue repair. This study focuses on the effects of ADSCs-Exos on cutaneous wound healing and the potential involvement of the long non-coding RNA (lncRNA) XIST/microRNA-96-5p (miR-96-5p)/discoidin domain receptor 2 (DDR2) axis. METHODS Exos were isolated from the ADSCs and identified. A mouse model of full-thickness skin wounds was established. The mice were treated with ADSC-Exos to evaluate the function of ADSC-Exos in wound healing. Mouse dermal fibroblasts (MDFs) were co-cultured with the ADSC-Exos for in vitro experiments. The most differentially expressed lncRNAs in mouse skin tissues after ADSC-Exo treatment were screened by microarray analysis. The downstream molecules were analyzed by bioinformatics tools. Gain- and loss-of-function studies were performed to examine the functions of the XIST/miR-96-5p/DDR2 axis in wound healing. RESULTS ADSC-Exos facilitated wound healing in mice, reduced inflammatory infiltration, and increased collagen deposition in the wound skin tissues. In vitro, the ADSC-Exos promoted proliferation, migration of the MDFs. XIST was the most upregulated lncRNA in MDFs after ADSC-Exo treatment. Downregulation of XIST suppressed the promoting role of ADSC-Exos in wound healing. XIST bound to miR-96-5p to restore the expression of DDR2 mRNA. Either silencing of miR-96-5p or overexpression of DDR2 restored the promoting functions of ADSC-Exos in proliferation and migration of MDFs. CONCLUSION This study demonstrates that ADSC-Exos-carried XIST accelerates cutaneous wound healing through suppressing miR-96-5p and restoring the DDR2 expression.
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Affiliation(s)
- Jinglin Zhu
- Department of Plastic Surgery 18, Plastic Surgery Hospital (Institute), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100144, PR China
| | - Hongguang Quan
- Department of General Surgery, Xuzhou Hospital of Traditional Chinese Medicine, the Affiliated Xuzhou Hospital of Nanjing University of Chinese Medicine, Xuzhou 221000, Jiangsu, PR China.
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Xu J, Cao W, Wang P, Liu H. Tumor-Derived Membrane Vesicles: A Promising Tool for Personalized Immunotherapy. Pharmaceuticals (Basel) 2022; 15:ph15070876. [PMID: 35890175 PMCID: PMC9318328 DOI: 10.3390/ph15070876] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/11/2022] [Accepted: 07/12/2022] [Indexed: 11/16/2022] Open
Abstract
Tumor-derived membrane vesicles (TDMVs) are non-invasive, chemotactic, easily obtained characteristics and contain various tumor-borne substances, such as nucleic acid and proteins. The unique properties of tumor cells and membranes make them widely used in drug loading, membrane fusion and vaccines. In particular, personalized vectors prepared using the editable properties of cells can help in the design of personalized vaccines. This review focuses on recent research on TDMV technology and its application in personalized immunotherapy. We elucidate the strengths and challenges of TDMVs to promote their application from theory to clinical practice.
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Affiliation(s)
- Jiabin Xu
- School of Stomatology, Xuzhou Medical University, Xuzhou 221004, China; (J.X.); (P.W.)
- Affiliated Stomatological Hospital of Xuzhou Medical University, Xuzhou 221004, China
| | - Wenqiang Cao
- Zhuhai Jinan Selenium Source Nanotechnology Co., Ltd., Jinan University, Zhuhai 519000, China;
| | - Penglai Wang
- School of Stomatology, Xuzhou Medical University, Xuzhou 221004, China; (J.X.); (P.W.)
- Affiliated Stomatological Hospital of Xuzhou Medical University, Xuzhou 221004, China
| | - Hong Liu
- Zhuhai Jinan Selenium Source Nanotechnology Co., Ltd., Jinan University, Zhuhai 519000, China;
- Correspondence:
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Hu JC, Zheng CX, Sui BD, Liu WJ, Jin Y. Mesenchymal stem cell-derived exosomes: A novel and potential remedy for cutaneous wound healing and regeneration. World J Stem Cells 2022; 14:318-329. [PMID: 35722196 PMCID: PMC9157601 DOI: 10.4252/wjsc.v14.i5.318] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 04/11/2022] [Accepted: 05/22/2022] [Indexed: 02/06/2023] Open
Abstract
Poor healing of cutaneous wounds is a common medical problem in the field of traumatology. Due to the intricate pathophysiological processes of wound healing, the use of conventional treatment methods, such as chemical molecule drugs and traditional dressings, have been unable to achieve satisfactory outcomes. Within recent years, explicit evidence suggests that mesenchymal stem cells (MSCs) have great therapeutic potentials on skin wound healing and regeneration. However, the direct application of MSCs still faces many challenges and difficulties. Intriguingly, exosomes as cell-secreted granular vesicles with a lipid bilayer membrane structure and containing specific components from the source cells may emerge to be excellent substitutes for MSCs. Exosomes derived from MSCs (MSC-exosomes) have been demonstrated to be beneficial for cutaneous wound healing and accelerate the process through a variety of mechanisms. These mechanisms include alleviating inflammation, promoting vascularization, and promoting proliferation and migration of epithelial cells and fibroblasts. Therefore, the application of MSC-exosomes may be a promising alternative to cell therapy in the treatment of cutaneous wounds and could promote wound healing through multiple mechanisms simultaneously. This review will provide an overview of the role and the mechanisms of MSC-derived exosomes in cutaneous wound healing, and elaborate the potentials and future perspectives of MSC-exosomes application in clinical practice.
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Affiliation(s)
- Jia-Chen Hu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
| | - Chen-Xi Zheng
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
| | - Bing-Dong Sui
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
| | - Wen-Jia Liu
- National and Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, Precision Medicine Institute, Institute for Stem Cell and Regenerative Medicine, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710032, Shaanxi Province, China
| | - Yan Jin
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
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38
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Yang ZL, Rao J, Lin FB, Liang ZY, Xu XJ, Lin YK, Chen XY, Wang CH, Chen CM. The Role of Exosomes and Exosomal Noncoding RNAs From Different Cell Sources in Spinal Cord Injury. Front Cell Neurosci 2022; 16:882306. [PMID: 35518647 PMCID: PMC9062236 DOI: 10.3389/fncel.2022.882306] [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: 02/23/2022] [Accepted: 03/21/2022] [Indexed: 11/13/2022] Open
Abstract
Spinal cord injury (SCI) not only affects the quality of life of patients but also poses a heavy burden on their families. Therefore, it is essential to prevent the occurrence of SCI; for unpreventable SCI, it is critical to develop effective treatments. In recent years, various major breakthroughs have been made in cell therapy to protect and regenerate the damaged spinal cord via various mechanisms such as immune regulation, paracrine signaling, extracellular matrix (ECM) modification, and lost cell replacement. Nevertheless, many recent studies have shown that the cell therapy has many disadvantages, such as tumorigenicity, low survival rate, and immune rejection. Because of these disadvantages, the clinical application of cell therapy is limited. In recent years, the role of exosomes in various diseases and their therapeutic potential have attracted much attention. The same is true for exosomal noncoding RNAs (ncRNAs), which do not encode proteins but affect transcriptional and translational processes by targeting specific mRNAs. This review focuses on the mechanism of action of exosomes obtained from different cell sources in the treatment of SCI and the regulatory role and therapeutic potential of exosomal ncRNAs. This review also discusses the future opportunities and challenges, proposing that exosomes and exosomal ncRNAs might be promising tools for the treatment of SCI.
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Affiliation(s)
| | | | | | | | | | | | | | - Chun-Hua Wang
- Department of Neurosurgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Chun-Mei Chen
- Department of Neurosurgery, Fujian Medical University Union Hospital, Fuzhou, China
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Wang N, Liu X, Tang Z, Wei X, Dong H, Liu Y, Wu H, Wu Z, Li X, Ma X, Guo Z. Increased BMSC exosomal miR-140-3p alleviates bone degradation and promotes bone restoration by targeting Plxnb1 in diabetic rats. J Nanobiotechnology 2022; 20:97. [PMID: 35236339 PMCID: PMC8889728 DOI: 10.1186/s12951-022-01267-2] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 01/16/2022] [Indexed: 12/23/2022] Open
Abstract
Background Diabetes mellitus (DM) is considered to be an important factor for bone degeneration disorders such as bone defect nonunion, which is characterized by physical disability and tremendous economy cost to families and society. Exosomal miRNAs of BMSCs have been reported to participate in osteoblastogenesis and modulating bone formation. However, their impacts on the development of bone degeneration in DM are not yet known. The role of miRNAs in BMSCs exosomes on regulating hyperglycemia bone degeneration was investigated in the present study. Results The osteogenic potential in bone defect repair of exosomes derived from diabetes mellitus BMSCs derived exosomes (DM-Exos) were revealed to be lower than that in normal BMSCs derived exosomes (N-Exos) in vitro and in vivo. Here, we demonstrate that miR-140-3p level was significantly altered in exosomes derived from BMSCs, ADSCs and serum from DM rats. In in vitro experiments, upregulated miR-140-3p exosomes promoted DM BMSCs differentiation into osteoblasts. The effects were exerted by miR-140-3p targeting plxnb1, plexin B1 is the receptor of semaphoring 4D(Sema4D) that inhibited osteocytes differentiation, thereby promoting bone formation. In DM rats with bone defect, miR-140-3p upregulated exosomes were transplanted into injured bone and accelerated bone regeneration. Besides, miR-140-3p in the exosomes was transferred into BMSCs and osteoblasts and promoted bone regeneration by targeting the plexin B1/RohA/ROCK signaling pathway. Conclusions Normal-Exos and miR-140-3p overexpressed-Exos accelerated diabetic wound healing by promoting the osteoblastogenesis function of BMSCs through inhibition plexin B1 expression which is the receptor of Sema4D and the plexin B1/RhoA/ROCK pathway compared with diabetes mellitus-Exos. This offers a new insight and a new therapy for treating diabetic bone unhealing. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s12951-022-01267-2.
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Affiliation(s)
- Ning Wang
- Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Xuanchen Liu
- Department of Nutrition, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Zhen Tang
- Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Xinghui Wei
- Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Hui Dong
- Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Yichao Liu
- Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Hao Wu
- Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, Shaanxi, China
| | - Zhigang Wu
- Department of Orthopedics, The 63750 Hospital of People's Liberation Army, Xi'an, 710043, Shaanxi, China
| | - Xiaokang Li
- Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, Shaanxi, China.
| | - Xue Ma
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Zheng Guo
- Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, Shaanxi, China.
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Chew BC, Liew FF, Tan HW, Chung I. Chemical Advances in Therapeutic Application of Exosomes and Liposomes. Curr Med Chem 2022; 29:4445-4473. [PMID: 35189798 DOI: 10.2174/0929867329666220221094044] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 11/30/2021] [Accepted: 12/08/2021] [Indexed: 11/22/2022]
Abstract
Exosomes and liposomes are vesicular nanoparticles that can encapsulate functional cargo. The chemical similarities between naturally occurring exosomes and synthetic liposomes have accelerated the development of exosome mimetics as a therapeutic drug delivery platform under physiological and pathological environments. To maximise the applications of exosomes and liposomes in the clinical setting, it is essential to look into their basic chemical properties and utilise these characteristics to optimise the preparation, loading, modification and hybridisation. This review summarises the chemical and biological properties of both exosomal and liposomal systems as well as some of the challenges related to their production and application. This article concludes with a discussion on potential perspectives for the integration of exosomal and liposomal technologies in mapping better approaches for their biomedical use, especially in therapeutics.
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Affiliation(s)
- Boon Cheng Chew
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Jalan Universiti, 50603 Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Fong Fong Liew
- Department of Oral Biology and Biomedical Science, Faculty of Dentistry, MAHSA University, Jalan SP2, Bandar Saujana Putra, 42610 Jenjarom, Selangor, Malaysia
| | - Hsiao Wei Tan
- Institute of Research Management and Services, Research and Innovation Management Complex, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Ivy Chung
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Jalan Universiti, 50603 Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia
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Kusuma GD, Li A, Zhu D, McDonald H, Inocencio IM, Chambers DC, Sinclair K, Fang H, Greening DW, Frith JE, Lim R. Effect of 2D and 3D Culture Microenvironments on Mesenchymal Stem Cell-Derived Extracellular Vesicles Potencies. Front Cell Dev Biol 2022; 10:819726. [PMID: 35237601 PMCID: PMC8882622 DOI: 10.3389/fcell.2022.819726] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 01/17/2022] [Indexed: 02/06/2023] Open
Abstract
Therapeutic benefits of mesenchymal stem cells (MSCs) are now widely believed to come from their paracrine signalling, i.e. secreted factors such as cytokines, chemokines, and extracellular vesicles (EVs). Cell-free therapy using EVs is an active and emerging field in regenerative medicine. Typical 2D cultures on tissue culture plastic is far removed from the physiological environment of MSCs. The application of 3D cell culture allows MSCs to adapt to their cellular environment which, in turn, influences their paracrine signalling activity. In this study we evaluated the impact of 3D MSCs culture on EVs secretion, cargo proteome composition, and functional assessment in immunomodulatory, anti-inflammatory and anti-fibrotic properties.MSC-EVs from 2D and 3D cultures expressed classical EV markers CD81, CD63, and CD9 with particle diameter of <100 nm. There were distinct changes in immunomodulatory potencies where 3D cultures exhibited reduced indoleamine 2,3-dioxygenase (IDO) activity and significantly reduced macrophage phagocytosis. Administration of 2D and 3D EVs following double dose bleomycin challenge in aged mice showed a marked increase of bodyweight loss in 3D group throughout days 7–28. Histopathological observations of lung tissues in 3D group showed increased collagen deposition, myofibroblast differentiation and leukocytes infiltrations. Assessment of lung mechanics showed 3D group did not improve lung function and instead exhibited increased resistance and tissue damping. Proteome profiling of MSC-EV composition revealed molecular enrichment of EV markers (compared to parental cells) and differential proteome between EVs from 2D and 3D culture condition associated with immune-based and fibrosis/extracellular matrix/membrane organization associated function.This study provides insight into distinct variation in EV protein composition dependent on the cellular microenvironment of the parental cells, which could have implications in their therapeutic effect and potency. Overall, this work suggests that EVs produced from 3D MSC cultures did not enhance typical MSC-EV properties expected from 2D cultures (immunomodulation, anti-fibrotic, anti-inflammatory). The outcome highlights critical differences between MSC-EVs obtained from different culture microenvironments, which should be considered when scaling up MSC culture for clinical manufacturing.
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Affiliation(s)
- Gina D. Kusuma
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
- *Correspondence: Gina D. Kusuma, ; Rebecca Lim,
| | - Anqi Li
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Dandan Zhu
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Hannah McDonald
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Ishmael M. Inocencio
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Daniel C. Chambers
- Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, QLD, Australia
- School of Clinical Medicine, Faculty of Health Sciences, University of Queensland, Brisbane, QLD, Australia
| | - Kenneth Sinclair
- Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, QLD, Australia
| | - Haoyun Fang
- Molecular Proteomics, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - David W. Greening
- Molecular Proteomics, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
- Baker Department of Cardiometabolic Health, The University of Melbourne, Melbourne, VIC, Australia
- Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Melbourne, VIC, Australia
- Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Jessica E. Frith
- Department of Materials Science and Engineering, Monash University, Melbourne, VIC, Australia
| | - Rebecca Lim
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
- *Correspondence: Gina D. Kusuma, ; Rebecca Lim,
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Jiang S, Chen H, He K, Wang J. Human bone marrow mesenchymal stem cells-derived exosomes attenuated prostate cancer progression via the miR-99b-5p/IGF1R axis. Bioengineered 2022; 13:2004-2016. [PMID: 35030978 PMCID: PMC8973722 DOI: 10.1080/21655979.2021.2009416] [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] [Indexed: 02/06/2023] Open
Abstract
MicroRNA-99b-5p (miR-99b-5p) has been shown to be enriched in serum exosomes of prostate cancer (PCa) patients treated with radiotherapy, while its function in PCa progression remains unclear. The expression levels of miR-99b-5p in PCa tissues, cancer cell lines and human bone marrow mesenchymal stem cells (HBMSCs), as well as HBMSCs-derived exosomes were assessed by quantitative real-time PCR (qRT-PCR). MiR-99b-5p mimics or inhibitor was transfected into HBMSCs, and HBMSCs-derived exosomes with abnormal expression of miR-99b-5p were used to stimulate PCa cell-line LNCaP cells. Cell proliferative rate was evaluated using Cell Counting Kit-8 (CCK-8) and 5‐ethynyl‐2′‐deoxyuridine (EdU) staining assays. Cell migration and invasion were analyzed by Transwell assay. The epithelial-mesenchymal transition (EMT) was evaluated by detecting EMT-related markers using Western blot analysis. The animal model was constructed to confirm the function of miR-99b-5p in vivo. The expression levels of MiR-99b-5p were decreased in PCa tissues and cell lines, while elevated in HBMSCs-derived exosomes. HBMSCs-derived exosomes significantly inhibited cell malignant phenotypes of PCa cells, and miR-99b-5p mimics transfected HBMSCs further enhanced the inhibitory effects of HBMSCs on PCa progression. In addition, miR-99b-5p inhibitor transfected HBMSCs-derived exosomes promoted the progression of PCa in vitro. Insulin-like growth factor 1 receptor (IGF1R) was identified as a downstream target of miR-99b-5p. Moreover, miR-99b-5p mimics transfected HBMSCs obviously inhibited tumor progression by downregulating IGF1R in animal model in vivo. Our results demonstrated that HBMSCs could attenuate PCa progression, and exosomal miR-99b-5p and IGF1R participated in the regulatory process, contributing to our understanding of the pathogenic mechanism of PCa.
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Affiliation(s)
- Shichun Jiang
- Department of Urology, Mianyang Central Hospital, Mianyang City, Sichuan Province, PR. China
| | - Haiyu Chen
- Department of Surgery, Haikou Hospital of Traditional Chinese Medicine, Haikou City, Hainan Province, PR. China
| | - Kai He
- Department of Urology, Mianyang Central Hospital, Mianyang City, Sichuan Province, PR. China
| | - Juan Wang
- Department of Surgery, Haikou Hospital of Traditional Chinese Medicine, Haikou City, Hainan Province, PR. China
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Intranasally Administered Extracellular Vesicles from Adipose Stem Cells Have Immunomodulatory Effects in a Mouse Model of Asthma. Stem Cells Int 2021; 2021:6686625. [PMID: 34899920 PMCID: PMC8664544 DOI: 10.1155/2021/6686625] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 06/02/2021] [Accepted: 07/14/2021] [Indexed: 12/27/2022] Open
Abstract
Asthma is a chronic eosinophilic airway disease characterized by type 2 helper T cell-driven inflammation. Adipose stem cells (ASCs) and the ASC culture supernatant are known to improve allergic airway inflammation; however, the immunomodulatory effects of ASC-derived extracellular vesicles (EVs) on allergic airway diseases remain unclear. Thus, we assessed the effects of ASC-derived EVs on allergic airway inflammation in a mouse model of asthma. EVs were isolated from the culture supernatant of murine ASCs and characterized. Six-week-old female C57BL/6 mice were sensitized to ovalbumin (OVA) by intraperitoneal injection and challenged intranasally with OVA. Before the OVA challenge, 10 μg/50 μl of ASC-derived EVs was administered intranasally to the experimental group. ASC-derived EVs significantly attenuated airway hyperresponsiveness (AHR) in asthmatic mice (p = 0.023). ASC-derived EVs resulted in a remarkable reduction of the total number of inflammatory cells (p = 0.005) and eosinophils (p = 0.023) in the bronchoalveolar lavage fluid (BALF), the degree of eosinophilic lung inflammation (p < 0.001), and the serum total and OVA-specific immunoglobulin (Ig)E (p = 0.048 and p = 0.001) and total IgG1 (p < 0.001). Interleukin- (IL-) 4 was significantly inhibited with ASC-derived EV pretreatment in the BALF and lung draining lymph nodes (LLNs) (p = 0.040 and p = 0.011). Furthermore, ASC-derived EV administration resulted in a significant increase of the regulatory T cell (Treg) populations in LLNs. ASC-derived EVs alleviated AHR and allergic airway inflammation caused by the induction of Treg expansion in a mouse model of asthma. There seems to be a role for ASC-derived EVs as a modifier in allergic airway disease.
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Mytidou C, Koutsoulidou A, Zachariou M, Prokopi M, Kapnisis K, Spyrou GM, Anayiotos A, Phylactou LA. Age-Related Exosomal and Endogenous Expression Patterns of miR-1, miR-133a, miR-133b, and miR-206 in Skeletal Muscles. Front Physiol 2021; 12:708278. [PMID: 34867435 PMCID: PMC8637414 DOI: 10.3389/fphys.2021.708278] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 10/26/2021] [Indexed: 12/12/2022] Open
Abstract
Skeletal muscle growth and maintenance depend on two tightly regulated processes, myogenesis and muscle regeneration. Both processes involve a series of crucial regulatory molecules including muscle-specific microRNAs, known as myomiRs. We recently showed that four myomiRs, miR-1, miR-133a, miR-133b, and miR-206, are encapsulated within muscle-derived exosomes and participate in local skeletal muscle communication. Although these four myomiRs have been extensively studied for their function in muscles, no information exists regarding their endogenous and exosomal levels across age. Here we aimed to identify any age-related changes in the endogenous and muscle-derived exosomal myomiR levels during acute skeletal muscle growth. The four endogenous and muscle-derived myomiRs were investigated in five skeletal muscles (extensor digitorum longus, soleus, tibialis anterior, gastrocnemius, and quadriceps) of 2-week–1-year-old wild-type male mice. The expression of miR-1, miR-133a, and miR-133b was found to increase rapidly until adolescence in all skeletal muscles, whereas during adulthood it remained relatively stable. By contrast, endogenous miR-206 levels were observed to decrease with age in all muscles, except for soleus. Differential expression of the four myomiRs is also inversely reflected on the production of two protein targets; serum response factor and connexin 43. Muscle-derived exosomal miR-1, miR-133a, and miR-133b levels were found to increase until the early adolescence, before reaching a plateau phase. Soleus was found to be the only skeletal muscle to release exosomes enriched in miR-206. In this study, we showed for the first time an in-depth longitudinal analysis of the endogenous and exosomal levels of the four myomiRs during skeletal muscle development. We showed that the endogenous expression and extracellular secretion of the four myomiRs are associated to the function and size of skeletal muscles as the mice age. Overall, our findings provide new insights for the myomiRs’ significant role in the first year of life in mice.
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Affiliation(s)
- Chrystalla Mytidou
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.,Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Andrie Koutsoulidou
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.,Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Margarita Zachariou
- Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.,Bioinformatics Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Marianna Prokopi
- Theramir Ltd., Limassol, Cyprus.,Department of Mechanical Engineering and Materials Science and Engineering, Cyprus University of Technology, Limassol, Cyprus
| | - Konstantinos Kapnisis
- Department of Mechanical Engineering and Materials Science and Engineering, Cyprus University of Technology, Limassol, Cyprus
| | - George M Spyrou
- Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.,Bioinformatics Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Andreas Anayiotos
- Department of Mechanical Engineering and Materials Science and Engineering, Cyprus University of Technology, Limassol, Cyprus
| | - Leonidas A Phylactou
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.,Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
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Cardiac Extracellular Matrix Hydrogel Enriched with Polyethylene Glycol Presents Improved Gelation Time and Increased On-Target Site Retention of Extracellular Vesicles. Int J Mol Sci 2021; 22:ijms22179226. [PMID: 34502146 PMCID: PMC8431142 DOI: 10.3390/ijms22179226] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/19/2021] [Accepted: 08/22/2021] [Indexed: 12/17/2022] Open
Abstract
Stem-cell-derived extracellular vesicles (EVs) have demonstrated multiple beneficial effects in preclinical models of cardiac diseases. However, poor retention at the target site may limit their therapeutic efficacy. Cardiac extracellular matrix hydrogels (cECMH) seem promising as drug-delivery materials and could improve the retention of EVs, but may be limited by their long gelation time and soft mechanical properties. Our objective was to develop and characterize an optimized product combining cECMH, polyethylene glycol (PEG), and EVs (EVs–PEG–cECMH) in an attempt to overcome their individual limitations: long gelation time of the cECMH and poor retention of the EVs. The new combined product presented improved physicochemical properties (60% reduction in half gelation time, p < 0.001, and threefold increase in storage modulus, p < 0.01, vs. cECMH alone), while preserving injectability and biodegradability. It also maintained in vitro bioactivity of its individual components (55% reduction in cellular senescence vs. serum-free medium, p < 0.001, similar to EVs and cECMH alone) and increased on-site retention in vivo (fourfold increase vs. EVs alone, p < 0.05). In conclusion, the combination of EVs–PEG–cECMH is a potential multipronged product with improved gelation time and mechanical properties, increased on-site retention, and maintained bioactivity that, all together, may translate into boosted therapeutic efficacy.
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46
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Exosomal miR-218-5p/miR-363-3p from Endothelial Progenitor Cells Ameliorate Myocardial Infarction by Targeting the p53/JMY Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5529430. [PMID: 34326916 PMCID: PMC8302385 DOI: 10.1155/2021/5529430] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 06/08/2021] [Accepted: 06/22/2021] [Indexed: 12/19/2022]
Abstract
Accumulating evidence has shown that endothelial progenitor cell-derived exosomes (EPC-Exos) can ameliorate myocardial fibrosis. The purpose of the present study was to investigate the effects of EPC-Exos-derived microRNAs (miRNAs) on myocardial infarction (MI). A miRNA-Seq dataset of miRNAs differentially expressed between EPCs and exosomes was collected. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the miRNA expression indicated by miRNA-Seq. Immunofluorescence, cell proliferation, and angiogenesis assays were employed to investigate the effects of miRNAs on cardiac fibroblasts (CFs) in vitro. Interactions between miRNAs and their respective targets were examined via immunoblotting, qRT-PCR, and luciferase reporter assays. An MI rat model was constructed, and various staining and immunohistochemical assays were performed to explore the mechanisms underlying the miRNA-mediated effects on MI. miR-363-3p and miR-218-5p were enriched in EPC-Exos, and miR-218-5p and miR-363-3p mimic or inhibitor enhanced or suppressed CF proliferation and angiogenesis, respectively. miR-218-5p and miR-363-3p regulated p53 and junction-mediating and regulatory protein (JMY) by binding to the promoter region of p53 and the 3′ untranslated region of JMY. Additionally, treatment of CFs with Exo-miR-218-5p or Exo-miR-363-3p upregulated p53 and downregulated JMY expression, promoted mesenchymal-endothelial transition, and inhibited myocardial fibrosis. Administration of exosomes containing miR-218-5p mimic or miR-363-3p mimic ameliorated left coronary artery ligation-induced MI and restored myocardial tissue integrity in the MI model rats. In summary, these results show that the protective ability of EPC-Exos against MI was mediated by the shuttled miR-218-5p or miR-363-3p via targeting of the p53/JMY signaling pathway.
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47
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Mytidou C, Koutsoulidou A, Katsioloudi A, Prokopi M, Kapnisis K, Michailidou K, Anayiotos A, Phylactou LA. Muscle-derived exosomes encapsulate myomiRs and are involved in local skeletal muscle tissue communication. FASEB J 2021; 35:e21279. [PMID: 33484211 DOI: 10.1096/fj.201902468rr] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 11/02/2020] [Accepted: 12/01/2020] [Indexed: 12/23/2022]
Abstract
Exosomes are extracellular vesicles that are released from most cell types encapsulating specific molecular cargo. Exosomes serve as mediators of cell-to-cell and tissue-to-tissue communications under normal and pathological conditions. It has been shown that exosomes carrying muscle-specific miRNAs, myomiRs, are secreted from skeletal muscle cells in vitro and are elevated in the blood of muscle disease patients. The aim of this study was to investigate the secretion of exosomes encapsulating the four myomiRs from skeletal muscle tissues and to assess their role in inter-tissue communication between neighboring skeletal muscles in vivo. We demonstrate, for the first time, that isolated, intact skeletal muscle tissues secrete exosomes encapsulating the four myomiRs, miR-1, miR-133a, miR-133b, and miR-206. Notably, we show that the sorting of the four myomiRs within exosomes varies between skeletal muscles of different muscle fiber-type composition. miR-133a and miR-133b downregulation in TA muscles caused a reduction of their levels in neighboring skeletal muscles and in serum exosomes. In conclusion, our results reveal that skeletal muscle-derived exosomes encapsulate the four myomiRs, some of which enter the blood, while a portion is used for the local communication between proximal muscle tissues. These findings provide important evidence regarding novel pathways implicated in skeletal muscle function.
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Affiliation(s)
- Chrystalla Mytidou
- Department of Molecular Genetics, Function & Therapy, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.,The Cyprus School of Molecular Medicine, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
| | - Andrie Koutsoulidou
- Department of Molecular Genetics, Function & Therapy, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.,The Cyprus School of Molecular Medicine, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
| | | | - Marianna Prokopi
- Theramir Ltd, Limassol, Cyprus.,Department of Mechanical Engineering and Materials Science and Engineering, Cyprus University of Technology, Lemesos, Cyprus.,Department of Research and Development, German Oncology Center, Limassol, Cyprus
| | - Konstantinos Kapnisis
- Department of Mechanical Engineering and Materials Science and Engineering, Cyprus University of Technology, Lemesos, Cyprus
| | - Kyriaki Michailidou
- The Cyprus School of Molecular Medicine, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.,Biostatistics Unit, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
| | - Andreas Anayiotos
- Department of Mechanical Engineering and Materials Science and Engineering, Cyprus University of Technology, Lemesos, Cyprus
| | - Leonidas A Phylactou
- Department of Molecular Genetics, Function & Therapy, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.,The Cyprus School of Molecular Medicine, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
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48
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Babaei M, Rezaie J. Application of stem cell-derived exosomes in ischemic diseases: opportunity and limitations. J Transl Med 2021; 19:196. [PMID: 33964940 PMCID: PMC8106139 DOI: 10.1186/s12967-021-02863-w] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 04/30/2021] [Indexed: 12/15/2022] Open
Abstract
Ischemic diseases characterized by an insufficient blood flow that leads to a decrease in oxygen and nutrient uptake by cells have emerged as an important contributor to both disability and death worldwide. Up-regulation of angiogenesis may be a key factor for the improvement of ischemic diseases. This article searched articles in PubMed with the following keywords: stem cells, exosomes, angiogenesis, ischemic diseases either alone or in grouping form. The most relevant selected items were stem cell-derived exosomes and ischemic diseases. A growing body of evidence indicates that stem cells produce exosomes, which is the novel emerging approach to cell-to-cell communication and offers a new standpoint on known therapeutic strategies of ischemic diseases. Exosomes transport biological molecules such as many types of proteins, RNAs, DNA fragments, signaling molecules, and lipids between cells. Different stem cells release exosomes representing beneficial effects on ischemic diseases as they promote angiogenesis both in vitro and in vivo experiments. Application of exosomes for therapeutic angiogenesis opened new opportunities in the regenerative medicine, however, some limitations regarding exosomes isolation and application remain concerned. In addition, most of the experiments were conducted in preclinical and therefore translation of these results from bench to bed requires more effort in this field. Exosomes from stem cells are a promising tool for the treatment of ischemic diseases. In addition, translation of pre-clinic results into clinic needs further studies in this field.
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Affiliation(s)
- Majid Babaei
- Social Determinants of Health Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Jafar Rezaie
- Solid Tumor Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, P.O. Box: 1138, 57147, Urmia, Iran.
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49
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Song H, Zhao J, Cheng J, Feng Z, Wang J, Momtazi-Borojeni AA, Liang Y. Extracellular Vesicles in chondrogenesis and Cartilage regeneration. J Cell Mol Med 2021; 25:4883-4892. [PMID: 33942981 PMCID: PMC8178250 DOI: 10.1111/jcmm.16290] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 12/16/2020] [Accepted: 01/06/2021] [Indexed: 12/18/2022] Open
Abstract
Extracellular vesicles (EVs), mainly exosomes and microvesicles, are bilayer lipids containing biologically active information, including nucleic acids and proteins. They are involved in cell communication and signalling, mediating many biological functions including cell growth, migration and proliferation. Recently, EVs have received great attention in the field of tissue engineering and regenerative medicine. Many in vivo and in vitro studies have attempted to evaluate the chondrogenesis potential of these microstructures and their roles in cartilage regeneration. EVs derived from mesenchymal stem cells (MSCs) or chondrocytes have been found to induce chondrocyte proliferation and chondrogenic differentiation of stem cells in vitro. Preclinical studies have shown that exosomes derived from MSCs have promising results in cartilage repair and in cell‐free therapy of osteoarthritis. This review will focus on the in vitro and in vivo chondrogenesis and cartilage regeneration of EVs as well as their potential in the treatment of osteoarthritis.
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Affiliation(s)
- Hong Song
- Department of Orthopedics, Guizhou Province Orthopedics Hospital, Guiyang, Guizhou, China
| | - Jiasong Zhao
- Department of International Ward, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jun Cheng
- Department of Spine Surgery, Chongqing Three Gorges Central Hospital, Chongqing, China
| | - Zhijie Feng
- Department of Geriatric Orthopaedics, Tangshan City Second Hospital, Hebei Province, Tangshan, China
| | - Jianhua Wang
- Department Bone Microsurgery, Sanya people's Hospital, Sanya, China
| | - Amir Abbas Momtazi-Borojeni
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yimin Liang
- Department of Orthopedics, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, China
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50
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Xia Y, Hu G, Chen Y, Yuan J, Zhang J, Wang S, Li Q, Wang Y, Deng Z. Embryonic Stem Cell Derived Small Extracellular Vesicles Modulate Regulatory T Cells to Protect against Ischemic Stroke. ACS NANO 2021; 15:7370-7385. [PMID: 33733738 DOI: 10.1021/acsnano.1c00672] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Stem cell derived small extracellular vesicles (sEVs) have been proved to promote neurological recovery after stroke. Recent studies demonstrate a phenomenal tissue repair ability in embryonic stem cell derived sEVs (ESC-sEVs). However, whether ESC-sEVs could protect against ischemic stroke remains unknown. Immune responses play an essential role in the pathogenesis of ischemic stroke, and modulating post-stroke immune responses ameliorates ischemia-induced brain damage. In this study, we aim to determine the therapeutic function of ESC-sEVs, specifically focusing on their role in immunomodulation after ischemic stroke. ESC-sEVs are intravenously administered after transient middle cerebral artery occlusion. ESC-sEVs significantly decrease leukocyte infiltration, inflammatory cytokine expression, neuronal death, and infarct volume and alleviate long-term neurological deficits and tissue loss after ischemic stroke. Interestingly, ESC-sEVs induce a marked increase in regulatory T cells (Tregs) after stroke. Further, ESC-sEV-afforded immunomodulatory function and neuroprotection against stroke are dependent on Tregs, as the depletion of Tregs almost completely abrogates the protective effects. Mechanistically, proteomic analysis reveals the enrichment of TGF-β, Smad2, and Smad4 proteins in ESC-sEVs, which could be delivered to activate the TGF-β/Smad pathway in CD4+ T cells and therefore induce Treg expansion. ESC-sEVs modulate neuroinflammation and protect against ischemic stroke through the expansion of Tregs, a process that is partially dependent on the activation of the TGF-β/Smad signaling pathway by the transfer of TGF-β, Smad2, and Smad4. The results suggest ESC-sEVs might be a candidate for immune modulation.
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Affiliation(s)
- Yuguo Xia
- Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Guowen Hu
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Yu Chen
- Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Ji Yuan
- Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Juntao Zhang
- Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Sifan Wang
- Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Qing Li
- Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Yang Wang
- Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Zhifeng Deng
- Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
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