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Nasrollahzadeh Saravi M, Mohseni M, Menbari Oskouie I, Razavi J, Delgado Cidranes E, Majidi Zolbin M. Exosome Therapy in Stress Urinary Incontinence: A Comprehensive Literature Review. Biomedicines 2025; 13:1229. [PMID: 40427055 PMCID: PMC12108756 DOI: 10.3390/biomedicines13051229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 02/18/2025] [Accepted: 02/26/2025] [Indexed: 05/29/2025] Open
Abstract
Stress urinary incontinence (SUI) is characterized by the involuntary leakage of urine when bladder pressure exceeds urethral closing pressure during routine activities such as physical exertion, coughing, exercise, or sneezing. SUI is the most prevalent form of urinary incontinence, with a reported prevalence ranging from 10% to 70%, and its incidence increases with age. As the global population continues to age, the prevalence and clinical significance of SUI are expected to rise accordingly. The pathophysiology of SUI is primarily driven by two mechanisms: urethral hypermobility, resulting from compromised supporting structures, and intrinsic urethral sphincter deficiency, characterized by the deterioration of urethral mucosa and muscle tone. Current treatment options for SUI include conservative management strategies, which heavily rely on patient adherence and are associated with high recurrence rates, and surgical interventions, such as sling procedures, which offer effective solutions but are costly and carry the risk of adverse side effects. These limitations highlight the urgent need for more effective and comprehensive treatment modalities. Exosomes, nano-sized (30-150 nm) extracellular vesicles secreted by nearly all cell types, have emerged as a novel therapeutic option due to their regenerative, anti-fibrotic, pro-angiogenic, anti-apoptotic, anti-inflammatory, and anti-hypoxic properties. These biological functions position exosomes as a promising alternative to conventional therapies for SUI. Exosome therapy has the potential to enhance tissue regeneration, restore urethral function, and repair nerve and muscle damage, thereby reducing symptom burden and improving patients' quality of life. Additionally, exosome-based treatments could offer a less invasive alternative to surgery, potentially decreasing the need for repeated interventions and minimizing complications associated with current procedures. In this literature review, we critically assess the current state of research on the potential use of exosomes in treating SUI, highlighting their therapeutic mechanisms and potential clinical benefits.
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Affiliation(s)
| | - Mahdi Mohseni
- Children’s Medical Center, Tehran University of Medical Sciences, Tehran 1419733151, Iran; (M.N.S.); (M.M.)
| | - Iman Menbari Oskouie
- Urology Research Center, Tehran University of Medical Sciences, Tehran 1419733151, Iran;
| | - Jafar Razavi
- Vali-E-Asr Reproductive Health Research Center, Family Health Research Institute, Tehran University of Medical Sciences, Tehran 1419733141, Iran;
| | - Ernesto Delgado Cidranes
- Pain Management Department, University Hospital Vithas Madrid La Milagrosa, 28010 Madrid, Spain;
| | - Masoumeh Majidi Zolbin
- Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell & Tissue Research Institute, Children’s Medical Center, Tehran University of Medical Sciences, Tehran 1419733151, Iran
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Goldschmidt-Clermont PJ, Khan A, Jimsheleishvili G, Graham P, Brooks A, Silvera R, Goldschmidt AJ, Pearse DD, Dietrich WD, Levi AD, Guest JD. Treating amyotrophic lateral sclerosis with allogeneic Schwann cell-derived exosomal vesicles: a case report. Neural Regen Res 2025; 20:1207-1216. [PMID: 38922880 PMCID: PMC11438342 DOI: 10.4103/nrr.nrr-d-23-01815] [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: 11/05/2023] [Revised: 01/05/2024] [Accepted: 02/24/2024] [Indexed: 06/28/2024] Open
Abstract
Schwann cells are essential for the maintenance and function of motor neurons, axonal networks, and the neuromuscular junction. In amyotrophic lateral sclerosis, where motor neuron function is progressively lost, Schwann cell function may also be impaired. Recently, important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been reported. This case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles, marking, to our knowledge, the first instance of such treatment. An 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral sclerosis. After initial diagnosis, the patient underwent a combination of generic riluzole, sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis, and taurursodiol. The patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron function. We confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired (senescent) and that exposure of the patient's Schwann cells to allogeneic Schwann cell-derived exosomal vesicles, cultured expanded from a cadaver donor improved their growth capacity in vitro. After a period of observation lasting 10 weeks, during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored, the patient received weekly consecutive infusions of 1.54 × 10 12 (×2), and then consecutive infusions of 7.5 × 10 12 (×6) allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco's phosphate-buffered saline. None of the infusions were associated with adverse events such as infusion reactions (allergic or otherwise) or changes in vital signs. Clinical lab serum neurofilament and cytokine levels measured prior to each infusion varied somewhat without a clear trend. A more sensitive in-house assay suggested possible inflammasome activation during the disease course. A trend for clinical stabilization was observed during the infusion period. Our study provides a novel approach to address impaired Schwann cells and possibly motor neuron function in patients with amyotrophic lateral sclerosis using allogeneic Schwann cell-derived exosomal vesicles. Initial findings suggest that this approach is safe.
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Affiliation(s)
| | - Aisha Khan
- Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - George Jimsheleishvili
- The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Patricia Graham
- The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Adriana Brooks
- The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Risset Silvera
- The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA
| | | | - Damien D. Pearse
- The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA
- Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - W. Dalton Dietrich
- The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA
- Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Allan D. Levi
- The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA
- Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - James D. Guest
- The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA
- Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
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Zhang H, Wang S, Zhang Q, Du X, Xu D, Wen J, Jin M, Liu J, Jin X, Wang M, Luo L, Li L. Indole-3-propionic acid promotes Schwann cell proliferation following peripheral nerve injury by activating the PI3K/AKT pathway. Neurotherapeutics 2025:e00578. [PMID: 40148157 DOI: 10.1016/j.neurot.2025.e00578] [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: 10/27/2024] [Revised: 02/10/2025] [Accepted: 03/12/2025] [Indexed: 03/29/2025] Open
Abstract
The proliferation of Schwann cells (SCs) is integral for axonal regeneration following peripheral nerve injury, and enhancing their proliferation can accelerate axonal regeneration. Indole-3-propionic acid (IPA), a metabolite of tryptophan synthesized by the intestinal microbiota, has potential in accelerating axonal regeneration in peripheral nerves. Nonetheless, the capacity of IPA to promote SC proliferation remains undetermined. Consequently, this study aimed to investigate the effects of IPA on SC proliferation and the underlying mechanisms. Therefore, we cultured RSC96 cells in vitro and used a Cell Counting Kit-8 (CCK8), an EdU Cell Proliferation Detection Kit (EdU), and a Cell Cycle and Apoptosis Assay Kit for the analyses. Additionally, we established a rat sciatic nerve crush injury model in vivo and performed immunofluorescence staining. These findings indicated that IPA enhanced SC proliferation. We further investigated the potential mechanism by which IPA promotes SC proliferation by conducting Western blotting and observed that IPA increased the levels of phosphorylated phosphatidylinositol 3-kinase/phosphatidylinositol 3-kinase (p-PI3K/PI3K) and phosphorylated protein kinase B/protein kinase B (p-AKT/AKT) in RSC96 cells, which suggested that IPA may promote the proliferation of RSC96 cells by activating the PI3K/AKT pathway. We cultured RSC96 cells in vitro, established a sciatic nerve crush model in vivo, and administered a PI3K inhibitor (LY294002) in combination with IPA treatment to validate this hypothesis. Our results revealed a reduction in the proliferation rate of RSC96 cells or SCs following the inhibition of p-PI3K/PI3K and p-AKT/AKT expression, as evidenced by the results of the EdU, CCK8 and immunofluorescence staining assays. These findings indicated that IPA may indeed promote SC proliferation through the activation of the PI3K/AKT pathway.
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Affiliation(s)
- Huimei Zhang
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Sijia Wang
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Qi Zhang
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Xinyu Du
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Danyang Xu
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Jinkun Wen
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Mingrui Jin
- School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Jing Liu
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Xiaobao Jin
- Guangdong Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Mengxia Wang
- Intensive Care Unit, Guangdong Second Provincial General Hospital, Guangzhou 510317, China
| | - Li Luo
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Medical Association, Guangzhou 510180, China.
| | - Lixia Li
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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Borger A, Haertinger M, Millesi F, Semmler L, Supper P, Stadlmayr S, Rad A, Radtke C. Conditioning period impacts the morphology and proliferative effect of extracellular vesicles derived from rat adipose tissue derived stromal cell. J Nanobiotechnology 2025; 23:164. [PMID: 40033315 PMCID: PMC11877948 DOI: 10.1186/s12951-025-03273-6] [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: 11/21/2024] [Accepted: 02/24/2025] [Indexed: 03/05/2025] Open
Abstract
A serum-free conditioning period is a crucial step during small extracellular vesicle (sEV) preparation ranging from 12 to 72h. There is a paucity of knowledge about downstream effects of serum-free conditioning on sEVs and the optimal duration of the conditioning period. The aim of this study was to investigate the influence of the serum-free conditioning period on the sEVs derived from primary adipose stromal cells (AdSCs) and their regenerative potential. Primary AdSCs were conditioned in serum-free medium for 72h. Conditioned medium was collected and refreshed every 24h obtaining three fractions, namely sEVs released after 24h (early), 24h to 48h (intermediate) and 48h to 72h (late). After sEV enrichment with ultracentrifugation, the sEV fractions were analyzed by their size, phenotypic expression, and morphology. Proliferation assays of primary Schwann cells after treatment with sEVs were performed. Particles meeting criteria to be classified as sEVs were detected in all fractions. However, sEVs differed by their size and phenotypic expression. A long conditioning period led to a heterogenous population of larger sEVs and increased protein per particle ratio. Moreover, the expression of tetraspanines was affected. Lastly, the proliferative effect of sEVs on Schwann cells decreased with increasing conditioning period. In conclusion, particles meeting the criteria of EVs are released by primary AdSCs over 72h under serum free conditioning. Nonetheless, they significantly differ in their proliferative effect on Schwann cells cultures.
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Affiliation(s)
- Anton Borger
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Maximilian Haertinger
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Flavia Millesi
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Lorenz Semmler
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Paul Supper
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Sarah Stadlmayr
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Anda Rad
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Christine Radtke
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
- Austrian Cluster for Tissue Regeneration, Vienna, Austria.
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Jung H, Jung Y, Seo J, Bae Y, Kim HS, Jeong W. Roles of extracellular vesicles from mesenchymal stem cells in regeneration. Mol Cells 2024; 47:100151. [PMID: 39547584 DOI: 10.1016/j.mocell.2024.100151] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/09/2024] [Accepted: 11/10/2024] [Indexed: 11/17/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are highly valued in regenerative medicine due to their ability to self-renew and differentiate into various cell types. Their therapeutic benefits are primarily due to their paracrine effects, in particular through extracellular vesicles (EVs), which are related to intercellular communication. Recent advances in EV production and extraction technologies highlight the potential of MSC-derived EVs (MSC-EVs) in tissue engineering and regenerative medicine. MSC-EVs offer several advantages over traditional cell therapies, including reduced toxicity and immunogenicity compared with whole MSCs. EVs carrying functional molecules such as growth factors, cytokines, and miRNAs play beneficial roles in tissue repair, fibrosis treatment, and scar prevention by promoting angiogenesis, skin cell migration, proliferation, extracellular matrix remodeling, and reducing inflammation. Despite the potential of MSC-EVs, there are several limitations to their use, including variability in quality, the need for standardized methods, low yield, and concerns about the composition of EVs and the potential risks. Overall, MSC-EVs are a promising alternative to cell-based therapies, and ongoing studies aim to understand their actions and optimize their use for better clinical outcomes in wound healing and skin regeneration.
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Affiliation(s)
- Hyeseong Jung
- Department of Biomedical Science, Catholic Kwandong University, Gangneung 25601, Republic of Korea
| | - Yuyeon Jung
- Department of Dental Hygiene, Catholic Kwandong University, Gangneung 25601, Republic of Korea
| | - Junsik Seo
- Department of Biomedical Science, Catholic Kwandong University, Gangneung 25601, Republic of Korea
| | - Yeongju Bae
- Department of Biomedical Science, Catholic Kwandong University, Gangneung 25601, Republic of Korea; Research Center for Marine Bio-Food and Medicine, Catholic Kwandong University, Gangneung 25601, Republic of Korea
| | - Han-Soo Kim
- Department of Biomedical Science, Catholic Kwandong University, Gangneung 25601, Republic of Korea
| | - Wooyoung Jeong
- Department of Biomedical Science, Catholic Kwandong University, Gangneung 25601, Republic of Korea; Research Center for Marine Bio-Food and Medicine, Catholic Kwandong University, Gangneung 25601, Republic of Korea.
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Zhu J, Nie G, Dai X, Wang D, Li S, Zhang C. Activating PPARβ/δ-Mediated Fatty Acid β-Oxidation Mitigates Mitochondrial Dysfunction Co-induced by Environmentally Relevant Levels of Molybdenum and Cadmium in Duck Kidneys. Biol Trace Elem Res 2024:10.1007/s12011-024-04450-8. [PMID: 39546187 DOI: 10.1007/s12011-024-04450-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 11/09/2024] [Indexed: 11/17/2024]
Abstract
Cadmium (Cd) and high molybdenum (Mo) pose deleterious effects on health. Prior studies have indicated that exposure to Mo and Cd leads to damage in duck kidneys, but limited studies have explored this damage from the perspective of fatty acid metabolism. In this study, 40 healthy 8-day-old ducks were randomly assigned to four groups and fed a basic diet containing Cd (4 mg/kg Cd) or Mo (100 mg/kg Mo) or both. Kidney tissues were harvested on the 16th week. Results demonstrated that Cd and/or Mo inhibited mitochondrial fatty acid β-oxidation and disrupted mitochondrial dynamics, along with significant suppression of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) protein in duck kidneys. In vitro study, duck renal tubular epithelial cells were exposed for 12 h to either Mo (480 μM Mo), Cd (2.5 μM Cd), and GW0742 (0.3 μM, a potent agonist of PPARβ/δ) alone or in combination. The results demonstrated that Cd and/or Mo led to marked fatty acid oxidation deficiency and mitochondrial dysfunction and that PPARβ/δ protein was involved in the process. Altogether, this study found that activating PPARβ/δ-mediated fatty acid β-oxidation mitigates mitochondrial dysfunction co-induced by Mo and Cd in duck kidneys.
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Affiliation(s)
- Jiamei Zhu
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, China
| | - Gaohui Nie
- Jiangxi Hongzhou Vocational College, Fengcheng, Jiangxi, China
| | - Xueyan Dai
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, China
| | - Dianyun Wang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, China
| | - ShanXin Li
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, China
| | - Caiying Zhang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, China.
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Pedersen C, Chen VT, Herbst P, Zhang R, Elfert A, Krishan A, Azar DT, Chang JH, Hu WY, Kremsmayer TP, Jalilian E, Djalilian AR, Guaiquil VH, Rosenblatt MI. Target specification and therapeutic potential of extracellular vesicles for regulating corneal angiogenesis, lymphangiogenesis, and nerve repair. Ocul Surf 2024; 34:459-476. [PMID: 39426677 PMCID: PMC11921040 DOI: 10.1016/j.jtos.2024.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 09/16/2024] [Accepted: 10/15/2024] [Indexed: 10/21/2024]
Abstract
Extracellular vesicles, including exosomes, are small extracellular vesicles that range in size from 30 nm to 10 μm in diameter and have specific membrane markers. They are naturally secreted and are present in various bodily fluids, including blood, urine, and saliva, and through the variety of their internal cargo, they contribute to both normal physiological and pathological processes. These processes include immune modulation, neuronal synapse formation, cell differentiation, cancer metastasis, angiogenesis, lymphangiogenesis, progression of infectious disease, and neurodegenerative disorders like Alzheimer's and Parkinson's disease. In recent years, interest has grown in the use of exosomes as a potential drug delivery system for various diseases and injuries. Importantly, exosomes originating from a patient's own cells exhibit minimal immunogenicity and possess remarkable stability along with inherent and adjustable targeting capabilities. This review explores the roles of exosomes in angiogenesis, lymphangiogenesis, and nerve repair with a specific emphasis on these processes within the cornea. Furthermore, it examines exosomes derived from specific cell types, discusses the advantages of exosome-based therapies in modulating these processes, and presents some of the most established methods for exosome isolation. Exosome-based treatments are emerging as potential minimally invasive and non-immunogenic therapies that modulate corneal angiogenesis and lymphangiogenesis, as well as enhance and accelerate endogenous corneal nerve repair.
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Affiliation(s)
- Cameron Pedersen
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Victoria T Chen
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Paula Herbst
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Runze Zhang
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Amr Elfert
- University of Illinois Cancer Center, Chicago, IL, USA
| | - Abhi Krishan
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Dimitri T Azar
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Jin-Hong Chang
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA; Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA.
| | - Wen-Yang Hu
- Department of Urology, University of Illinois at Chicago, Chicago, IL, USA
| | - Tobias P Kremsmayer
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Elmira Jalilian
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA; Richard and Loan Hill Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, 60607, USA
| | - Ali R Djalilian
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Victor H Guaiquil
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Mark I Rosenblatt
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
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8
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Rad A, Weigl L, Steinecker-Frohnwieser B, Stadlmayr S, Millesi F, Haertinger M, Borger A, Supper P, Semmler L, Wolf S, Naghilou A, Weiss T, Kress HG, Radtke C. Nuclear Magnetic Resonance Treatment Induces ßNGF Release from Schwann Cells and Enhances the Neurite Growth of Dorsal Root Ganglion Neurons In Vitro. Cells 2024; 13:1544. [PMID: 39329728 PMCID: PMC11430304 DOI: 10.3390/cells13181544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 09/05/2024] [Accepted: 09/08/2024] [Indexed: 09/28/2024] Open
Abstract
Peripheral nerve regeneration depends on close interaction between neurons and Schwann cells (SCs). After nerve injury, SCs produce growth factors and cytokines that are crucial for axon re-growth. Previous studies revealed the supernatant of SCs exposed to nuclear magnetic resonance therapy (NMRT) treatment to increase survival and neurite formation of rat dorsal root ganglion (DRG) neurons in vitro. The aim of this study was to identify factors involved in transferring the observed NMRT-induced effects to SCs and consequently to DRG neurons. Conditioned media of NMRT-treated (CM NMRT) and untreated SCs (CM CTRL) were tested by beta-nerve growth factor (ßNGF) ELISA and multiplex cytokine panels to profile secreted factors. The expression of nociceptive transient receptor potential vanilloid 1 (TRPV1) channels was assessed and the intracellular calcium response in DRG neurons to high-potassium solution, capsaicin or adenosine triphosphate was measured mimicking noxious stimuli. NMRT induced the secretion of ßNGF and pro-regenerative-signaling factors. Blocking antibody experiments confirmed ßNGF as the main factor responsible for neurotrophic/neuritogenic effects of CM NMRT. The TRPV1 expression or sensitivity to specific stimuli was not altered, whereas the viability of cultured DRG neurons was increased. Positive effects of CM NMRT supernatant on DRG neurons are primarily mediated by increased ßNGF levels.
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Affiliation(s)
- Anda Rad
- Research Laboratory of the Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Waehringerstrasse 18-20, 1090 Vienna, Austria; (A.R.); (S.S.); (F.M.); (M.H.); (A.B.); (P.S.); (L.S.); (S.W.); (A.N.); (C.R.)
| | - Lukas Weigl
- Clinical Department of Special Anesthesia and Pain Therapy, Department of Anaesthesia, Intensive Care Medicine and Pain Medicine, Medical University of Vienna, Waehringerstrasse 18-20, 1090 Vienna, Austria;
| | | | - Sarah Stadlmayr
- Research Laboratory of the Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Waehringerstrasse 18-20, 1090 Vienna, Austria; (A.R.); (S.S.); (F.M.); (M.H.); (A.B.); (P.S.); (L.S.); (S.W.); (A.N.); (C.R.)
| | - Flavia Millesi
- Research Laboratory of the Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Waehringerstrasse 18-20, 1090 Vienna, Austria; (A.R.); (S.S.); (F.M.); (M.H.); (A.B.); (P.S.); (L.S.); (S.W.); (A.N.); (C.R.)
| | - Maximilian Haertinger
- Research Laboratory of the Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Waehringerstrasse 18-20, 1090 Vienna, Austria; (A.R.); (S.S.); (F.M.); (M.H.); (A.B.); (P.S.); (L.S.); (S.W.); (A.N.); (C.R.)
| | - Anton Borger
- Research Laboratory of the Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Waehringerstrasse 18-20, 1090 Vienna, Austria; (A.R.); (S.S.); (F.M.); (M.H.); (A.B.); (P.S.); (L.S.); (S.W.); (A.N.); (C.R.)
| | - Paul Supper
- Research Laboratory of the Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Waehringerstrasse 18-20, 1090 Vienna, Austria; (A.R.); (S.S.); (F.M.); (M.H.); (A.B.); (P.S.); (L.S.); (S.W.); (A.N.); (C.R.)
| | - Lorenz Semmler
- Research Laboratory of the Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Waehringerstrasse 18-20, 1090 Vienna, Austria; (A.R.); (S.S.); (F.M.); (M.H.); (A.B.); (P.S.); (L.S.); (S.W.); (A.N.); (C.R.)
| | - Sonja Wolf
- Research Laboratory of the Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Waehringerstrasse 18-20, 1090 Vienna, Austria; (A.R.); (S.S.); (F.M.); (M.H.); (A.B.); (P.S.); (L.S.); (S.W.); (A.N.); (C.R.)
| | - Aida Naghilou
- Research Laboratory of the Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Waehringerstrasse 18-20, 1090 Vienna, Austria; (A.R.); (S.S.); (F.M.); (M.H.); (A.B.); (P.S.); (L.S.); (S.W.); (A.N.); (C.R.)
- Medical Systems Biophysics and Bioengineering, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands
| | - Tamara Weiss
- Research Laboratory of the Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Waehringerstrasse 18-20, 1090 Vienna, Austria; (A.R.); (S.S.); (F.M.); (M.H.); (A.B.); (P.S.); (L.S.); (S.W.); (A.N.); (C.R.)
| | - Hans G. Kress
- Clinical Department of Special Anesthesia and Pain Therapy, Department of Anaesthesia, Intensive Care Medicine and Pain Medicine, Medical University of Vienna, Waehringerstrasse 18-20, 1090 Vienna, Austria;
- Ludwig Boltzmann Institute for Arthritis and Rehabilitation, Hofmanning 214, 8962 Groebming, Austria
| | - Christine Radtke
- Research Laboratory of the Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Waehringerstrasse 18-20, 1090 Vienna, Austria; (A.R.); (S.S.); (F.M.); (M.H.); (A.B.); (P.S.); (L.S.); (S.W.); (A.N.); (C.R.)
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9
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Yang S, Sun Y, Yan C. Recent advances in the use of extracellular vesicles from adipose-derived stem cells for regenerative medical therapeutics. J Nanobiotechnology 2024; 22:316. [PMID: 38844939 PMCID: PMC11157933 DOI: 10.1186/s12951-024-02603-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 05/28/2024] [Indexed: 06/09/2024] Open
Abstract
Adipose-derived stem cells (ADSCs) are a subset of mesenchymal stem cells (MSCs) isolated from adipose tissue. They possess remarkable properties, including multipotency, self-renewal, and easy clinical availability. ADSCs are also capable of promoting tissue regeneration through the secretion of various cytokines, factors, and extracellular vesicles (EVs). ADSC-derived EVs (ADSC-EVs) act as intercellular signaling mediators that encapsulate a range of biomolecules. These EVs have been found to mediate the therapeutic activities of donor cells by promoting the proliferation and migration of effector cells, facilitating angiogenesis, modulating immunity, and performing other specific functions in different tissues. Compared to the donor cells themselves, ADSC-EVs offer advantages such as fewer safety concerns and more convenient transportation and storage for clinical application. As a result, these EVs have received significant attention as cell-free therapeutic agents with potential future application in regenerative medicine. In this review, we focus on recent research progress regarding regenerative medical use of ADSC-EVs across various medical conditions, including wound healing, chronic limb ischemia, angiogenesis, myocardial infarction, diabetic nephropathy, fat graft survival, bone regeneration, cartilage regeneration, tendinopathy and tendon healing, peripheral nerve regeneration, and acute lung injury, among others. We also discuss the underlying mechanisms responsible for inducing these therapeutic effects. We believe that deciphering the biological properties, therapeutic effects, and underlying mechanisms associated with ADSC-EVs will provide a foundation for developing a novel therapeutic approach in regenerative medicine.
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Affiliation(s)
- Song Yang
- Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
| | - Yiran Sun
- School of Pharmacy, Chengdu Medical College, Chengdu, 610500, People's Republic of China.
| | - Chenchen Yan
- School of Pharmacy, Chengdu Medical College, Chengdu, 610500, People's Republic of China
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10
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Mushtaq M, Zineldeen DH, Mateen MA, Haider KH. Mesenchymal stem cells' "garbage bags" at work: Treating radial nerve injury with mesenchymal stem cell-derived exosomes. World J Stem Cells 2024; 16:467-478. [PMID: 38817330 PMCID: PMC11135253 DOI: 10.4252/wjsc.v16.i5.467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 04/03/2024] [Accepted: 04/25/2024] [Indexed: 05/24/2024] Open
Abstract
Unlike central nervous system injuries, peripheral nerve injuries (PNIs) are often characterized by more or less successful axonal regeneration. However, structural and functional recovery is a senile process involving multifaceted cellular and molecular processes. The contemporary treatment options are limited, with surgical intervention as the gold-standard method; however, each treatment option has its associated limitations, especially when the injury is severe with a large gap. Recent advancements in cell-based therapy and cell-free therapy approaches using stem cell-derived soluble and insoluble components of the cell secretome are fast-emerging therapeutic approaches to treating acute and chronic PNI. The recent pilot study is a leap forward in the field, which is expected to pave the way for more enormous, systematic, and well-designed clinical trials to assess the therapeutic efficacy of mesenchymal stem cell-derived exosomes as a bio-drug either alone or as part of a combinatorial approach, in an attempt synergize the best of novel treatment approaches to address the complexity of the neural repair and regeneration.
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Affiliation(s)
- Mazhar Mushtaq
- Department of Basic Sciences, Sulaiman AlRajhi University, Albukairiyah 52736, AlQaseem, Saudi Arabia
| | - Doaa Hussein Zineldeen
- Department of Basic Sciences, Sulaiman AlRajhi University, Albukairiyah 52736, AlQaseem, Saudi Arabia
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Tanta University, Tanta 6632110, Egypt
| | - Muhammad Abdul Mateen
- Department of Basic Sciences, Sulaiman AlRajhi University, Albukairiyah 52736, AlQaseem, Saudi Arabia
| | - Khawaja Husnain Haider
- Department of Basic Sciences, Sulaiman AlRajhi University, Albukairiyah 52736, AlQaseem, Saudi Arabia.
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11
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Stadlmayr S, Peter K, Millesi F, Rad A, Wolf S, Mero S, Zehl M, Mentler A, Gusenbauer C, Konnerth J, Schniepp HC, Lichtenegger H, Naghilou A, Radtke C. Comparative Analysis of Various Spider Silks in Regard to Nerve Regeneration: Material Properties and Schwann Cell Response. Adv Healthc Mater 2024; 13:e2302968. [PMID: 38079208 PMCID: PMC11468126 DOI: 10.1002/adhm.202302968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 11/20/2023] [Indexed: 12/26/2023]
Abstract
Peripheral nerve reconstruction through the employment of nerve guidance conduits with Trichonephila dragline silk as a luminal filling has emerged as an outstanding preclinical alternative to avoid nerve autografts. Yet, it remains unknown whether the outcome is similar for silk fibers harvested from other spider species. This study compares the regenerative potential of dragline silk from two orb-weaving spiders, Trichonephila inaurata and Nuctenea umbratica, as well as the silk of the jumping spider Phidippus regius. Proliferation, migration, and transcriptomic state of Schwann cells seeded on these silks are investigated. In addition, fiber morphology, primary protein structure, and mechanical properties are studied. The results demonstrate that the increased velocity of Schwann cells on Phidippus regius fibers can be primarily attributed to the interplay between the silk's primary protein structure and its mechanical properties. Furthermore, the capacity of silk fibers to trigger cells toward a gene expression profile of a myelinating Schwann cell phenotype is shown. The findings for the first time allow an in-depth comparison of the specific cellular response to various native spider silks and a correlation with the fibers' material properties. This knowledge is essential to open up possibilities for targeted manufacturing of synthetic nervous tissue replacement.
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Affiliation(s)
- Sarah Stadlmayr
- Department of PlasticReconstructive and Aesthetic SurgeryMedical University of ViennaVienna1090Austria
- Austrian Cluster for Tissue RegenerationViennaAustria
| | - Karolina Peter
- Institute for Physics and Materials ScienceUniversity of Natural Resources and Life SciencesVienna1190Austria
| | - Flavia Millesi
- Department of PlasticReconstructive and Aesthetic SurgeryMedical University of ViennaVienna1090Austria
- Austrian Cluster for Tissue RegenerationViennaAustria
| | - Anda Rad
- Department of PlasticReconstructive and Aesthetic SurgeryMedical University of ViennaVienna1090Austria
| | - Sonja Wolf
- Department of PlasticReconstructive and Aesthetic SurgeryMedical University of ViennaVienna1090Austria
| | - Sascha Mero
- Department of PlasticReconstructive and Aesthetic SurgeryMedical University of ViennaVienna1090Austria
| | - Martin Zehl
- Department of Analytical ChemistryFaculty of ChemistryUniversity of ViennaVienna1090Austria
| | - Axel Mentler
- Institute of Soil ResearchUniversity of Natural Resources and Life SciencesVienna1190Austria
| | - Claudia Gusenbauer
- Institute of Wood Technology and Renewable MaterialsUniversity of Natural Resources and Life SciencesTulln an der Donau3430Austria
| | - Johannes Konnerth
- Institute of Wood Technology and Renewable MaterialsUniversity of Natural Resources and Life SciencesTulln an der Donau3430Austria
| | | | - Helga Lichtenegger
- Institute for Physics and Materials ScienceUniversity of Natural Resources and Life SciencesVienna1190Austria
| | - Aida Naghilou
- Department of PlasticReconstructive and Aesthetic SurgeryMedical University of ViennaVienna1090Austria
- Austrian Cluster for Tissue RegenerationViennaAustria
- Medical Systems Biophysics and BioengineeringLeiden Academic Centre for Drug ResearchLeiden UniversityLeiden2333The Netherlands
| | - Christine Radtke
- Department of PlasticReconstructive and Aesthetic SurgeryMedical University of ViennaVienna1090Austria
- Austrian Cluster for Tissue RegenerationViennaAustria
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12
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Zhao C, Luo Q, Huang J, Su S, Zhang L, Zheng D, Chen M, Lin X, Zhong J, Li L, Ling K, Zhang S. Extracellular Vesicles Derived from Human Adipose-Derived Mesenchymal Stem Cells Alleviate Sepsis-Induced Acute Lung Injury through a MicroRNA-150-5p-Dependent Mechanism. ACS Biomater Sci Eng 2024; 10:946-959. [PMID: 38154081 DOI: 10.1021/acsbiomaterials.3c00614] [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] [Indexed: 12/30/2023]
Abstract
Extracellular vesicles (EVs) derived from human adipose mesenchymal stem cells (hADSCs) may exert a therapeutic benefit in alleviating sepsis-induced organ dysfunction by delivering cargos that include RNAs and proteins to target cells. The current study aims to explore the protective effect of miR-150-5p delivered by hADSC-EVs on sepsis-induced acute lung injury (ALI). We noted low expression of miR-150-5p in plasma and bronchoalveolar lavage fluid samples from patients with sepsis-induced ALI. The hADSC-EVs were isolated and subsequently cocultured with macrophages. It was established that hADSC-EVs transferred miR-150-5p to macrophages, where miR-150-5p targeted HMGA2 to inhibit its expression and, consequently, inactivated the MAPK pathway. This effect contributed to the promotion of M2 polarization of macrophages and the inhibition of proinflammatory cytokines. Further, mice were made septic by cecal ligation and puncture in vivo and treated with hADSC-EVs to elucidate the effect of hADSC-EVs on sepsis-induced ALI. The in vivo experimental results confirmed a suppressive role of hADSC-EVs in sepsis-induced ALI. Our findings suggest that hADSC-EV-mediated transfer of miR-150-5p may be a novel mechanism underlying the paracrine effects of hADSC-EVs on the M2 polarization of macrophages in sepsis-induced ALI.
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Affiliation(s)
- Chengkuan Zhao
- Department of Pharmacy, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510220, P.R. China
| | - Qianhua Luo
- Department of Pharmacology, Guangdong Second Provincial General Hospital, Guangzhou 510317, P.R. China
- Jinshazhou Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510168, P.R. China
| | - Jianxiang Huang
- College of Pharmacy, Jinan University, Guangzhou 510220, P.R. China
| | - Siman Su
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, P.R. China
| | - Lijuan Zhang
- Department of Pharmacy, YueBei People's Hospital (YueBei People's Hospital affiliated to Shantou University Medical College), ShaoGuan 512000, P.R. China
| | - Danling Zheng
- Department of Pharmacy, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510220, P.R. China
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, P.R. China
| | - Meini Chen
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, P.R. China
| | - Xinyue Lin
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, P.R. China
| | - Jialin Zhong
- Department of Pharmacy, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510220, P.R. China
| | - Li Li
- Department of Pharmacy, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510220, P.R. China
| | - Kai Ling
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, P.R. China
| | - Shuyao Zhang
- Department of Pharmacy, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510220, P.R. China
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13
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Dong X, Dong JF, Zhang J. Roles and therapeutic potential of different extracellular vesicle subtypes on traumatic brain injury. Cell Commun Signal 2023; 21:211. [PMID: 37596642 PMCID: PMC10436659 DOI: 10.1186/s12964-023-01165-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Accepted: 05/13/2023] [Indexed: 08/20/2023] Open
Abstract
Traumatic brain injury (TBI) is a leading cause of injury-related disability and death around the world, but the clinical stratification, diagnosis, and treatment of complex TBI are limited. Due to their unique properties, extracellular vesicles (EVs) are emerging candidates for being biomarkers of traumatic brain injury as well as serving as potential therapeutic targets. However, the effects of different extracellular vesicle subtypes on the pathophysiology of traumatic brain injury are very different, or potentially even opposite. Before extracellular vesicles can be used as targets for TBI therapy, it is necessary to classify different extracellular vesicle subtypes according to their functions to clarify different strategies for EV-based TBI therapy. The purpose of this review is to discuss contradictory effects of different EV subtypes on TBI, and to propose treatment ideas based on different EV subtypes to maximize their benefits for the recovery of TBI patients. Video Abstract.
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Affiliation(s)
- Xinlong Dong
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 119, Nansihuan West Road, Fengtai District, Beijing, China.
- Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
| | - Jing-Fei Dong
- Bloodworks Research Institute, Seattle, WA, USA
- Division of Hematology, Department of Medicine, School of Medicine, University of Washington, Seattle, WA, USA
| | - Jianning Zhang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
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14
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Ding JY, Chen MJ, Wu LF, Shu GF, Fang SJ, Li ZY, Chu XR, Li XK, Wang ZG, Ji JS. Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: roles, opportunities and challenges. Mil Med Res 2023; 10:36. [PMID: 37587531 PMCID: PMC10433599 DOI: 10.1186/s40779-023-00472-w] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 07/24/2023] [Indexed: 08/18/2023] Open
Abstract
Skin wounds are characterized by injury to the skin due to trauma, tearing, cuts, or contusions. As such injuries are common to all human groups, they may at times represent a serious socioeconomic burden. Currently, increasing numbers of studies have focused on the role of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in skin wound repair. As a cell-free therapy, MSC-derived EVs have shown significant application potential in the field of wound repair as a more stable and safer option than conventional cell therapy. Treatment based on MSC-derived EVs can significantly promote the repair of damaged substructures, including the regeneration of vessels, nerves, and hair follicles. In addition, MSC-derived EVs can inhibit scar formation by affecting angiogenesis-related and antifibrotic pathways in promoting macrophage polarization, wound angiogenesis, cell proliferation, and cell migration, and by inhibiting excessive extracellular matrix production. Additionally, these structures can serve as a scaffold for components used in wound repair, and they can be developed into bioengineered EVs to support trauma repair. Through the formulation of standardized culture, isolation, purification, and drug delivery strategies, exploration of the detailed mechanism of EVs will allow them to be used as clinical treatments for wound repair. In conclusion, MSC-derived EVs-based therapies have important application prospects in wound repair. Here we provide a comprehensive overview of their current status, application potential, and associated drawbacks.
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Affiliation(s)
- Jia-Yi Ding
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Min-Jiang Chen
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Ling-Feng Wu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, Zhejiang, China
| | - Gao-Feng Shu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China
- Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, Zhejiang, China
| | - Shi-Ji Fang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China
- Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, Zhejiang, China
| | - Zhao-Yu Li
- Department of Overseas Education College, Jimei University, Xiamen, 361021, Fujian, China
| | - Xu-Ran Chu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Department of Medicine II, Internal Medicine, Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, 35392, Giessen, Germany
- Pulmonary and Critical Care, Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, 35392, Giessen, Germany
| | - Xiao-Kun Li
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
| | - Zhou-Guang Wang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China.
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
| | - Jian-Song Ji
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China.
- Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, Zhejiang, China.
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15
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Naghilou A, Peter K, Millesi F, Stadlmayr S, Wolf S, Rad A, Semmler L, Supper P, Ploszczanski L, Liu J, Burghammer M, Riekel C, Bismarck A, Backus EHG, Lichtenegger H, Radtke C. Insights into the material properties of dragline spider silk affecting Schwann cell migration. Int J Biol Macromol 2023:125398. [PMID: 37330085 DOI: 10.1016/j.ijbiomac.2023.125398] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 06/09/2023] [Accepted: 06/13/2023] [Indexed: 06/19/2023]
Abstract
Dragline silk of Trichonephila spiders has attracted attention in various applications. One of the most fascinating uses of dragline silk is in nerve regeneration as a luminal filling for nerve guidance conduits. In fact, conduits filled with spider silk can measure up to autologous nerve transplantation, but the reasons behind the success of silk fibers are not yet understood. In this study dragline fibers of Trichonephila edulis were sterilized with ethanol, UV radiation, and autoclaving and the resulting material properties were characterized with regard to the silk's suitability for nerve regeneration. Rat Schwann cells (rSCs) were seeded on these silks in vitro and their migration and proliferation were investigated as an indication for the fiber's ability to support the growth of nerves. It was found that rSCs migrate faster on ethanol treated fibers. To elucidate the reasons behind this behavior, the fiber's morphology, surface chemistry, secondary protein structure, crystallinity, and mechanical properties were studied. The results demonstrate that the synergy of dragline silk's stiffness and its composition has a crucial effect on the migration of rSCs. These findings pave the way towards understanding the response of SCs to silk fibers as well as the targeted production of synthetic alternatives for regenerative medicine applications.
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Affiliation(s)
- Aida Naghilou
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria; Austrian Cluster for Tissue Regeneration, Vienna, Austria.
| | - Karolina Peter
- University of Natural Resources and Life Sciences, Department of Material Sciences and Process Engineering, Institute of Physics and Materials Science, Peter-Jordan-Strasse 82, 1190 Vienna, Austria
| | - Flavia Millesi
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria; Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Sarah Stadlmayr
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria; Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Sonja Wolf
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria; Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Anda Rad
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria; Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Lorenz Semmler
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria; Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Paul Supper
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria; Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Leon Ploszczanski
- University of Natural Resources and Life Sciences, Department of Material Sciences and Process Engineering, Institute of Physics and Materials Science, Peter-Jordan-Strasse 82, 1190 Vienna, Austria
| | - Jiliang Liu
- European Synchrotron Radiation Facility, 71 avenue des Martyrs, 38000 Grenoble, France
| | - Manfred Burghammer
- European Synchrotron Radiation Facility, 71 avenue des Martyrs, 38000 Grenoble, France
| | - Christian Riekel
- European Synchrotron Radiation Facility, 71 avenue des Martyrs, 38000 Grenoble, France
| | - Alexander Bismarck
- University of Vienna, Faculty of Chemistry, Institute of Materials Chemistry & Research, Währingerstraße 42, 1090 Vienna, Austria
| | - Ellen H G Backus
- University of Vienna, Faculty of Chemistry, Institute of Physical Chemistry, Währingerstraße 42, 1090 Vienna, Austria
| | - Helga Lichtenegger
- University of Natural Resources and Life Sciences, Department of Material Sciences and Process Engineering, Institute of Physics and Materials Science, Peter-Jordan-Strasse 82, 1190 Vienna, Austria
| | - Christine Radtke
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria; Austrian Cluster for Tissue Regeneration, Vienna, Austria
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16
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Wang DR, Pan J. Extracellular vesicles: Emerged as a promising strategy for regenerative medicine. World J Stem Cells 2023; 15:165-181. [PMID: 37181006 PMCID: PMC10173817 DOI: 10.4252/wjsc.v15.i4.165] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/30/2023] [Accepted: 03/20/2023] [Indexed: 04/26/2023] Open
Abstract
Cell transplantation therapy has certain limitations including immune rejection and limited cell viability, which seriously hinder the transformation of stem cell-based tissue regeneration into clinical practice. Extracellular vesicles (EVs) not only possess the advantages of its derived cells, but also can avoid the risks of cell transplantation. EVs are intelligent and controllable biomaterials that can participate in a variety of physiological and pathological activities, tissue repair and regeneration by transmitting a variety of biological signals, showing great potential in cell-free tissue regeneration. In this review, we summarized the origins and characteristics of EVs, introduced the pivotal role of EVs in diverse tissues regeneration, discussed the underlying mechanisms, prospects, and challenges of EVs. We also pointed out the problems that need to be solved, application directions, and prospects of EVs in the future and shed new light on the novel cell-free strategy for using EVs in the field of regenerative medicine.
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Affiliation(s)
- Dian-Ri Wang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jian Pan
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
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17
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Bian Z, Wang X, Zhu R, Chen S. miR-21-5p in extracellular vesicles obtained from adipose tissue-derived stromal cells facilitates tubular epithelial cell repair in acute kidney injury. Cytotherapy 2023; 25:310-322. [PMID: 36244909 DOI: 10.1016/j.jcyt.2022.08.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 07/28/2022] [Accepted: 08/08/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND AIMS Acute kidney injury (AKI) is often associated with poor patient outcomes. Extracellular vesicles (EVs) have a marked therapeutic effect on renal recovery. This study sought to explore the functional mechanism of EVs from adipose tissue-derived stromal cells (ADSCs) in tubular epithelial cell (TEC) repair in AKI. METHODS ADSCs were cultured and EVs were isolated and identified. In vivo and in vitro AKI models were established using lipopolysaccharide (LPS). RESULTS EVs increased human kidney 2 (HK-2) cell viability; decreased terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and levels of kidney injury molecule 1, cleaved caspase-1, apoptosis-associated speck-like protein containing a CARD, gasdermin D-N, IL-18 and IL-1β; and elevated pro-caspase-1. EVs carried miR-21-5p into LPS-induced HK-2 cells. Silencing miR-21-5p partly eliminated the ability of EVs to suppress HK-2 cell pyroptosis and inflammation. miR-21-5p targeted toll-like receptor 4 (TLR4) and inhibited TEC pyroptosis and inflammation after AKI by inhibiting TLR4. TLR4 overexpression blocked the inhibitory effects of EVs on TEC pyroptosis and inflammation. EVs suppressed the nuclear factor-κB/NOD-like receptor family pyrin domain-containing 3 (NF-κB/NLRP3) pathway via miR-21-5p/TLR4. Finally, AKI mouse models were established and in vivo assays verified that ADSC-EVs reduced TEC pyroptosis and inflammatory response and potentiated cell repair by mediating miR-21-5p in AKI mice. CONCLUSIONS ADSC-EVs inhibited inflammation and TEC pyroptosis and promoted TEC repair in AKI by mediating miR-21-5p to target TLR4 and inhibiting the NF-κB/NLRP3 pathway.
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Affiliation(s)
- Zhixiang Bian
- Department of Nephrology, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, People's Republic of China
| | - Xiangxiang Wang
- Department of Nephrology, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, People's Republic of China
| | - Rui Zhu
- Department of Nephrology, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, People's Republic of China.
| | - Shunjie Chen
- Department of Nephrology, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, People's Republic of China.
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18
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Moccia V, Sammarco A, Ferro S, Cavicchioli L, Zappulli V. Characterization and function of extracellular vesicles in a canine mammary tumour cell line: Ultracentrifugation versus size exclusion chromatography. Vet Comp Oncol 2023; 21:36-44. [PMID: 36111535 DOI: 10.1111/vco.12858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 06/20/2022] [Accepted: 09/06/2022] [Indexed: 11/30/2022]
Abstract
Extracellular vesicles (EVs) are cell-derived membrane-bound vesicles involved in many biological processes such as tumour progression. For years, ultracentrifugation (UC) has been considered the gold standard for EV isolation but limited purity and integrity allowed the diffusion of alternative techniques. In this study, EVs were isolated from a canine mammary tumour cell line using UC and size exclusion chromatography (SEC) and analysed for size and concentration by nanoparticle tracking analysis (NTA) and for protein expression by western blot (WB). EV autocrine effect on cell proliferation, migration and invasiveness was then evaluated in vitro. In all samples, particles were in the EV size range (50-1000 nm), with a higher concentration in UC than in SEC samples (1011 and 1010 particles/ml respectively), and expressed EV markers (Alix, CD9). Functional assays did not show statistically significant difference among conditions, but EV treatment slightly increased cell proliferation and invasiveness and treatment with SEC-isolated EVs slightly enhanced cell migration compared to UC-isolated EVs. In conclusion, the main differences between the two isolation techniques are the quantity of the final EV-product and slight differences on EV functionality, which should be further explored to better highlight the real autocrine effect of tumoral EVs.
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Affiliation(s)
- Valentina Moccia
- Department of Comparative Biomedicine and Food Science, University of Padua, Padua, Italy
| | - Alessandro Sammarco
- Department of Comparative Biomedicine and Food Science, University of Padua, Padua, Italy.,Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA
| | - Silvia Ferro
- Department of Comparative Biomedicine and Food Science, University of Padua, Padua, Italy
| | - Laura Cavicchioli
- Department of Comparative Biomedicine and Food Science, University of Padua, Padua, Italy
| | - Valentina Zappulli
- Department of Comparative Biomedicine and Food Science, University of Padua, Padua, Italy
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19
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Chen SH, Kao HK, Wun JR, Chou PY, Chen ZY, Chen SH, Hsieh ST, Fang HW, Lin FH. Thermosensitive hydrogel carrying extracellular vesicles from adipose-derived stem cells promotes peripheral nerve regeneration after microsurgical repair. APL Bioeng 2022; 6:046103. [PMID: 36345317 PMCID: PMC9637024 DOI: 10.1063/5.0118862] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 10/02/2022] [Indexed: 11/06/2022] Open
Abstract
Peripheral nerve injuries are commonly occurring traumas of the extremities; functional recovery is hindered by slow nerve regeneration (<1 mm/day) following microsurgical repair and subsequent muscle atrophy. Functional recovery after peripheral nerve repair is highly dependent on local Schwann cell activity and axon regeneration speed. Herein, to promote nerve regeneration, paracrine signals of adipose-derived stem cells were applied in the form of extracellular vesicles (EVs) loaded in a thermosensitive hydrogel (PALDE) that could solidify rapidly and sustain high EV concentration around a repaired nerve during surgery. Cell experiments revealed that PALDE hydrogel markedly promotes Schwann-cell migration and proliferation and axon outgrowth. In a rat sciatic nerve repair model, the PALDE hydrogel increased repaired-nerve conduction efficacy; contraction force of leg muscles innervated by the repaired nerve also recovered. Electromicroscopic examination of downstream nerves indicated that fascicle diameter and myeline thickness in the PALDE group (1.91 ± 0.61 and 1.06 ± 0.40 μm, respectively) were significantly higher than those in PALD and control groups. Thus, this EV-loaded thermosensitive hydrogel is a potential cell-free therapeutic modality to improve peripheral-nerve regeneration, offering sustained and focused EV release around the nerve-injury site to overcome rapid clearance and maintain EV bioactivity in vivo.
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Affiliation(s)
| | - Huang-Kai Kao
- Department of Plastic and Reconstructive Surgery, Chang-Gung Memorial Hospital, Chang-Gung University and Medical College, Taoyuan, Taiwan
| | - Jing-Ru Wun
- Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei, Taiwan
| | - Pang-Yun Chou
- Department of Plastic and Reconstructive Surgery, Chang-Gung Memorial Hospital, Chang-Gung University and Medical College, Taoyuan, Taiwan
| | | | | | | | - Hsu-Wei Fang
- Authors to whom correspondence should be addressed: and
| | - Feng-Huei Lin
- Authors to whom correspondence should be addressed: and
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20
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Liu B, Kong Y, Shi W, Kuss M, Liao K, Hu G, Xiao P, Sankarasubramanian J, Guda C, Wang X, Lei Y, Duan B. Exosomes derived from differentiated human ADMSC with the Schwann cell phenotype modulate peripheral nerve-related cellular functions. Bioact Mater 2022; 14:61-75. [PMID: 35310346 PMCID: PMC8892082 DOI: 10.1016/j.bioactmat.2021.11.022] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 11/09/2021] [Accepted: 11/23/2021] [Indexed: 02/07/2023] Open
Abstract
Peripheral nerve regeneration remains a significant clinical challenge due to the unsatisfactory functional recovery and public health burden. Exosomes, especially those derived from mesenchymal stem cells (MSCs), are promising as potential cell-free therapeutics and gene therapy vehicles for promoting neural regeneration. In this study, we reported the differentiation of human adipose derived MSCs (hADMSCs) towards the Schwann cell (SC) phenotype (hADMSC-SCs) and then isolated exosomes from hADMSCs with and without differentiation (i.e., dExo vs uExo). We assessed and compared the effects of uExo and dExo on antioxidative, angiogenic, anti-inflammatory, and axon growth promoting properties by using various peripheral nerve-related cells. Our results demonstrated that hADMSC-SCs secreted more neurotrophic factors and other growth factors, compared to hADMSCs without differentiation. The dExo isolated from hADMSC-SCs protected rat SCs from oxidative stress and enhanced HUVEC migration and angiogenesis. Compared to uExo, dExo also had improved performances in downregulating pro-inflammatory gene expressions and cytokine secretions and promoting axonal growth of sensory neurons differentiated from human induced pluripotent stem cells. Furthermore, microRNA (miRNA) sequencing analysis revealed that exosomes and their parent cells shared some similarities in their miRNA profiles and exosomes displayed a distinct miRNA signature. Many more miRNAs were identified in dExo than in uExo. Several upregulated miRNAs, like miRNA-132-3p and miRNA-199b-5p, were highly related to neuroprotection, anti-inflammation, and angiogenesis. The dExo can effectively modulate various peripheral nerve-related cellular functions and is promising for cell-free biological therapeutics to enhance neural regeneration.
Exosomes were isolated from hADMSCs with and without differentiation towards SC phenotype (i.e., dExo vs uExo). hADMSC-SCs secreted more growth factors compared to hADMSCs without differentiation. The dExo protected rat SCs from oxidative stress and enhanced endothelial cell migration and angiogenesis. dExo promoted axonal growth of sensory neurons differentiated from hiPSCs. miRNA sequencing analysis unveiled and compared the exosomal and cellular miRNA profiles.
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21
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Jia Z, Kang B, Cai Y, Chen C, Yu Z, Li W, Zhang W. Cell-free fat extract attenuates osteoarthritis via chondrocytes regeneration and macrophages immunomodulation. Stem Cell Res Ther 2022; 13:133. [PMID: 35365233 PMCID: PMC8973552 DOI: 10.1186/s13287-022-02813-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 03/02/2022] [Indexed: 01/15/2023] Open
Abstract
Background The prevalence of osteoarthritis (OA) is increasing, yet clinically effective and economical treatments are unavailable. We have previously proposed a cell-free fat extract (CEFFE) containing multiple cytokines, which possessed antiapoptotic, anti-oxidative, and proliferation promotion functions, as a “cell-free” strategy. In this study, we aimed to evaluate the therapeutic effect of CEFFE in vivo and in vitro. Methods In vivo study, sodium iodoacetate-induced OA rats were treated with CEFFE by intra-articular injections for 8 weeks. Behavioral experiments were performed every two weeks. Histological analyses, anti-type II collagen, and toluidine staining provided structural evaluation. Macrophage infiltration was assessed by anti-CD68 and anti-CD206 staining. In vitro study, the effect of CEFFE on macrophage polarization and secretory factors was evaluated by flow cytometry, immunofluorescence, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The effect of CEFFE on cartilage regeneration was accessed by cell counting kit-8 assay and qRT-PCR. The generation of reactive oxygen species (ROS) and levels of ROS-related enzymes were investigated by qRT-PCR and western blotting. Results In rat models with sodium iodoacetate (MIA)-induced OA, CEFFE increased claw retraction pressure while decreasing bipedal pressure in a dose-dependent manner. Moreover, CEFFE promoted cartilage structure restoration and increased the proportion of CD206+ macrophages in the synovium. In vitro, CEFFE decreased the proportion of CD86+ cells and reduced the expression of pro-inflammatory factors in LPS + IFN-γ induced Raw 264.7. In addition, CEFFE decreased the expression of interleukin-6 and ADAMTs-5 and promoted the expression of SOX-9 in mouse primary chondrocytes. Besides, CEFFE reduced the intracellular levels of reactive oxygen species in both in vitro models through regulating ROS-related enzymes. Conclusions CEFFE inhibits the progression of OA by promoting cartilage regeneration and limiting low-grade joint inflammation. Graphical abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02813-3.
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Affiliation(s)
- Zhuoxuan Jia
- Department of Plastic and Reconstructive Surgery, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, National Tissue Engineering Center of China, 639 ZhiZaoJu Road, Shanghai, 200011, China
| | - Bijun Kang
- Department of Plastic and Reconstructive Surgery, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, National Tissue Engineering Center of China, 639 ZhiZaoJu Road, Shanghai, 200011, China
| | - Yizuo Cai
- Department of Plastic and Reconstructive Surgery, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, National Tissue Engineering Center of China, 639 ZhiZaoJu Road, Shanghai, 200011, China
| | - Chingyu Chen
- Department of Plastic and Reconstructive Surgery, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, National Tissue Engineering Center of China, 639 ZhiZaoJu Road, Shanghai, 200011, China
| | - Zheyuan Yu
- Department of Plastic and Reconstructive Surgery, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, National Tissue Engineering Center of China, 639 ZhiZaoJu Road, Shanghai, 200011, China.
| | - Wei Li
- Department of Plastic and Reconstructive Surgery, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, National Tissue Engineering Center of China, 639 ZhiZaoJu Road, Shanghai, 200011, China.
| | - Wenjie Zhang
- Department of Plastic and Reconstructive Surgery, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, National Tissue Engineering Center of China, 639 ZhiZaoJu Road, Shanghai, 200011, China.
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22
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Wan R, Hussain A, Behfar A, Moran SL, Zhao C. The Therapeutic Potential of Exosomes in Soft Tissue Repair and Regeneration. Int J Mol Sci 2022; 23:ijms23073869. [PMID: 35409228 PMCID: PMC8998690 DOI: 10.3390/ijms23073869] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/28/2022] [Accepted: 03/28/2022] [Indexed: 12/12/2022] Open
Abstract
Soft tissue defects are common following trauma and tumor extirpation. These injuries can result in poor functional recovery and lead to a diminished quality of life. The healing of skin and muscle is a complex process that, at present, leads to incomplete recovery and scarring. Regenerative medicine may offer the opportunity to improve the healing process and functional outcomes. Barriers to regenerative strategies have included cost, regulatory hurdles, and the need for cell-based therapies. In recent years, exosomes, or extracellular vesicles, have gained tremendous attention in the field of soft tissue repair and regeneration. These nanosized extracellular particles (30-140 nm) can break the cellular boundaries, as well as facilitate intracellular signal delivery in various regenerative physiologic and pathologic processes. Existing studies have established the potential of exosomes in regenerating tendons, skeletal muscles, and peripheral nerves through different mechanisms, including promoting myogenesis, increasing tenocyte differentiation and enhancing neurite outgrowth, and the proliferation of Schwann cells. These exosomes can be stored for immediate use in the operating room, and can be produced cost efficiently. In this article, we critically review the current advances of exosomes in soft tissue (tendons, skeletal muscles, and peripheral nerves) healing. Additionally, new directions for clinical applications in the future will be discussed.
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Affiliation(s)
- Rou Wan
- Division of Plastic Surgery, Mayo Clinic, Rochester, MN 55905, USA; (R.W.); (A.H.); (S.L.M.)
| | - Arif Hussain
- Division of Plastic Surgery, Mayo Clinic, Rochester, MN 55905, USA; (R.W.); (A.H.); (S.L.M.)
| | - Atta Behfar
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA;
- Van Cleve Cardiac Regenerative Medicine Program, Center for Regenerative Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Steven L. Moran
- Division of Plastic Surgery, Mayo Clinic, Rochester, MN 55905, USA; (R.W.); (A.H.); (S.L.M.)
| | - Chunfeng Zhao
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA
- Correspondence:
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23
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Mann A, Steinecker-Frohnwieser B, Naghilou A, Millesi F, Supper P, Semmler L, Wolf S, Marinova L, Weigl L, Weiss T, Radtke C. Nuclear Magnetic Resonance Treatment Accelerates the Regeneration of Dorsal Root Ganglion Neurons in vitro. Front Cell Neurosci 2022; 16:859545. [PMID: 35418835 PMCID: PMC8995532 DOI: 10.3389/fncel.2022.859545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 03/03/2022] [Indexed: 11/15/2022] Open
Abstract
Functional recovery from peripheral nerve injuries depends on a multitude of factors. Schwann cells (SCs) are key players in the regenerative process as they develop repair-specific functions to promote axon regrowth. However, chronically denervated SCs lose their repair phenotype, which is considered as a main reason for regeneration failure. Previous studies reported a modulatory effect of low nuclear magnetic resonance therapy (NMRT) on cell proliferation and gene expression. To provide first insight into a possible effect of NMRT on cells involved in peripheral nerve regeneration, this study investigated whether NMRT is able to influence the cellular behavior of primary SC and dorsal root ganglion (DRG) neuron cultures in vitro. The effect of NMRT on rat SCs was evaluated by comparing the morphology, purity, proliferation rate, and expression levels of (repair) SC associated genes between NMRT treated and untreated SC cultures. In addition, the influence of (1) NMRT and (2) medium obtained from NMRT treated SC cultures on rat DRG neuron regeneration was examined by analyzing neurite outgrowth and the neuronal differentiation status. Our results showed that NMRT stimulated the proliferation of SCs without changing their morphology, purity, or expression of (repair) SC associated markers. Furthermore, NMRT promoted DRG neuron regeneration shown by an increased cell survival, enhanced neurite network formation, and progressed neuronal differentiation status. Furthermore, the medium of NMRT treated SC cultures was sufficient to support DRG neuron survival and neurite outgrowth. These findings demonstrate a beneficial impact of NMRT on DRG neuron survival and neurite formation, which is primarily mediated via SC stimulation. Our data suggest that NMRT could be suitable as a non-invasive auxiliary treatment option for peripheral nerve injuries and encourage future studies that investigate the effect of NMRT in a physiological context.
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Affiliation(s)
- Anda Mann
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
| | | | - Aida Naghilou
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
| | - Flavia Millesi
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Paul Supper
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
| | - Lorenz Semmler
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
| | - Sonja Wolf
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
| | - Lena Marinova
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
| | - Lukas Weigl
- Department of Special Anesthesia and Pain Therapy, Medical University of Vienna, Vienna, Austria
| | - Tamara Weiss
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
- *Correspondence: Tamara Weiss,
| | - Christine Radtke
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
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24
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MUW researcher of the month. Wien Klin Wochenschr 2022; 134:91-93. [PMID: 35113205 DOI: 10.1007/s00508-022-02003-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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25
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Tang N, Wang X, Zhu J, Sun K, Li S, Tao K. Labelling stem cells with a nanoprobe for evaluating the homing behaviour in facial nerve injury repair. Biomater Sci 2022; 10:808-818. [PMID: 34989358 DOI: 10.1039/d1bm01823j] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
It is crucial and clinically relevant to clarify the homing efficiency and retention of stem cells in different implanting strategies of cell therapy for various injuries. However, the need for a tool for investigating the mechanisms is still unmet. We herein introduce multi-modal BaGdF5:Yb,Tm nanoparticles as a nanoprobe to label adipose-derived stem cells (ADSCs) and detect the homing behavior with a micro-computed tomography (micro-CT) imaging technique. The migration of cells injected locally or intravenously, with or without a chemokine, CXCL 12, was compared. A higher homing efficiency of ADSCs was observed in both intravenously injected groups, in contrast to the low efficiency of cell retention in local implantation. Meanwhile, CXCL 12 promoted the homing of ADSCs, especially in the intravenous route. Nonetheless, the administration of CXCL 12 showed its therapeutic efficacy, whereas intravenous injection of ADSCs almost did not. Our work provided a tool for in vivo imaging of the behavior of implanted cells in preclinical studies of cell therapy, and more importantly, implied that the parameters for implanting stem cells in clinical operation should be carefully considered.
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Affiliation(s)
- Na Tang
- State Key Lab of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, P. R. China.
| | - Xueyi Wang
- Department of Neurosurgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P. R. China.
| | - Jin Zhu
- Department of Neurosurgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P. R. China.
| | - Kang Sun
- State Key Lab of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, P. R. China.
| | - Shiting Li
- Department of Neurosurgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P. R. China.
| | - Ke Tao
- State Key Lab of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, P. R. China.
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26
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Zhang Z, Zhang M, Zhang Z, Sun Y, Wang J, Chang C, Zhu X, Li M, Liu Y. ADSCs Combined with Melatonin Promote Peripheral Nerve Regeneration through Autophagy. Int J Endocrinol 2022; 2022:5861553. [PMID: 35910940 PMCID: PMC9329031 DOI: 10.1155/2022/5861553] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 05/02/2022] [Accepted: 06/14/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND In the early stage of nerve injury, damaged tissue is cleared by autophagy. ADSCs can promote nerve axon regeneration. However, the microenvironment of the injury was changed, and ADSCs are easily apoptotic after transplantation. Mel plays a role in the apoptosis, proliferation, and differentiation of ADSCs. Therefore, we investigated whether Mel combined with ADSCs promoted peripheral nerve regeneration by enhancing early autophagy of injured nerves. MATERIALS AND METHODS SD rats were randomly split into the control group, model group, Mel group, ADSCs group, ADSCs + Mel group, and 3-MA group. On day 7, autophagy was observed and gait was detected on days 7, 14, 21, and 28. On the 28th day, the sciatic nerve of rats' renewal was detected. RESULTS After 1 w, compare with the model group, the number of autophagosomes and lysosomes and the expressions of protein of LC3-II/LC3-I and Beclin-1 in the ADSCs + Mel group were prominently increased, while the 3-MA group was significantly decreased. After 4 w, the function of the sciatic nerve in ADSCs + Mel was similar to that in the control group. Compared with the model group, the ADSCs + Mel group significantly increased myelin regeneration and the number of motor neurons and reduced gastrocnemius atrophy. CONCLUSIONS It was confirmed that ADSCs combined with Mel could promote sciatic nerve regeneration in rats by changing the early autophagy activity of the injured sciatic nerve.
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Affiliation(s)
- Ziqiang Zhang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan 471000, China
| | - Mengyu Zhang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan 471000, China
| | - Zhixiang Zhang
- College of Life Science, Yangtze University, Jingzhou, Hubei 434023, China
| | - Yingying Sun
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan 471000, China
| | - Jiajia Wang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan 471000, China
| | - Chenhao Chang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan 471000, China
| | - Xinyan Zhu
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan 471000, China
| | - Monan Li
- School of Materials Science and Engineering, Henan University of Science and Technology, Luoyang, Henan 471000, China
| | - Yumei Liu
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan 471000, China
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27
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Wong FC, Ye L, Demir IE, Kahlert C. Schwann cell-derived exosomes: Janus-faced mediators of regeneration and disease. Glia 2021; 70:20-34. [PMID: 34519370 DOI: 10.1002/glia.24087] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 08/23/2021] [Accepted: 08/25/2021] [Indexed: 12/20/2022]
Abstract
The phenotypic plasticity of Schwann cells (SCs) has contributed to the regenerative potential of the peripheral nervous system (PNS), but also pathological processes. This double-sided effect has led to an increasing attention to the role of extracellular vesicles (EVs) or exosomes in SCs to examine the intercellular communication between SCs and their surroundings. Here, we first describe the current knowledge of SC and EV biology, which forms the basis for the updates on advances in SC-derived exosomes research. We seek to explore in-depth the exosome-mediated molecular mechanisms involved in the regulation of SCs and their microenvironment. This review concludes with potential applications of SC-derived exosomes as delivery vehicles for therapeutics and biomarkers. The goal of this review is to emphasize the crucial role of SC-derived exosomes in the functional integration of the PNS, highlighting an emerging area in which there is much to explore and re-explore.
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Affiliation(s)
- Fang Cheng Wong
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Linhan Ye
- Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany.,Germany German Cancer Consortium (DKTK), Partner Site, Munich, Germany.,CRC 1321 Modelling and Targeting Pancreatic Cancer, Munich, Germany
| | - Ihsan Ekin Demir
- Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany.,Germany German Cancer Consortium (DKTK), Partner Site, Munich, Germany.,Department of General Surgery, HPB-Unit, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey.,CRC 1321 Modelling and Targeting Pancreatic Cancer, Munich, Germany.,Else Kröner Clinician Scientist Professor for "Translational Pancreatic Surgery
| | - Christoph Kahlert
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,National Center for Tumor Diseases (NCT/UCC), Dresden, Germany
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Man K, Brunet MY, Fernandez‐Rhodes M, Williams S, Heaney LM, Gethings LA, Federici A, Davies OG, Hoey D, Cox SC. Epigenetic reprogramming enhances the therapeutic efficacy of osteoblast-derived extracellular vesicles to promote human bone marrow stem cell osteogenic differentiation. J Extracell Vesicles 2021; 10:e12118. [PMID: 34262674 PMCID: PMC8263905 DOI: 10.1002/jev2.12118] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 05/18/2021] [Accepted: 06/16/2021] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs) are emerging in tissue engineering as promising acellular tools, circumventing many of the limitations associated with cell-based therapies. Epigenetic regulation through histone deacetylase (HDAC) inhibition has been shown to increase differentiation capacity. Therefore, this study aimed to investigate the potential of augmenting osteoblast epigenetic functionality using the HDAC inhibitor Trichostatin A (TSA) to enhance the therapeutic efficacy of osteoblast-derived EVs for bone regeneration. TSA was found to substantially alter osteoblast epigenetic function through reduced HDAC activity and increased histone acetylation. Treatment with TSA also significantly enhanced osteoblast alkaline phosphatase activity (1.35-fold), collagen production (2.8-fold) and calcium deposition (1.55-fold) during osteogenic culture (P ≤ 0.001). EVs derived from TSA-treated osteoblasts (TSA-EVs) exhibited reduced particle size (1-05-fold) (P > 0.05), concentration (1.4-fold) (P > 0.05) and protein content (1.16-fold) (P ≤ 0.001) when compared to untreated EVs. TSA-EVs significantly enhanced the proliferation (1.13-fold) and migration (1.3-fold) of human bone marrow stem cells (hBMSCs) when compared to untreated EVs (P ≤ 0.05). Moreover, TSA-EVs upregulated hBMSCs osteoblast-related gene and protein expression (ALP, Col1a, BSP1 and OCN) when compared to cells cultured with untreated EVs. Importantly, TSA-EVs elicited a time-dose dependent increase in hBMSCs extracellular matrix mineralisation. MicroRNA profiling revealed a set of differentially expressed microRNAs from TSA-EVs, which were osteogenic-related. Target prediction demonstrated these microRNAs were involved in regulating pathways such as 'endocytosis' and 'Wnt signalling pathway'. Moreover, proteomics analysis identified the enrichment of proteins involved in transcriptional regulation within TSA-EVs. Taken together, our findings suggest that altering osteoblasts' epigenome accelerates their mineralisation and promotes the osteoinductive potency of secreted EVs partly due to the delivery of pro-osteogenic microRNAs and transcriptional regulating proteins. As such, for the first time we demonstrate the potential to harness epigenetic regulation as a novel engineering approach to enhance EVs therapeutic efficacy for bone repair.
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Affiliation(s)
- Kenny Man
- School of Chemical EngineeringUniversity of BirminghamBirminghamUK
| | | | | | - Soraya Williams
- School of Sport, Exercise and Health SciencesLoughborough UniversityLoughboroughUK
| | - Liam M. Heaney
- School of Sport, Exercise and Health SciencesLoughborough UniversityLoughboroughUK
| | - Lee A. Gethings
- Waters CorporationStamford AvenueWilmslowUK
- Division of Infection, Immunity and Respiratory MedicineFaculty of Biology, Medicine and HealthManchester Institute of BiotechnologyUniversity of ManchesterManchesterUK
| | - Angelica Federici
- Trinity Biomedical Sciences InstituteTrinity CollegeTrinity Centre for Biomedical EngineeringDublinIreland
- Department of Mechanical, Manufacturing, and Biomedical EngineeringSchool of EngineeringTrinity College DublinIreland
- Trinity College Dublin & RCSIAdvanced Materials and Bioengineering Research CentreDublinIreland
| | - Owen G. Davies
- School of Sport, Exercise and Health SciencesLoughborough UniversityLoughboroughUK
| | - David Hoey
- Trinity Biomedical Sciences InstituteTrinity CollegeTrinity Centre for Biomedical EngineeringDublinIreland
- Department of Mechanical, Manufacturing, and Biomedical EngineeringSchool of EngineeringTrinity College DublinIreland
- Trinity College Dublin & RCSIAdvanced Materials and Bioengineering Research CentreDublinIreland
| | - Sophie C. Cox
- School of Chemical EngineeringUniversity of BirminghamBirminghamUK
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Shao M, Jin M, Xu S, Zheng C, Zhu W, Ma X, Lv F. Exosomes from Long Noncoding RNA-Gm37494-ADSCs Repair Spinal Cord Injury via Shifting Microglial M1/M2 Polarization. Inflammation 2021; 43:1536-1547. [PMID: 32307615 DOI: 10.1007/s10753-020-01230-z] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Spinal cord injury (SCI) may lead to severe motor and sensory dysfunction, causing high mortality and disability rates. Adipose tissue-derived mesenchymal stem/stromal cells (ADSCs), especially hypoxia-pretreated ADSCs, represent an effective therapy for SCI by promoting the secretion of exosomes (Exos). Here, we investigated the therapeutic efficacy of exosomes secreted by ADSCs under hypoxia (HExos) and explored potential target molecules. We utilized nanoparticle tracking analysis, electron microscopy, qRT-PCR, and western blotting to analyze differences between HExos and Exos groups. The expression of long noncoding RNAs (lncRNAs) was examined by high-throughput sequencing. The therapeutic effects of different Exos treatments were compared in vitro and in an SCI model in vivo. The interaction between lncRNAs, microRNAs, and mRNA was examined by luciferase reporter experiments. We employed enzyme-linked immunosorbent assay and immunofluorescence to measure inflammatory factor expression and microglial polarization. The results showed that HExos was more effective than Exos for repairing SCI by suppressing inflammatory factor expression, promoting functional recovery, and shifting microglia from M1 to M2 polarization. High-throughput sequencing showed that LncGm37494 expression was significantly higher in HExos than Exos, and its upregulation promoted microglial M1/M2 polarization by inhibiting miR-130b-3p and promoting PPARγ expression, as shown by luciferase reporter experiments. Exos from lncGm37494 overexpressing ADSCs showed a similar therapeutic effect than HExos. The results indicated that HExos repair SCI by delivering lncGm37494, advising that lncGm3749 functions importantly in microenvironmental regulation and shows possibility for SCI treatments.
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Affiliation(s)
- Minghao Shao
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Mingming Jin
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China
| | - Shun Xu
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Chaojun Zheng
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Wei Zhu
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Xiaosheng Ma
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Feizhou Lv
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200040, China.
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Nowzari F, Wang H, Khoradmehr A, Baghban M, Baghban N, Arandian A, Muhaddesi M, Nabipour I, Zibaii MI, Najarasl M, Taheri P, Latifi H, Tamadon A. Three-Dimensional Imaging in Stem Cell-Based Researches. Front Vet Sci 2021; 8:657525. [PMID: 33937378 PMCID: PMC8079735 DOI: 10.3389/fvets.2021.657525] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 03/19/2021] [Indexed: 12/14/2022] Open
Abstract
Stem cells have an important role in regenerative therapies, developmental biology studies and drug screening. Basic and translational research in stem cell technology needs more detailed imaging techniques. The possibility of cell-based therapeutic strategies has been validated in the stem cell field over recent years, a more detailed characterization of the properties of stem cells is needed for connectomics of large assemblies and structural analyses of these cells. The aim of stem cell imaging is the characterization of differentiation state, cellular function, purity and cell location. Recent progress in stem cell imaging field has included ultrasound-based technique to study living stem cells and florescence microscopy-based technique to investigate stem cell three-dimensional (3D) structures. Here, we summarized the fundamental characteristics of stem cells via 3D imaging methods and also discussed the emerging literatures on 3D imaging in stem cell research and the applications of both classical 2D imaging techniques and 3D methods on stem cells biology.
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Affiliation(s)
- Fariborz Nowzari
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Huimei Wang
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Institute of Acupuncture and Moxibustion, Fudan Institutes of Integrative Medicine, Fudan University, Shanghai, China
| | - Arezoo Khoradmehr
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Mandana Baghban
- Department of Obstetrics and Gynecology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Neda Baghban
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Alireza Arandian
- Laser and Plasma Research Institute, Shahid Beheshti University, Tehran, Iran
| | - Mahdi Muhaddesi
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Iraj Nabipour
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Mohammad I. Zibaii
- Laser and Plasma Research Institute, Shahid Beheshti University, Tehran, Iran
| | - Mostafa Najarasl
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Payam Taheri
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Hamid Latifi
- Laser and Plasma Research Institute, Shahid Beheshti University, Tehran, Iran
- Department of Physics, Shahid Beheshti University, Tehran, Iran
| | - Amin Tamadon
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
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Reconstruction of Critical Nerve Defects Using Allogenic Nerve Tissue: A Review of Current Approaches. Int J Mol Sci 2021; 22:ijms22073515. [PMID: 33805321 PMCID: PMC8036990 DOI: 10.3390/ijms22073515] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 03/23/2021] [Accepted: 03/25/2021] [Indexed: 12/12/2022] Open
Abstract
Regardless of the nerve defect length, nerve injury is a debilitating condition for the affected patient that results in loss of sensory and motor function. These functional impairments can have a profound impact on the patient’s quality of life. Surgical approaches for the treatment of short segment nerve defects are well-established. Autologous nerve transplantation, considered the gold standard, and the use of artificial nerve grafts are safe and successful procedures for short segment nerve defect reconstruction. Long segment nerve defects which extend 3.0 cm or more are more problematic for repair. Methods for reconstruction of long defects are limited. Artificial nerve grafts often fail to regenerate and autologous nerve grafts are limited in length and number. Cadaveric processed/unprocessed nerve allografts are a promising alternative in nerve surgery. This review gives a systematic overview on pre-clinical and clinical approaches in nerve allograft transplantation.
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32
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Lou S, Duan Y, Nie H, Cui X, Du J, Yao Y. Mesenchymal stem cells: Biological characteristics and application in disease therapy. Biochimie 2021; 185:9-21. [PMID: 33711361 DOI: 10.1016/j.biochi.2021.03.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 03/05/2021] [Accepted: 03/05/2021] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells. In addition to the capacity for self-renewal and multipotential differentiation, MSCs also have the following characteristics. MSCs can exert immunomodulatory functions through interaction with innate or adaptive immune cells, MSCs with poor immunogenicity can be used for allogeneic transplantation, and MSCs can "home" to inflammation and tumour sites. Based on these biological properties, MSCs demonstrate broad clinical application prospects in the treatment of tissue injury, autoimmune diseases, transplantation, cancer and other inflammation-related diseases. In this review we describe the biological characteristics of MSCs and discuss the research advances of MSCs in regenerative medicine, immunomodulation, oncology, and COVID-19, to fully understand the range of diseases in which MSC therapy may be beneficial.
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Affiliation(s)
- Songyue Lou
- School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Yongtao Duan
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Henan, 450018, China.
| | - Huizong Nie
- School of Life Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Xujie Cui
- School of Life Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Jialing Du
- School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Yongfang Yao
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Henan, 450018, China; School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
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Fuloria S, Subramaniyan V, Dahiya R, Dahiya S, Sudhakar K, Kumari U, Sathasivam K, Meenakshi DU, Wu YS, Sekar M, Malviya R, Singh A, Fuloria NK. Mesenchymal Stem Cell-Derived Extracellular Vesicles: Regenerative Potential and Challenges. BIOLOGY 2021; 10:172. [PMID: 33668707 PMCID: PMC7996168 DOI: 10.3390/biology10030172] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/09/2021] [Accepted: 02/19/2021] [Indexed: 02/07/2023]
Abstract
Evidence suggests that stem cells exert regenerative potential via the release of extracellular vesicles. Mesenchymal stem cell extracellular vesicles (MSCEVs) offer therapeutic benefits for various pathophysiological ailments by restoring tissues. Facts suggest that MSCEV action can be potentiated by modifying the mesenchymal stem cells culturing methodology and bioengineering EVs. Limited clinical trials of MSCEVs have questioned their superiority, culturing quality, production scale-up and isolation, and administration format. Translation of preclinically successful MSCEVs into a clinical platform requires paying attention to several critical matters, such as the production technique, quantification/characterization, pharmacokinetics/targeting/transfer to the target site, and the safety profile. Keeping these issues as a priority, the present review was designed to highlight the challenges in translating preclinical MSCEV research into clinical platforms and provide evidence for the regenerative potential of MSCEVs in various conditions of the liver, kidney, heart, nervous system, bone, muscle, cartilage, and other organs/tissues.
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Affiliation(s)
| | - Vetriselvan Subramaniyan
- Faculty of Medicine, Bioscience and Nursing, MAHSA University, Kuala Lumpur 42610, Malaysia; (V.S.); (Y.S.W.)
| | - Rajiv Dahiya
- School of Pharmacy, Faculty of Medical Sciences, The University of the West Indies, St. Augustine, Trinidad and Tobago;
| | - Sunita Dahiya
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00936, USA;
| | - Kalvatala Sudhakar
- School of Pharmaceutical Sciences (LIT-Pharmacy), Lovely Professional University, Jalandhar 144411, India;
| | - Usha Kumari
- Faculty of Medicine, AIMST University, Kedah 08100, Malaysia;
| | | | | | - Yuan Seng Wu
- Faculty of Medicine, Bioscience and Nursing, MAHSA University, Kuala Lumpur 42610, Malaysia; (V.S.); (Y.S.W.)
| | - Mahendran Sekar
- Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh 30450, Malaysia;
| | - Rishabha Malviya
- Department of Pharmacy, SMAS, Galgotias University, Greater Noida 203201, India; (R.M.); (A.S.)
| | - Amit Singh
- Department of Pharmacy, SMAS, Galgotias University, Greater Noida 203201, India; (R.M.); (A.S.)
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34
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Millesi F, Weiss T, Mann A, Haertinger M, Semmler L, Supper P, Pils D, Naghilou A, Radtke C. Defining the regenerative effects of native spider silk fibers on primary Schwann cells, sensory neurons, and nerve-associated fibroblasts. FASEB J 2021; 35:e21196. [PMID: 33210360 PMCID: PMC7894153 DOI: 10.1096/fj.202001447r] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 09/25/2020] [Accepted: 10/30/2020] [Indexed: 01/09/2023]
Abstract
The search for a suitable material to promote regeneration after long-distance peripheral nerve defects turned the spotlight on spider silk. Nerve conduits enriched with native spider silk fibers as internal guiding structures previously demonstrated a regenerative outcome similar to autologous nerve grafts in animal studies. Nevertheless, spider silk is a natural material with associated limitations for clinical use. A promising alternative is the production of recombinant silk fibers that should mimic the outstanding properties of their native counterpart. However, in vitro data on the regenerative features that native silk fibers provide for cells involved in nerve regeneration are scarce. Thus, there is a lack of reference parameters to evaluate whether recombinant silk fiber candidates will be eligible for nerve repair in vivo. To gain insight into the regenerative effect of native spider silk, our study aims to define the behavioral response of primary Schwann cells (SCs), nerve-associated fibroblasts (FBs), and dorsal root ganglion (DRG) neurons cultured on native dragline silk from the genus Nephila and on laminin coated dishes. The established multi-color immunostaining panels together with confocal microscopy and live cell imaging enabled the analysis of cell identity, morphology, proliferation, and migration on both substrates in detail. Our findings demonstrated that native spider silk rivals laminin coating as it allowed attachment and proliferation and supported the characteristic behavior of all tested cell types. Axonal out-growth of DRG neurons occurred along longitudinally aligned SCs that formed sustained bundled structures resembling Bungner bands present in regenerating nerves. The migration of SCs along the silk fibers achieved the reported distance of regenerating axons of about 1 mm per day, but lacked directionality. Furthermore, rFBs significantly reduced the velocity of rSCs in co-cultures on silk fibers. In summary, this study (a) reveals features recombinant silk must possess and what modifications or combinations could be useful for enhanced nerve repair and (b) provides assays to evaluate the regenerative performance of silk fibers in vitro before being applied as internal guiding structure in nerve conduits in vivo.
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Affiliation(s)
- Flavia Millesi
- Research Laboratory of the Division of Plastic and Reconstructive SurgeryDepartment of SurgeryMedical University of ViennaViennaAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
| | - Tamara Weiss
- Research Laboratory of the Division of Plastic and Reconstructive SurgeryDepartment of SurgeryMedical University of ViennaViennaAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
| | - Anda Mann
- Research Laboratory of the Division of Plastic and Reconstructive SurgeryDepartment of SurgeryMedical University of ViennaViennaAustria
| | - Maximilian Haertinger
- Research Laboratory of the Division of Plastic and Reconstructive SurgeryDepartment of SurgeryMedical University of ViennaViennaAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
| | - Lorenz Semmler
- Research Laboratory of the Division of Plastic and Reconstructive SurgeryDepartment of SurgeryMedical University of ViennaViennaAustria
| | - Paul Supper
- Research Laboratory of the Division of Plastic and Reconstructive SurgeryDepartment of SurgeryMedical University of ViennaViennaAustria
| | - Dietmar Pils
- Division of General SurgeryDepartment of SurgeryComprehensive Cancer Center ViennaMedical University of ViennaViennaAustria
| | - Aida Naghilou
- Research Laboratory of the Division of Plastic and Reconstructive SurgeryDepartment of SurgeryMedical University of ViennaViennaAustria
| | - Christine Radtke
- Research Laboratory of the Division of Plastic and Reconstructive SurgeryDepartment of SurgeryMedical University of ViennaViennaAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
- Division of Plastic and Reconstructive SurgeryDepartment of SurgeryMedical University of ViennaViennaAustria
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Wąchalska M, Rychłowski M, Grabowska K, Kowal K, Narajczyk M, Bieńkowska-Szewczyk K, Lipińska AD. Palmitoylated mNeonGreen Protein as a Tool for Visualization and Uptake Studies of Extracellular Vesicles. MEMBRANES 2020; 10:membranes10120373. [PMID: 33260914 PMCID: PMC7768372 DOI: 10.3390/membranes10120373] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/19/2020] [Accepted: 11/24/2020] [Indexed: 01/08/2023]
Abstract
Extracellular vesicles (EVs) are membranous nanoparticles released by cells as vital mediators of intercellular communication. As such, EVs have become an attractive target for pathogens and cancer cells, which can take control over their cargo composition, as well as their trafficking, shaping the pathogenesis. Despite almost four decades of research on EVs, the number of specific and efficient EV labeling methods is limited, and there is still no universal method for the visualization of their transport in living cells. Lipophilic dyes that non-specifically intercalate into the EVs membranes may diffuse to other membranes, leading to the misinterpretation of the results. Here, we propose a palmitoylated fluorescent mNeonGreen (palmNG) protein as an alternative to chemical dyes for EVs visualization. The Branchiostoma lanceolatum-derived mNeonGreen is a brighter, more stable, and less sensitive to laser-induced bleaching alternative to green fluorescent protein (GFP), which makes it a more potent tag in a variety of fluorescence-based techniques. A palmNG-expressing stable human melanoma cell line was generated using retrovirus gene transfer and cell sorting. This protein partially localizes to cellular membranes, and can be detected inside size-exclusion (SEC)-purified EVs. With the use of flow cytometry and fluorescent confocal microscopy, we performed qualitative and quantitative analyses of palmNG-EVs uptake in recipient human hepatoma cells, in comparison to PKH67-labeled vesicles. Our findings confirm that membrane-embedded mNeonGreen can be successfully applied as a tool in EVs transfer and uptake studies.
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Affiliation(s)
- Magda Wąchalska
- Laboratory of Virus Molecular Biology, Intercollegiate Faculty of Biotechnology, University of Gdańsk, Abrahama 58, 80-307 Gdańsk, Poland; (M.W.); (M.R.); (K.G.); (K.K.); (K.B.-S.)
| | - Michał Rychłowski
- Laboratory of Virus Molecular Biology, Intercollegiate Faculty of Biotechnology, University of Gdańsk, Abrahama 58, 80-307 Gdańsk, Poland; (M.W.); (M.R.); (K.G.); (K.K.); (K.B.-S.)
| | - Kinga Grabowska
- Laboratory of Virus Molecular Biology, Intercollegiate Faculty of Biotechnology, University of Gdańsk, Abrahama 58, 80-307 Gdańsk, Poland; (M.W.); (M.R.); (K.G.); (K.K.); (K.B.-S.)
| | - Kinga Kowal
- Laboratory of Virus Molecular Biology, Intercollegiate Faculty of Biotechnology, University of Gdańsk, Abrahama 58, 80-307 Gdańsk, Poland; (M.W.); (M.R.); (K.G.); (K.K.); (K.B.-S.)
| | - Magdalena Narajczyk
- Laboratory of Electron Microscopy, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland;
| | - Krystyna Bieńkowska-Szewczyk
- Laboratory of Virus Molecular Biology, Intercollegiate Faculty of Biotechnology, University of Gdańsk, Abrahama 58, 80-307 Gdańsk, Poland; (M.W.); (M.R.); (K.G.); (K.K.); (K.B.-S.)
| | - Andrea D. Lipińska
- Laboratory of Virus Molecular Biology, Intercollegiate Faculty of Biotechnology, University of Gdańsk, Abrahama 58, 80-307 Gdańsk, Poland; (M.W.); (M.R.); (K.G.); (K.K.); (K.B.-S.)
- Correspondence:
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36
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Correlating the secondary protein structure of natural spider silk with its guiding properties for Schwann cells. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2020; 116:111219. [DOI: 10.1016/j.msec.2020.111219] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 06/02/2020] [Accepted: 06/18/2020] [Indexed: 02/06/2023]
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37
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Tsiapalis D, O’Driscoll L. Mesenchymal Stem Cell Derived Extracellular Vesicles for Tissue Engineering and Regenerative Medicine Applications. Cells 2020; 9:E991. [PMID: 32316248 PMCID: PMC7226943 DOI: 10.3390/cells9040991] [Citation(s) in RCA: 206] [Impact Index Per Article: 41.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 04/09/2020] [Accepted: 04/14/2020] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are being extensively investigated for their potential in tissue engineering and regenerative medicine. However, recent evidence suggests that the beneficial effects of MSCs may be manifest by their released extracellular vesicles (EVs); typically not requiring the administration of MSCs. This evidence, predominantly from pre-clinical in vitro and in vivo studies, suggests that MSC-EVs may exhibit substantial therapeutic properties in many pathophysiological conditions, potentially restoring an extensive range of damaged or diseased tissues and organs. These benefits of MSC EVs are apparently found, regardless of the anatomical or body fluid origin of the MSCs (and include e.g., bone marrow, adipose tissue, umbilical cord, urine, etc). Furthermore, early indications suggest that the favourable effects of MSC-EVs could be further enhanced by modifying the way in which the donor MSCs are cultured (for example, in hypoxic compared to normoxic conditions, in 3D compared to 2D culture formats) and/or if the EVs are subsequently bio-engineered (for example, loaded with specific cargo). So far, few human clinical trials of MSC-EVs have been conducted and questions remain unanswered on whether the heterogeneous population of EVs is beneficial or some specific sub-populations, how best we can culture and scale-up MSC-EV production and isolation for clinical utility, and in what format they should be administered. However, as reviewed here, there is now substantial evidence supporting the use of MSC-EVs in tissue engineering and regenerative medicine and further research to establish how best to exploit this approach for societal and economic benefit is warranted.
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Affiliation(s)
| | - Lorraine O’Driscoll
- School of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland;
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