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Fatima A, Attem J, Esam S, Vemuganti GK. Extracellular Vesicles of Tears and Ocular Surface: An Enigma. Curr Eye Res 2025:1-15. [PMID: 40390228 DOI: 10.1080/02713683.2025.2503214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 04/26/2025] [Accepted: 04/29/2025] [Indexed: 05/21/2025]
Abstract
PURPOSE A stable ocular surface is crucial for maintaining ocular health by protecting against various infections. This is achieved by coordinated function of ocular structures (cornea, limbus, conjunctiva), innervation, and the tear film which forms a protective barrier over the ocular surface ensuring proper hydration, lubrication, and overall ocular comfort. This complex three-layered tear film secreted by different sources ensures its stability by adhesion to the corneal epithelium. Ocular surface fluid kinetics and tear secretion involve complex processes influenced by neural regulation, environmental factors, and molecular composition. Recent advances in cell biology and secretome has unravelled the mysteries of cellular cargo of almost every cell and system i.e. the extracellular vesicles (EVs) which facilitate intercellular communication. EVs are of different sizes, amongst which small EVs (sEVs) potentially are more informative than other EVs. METHODS An extensive review of literature on sEVs in tears and ocular surface was conducted. RESULTS Emerging literature on sEVs derived from ocular surface structures such as cornea and limbal stem cells contribute to corneal wound healing, regeneration and reduced fibrosis by the activation of specific proteins. A recent study documents that homeostasis between cornea and conjunctiva is maintained by the expression of specific genes triggering trans differentiation in diseased conditions. There is also mounting evidence on role of tear-derived sEVs in normal and diseased states. The approach in which tear layers secreted from three different sources form into a single tri-layered stable biofilm covering the entire ocular surface remains elusive. Hence not surprisingly, the tear sEVs therefore have been referred to as one entity and not attributed to any of the 3 different sources that they originate from. CONCLUSION This review attempts to present the recent concepts of sEVs, ocular surface, tears and highlight the gaps in our understanding of tear-derived exosomes and its potential role in homeostasis and disease conditions.
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Affiliation(s)
- Asra Fatima
- School of Medical Science, University of Hyderabad, Hyderabad, India
| | - Jyothi Attem
- School of Medical Science, University of Hyderabad, Hyderabad, India
| | - Sandhya Esam
- School of Medical Science, University of Hyderabad, Hyderabad, India
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Song S, Cheng Y, Li W, Yu H, Li Z, Li J, Li M, Huang Q, Liu Y, Ling S. Irradiated umbilical cord mesenchymal stem cell-coated high oxygen-permeable hydrogel lenses inhibit corneal inflammation and neovascularization after corneal alkali burns. Sci Rep 2025; 15:10401. [PMID: 40140459 PMCID: PMC11947097 DOI: 10.1038/s41598-025-95007-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Accepted: 03/18/2025] [Indexed: 03/28/2025] Open
Abstract
Corneal alkali burns can cause persistent inflammation and corneal neovascularization. In this study, we divided corneal alkali burned rabbits into the untreated group, the blank lens group, the radiation-treated umbilical cord mesenchymal stem cells (UCMSC) lens group, and the UCMSC I.V. group, and then measured corneal inflammation, neovascularization and corneal injury repair via slit lamp microscopy, captured anterior segment optical coherence tomography (AS-OCT), and performed hematoxylin-eosin staining. Compared with those in the other experimental groups, radiation-treated UCMSC lenses significantly decreased inflammatory index (IF) scores, areas of corneal blood vessels and corneal epithelial injury. The expression of interleukin (IL)-17 in corneas treated with radiation-treated UCMSC lenses was lower than that in corneas treated with blank lenses, and radiation-treated UCMSC lenses exhibited greater expression of IL-4 and signal transducer and activator of transcription 1 (STAT1), while the expression of cluster of differentiation-3G (CD3G), a linker for the activation of T cells (LAT), IL-6, IL-1B, CC chemokine receptor 6 (CCR6) and IL-23 exhibited the opposite effects (all P < 0.05). Our findings demonstrated that irradiated UCMSC-coated high oxygen-permeable hydrogel lenses on the ocular surface inhibited corneal angiogenesis and inflammation after corneal alkaline burns. The downregulation of Th17 cell differentiation might be responsible for these effects.
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Affiliation(s)
- Siqi Song
- Department of Ophthalmology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Yaqi Cheng
- Department of Ophthalmology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Weihua Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-sen University, Guangzhou, 510060, China
| | - Huan Yu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-sen University, Guangzhou, 510060, China
| | - Zhiquan Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-sen University, Guangzhou, 510060, China
| | - Jianbing Li
- Department of Ophthalmology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Meng Li
- Department of Ophthalmology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Qunai Huang
- Department of Ophthalmology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Yingjie Liu
- Department of Ophthalmology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Shiqi Ling
- Department of Ophthalmology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, P.R. China.
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Liu S, Wang T, Liu Y, Li Y, Ma J, Hu Q, Wang H, Zhang X. Human placental mesenchymal stem cells ameliorates premature ovarian insufficiency via modulating gut microbiota and suppressing the inflammation in rats. PLoS One 2025; 20:e0313763. [PMID: 40043087 PMCID: PMC11882084 DOI: 10.1371/journal.pone.0313763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 10/31/2024] [Indexed: 05/13/2025] Open
Abstract
The core objective of this study was to explore the effects and potential mechanism of human placental mesenchymal stem cells (PMSCs) in improving early-onset ovarian dysfunction (POI). Mesenchymal stem cells with multidirectional differentiation ability were isolated from human placenta tissue and a culture system of human PMSCs was constructed for this study. Subsequently, we successfully constructed POI rat models using cisplatin induction. We randomly divided these models into four groups: CON group (blank control), MOD group (POI model), MED group (hormone therapy), and PMSC group (PMSCs therapy). Then, we compared the differences in estrus cycle, ovarian index, ovarian weight, and ovarian histopathological features, as well as hormones and inflammatory factors in rats of diverse groups. The content of lipopolysaccharide (LPS) in plasma was determined by limulus reagent kit. 16S rDNA sequencing was used to evaluate the changes in gut flora composition. Further, we investigated short-chain fatty acids (SCFAs) in the metabolites of rat gut microbiota by gas chromatography-mass spectrometry (GC-MS). As a result, we successfully established an efficient cell culture system of human placental mesenchymal stem cells (PMSCs) in vitro. Then, we evaluated the effects of PMSC intervention on POI rats: Compared to the untreated MOD group, the estrous cycle of rats in the PMSC group gradually became regular, the ovarian weight and ovarian index were significantly increased, and the ovarian tissue structure was improved by showing an increase in the number of follicles and a decrease in the number of atretic follicles. Moreover, PMSC intervention significantly affected plasma sex hormones by a major impact on follicle stimulating hormone (FSH) and Estradiol (E2). In terms of inflammatory factors, PMSC intervention decreased the levels of proinflammatory cytokines including interleukin (IL)-1β, IL-33, IL-6, and tumor necrosis factor (TNF)-α in plasma and ovarian tissue of POI rats. Meanwhile, the expression of anti-inflammatory cytokine IL-10 was increased. In addition, we found that there was ectopic lipopolysaccharide (LPS) in the blood of POI rats, which could be significantly reduced by PMSC intervention. Intestinal microbiota sequencing and analysis showed that after PMSC intervention, the phyla abundances of Firmicutes, Bacteroides, and Proteobacteria showed remarkable differences between the MOD and PMSC groups (P < 0.05). Further genus analysis showed that PMSC treatment had a major influence in gut microbitoa by increasing the abundances of Turicibacter and Desulfovibrio, as well as reducing Alloprevotella, Parabacteroides, Rikenellaceae_RC9_gut_group, and Rikenella. The changes of SCFAs in intestinal microbial metabolites of rats after PMSC intervention were analyzed: caproic acid level was markedly increased, butyric acid showed a decreased trend. Notably, we found a closed and complicated potential correlation among differential microbiota, inflammatory factors and hormones after PMSCs intervention. Collectively, this study have successfully established a suitable cultured PMSCs that can effectively promote the improvement of reproductive function in POI rats and achieve therapeutic effects by regulating the inflammatory response and reshaping the gut intestinal microbiota.
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Affiliation(s)
- Shudan Liu
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia, China
- Ningxia Medical University General Hospital, Yinchuan, Ningxia, China
| | - Ting Wang
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Yuanyuan Liu
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Yiwei Li
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Junbai Ma
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Qikuan Hu
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Hao Wang
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Xiaoxia Zhang
- College of Traditional Chinese Medicine, Ningxia Medical University, Yinchuan, Ningxia, China
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De Miguel MP, Cadenas-Martin M, Stokking M, Martin-Gonzalez AI. Biomedical Application of MSCs in Corneal Regeneration and Repair. Int J Mol Sci 2025; 26:695. [PMID: 39859409 PMCID: PMC11766311 DOI: 10.3390/ijms26020695] [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: 11/29/2024] [Revised: 01/10/2025] [Accepted: 01/11/2025] [Indexed: 01/27/2025] Open
Abstract
The World Health Organization estimates that approximately 285 million people suffer from visual impairments, around 5% of which are caused by corneal pathologies. Currently, the most common clinical treatment consists of a corneal transplant (keratoplasty) from a human donor. However, worldwide demand for donor corneas amply exceeds the available supply. Lamellar keratoplasty (transplantation replacement of only one of the three layers of the cornea) is partially solving the problem of cornea undersupply. Obviously, cell therapy applied to every one of these layers will expand current therapeutic options, reducing the cost of ophthalmological interventions and increasing the effectiveness of surgery. Mesenchymal stem cells (MSCs) are adult stem cells with the capacity for self-renewal and differentiation into different cell lineages. They can be obtained from many human tissues, such as bone marrow, umbilical cord, adipose tissue, dental pulp, skin, and cornea. Their ease of collection and advantages over embryonic stem cells or induced pluripotent stem cells make them a very practical source for experimental and potential clinical applications. In this review, we focus on recent advances using MSCs from different sources to replace the damaged cells of the three corneal layers, at both the preclinical and clinical levels for specific corneal diseases.
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Affiliation(s)
- Maria P. De Miguel
- Cell Engineering Laboratory, La Paz University Hospital Health Research Institute, IdiPAZ, 28046 Madrid, Spain; (M.C.-M.); (M.S.); (A.I.M.-G.)
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Xia R, Li M, Huang B. A new strategy for drug delivery systems in oral diseases using stem cell-derived extracellular vesicles: review and new perspectives. Postgrad Med J 2024:qgae187. [PMID: 39722492 DOI: 10.1093/postmj/qgae187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 10/29/2024] [Accepted: 12/04/2024] [Indexed: 12/28/2024]
Abstract
Extracellular vesicles (EVs) are membrane vesicles derived from cells and serve as an endogenous mechanism for intercellular communication. Since the discovery of their capacity to effectively transfer biological information, their potential as drug delivery vehicles has garnered significant scientific interest. Particularly, EVs derived from mesenchymal cells (MSC-EVs) have emerged as a highly promising method for drug delivery. They can transport bioactive molecules, such as nucleic acids, lipids, and proteins, and possess the ability to modulate immune responses, transmit information, and target specific cells. EVs offer several advantages over conventional drug delivery systems, including their capacity to traverse natural barriers, inherent cell targeting capabilities, and stability in circulation. Compared to their parent cells, EVs exhibit low immunogenicity, ease of storage and transport, and a reduced risk of tumorigenesis. The diagnosis and treatment of oral diseases often involve invasive measures, and MSC-EVs have demonstrated initial efficacy in oral disease treatment. This review explores the application of MSC-EVs in maxillofacial tissue regeneration, periodontitis, temporomandibular joint osteoarthritis, Sjögren's Syndrome, oral cancer, and other oral diseases. Additionally, it outlines potential future directions for the development of MSC-EVs. This review aims to provide a comprehensive understanding of MSC-EVs in oral disease treatment and to stimulate interest in their applications for targeted drug delivery.
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Affiliation(s)
- Ruyang Xia
- State Key Laboratory of Oral Diseases and National Center of Stomatology and General Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Maojiao Li
- State Key Laboratory of Oral Diseases and National Center of Stomatology and General Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Bo Huang
- State Key Laboratory of Oral Diseases and National Center of Stomatology and General Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
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Hassanpour Khodaei S, Sabetkam S, Kalarestaghi H, Dizaji Asl K, Mazloumi Z, Bahramloo M, Norouzi N, Naderali E, Rafat A. Mesenchymal stem cells and mesenchymal stem cell-derived exosomes: attractive therapeutic approaches for female reproductive dysfunction. Mol Biol Rep 2024; 52:10. [PMID: 39576370 DOI: 10.1007/s11033-024-10106-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Accepted: 11/11/2024] [Indexed: 11/24/2024]
Abstract
Infertility is a reproductive health problem in the male or female reproductive system. Traditional assisted reproductive technology (ART) has been unable to solve various cases of infertility for years. Clinical researchers have sought to treat infertility using new methods that are more effective and noninvasive than the old methods. Recently, Mesenchymal stem cells (MSCs) and MSCs-derived Exosomes (MSC-Exos) via paracrine activity play an important role in treating various causes of infertility and improving pregnancy outcomes. In this review, we focus on the roles of MSCs and MSC-Exos cell therapy in female infertility in the different types of female reproductive disorders.
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Affiliation(s)
- Sepideh Hassanpour Khodaei
- Department of Dentistry, Eastern Mediterranean University (EMU) Famagusta, North Cyprus Mersin 10, Famagusta, Turkey
| | - Shahnaz Sabetkam
- Department of Anatomy, Faculty of Medicine, University of Kyrenia, Kyrenia, Northern Cyprus
| | - Hossein Kalarestaghi
- Research Laboratory for Embryology and Stem Cell, Department of Anatomical Sciences, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Khadijeh Dizaji Asl
- Department of Histopathology and Anatomy, Faculty of Medical Sciences, Tabriz Medical Sciences, Islamic Azad University, Tabriz, Iran
| | - Zeinab Mazloumi
- Department of Medical Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammadmahdi Bahramloo
- Department of Medical Sciences, Student Research Committee, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Nahid Norouzi
- Nursing Trauma Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Elahe Naderali
- Department of Anatomical Sciences, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Ali Rafat
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Al Monla R, Daien V, Michon F. Advanced bioengineering strategies broaden the therapeutic landscape for corneal failure. Front Bioeng Biotechnol 2024; 12:1480772. [PMID: 39605752 PMCID: PMC11598527 DOI: 10.3389/fbioe.2024.1480772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 10/30/2024] [Indexed: 11/29/2024] Open
Abstract
The cornea acts as the eye foremost protective layer and is essential for its focusing power. Corneal blindness may arise from physical trauma or conditions like dystrophies, keratitis, keratoconus, or ulceration. While conventional treatments involve medical therapies and donor allografts-sometimes supplemented with keratoprostheses-these options are not suitable for all corneal defects. Consequently, the development of bioartificial corneal tissue has emerged as a critical research area, aiming to address the global shortage of human cornea donors. Bioengineered corneas hold considerable promise as substitutes, with the potential to replace either specific layers or the entire thickness of damaged corneas. This review first delves into the structural anatomy of the human cornea, identifying key attributes necessary for successful corneal tissue bioengineering. It then examines various corneal pathologies, current treatments, and their limitations. Finally, the review outlines the primary approaches in corneal tissue engineering, exploring cell-free, cell-based, and scaffold-based options as three emerging strategies to address corneal failure.
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Affiliation(s)
- Reem Al Monla
- Institute for Neurosciences of Montpellier, INSERM, University of Montpellier, Montpellier, France
| | - Vincent Daien
- Department of Ophthalmology, Gui de Chauliac Hospital, Montpellier, France
- Sydney Medical School, The Save Sight Institute, The University of Sydney, Sydney, NSW, Australia
| | - Frederic Michon
- Institute for Neurosciences of Montpellier, INSERM, University of Montpellier, Montpellier, France
- Department of Ophthalmology, Gui de Chauliac Hospital, Montpellier, France
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Saraf N, Ramachandran RA, Cao M, Lemoff A, Baniasadi H, Robertson DM. Serum-derived extracellular vesicles for the treatment of severe ocular surface disease. Ocul Surf 2024; 34:317-325. [PMID: 39159888 DOI: 10.1016/j.jtos.2024.08.009] [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: 01/20/2024] [Revised: 06/12/2024] [Accepted: 08/09/2024] [Indexed: 08/21/2024]
Abstract
PURPOSE Autologous serum is widely used for the treatment of severe ocular surface disease with mixed efficacy. Extracellular vesicles (EVs) are small membrane bound structures present in all body fluids, including serum. This study compared the proteomic, metabolomic, and inflammatory cytokine composition of serum-derived EVs (SDEVs) to that of the soluble free protein fraction and the subsequent capacity of SDEVs to induce corneal epithelial cell migration and inflammation. METHODS SDEVs were isolated from human serum using size exclusion chromatography. SDEVs were analyzed using nanoparticle tracking analysis, transmission electron microscopy, and western blotting. The effects of SDEVs on corneal epithelial cell migration were tested using a standard scratch assay. Inflammatory cytokines in SDEVs and the free protein fraction were quantified using a microarray. A mutli-omics approach was further used to define SDEV cargo. The ability of SDEVs to modulate inflammation in corneal epithelial cells was quantified using ELISAs. RESULTS Western blot and TEM confirmed the presence of SDEVs. Proinflammatory cytokines, along with complement proteins and TGF-β, were decreased in SDEVs compared to serum. Metabolites present in SDEVs were mostly involved in amino acid biosynthesis, the TCA cycle and oxidative phosphorylation. SDEVs exhibited pro-migratory effects similar to serum however, SDEVs did not induce secretion of IL-6 or IL-8. CONCLUSIONS SDEVs exhibit reduced levels of pro-inflammatory cytokines while retaining the beneficial wound healing properties of serum. Unlike serum, SDEVs do not induce inflammation. SDEVs may represent an alternative option for patients with severe ocular surface disease where traditional autologous serum has failed.
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Affiliation(s)
- Namita Saraf
- Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA
| | | | - Mou Cao
- UT Southwestern Medical Center, Dallas, TX, USA
| | - Andrew Lemoff
- Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX, USA
| | - Hamid Baniasadi
- Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX, USA
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Yi S, Kim J, Kim MJ, Yae CG, Kim KH, Kim HK. Development of human amniotic epithelial cell-derived extracellular vesicles as cell-free therapy for dry eye disease. Ocul Surf 2024; 34:370-380. [PMID: 39332677 DOI: 10.1016/j.jtos.2024.09.006] [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: 01/30/2024] [Revised: 08/16/2024] [Accepted: 09/24/2024] [Indexed: 09/29/2024]
Abstract
PURPOSE This study aimed to investigate the therapeutic potential of extracellular vesicles (EVs) derived from human amniotic epithelial cells (hAEC-EVs) for Dry Eye Disease (DED) treatment. METHODS Highly purified EVs were isolated from the culture supernatants of hAECs, which obtained from term placenta and characterized. Proteomic contents were analyzed for assessing its biological function related to the therapeutic potentials for DED. Subsequently, we examined the therapeutic efficacy of hAEC-EVs on human corneal epithelial cells exposed to hyperosmotic stress and in an experimental DED mouse model induced by desiccation stress. RESULTS Proteomic analysis of hAEC-EVs revealed proteins linked to cell proliferation and anti-inflammatory responses. We demonstrated efficient uptake of hAEC-EVs by ocular surface cells. Under DED conditions, EV treatment increased corneal epithelial cell proliferation and migration, and concurrently reducing inflammatory cytokines. In the DED mouse model, hAEC-EVs showed significant improvements in corneal staining score, tear secretion, corneal irregularity, and conjunctival goblet cell density. Additionally, hAEC-EVs exhibited a mitigating effect on ocular surface inflammation induced by desiccation. CONCLUSIONS These findings suggest that hAEC-EVs hold potential as a cell-free therapy for corneal epithelial defects and ocular surface diseases, presenting a promising treatment option for DED.
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Affiliation(s)
- Soojin Yi
- Department of Ophthalmology, School of Medicine, Kyungpook National University, Jung-gu, Daegu, Republic of Korea; Bio-Medical Institute, Kyungpook National University Hospital, Jung-gu, Daegu, Republic of Korea; Department of Biomedical Science, The Graduate School, Kyungpook National University, Jung-gu, Daegu, Republic of Korea
| | - Jeongho Kim
- Department of Ophthalmology, School of Medicine, Kyungpook National University, Jung-gu, Daegu, Republic of Korea; Bio-Medical Institute, Kyungpook National University Hospital, Jung-gu, Daegu, Republic of Korea
| | - Mi Ju Kim
- Department of Obstetrics and Gynecology, School of Medicine, Kyungpook National University, Jung-gu, Daegu, Republic of Korea
| | - Che Gyem Yae
- Department of Ophthalmology, School of Medicine, Kyungpook National University, Jung-gu, Daegu, Republic of Korea
| | - Ki Hean Kim
- Department of Mechanical Engineering, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea.
| | - Hong Kyun Kim
- Department of Ophthalmology, School of Medicine, Kyungpook National University, Jung-gu, Daegu, Republic of Korea; Bio-Medical Institute, Kyungpook National University Hospital, Jung-gu, Daegu, Republic of Korea.
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Wu S, Zhou Z, Li Y, Jiang J. Advancements in diabetic foot ulcer research: Focus on mesenchymal stem cells and their exosomes. Heliyon 2024; 10:e37031. [PMID: 39286219 PMCID: PMC11403009 DOI: 10.1016/j.heliyon.2024.e37031] [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: 06/18/2024] [Revised: 08/11/2024] [Accepted: 08/26/2024] [Indexed: 09/19/2024] Open
Abstract
Diabetes represents a widely acknowledged global public health concern. Diabetic foot ulcer (DFU) stands as one of the most severe complications of diabetes, its occurrence imposing a substantial economic burden on patients, profoundly impacting their quality of life. Despite the deepening comprehension regarding the pathophysiology and cellular as well as molecular responses of DFU, the current therapeutic arsenal falls short of efficacy, failing to offer a comprehensive remedy for deep-seated chronic wounds and microvascular occlusions. Conventional treatments merely afford symptomatic alleviation or retard the disease's advancement, devoid of the capacity to effectuate further restitution of compromised vasculature and nerves. An escalating body of research underscores the prominence of mesenchymal stem cells (MSCs) owing to their paracrine attributes and anti-inflammatory prowess, rendering them a focal point in the realm of chronic wound healing. Presently, MSCs have been validated as a highly promising cellular therapeutic approach for DFU, capable of effectuating cellular repair, epithelialization, granulation tissue formation, and neovascularization by means of targeted differentiation, angiogenesis promotion, immunomodulation, and paracrine activities, thereby fostering wound healing. The secretome of MSCs comprises cytokines, growth factors, chemokines, alongside exosomes harboring mRNA, proteins, and microRNAs, possessing immunomodulatory and regenerative properties. The present study provides a systematic exposition on the etiology of DFU and elucidates the intricate molecular mechanisms and diverse functionalities of MSCs in the context of DFU treatment, thereby furnishing pioneering perspectives aimed at harnessing the therapeutic potential of MSCs for DFU management and advancing wound healing processes.
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Affiliation(s)
- ShuHui Wu
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - ZhongSheng Zhou
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yang Li
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jinlan Jiang
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
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11
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Su Y, Chen M, Xu W, Gu P, Fan X. Advances in Extracellular-Vesicles-Based Diagnostic and Therapeutic Approaches for Ocular Diseases. ACS NANO 2024; 18:22793-22828. [PMID: 39141830 PMCID: PMC11363148 DOI: 10.1021/acsnano.4c08486] [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: 06/25/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/16/2024]
Abstract
Extracellular vesicles (EVs) are nanoscale membrane vesicles of various sizes that can be secreted by most cells. EVs contain a diverse array of cargo, including RNAs, lipids, proteins, and other molecules with functions of intercellular communication, immune modulation, and regulation of physiological and pathological processes. The biofluids in the eye, including tears, aqueous humor, and vitreous humor, are important sources for EV-based diagnosis of ocular disease. Because the molecular cargos may reflect the biology of their parental cells, EVs in these biofluids, as well as in the blood, have been recognized as promising candidates as biomarkers for early diagnosis of ocular disease. Moreover, EVs have also been used as therapeutics and targeted drug delivery nanocarriers in many ocular disorders because of their low immunogenicity and superior biocompatibility in nature. In this review, we provide an overview of the recent advances in the field of EV-based studies on the diagnosis and therapeutics of ocular disease. We summarized the origins of EVs applied in ocular disease, assessed different methods for EV isolation from ocular biofluid samples, highlighted bioengineering strategies of EVs as drug delivery systems, introduced the latest applications in the diagnosis and treatment of ocular disease, and presented their potential in the current clinical trials. Finally, we briefly discussed the challenges of EV-based studies in ocular disease and some issues of concern for better focusing on clinical translational studies of EVs in the future.
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Affiliation(s)
- Yun Su
- Department
of Ophthalmology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- Shanghai
Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| | - Moxin Chen
- Department
of Ophthalmology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- Shanghai
Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| | - Wei Xu
- Department
of Ophthalmology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- Shanghai
Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| | - Ping Gu
- Department
of Ophthalmology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- Shanghai
Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| | - Xianqun Fan
- Department
of Ophthalmology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- Shanghai
Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
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12
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Erkoc-Biradli FZ, Erenay B, Ozgun A, Öztatlı H, Işık F, Ateş U, Rasier R, Garipcan B. Mesenchymal stem cells derived-exosomes enhanced amniotic membrane extract promotes corneal keratocyte proliferation. Biotechnol Prog 2024; 40:e3465. [PMID: 38602120 DOI: 10.1002/btpr.3465] [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: 08/23/2023] [Revised: 03/20/2024] [Accepted: 03/26/2024] [Indexed: 04/12/2024]
Abstract
Amniotic membrane extract (AME) and Wharton's jelly mesenchymal stem cells derived-exosomes (WJ-MSC-Exos) are promising therapeutic solutions explored for their potential in tissue engineering and regenerative medicine, particularly in skin and corneal wound healing applications. AME is an extract form of human amniotic membrane and known to contain a plethora of cytokines and growth factors, making it a highly attractive option for topical applications. Similarly, WJ-MSC-Exos have garnered significant interest for their wound healing properties. Although WJ-MSC-Exos and AME have been used separately for wound healing research, their combined synergistic effects have not been studied extensively. In this study, we evaluated the effects of both AME and WJ-MSC-Exos, individually and together, on the proliferation of corneal keratocytes as well as their ability to promote in vitro cell migration, wound healing, and their impact on cellular morphology. Our findings indicated that the presence of both exosomes (3 × 105 Exo/mL) and AME (50 μg/mL) synergistically enhance the proliferation of corneal keratocytes. Combined use of these solutions (3 × 105 Exo/mL + 50 μg/mL) increased cell proliferation compared to only 50 μg/mL AME treatment on day 3 (**** p < 0.0001). This mixture treatment (3 × 105 Exo/mL + 50 μg/mL) increased wound closure rate compared to isolated WJ-MSC-Exo treatment (3 × 105 Exo/mL) (*p < 0.05). Overall, corneal keratocytes treated with AME and WJ-MSC-Exo (3 × 105 Exo/mL + 50 μg/mL) mixture resulted in enhanced proliferation and wound healing tendency. Utilization of combined use of AME and WJ-MSC-Exo can pave the way for a promising foundation for corneal repair research.
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Affiliation(s)
- Fatma Zehra Erkoc-Biradli
- Biomimetics and Bioinspired Biomaterials Research Laboratory, Institute of Biomedical Engineering, Bogaziçi University, Istanbul, Turkey
| | - Berkay Erenay
- Biomimetics and Bioinspired Biomaterials Research Laboratory, Institute of Biomedical Engineering, Bogaziçi University, Istanbul, Turkey
| | - Alp Ozgun
- Ottawa Hospital Research Institute, Ottawa, Canada
| | - Hayriye Öztatlı
- Biomimetics and Bioinspired Biomaterials Research Laboratory, Institute of Biomedical Engineering, Bogaziçi University, Istanbul, Turkey
| | - Ferda Işık
- Stembio Cord Blood Cell & Tissue Center, Kocaeli, Turkey
| | - Utku Ateş
- Stembio Cord Blood Cell & Tissue Center, Kocaeli, Turkey
| | - Rıfat Rasier
- Department of Ophthalmology, İstinye University, Istanbul, Turkey
| | - Bora Garipcan
- Biomimetics and Bioinspired Biomaterials Research Laboratory, Institute of Biomedical Engineering, Bogaziçi University, Istanbul, Turkey
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13
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Tati V, Mitra S, Basu S, Shukla S. Bone marrow mesenchymal stem cell-derived extracellular vesicles promote corneal epithelial repair and suppress apoptosis via modulation of Caspase-3 in vitro. FEBS Open Bio 2024; 14:968-982. [PMID: 38684330 PMCID: PMC11494918 DOI: 10.1002/2211-5463.13804] [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: 11/03/2023] [Revised: 02/21/2024] [Accepted: 04/10/2024] [Indexed: 05/02/2024] Open
Abstract
Corneal injuries are the major cause of blindness and visual impairment. Available treatments are limited by their efficacy and side effects. Mesenchymal stem cell-derived extracellular vesicles are presumed as functional equivalents and potential candidates for cell-free therapy. This study reports isolation and characterization of extracellular vesicles from human bone marrow mesenchymal stem cells and evaluates their role in mediating epithelial repair and apoptosis in cultured corneal epithelial cells through scratch assay, PCR, immunofluorescence, and flow cytometry in vitro. The isolated extracellular vesicles were spherical, < 150 nm in diameter, and characterized as CD9+, CD63+, CD81+, TSG101+, and Calnexin-. Further, these vesicles promoted corneal epithelial repair by enhancing proliferation and suppressed apoptosis by regulating the expression of BAD, P53, BCL-2, and cleaved CASPASE-3. Thus, our results suggest that BM-MSC-EVs might have the potential to be used for the treatment of injury-induced corneal epithelial defects. Clinical translation of this work would require further investigations.
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Affiliation(s)
- Vasudeva Tati
- Prof. Brien Holden Eye Research Centre, Hyderabad Eye Research FoundationL V Prasad Eye InstituteHyderabadIndia
- Sudhakar and Sreekanth Ravi Stem Cell Biology Laboratory, Centre for Ocular RegenerationL V Prasad Eye InstituteHyderabadIndia
| | - Sreya Mitra
- Prof. Brien Holden Eye Research Centre, Hyderabad Eye Research FoundationL V Prasad Eye InstituteHyderabadIndia
- Sudhakar and Sreekanth Ravi Stem Cell Biology Laboratory, Centre for Ocular RegenerationL V Prasad Eye InstituteHyderabadIndia
| | - Sayan Basu
- Prof. Brien Holden Eye Research Centre, Hyderabad Eye Research FoundationL V Prasad Eye InstituteHyderabadIndia
- Sudhakar and Sreekanth Ravi Stem Cell Biology Laboratory, Centre for Ocular RegenerationL V Prasad Eye InstituteHyderabadIndia
- Shantilal Shanghvi Cornea Institute, L V Prasad Eye InstituteHyderabadIndia
| | - Sachin Shukla
- Prof. Brien Holden Eye Research Centre, Hyderabad Eye Research FoundationL V Prasad Eye InstituteHyderabadIndia
- Sudhakar and Sreekanth Ravi Stem Cell Biology Laboratory, Centre for Ocular RegenerationL V Prasad Eye InstituteHyderabadIndia
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14
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Kistenmacher S, Schwämmle M, Martin G, Ulrich E, Tholen S, Schilling O, Gießl A, Schlötzer-Schrehardt U, Bucher F, Schlunck G, Nazarenko I, Reinhard T, Polisetti N. Enrichment, Characterization, and Proteomic Profiling of Small Extracellular Vesicles Derived from Human Limbal Mesenchymal Stromal Cells and Melanocytes. Cells 2024; 13:623. [PMID: 38607062 PMCID: PMC11011788 DOI: 10.3390/cells13070623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 03/27/2024] [Accepted: 03/28/2024] [Indexed: 04/13/2024] Open
Abstract
Limbal epithelial progenitor cells (LEPC) rely on their niche environment for proper functionality and self-renewal. While extracellular vesicles (EV), specifically small EVs (sEV), have been proposed to support LEPC homeostasis, data on sEV derived from limbal niche cells like limbal mesenchymal stromal cells (LMSC) remain limited, and there are no studies on sEVs from limbal melanocytes (LM). In this study, we isolated sEV from conditioned media of LMSC and LM using a combination of tangential flow filtration and size exclusion chromatography and characterized them by nanoparticle tracking analysis, transmission electron microscopy, Western blot, multiplex bead arrays, and quantitative mass spectrometry. The internalization of sEV by LEPC was studied using flow cytometry and confocal microscopy. The isolated sEVs exhibited typical EV characteristics, including cell-specific markers such as CD90 for LMSC-sEV and Melan-A for LM-sEV. Bioinformatics analysis of the proteomic data suggested a significant role of sEVs in extracellular matrix deposition, with LMSC-derived sEV containing proteins involved in collagen remodeling and cell matrix adhesion, whereas LM-sEV proteins were implicated in other cellular bioprocesses such as cellular pigmentation and development. Moreover, fluorescently labeled LMSC-sEV and LM-sEV were taken up by LEPC and localized to their perinuclear compartment. These findings provide valuable insights into the complex role of sEV from niche cells in regulating the human limbal stem cell niche.
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Affiliation(s)
- Sebastian Kistenmacher
- Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Killianstrasse 5, 79106 Freiburg, Germany
| | - Melanie Schwämmle
- Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Killianstrasse 5, 79106 Freiburg, Germany
- Faculty of Biology, University of Freiburg, Schaenzlestrasse 1, D–79104 Freiburg, Germany
| | - Gottfried Martin
- Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Killianstrasse 5, 79106 Freiburg, Germany
| | - Eva Ulrich
- Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Killianstrasse 5, 79106 Freiburg, Germany
| | - Stefan Tholen
- Institute of Surgical Pathology, Faculty of Medicine, Freiburg, Medical Center, University of Freiburg, 79085 Freiburg im Breisgau, Germany
| | - Oliver Schilling
- Institute of Surgical Pathology, Faculty of Medicine, Freiburg, Medical Center, University of Freiburg, 79085 Freiburg im Breisgau, Germany
| | - Andreas Gießl
- Department of Ophthalmology, University Hospital Erlangen, Friedrich-Alexander-University of Erlan-gen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany
| | - Ursula Schlötzer-Schrehardt
- Department of Ophthalmology, University Hospital Erlangen, Friedrich-Alexander-University of Erlan-gen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany
| | - Felicitas Bucher
- Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Killianstrasse 5, 79106 Freiburg, Germany
| | - Günther Schlunck
- Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Killianstrasse 5, 79106 Freiburg, Germany
| | - Irina Nazarenko
- Institute for Infection Prevention and Hospital Epidemiology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Thomas Reinhard
- Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Killianstrasse 5, 79106 Freiburg, Germany
| | - Naresh Polisetti
- Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Killianstrasse 5, 79106 Freiburg, Germany
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15
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Xiao Y, Wu M, Xue C, Wang Y. Recent Advances in the Development of Membrane-derived Vesicles for Cancer Immunotherapy. Curr Drug Deliv 2024; 21:403-420. [PMID: 37143265 DOI: 10.2174/1567201820666230504120841] [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: 01/17/2023] [Revised: 03/01/2023] [Accepted: 03/13/2023] [Indexed: 05/06/2023]
Abstract
The surface proteins on cell membranes enable the cells to have different properties, such as high biocompatibility, surface modifiability, and homologous targeting ability. Cell-membrane-derived vesicles have features identical to those of their parental cells, which makes them one of the most promising materials for drug delivery. Recently, as a result of the impressive effects of immunotherapy in cancer treatment, an increasing number of researchers have used cell-membrane-derived vesicles to enhance immune responses. To be more specific, the membrane vesicles derived from immune cells, tumor cells, bacteria, or engineered cells have the antigen presentation capacity and can trigger strong anti-tumor effects of the immune system. In this review, we first indicated a brief description of the vesicles and then introduced the detection technology and drug-loading methods for them. Secondly, we concluded the characteristics and applications of vesicles derived from different sources in cancer immunotherapy.
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Affiliation(s)
- Yuai Xiao
- Department of Plastic Surgery, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Minliang Wu
- Department of Plastic Surgery, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Chunyu Xue
- Department of Plastic Surgery, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Yuchong Wang
- Department of Plastic Surgery, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
- School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
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16
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Loiseau A, Raîche-Marcoux G, Maranda C, Bertrand N, Boisselier E. Animal Models in Eye Research: Focus on Corneal Pathologies. Int J Mol Sci 2023; 24:16661. [PMID: 38068983 PMCID: PMC10706114 DOI: 10.3390/ijms242316661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 09/27/2023] [Accepted: 11/19/2023] [Indexed: 12/18/2023] Open
Abstract
The eye is a complex sensory organ that enables visual perception of the world. The dysfunction of any of these tissues can impair vision. Conduction studies on laboratory animals are essential to ensure the safety of therapeutic products directly applied or injected into the eye to treat ocular diseases before eventually proceeding to clinical trials. Among these tissues, the cornea has unique homeostatic and regenerative mechanisms for maintaining transparency and refraction of external light, which are essential for vision. However, being the outermost tissue of the eye and directly exposed to the external environment, the cornea is particularly susceptible to injury and diseases. This review highlights the evidence for selecting appropriate animals to better understand and treat corneal diseases, which rank as the fifth leading cause of blindness worldwide. The development of reliable and human-relevant animal models is, therefore, a valuable research tool for understanding and translating fundamental mechanistic findings, as well as for assessing therapeutic potential in humans. First, this review emphasizes the unique characteristics of animal models used in ocular research. Subsequently, it discusses current animal models associated with human corneal pathologies, their utility in understanding ocular disease mechanisms, and their role as translational models for patients.
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Affiliation(s)
- Alexis Loiseau
- Faculty of Medicine, Department of Ophthalmology and Otolaryngology—Head and Neck Surgery, CHU de Québec Research Center, Université Laval, Québec, QC G1S 4L8, Canada; (G.R.-M.); (C.M.)
| | - Gabrielle Raîche-Marcoux
- Faculty of Medicine, Department of Ophthalmology and Otolaryngology—Head and Neck Surgery, CHU de Québec Research Center, Université Laval, Québec, QC G1S 4L8, Canada; (G.R.-M.); (C.M.)
| | - Cloé Maranda
- Faculty of Medicine, Department of Ophthalmology and Otolaryngology—Head and Neck Surgery, CHU de Québec Research Center, Université Laval, Québec, QC G1S 4L8, Canada; (G.R.-M.); (C.M.)
| | - Nicolas Bertrand
- Faculty of Pharmacy, CHU de Quebec Research Center, Université Laval, Québec, QC G1V 4G2, Canada;
| | - Elodie Boisselier
- Faculty of Medicine, Department of Ophthalmology and Otolaryngology—Head and Neck Surgery, CHU de Québec Research Center, Université Laval, Québec, QC G1S 4L8, Canada; (G.R.-M.); (C.M.)
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17
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Bhujel B, Oh SH, Kim CM, Yoon YJ, Kim YJ, Chung HS, Ye EA, Lee H, Kim JY. Mesenchymal Stem Cells and Exosomes: A Novel Therapeutic Approach for Corneal Diseases. Int J Mol Sci 2023; 24:10917. [PMID: 37446091 DOI: 10.3390/ijms241310917] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 06/25/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
The cornea, with its delicate structure, is vulnerable to damage from physical, chemical, and genetic factors. Corneal transplantation, including penetrating and lamellar keratoplasties, can restore the functions of the cornea in cases of severe damage. However, the process of corneal transplantation presents considerable obstacles, including a shortage of available donors, the risk of severe graft rejection, and potentially life-threatening complications. Over the past few decades, mesenchymal stem cell (MSC) therapy has become a novel alternative approach to corneal regeneration. Numerous studies have demonstrated the potential of MSCs to differentiate into different corneal cell types, such as keratocytes, epithelial cells, and endothelial cells. MSCs are considered a suitable candidate for corneal regeneration because of their promising therapeutic perspective and beneficial properties. MSCs compromise unique immunomodulation, anti-angiogenesis, and anti-inflammatory properties and secrete various growth factors, thus promoting corneal reconstruction. These effects in corneal engineering are mediated by MSCs differentiating into different lineages and paracrine action via exosomes. Early studies have proven the roles of MSC-derived exosomes in corneal regeneration by reducing inflammation, inhibiting neovascularization, and angiogenesis, and by promoting cell proliferation. This review highlights the contribution of MSCs and MSC-derived exosomes, their current usage status to overcome corneal disease, and their potential to restore different corneal layers as novel therapeutic agents. It also discusses feasible future possibilities, applications, challenges, and opportunities for future research in this field.
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Affiliation(s)
- Basanta Bhujel
- Department of Ophthalmology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-Ro, Songpa-Gu, Seoul 05505, Republic of Korea
| | - Se-Heon Oh
- Department of Ophthalmology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-Ro, Songpa-Gu, Seoul 05505, Republic of Korea
| | - Chang-Min Kim
- Department of Ophthalmology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-Ro, Songpa-Gu, Seoul 05505, Republic of Korea
| | - Ye-Ji Yoon
- Department of Ophthalmology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-Ro, Songpa-Gu, Seoul 05505, Republic of Korea
| | - Young-Jae Kim
- Department of Ophthalmology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-Ro, Songpa-Gu, Seoul 05505, Republic of Korea
| | - Ho-Seok Chung
- Department of Ophthalmology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-Ro, Songpa-Gu, Seoul 05505, Republic of Korea
| | - Eun-Ah Ye
- Department of Ophthalmology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-Ro, Songpa-Gu, Seoul 05505, Republic of Korea
| | - Hun Lee
- Department of Ophthalmology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-Ro, Songpa-Gu, Seoul 05505, Republic of Korea
| | - Jae-Yong Kim
- Department of Ophthalmology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-Ro, Songpa-Gu, Seoul 05505, Republic of Korea
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18
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Massoumi H, Amin S, Soleimani M, Momenaei B, Ashraf MJ, Guaiquil VH, Hematti P, Rosenblatt MI, Djalilian AR, Jalilian E. Extracellular-Vesicle-Based Therapeutics in Neuro-Ophthalmic Disorders. Int J Mol Sci 2023; 24:9006. [PMID: 37240353 PMCID: PMC10219002 DOI: 10.3390/ijms24109006] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/09/2023] [Accepted: 05/17/2023] [Indexed: 05/28/2023] Open
Abstract
Extracellular vesicles (EVs) have been recognized as promising candidates for developing novel therapeutics for a wide range of pathologies, including ocular disorders, due to their ability to deliver a diverse array of bioactive molecules, including proteins, lipids, and nucleic acids, to recipient cells. Recent studies have shown that EVs derived from various cell types, including mesenchymal stromal cells (MSCs), retinal pigment epithelium cells, and endothelial cells, have therapeutic potential in ocular disorders, such as corneal injury and diabetic retinopathy. EVs exert their effects through various mechanisms, including promoting cell survival, reducing inflammation, and inducing tissue regeneration. Furthermore, EVs have shown promise in promoting nerve regeneration in ocular diseases. In particular, EVs derived from MSCs have been demonstrated to promote axonal regeneration and functional recovery in various animal models of optic nerve injury and glaucoma. EVs contain various neurotrophic factors and cytokines that can enhance neuronal survival and regeneration, promote angiogenesis, and modulate inflammation in the retina and optic nerve. Additionally, in experimental models, the application of EVs as a delivery platform for therapeutic molecules has revealed great promise in the treatment of ocular disorders. However, the clinical translation of EV-based therapies faces several challenges, and further preclinical and clinical studies are needed to fully explore the therapeutic potential of EVs in ocular disorders and to address the challenges for their successful clinical translation. In this review, we will provide an overview of different types of EVs and their cargo, as well as the techniques used for their isolation and characterization. We will then review the preclinical and clinical studies that have explored the role of EVs in the treatment of ocular disorders, highlighting their therapeutic potential and the challenges that need to be addressed for their clinical translation. Finally, we will discuss the future directions of EV-based therapeutics in ocular disorders. Overall, this review aims to provide a comprehensive overview of the current state of the art of EV-based therapeutics in ophthalmic disorders, with a focus on their potential for nerve regeneration in ocular diseases.
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Affiliation(s)
- Hamed Massoumi
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; (H.M.)
- The Richard and Loan Hill Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL 60607, USA
| | - Sohil Amin
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; (H.M.)
| | - Mohammad Soleimani
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; (H.M.)
| | - Bita Momenaei
- Wills Eye Hospital, Mid Atlantic Retina, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Mohammad Javad Ashraf
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; (H.M.)
| | - Victor H. Guaiquil
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; (H.M.)
| | - Peiman Hematti
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Mark I. Rosenblatt
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; (H.M.)
| | - Ali R. Djalilian
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; (H.M.)
| | - Elmira Jalilian
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA; (H.M.)
- The Richard and Loan Hill Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL 60607, USA
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19
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Lee JY, Knight RJ, Deng SX. Future regenerative therapies for corneal disease. Curr Opin Ophthalmol 2023; 34:267-272. [PMID: 36602407 DOI: 10.1097/icu.0000000000000938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
PURPOSE OF REVIEW To highlight the progress and future direction of stem-cell based regenerative therapies for the treatment of corneal disease. RECENT FINDINGS Corneal stem cell-based therapies, such as limbal stem cell transplantation, corneal stromal stem cell transplantation, endothelial stem cell transplantation, and stem cell-derived extracellular vesicles have demonstrated promising results in the laboratory. Although most are still in preclinical development or early phase clinical trials, these stem cell-based therapies hold potential to facilitate tissue regeneration, restore native function, and inhibit pathologic disease processes such as fibrosis, inflammation, and neovascularization. SUMMARY Stem cell-based therapy offers a promising therapeutic option that can circumvent several of the challenges and limitations of traditional surgical treatment. This concise review summarizes the progress in stem-cell based therapies for corneal diseases along with their history, underlying mechanisms, limitations, and future areas for development.
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Affiliation(s)
- John Y Lee
- Stein Eye Institute, Department of Ophthalmology, David Geffen School of Medicine
| | - Robert J Knight
- Stein Eye Institute, Department of Ophthalmology, David Geffen School of Medicine
| | - Sophie X Deng
- Stein Eye Institute, Department of Ophthalmology, David Geffen School of Medicine
- Molecular Biology Institute, University of California, Los Angeles, California, USA
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20
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Ren H, Liu M, Jihu Y, Zeng H, Yao C, Yan H. Hypoxia activates the PI3K/AKT/HIF-1α pathway to promote the anti-inflammatory effect of adipose mesenchymal stem cells. Acta Histochem 2023; 125:152042. [PMID: 37137202 DOI: 10.1016/j.acthis.2023.152042] [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: 03/04/2023] [Revised: 04/20/2023] [Accepted: 04/22/2023] [Indexed: 05/05/2023]
Abstract
This study aimed to investigate the effect of hypoxia on the anti-inflammatory effect of adipose-derived mesenchymal stem cells (AMSCs) in vitro and its possible mechanism. AMSCs were cultured in vitro in a hypoxic environment with 3% O2, and a normoxic (21% O2) environment was used as the control. The cells were identified by in vitro adipogenic and osteogenic differentiation and cell surface antigen detection, and the cell viability were detected. The effect of hypoxic AMSCs on macrophage inflammation was analyzed by co-culture. The results showed that under hypoxia, AMSCs had better viability, significantly downregulated the expression of inflammatory factors, alleviated macrophage inflammation, and activated the PI3K/AKT/HIF-1α pathway.
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Affiliation(s)
- Hongjing Ren
- Southwest Medical University, NO.1 Section 1, Xianglin Road, Luzhou City, Sichuan Province 646000, China
| | - Mengchang Liu
- Southwest Medical University, NO.1 Section 1, Xianglin Road, Luzhou City, Sichuan Province 646000, China
| | - Yueda Jihu
- Southwest Medical University, NO.1 Section 1, Xianglin Road, Luzhou City, Sichuan Province 646000, China
| | - Huizhen Zeng
- Southwest Medical University, NO.1 Section 1, Xianglin Road, Luzhou City, Sichuan Province 646000, China
| | - Chong Yao
- Southwest Medical University, NO.1 Section 1, Xianglin Road, Luzhou City, Sichuan Province 646000, China
| | - Hong Yan
- Department of Plastic and Burn Surgery, Affiliated Hospital of Southwest Medical University, National Key Clinical Construction Specialty, Wound Repair and Regeneration Laboratory, NO.25 Taiping Street, Jiangyang District, Luzhou 646000 Sichuan Province, China.
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21
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Wu KY, Ahmad H, Lin G, Carbonneau M, Tran SD. Mesenchymal Stem Cell-Derived Exosomes in Ophthalmology: A Comprehensive Review. Pharmaceutics 2023; 15:1167. [PMID: 37111652 PMCID: PMC10142951 DOI: 10.3390/pharmaceutics15041167] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/26/2023] [Accepted: 04/03/2023] [Indexed: 04/29/2023] Open
Abstract
Over the past decade, the field of mesenchymal stem cell (MSC) therapy has exhibited rapid growth. Due to their regenerative, reparatory, and immunomodulatory capacities, MSCs have been widely investigated as therapeutic agents in the cell-based treatment of chronic ophthalmic pathologies. However, the applicability of MSC-based therapy is limited by suboptimal biocompatibility, penetration, and delivery to the target ocular tissues. An emerging body of research has elucidated the role of exosomes in the biological functions of MSCs, and that MSC-derived extracellular vesicles (EVs) possess anti-inflammatory, anti-apoptotic, tissue repairing, neuroprotective, and immunomodulatory properties similar to MSCs. The recent advances in MSCs-derived exosomes can serve as solutions to the challenges faced by MSCs-therapy. Due to their nano-dimensions, MSC-derived exosomes can rapidly penetrate biological barriers and reach immune-privileged organs, allowing for efficient delivery of therapeutic factors such as trophic and immunomodulatory agents to ocular tissues that are typically challenging to target by conventional therapy and MSCs transplantation. In addition, the use of EVs minimizes the risks associated with mesenchymal stem cell transplantation. In this literature review, we focus on the studies published between 2017 and 2022, highlighting the characteristics of EVs derived from MSCs and their biological functions in treating anterior and posterior segment ocular diseases. Additionally, we discuss the potential use of EVs in clinical settings. Rapid advancements in regenerative medicine and exosome-based drug delivery, in conjunction with an increased understanding of ocular pathology and pharmacology, hold great promise for the treatment of ocular diseases. The potential of exosome-based therapies is exciting and can revolutionize the way we approach these ocular conditions.
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Affiliation(s)
- Kevin Y. Wu
- Department of Surgery—Division of Ophthalmology, University of Sherbrooke, Sherbrooke, QC J1G 2E8, Canada
| | - Hamza Ahmad
- Faculty of Medicine, McGill University, Montreal, QC H3A 0G4, Canada
| | - Grace Lin
- Faculty of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Marjorie Carbonneau
- Department of Surgery—Division of Ophthalmology, University of Sherbrooke, Sherbrooke, QC J1G 2E8, Canada
| | - Simon D. Tran
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC H3A 1G1, Canada
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Liu A, Hefley B, Escandon P, Nicholas SE, Karamichos D. Salivary Exosomes in Health and Disease: Future Prospects in the Eye. Int J Mol Sci 2023; 24:ijms24076363. [PMID: 37047335 PMCID: PMC10094317 DOI: 10.3390/ijms24076363] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/21/2023] [Accepted: 03/24/2023] [Indexed: 03/30/2023] Open
Abstract
Exosomes are a group of vesicles that package and transport DNA, RNA, proteins, and lipids to recipient cells. They can be derived from blood, saliva, urine, and/or other biological tissues. Their impact on several diseases, such as neurodegenerative, autoimmune, and ocular diseases, have been reported, but not fully unraveled. The exosomes that are derived from saliva are less studied, but offer significant advantages over exosomes from other sources, due to their accessibility and ease of collection. Thus, their role in the pathophysiology of diseases is largely unknown. In the context of ocular diseases, salivary exosomes have been under-utilized, thus creating an enormous gap in the literature. The current review discusses the state of exosomes research on systemic and ocular diseases and highlights the role and potential of salivary exosomes as future ocular therapeutic vehicles.
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Affiliation(s)
- Angela Liu
- Texas College of Osteopathic Medicine, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA
- North Texas Eye Research Institute, University of North Texas Health Science Center, 3430 Camp Bowie Blvd., Fort Worth, TX 76107, USA
| | - Brenna Hefley
- North Texas Eye Research Institute, University of North Texas Health Science Center, 3430 Camp Bowie Blvd., Fort Worth, TX 76107, USA
- Department of Pharmaceutical Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA
| | - Paulina Escandon
- North Texas Eye Research Institute, University of North Texas Health Science Center, 3430 Camp Bowie Blvd., Fort Worth, TX 76107, USA
- Department of Pharmaceutical Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA
| | - Sarah E. Nicholas
- North Texas Eye Research Institute, University of North Texas Health Science Center, 3430 Camp Bowie Blvd., Fort Worth, TX 76107, USA
- Department of Pharmaceutical Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA
| | - Dimitrios Karamichos
- North Texas Eye Research Institute, University of North Texas Health Science Center, 3430 Camp Bowie Blvd., Fort Worth, TX 76107, USA
- Department of Pharmaceutical Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA
- Correspondence: ; Tel.: +1-817-735-2101
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Zhou J, Ding Y, Zhang Y, Zheng D, Yan L, Guo M, Mao Y, Yang L. Exosomes from bone marrow-derived mesenchymal stem cells facilitate corneal wound healing via regulating the p44/42 MAPK pathway. Graefes Arch Clin Exp Ophthalmol 2023; 261:723-734. [PMID: 36576571 DOI: 10.1007/s00417-022-05956-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 12/04/2022] [Accepted: 12/21/2022] [Indexed: 12/29/2022] Open
Abstract
PURPOSE This study was aimed at exploring the function of Exosomes isolated from bone marrow-derived mesenchymal stem cells (BMSC-Exos) in corneal wound healing and at revealing the underlying mechanisms involving the p44/42 mitogen-activated protein kinase (MAPK) pathway. METHODS The isolated BMSC-Exos were identified by transmission electron microscopy, Western blot, and nanoparticle tracking analysis. After coculture with BMSC-Exos, the proliferation and migration of human corneal epithelial cells (HCEs) were evaluated. The protein expression of p-MEK/MEK and p44/42 MAPK was detected by Western blot. A mouse model of alkali-burned cornea was established via NaOH exposure. After injection with BMSC-Exos, the pathological changes and expression of α-SMA (a fibrosis marker) and CD31 (a vascularization marker) in corneal tissues were detected. RESULTS BMSC-Exos enhanced the proliferation and migration of HCEs in a dose-dependent manner. The p44/42 MAPK pathway was activated by the treatment of BMSC-Exos, and its blocking using U0126 partially abrogated the effects of BMSC-Exos on promoting the proliferation and migration of HCEs. In vivo, the injection of BMSC-Exos facilitated the remission of the pathological changes (inflammation) and weakened the upregulation of α-SMA (fibrosis) and CD31 (vascularization) in corneal tissues of mice with alkali-burn injury. CONCLUSION BMSC-Exos promoted the proliferation and migration of HCEs via activating the p44/42 MAPK pathway in vitro and also inhibited alkali burn-induced inflammation, fibrosis, and vascularization in corneal tissues in vivo. BMSC-Exos may be promising resources for promoting corneal wound healing.
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Affiliation(s)
- Jin Zhou
- Department of Ophthalmology, Guangzhou Women and Children's Medical Center, No. 9, Jinsui Road, Tianhe District, Guangzhou City, 510623, China.
| | - Yuanyuan Ding
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou City, 510515, China
| | - Yongqiang Zhang
- Department of Ophthalmology, Beijing Children's Hospital East Branch, Beijing City, 100002, China
| | - Dehui Zheng
- Department of Ophthalmology, Guangzhou Women and Children's Medical Center, No. 9, Jinsui Road, Tianhe District, Guangzhou City, 510623, China
| | - Lifeng Yan
- Department of Ophthalmology, Guangzhou Women and Children's Medical Center, No. 9, Jinsui Road, Tianhe District, Guangzhou City, 510623, China
| | - Mengxiang Guo
- Department of Ophthalmology, Guangzhou Women and Children's Medical Center, No. 9, Jinsui Road, Tianhe District, Guangzhou City, 510623, China
| | - Yani Mao
- Department of Ophthalmology, Guangzhou Women and Children's Medical Center, No. 9, Jinsui Road, Tianhe District, Guangzhou City, 510623, China
| | - Lihong Yang
- Department of Ophthalmology, Guangzhou Women and Children's Medical Center, No. 9, Jinsui Road, Tianhe District, Guangzhou City, 510623, China
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24
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Soleimani M, Masoumi A, Momenaei B, Cheraqpour K, Koganti R, Chang AY, Ghassemi M, Djalilian AR. Applications of mesenchymal stem cells in ocular surface diseases: sources and routes of delivery. Expert Opin Biol Ther 2023; 23:509-525. [PMID: 36719365 PMCID: PMC10313829 DOI: 10.1080/14712598.2023.2175605] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 01/30/2023] [Indexed: 02/01/2023]
Abstract
INTRODUCTION Mesenchymal stem cells (MSCs) are novel, promising agents for treating ocular surface disorders. MSCs can be isolated from several tissues and delivered by local or systemic routes. They produce several trophic factors and cytokines, which affect immunomodulatory, transdifferentiating, angiogenic, and pro-survival pathways in their local microenvironment via paracrine secretion. Moreover, they exert their therapeutic effect through a contact-dependent manner. AREAS COVERED In this review, we discuss the characteristics, sources, delivery methods, and applications of MSCs in ocular surface disorders. We also explore the potential application of MSCs to inhibit senescence at the ocular surface. EXPERT OPINION Therapeutic application of MSCs in ocular surface disorders are currently under investigation. One major research area is corneal epitheliopathies, including chemical or thermal burns, limbal stem cell deficiency, neurotrophic keratopathy, and infectious keratitis. MSCs can promote corneal epithelial repair and prevent visually devastating sequelae of non-healing wounds. However, the optimal dosages and delivery routes have yet to be determined and further clinical trials are needed to address these fundamental questions.
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Affiliation(s)
- Mohammad Soleimani
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Masoumi
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Bita Momenaei
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Kasra Cheraqpour
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Raghuram Koganti
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Arthur Y Chang
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Mahmoud Ghassemi
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Ali R Djalilian
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
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25
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Ma X, Liu B, Fan L, Liu Y, Zhao Y, Ren T, Li Y, Li Y. Native and engineered exosomes for inflammatory disease. NANO RESEARCH 2022; 16:6991-7006. [PMID: 36591564 PMCID: PMC9793369 DOI: 10.1007/s12274-022-5275-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/28/2022] [Accepted: 10/31/2022] [Indexed: 05/24/2023]
Abstract
Exosomes are extracellular vesicles which carry specific molecular information from donor cells and act as an intercellular communication vehicle, which have emerged as a novel cell-free strategy for the treatment of many diseases including inflammatory disease. Recently, rising studies have developed exosome-based strategies for novel inflammation therapy due to their biocompatibility and bioactivity. Researchers not only use native exosomes as therapeutic agents for inflammation, but also strive to make up for the natural defects of exosomes through engineering methods to improve and update the property of exosomes for enhanced therapeutic effects. The engineered exosomes can improve cargo-loading efficiency, targeting ability, stability, etc., to achieve combined and diverse treatment strategies in inflammation diseases. Herein, a comprehensive overview of the recent advances in application studies of native and engineered exosomes as well as the engineered methods is provided. Meanwhile, potential application prospects, possible challenges, and the development of clinical researches of exosome treatment strategy are concluded from plentiful examples, which may be able to provide guidance and suggestions for the future research and application of exosomes.
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Affiliation(s)
- Xiaoyi Ma
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Bingbing Liu
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Limin Fan
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Yiqiong Liu
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Yuge Zhao
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Tianbin Ren
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Yan Li
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Yongyong Li
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
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Mesenchymal Stromal Cells-Derived Extracellular Vesicles Regulate Dendritic Cell Functions in Dry Eye Disease. Cells 2022; 12:cells12010033. [PMID: 36611828 PMCID: PMC9818747 DOI: 10.3390/cells12010033] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 12/11/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
We explored the therapeutic efficacy of Mesenchymal stromal cells-derived extracellular vesicles (MSC-EVs) and its inhibition of the functions of dendritic cells (DCs) in dry eye disease (DED). MSC-EVs were isolated from the culture supernatants of mesenchymal stromal cells (MSCs) and characterized. In vitro, human corneal epithelial cells (HCECs) were cultured in hyperosmotic medium to simulate the DED hyperosmotic environment and treated with MSC-EVs. Cell viability was assessed, and the expression of inflammatory cytokines was quantified. Next, we induced DED in female C57BL/6 mice and divided the mice into groups treated with either MSC-EVs or phosphate buffer solution (PBS) eye drops. Disease severity was assessed; mRNA expression of inflammatory cytokines was analyzed by RT-PCR; and Th17 cells were detected by flow cytometry. Lastly, we evaluated DCs by immunofluorescence and flow cytometric analysis to assess its amounts and maturation. MSC-EVs showed protective effects on HCECs under hyperosmotic stress in vitro, suppressing the expression of inflammatory cytokines. In vivo, mice topically treated with MSC-Evs presented reduced DED disease severity compared to PBS-treated mice. MSC-Evs downregulated the expression of inflammatory cytokines, including TNF-α, IL-6, and IL-1β, as well as the frequency of Th17 cells. Further investigation showed that MSC-EVs suppressed the increase of amounts and the maturation of DCs in DED. Changes of morphological characters of DCs were also inhibited by MSC-EVs. Our study revealed that MSC-EVs suppressed ocular surface inflammation by inhibiting DCs activation-mediated Th17 immune responses, explicating the therapeutic potential of MSC-EVs in DED and other ocular surface diseases.
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27
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Lyu N, Knight R, Robertson SYT, Dos Santos A, Zhang C, Ma C, Xu J, Zheng J, Deng SX. Stability and Function of Extracellular Vesicles Derived from Immortalized Human Corneal Stromal Stem Cells: A Proof of Concept Study. AAPS J 2022; 25:8. [PMID: 36471035 DOI: 10.1208/s12248-022-00767-1] [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: 07/30/2022] [Accepted: 10/28/2022] [Indexed: 12/12/2022] Open
Abstract
With significant advancement and development of extracellular vesicle (EV)-based therapies, there is a growing need to understand how their storage affects their physical and functional characteristics. EVs were isolated from the conditioned medium of a corneal stromal stem cell line (imCSSC) using Total Exosome isolation kit (TEI) and ultracentrifugation (UC) combined protocol. Purified EVs were stored at 4°C, - 80°C, room temperature (RT) after lyophilization with or without trehalose for 4 weeks. EVs stored at - 80°C and RT (lyophilization with trehalose) demonstrated a comparable morphology, while the freeze-dried samples without trehalose showed aggregation and degradation under a transmission electron microscope (TEM). Lyophilized samples without trehalose demonstrated a decreased particle concentration, recovery rate and protein concentration, which was remediated by the addition of trehalose. EVs stored at - 80℃ showed no change in the protein expression of CD9, CD63, and CD81. Regardless of the storage condition, all EV samples investigated reduced inflammation, as well as inhibited expression of fibrotic markers in vitro. Lyophilization of EVs with trehalose was a feasible storage method that retained the physical property and in vitro biological activities of EVs after 4 weeks of storage, while - 80°C offered the best retention of imCSSC-derived EV physical properties. For the first time, this data demonstrated a practical and translatable method for the storage of CSSC-derived EVs for clinical use.
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Affiliation(s)
- Ning Lyu
- Stein Eye Institute, University of California Los Angeles, Los Angeles, California, USA.,Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; NHC Key Laboratory of Myopia (Fudan University); Key Laboratory of Myopia, Shanghai Key Laboratory of Visual Impairment and Restoration, Chinese Academy of Medical Sciences, Shanghai, 200031, China
| | - Robert Knight
- Stein Eye Institute, University of California Los Angeles, Los Angeles, California, USA
| | - Sarah Y T Robertson
- Stein Eye Institute, University of California Los Angeles, Los Angeles, California, USA
| | - Aurelie Dos Santos
- Stein Eye Institute, University of California Los Angeles, Los Angeles, California, USA
| | - Chi Zhang
- Stein Eye Institute, University of California Los Angeles, Los Angeles, California, USA
| | - Chao Ma
- Stein Eye Institute, University of California Los Angeles, Los Angeles, California, USA
| | - Jianjiang Xu
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; NHC Key Laboratory of Myopia (Fudan University); Key Laboratory of Myopia, Shanghai Key Laboratory of Visual Impairment and Restoration, Chinese Academy of Medical Sciences, Shanghai, 200031, China
| | - Jie Zheng
- Stein Eye Institute, University of California Los Angeles, Los Angeles, California, USA
| | - Sophie X Deng
- Stein Eye Institute, University of California Los Angeles, Los Angeles, California, USA.
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28
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Saccu G, Menchise V, Gai C, Bertolin M, Ferrari S, Giordano C, Manco M, Dastrù W, Tolosano E, Bussolati B, Calautti E, Camussi G, Altruda F, Fagoonee S. Bone Marrow Mesenchymal Stromal/Stem Cell-Derived Extracellular Vesicles Promote Corneal Wound Repair by Regulating Inflammation and Angiogenesis. Cells 2022; 11:3892. [PMID: 36497151 PMCID: PMC9736484 DOI: 10.3390/cells11233892] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 11/22/2022] [Accepted: 11/28/2022] [Indexed: 12/05/2022] Open
Abstract
Severe corneal damage leads to complete vision loss, thereby affecting life quality and impinging heavily on the healthcare system. Current clinical approaches to manage corneal wounds suffer from severe drawbacks, thus requiring the development of alternative strategies. Of late, mesenchymal stromal/stem cell (MSC)-derived extracellular vesicles (EVs) have become a promising tool in the ophthalmic field. In the present study, we topically delivered bone-marrow-derived MSC-EVs (BMSC-EVs), embedded in methylcellulose, in a murine model of alkali-burn-induced corneal damage in order to evaluate their role in corneal repair through histological and molecular analyses, with the support of magnetic resonance imaging. Our data show that BMSC-EVs, used for the first time in this specific formulation on the damaged cornea, modulate cell death, inflammation and angiogenetic programs in the injured tissue, thus leading to a faster recovery of corneal damage. These results were confirmed on cadaveric donor-derived human corneal epithelial cells in vitro. Thus, BMSC-EVs modulate corneal repair dynamics and are promising as a new cell-free approach for intervening on burn wounds, especially in the avascularized region of the eye.
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Affiliation(s)
- Gabriele Saccu
- Molecular Biotechnology Center “Guido Tarone”, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy
| | - Valeria Menchise
- Institute of Biostructure and Bioimaging, National Research Council (CNR), Molecular Biotechnology Center “Guido Tarone”, 10126 Turin, Italy
| | - Chiara Gai
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy
| | | | | | - Cristina Giordano
- Ophthalmology Veterinary Practice, C.so Galileo Ferraris 121, 10126 Turin, Italy
| | - Marta Manco
- Molecular Biotechnology Center “Guido Tarone”, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy
| | - Walter Dastrù
- Molecular Biotechnology Center “Guido Tarone”, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy
| | - Emanuela Tolosano
- Molecular Biotechnology Center “Guido Tarone”, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy
| | - Benedetta Bussolati
- Molecular Biotechnology Center “Guido Tarone”, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy
| | - Enzo Calautti
- Molecular Biotechnology Center “Guido Tarone”, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy
| | - Giovanni Camussi
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy
| | - Fiorella Altruda
- Molecular Biotechnology Center “Guido Tarone”, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy
| | - Sharmila Fagoonee
- Institute of Biostructure and Bioimaging, National Research Council (CNR), Molecular Biotechnology Center “Guido Tarone”, 10126 Turin, Italy
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Li J, Wei C, Yang Y, Gao Z, Guo Z, Qi F. Apoptotic bodies extracted from adipose mesenchymal stem cells carry microRNA-21-5p to induce M2 polarization of macrophages and augment skin wound healing by targeting KLF6. Burns 2022; 48:1893-1908. [PMID: 35016791 DOI: 10.1016/j.burns.2021.12.010] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 12/21/2021] [Accepted: 12/30/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Adipose-derived mesenchymal stem cells (adMSCs) are suggested as potential tools for the treatment of regenerative diseases, including tissue repair. This study aimed to explore the function of adMSC-derived apoptotic bodies in skin wound healing and the molecules of action. METHODS The acquired adMSCs and their-derived apoptotic bodies were identified. A murine model of full-thickness skin wounds was treated with apoptotic bodies. The wound healing process of mice and the pathological changes in wound tissues were examined. Ana-1 macrophages were treated with lipopolysaccharide (LPS) and apoptotic bodies for in vitro experiments. Polarization of macrophages was examined by immunofluorescence staining of the specific biomarkers and ELISA kits. Dermal microvascular endothelial cells (DMECs) or dermal fibroblasts (DFs) were co-cultured with apoptotic bodies or the LPS- and apoptotic bodies-treated Ana-1 cells. Downstream molecules mediated by apoptotic bodies were screened by microarray and bioinformatic analyses. RESULTS Apoptotic bodies treatment accelerated skin wound healing in mice and promoted formation of granulation tissues and blood vessels in wound tissues. Apoptotic bodies treatment induced M2 polarization of macrophages. The angiogenesis ability of DMECs, and the viability and migration of DFs were increased when co-cultured with the apoptotic bodies-treated Ana-1 cells. MicroRNA (miR)-21-5p was abundantly expressed in ABs, and kruppel like factor 6 (KLF6) mRNA was confirmed as a target of miR-21-5p. Overexpression of KLF6 reduced M2 polarization of macrophages and blocked the promoting effect of apoptotic bodies on wound healing in vitro and in vivo. CONCLUSION miR-21-5p carried by adMSC-derived apoptotic bodies targets KLF6 to induce M2 polarization of macrophages and augment skin wound healing.
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Affiliation(s)
- Jianrui Li
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Chuanyuan Wei
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Yang Yang
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Zixu Gao
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Zheng Guo
- Centre for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Joondalup 6027, Australia
| | - Fazhi Qi
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China.
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Yudintceva N, Mikhailova N, Fedorov V, Samochernych K, Vinogradova T, Muraviov A, Shevtsov M. Mesenchymal Stem Cells and MSCs-Derived Extracellular Vesicles in Infectious Diseases: From Basic Research to Clinical Practice. Bioengineering (Basel) 2022; 9:662. [PMID: 36354573 PMCID: PMC9687734 DOI: 10.3390/bioengineering9110662] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/30/2022] [Accepted: 11/04/2022] [Indexed: 08/10/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are attractive in various fields of regenerative medicine due to their therapeutic potential and complex unique properties. Basic stem cell research and the global COVID-19 pandemic have given impetus to the development of cell therapy for infectious diseases. The aim of this review was to systematize scientific data on the applications of mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) in the combined treatment of infectious diseases. Application of MSCs and MSC-EVs in the treatment of infectious diseases has immunomodulatory, anti-inflammatory, and antibacterial effects, and also promotes the restoration of the epithelium and stimulates tissue regeneration. The use of MSC-EVs is a promising cell-free treatment strategy that allows solving the problems associated with the safety of cell therapy and increasing its effectiveness. In this review, experimental data and clinical trials based on MSCs and MSC-EVs for the treatment of infectious diseases are presented. MSCs and MSC-EVs can be a promising tool for the treatment of various infectious diseases, particularly in combination with antiviral drugs. Employment of MSC-derived EVs represents a more promising strategy for cell-free treatment, demonstrating a high therapeutic potential in preclinical studies.
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Affiliation(s)
- Natalia Yudintceva
- Institute of Cytology of the Russian Academy of Sciences (RAS), St. Petersburg 194064, Russia
- Personalized Medicine Centre, Almazov National Medical Research Centre, St. Petersburg 197341, Russia
| | - Natalia Mikhailova
- Institute of Cytology of the Russian Academy of Sciences (RAS), St. Petersburg 194064, Russia
| | - Viacheslav Fedorov
- Personalized Medicine Centre, Almazov National Medical Research Centre, St. Petersburg 197341, Russia
| | - Konstantin Samochernych
- Personalized Medicine Centre, Almazov National Medical Research Centre, St. Petersburg 197341, Russia
| | - Tatiana Vinogradova
- Saint-Petersburg State Research Institute of Phthisiopulmonology of the Ministry of Health of the Russian Federation, St. Petersburg 191036, Russia
| | - Alexandr Muraviov
- Saint-Petersburg State Research Institute of Phthisiopulmonology of the Ministry of Health of the Russian Federation, St. Petersburg 191036, Russia
| | - Maxim Shevtsov
- Institute of Cytology of the Russian Academy of Sciences (RAS), St. Petersburg 194064, Russia
- Personalized Medicine Centre, Almazov National Medical Research Centre, St. Petersburg 197341, Russia
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31
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Recent Advancements in Molecular Therapeutics for Corneal Scar Treatment. Cells 2022; 11:cells11203310. [PMID: 36291182 PMCID: PMC9600986 DOI: 10.3390/cells11203310] [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: 07/14/2022] [Revised: 10/10/2022] [Accepted: 10/12/2022] [Indexed: 11/17/2022] Open
Abstract
The process of corneal wound healing is complex and induces scar formation. Corneal scarring is a leading cause of blindness worldwide. The fibrotic healing of a major ocular wound disrupts the highly organized fibrillar collagen arrangement of the corneal stroma, rendering it opaque. The process of regaining this organized extracellular matrix (ECM) arrangement of the stromal layer to restore corneal transparency is complicated. The surface retention capacity of ocular drugs is poor, and there is a large gap between suitable corneal donors and clinical requirements. Therefore, a more efficient way of treating corneal scarring is needed. The eight major classes of interventions targeted as therapeutic tools for healing scarred corneas include those based on exosomes, targeted gene therapy, microRNAs, recombinant viral vectors, histone deacetylase inhibitors, bioactive molecules, growth factors, and nanotechnology. This review highlights the recent advancements in molecular therapeutics to restore a cornea without scarring. It also provides a scope to overcome the limitations of present studies and perform robust clinical research using these strategies.
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Corneal Regeneration Using Adipose-Derived Mesenchymal Stem Cells. Cells 2022; 11:cells11162549. [PMID: 36010626 PMCID: PMC9406486 DOI: 10.3390/cells11162549] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/12/2022] [Accepted: 08/12/2022] [Indexed: 11/28/2022] Open
Abstract
Adipose-derived stem cells are a subtype of mesenchymal stem cell that offers the important advantage of being easily obtained (in an autologous manner) from low invasive procedures, rendering a high number of multipotent stem cells with the potential to differentiate into several cellular lineages, to show immunomodulatory properties, and to promote tissue regeneration by a paracrine action through the secretion of extracellular vesicles containing trophic factors. This secretome is currently being investigated as a potential source for a cell-free based regenerative therapy for human tissues, which would significantly reduce the involved costs, risks and law regulations, allowing for a broader application in real clinical practice. In the current article, we will review the existing preclinical and human clinical evidence regarding the use of such adipose-derived mesenchymal stem cells for the regeneration of the three main layers of the human cornea: the epithelium (derived from the surface ectoderm), the stroma (derived from the neural crest mesenchyme), and the endothelium (derived from the neural crest cells).
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Manukonda R, Attem J, Yenuganti VR, Kaliki S, Vemuganti GK. Exosomes in the visual system: New avenues in ocular diseases. Tumour Biol 2022; 44:129-152. [PMID: 35964221 DOI: 10.3233/tub-211543] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Exosomes are a subgroup of membrane-bound extracellular vesicles secreted by all cell types and present virtually in all biological fluids. The composition of exosomes in the same cell type varies in healthy and disease conditions. Hence, exosomes research is a prime focus area for clinical research in cancer and numerous age-related metabolic syndromes. Functions of exosomes include crucial cell-to-cell communication that mediates complex cellular processes, such as antigen presentation, stem cell differentiation, and angiogenesis. However, very few studies reported the presence and role of exosomes in normal physiological and pathological conditions of specialized ocular tissues of the eye and ocular cancers. The eye being a protected sense organ with unique connectivity with the rest of the body through the blood and natural passages, we believe that the role of exosomes in ocular tissues will significantly improve our understanding of ocular diseases and their interactions with the rest of the body. We present a review that highlights the existence and function of exosomes in various ocular tissues, their role in the progression of some of the neoplastic and non-neoplastic conditions of the eyes.
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Affiliation(s)
- Radhika Manukonda
- School of Medical Sciences, University of Hyderabad, Hyderabad, India.,The Operation Eyesight Universal Institute for Eye Cancer, LV Prasad Eye Institute, Hyderabad, Telangana, India.,Brien Holden Eye Research Center, L. V. Prasad Eye Institute, Hyderabad, Telangana, India
| | - Jyothi Attem
- School of Medical Sciences, University of Hyderabad, Hyderabad, India
| | - Vengala Rao Yenuganti
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Swathi Kaliki
- The Operation Eyesight Universal Institute for Eye Cancer, LV Prasad Eye Institute, Hyderabad, Telangana, India.,Brien Holden Eye Research Center, L. V. Prasad Eye Institute, Hyderabad, Telangana, India
| | - Geeta K Vemuganti
- School of Medical Sciences, University of Hyderabad, Hyderabad, India
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Liu X, Li X, Wu G, Qi P, Zhang Y, Liu Z, Li X, Yu Y, Ye X, Li Y, Yang D, Teng Y, Shi C, Jin X, Qi S, Liu Y, Wang S, Liu Y, Cao F, Kong Q, Wang Z, Zhang H. Umbilical Cord Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Deliver miR-21 to Promote Corneal Epithelial Wound Healing through PTEN/PI3K/Akt Pathway. Stem Cells Int 2022; 2022:1252557. [PMID: 35873535 PMCID: PMC9303509 DOI: 10.1155/2022/1252557] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 05/19/2022] [Accepted: 06/23/2022] [Indexed: 12/30/2022] Open
Abstract
Objective Rapid restoration of corneal epithelium integrity after injury is particularly important for preserving corneal transparency and vision. Mesenchymal stem cells (MSCs) can be taken into account as the promising regenerative therapeutics for improvement of wound healing processes based on the variety of the effective components. The extracellular vesicles form MSCs, especially exosomes, have been considered as important paracrine mediators though transferring microRNAs into recipient cell. This study investigated the mechanism of human umbilical cord MSC-derived small extracellular vesicles (HUMSC-sEVs) on corneal epithelial wound healing. Methods HUMSC-sEVs were identified by transmission electron microscopy, nanoparticle tracking analysis, and Western blot. Corneal fluorescein staining and histological staining were evaluated in a corneal mechanical wound model. Changes in HCEC proliferation after HUMSC-sEVs or miR-21 mimic treatment were evaluated by CCK-8 and EdU assays, while migration was assessed by in vitro scratch wound assay. Full-length transcriptome sequencing was performed to identify the differentially expressed genes associated with HUMSC-sEVs treatment, followed by validation via real-time PCR and Western blot. Results The sEVs derived from HUMSCs can significantly promote corneal epithelial cell proliferation, migration in vitro, and corneal epithelial wound healing in vivo. Similar effects were obtained after miR-21 transfection, while the beneficial effects of HUMSC-sEVs were partially negated by miR-21 knockdown. Results also show that the benefits are associated with decreased PTEN level and activated the PI3K/Akt signaling pathway in HCECs. Conclusion HUMSC-sEVs could enhance the recovery of corneal epithelial wounds though restraining PTEN by transferring miR-21 and may represent a promising novel therapeutic agent for corneal wound repair.
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Affiliation(s)
- Xiaolong Liu
- Central Laboratory, First Affiliated Hospital, Harbin Medical University, Harbin, China
- College of Life Science, Northeast Agricultural University, Harbin, China
| | - Xuran Li
- Eye Hospital, First Affiliated Hospital, Harbin Medical University, Harbin, China
- NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, China
| | - Guangyuan Wu
- Central Laboratory, First Affiliated Hospital, Harbin Medical University, Harbin, China
- NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, China
| | - Pengfei Qi
- Central Laboratory, First Affiliated Hospital, Harbin Medical University, Harbin, China
- NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, China
| | - Yanyan Zhang
- Eye Hospital, First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Zhiyu Liu
- Department of Laboratory Diagnostics, First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Xinyue Li
- Eye Hospital, First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Yu Yu
- Eye Hospital, First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Xiangmei Ye
- Central Laboratory, First Affiliated Hospital, Harbin Medical University, Harbin, China
- NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, China
| | - Yang Li
- Central Laboratory, First Affiliated Hospital, Harbin Medical University, Harbin, China
- NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, China
| | - Dongguang Yang
- Central Laboratory, First Affiliated Hospital, Harbin Medical University, Harbin, China
- NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, China
| | - Yueqiu Teng
- Central Laboratory, First Affiliated Hospital, Harbin Medical University, Harbin, China
- NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, China
| | - Ce Shi
- Central Laboratory, First Affiliated Hospital, Harbin Medical University, Harbin, China
- NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, China
| | - Xin Jin
- Eye Hospital, First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Sen Qi
- Department of Hematology, First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Yuting Liu
- Eye Hospital, First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Shudan Wang
- Eye Hospital, First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Ying Liu
- Eye Hospital, First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Fenglin Cao
- Central Laboratory, First Affiliated Hospital, Harbin Medical University, Harbin, China
- NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, China
| | - Qingran Kong
- College of Life Science, Northeast Agricultural University, Harbin, China
| | - Zhenkun Wang
- Central Laboratory, First Affiliated Hospital, Harbin Medical University, Harbin, China
- NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, China
| | - Hong Zhang
- Eye Hospital, First Affiliated Hospital, Harbin Medical University, Harbin, China
- NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, China
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Yu S, Chen X, Liu Y, Zhuang XY, Wang AC, Liu XM, Zhu S. Exosomes derived from stem cells from the apical papilla alleviate inflammation in rat pulpitis by upregulating regulatory T cells. Int Endod J 2022; 55:517-530. [PMID: 35274316 DOI: 10.1111/iej.13721] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 03/04/2022] [Indexed: 11/28/2022]
Abstract
AIM To evaluate the effects of exosomes derived from stem cells from the apical papilla (SCAP-Exos) in rats with experimentally induced pulpitis and the effects of SCAP-Exos on the conversion of regulatory T cells (Tregs) and methylation status of the Foxp3 locus in Tregs in vitro. METHODOLOGY SCAP-Exos were isolated and identified using transmission electron microscopy, western blotting, and nanoparticle tracking analysis. Lipopolysaccharide was used to experimentally induced pulpitis in rats, and the effects of SCAP-Exos on the rats with pulpitis were detected using haematoxylin-eosin staining and immunofluorescence staining. CD4+CD25- T cells were treated with different doses of SCAP-Exos, and flow cytometric analysis was used to assess the effects of SCAP-Exos on Treg proliferation and conversion. An enzyme-linked immunosorbent assay (ELISA) was used to evaluate the expression of interleukin 10 (IL-10). MethylTarget® technology was used to measure the methylation level of the Foxp3 locus in T cells. The expression levels of ten-eleven-translocation (Tet) 1, Tet2, and Tet3 in T cells were detected by real-time PCR and western blotting. RESULTS SCAP-Exos had an elliptical vesicle-like structure with a diameter of approximately 143.7 nm and expressed the exosomal markers Alix and CD9. SCAP-Exo administration increased Treg accumulation in the inflamed dental pulp and alleviated inflammation in the dental pulp in vivo. SCAP-Exos promoted Treg conversion in vitro. Mechanistically, SCAP-Exos promoted Tet2-mediated Foxp3 demethylation to maintain the stable expression of Foxp3. CONCLUSIONS SCAP-Exos promoted Treg conversion and effectively alleviated inflammation in the dental pulp of rats. This study shows that SCAP-Exos can regulate the local immune microenvironment to favour tissue regeneration, thus providing a potential novel strategy utilising SCAP-Exos as a cell-free approach to treat early inflammation of dental pulp in immature permanent teeth in the clinic.
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Affiliation(s)
- S Yu
- Department of Paediatric Dentistry, School and Hospital of Stomatology, China Medical University, Shenyang, China; Liaoning Province Key Laboratory of Oral Disease, Shenyang, China
| | - X Chen
- Department of Paediatric Dentistry, School and Hospital of Stomatology, China Medical University, Shenyang, China; Liaoning Province Key Laboratory of Oral Disease, Shenyang, China
| | - Y Liu
- Department of Paediatric Dentistry, School and Hospital of Stomatology, China Medical University, Shenyang, China; Liaoning Province Key Laboratory of Oral Disease, Shenyang, China
| | - X Y Zhuang
- Department of Paediatric Dentistry, School and Hospital of Stomatology, China Medical University, Shenyang, China; Liaoning Province Key Laboratory of Oral Disease, Shenyang, China
| | - A C Wang
- Department of Paediatric Dentistry, School and Hospital of Stomatology, China Medical University, Shenyang, China; Liaoning Province Key Laboratory of Oral Disease, Shenyang, China
| | - X M Liu
- Department of Paediatric Dentistry, School and Hospital of Stomatology, China Medical University, Shenyang, China; Liaoning Province Key Laboratory of Oral Disease, Shenyang, China
| | - S Zhu
- Department of Paediatric Dentistry, School and Hospital of Stomatology, China Medical University, Shenyang, China; Liaoning Province Key Laboratory of Oral Disease, Shenyang, China
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Ariesta Shinta Dewi P, Sitompul R, Adiwinata Pawitan J, Naroeni A, Dewayani Antarianto R. Improvement of Corneal Nerve Regeneration in Diabetic Rats Using Wharton's Jelly-Derived Mesenchymal Stem Cells and their Conditioned Medium. INTERNATIONAL JOURNAL OF MOLECULAR AND CELLULAR MEDICINE 2022; 11:180-196. [PMID: 37605742 PMCID: PMC10440006 DOI: 10.22088/ijmcm.bums.11.3.180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 12/22/2022] [Accepted: 03/06/2023] [Indexed: 08/23/2023]
Abstract
To investigate the efficacy of Wharton's jelly mesenchymal stem cells (WJSCs) and their conditioned medium (CM) for corneal nerve regeneration in rats with diabetic keratopathy. Streptozotocin (STZ)-induced male diabetic (DM) rats (250-300 g) were divided into four groups (n=7/group): Control, DM, DM with WJSCs (DM+WJ), and DM with CM treatment (DM+CM). DM+WJ and DM+CM group received WJSCs or CM, respectively, topically with eye drops. Corneal sensibility, corneal epithelial layer integrity, histology, expression of GAP-43 and TUBB3 on mRNA level and their immunohistochemical expression were examined after two weeks of treatment. There were changes in corneal sensibility and corneal integrity between normal control and diabetic groups with/without WJSC or CM injection. Total central corneal thickness was significantly higher in DM+CM (249.81 ± 43.85 μm) than in control (174.72 ± 44.12 μm, P=0.004) and DM groups (190.15 ± 9.63 μm, P=0.03). GAP-43 mRNA expression levels of DM+WJ and DM+CM groups were higher compared with DM and control groups. TUBB3 mRNA level was increased after CM (P=0.047), but not after WJSCs treatment (P=1.00). GAP-43 and TUBB3 immunohistochemical expression of nerve fibers along the epithelial layer significantly increased in DM+WJ and DM+CM compared with DM group. Our findings showed that WJSCs and their CM improved corneal nerve regeneration in rats with diabetic keratopathy.
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Affiliation(s)
- Pitra Ariesta Shinta Dewi
- Doctoral Programme Biomedical Sciences, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia.
| | - Ratna Sitompul
- Department of Ophthalmology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
| | - Jeanne Adiwinata Pawitan
- Department of Histology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
- Stem Cell Medical Technology Integrated Service Unit, Dr. Cipto Mangunkusumo General Hospital, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia.
- Stem Cell and Tissue Engineering (SCTE) Research Center, Indonesia Medical Education and Research Institute (IMERI), Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
| | - Aroem Naroeni
- Stem Cell Medical Technology Integrated Service Unit, Dr. Cipto Mangunkusumo General Hospital, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia.
- Virology and Cancer Pathobiology Research Center, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
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Pan J, Luo X, Zhao S, Li J, Jiang Z. miR-340-5p mediates the therapeutic effect of mesenchymal stem cells on corneal neovascularization. Graefes Arch Clin Exp Ophthalmol 2021; 260:497-507. [PMID: 34495369 DOI: 10.1007/s00417-021-05394-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 08/09/2021] [Accepted: 08/23/2021] [Indexed: 10/20/2022] Open
Abstract
BACKGROUND Our previous study revealed that mesenchymal stem cells (MSCs) inhibited angiogenesis via miRNA-mediated repression of prospero homeobox 1 (PROX1). This study aimed to verify whether miR-340-5p participates in the therapeutic effect of MSCs on corneal neovascularization (CNV) via repressing PROX1 and epithelial membrane protein 2 (EMP2). MATERIALS AND METHODS The rat CNV model was established by corneal alkali burn. The binding relationship between miR-340-5p and 3'-untranslational regions (3'UTRs) of EMP2 and PROX1 was confirmed using dual-luciferase reporter assay. After culturing corneal epithelial cells (CECs) using MSC supernatants, the vascular endothelial growth factor (VEGF) level in CEC supernatants and the CEC viability were detected. The role of miR-340-5p in the therapeutic effect of MSC on CNV was determined via lentivirus-mediated miR-340-5p intervention in vivo. RESULTS The expression of miR-340-5p was reduced and EMP2 and PROX1 were increased in CNV corneal tissues. The lentivirus-mediated overexpression of miR-340-5p inhibited the expressions of EMP2 and PROX1. The dual-luciferase reporter assay confirmed that miR-340-5p could bind with the 3'UTRs of EMP2 and PROX1. miR-340-5p was enriched in MSC supernatants and the culture of CECs using MSC supernatants increased the miR-340-5p expression in CECs. After being cultured in miR-340-5p-knocking down MSC supernatants, the expressions of EMP2 and PROX1 were increased, and the VEGF level and CEC viability were restored. The in vivo experiments also indicated that the therapeutic effect of MSCs was mediated by miR-340-5p. CONCLUSIONS miR-340-5p mediates the therapeutic effect of MSCs on CNV via binding and repressing the expressions of EMP2 and PROX1.
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Affiliation(s)
- Jian Pan
- Department of Ophthalmology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang Street, Ouhai District, Wenzhou, 325000, Zhejiang, China
| | - Xu Luo
- Burn and Wound Healing Center, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang Street, Ouhai District, Wenzhou, 325000, Zhejiang, China.,Wound Repair Department, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, No. 2 Zhongloudi Street, Kecheng District, Quzhou, 324000, Zhejiang, China
| | - Shujue Zhao
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang Street, Ouhai District, Wenzhou, 325000, Zhejiang, China
| | - Jianmin Li
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang Street, Ouhai District, Wenzhou, 325000, Zhejiang, China
| | - Zipei Jiang
- Department of Ophthalmology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang Street, Ouhai District, Wenzhou, 325000, Zhejiang, China.
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McKay TB, Yeung V, Hutcheon AEK, Guo X, Zieske JD, Ciolino JB. Extracellular Vesicles in the Cornea: Insights from Other Tissues. Anal Cell Pathol (Amst) 2021; 2021:9983900. [PMID: 34336556 PMCID: PMC8324376 DOI: 10.1155/2021/9983900] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 07/10/2021] [Indexed: 02/07/2023] Open
Abstract
Extracellular vesicles (EVs) are phospholipid bilayer-bound particles secreted by cells that have been found to be important in mediating cell-cell communication, signal transduction, and extracellular matrix remodeling. Their role in both physiological and pathological processes has been established in different tissues throughout the human body. The human cornea functions as a transparent and refractive barrier that protects the intraocular elements from the external environment. Injury, infection, or disease may cause the loss of corneal clarity by altering extracellular matrix organization within the stroma that may lead to detrimental effects on visual acuity. Over the years, numerous studies have identified many of the growth factors (e.g., transforming growth factor-β1, thrombospondin-1, and platelet-derived growth factor) important in corneal wound healing and scarring. However, the functional role of bound factors encapsulated in EVs in the context of corneal biology is less defined. In this review, we describe the discovery and characterization of EVs in the cornea. We focus on EV-matrix interactions, potential functions during corneal wound healing, and the bioactivity of mesenchymal stem cell-derived EVs. We also discuss the development of EVs as stable, drug-loaded therapeutics for ocular applications.
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Affiliation(s)
- Tina B. McKay
- Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA
| | - Vincent Yeung
- Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA
| | - Audrey E. K. Hutcheon
- Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA
| | - Xiaoqing Guo
- Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA
| | - James D. Zieske
- Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA
| | - Joseph B. Ciolino
- Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA
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Pethe P, Kale V. Placenta: A gold mine for translational research and regenerative medicine. Reprod Biol 2021; 21:100508. [PMID: 33930790 DOI: 10.1016/j.repbio.2021.100508] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 04/15/2021] [Accepted: 04/17/2021] [Indexed: 02/06/2023]
Abstract
Stem cell therapy has gained much impetus in regenerative medicine due to some of the encouraging results obtained in the laboratory as well as in translational/clinical studies. Although stem cells are of various types and their therapeutic potential has been documented in several studies, mesenchymal stromal/stem cells (MSCs) have an edge, as in addition to being multipotent, these cells are easy to obtain and expand, pose fewer ethical issues, and possess immense regenerative potential when used in a scientifically correct manner. Currently, MSCs are being sourced from various tissues such as bone marrow, cord, cord blood, adipose tissue, dental tissue, etc., and, quite often, the choice depends on the availability of the source. One such rich source of tissue suitable for obtaining good quality MSCs in large numbers is the placenta obtained in a full-term delivery leading to a healthy child's birth. Several studies have demonstrated the regenerative potential of human placenta-derived MSCs (hPMSC), and most show that these MSCs possess comparable, in some instances, even better, therapeutic potential as that shown by human bone marrow-derived (hBMSC) or human umbilical cord-derived (hUC-MSC) MSCs. The placenta can be easily sourced from the OB/GYN department of any hospital, and if its derivatives such as hPMSC or their EVs are produced under GMP conditions, it could serve as a gold mine for translational/clinical research. Here, we have reviewed recent studies revealing the therapeutic potential of hPMSC and their extracellular vesicles (EVs) published over the past three years.
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Affiliation(s)
- Prasad Pethe
- Symbiosis Centre for Stem Cell Research, Symbiosis International University, Pune, 412115, India
| | - Vaijayanti Kale
- Symbiosis Centre for Stem Cell Research, Symbiosis International University, Pune, 412115, India.
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Fu YX, Ji J, Shan F, Li J, Hu R. Human mesenchymal stem cell treatment of premature ovarian failure: new challenges and opportunities. Stem Cell Res Ther 2021; 12:161. [PMID: 33658073 PMCID: PMC7931610 DOI: 10.1186/s13287-021-02212-0] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 02/04/2021] [Indexed: 12/12/2022] Open
Abstract
Premature ovarian failure (POF) is one of the common disorders found in women leading to 1% female infertility. Clinical features of POF are hypoestrogenism or estrogen deficiency, increased gonadotropin level, and, most importantly, amenorrhea. With the development of regenerative medicine, human mesenchymal stem cell (hMSC) therapy brings new prospects for POF. This study aimed to describe the types of MSCs currently available for POF therapy, their biological characteristics, and their mechanism of action. It reviewed the latest findings on POF to provide the theoretical basis for further investigation and clinical therapy.
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Affiliation(s)
- Yun-Xing Fu
- Ningxia Medical University, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Jing Ji
- Ningxia Medical University, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Fang Shan
- Ningxia Medical University, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Jialing Li
- Ningxia Medical University, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Rong Hu
- Reproductive Medicine Center, General Hospital of Ningxia Medical University, Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan, 750004, Ningxia, China.
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Therapeutic Application of Exosomes in Inflammatory Diseases. Int J Mol Sci 2021; 22:ijms22031144. [PMID: 33498928 PMCID: PMC7865921 DOI: 10.3390/ijms22031144] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/20/2021] [Accepted: 01/22/2021] [Indexed: 02/07/2023] Open
Abstract
Immunomodulation is on the cusp of being an important therapy for treating many diseases, due to the significant role of the immune system in defending the human body. Although the immune system is an essential defense system, overactivity can result in diverse sicknesses such as inflammation and autoimmune disease. Exosomes are emerging as a state-of-the-art therapeutic strategy for treating an overactive immune system. Thus, in this review, we will thoroughly review therapeutic applications of exosomes in various inflammatory and autoimmune diseases. Finally, issues for an outlook to the future of exosomal therapy will be introduced.
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Deng SX, Dos Santos A, Gee S. Therapeutic Potential of Extracellular Vesicles for the Treatment of Corneal Injuries and Scars. Transl Vis Sci Technol 2020; 9:1. [PMID: 33200043 PMCID: PMC7645240 DOI: 10.1167/tvst.9.12.1] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Accepted: 09/09/2020] [Indexed: 12/13/2022] Open
Abstract
Infection, trauma, and chemical exposure of the ocular surface can severely damage the cornea, resulting in visually significant stromal scars. Current medical treatments are ineffective in mitigating corneal scarring, and corneal transplantation is the only therapy able to restore vision in these eyes. However, because of a severe shortage of corneal tissues, risks of blinding complications associated with corneal transplants, and a higher rate of graft failure in these eyes, an effective and deliverable alternative therapy for the prevention and treatment of corneal scarring remains a significant unmet medical need globally. In recent years, the therapeutic potential of extracellular vesicles (EVs) secreted by cells to mediate cell-cell communication has been a topic of increasing interest. EVs derived from mesenchymal stem cells, in particular human corneal stromal stem cells, have antifibrotic, anti-inflammatory, and regenerative effects in injured corneas. The exact mechanism of action of these functional EVs are largely unknown. Therapeutic development of EVs is at an early stage and warrants further preclinical studies.
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Affiliation(s)
- Sophie X. Deng
- Stein Eye Institute, University of California Los Angeles, Los Angeles, California, USA
| | - Aurelie Dos Santos
- Stein Eye Institute, University of California Los Angeles, Los Angeles, California, USA
| | - Serina Gee
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
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Liu HC, Xie Y, Deng CH, Liu GH. Stem cell-based therapies for fertility preservation in males: Current status and future prospects. World J Stem Cells 2020; 12:1097-1112. [PMID: 33178394 PMCID: PMC7596443 DOI: 10.4252/wjsc.v12.i10.1097] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/13/2020] [Accepted: 08/26/2020] [Indexed: 02/06/2023] Open
Abstract
With the decline in male fertility in recent years, strategies for male fertility preservation have received increasing attention. In this study, by reviewing current treatments and recent publications, we describe research progress in and the future directions of stem cell-based therapies for male fertility preservation, focusing on the use of spermatogonial stem cells (SSCs), SSC niches, SSC-based testicular organoids, other stem cell types such as mesenchymal stem cells, and stem cell-derived extracellular vesicles. In conclusion, a more comprehensive understanding of the germ cell microenvironment, stem cell-derived extracellular vesicles, and testicular organoids will play an important role in achieving male fertility preservation.
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Affiliation(s)
- Han-Chao Liu
- Department of Andrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
| | - Yun Xie
- Department of Andrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
| | - Chun-Hua Deng
- Department of Andrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
| | - Gui-Hua Liu
- Reproductive Medicine Research Center, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, Guangdong Province, China
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Hou H, Zhang L, Duan L, Liu Y, Han Z, Li Z, Cao X. Spatio-Temporal Metabolokinetics and Efficacy of Human Placenta-Derived Mesenchymal Stem/Stromal Cells on Mice with Refractory Crohn's-like Enterocutaneous Fistula. Stem Cell Rev Rep 2020; 16:1292-1304. [PMID: 33011925 DOI: 10.1007/s12015-020-10053-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/29/2020] [Indexed: 12/14/2022]
Abstract
Crohn's disease (CD) with externally fistulizing openings indicates the aggressive and relapsing manifestation and results in undesirable long-term outcomes of patients. MSC-based approach combined with multidisciplinary strategy has mandated a redefinition of the administration and management of numerous recurrent and refractory diseases whereas the spatio-temporal evaluation of the metabolokinetics and efficacy of MSCs on intractable CD with enterocutaneous fistula (EF) are largely inaccessible and dauntingly complex. Herein, we primitively established dual-fluorescence expressing placenta-derived MSCs (DF-MSCs) and explored their multidimensional attributes, including cytomorphology, immunophenotying, multilineage differentiation and long-term proliferation, together with the recognition of bifluorescence intensity (BLI). Then, with the aid of in vivo living imaging, clinicopathological or inflammatory cytokine examinations and in vitro analyses, we systematically and meticulously dissected the metabolokinetics and curative effect of MSCs on mice with refractory Crohn's-like EF (EF mice), together with revealing the underlying mechanism including reactive oxygen species (ROS) and neovascularization. Strikingly, the DF-MSCs exhibited stabilized BLI and biological properties. The spatio-temporal distribution and therapeutic process of MSCs in EF mice were intuitively delineated. Meanwhile, our data indicated the curative mechanisms of DF-MSCs by simultaneously downregulating ROS and accelerating neovascularization. Collectively, we systematically illuminated the spatio-temporal biofunction and mechanism of DF-MSCs on EF mice. Our findings have supplied new references for safety and effectiveness assessments as well as the establishment of guidelines for optimal administrations of MSC-based cytotherapy in preclinical studies, which collectively indicates the prospect of P-MSC administration in clinical trials during a wide spectrum of disease remodeling including the fistulizing CD. Graphical abstract.
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Affiliation(s)
- Huixing Hou
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, 300052, China
| | - Leisheng Zhang
- The Postdoctoral Research Station, School of Medicine, Nankai University, Tianjin, 300071, China. .,State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Disease, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People's Republic of China. .,Precision Medicine Division, Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd, Tianjin, 301700, China.
| | - Liyun Duan
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, 300052, China
| | - Yuanyuan Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, 300052, China
| | - Zhongchao Han
- State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Disease, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People's Republic of China.,Precision Medicine Division, Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd, Tianjin, 301700, China
| | - Zongjin Li
- The Postdoctoral Research Station, School of Medicine, Nankai University, Tianjin, 300071, China.
| | - Xiaocang Cao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, 300052, China.
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Zhang C, Shang Y, Chen X, Midgley AC, Wang Z, Zhu D, Wu J, Chen P, Wu L, Wang X, Zhang K, Wang H, Kong D, Yang Z, Li Z, Chen X. Supramolecular Nanofibers Containing Arginine-Glycine-Aspartate (RGD) Peptides Boost Therapeutic Efficacy of Extracellular Vesicles in Kidney Repair. ACS NANO 2020; 14:12133-12147. [PMID: 32790341 DOI: 10.1021/acsnano.0c05681] [Citation(s) in RCA: 136] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2023]
Abstract
Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSC-EVs) have been recognized as a promising cell-free therapy for acute kidney injury (AKI), which avoids safety concerns associated with direct cell engraftment. However, low stability and retention of MSC-EVs have limited their therapeutic efficacy. RGD (Arg-Gly-Asp) peptide binds strongly to integrins, which have been identified on the surface of MSC-EV membranes; yet RGD has not been applied to EV scaffolds to enhance and prolong bioavailability. Here, we developed RGD hydrogels, which we hypothesized could augment MSC-EV efficacy in the treatment of AKI models. In vivo tracking of the labeled EVs revealed that RGD hydrogels increased retention and stability of EVs. Integrin gene knockdown experiments confirmed that EV-hydrogel interaction was mediated by RGD-integrin binding. Upon intrarenal injection into mouse AKI models, EV-RGD hydrogels provided superior rescuing effects to renal function, attenuated histopathological damage, decreased tubular injury, and promoted cell proliferation in early phases of AKI. RGD hydrogels also augmented antifibrotic effects of MSC-EVs in chronic stages. Further analysis revealed that the presence of microRNA let-7a-5p in MSC-EVs served as the mechanism contributing to the reduced cell apoptosis and elevated cell autophagy in AKI. In conclusion, RGD hydrogels facilitated MSC-derived let-7a-5p-containing EVs, improving reparative potential against AKI. This study developed an RGD scaffold to increase the EV integrin-mediated loading and in turn improved therapeutic efficacy in renal repair; therefore this strategy shed light on MSC-EV application as a cell-free treatment for potentiated efficiency.
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Affiliation(s)
- Chuyue Zhang
- School of Medicine, Nankai University, Tianjin 300071, China
- Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Chinese PLA Institute of Nephrology, Beijing Key Laboratory of Kidney Diseases, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Yuna Shang
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Key Laboratory of Bioactive Materials, Ministry of Education, Collaborative Innovation Center of Chemical Science and Engineering, and National Institute of Functional Materials, Nankai University, Tianjin 300071, China
| | - Xiaoniao Chen
- Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Chinese PLA Institute of Nephrology, Beijing Key Laboratory of Kidney Diseases, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
- Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Adam C Midgley
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Key Laboratory of Bioactive Materials, Ministry of Education, Collaborative Innovation Center of Chemical Science and Engineering, and National Institute of Functional Materials, Nankai University, Tianjin 300071, China
| | - Zhongyan Wang
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Key Laboratory of Bioactive Materials, Ministry of Education, Collaborative Innovation Center of Chemical Science and Engineering, and National Institute of Functional Materials, Nankai University, Tianjin 300071, China
| | - Dashuai Zhu
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Jie Wu
- Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Chinese PLA Institute of Nephrology, Beijing Key Laboratory of Kidney Diseases, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Pu Chen
- Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Chinese PLA Institute of Nephrology, Beijing Key Laboratory of Kidney Diseases, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Lingling Wu
- Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Chinese PLA Institute of Nephrology, Beijing Key Laboratory of Kidney Diseases, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Xu Wang
- Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Chinese PLA Institute of Nephrology, Beijing Key Laboratory of Kidney Diseases, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Kaiyue Zhang
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Hongfeng Wang
- Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Chinese PLA Institute of Nephrology, Beijing Key Laboratory of Kidney Diseases, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Deling Kong
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Key Laboratory of Bioactive Materials, Ministry of Education, Collaborative Innovation Center of Chemical Science and Engineering, and National Institute of Functional Materials, Nankai University, Tianjin 300071, China
| | - Zhimou Yang
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Key Laboratory of Bioactive Materials, Ministry of Education, Collaborative Innovation Center of Chemical Science and Engineering, and National Institute of Functional Materials, Nankai University, Tianjin 300071, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Zongjin Li
- School of Medicine, Nankai University, Tianjin 300071, China
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, Henan 453003, China
| | - Xiangmei Chen
- School of Medicine, Nankai University, Tianjin 300071, China
- Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Chinese PLA Institute of Nephrology, Beijing Key Laboratory of Kidney Diseases, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
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Zhang K, Chen S, Sun H, Wang L, Li H, Zhao J, Zhang C, Li N, Guo Z, Han Z, Han ZC, Zheng G, Chen X, Li Z. In vivo two-photon microscopy reveals the contribution of Sox9 + cell to kidney regeneration in a mouse model with extracellular vesicle treatment. J Biol Chem 2020; 295:12203-12213. [PMID: 32641493 PMCID: PMC7443503 DOI: 10.1074/jbc.ra120.012732] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 07/02/2020] [Indexed: 01/05/2023] Open
Abstract
Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have been shown to stimulate regeneration in the treatment of kidney injury. Renal regeneration is also thought to be stimulated by the activation of Sox9+ cells. However, whether and how the activation mechanisms underlying EV treatment and Sox9+ cell-dependent regeneration intersect is unclear. We reasoned that a high-resolution imaging platform in living animals could help to untangle this system. To test this idea, we first applied EVs derived from human placenta-derived MSCs (hP-MSCs) to a Sox9-CreERT2; R26mTmG transgenic mouse model of acute kidney injury (AKI). Then, we developed an abdominal imaging window in the mouse and tracked the Sox9+ cells in the inducible Sox9-Cre transgenic mice via in vivo lineage tracing with two-photon intravital microscopy. Our results demonstrated that EVs can travel to the injured kidneys post intravenous injection as visualized by Gaussia luciferase imaging and markedly increase the activation of Sox9+ cells. Moreover, the two-photon living imaging of lineage-labeled Sox9+ cells showed that the EVs promoted the expansion of Sox9+ cells in kidneys post AKI. Histological staining results confirmed that the descendants of Sox9+ cells contributed to nephric tubule regeneration which significantly ameliorated the renal function after AKI. In summary, intravital lineage tracing with two-photon microscopy through an embedded abdominal imaging window provides a practical strategy to investigate the beneficial functions and to clarify the mechanisms of regenerative therapies in AKI.
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Affiliation(s)
- Kaiyue Zhang
- Nankai University School of Medicine, Tianjin, China; The Key Laboratory of Bioactive Materials, Ministry of Education, the College of Life Sciences, Nankai University, Tianjin, China
| | - Shang Chen
- Nankai University School of Medicine, Tianjin, China; The Key Laboratory of Bioactive Materials, Ministry of Education, the College of Life Sciences, Nankai University, Tianjin, China
| | - Huimin Sun
- Nankai University School of Medicine, Tianjin, China
| | - Lina Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Huifang Li
- Nankai University School of Medicine, Tianjin, China
| | - Jinglei Zhao
- Nankai University School of Medicine, Tianjin, China
| | - Chuyue Zhang
- State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, China
| | - Nana Li
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Zhikun Guo
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Zhibo Han
- Jiangxi Engineering Research Center for Stem Cell, Shangrao, Jiangxi, China; Tianjin Key Laboratory of Engineering Technologies for Cell Pharmaceutical, National Engineering Research Center of Cell Products, AmCellGene Co., Ltd., Tianjin, China
| | - Zhong-Chao Han
- Jiangxi Engineering Research Center for Stem Cell, Shangrao, Jiangxi, China; Tianjin Key Laboratory of Engineering Technologies for Cell Pharmaceutical, National Engineering Research Center of Cell Products, AmCellGene Co., Ltd., Tianjin, China; Beijing Engineering Laboratory of Perinatal Stem Cells, Beijing Institute of Health and Stem Cells, Health & Biotech Co., Beijing, China
| | - Guoguang Zheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Xiangmei Chen
- State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, China
| | - Zongjin Li
- Nankai University School of Medicine, Tianjin, China; The Key Laboratory of Bioactive Materials, Ministry of Education, the College of Life Sciences, Nankai University, Tianjin, China; State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, China; Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China.
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Duan L, Huang H, Zhao X, Zhou M, Chen S, Wang C, Han Z, Han ZC, Guo Z, Li Z, Cao X. Extracellular vesicles derived from human placental mesenchymal stem cells alleviate experimental colitis in mice by inhibiting inflammation and oxidative stress. Int J Mol Med 2020; 46:1551-1561. [PMID: 32945344 PMCID: PMC7447323 DOI: 10.3892/ijmm.2020.4679] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Accepted: 07/02/2020] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are pluripotent cells that can be applied to the treatment of immune disorders, including inflammatory bowel disease (IBD). The therapeutic effects of MSCs have been mostly attributed to the secretion of soluble factors with paracrine actions, such as extracellular vesicles (EVs), which may play a relevant role in the repair of damaged tissues. In the present study, a mouse model of colitis was induced with the use of trinitrobenzene sulfonic acid (TNBS). EVs derived from human placental mesenchymal stem cells (hP‑MSCs) were used for the treatment of colitis by in situ injection. Clinical scores were applied to verify the therapeutic effects of EVs on mice with colitis. Inflammation in the colon was evaluated by measuring the levels of various inflammatory cytokines. The content of reactive oxygen species (ROS) was detected by the use of molecular imaging methods for real‑time tracking and the therapeutic effects of EVs on mucosal healing in mice with colitis were evaluated. The results revealed that the injection of EVs regulated the balance of pro‑inflammatory and anti‑inflammatory cytokines in colon tissue. Treatment with EVs also suppressed oxidative stress by decreasing the activity of myeloperoxidase (MPO) and ROS. Histological analysis further confirmed that the EVs significantly promoted mucosal healing, as reflected by the promotion of the proliferation of colonic epithelial cells and the maintenance of tight junctions. Taken together, the findings of the present study demonstrated that EVs derived from hP‑MSCs alleviated TNBS‑induced colitis by inhibiting inflammation and oxidative stress. These findings may provide a novel theoretical basis for the EV‑based treatment of IBD.
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Affiliation(s)
- Liyun Duan
- Department of Hepato-Gastroenterology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300071, P.R. China
| | - Haoyan Huang
- School of Medicine, Nankai University, Tianjin 300071, P.R. China
| | - Xiaotong Zhao
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Manqian Zhou
- Department of Radiation Oncology, Tianjin Union Medical Center, Tianjin 300121, P.R. China
| | - Shang Chen
- School of Medicine, Nankai University, Tianjin 300071, P.R. China
| | - Chen Wang
- School of Medicine, Nankai University, Tianjin 300071, P.R. China
| | - Zhibo Han
- Beijing Engineering Laboratory of Perinatal Stem Cells, Beijing Institute of Health and Stem Cells, Health and Biotech Co., Beijing 100176, P.R. China
| | - Zhong-Chao Han
- Beijing Engineering Laboratory of Perinatal Stem Cells, Beijing Institute of Health and Stem Cells, Health and Biotech Co., Beijing 100176, P.R. China
| | - Zhikun Guo
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Zongjin Li
- School of Medicine, Nankai University, Tianjin 300071, P.R. China
| | - Xiaocang Cao
- Department of Hepato-Gastroenterology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300071, P.R. China
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48
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Zhou T, Li HY, Liao C, Lin W, Lin S. Clinical Efficacy and Safety of Mesenchymal Stem Cells for Systemic Lupus Erythematosus. Stem Cells Int 2020; 2020:6518508. [PMID: 32322279 PMCID: PMC7157802 DOI: 10.1155/2020/6518508] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 02/02/2020] [Accepted: 02/29/2020] [Indexed: 02/05/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is a polymorphic, multisystemic autoimmune disease that causes multiorgan damage in which cellular communication occurs through the involvement of autoantibodies directed against autoantigen production. Mesenchymal stem cells (MSCs), which have strong protective and immunomodulatory abilities, are obtained not only from bone marrow but also from medical waste such as adipose tissue and umbilical cord tissue and have been recognized as a promising tool for the treatment of various autoimmune diseases and inflammatory disorders. This meta-analysis is aimed at assessing whether MSCs can become a new treatment for SLE with good efficacy and safety. Based on predetermined criteria, a bibliographical search was performed from January 1, 2000, to July 31, 2019, by searching the following databases: ISI Web of Science, Embase, PubMed, the Cochrane Library, and the Chinese Biomedical Literature Database (CBM). Eligible studies and data were identified. Statistical analysis was conducted to assess the efficacy (proteinuria, systemic lupus erythematosus disease activity index (SLEDAI), Scr, BUN, albumin, C3, and C4) and safety (rate of adverse events) of MSCs for SLE using Cochrane Review Manager Version 5.3. Ten studies fulfilled the inclusion criteria and were eligible for this meta-analysis, which comprised 8 prospective or retrospective case series and four randomized controlled trails (RCTs) studies. In the RCT, the results indicated that the MSC group had lower proteinuria than the control group at 3 months and 6 months and the MSC group displayed a lower SLEDAI than the control group at 2 months and 6 months. Furthermore, the MSC group showed a lower rate of adverse events than the control group (OR = 0.26, 95% CI: 0.07, 0.89, P = 0.03). In the case series trials, the results indicated that the MSC group had lower proteinuria at 1 month, 2 months, 3 months, 4 months, 6 months, and 12 months. In conclusion, MSCs might be a promising therapeutic agent for patients with SLE.
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Affiliation(s)
- Tianbiao Zhou
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, 515041 Shantou, China
| | - Hong-Yan Li
- Department of Nephrology, Huadu District People's Hospital of Guangzhou, Southern Medical University, 510800 Guangzhou, China
| | - Chunling Liao
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, 515041 Shantou, China
| | - Wenshan Lin
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, 515041 Shantou, China
| | - Shujun Lin
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, 515041 Shantou, China
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49
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Su VYF, Chiou SH, Lin CS, Mo MH, Yang KY. Induced Pluripotent Stem Cells Attenuate Endothelial Leakage in Acute Lung Injury via Tissue Inhibitor of Metalloproteinases-1 to Reduce Focal Adhesion Kinase Activity. Stem Cells 2019; 37:1516-1527. [PMID: 31588644 DOI: 10.1002/stem.3093] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 08/05/2019] [Accepted: 08/15/2019] [Indexed: 12/18/2022]
Abstract
Induced pluripotent stem cells (iPSCs) can reduce the severity of endotoxin-induced acute lung injury (ALI). However, the interaction between iPSCs and vascular endothelium remains unclear. In this study, we investigated the effects of iPSCs in moderating pulmonary endothelial leakage in endotoxin-induced ALI. Murine iPSCs were delivered intravenously to male C57BL/6 mice (8-12 weeks old) 4 hours after intratracheal lipopolysaccharide (LPS) delivery. Histology, blood and bronchoalveolar lavage fluid (BALF) cytokine and junctional protein assays, and regulatory signaling pathway assays were performed 24 hours later. Human umbilical vein endothelial cells (HUVECs) were used as a model of junctional protein-expressing cells and stimulated with LPS. Our results showed that iPSC treatment alleviated histological signs of ALI, protein leakage, and proinflammatory cytokines. iPSC therapy restored vascular endothelial cadherin (VE-cadherin) expression in ALI mouse lungs. In HUVECs, human iPSCs (hiPSCs) restored disrupted VE-cadherin expression and reduced the activity of Snail and focal adhesion kinase (FAK) phosphorylation in Tyr397 in response to LPS. iPSC-conditioned medium contained extra antiangiogenic factor of tissue inhibitor of metalloproteinases-1 (TIMP-1) compared with control medium. TIMP-1 inhibition diminished the beneficial effects of iPSC-conditioned medium in ALI mice. Our study suggested that iPSCs attenuate endothelial cell leakage in endotoxin-induced ALI via a mechanism involving TIMP-1 and the FAK/Snail pathway. Stem Cells 2019;37:1516-1527.
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Affiliation(s)
- Vincent Yi-Fong Su
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Internal Medicine, Taipei City Hospital, Taipei City Government, Taipei, Taiwan.,Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Shih-Hwa Chiou
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan.,Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
| | - Chi-Shiuan Lin
- Center for Traditional Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Chinese Medicine for Post-Baccalaureate of I-Shou University, Kaohsiung, Taiwan
| | - Min-Hsiang Mo
- Department of Biomedical, MetaTech (AP) Inc, New Taipei City, Taiwan.,Institute of Molecular Biotechnology, Dayeh University, Taipei, Taiwan
| | - Kuang-Yao Yang
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
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