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Xu Y, Wei C, Ma L, Zhao L, Li D, Lin Y, Zhou Q, Xie L, Wang F. 3D mesenchymal stem cell exosome-functionalized hydrogels for corneal wound healing. J Control Release 2025; 380:630-646. [PMID: 39955036 DOI: 10.1016/j.jconrel.2025.02.030] [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: 11/14/2024] [Revised: 01/06/2025] [Accepted: 02/12/2025] [Indexed: 02/17/2025]
Abstract
Mesenchymal stem cell (MSC)-derived exosomes have the potential to sustain immune homeostasis and facilitate tissue regeneration, and those effects can be potentiated under three-dimensional (3D) cell culture conditions. Nevertheless, whether exosomes derived from 3D-cultured MSCs (3D-Exos) exert therapeutic effects on the injured corneas and the underlying mechanism remain unclear. In this study, MSCs are cultured in a gelatin methacryloyl (GelMA) hydrogel to produce 3D-Exos. In vitro experiments revealed that the 3D-cultured MSCs maintained their stemness, the exosomes were produced in better yield, and the generated 3D-Exos possess exceptional anti-inflammatory, pro-proliferative and tissue remodeling properties. Moreover, the 3D-Exos that were delivered by the GelMA hydrogel displayed a sustained release profile for multi-dimensional injured cornea repair. Extensive in vitro studies further demonstrated that, compared with the two-dimensional (2D)-Exo-hydrogel treatment, 3D-Exo-hydrogel treatment yielded better recovery of corneal morphology and function, as revealed by mitigated inflammation, promoted corneal epithelium and limbus repair, and reduced scar formation in the stroma. Mechanistically, the 3D-Exos promoted the proliferation of cornea-derived cells and reduced the release of inflammatory factors via miR-150-5p targeting of the PDCD4 gene. Overall, the developed 3D-Exo-hydrogel sustained release system may represent a promising cell-free strategy for the treatment of various corneal diseases.
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Affiliation(s)
- Yuehe Xu
- Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, State Key Laboratory Cultivation Base, Shandong Key Laboratory of Eye Diseases, School of Ophthalmology, Shandong First Medical University, Qingdao 266071, China
| | - Chao Wei
- Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, State Key Laboratory Cultivation Base, Shandong Key Laboratory of Eye Diseases, School of Ophthalmology, Shandong First Medical University, Qingdao 266071, China
| | - Li Ma
- Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, State Key Laboratory Cultivation Base, Shandong Key Laboratory of Eye Diseases, School of Ophthalmology, Shandong First Medical University, Qingdao 266071, China
| | - Long Zhao
- Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, State Key Laboratory Cultivation Base, Shandong Key Laboratory of Eye Diseases, School of Ophthalmology, Shandong First Medical University, Qingdao 266071, China
| | - Dongfang Li
- Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, State Key Laboratory Cultivation Base, Shandong Key Laboratory of Eye Diseases, School of Ophthalmology, Shandong First Medical University, Qingdao 266071, China
| | - Yiliang Lin
- Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore 117585, Singapore
| | - Qingjun Zhou
- Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, State Key Laboratory Cultivation Base, Shandong Key Laboratory of Eye Diseases, School of Ophthalmology, Shandong First Medical University, Qingdao 266071, China
| | - Lixin Xie
- Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, State Key Laboratory Cultivation Base, Shandong Key Laboratory of Eye Diseases, School of Ophthalmology, Shandong First Medical University, Qingdao 266071, China
| | - Fuyan Wang
- Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, State Key Laboratory Cultivation Base, Shandong Key Laboratory of Eye Diseases, School of Ophthalmology, Shandong First Medical University, Qingdao 266071, China.
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Choi WG, Ko SJ, Jung D, Kim SC, Choi NR, Park JW, Kim BJ. Therapeutic Effects of Zanthoxyli Pericarpium on Intestinal Inflammation and Network Pharmacological Mechanism Analysis in a Dextran Sodium Sulfate-Induced Colitis Mouse Model. Nutrients 2024; 16:3521. [PMID: 39458516 PMCID: PMC11510417 DOI: 10.3390/nu16203521] [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: 09/05/2024] [Revised: 10/04/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024] Open
Abstract
(1) Background: IBD (inflammatory bowel disease) is characterized by chronic intestinal inflammation leading to persistent symptoms and a lack of effective treatments. ZP (Zanthoxyli Pericarpium) has been used in traditional Chinese medicine for its anti-inflammatory and antioxidant properties for the management of intestinal disorders. (2) Methods: This study aimed to investigate the components of ZP, their specific targets, and associated diseases using the TCMSP (Traditional Chinese Medicine Systems Pharmacology) analysis platform, TCMBank database, and ETCM2.0 (Encyclopedia of Traditional Chinese Medicine 2.0) database. Additionally, we explored the protective effects of ZP on the colon and the underlying molecular mechanisms in the treatment of IBD. (3) Results: We identified 59 compounds in ZP that target 38 genes related to IBD, including PTGS2, PPARG, and GPBAR1. In a mice model of DSS (dextran sodium sulfate)-induced colitis, ZP significantly reduced colonic epithelial damage and oxidative stress markers, such as iNOS and nitrotyrosine, demonstrating its antioxidant properties. (4) Conclusions: These findings suggest that ZP has protective effects against DSS-induced colonic damage owing to its anti-inflammatory and antioxidant properties, making it a potential candidate for IBD treatment. However, further research and clinical trials are required to confirm its therapeutic potential and safety in humans.
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Affiliation(s)
- Woo-Gyun Choi
- Department of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea; (W.-G.C.); (N.-R.C.)
| | - Seok-Jae Ko
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea;
- Department of Gastroenterology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Daehwa Jung
- Department of Pharmaceutical Engineering, Daegu Hanny University, Gyeongsan 38610, Republic of Korea;
| | - Sang Chan Kim
- College of Oriental Medicine, Daegu Haany University, Gyeongsan 38610, Republic of Korea;
| | - Na-Ri Choi
- Department of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea; (W.-G.C.); (N.-R.C.)
- Department of Korean Medical Science, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea
| | - Jae-Woo Park
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea;
- Department of Gastroenterology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Byung Joo Kim
- Department of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea; (W.-G.C.); (N.-R.C.)
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Regmi S, Pathak S, Chaudhary D, Kim JO, Nam JW, Kim HS, Jiang HL, Ryu D, Sung JH, Yook S, Jeong JH. Endogenous stem cell mobilization and localized immunosuppression synergistically ameliorate DSS-induced Colitis in mice. Stem Cell Res Ther 2024; 15:167. [PMID: 38872206 PMCID: PMC11170870 DOI: 10.1186/s13287-024-03777-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 05/28/2024] [Indexed: 06/15/2024] Open
Abstract
BACKGROUND Stem cell therapy is a promising alternative for inflammatory diseases and tissue injury treatment. Exogenous delivery of mesenchymal stem cells is associated with instant blood-mediated inflammatory reactions, mechanical stress during administration, and replicative senescence or change in phenotype during long-term culture in vitro. In this study, we aimed to mobilize endogenous hematopoietic stem cells (HSCs) using AMD-3100 and provide local immune suppression using FK506, an immunosuppressive drug, for the treatment of inflammatory bowel diseases. METHODS Reactive oxygen species (ROS)-responsive FK506-loaded thioketal microspheres were prepared by emulsification solvent-evaporation method. Thioketal vehicle based FK506 microspheres and AMD3100 were co-administered into male C57BL6/J mice with dextran sulfate sodium (DSS) induced colitis. The effect of FK506-loaded thioketal microspheres in colitis mice were evaluated using disease severity index, myeloperoxidase activity, histology, flow cytometry, and gene expression by qRT-PCR. RESULTS The delivery of AMD-3100 enhanced mobilization of HSCs from the bone marrow into the inflamed colon of mice. Furthermore, targeted oral delivery of FK506 in an inflamed colon inhibited the immune activation in the colon. In the DSS-induced colitis mouse model, the combination of AMD-3100 and FK506-loaded thioketal microspheres ameliorated the disease, decreased immune cell infiltration and activation, and improved body weight, colon length, and epithelial healing process. CONCLUSION This study shows that the significant increase in the percentage of mobilized hematopoietic stem cells in the combination therapy of AMD and oral FK506 microspheres may contribute to a synergistic therapeutic effect. Thus, low-dose local delivery of FK506 combined with AMD3100 could be a promising alternative treatment for inflammatory bowel diseases.
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Affiliation(s)
- Shobha Regmi
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
- Interventional Radiology Innovation at Stanford, Department of Radiology, School of Medicine, Stanford University, Stanford, CA, 94304, USA
| | - Shiva Pathak
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
- Division of Blood and Marrow Transplantation, School of Medicine, Stanford University, Stanford, CA, 94305, USA
| | - Dinesh Chaudhary
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Jong Oh Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
| | - Joo-Won Nam
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
| | - Hyung-Sik Kim
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan, 50612, Republic of Korea
- Dental and Life Science Institute, Pusan National University, Yangsan, 50612, Republic of Korea
| | - Hu-Lin Jiang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing, 210009, China
- Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, 210009, China
- NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing, 210009, China
| | - Dongryeol Ryu
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Jong-Hyuk Sung
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 21983, Republic of Korea.
- Epibiotech Co. Ltd., Incheon, 21983, Republic of Korea.
| | - Simmyung Yook
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
| | - Jee-Heon Jeong
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
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Hao J, Ma A, Sun C, Qin H, Zhu Y, Li G, Wang H, Wang H. Melatonin pretreatment improves endometrial regenerative cell-mediated therapeutic effects in experimental colitis. Int Immunopharmacol 2024; 133:112092. [PMID: 38626548 DOI: 10.1016/j.intimp.2024.112092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 04/04/2024] [Accepted: 04/11/2024] [Indexed: 04/18/2024]
Abstract
BACKGROUND Endometrial regenerative cells (ERCs) have been proven to be an effective strategy for attenuating experimental colitis, but the complex in vivo microenvironment such as oxidative stress may largely limit and weaken ERC efficacy. Melatonin (MT) works as an anti-oxidative agent in a variety of preclinical diseases, and has been identified to promote mesenchymal stem cell-mediated therapeutic effects in different diseases. However, the ability of MT to enhance ERC-mediated effects in colitis is currently poorly understood. METHODS Menstrual blood was collected from healthy female volunteers to obtain ERCs and identified. In vitro, H2O2-induced oxidative stress was introduced to test if MT could prevent ERCs from damage through detection of intracellular reactive oxidative species (ROS) and apoptosis assay. In vivo, dextran sodium sulfate (DSS)-induced acute colitis was treated by ERCs and MT-primed ERCs, therapeutic effects were assayed by the disease activity index (DAI), histological features, and macrophage and CD4+ T cell in the spleen and colon, and cytokine profiles in the sera and colon were also measured. RESULTS In vitro, ERCs that underwent MT-precondition were found to possess more anti-oxidative potency in comparison to naïve ERCs, which were characterized by decreased apoptosis rate and intracellular ROS under H2O2 stimulation. In vivo, MT pretreatment can significantly enhance the therapeutic effects of ERCs in the attenuation of experimental colitis, including decreased DAI index and damage score. In addition, MT pretreatment was found to promote ERC-mediated inhibition of Th1, Th17, and M1 macrophage and pro-inflammatory cytokines, increase of Treg, and immunomodulation of cytokines in the spleen and colon. CONCLUSIONS MT pretreatment facilitates the promotion of cell viability under oxidative stress in vitro, while also enhancing ERC-mediated therapeutic effects in experimental colitis.
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Affiliation(s)
- Jingpeng Hao
- Department of Anorectal Surgery, The Second Hospital of Tianjin Medical University, Tianjin, China.
| | - Ai Ma
- Department of Laboratory, The Second Hospital of Tianjin Medical University, Tianjin, China.
| | - Chenglu Sun
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China.
| | - Hong Qin
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China.
| | - Yanglin Zhu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China.
| | - Guangming Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China.
| | - Hongda Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China.
| | - Hao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China.
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Nguyen TT, Kil YS, Sung JH, Youn YS, Jeong JH, Lee JH, Jiang HL, Yook S, Nam JW, Jeong JH. Fabrication of stem cell heterospheroids with sustained-release chitosan and poly(lactic-co-glycolic acid) microspheres to guide cell fate toward chondrogenic differentiation. Int J Biol Macromol 2024; 263:130356. [PMID: 38395283 DOI: 10.1016/j.ijbiomac.2024.130356] [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: 10/30/2023] [Revised: 02/19/2024] [Accepted: 02/19/2024] [Indexed: 02/25/2024]
Abstract
Mesenchymal stem cell (MSC)-based therapies show great potential in treating various diseases. However, control of the fate of injected cells needs to be improved. In this work, we developed an efficient methodology for modulating chondrogenic differentiation of MSCs. We fabricated heterospheroids with two sustained-release depots, a quaternized chitosan microsphere (QCS-MP) and a poly (lactic-co-glycolic acid) microsphere (PLGA-MP). The results show that heterospheroids composed of 1 × 104 to 5 × 104 MSCs formed rapidly during incubation in methylcellulose medium and maintained high cell viability in long-term culture. The MPs were uniformly distributed in the heterospheroids, as shown by confocal laser scanning microscopy. Incorporation of transforming growth factor beta 3 into QCS-MPs and of dexamethasone into PLGA-MPs significantly promoted the expression of chondrogenic genes and high accumulation of glycosaminoglycan in heterospheroids. Changes in crucial metabolites in the dual drug depot-engineered heterospheroids were also evaluated using 1H NMR-based metabolomics analysis to verify their successful chondrogenic differentiation. Our heterospheroid fabrication platform could be used in tissue engineering to study the effects of various therapeutic agents on stem cell fate.
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Affiliation(s)
- Tiep Tien Nguyen
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Gyeonggi 16419, Republic of Korea; College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea; Epibiotech Co. Ltd., Incheon 21983, Republic of Korea
| | - Yun-Seo Kil
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea; College of Pharmacy, Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae, Gyeongnam 50834, Republic of Korea
| | - Jong-Hyuk Sung
- Epibiotech Co. Ltd., Incheon 21983, Republic of Korea; College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, Republic of Korea
| | - Yu Seok Youn
- School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi 16419, Republic of Korea
| | - Ji Hoon Jeong
- School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi 16419, Republic of Korea
| | - Jung Heon Lee
- School of Advanced Materials Science and Engineering, Sungkyunkwan University, Suwon, Gyeonggi 16419, Republic of Korea
| | - Hu-Lin Jiang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China; NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing 210009, China
| | - Simmyung Yook
- College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea; School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi 16419, Republic of Korea; Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon 16419, Republic of Korea.
| | - Joo-Won Nam
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea.
| | - Jee-Heon Jeong
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Gyeonggi 16419, Republic of Korea.
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Wong C, Stoilova I, Gazeau F, Herbeuval JP, Fourniols T. Mesenchymal stromal cell derived extracellular vesicles as a therapeutic tool: immune regulation, MSC priming, and applications to SLE. Front Immunol 2024; 15:1355845. [PMID: 38390327 PMCID: PMC10881725 DOI: 10.3389/fimmu.2024.1355845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 01/24/2024] [Indexed: 02/24/2024] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a dysfunction of the immune system. Mesenchymal stromal cell (MSCs) derived extracellular vesicles (EVs) are nanometer-sized particles carrying a diverse range of bioactive molecules, such as proteins, miRNAs, and lipids. Despite the methodological disparities, recent works on MSC-EVs have highlighted their broad immunosuppressive effect, thus driving forwards the potential of MSC-EVs in the treatment of chronic diseases. Nonetheless, their mechanism of action is still unclear, and better understanding is needed for clinical application. Therefore, we describe in this review the diverse range of bioactive molecules mediating their immunomodulatory effect, the techniques and possibilities for enhancing their immune activity, and finally the potential application to SLE.
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Affiliation(s)
- Christophe Wong
- EVerZom, Paris, France
- Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 8601, Université Paris Cité, Paris, France
- Chemistry and Biology, Modeling and Immunology for Therapy (CBMIT), Université Paris Cité, Paris, France
| | - Ivana Stoilova
- Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 8601, Université Paris Cité, Paris, France
- Chemistry and Biology, Modeling and Immunology for Therapy (CBMIT), Université Paris Cité, Paris, France
| | - Florence Gazeau
- Matière et Systèmes Complexes (MSC) UMR CNRS 7057, Université Paris Cité, Paris, France
| | - Jean-Philippe Herbeuval
- Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 8601, Université Paris Cité, Paris, France
- Chemistry and Biology, Modeling and Immunology for Therapy (CBMIT), Université Paris Cité, Paris, France
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Zhou Z, Wang J, Jiang C, Xu K, Xu T, Yu X, Fang J, Yang Y, Dai X. Advances in Hydrogels for Meniscus Tissue Engineering: A Focus on Biomaterials, Crosslinking, Therapeutic Additives. Gels 2024; 10:114. [PMID: 38391445 PMCID: PMC10887778 DOI: 10.3390/gels10020114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 01/23/2024] [Accepted: 01/26/2024] [Indexed: 02/24/2024] Open
Abstract
Meniscus tissue engineering (MTE) has emerged as a promising strategy for meniscus repair and regeneration. As versatile platforms, hydrogels have gained significant attention in this field, as they possess tunable properties that allow them to mimic native extracellular matrices and provide a suitable microenvironment. Additionally, hydrogels can be minimally invasively injected and can be adjusted to match the shape of the implant site. They can conveniently and effectively deliver bioactive additives and demonstrate good compatibility with other functional materials. These inherent qualities have made hydrogel a promising candidate for therapeutic approaches in meniscus repair and regeneration. This article provides a comprehensive review of the advancements made in the research on hydrogel application for meniscus tissue engineering. Firstly, the biomaterials and crosslinking strategies used in the formation of hydrogels are summarized and analyzed. Subsequently, the role of therapeutic additives, including cells, growth factors, and other active products, in facilitating meniscus repair and regeneration is thoroughly discussed. Furthermore, we summarize the key issues for designing hydrogels used in MTE. Finally, we conclude with the current challenges encountered by hydrogel applications and suggest potential solutions for addressing these challenges in the field of MTE. We hope this review provides a resource for researchers and practitioners interested in this field, thereby facilitating the exploration of new design possibilities.
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Affiliation(s)
- Zhuxing Zhou
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou 310000, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou 310000, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou 310000, China
| | - Jiajie Wang
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou 310000, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou 310000, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou 310000, China
| | - Chaoqian Jiang
- School of Materials and Engineering, Zhengzhou University, Zhengzhou 450001, China
| | - Kaiwang Xu
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou 310000, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou 310000, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou 310000, China
| | - Tengjing Xu
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou 310000, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou 310000, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou 310000, China
| | - Xinning Yu
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou 310000, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou 310000, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou 310000, China
| | - Jinghua Fang
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou 310000, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou 310000, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou 310000, China
| | - Yanyu Yang
- School of Materials and Engineering, Zhengzhou University, Zhengzhou 450001, China
| | - Xuesong Dai
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou 310000, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou 310000, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou 310000, China
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Chen Z, Yao MW, Shen ZL, Li SD, Xing W, Guo W, Li Z, Wu XF, Ao LQ, Lu WY, Lian QZ, Xu X, Ao X. Interferon-gamma and tumor necrosis factor-alpha synergistically enhance the immunosuppressive capacity of human umbilical-cord-derived mesenchymal stem cells by increasing PD-L1 expression. World J Stem Cells 2023; 15:787-806. [PMID: 37700823 PMCID: PMC10494569 DOI: 10.4252/wjsc.v15.i8.787] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 06/20/2023] [Accepted: 07/24/2023] [Indexed: 08/25/2023] Open
Abstract
BACKGROUND The immunosuppressive capacity of mesenchymal stem cells (MSCs) is dependent on the "license" of several proinflammatory factors to express immunosuppressive factors such as programmed cell death 1 ligand 1 (PD-L1), which determines the clinical therapeutic efficacy of MSCs for inflammatory or immune diseases. In MSCs, interferon-gamma (IFN-γ) is a key inducer of PD-L1 expression, which is synergistically enhanced by tumor necrosis factor-alpha (TNF-α); however, the underlying mechanism is unclear. AIM To reveal the mechanism of pretreated MSCs express high PD-L1 and explore the application of pretreated MSCs in ulcerative colitis. METHODS We assessed PD-L1 expression in human umbilical-cord-derived MSCs (hUC-MSCs) induced by IFN-γ and TNF-α, alone or in combination. Additionally, we performed signal pathway inhibitor experiments as well as RNA interference experiments to elucidate the molecular mechanism by which IFN-γ alone or in combination with TNF-α induces PD-L1 expression. Moreover, we used luciferase reporter gene experiments to verify the binding sites of the transcription factors of each signal transduction pathway to the targeted gene promoters. Finally, we evaluated the immunosuppressive capacity of hUC-MSCs treated with IFN-γ and TNF-α in both an in vitro mixed lymphocyte culture assay, and in vivo in mice with dextran sulfate sodium-induced acute colitis. RESULTS Our results suggest that IFN-γ induction alone upregulates PD-L1 expression in hUC-MSCs while TNF-α alone does not, and that the co-induction of IFN-γ and TNF-α promotes higher expression of PD-L1. IFN-γ induces hUC-MSCs to express PD-L1, in which IFN-γ activates the JAK/STAT1 signaling pathway, up-regulates the expression of the interferon regulatory factor 1 (IRF1) transcription factor, promotes the binding of IRF1 and the PD-L1 gene promoter, and finally promotes PD-L1 mRNA. Although TNF-α alone did not induce PD-L1 expression in hUC-MSCs, the addition of TNF-α significantly enhanced IFN-γ-induced JAK/STAT1/IRF1 activation. TNF-α up-regulated IFN-γ receptor expression through activation of the nuclear factor kappa-B signaling pathway, which significantly enhanced IFN-γ signaling. Finally, co-induced hUC-MSCs have a stronger inhibitory effect on lymphocyte proliferation, and significantly ameliorate weight loss, mucosal damage, inflammatory cell infiltration, and up-regulation of inflammatory factors in colitis mice. CONCLUSION Overall, our results suggest that IFN-γ and TNF-α enhance both the immunosuppressive ability of hUC-MSCs and their efficacy in ulcerative colitis by synergistically inducing high expression of PD-L1.
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Affiliation(s)
- Zhuo Chen
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
- College of Basic Medical Sciences, Army Medical University, Chongqing 400038, China
| | - Meng-Wei Yao
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Zhi-Lin Shen
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Shi-Dan Li
- Department of Orthopedics, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Wei Xing
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Wei Guo
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Zhan Li
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Xiao-Feng Wu
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Luo-Quan Ao
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Wen-Yong Lu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, The South of Shangcai Village, Wenzhou 325005, Zhejiang Province, China
| | - Qi-Zhou Lian
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
| | - Xiang Xu
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Xiang Ao
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
- Department of Orthopedics, 953 Hospital of PLA Army, Shigatse Branch of Xinqiao Hospital, Army Medical University, Shigatse 857000, Tibet Autonomous Region, China.
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9
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Kasravi M, Ahmadi A, Babajani A, Mazloomnejad R, Hatamnejad MR, Shariatzadeh S, Bahrami S, Niknejad H. Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine. Biomater Res 2023; 27:10. [PMID: 36759929 PMCID: PMC9912640 DOI: 10.1186/s40824-023-00348-z] [Citation(s) in RCA: 79] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 01/30/2023] [Indexed: 02/11/2023] Open
Abstract
Tissue-engineered decellularized extracellular matrix (ECM) scaffolds hold great potential to address the donor shortage as well as immunologic rejection attributed to cells in conventional tissue/organ transplantation. Decellularization, as the key process in manufacturing ECM scaffolds, removes immunogen cell materials and significantly alleviates the immunogenicity and biocompatibility of derived scaffolds. However, the application of these bioscaffolds still confronts major immunologic challenges. This review discusses the interplay between damage-associated molecular patterns (DAMPs) and antigens as the main inducers of innate and adaptive immunity to aid in manufacturing biocompatible grafts with desirable immunogenicity. It also appraises the impact of various decellularization methodologies (i.e., apoptosis-assisted techniques) on provoking immune responses that participate in rejecting allogenic and xenogeneic decellularized scaffolds. In addition, the key research findings regarding the contribution of ECM alterations, cytotoxicity issues, graft sourcing, and implantation site to the immunogenicity of decellularized tissues/organs are comprehensively considered. Finally, it discusses practical solutions to overcome immunogenicity, including antigen masking by crosslinking, sterilization optimization, and antigen removal techniques such as selective antigen removal and sequential antigen solubilization.
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Affiliation(s)
- Mohammadreza Kasravi
- grid.411600.2Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985711151 Iran ,grid.411600.2Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Armin Ahmadi
- grid.411600.2Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985711151 Iran
| | - Amirhesam Babajani
- grid.411600.2Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985711151 Iran
| | - Radman Mazloomnejad
- grid.411600.2Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985711151 Iran
| | - Mohammad Reza Hatamnejad
- grid.411600.2Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Siavash Shariatzadeh
- grid.19006.3e0000 0000 9632 6718Department of Surgery, University of California Los Angeles, Los Angeles, California USA
| | - Soheyl Bahrami
- grid.454388.60000 0004 6047 9906Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in AUVA Research Center, Vienna, Austria
| | - Hassan Niknejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985711151, Iran.
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Mao Q, Pan H, Zhang Y, Zhang Y, Zhu Q, Hong Y, Huang Z, Li Y, Feng X, Fang Y, Chen W, Chen P, Shen B, Ouyang H, Liang Y. GelNB molecular coating as a biophysical barrier to isolate intestinal irritating metabolites and regulate intestinal microbial homeostasis in the treatment of inflammatory bowel disease. Bioact Mater 2023; 19:251-267. [PMID: 35510173 PMCID: PMC9046703 DOI: 10.1016/j.bioactmat.2022.04.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 03/23/2022] [Accepted: 04/01/2022] [Indexed: 11/26/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic, immune-mediated inflammatory disease characterized by the destruction of the structure and function of the intestinal epithelial barrier. Due to the poor remission effect and severe adverse events associated with current clinical medications, IBD remains an incurable disease. Here, we demonstrated a novel treatment strategy with high safety and effective inflammation remission via tissue-adhesive molecular coating. The molecular coating is composed of o-nitrobenzaldehyde (NB)-modified Gelatin (GelNB), which can strongly bond with –NH2 on the intestinal surface of tissue to form a thin biophysical barrier. We found that this molecular coating was able to stay on the surface of the intestine for long periods of time, effectively protecting the damaged intestinal epithelium from irritations of external intestinal metabolites and harmful flora. In addition, our results showed that this coating not only provided a beneficial environment for cell migration and proliferation to promote intestinal repair and regeneration, but also achieved a better outcome of IBD by reducing intestinal inflammation. Moreover, the in vivo experiments showed that the GelNB was better than the classic clinical medication—mesalazine. Therefore, our molecular coating showed potential as a promising strategy for the prevention and treatment of IBD.
GelNB molecular coating can protect the intestinal epithelium from irritations of intestinal metabolites and harmful flora. GelNB molecular coating not only promote intestinal repair and regeneration, but also reduce intestinal inflammation. GelNB molecular coating shows potential as a promising strategy for the prevention and treatment of IBD.
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Affiliation(s)
- Qijiang Mao
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- Key Laboratory of Laparoscopic Technology of Zhejiang province, Hangzhou, 310016, China
- Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou, 310028, China
| | - Haoqi Pan
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
| | - Yiyin Zhang
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
| | - Yi Zhang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiuwen Zhu
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Yi Hong
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhengze Huang
- Key Laboratory of Laparoscopic Technology of Zhejiang province, Hangzhou, 310016, China
| | - Yang Li
- The State Key Laboratory of Fluid Power and Mechatronic Systems, School of Mechanical Engineering, Zhejiang University, Hangzhou, 310028, China
| | - Xu Feng
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
| | - Yifeng Fang
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
| | - WenChao Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
| | - Pengfei Chen
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, Zhejiang, 310016, China
| | - Bo Shen
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- Key Laboratory of Laparoscopic Technology of Zhejiang province, Hangzhou, 310016, China
- Corresponding author. Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
| | - Hongwei Ouyang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
- Corresponding author. Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China.
| | - Yuelong Liang
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- Key Laboratory of Laparoscopic Technology of Zhejiang province, Hangzhou, 310016, China
- Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou, 310028, China
- Corresponding author. Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
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11
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Ahn JS, Shin YY, Oh SJ, Song MH, Kang MJ, Park SY, Nguyen PT, Nguyen DK, Kim HK, Han J, Vasileva EA, Mishchenko NP, Fedoreyev SA, Stonik VA, Seo Y, Lee BC, Kim HS. Implication of Echinochrome A in the Plasticity and Damage of Intestinal Epithelium. Mar Drugs 2022; 20:715. [PMID: 36421992 PMCID: PMC9693993 DOI: 10.3390/md20110715] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/05/2022] [Accepted: 11/10/2022] [Indexed: 05/31/2024] Open
Abstract
The diverse therapeutic feasibility of the sea urchin-derived naphthoquinone pigment, Echinochrome A (Ech A), has been studied. Simple and noninvasive administration routes should be explored, to obtain the feasibility. Although the therapeutic potential has been proven through several preclinical studies, the biosafety of orally administered Ech A and its direct influence on intestinal cells have not been evaluated. To estimate the bioavailability of Ech A as an oral administration drug, small intestinal and colonic epithelial organoids were developed from mice and humans. The morphology and cellular composition of intestinal organoids were evaluated after Ech A treatment. Ech A treatment significantly increased the expression of LGR5 (~2.38-fold change, p = 0.009) and MUC2 (~1.85-fold change, p = 0.08). Notably, in the presence of oxidative stress, Ech A attenuated oxidative stress up to 1.8-fold (p = 0.04), with a restored gene expression of LGR5 (~4.11-fold change, p = 0.0004), as well as an increased expression of Ly6a (~3.51-fold change, p = 0.005) and CLU (~2.5-fold change, p = 0.01), markers of revival stem cells. In conclusion, Ech A is harmless to intestinal tissues; rather, it promotes the maintenance and regeneration of the intestinal epithelium, suggesting possible beneficial effects on the intestine when used as an oral medication.
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Affiliation(s)
- Ji-Su Ahn
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
- Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Ye Young Shin
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
- Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Su-Jeong Oh
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
- Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Min-Hye Song
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Min-Jung Kang
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - So Yeong Park
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
- Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Phuong Thao Nguyen
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
- Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Dang Khoa Nguyen
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
- Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Hyoung Kyu Kim
- Basic Research Laboratory, Department of Physiology, College of Medicine, Smart Marine Therapeutic Center, Cardiovascular and Metabolic Disease Center, Inje University, Busan 614-735, Republic of Korea
| | - Jin Han
- Basic Research Laboratory, Department of Physiology, College of Medicine, Smart Marine Therapeutic Center, Cardiovascular and Metabolic Disease Center, Inje University, Busan 614-735, Republic of Korea
| | - Elena A Vasileva
- G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch of the Russian Academy of Science, 690022 Vladivostok, Russia
| | - Natalia P Mishchenko
- G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch of the Russian Academy of Science, 690022 Vladivostok, Russia
| | - Sergey A Fedoreyev
- G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch of the Russian Academy of Science, 690022 Vladivostok, Russia
| | - Valentin A Stonik
- G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch of the Russian Academy of Science, 690022 Vladivostok, Russia
| | - Yoojin Seo
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Byung-Chul Lee
- Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Hyung-Sik Kim
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
- Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
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12
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Curcumin-laden ECM-mimicking microfibers assemble with mesenchymal stem cells to generate heterospheroids and enhance cell viability and function. J IND ENG CHEM 2022. [DOI: 10.1016/j.jiec.2022.08.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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13
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Nguyen TT, Pham DV, Park J, Phung CD, Nepal MR, Pandit M, Shrestha M, Son Y, Joshi M, Jeong TC, Park PH, Choi DY, Chang JH, Kim JH, Kim JR, Kim IK, Yong CS, Kim JO, Sung JH, Jiang HL, Kim HS, Yook S, Jeong JH. Engineering of hybrid spheroids of mesenchymal stem cells and drug depots for immunomodulating effect in islet xenotransplantation. SCIENCE ADVANCES 2022; 8:eabn8614. [PMID: 36001671 PMCID: PMC9401619 DOI: 10.1126/sciadv.abn8614] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 07/11/2022] [Indexed: 06/15/2023]
Abstract
Immunomodulation is an essential consideration for cell replacement procedures. Unfortunately, lifelong exposure to nonspecific systemic immunosuppression results in immunodeficiency and has toxic effects on nonimmune cells. Here, we engineered hybrid spheroids of mesenchymal stem cells (MSCs) with rapamycin-releasing poly(lactic-co-glycolic acid) microparticles (RAP-MPs) to prevent immune rejection of islet xenografts in diabetic C57BL/6 mice. Hybrid spheroids were rapidly formed by incubating cell-particle mixture in methylcellulose solution while maintaining high cell viability. RAP-MPs were uniformly distributed in hybrid spheroids and sustainably released RAP for ~3 weeks. Locoregional transplantation of hybrid spheroids containing low doses of RAP-MPs (200- to 4000-ng RAP per recipient) significantly prolonged islet survival times and promoted the generation of regional regulatory T cells. Enhanced programmed death-ligand 1 expression by MSCs was found to be responsible for the immunomodulatory performance of hybrid spheroids. Our results suggest that these hybrid spheroids offer a promising platform for the efficient use of MSCs in the transplantation field.
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Affiliation(s)
- Tiep Tien Nguyen
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
- College of Pharmacy, Keimyung University, Daegu, 42601, Republic of Korea
| | - Duc-Vinh Pham
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
| | - Junhyeung Park
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
| | - Cao Dai Phung
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
| | - Mahesh Raj Nepal
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
| | - Mahesh Pandit
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
| | - Manju Shrestha
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
| | - Youlim Son
- College of Medicine, Yeungnam University, Daegu, 42415, Republic of Korea
| | - Mili Joshi
- College of Medicine, Yeungnam University, Daegu, 42415, Republic of Korea
| | - Tae Cheon Jeong
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
| | - Pil-Hoon Park
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
| | - Dong-Young Choi
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
| | - Jae-Hoon Chang
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
| | - Ju-Hyun Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
| | - Jae-Ryong Kim
- College of Medicine, Yeungnam University, Daegu, 42415, Republic of Korea
| | - Il-Kug Kim
- College of Medicine, Yeungnam University, Daegu, 42415, Republic of Korea
| | - Chul Soon Yong
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
| | - Jong Oh Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
| | - Jong-Hyuk Sung
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 21983, Republic of Korea
- Epibiotech Co. Ltd., Incheon, 21983, Republic of Korea
| | - Hu-Lin Jiang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing, 210009, China
- Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, 210009, China
- NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing, 210009, China
| | - Hyung-Sik Kim
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan, 50612, Republic of Korea
- Dental and Life Science Institute, Pusan National University, Yangsan, 50612, Republic of Korea
| | - Simmyung Yook
- College of Pharmacy, Keimyung University, Daegu, 42601, Republic of Korea
| | - Jee-Heon Jeong
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, 16419, Republic of Korea
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14
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Biological Activities Underlying the Therapeutic Effect of Quercetin on Inflammatory Bowel Disease. Mediators Inflamm 2022; 2022:5665778. [PMID: 35915741 PMCID: PMC9338876 DOI: 10.1155/2022/5665778] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 07/15/2022] [Indexed: 11/18/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic autoimmune disorder stemming from unrestrained immune activation and subsequent destruction of colon tissue. Genetic susceptibility, microbiota remodeling, and environmental cues are involved in IBD pathogenesis. Up to now, there are limited treatment options for IBD, so better therapies for IBD are eagerly needed. The therapeutic effects of naturally occurring compounds have been extensively investigated, among which quercetin becomes an attractive candidate owing to its unique biochemical properties. To facilitate the clinical translation of quercetin, we aimed to get a comprehensive understanding of the cellular and molecular mechanisms underlying the anti-IBD role of quercetin. We summarized that quercetin exerts the anti-IBD effect through consolidating the intestinal mucosal barrier, enhancing the diversity of colonic microbiota, restoring local immune homeostasis, and restraining the oxidative stress response. We also delineated the effect of quercetin on gut microbiome and discussed the potential side effects of quercetin administration. Besides, quercetin could serve as a prodrug, and the bioavailability of quercetin is improved through chemical modifications or the utilization of effective drug delivery systems. Altogether, these lines of evidence hint the feasibility of quercetin as a candidate compound for IBD treatment.
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15
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Xu Y, Tang X, Fang A, Yan J, Kofi Wiredu Ocansey D, Zhang X, Mao F. HucMSC-Ex carrying miR-203a-3p.2 ameliorates colitis through the suppression of caspase11/4-induced macrophage pyroptosis. Int Immunopharmacol 2022; 110:108925. [PMID: 35724605 DOI: 10.1016/j.intimp.2022.108925] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 05/17/2022] [Accepted: 05/21/2022] [Indexed: 12/27/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a kind of chronic, idiopathic, and recurrent inflammation, associated with dysregulated intestinal mucosal immunity. Caspase (casp) 11/4-induced macrophage pyroptosis contributes to the development of inflammation, while human umbilical cord mesenchymal stem cell-secreted exosomes (hucMSC-Ex) play a reparative role in IBD. OBJECTIVE The present study focused on the treatment of IBD with hucMSC-Ex and its regulatory mechanism via the casp11/4 pathway. METHODS BALB/c mice were used to establish a dextran sulfate sodium (DSS)-induced colitis model, and hucMSC-Ex was administered intravenously to estimate its therapeutic effect. In vitro, RAW264.7 cells line, THP-1 cells line, and mouse peritoneal macrophages (MPMs) were stimulated with lipopolysaccharides (LPS) to activate an inflammatory environment of pyroptosis, followed by repairing with hucMSC-Ex. MicroRNA mimics and inhibitors were provided to verify the role of miR-203a-3p.2 from hucMSC-Ex in inflammation. The results were analyzed by Western blot, RT-qPCR、ELISA, and LDH secretion. RESULTS HucMSC-Ex inhibited the activation of casp11 and reduced the secretion of interleukin (IL)-1β, IL-6, and casp11, which relieved macrophage pyroptosis to alleviate murine colitis. A consistent outcome was revealed in the cell experiments, where hucMSC-Ex contributed to a decreased casp11/4 expression, and lactate dehydrogenase (LDH) release, as a marker of cell damage. Moreover, miR-203a-3p.2 from hucMSC-Ex functioned as an effective mediator in the interaction with casp4 in THP-1 macrophage pyroptosis. CONCLUSION HucMSC-Ex ameliorates colitis through the suppression of casp11/4-induced macrophage pyroptosis, and hucMSC-Ex carrying miR-203a-3p.2 inhibits casp4-induced macrophage pyroptosis in an inflammatory environment.
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Affiliation(s)
- Yuting Xu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China
| | - Xiaohua Tang
- The People's Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, Zhenjiang, Jiangsu, 212300, PR China
| | - Anning Fang
- Department of Basic Medicine, Anhui Medical College; Hefei, Anhui 230601, PR China
| | - Jialai Yan
- Medical Technology School, Anhui Medical Colleg, Hefei, Anhui 230061, PR China
| | - Dickson Kofi Wiredu Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China; Directorate of University Health Services, University of Cape Coast, Cape Coast, Ghana
| | - Xu Zhang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China.
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16
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Osouli-Bostanabad K, Masalehdan T, Kapsa RMI, Quigley A, Lalatsa A, Bruggeman KF, Franks SJ, Williams RJ, Nisbet DR. Traction of 3D and 4D Printing in the Healthcare Industry: From Drug Delivery and Analysis to Regenerative Medicine. ACS Biomater Sci Eng 2022; 8:2764-2797. [PMID: 35696306 DOI: 10.1021/acsbiomaterials.2c00094] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Three-dimensional (3D) printing and 3D bioprinting are promising technologies for a broad range of healthcare applications from frontier regenerative medicine and tissue engineering therapies to pharmaceutical advancements yet must overcome the challenges of biocompatibility and resolution. Through comparison of traditional biofabrication methods with 3D (bio)printing, this review highlights the promise of 3D printing for the production of on-demand, personalized, and complex products that enhance the accessibility, effectiveness, and safety of drug therapies and delivery systems. In addition, this review describes the capacity of 3D bioprinting to fabricate patient-specific tissues and living cell systems (e.g., vascular networks, organs, muscles, and skeletal systems) as well as its applications in the delivery of cells and genes, microfluidics, and organ-on-chip constructs. This review summarizes how tailoring selected parameters (i.e., accurately selecting the appropriate printing method, materials, and printing parameters based on the desired application and behavior) can better facilitate the development of optimized 3D-printed products and how dynamic 4D-printed strategies (printing materials designed to change with time or stimulus) may be deployed to overcome many of the inherent limitations of conventional 3D-printed technologies. Comprehensive insights into a critical perspective of the future of 4D bioprinting, crucial requirements for 4D printing including the programmability of a material, multimaterial printing methods, and precise designs for meticulous transformations or even clinical applications are also given.
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Affiliation(s)
- Karim Osouli-Bostanabad
- Biomaterials, Bio-engineering and Nanomedicine (BioN) Lab, Institute of Biomedical and Biomolecular, Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, White Swan Road, Portsmouth PO1 2DT, United Kingdom
| | - Tahereh Masalehdan
- Department of Materials Engineering, Institute of Mechanical Engineering, University of Tabriz, Tabriz 51666-16444, Iran
| | - Robert M I Kapsa
- Biomedical and Electrical Engineering, School of Engineering, RMIT University, Melbourne, Victoria 3000, Australia.,Department of Medicine, St Vincent's Hospital Melbourne, University of Melbourne, Fitzroy, Victoria 3065, Australia
| | - Anita Quigley
- Biomedical and Electrical Engineering, School of Engineering, RMIT University, Melbourne, Victoria 3000, Australia.,Department of Medicine, St Vincent's Hospital Melbourne, University of Melbourne, Fitzroy, Victoria 3065, Australia
| | - Aikaterini Lalatsa
- Biomaterials, Bio-engineering and Nanomedicine (BioN) Lab, Institute of Biomedical and Biomolecular, Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, White Swan Road, Portsmouth PO1 2DT, United Kingdom
| | - Kiara F Bruggeman
- Laboratory of Advanced Biomaterials, Research School of Chemistry and the John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia.,Research School of Electrical, Energy and Materials Engineering, The Australian National University, Canberra, Australian Capital Territory 2601, Australia
| | - Stephanie J Franks
- Laboratory of Advanced Biomaterials, Research School of Chemistry and the John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia
| | - Richard J Williams
- Institute of Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Waurn Ponds, Victoria 3216, Australia
| | - David R Nisbet
- Laboratory of Advanced Biomaterials, Research School of Chemistry and the John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia.,The Graeme Clark Institute, The University of Melbourne, Melbourne, Victoria 3010, Australia.,Department of Biomedical Engineering, Faculty of Engineering and Information Technology, The University of Melbourne, Melbourne, Victoria 3010, Australia
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17
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Huldani H, Margiana R, Ahmad F, Opulencia MJC, Ansari MJ, Bokov DO, Abdullaeva NN, Siahmansouri H. Immunotherapy of inflammatory bowel disease (IBD) through mesenchymal stem cells. Int Immunopharmacol 2022; 107:108698. [PMID: 35306284 DOI: 10.1016/j.intimp.2022.108698] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/02/2022] [Accepted: 03/10/2022] [Indexed: 02/07/2023]
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18
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Liu X, Hu L, Liu F. Mesenchymal stem cell-derived extracellular vesicles for cell-free therapy of ocular diseases. EXTRACELLULAR VESICLES AND CIRCULATING NUCLEIC ACIDS 2022; 3:102-117. [PMID: 39698446 PMCID: PMC11648472 DOI: 10.20517/evcna.2022.08] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/31/2022] [Accepted: 04/18/2022] [Indexed: 12/20/2024]
Abstract
Mesenchymal stem cells-derived extracellular vesicles (MSC-EVs) have noticeably attracted clinicians' attention in treating ocular diseases. As the paracrine factor of MSCs and an alternative for cell-free therapies, MSC-EVs can be conveniently dropped over the ocular surface or diffused through the retina upon intravitreal injection, without increasing the risks of cellular rejection and tumor formation. For clinical translation, a standardized and scalable production, as well as reprogramming the MSC-EVs, are highly encouraged. This review aims to assess the potential approaches for EV production and functional modification, in addition to summarizing the worldwide clinical trials initiated for various physiological systems and the specific biochemical effects of MSC-EVs on the therapy of eye diseases. Recent advances in the therapy of ocular diseases based on MSC-EVs are reviewed, and the associated challenges and prospects are discussed as well.
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Affiliation(s)
- Xiaoling Liu
- Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Liang Hu
- Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Fei Liu
- Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
- Wenzhou Institute, University of Chinese Academy of Science, Wenzhou 325000, Zhejiang, China
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19
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Improving the Efficacy of Mesenchymal Stem/Stromal-Based Therapy for Treatment of Inflammatory Bowel Diseases. Biomedicines 2021; 9:biomedicines9111507. [PMID: 34829736 PMCID: PMC8615066 DOI: 10.3390/biomedicines9111507] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/14/2021] [Accepted: 10/14/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBD) consisting of persistent and relapsing inflammatory processes of the intestinal mucosa are caused by genetic, environmental, and commensal microbiota factors. Despite recent advances in clinical treatments aiming to decrease inflammation, nearly 30% of patients treated with biologicals experienced drawbacks including loss of response, while others can develop severe side effects. Hence, novel effective treatments are highly needed. Mesenchymal stem/stromal cell (MSCs) therapy is an innovative therapeutic alternative currently under investigation for IBD. MSCs have the inherent capacity of modulating inflammatory immune responses as well as regenerating damaged tissues and are therefore a prime candidate to use as cell therapy in patients with IBD. At present, MSC-based therapy has been shown preclinically to modulate intestinal inflammation, whilst the safety of MSC-based therapy has been demonstrated in clinical trials. However, the successful results in preclinical studies have not been replicated in clinical trials. In this review, we will summarize the protocols used in preclinical and clinical trials and the novel approaches currently under investigation which aim to increase the beneficial effects of MSC-based therapy for IBD.
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20
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Jiang L, Luo S, Qiu T, Li Q, Jiang C, Sun X, Yang G, Zhang C, Liu X, Jiang L. Bidirectional role of reactive oxygen species during inflammasome activation in acrolein-induced human EAhy926 cells pyroptosis. Toxicol Mech Methods 2021; 31:680-689. [PMID: 34238121 DOI: 10.1080/15376516.2021.1953204] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Acrolein, a known toxin in tobacco smoke, has been demonstrated to be associated with inflammatory cardiovascular diseases, such as atherosclerosis. However, the definite mechanism of acrolein-induced inflammation remains unclear. Here, we report that acrolein induces reactive oxygen species (ROS) production in EAhy926 cells. Additionally, acrolein induces EAhy926 cells' inflammatory response and pyroptosis by activating NOD-like receptor protein 3 (NLRP3) inflammasome. Also, acrolein-induced cytotoxicity could be attenuated by N-acetyl-L-cysteine (NAC). Furthermore, acrolein upregulates the level of autophagy which can be reversed by NAC. Notably, the present study also indicates that autophagy inhibited by inhibitor 3-methyladenine (3MA) and siAtg7 exacerbate acrolein-induced NLRP3 inflammasome activation and pyroptosis. In summary, acrolein induced cytotoxicity by ROS-mediated NLRP3 inflammasome activation, and ROS upregulates the level of autophagy to inhibit the NLRP3 inflammasome excessive activation, indicating the bidirectional role of ROS in acrolein-induced cellular inflammation. Our results may provide novel mechanistic insights into acrolein-induced cardiovascular toxicity.
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Affiliation(s)
- Liping Jiang
- Preventive Medicine Laboratory, College of Public Health, Dalian Medical University, Dalian, Liaoning, China
| | - Songsong Luo
- Department of Internal Medicine, The Affiliated Zhong Shan Hospital of Dalian University, Dalian, Liaoning, China
| | - Tianming Qiu
- Department of Occupational and Environmental Health, College of Public Health, Dalian Medical University, Dalian, Liaoning, China
| | | | - Chunteng Jiang
- Department of Internal Medicine, The Affiliated Zhong Shan Hospital of Dalian University, Dalian, Liaoning, China
| | - Xiance Sun
- Department of Occupational and Environmental Health, College of Public Health, Dalian Medical University, Dalian, Liaoning, China
| | - Guang Yang
- Department of Nutrition and Food Safety, College of Public Health, Dalian Medical University, Dalian, Liaoning, China
| | - Cong Zhang
- Department of Nutrition and Food Safety, College of Public Health, Dalian Medical University, Dalian, Liaoning, China
| | - Xiaofang Liu
- Department of Nutrition and Food Safety, College of Public Health, Dalian Medical University, Dalian, Liaoning, China
| | - Lijie Jiang
- Department of Internal Medicine, The Affiliated Zhong Shan Hospital of Dalian University, Dalian, Liaoning, China
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21
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Superoxide Dismutase 3-Transduced Mesenchymal Stem Cells Preserve Epithelial Tight Junction Barrier in Murine Colitis and Attenuate Inflammatory Damage in Epithelial Organoids. Int J Mol Sci 2021; 22:ijms22126431. [PMID: 34208517 PMCID: PMC8233984 DOI: 10.3390/ijms22126431] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 06/04/2021] [Accepted: 06/11/2021] [Indexed: 01/08/2023] Open
Abstract
Superoxide dismutase 3 (SOD3), also known as extracellular superoxide dismutase, is an enzyme that scavenges reactive oxygen species (ROS). It has been reported that SOD3 exerts anti-inflammatory abilities in several immune disorders. However, the effect of SOD3 and the underlying mechanism in inflammatory bowel disease (IBD) have not been uncovered. Therefore, in the present study, we investigated whether SOD3 can protect intestinal cells or organoids from inflammation-mediated epithelial damage. Cells or mice were treated with SOD3 protein or SOD3-transduced mesenchymal stem cells (MSCs). Caco-2 cells or intestinal organoids stimulated with pro-inflammatory cytokines were used to evaluate the protective effect of SOD3 on epithelial junctional integrity. Dextran sulfate sodium (DSS)-induced colitis mice received SOD3 or SOD3-transduced MSCs (SOD3-MSCs), and were assessed for severity of disease and junctional protein expression. The activation of the mitogen-activated protein kinase (MAPK) pathway and elevated expression of cytokine-encoding genes decreased in TNF-α-treated Caco-2 cells or DSS-induced colitis mice when treated with SOD3 or SOD3-MSCs. Moreover, the SOD3 supply preserved the expression of tight junction (ZO-1, occludin) or adherence junction (E-cadherin) proteins when inflammation was induced. SOD3 also exerted a protective effect against cytokine- or ROS-mediated damage to intestinal organoids. These results indicate that SOD3 can effectively alleviate enteritis symptoms by maintaining the integrity of epithelial junctions and regulating inflammatory- and oxidative stress.
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22
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Strategies to Potentiate Paracrine Therapeutic Efficacy of Mesenchymal Stem Cells in Inflammatory Diseases. Int J Mol Sci 2021; 22:ijms22073397. [PMID: 33806241 PMCID: PMC8037333 DOI: 10.3390/ijms22073397] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 03/23/2021] [Accepted: 03/23/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have been developed as cell therapeutics for various immune disorders using their immunoregulatory properties mainly exerted by their paracrine functions. However, variation among cells from different donors, as well as rapid clearance after transplantation have impaired the uniform efficacy of MSCs and limited their application. Recently, several strategies to overcome this limitation have been suggested and proven in pre-clinical settings. Therefore, in this review article, we will update the knowledge on bioengineering strategies to improve the immunomodulatory functions of MSCs, including genetic modification and physical engineering.
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