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Chen QH, Zheng JY, Wang DC. Asthma and stem cell therapy. World J Stem Cells 2025; 17:103599. [DOI: 10.4252/wjsc.v17.i2.103599] [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: 11/28/2024] [Revised: 12/23/2024] [Accepted: 02/05/2025] [Indexed: 02/24/2025] Open
Abstract
The global incidence of asthma, a leading respiratory disorder affecting more than 235 million people, has dramatically increased in recent years. Characterized by chronic airway inflammation and an imbalanced response to airborne irritants, this chronic condition is associated with elevated levels of inflammatory factors and symptoms such as dyspnea, cough, wheezing, and chest tightness. Conventional asthma therapies, such as corticosteroids, long-acting β-agonists, and anti-inflammatory agents, often evoke diverse adverse reactions and fail to reduce symptoms and hospitalization rates over the long term effectively. These limitations have prompted researchers to explore innovative therapeutic strategies, including stem cell-related interventions, offering hope to those afflicted with this incurable disease. In this review, we describe the characteristics of stem cells and critically assess the potential and challenges of stem cell-based therapies to improve disease management and treatment outcomes for asthma and other diseases.
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Affiliation(s)
- Qiong-Hua Chen
- Department of Respiratory Medicine, Quanzhou Women’s and Children’s Hospital, Clinical Medical College of Fujian Medical University, Quanzhou 362000, Fujian Province, China
| | - Jing-Yang Zheng
- Department of Respiratory Medicine, Quanzhou Women’s and Children’s Hospital, Clinical Medical College of Fujian Medical University, Quanzhou 362000, Fujian Province, China
| | - Da-Chun Wang
- The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Medical School at Houston, Houston, TX 77030, United States
- Stem Cell Laboratory, Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian Province, China
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Zhu G, Yu H, Li X, Ye W, Chen X, Gu W. CD147 mitochondria translocation induced airway remodeling in asthmatic mouse models by regulating M2 macrophage polarization via ANT1-mediated mitophagy. Am J Physiol Cell Physiol 2025; 328:C604-C616. [PMID: 39740799 DOI: 10.1152/ajpcell.00735.2024] [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: 09/30/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 01/02/2025]
Abstract
CD147 has the potential to serve as a specific target with therapeutic characteristics in several respiratory diseases. Studies have demonstrated that CD147 regulates levels of oxidative phosphorylation (OXPHOS) through the process of mitochondrial translocations. However, there is still limited insight in the distinct mechanism of CD147 in asthmatic macrophages. Here, we found that CD147 expression levels increased significantly both in vivo and in vitro. CD147 undergoes mitochondrial translocation in M2 macrophages. Reducing the expression of CD147 resulted in a decline in M2 polarization levels within macrophages, as well as a decrease in the levels of mitochondrial respiratory chain complexes I, II, and IV proteins. This effect may be attained by interacting with adenine nucleotide translocase 1 (ANT1), subsequently impacting the levels of mitophagy. We also discovered that CD147 knockdown significantly reduced airway remodeling and inflammation in addition to lowering the polarization level of M2 in the lung tissues of chronic asthmatic model mice. The findings represent the first evidence of the distinct function of CD147 in the process of airway remodeling in asthma.NEW & NOTEWORTHY The interaction between CD147 and ANT1 in M2 macrophages occurs via mitochondrial translocation, resulting in alterations in ANT1 expression levels. This, in turn, triggers the activation of the mitophagy pathway, leading to modifications in OXPHOS levels. Ultimately, these changes contribute to the enhancement of M2 polarization, thereby exacerbating airway remodeling in asthma.
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Affiliation(s)
- Guiyin Zhu
- Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Haiyang Yu
- Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Xiaoming Li
- Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Wenjing Ye
- Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Xi Chen
- Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Wen Gu
- Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
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Saleem M, Shahzad KA, Marryum M, Singh S, Zhou Q, Du S, Wang S, Shao C, Shaikh II. Exosome-based therapies for inflammatory disorders: a review of recent advances. Stem Cell Res Ther 2024; 15:477. [PMID: 39695750 DOI: 10.1186/s13287-024-04107-2] [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: 10/26/2024] [Accepted: 12/09/2024] [Indexed: 12/20/2024] Open
Abstract
Exosomes, small extracellular vesicles secreted by cells, have emerged as focal mediators in intercellular communication and therapeutic interventions across diverse biomedical fields. Inflammatory disorders, including inflammatory bowel disease, acute liver injury, lung injury, neuroinflammation, and myocardial infarction, are complex conditions that require innovative therapeutic approaches. This review summarizes recent advances in exosome-based therapies for inflammatory disorders, highlighting their potential as diagnostic biomarkers and therapeutic agents. Exosomes have shown promise in reducing inflammation, promoting tissue repair, and improving functional outcomes in preclinical models of inflammatory disorders. However, further research is needed to overcome the challenges associated with exosome isolation, characterization, and delivery, as well as to fully understand their mechanisms of action. Current limitations and future directions in exosome research underscore the need for enhanced isolation techniques and deeper mechanistic insights to harness exosomes' full therapeutic potential in clinical applications. Despite these challenges, exosome-based therapies hold great potential for the treatment of inflammatory disorders and may offer a new paradigm for personalized medication.
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Affiliation(s)
- Mavra Saleem
- Department of Zoology, The Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan
| | - Khawar Ali Shahzad
- Department of Zoology, The Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan
- Department of ORL-HNS, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Munazzah Marryum
- Department of Zoology, The Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan
| | - Shekhar Singh
- Lishui People's Hospital, Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui, 323000, Zhejiang, China
| | - Quan Zhou
- Lishui People's Hospital, Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui, 323000, Zhejiang, China
| | - Siting Du
- Lishui People's Hospital, Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui, 323000, Zhejiang, China
| | - Shuanghu Wang
- Lishui People's Hospital, Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui, 323000, Zhejiang, China
| | - Chuxiao Shao
- Lishui People's Hospital, Central Laboratory of The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, Zhejiang, China
| | - Imran Ibrahim Shaikh
- Lishui People's Hospital, Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui, 323000, Zhejiang, China.
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Liu T, Ran C, Zhao D, Yang F, Guo Q, Yang J, Zhang X. Mesenchymal stem cells and their exosomes mitigate osteoarthritis by restoring the balance between proinflammatory Teffs and Tregs. FRONTIERS IN AGING 2024; 5:1509014. [PMID: 39629263 PMCID: PMC11611854 DOI: 10.3389/fragi.2024.1509014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 11/08/2024] [Indexed: 12/07/2024]
Abstract
Osteoarthritis (OA) is a degenerative joint disease caused by chronic inflammation that damages articular cartilage. In addition to the wear and tear of joints, aberrant remodelling driven by a significant presence of inflammatory mediators within the joint is one of the key mechanisms in the pathogenesis of OA. Among these factors, hyperactivation of Teffs subsets plays a crucial role in promoting this pathological process. The immune imbalance between proinflammatory CD4+ effector T cells (proinflammatory Teffs) and Tregs could be a crucial factor in the pathogenesis of OA. Therefore, correcting the imbalance of Tregs/proinflammatory Teffs may slow or inhibit the occurrence and development of OA, which could be a potential target for the treatment of OA. Mesenchymal stem cells (MSCs) possess anti-inflammatory and immunomodulatory properties, regulating both adaptive and innate immunity through mechanisms involving soluble factors such as IDO, PGE2, and TGF-β, as well as cell-to-cell contact and exosomes. Correcting the imbalance between Tregs and proinflammatory Teffs may be one of the mechanisms of MSCs in the treatment of OA. Therefore, this review aims to summarize the relationship between OA and the immune imbalance between Tregs and proinflammatory Teffs, the immunoregulatory role of Tregs in OA, and the role of MSCs and their exosomes in correcting the imbalance between Tregs and proinflammatory Teffs.
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Affiliation(s)
- Tianhao Liu
- Zhongshan Clinical College, Dalian University, Dalian, Liaoning, China
| | - Chunxiao Ran
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
| | - Dewei Zhao
- Zhongshan Clinical College, Dalian University, Dalian, Liaoning, China
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
| | - Fan Yang
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
| | - Qiang Guo
- Zhongshan Clinical College, Dalian University, Dalian, Liaoning, China
| | - Jiahui Yang
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
| | - Xiuzhi Zhang
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
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Ou H, Yang Q, Zhang Y, Tang X, Xiao M, Li S, Lei L, Xie Z. The role of cells and their derivatives in otorhinolaryngologic diseases treatment. Life Sci 2024; 352:122898. [PMID: 38997061 DOI: 10.1016/j.lfs.2024.122898] [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: 04/13/2024] [Revised: 06/23/2024] [Accepted: 07/05/2024] [Indexed: 07/14/2024]
Abstract
Otolaryngology is an important specialty in the field of surgery that deals with the diagnosis and treatment of the ear, nose, throat, trachea, as well as related anatomical structures. Various otolaryngological disorders are difficult to treat using established pharmacological and surgical approaches. The advent of molecular and cellular therapies led to further progress in this respect. This article reviews the therapeutic strategies of using stem cells, immune cells, and chondrocytes in otorhinolaryngology. As the most widely recognized cell derivatives, exosomes were also systematically reviewed for their therapeutic potential in head and neck cancer, otitis media, and allergic rhinitis. Finally, we summarize the limitations of stem cells, chondrocytes, and exosomes, as well as possible solutions, and provide an outlook on the future direction of cell- and derivative-based therapies in otorhinolaryngology, to offer a theoretical foundation for the clinical translation of this therapeutic modality.
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Affiliation(s)
- Haibo Ou
- Department of Otorhinolaryngology Head and Neck Surgery, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China
| | - Qian Yang
- Department of Otorhinolaryngology Head and Neck Surgery, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China
| | - Yuming Zhang
- Department of Otorhinolaryngology Head and Neck Surgery, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China
| | - Xiaojun Tang
- Department of Otorhinolaryngology Head and Neck Surgery, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China
| | - Minna Xiao
- Department of Otorhinolaryngology Head and Neck Surgery, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China
| | - Shisheng Li
- Department of Otorhinolaryngology Head and Neck Surgery, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China
| | - Lanjie Lei
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Institute of Translational Medicine, Zhejiang Shuren University, Hangzhou 310015, Zhejiang, China.
| | - Zuozhong Xie
- Department of Otorhinolaryngology Head and Neck Surgery, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China.
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Yu H, Zhu G, Qin Q, Wang X, Guo X, Gu W. Mesenchymal Stromal Cell Therapy Alleviates Ovalbumin-Induced Chronic Airway Remodeling by Suppressing M2 Macrophage Polarization. Inflammation 2024; 47:1298-1312. [PMID: 38316671 DOI: 10.1007/s10753-024-01977-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 01/15/2024] [Accepted: 01/16/2024] [Indexed: 02/07/2024]
Abstract
Chronic asthma is characterized by airway hyperresponsiveness, inflammation, and remodeling. Previous studies have shown that mesenchymal stromal/stem cells (MSCs) exert anti-inflammatory effects on asthma via regulation of the immune cells. However, the therapeutic mechanism of MSCs, especially the mechanism of airway remodeling in chronic asthma, remains to be elucidated. Here, we aimed to investigate the therapeutic effect of MSCs on airway remodeling in chronic asthma and explored the mechanisms by analyzing the polarization phenotype of macrophages in the lungs. We established a mouse model of chronic asthma induced by ovalbumin (OVA) and evaluated the effect of MSCs on airway remodeling. The data showed that MSCs treatment before the challenge exerted protective effects on OVA-induced chronic asthma, i.e., decreased the inflammatory cell infiltration, Th2 cytokine levels, subepithelial extracellular matrix deposition, and transforming growth factor β (TGF-β)/Smad signaling. Additionally, we found that MSCs treatment markedly suppressed macrophage M2 polarization in lung tissue. At the same time, MSCs treatment inhibited NF-κB p65 nuclear translocation, ER stress, and oxidative stress in the OVA-induced chronic allergic airway remodeling mice model. In conclusion, these results demonstrated that MSCs treatment prevents OVA-induced chronic airway remodeling by suppressing macrophage M2 polarization, which may be associated with the dual inhibition of ER stress and oxidative stress. This discovery may provide a new theoretical basis for the future clinical application of MSCs.
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Affiliation(s)
- Haiyang Yu
- Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China
| | - Guiyin Zhu
- Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China
| | - Qiangqiang Qin
- Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China
| | - Xueting Wang
- Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China
| | - Xuejun Guo
- Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China.
| | - Wen Gu
- Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China.
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Guo S, Wang D. Novel insights into the potential applications of stem cells in pulmonary hypertension therapy. Respir Res 2024; 25:237. [PMID: 38849894 PMCID: PMC11162078 DOI: 10.1186/s12931-024-02865-4] [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: 10/07/2023] [Accepted: 06/04/2024] [Indexed: 06/09/2024] Open
Abstract
Pulmonary hypertension (PH) refers to a group of deadly lung diseases characterized by vascular lesions in the microvasculature and a progressive increase in pulmonary vascular resistance. The prevalence of PH has increased over time. Currently, the treatment options available for PH patients have limited efficacy, and none of them can fundamentally reverse pulmonary vascular remodeling. Stem cells represent an ideal seed with proven efficacy in clinical studies focusing on liver, cardiovascular, and nerve diseases. Since the potential therapeutic effect of mesenchymal stem cells (MSCs) on PH was first reported in 2006, many studies have demonstrated the efficacy of stem cells in PH animal models and suggested that stem cells can help slow the deterioration of lung tissue. Existing PH treatment studies basically focus on the paracrine action of stem cells, including protein regulation, exosome pathway, and cell signaling; however, the specific mechanisms have not yet been clarified. Apoptotic and afunctional pulmonary microvascular endothelial cells (PMVECs) and alveolar epithelial cells (AECs) are two fundamental promoters of PH although they have not been extensively studied by researchers. This review mainly focuses on the supportive communication and interaction between PMVECs and AECs as well as the potential restorative effect of stem cells on their injury. In the future, more studies are needed to prove these effects and explore more radical cures for PH.
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Affiliation(s)
- Sijia Guo
- Stem Cell Laboratory, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
| | - Dachun Wang
- Stem Cell Laboratory, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
- The Brown Foundation Institute of Molecular Medicine for the prevention of Human Diseases, University of Texas Medical School at Houston, Houston, TX, USA
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He BX, Fang SB, Xie YC, Lou DX, Wu ZC, Li CG, Liu XQ, Zhou ZR, Huang LX, Tian T, Chen DH, Fu QL. Small extracellular vesicles derived from human mesenchymal stem cells prevent Th17-dominant neutrophilic airway inflammation via immunoregulation on Th17 cells. Int Immunopharmacol 2024; 133:112126. [PMID: 38669946 DOI: 10.1016/j.intimp.2024.112126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 04/18/2024] [Accepted: 04/18/2024] [Indexed: 04/28/2024]
Abstract
Type 17 helper T cells (Th17)-dominant neutrophilic airway inflammation is critical in the pathogenesis of steroid-resistant airway inflammation such as severe asthma. Small extracellular vesicles (sEV) derived from human mesenchymal stem cells (MSCs) display extensive therapeutic effects and advantages in many diseases. However, the role of MSC-sEV in Th17-dominant neutrophilic airway inflammation and the related mechanisms are still poorly studied. Here we found that MSC-sEV significantly alleviated the infiltration of inflammatory cells in peribronchial interstitial tissues and reduced levels of inflammatory cells, especially neutrophils, in bronchoalveolar lavage fluids (BALF) of mice with neutrophilic airway inflammation. Consistently, MSC-sEV significantly decreased levels of IL-17A in BALF and Th17 in lung tissues. Furthermore, we found that labelled MSC-sEV were taken up by human CD4+ T cells most obviously at 12 h after incubation, and distributed mostly in mouse lungs. More importantly, potential signaling pathways involved in the MSC-sEV mediated inhibition of Th17 polarization were found using RNA sequencing. Using Western blot, JAK2-STAT3 pathway was identified as an important role in the inhibition of Th17 polarization by MSC-sEV. We found that proteins in MSC-sEV were mostly involved in the therapeutic effects of MSC-sEV. In total, our study suggested that MSC-sEV could be a potential therapeutic strategy for the treatment of neutrophilic airway inflammation.
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Affiliation(s)
- Bi-Xin He
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shu-Bing Fang
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ying-Chun Xie
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dong-Xiao Lou
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Zi-Cong Wu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Chan-Gu Li
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Xiao-Qing Liu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhi-Rou Zhou
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Long-Xin Huang
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Tian Tian
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - De-Hua Chen
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qing-Ling Fu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
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Fujita Y, Kadota T, Kaneko R, Hirano Y, Fujimoto S, Watanabe N, Kizawa R, Ohtsuka T, Kuwano K, Ochiya T, Araya J. Mitigation of acute lung injury by human bronchial epithelial cell-derived extracellular vesicles via ANXA1-mediated FPR signaling. Commun Biol 2024; 7:514. [PMID: 38710749 PMCID: PMC11074269 DOI: 10.1038/s42003-024-06197-3] [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: 10/15/2023] [Accepted: 04/15/2024] [Indexed: 05/08/2024] Open
Abstract
Acute lung injury (ALI) is characterized by respiratory failure resulting from the disruption of the epithelial and endothelial barriers as well as immune system. In this study, we evaluated the therapeutic potential of airway epithelial cell-derived extracellular vesicles (EVs) in maintaining lung homeostasis. We isolated human bronchial epithelial cell-derived EVs (HBEC-EVs), which endogenously express various immune-related surface markers and investigated their immunomodulatory potential in ALI. In ALI cellular models, HBEC-EVs demonstrated immunosuppressive effects by reducing the secretion of proinflammatory cytokines in both THP-1 macrophages and HBECs. Mechanistically, these effects were partially ascribed to nine of the top 10 miRNAs enriched in HBEC-EVs, governing toll-like receptor-NF-κB signaling pathways. Proteomic analysis revealed the presence of proteins in HBEC-EVs involved in WNT and NF-κB signaling pathways, pivotal in inflammation regulation. ANXA1, a constituent of HBEC-EVs, interacts with formyl peptide receptor (FPR)2, eliciting anti-inflammatory responses by suppressing NF-κB signaling in inflamed epithelium, including type II alveolar epithelial cells. In a mouse model of ALI, intratracheal administration of HBEC-EVs reduced lung injury, inflammatory cell infiltration, and cytokine levels. Collectively, these findings suggest the therapeutic potential of HBEC-EVs, through their miRNAs and ANXA1 cargo, in mitigating lung injury and inflammation in ALI patients.
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Affiliation(s)
- Yu Fujita
- Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
- Division of Next-Generation Drug Development, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan.
- Center for Exosome Medical Research, The Jikei University School of Medicine, Tokyo, Japan.
| | - Tsukasa Kadota
- Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Reika Kaneko
- Division of Next-Generation Drug Development, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan
| | - Yuta Hirano
- Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Shota Fujimoto
- Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Naoaki Watanabe
- Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Ryusuke Kizawa
- Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
- Division of Next-Generation Drug Development, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan
| | - Takashi Ohtsuka
- Division of Thoracic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Kazuyoshi Kuwano
- Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Takahiro Ochiya
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
| | - Jun Araya
- Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
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Tang M, Da X, Xu Z, Zhao X, Zhou H. UHPLC/MS-based metabolomics of asthmatic mice reveals metabolic changes in group 2 innate lymphoid cells. Int Immunopharmacol 2024; 130:111775. [PMID: 38430805 DOI: 10.1016/j.intimp.2024.111775] [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: 12/07/2023] [Revised: 02/22/2024] [Accepted: 02/26/2024] [Indexed: 03/05/2024]
Abstract
Helper Th2-type immune responses are essential in allergic airway diseases, including asthma and allergic rhinitis. Recent studies have indicated that group 2 innate lymphoid cells (ILC2s) play a crucial role in the occurrence and development of asthma. However, the metabolic profile of ILC2s and their regulatory mechanisms in asthma remain unclear. Therefore, we established two asthma mouse models: an ovalbumin (OVA)-induced asthma model and an IL-33-induced asthma model. We then used ultra-high-performance liquid chromatography/mass spectrometry (UHPLC/MS) to conduct high-throughput untargeted metabolic analysis of ILC2s in the lung tissues of the asthma models. The identified metabolites primarily consisted of lipids, lipid-like molecules, benzene, organic acids, derivatives, and organic oxidation compounds. Specifically, 34 differentially accumulated metabolites influenced the metabolic profiles of the control and OVA-induced asthma model groups. Moreover, the accumulation of 39 metabolites significantly differed between the Interleukin 33 (IL-33) and control groups. These differentially accumulated metabolites were mainly involved in pathways such as sphingolipid, oxidative phosphorylation, and fatty acid metabolism. This metabolomic study revealed, for the first time, the key metabolites and metabolic pathways of ILC2s, revealing new aspects of cellular metabolism in the context of airway inflammation. These findings not only contribute to unraveling the pathogenesis of asthma but also provide a crucial theoretical foundation for the future development of therapeutic strategies targeting ILC2s.
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Affiliation(s)
- Min Tang
- Department of Pediatrics, Provincial Hospital affiliated to Anhui Medical University, Hefei, China
| | - Xianzong Da
- Department of Pediatrics, Provincial Hospital affiliated to Anhui Medical University, Hefei, China
| | - Zhiwei Xu
- Department of Pediatrics, Bengbu Medical College, Bengbu, China
| | - Xiaoman Zhao
- Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, China
| | - Haoquan Zhou
- Department of Pediatrics, Provincial Hospital affiliated to Anhui Medical University, Hefei, China; Department of Pediatrics, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China.
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Hazrati A, Malekpour K, Khorramdelazad H, Rajaei S, Hashemi SM. Therapeutic and immunomodulatory potentials of mesenchymal stromal/stem cells and immune checkpoints related molecules. Biomark Res 2024; 12:35. [PMID: 38515166 PMCID: PMC10958918 DOI: 10.1186/s40364-024-00580-2] [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: 01/05/2024] [Accepted: 03/07/2024] [Indexed: 03/23/2024] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) are used in many studies due to their therapeutic potential, including their differentiative ability and immunomodulatory properties. These cells perform their therapeutic functions by using various mechanisms, such as the production of anti-inflammatory cytokines, growth factors, direct cell-to-cell contact, extracellular vesicles (EVs) production, and mitochondrial transfer. However, mechanisms related to immune checkpoints (ICPs) and their effect on the immunomodulatory ability of MSCs are less discussed. The main function of ICPs is to prevent the initiation of unwanted responses and to regulate the immune system responses to maintain the homeostasis of these responses. ICPs are produced by various types of immune system regulatory cells, and defects in their expression and function may be associated with excessive responses that can ultimately lead to autoimmunity. Also, by expressing different types of ICPs and their ligands (ICPLs), tumor cells prevent the formation and durability of immune responses, which leads to tumors' immune escape. ICPs and ICPLs can be produced by MSCs and affect immune cell responses both through their secretion into the microenvironment or direct cell-to-cell interaction. Pre-treatment of MSCs in inflammatory conditions leads to an increase in their therapeutic potential. In addition to the effect that inflammatory environments have on the production of anti-inflammatory cytokines by MSCs, they can increase the expression of various types of ICPLs. In this review, we discuss different types of ICPLs and ICPs expressed by MSCs and their effect on their immunomodulatory and therapeutic potential.
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Affiliation(s)
- Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Khorramdelazad
- Department of Immunology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Samira Rajaei
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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12
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Hyun SY, Kim EY, Kang M, Park JW, Hong KS, Chung HM, Choi WS, Park SP, Noh G, Kim HS. Embryonic-stem-cell-derived mesenchymal stem cells relieve experimental contact urticaria by regulating the functions of mast cells and T cells. Sci Rep 2023; 13:22694. [PMID: 38123643 PMCID: PMC10733409 DOI: 10.1038/s41598-023-50258-2] [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: 03/20/2023] [Accepted: 12/18/2023] [Indexed: 12/23/2023] Open
Abstract
Contact urticaria (CU) is an inflammatory skin disorder triggered by specific substances upon skin contact, leading to immediate acute or chronic manifestations characterized by swelling and redness. While mesenchymal stem cells (MSCs) are increasingly recognized for their therapeutic potential in immune diseases, research on the efficacy and mechanisms of stem cell therapy for urticaria remains scarce. This study investigates the regulatory role of embryonic-stem-cell-derived multipotent MSCs (M-MSCs) administered in a CU mouse model. Therapeutic effects of M-MSC administration were assessed in a Trimellitic anhydride-induced contact urticaria model, revealing significant inhibition of urticarial reactions, including ear swelling, itchiness, and skin lesion. Moreover, M-MSC administration exerted control over effector T cell activities in major lymphoid and peripheral tissues, while also suppressing mast cell degranulation in peripheral tissues. Notably, the inhibitory effects mediated by M-MSCs were found to be TGF-β-dependent. Our study demonstrates the capacity of M-MSCs to regulate contact urticaria in a murine model, harmonizing the activation of inflammatory T cells and mast cells. Additionally, we suggest that TGF-β derived from M-MSCs could play a pivotal role as an inhibitory mechanism in contact urticaria.
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Affiliation(s)
- Seung Yeun Hyun
- Department of Biomedical Sciences, College of Natural Science and Department of Health Sciences, The Graduate School of Dong-A University, Busan, 49315, Korea
| | | | - Minseong Kang
- Department of Biomedical Sciences, College of Natural Science and Department of Health Sciences, The Graduate School of Dong-A University, Busan, 49315, Korea
| | - Jeong Won Park
- Department of Biomedical Sciences, College of Natural Science and Department of Health Sciences, The Graduate School of Dong-A University, Busan, 49315, Korea
| | | | - Hyung-Min Chung
- Mirae Cell Bio Co., Ltd., Seoul, 04795, Korea
- School of Medicine, Konkuk University, Seoul, 05029, Korea
| | - Wahn Soo Choi
- School of Medicine, Konkuk University, Seoul, 05029, Korea
| | - Se-Pill Park
- Mirae Cell Bio Co., Ltd., Seoul, 04795, Korea.
- Department of Bio Medical Informatics, College of Applied Life Sciences, Jeju National University, Jeju, 63243, Korea.
| | - Geunwoong Noh
- Department of Allergy, Allergy and Clinical Immunology Center, Cheju Halla General Hospital, Jeju, 63127, Korea.
| | - Hyuk Soon Kim
- Department of Biomedical Sciences, College of Natural Science and Department of Health Sciences, The Graduate School of Dong-A University, Busan, 49315, Korea.
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13
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Wu J, Huang QM, Liu Y, Zhou J, Tang WR, Wang XY, Wang LF, Zhang ZH, Tan HL, Guan XH, Deng KY, Xin HB. Long-term hypoxic hUCMSCs-derived extracellular vesicles alleviates allergic rhinitis through triggering immunotolerance of their VEGF-mediated inhibition of dendritic cells maturation. Int Immunopharmacol 2023; 124:110875. [PMID: 37742368 DOI: 10.1016/j.intimp.2023.110875] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/18/2023] [Accepted: 08/27/2023] [Indexed: 09/26/2023]
Abstract
BACKGROUND Extensions of mesenchymal stem cells (MSCs) in vitro may lead to the loss of their biological functions. However, hypoxic culturation has been shown to enhance the proliferation, survival, and immunomodulatory capacity of MSCs. OBJECTIVE We aimed to investigate the effects of long-term hypoxic cultivation on the properties of human umbilical cord-derived MSCs (hUCMSCs) and the therapeutic effects of their extracellular vesicles (EVs) in allergic rhinitis (AR). METHODS Proliferation, senescence, telomerase activity and multipotent properties of hUCMSCs were analyzed under long-term culturation of hypoxia (1%) or normoxia (21%), and the therapeutic effects of their conditional medium (CM) and EVs were evaluated in OVA-induced AR mice. Effects of hypoxia-EVs (Hy-EVs) or normoxia-EVs (No-EVs) on human monocyte-derived dendritic cells (DCs) were investigated, and the possible mechanisms of Hy-EVs in induction of immunotolerance were further explored. RESULTS Long-term hypoxia significantly promoted the proliferation, inhibited cell senescence, maintained the multipotent status of hUCMSCs. Hy-CM and Hy-EVs showed better therapeutic effects in AR mice compared to No-EVs, seen as improvement of AR-related behaviors such as rubbing and sneezing, and attenuation of inflammation in nasal tissues. In addition, Hy-EVs significantly reduced the expressions of HLA-DR, CD80, CD40, and CD83 induced by OVA plus LPS in DCs, inhibiting the maturation of DCs. Furthermore, we observed that VEGF was remarkably enriched in Hy-EVs, but not in No-EVs, and the inhibition of DCs maturation was markedly neutralized by VEGF antibodies, suggesting that VEGF derived from Hy-EVs was responsible for the inhibition of DCs maturation. CONCLUSION Our results demonstrated that long-term hypoxia significantly promoted the proliferation, inhibited cell senescence, maintained the multipotent status of hUCMSCs, and hypoxia treated hUCMSCs-derived EVs enhanced their therapeutic effects in AR mice through VEGF-mediated inhibition of DCs maturation.
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Affiliation(s)
- Jie Wu
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, China; College of Life Science, Nanchang University, Nanchang 330031, China; Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang 330052, China
| | - Qi-Ming Huang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, China; College of Life Science, Nanchang University, Nanchang 330031, China
| | - Yu Liu
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, China; Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang 330052, China
| | - Juan Zhou
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Nanchang University, Nanchang 330052, China
| | - Wen-Rong Tang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, China
| | - Xiao-Yu Wang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, China
| | - Lin-Fang Wang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, China
| | - Zhou-Hang Zhang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, China
| | - Hui-Lan Tan
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, China
| | - Xiao-Hui Guan
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, China.
| | - Ke-Yu Deng
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, China; College of Life Science, Nanchang University, Nanchang 330031, China.
| | - Hong-Bo Xin
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, China; College of Life Science, Nanchang University, Nanchang 330031, China.
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14
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Hong D, Hu Z, Weng J, Yang L, Xiong Y, Liu Y. Effect of mesenchymal stem cell therapy in animal models of allergic rhinitis: A systematic review and meta-analysis. Int Immunopharmacol 2023; 124:111003. [PMID: 37806104 DOI: 10.1016/j.intimp.2023.111003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 09/06/2023] [Accepted: 09/25/2023] [Indexed: 10/10/2023]
Abstract
BACKGROUND Allergic rhinitis (AR) is a worldwide problem that affects people of all ages, impairing patients' physical and mental health and causing great social expenditure. Animal studies have suggested the potential efficacy of mesenchymal stem cell (MSC) therapy in treating AR. Our meta-analysis was performed to evaluate the effect of MSC therapy in animal models of AR by pooling animal studies. METHODS The search was executed in PubMed, Embase, Web of Science, OVID, and the Cochrane Library for relevant studies up to February 2023. The applicable data were extracted from the eligible studies, and the risk of bias was assessed for each study. The meta-analysis was conducted using Review Manager (version 5.4.1) and Stata (version 15.1). RESULTS A total of 12 studies were included in the final analysis. Compared to the model control group, the MSC therapy group presented lower frequency of sneezing [(Standardized mean difference (SMD) -1.87, 95% CI -2.30 to -1.43)], nasal scratching (SMD -1.41, 95% CI -1.83 to -0.99), and overall nasal symptoms (SMD -1.88, 95% CI -3.22 to -0.54). There were also remarkable reductions after transplantation with MSCs in the levels of total immunoglobulin E (IgE) (SMD -1.25, 95% CI -1.72 to -0.79), allergen-specific IgE (SMD -1.79, 95% CI -2.25 to -1.32), and allergen-specific immunoglobulin G1 (SMD -1.29, 95% CI -2.03) in serum, as well as the count of eosinophils (EOS) in nasal mucosa (SMD -3.48, 95% CI -4.48 to -2.49). In terms of cytokines, MSC therapy significantly decreased both protein and mRNA levels of T helper cell 2 (Th2)-related cytokines, including interleukin (IL)-4, IL-5, IL-10, and IL-13. CONCLUSION MSC therapy has the potential to be an effective clinical treatment for AR patients by attenuating Th2 immune responses, reducing secretion of IgE and nasal infiltration of EOS, and consequently alleviating nasal symptoms.
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Affiliation(s)
- Dongdong Hong
- Department of Otorhinolaryngology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China
| | - Zhen Hu
- Department of Otorhinolaryngology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China
| | - Juanling Weng
- Department of Otorhinolaryngology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China
| | - Long Yang
- Department of Otorhinolaryngology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China
| | - Yalan Xiong
- Department of Otorhinolaryngology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China
| | - Yuanxian Liu
- Department of Otorhinolaryngology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China.
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15
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Peng YQ, Deng XH, Xu ZB, Wu ZC, Fu QL. Mesenchymal stromal cells and their small extracellular vesicles in allergic diseases: From immunomodulation to therapy. Eur J Immunol 2023; 53:e2149510. [PMID: 37572379 DOI: 10.1002/eji.202149510] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 06/09/2023] [Accepted: 08/10/2023] [Indexed: 08/14/2023]
Abstract
Mesenchymal stromal cells (MSCs) have long been considered a potential tool for treatment of allergic inflammatory diseases, owing to their immunomodulatory characteristics. In recent decades, the medical utility of MSCs has been evaluated both in vitro and in vivo, providing a foundation for therapeutic applications. However, the existing limitations of MSC therapy indicate the necessity for novel therapies. Notably, small extracellular vesicles (sEV) derived from MSCs have emerged rapidly as candidates instead of their parental cells. The acquisition of abundant and scalable MSC-sEV is an obstacle for clinical applications. The potential application of MSC-sEV in allergic diseases has attracted increasing attention from researchers. By carrying biological microRNAs or active proteins, MSC-sEV can modulate the function of various innate and adaptive immune cells. In this review, we summarise the recent advances in the immunomodulatory properties of MSCs in allergic diseases, the cellular sources of MSC-sEV, and the methods for obtaining high-quality human MSC-sEV. In addition, we discuss the immunoregulatory capacity of MSCs and MSC-sEV for the treatment of asthma, atopic dermatitis, and allergic rhinitis, with a special emphasis on their immunoregulatory effects and the underlying mechanisms of immune cell modulation.
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Affiliation(s)
- Ya-Qi Peng
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Otolaryngology-Head and Neck Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Xiao-Hui Deng
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Zhi-Bin Xu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zi-Cong Wu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qing-Ling Fu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China
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16
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Jin J, Fan YJ, Nguyen TV, Yu ZN, Song CH, Lee SY, Shin HS, Chai OH. Fallopia japonica Root Extract Ameliorates Ovalbumin-Induced Airway Inflammation in a CARAS Mouse Model by Modulating the IL-33/TSLP/NF-κB Signaling Pathway. Int J Mol Sci 2023; 24:12514. [PMID: 37569890 PMCID: PMC10420321 DOI: 10.3390/ijms241512514] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/04/2023] [Accepted: 08/04/2023] [Indexed: 08/13/2023] Open
Abstract
Fallopia japonica (Asian knotweed) is a medicinal herb traditionally used to treat inflammation, among other conditions. However, the effects of F. japonica root extract (FJE) on airway inflammation associated with combined allergic rhinitis and asthma (CARAS) and the related mechanisms have not been investigated. This study examined the effect of FJE against CARAS in an ovalbumin (OVA)-induced CARAS mouse model. Six-week-old male BALB/c mice were randomly segregated into six groups. Mice were sensitized intraperitoneally with OVA on days 1, 8, and 15, and administered saline, Dexamethasone (1.5 mg/kg), or FJE (50, 100, or 200 mg/kg) once a day for 16 days. Nasal symptoms, inflammatory cells, OVA-specific immunoglobulins, cytokine production, mast cell activation, and nasal histopathology were assessed. Administration of FJE down-regulated OVA-specific IgE and up-regulated OVA-specific IgG2a in serum. FJE reduced the production of T helper (Th) type 2 cytokines, and the Th1 cytokine levels were enhanced in nasal and bronchoalveolar lavage fluid. Moreover, FJE positively regulated allergic responses by reducing the accumulation of inflammatory cells, improving nasal and lung histopathological characteristics, and inhibiting inflammation-associated cytokines. FJE positively modulated the IL-33/TSLP/NF-B signaling pathway, which is involved in regulating inflammatory cells, immunoglobulin levels, and pro-inflammatory cytokines at the molecular level.
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Affiliation(s)
- Juan Jin
- Department of Anatomy, Jeonbuk National University Medical School, Jeonju 54896, Republic of Korea; (J.J.); (T.V.N.)
| | - Yan Jing Fan
- Department of Anatomy, Jeonbuk National University Medical School, Jeonju 54896, Republic of Korea; (J.J.); (T.V.N.)
| | - Thi Van Nguyen
- Department of Anatomy, Jeonbuk National University Medical School, Jeonju 54896, Republic of Korea; (J.J.); (T.V.N.)
| | - Zhen Nan Yu
- Department of Anatomy, Jeonbuk National University Medical School, Jeonju 54896, Republic of Korea; (J.J.); (T.V.N.)
| | - Chang Ho Song
- Department of Anatomy, Jeonbuk National University Medical School, Jeonju 54896, Republic of Korea; (J.J.); (T.V.N.)
- Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju 54896, Republic of Korea
| | - So-Yong Lee
- Department of Food Biotechnology, Korea University of Science and Technology, Daejeon 34113, Republic of Korea (H.S.S.)
- Department of Food Functionality Research, Korea Food Research Institute, Wanju 55365, Republic of Korea
| | - Hee Soon Shin
- Department of Food Biotechnology, Korea University of Science and Technology, Daejeon 34113, Republic of Korea (H.S.S.)
- Department of Food Functionality Research, Korea Food Research Institute, Wanju 55365, Republic of Korea
| | - Ok Hee Chai
- Department of Anatomy, Jeonbuk National University Medical School, Jeonju 54896, Republic of Korea; (J.J.); (T.V.N.)
- Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju 54896, Republic of Korea
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17
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Liu XQ, Peng YQ, Huang LX, Li CG, Kuang PP, Chen DH, Wu ZC, He BX, Zhou ZR, Fu QL. Dendritic cells mediated by small extracellular vesicles derived from MSCs attenuated the ILC2 activity via PGE2 in patients with allergic rhinitis. Stem Cell Res Ther 2023; 14:180. [PMID: 37488601 PMCID: PMC10367306 DOI: 10.1186/s13287-023-03408-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 07/06/2023] [Indexed: 07/26/2023] Open
Abstract
BACKGROUND Mesenchymal stromal cells-derived small extracellular vesicles (MSC-sEVs) have recently attracted considerable attention because of their therapeutic potential in various immune diseases. We previously reported that MSC-sEVs could exert immunomodulatory roles in allergic airway inflammation by regulating group 2 innate lymphoid cell (ILC2) and dendritic cell (DC) functions. Therefore, this study aimed to investigate the indirect effects of MSC-sEVs on ILC2s from patients with allergic rhinitis (AR) via DCs. METHODS Here, we isolated sEVs from induced pluripotent stem cells-MSCs using anion-exchange chromatography and mature DCs (mDCs) were treated with MSC-sEVs. sEV-mDCs were co-cultured with peripheral blood mononuclear cells from patients with AR or purified ILC2s. The levels of IL-13 and GATA3 in ILC2s were examined by flow cytometry. Bulk RNA sequence for mDCs and sEV-mDCs was employed to further probe the potential mechanisms, which were then validated in the co-culture systems. RESULTS sEV-mDCs showed impaired capacity in priming the levels of IL-13 and GATA3 in ILC2s when compared with mDCs. Furthermore, there was higher PGE2 and IL-10 production from sEV-mDCs, and the blockade of them especially the former one reversed the inhibitory effects of sEV-mDCs. CONCLUSIONS We demonstrated that MSC-sEVs were able to dampen the activating effects of mDCs on ILC2s in patients with AR. Mechanismly, the PGE2-EP2/4 axis played an essential role in the immunomodulatory effects of sEV-mDCs on ILC2s. Herein, we provided new insights into the mechanism underlying the therapeutic effects of MSC-sEVs in allergic airway inflammation.
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Affiliation(s)
- Xiao-Qing Liu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China
- Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Ya-Qi Peng
- Department of Otolaryngology-Head and Neck Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People's Republic of China
| | - Long-Xin Huang
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China
- Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Chan-Gu Li
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China
- Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Peng-Peng Kuang
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China
- Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - De-Hua Chen
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China
- Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Zi-Cong Wu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China
| | - Bi-Xin He
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China
- Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Zhi-Rou Zhou
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China
- Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Qing-Ling Fu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China.
- Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.
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18
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Gholami M, Ghorban K, Sadeghi M, Dadmanesh M, Rouzbahani NH, Dehnavi S. Mesenchymal stem cells and allergic airway inflammation; a therapeutic approach to induce immunoregulatory responses. Int Immunopharmacol 2023; 120:110367. [PMID: 37230032 DOI: 10.1016/j.intimp.2023.110367] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 05/07/2023] [Accepted: 05/18/2023] [Indexed: 05/27/2023]
Abstract
Allergic airway inflammations are among the essential disorders worldwide that are already considered a significant concern. Mesenchymal stem cells (MSCs) are stromal cells with regenerative potential and immunomodulatory characteristics and are widely administered for tissue repair as an immunoregulatory agent in different inflammatory diseases. The current review summarized primary studies conducted to evaluate the therapeutic potential of MSCs for allergic airway disorders. In this case, modulation of airway pathologic inflammation and infiltration of inflammatory cells were examined, and modulation of the Th1/Th2 cellular balance and humoral responses. Also, the effects of MSCs on the Th17/Treg ratio and inducing Treg immunoregulatory responses along with macrophage and dendritic cell function were evaluated.
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Affiliation(s)
- Mohammad Gholami
- Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran; Department of Medical Microbiology, Faculty of Medicine, Aja University of Medical Sciences, Tehran, Iran
| | - Khodayar Ghorban
- Department of Immunology, Faculty of Medicine, Aja University of Medical Sciences, Tehran, Iran
| | - Mahvash Sadeghi
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Maryam Dadmanesh
- Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran; Department of Infectious Diseases, School Of Medicine, Aja University of Medical Sciences, Tehran, Iran
| | - Negin Hosseini Rouzbahani
- Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran; Department of Immunology, Faculty of Medicine, Aja University of Medical Sciences, Tehran, Iran
| | - Sajad Dehnavi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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19
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Carr BJ. Regenerative Medicine and Rehabilitation Therapy in the Canine. Vet Clin North Am Small Anim Pract 2023; 53:801-827. [PMID: 36997410 DOI: 10.1016/j.cvsm.2023.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/30/2023]
Abstract
Regenerative medicine is used in the canine to optimize tissue healing and treat osteoarthritis and soft tissue injuries. Rehabilitation therapy is also often implemented in the treatment and management of musculoskeletal conditions in the canine. Initial experimental studies have shown that regenerative medicine and rehabilitation therapy may work safely and synergistically to enhance tissue healing. Although additional study is required to define optional rehabilitation therapy protocols after regenerative medicine therapy in the canine, certain fundamental principles of rehabilitation therapy still apply to patients treated with regenerative medicine.
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20
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Zahmatkesh E, Khoshdel Rad N, Hossein-Khannazer N, Mohamadnejad M, Gramignoli R, Najimi M, Malekzadeh R, Hassan M, Vosough M. Cell and cell-derivative-based therapy for liver diseases: current approaches and future promises. Expert Rev Gastroenterol Hepatol 2023; 17:237-249. [PMID: 36692130 DOI: 10.1080/17474124.2023.2172398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
INTRODUCTION According to the recent updates from World Health Organization, liver diseases are the 12th most common cause of mortality. Currently, orthotopic liver transplantation (OLT) is the most effective and the only treatment for end-stage liver diseases. Owing to several shortcomings like finite numbers of healthy organ donors, lifelong immunosuppression, and complexity of the procedure, cell and cell-derivatives therapies have emerged as a potential therapeutic alternative for liver diseases. Various cell types and therapies have been proposed and their therapeutic effects evaluated in preclinical or clinical studies, including hepatocytes, hepatocyte-like cells (HLCs) derived from stem cells, human liver stem cells (HLSCs), combination therapies with various types of cells, organoids, and implantable cell-biomaterial constructs with synthetic and natural polymers or even decellularized extracellular matrix (ECM). AREAS COVERED In this review, we highlighted the current status of cell and cell-derivative-based therapies for liver diseases. Furthermore, we discussed future prospects of using HLCs, liver organoids, and their combination therapies. EXPERT OPINION Promising application of stem cell-based techniques including iPSC technology has been integrated into novel techniques such as gene editing, directed differentiation, and organoid technology. iPSCs offer promising prospects to represent novel therapeutic strategies and modeling liver diseases.
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Affiliation(s)
- Ensieh Zahmatkesh
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Niloofar Khoshdel Rad
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Nikoo Hossein-Khannazer
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Mohamadnejad
- Cell-Based Therapies Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Roberto Gramignoli
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain, Brussels, Belgium
| | - Reza Malekzadeh
- Digestive Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
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21
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Liu X, Yang Y, Li Y, Zhang Q, Wang J, Guo J, Song Z, Liu Z, Zhang Y, Song X. Network Pharmacology-Based Approach for Investigating the Role of Xanthii Fructus in Treatment of Allergic Rhinitis. Chem Biodivers 2023; 20:e202200785. [PMID: 36855022 DOI: 10.1002/cbdv.202200785] [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: 08/21/2022] [Revised: 02/22/2023] [Accepted: 02/28/2023] [Indexed: 03/02/2023]
Abstract
Xanthii Fructus (XF) has been used for treatment of allergic rhinitis (AR), but its pharmacological mechanism of action remains unclear. We aimed to explore the potential mechanism of XF in treatment of AR by using a network pharmacology approach combined with in vivo verification experiments in this study. We identified 945 AR-related pathogenic genes, 11 active components in XF and 178 targets of those active components by corresponding databases. Finally, 54 targets of active components from XF in treatment of AR were identified by the Protein-protein interaction (PPI) network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, among which Tumor Necrosis Factor (TNF), Mitogen-activated Protein Kinase 3 (MAPK3), Prostaglandin G/H Synthase 2 (PTGS2), Epidermal Growth Factor Receptor (EGFR) showed strongest interactions. The molecular docking analysis showed that moupinamide could bind to EGFR at LEU704 and LEU703, and PTGS2 at TRP387; 24-Ethylcholest-4-en-3-one was identified to bind to MAPK3 at THR347. The validation of quantitative real-time reverse transcription PCR (RT-PCR) showed that XF decreased the levels of MAPK3, PTGS2, and EGFR expression in the nasal mucosa from AR mice gavaged with an XF water decoction. Meanwhile, the levels of interleukin (IL)-4, IL-5 and IL-13were also decreased after the treatment of XF by Enzyme-linked immunosorbent assay (ELISA). Our results provide the pharmacological mechanism and possible intervention targets of XF in treatment of AR.
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Affiliation(s)
- Xinyue Liu
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, China.,Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, 264000, Yantai, China
| | - Yujuan Yang
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, China.,Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, 264000, Yantai, China
| | - Yumei Li
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, China.,Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, 264000, Yantai, China
| | - Qiang Zhang
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, China.,Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, 264000, Yantai, China
| | - Jianwei Wang
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, China.,Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, 264000, Yantai, China
| | - Jing Guo
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, China.,Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, 264000, Yantai, China
| | - Zheying Song
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, China.,Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, 264000, Yantai, China
| | - Zhen Liu
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, China.,Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, 264000, Yantai, China
| | - Yu Zhang
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, China.,Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, 264000, Yantai, China
| | - Xicheng Song
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, China.,Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, 264000, Yantai, China
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22
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Lv Z, Cai X, Bian Y, Wei Z, Zhu W, Zhao X, Weng X. Advances in Mesenchymal Stem Cell Therapy for Osteoarthritis: From Preclinical and Clinical Perspectives. Bioengineering (Basel) 2023; 10:bioengineering10020195. [PMID: 36829689 PMCID: PMC9952673 DOI: 10.3390/bioengineering10020195] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/21/2023] [Accepted: 01/28/2023] [Indexed: 02/05/2023] Open
Abstract
The prevalence of osteoarthritis (OA), a degenerative disorder of joints, has substantially increased in recent years. Its key pathogenic hallmarks include articular cartilage destruction, synovium inflammation, and bone remodeling. However, treatment outcomes are unsatisfactory. Until recently, common therapy methods, such as analgesic and anti-inflammatory treatments, were aimed to treat symptoms that cannot be radically cured. Mesenchymal stem cells (MSCs), i.e., mesoderm non-hematopoietic cells separated from bone marrow, adipose tissue, umbilical cord blood, etc., have been intensively explored as an emerging technique for the treatment of OA over the last few decades. According to existing research, MSCs may limit cartilage degradation in OA by interfering with cellular immunity and secreting a number of active chemicals. This study aimed to examine the potential mechanism of MSCs in the treatment of OA and conduct a thorough review of both preclinical and clinical data.
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Affiliation(s)
- Zehui Lv
- Department of Orthopaedics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Xuejie Cai
- Department of Orthopaedics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Yixin Bian
- Department of Orthopaedics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Zhanqi Wei
- Department of Orthopaedics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Wei Zhu
- Department of Orthopaedics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Xiuli Zhao
- Department of Medical Genetics, Institute of Basic Medical Sciences, School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
- Correspondence: (X.Z.); (X.W.)
| | - Xisheng Weng
- Department of Orthopaedics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
- Department of State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
- Correspondence: (X.Z.); (X.W.)
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23
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Huang S, Li Y, Zeng J, Chang N, Cheng Y, Zhen X, Zhong D, Chen R, Ma G, Wang Y. Mesenchymal Stem/Stromal Cells in Asthma Therapy: Mechanisms and Strategies for Enhancement. Cell Transplant 2023; 32:9636897231180128. [PMID: 37318186 DOI: 10.1177/09636897231180128] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023] Open
Abstract
Asthma is a complex and heterogeneous disease characterized by chronic airway inflammation, airway hyperresponsiveness, and airway remodeling. Most asthmatic patients are well-established using standard treatment strategies and advanced biologicals. However, a small group of patients who do not respond to biological treatments or are not effectively controlled by available treatment strategies remain a clinical challenge. Therefore, new therapies are urgently needed for poorly controlled asthma. Mesenchymal stem/stromal cells (MSCs) have shown therapeutic potential in relieving airway inflammation and repairing impaired immune balance in preclinical trials owing to their immunomodulatory abilities. Noteworthy, MSCs exerted a therapeutic effect on steroid-resistant asthma with rare side effects in asthmatic models. Nevertheless, adverse factors such as limited obtained number, nutrient and oxygen deprivation in vitro, and cell senescence or apoptosis affected the survival rate and homing efficiency of MSCs, thus limiting the efficacy of MSCs in asthma. In this review, we elaborate on the roles and underlying mechanisms of MSCs in the treatment of asthma from the perspective of their source, immunogenicity, homing, differentiation, and immunomodulatory capacity and summarize strategies to improve their therapeutic effect.
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Affiliation(s)
- Si Huang
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Yiyang Li
- Department of Pediatrics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jieqing Zeng
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Ning Chang
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Yisen Cheng
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Xiangfan Zhen
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Dan Zhong
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Riling Chen
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Guoda Ma
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Yajun Wang
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
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24
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Czerwaty K, Dżaman K, Miechowski W. Application of Extracellular Vesicles in Allergic Rhinitis: A Systematic Review. Int J Mol Sci 2022; 24:ijms24010367. [PMID: 36613810 PMCID: PMC9820222 DOI: 10.3390/ijms24010367] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/19/2022] [Accepted: 12/23/2022] [Indexed: 12/28/2022] Open
Abstract
The pathophysiology of allergic rhinitis (AR), one of the most common diseases in the world, is still not sufficiently understood. Extracellular vesicles (EVs), which are secreted by host and bacteria cells and take part in near and distant intracellular communication, can provide information about AR. Recently, attention has been drawn to the potential use of EVs as biomarkers, vaccines, or transporters for drug delivery. In this review, we present an up-to-date literature overview on EVs in AR to reveal their potential clinical significance in this condition. A comprehensive and systematic literature search was conducted following PRISMA statement guidelines for original, completed articles, available in English concerning EVs and AR. For this purpose, PubMed/MEDLINE, Scopus, Web of Science, and Cochrane, were searched up until 10 Novenmber 2022. From 275 records, 18 articles were included for analysis. The risk of bias was assessed for all studies as low or moderate risk of overall bias using the Office and Health Assessment and Translation Risk of Bias Rating Tool for Human and Animal Studies. We presented the role of exosomes in the pathophysiology of AR and highlighted the possibility of using exosomes as biomarkers and treatment in this disease.
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Affiliation(s)
- Katarzyna Czerwaty
- Department of Otolaryngology, Centre of Postgraduate Medical Education, Marymoncka 99/103, 01-813 Warsaw, Poland
| | - Karolina Dżaman
- Department of Otolaryngology, Centre of Postgraduate Medical Education, Marymoncka 99/103, 01-813 Warsaw, Poland
| | - Wiktor Miechowski
- Department of Otolaryngology, Centre of Postgraduate Medical Education, Marymoncka 99/103, 01-813 Warsaw, Poland
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25
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Yan L, Zheng H, Zhang H, Dai L, Zhang Q. Is mesenchymal stem cell effective for allergic rhinitis? A protocol for a systematic review and meta-analysis. BMJ Open 2022; 12:e062435. [PMID: 36270760 PMCID: PMC9594526 DOI: 10.1136/bmjopen-2022-062435] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
INTRODUCTION Allergic rhinitis (AR) is a kind of widespread but unrecognised inflammatory disorder of nasal mucosa, characterised by itching, sneezing, runny nose and nasal congestion. The efficacy of mesenchymal stem cells (MSCs) in the treatment of AR remains controversial. This protocol describes a systematic review and meta-analysis approach to assess the efficacy and safety of MSCs in the treatment of AR. METHODS AND ANALYSIS Eight databases (PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, VIP and Wanfang) will be searched from the database inception to 1 December 2023. All randomised controlled trials related to MSCs for AR will be included. The primary outcomes will be therapeutic effect, serum IgE index and Visual Analogue Scale score for nasal symptoms. Risk of bias will be assessed using the Cochrane Collaboration's tool for assessing risk of bias. Article selection, data extraction and risk of bias assessment will be performed in duplicate by two independent reviewers. ETHICS AND DISSEMINATION Ethics approval is not required because individual patient data are not included. This protocol was registered in the international Prospective Register of Systematic Reviews on 22 January 2022. The systematic review and meta-analysis will be submitted for publication in a peer-reviewed journal. The findings will also be disseminated through conference presentations. PROSPERO REGISTRATION NUMBER CRD42022303146.
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Affiliation(s)
- Le Yan
- School of Medical and Life Sciences, Chengdu College of Traditional Chinese Medicine, Chengdu, China
| | - Hanxue Zheng
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese, Chengdu, Sichuan, China
| | - Huiping Zhang
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lintong Dai
- Panzhihua City Hospital of Integrated Traditional Chinese and Western Medicine, Panzhihua, Sichuan, China
| | - Qinxiu Zhang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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26
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Liu Z, Sun Q, Liu X, Song Z, Song F, Lu C, Zhang Y, Song X, Yang Y, Li Y. Network pharmacology analysis and experimental verification reveal the mechanism of the traditional Chinese medicine YU-Pingfeng San alleviating allergic rhinitis inflammatory responses. FRONTIERS IN PLANT SCIENCE 2022; 13:934130. [PMID: 36017263 PMCID: PMC9396374 DOI: 10.3389/fpls.2022.934130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 07/13/2022] [Indexed: 06/15/2023]
Abstract
YU-Pingfeng San (YPFS) can regulate inflammatory response to alleviate the symptoms of nasal congestion and runny rose in allergic rhinitis (AR). However, the mechanism of action remains unclear. In this study, 30 active ingredients of three effective herbs included in YPFS and 140 AR/YPFS-related genes were identified by database analysis. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the targets were mainly enriched in immune inflammatory-related biological processes and pathways. Finally, three hub gene targeting epidermal growth factor receptor (EGFR), mitogen-activated protein kinase 1 (MAPK1), and protein kinase B1 (AKT1) related to YPFS and AR were identified by network pharmacology analysis. YPFS treatment decreased the expression of EGFR, MAPK1, and AKT1 in ovalbumin (OVA)-induced AR mice and impaired the production of inflammatory factors interleukin (IL)-4, IL-5, and IL-13, thus alleviating immunoglobulin E (IgE) production and the symptoms of scratching nose in AR. Through molecular docking analysis, we found that the active ingredients decursin, anomalin, and wogonin of YPFS could bind to EGFR, MAPK1, and AKT1 proteins. Moreover, decursin treatment impaired the expression of IL-4 and IL-5 in human PBMCs. These results suggested that YPFS could alleviate the AR inflammatory responses by targeting EGFR, MAPK1, and AKT1, showing the mechanism of action of YPFS in AR treatment.
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Affiliation(s)
- Zhen Liu
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
| | - Qi Sun
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
| | - Xinyue Liu
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
| | - Zheying Song
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
- Clinical Medicine College, Weifang Medical University, Weifang, China
| | - Fei Song
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
- Second Clinical Medicine College, Binzhou Medical University, Yantai, China
| | - Congxian Lu
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
| | - Yu Zhang
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
| | - Xicheng Song
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
| | - Yujuan Yang
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
| | - Yumei Li
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
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Nozari P, Mokhtari P, Nemati M, Zainodini N, Taghipour Z, Asadi F, Ayoobi F, Jafarzadeh A. Investigation of the effect of IFN-γ/TNF-α-treated mesenchymal stem cells on Th9- and Treg cell-related parameters in a mouse model of ovalbumin-induced allergic asthma. Immunopharmacol Immunotoxicol 2022; 44:773-785. [PMID: 35620857 DOI: 10.1080/08923973.2022.2082977] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Th9- and regulatory T (Treg) cells exert pro- and anti-allergic activity, respectively. Mesenchymal stem cell (MSC)-related immunomodulatory impacts can be enhanced by inflammatory cytokines. Here, the modulatory effects of IFN-γ/TNF-α-induced MSCs on Th9- and Treg cell-related parameters were investigated using an asthma model. METHODS Allergic asthma was induced in BALB/c mice using sensitized and challenging with ovalbumin (OVA). The asthmatic groups were treated intraperitoneally with PBS, MSCs, IFN-γ-induced MSCs, TNF-α-induced MSCs and "IFN-γ + TNF-α"-induced MSCs before the challenge phase. The mice were sacrificed 24 hours after challenge. The serum IL-9 and IL-35 levels, as well as gene expression of IL-9, PU.1, IL-35-EBI3 and FOXP3 in the lung tissues were assessed using ELISA and real time-PCR, respectively. RESULTS The differences of Th9 and Treg-related parameters were not significant between untreated asthmatic mice and those treated with non-induced MSCs. In comparison with untreated asthmatic group, treatment with IFN-γ-induced MSCs significantly reduced serum IL-9 levels, reduced lung expression of IL-9 and PU.1, while increasing serum IL-35 levels as well as lung expression of FOXP3; treatment with TNF-α-induced MSCs significantly reduced serum IL-9 levels as well as lung expression of IL-9, and treatment with "IFN-γ + TNF-α"-induced MSCs significantly modulated all investigated Th9 and Treg-related parameters. In comparison to mice treated with non-induced MSCs, serum IL-9 levels were remarkably decreased in mice treated with IFN-γ-induced and "IFN-γ + TNF-α"-induced MSCs. CONCLUSIONS IFN-γ-and "IFN-γ + TNF-α" treated MSCs exerted almost comparable impacts, but were more efficient than TNF-α-exposed MSCs. Thus, IFN-γ alone can be sufficient to promote immunomodulatory effects of MSCs.
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Affiliation(s)
- Parvin Nozari
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Pejman Mokhtari
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Maryam Nemati
- Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.,Department of Haematology and Laboratory Sciences, School of Para-Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Nahid Zainodini
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Zahra Taghipour
- Department of Histology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Fatemeh Asadi
- Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Fatemeh Ayoobi
- Non-Communicable Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Abdollah Jafarzadeh
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran.,Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
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Bhure TS, Das P, Jukanti A, Mishra DK, Sahu SK, Basu S, Shukla S. Mesenchymal stem cell therapy for alleviating ocular surface inflammation in allergic conjunctivitis. Med Hypotheses 2022. [DOI: 10.1016/j.mehy.2022.110813] [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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29
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Wang X, Han X, Qiu Y, Sun J. Magnetic Nano-Sized SDF-1 Particles Show Promise for Application in Stem Cell-Based Repair of Damaged Tissues. Front Bioeng Biotechnol 2022; 10:831256. [PMID: 35573238 PMCID: PMC9091189 DOI: 10.3389/fbioe.2022.831256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 02/24/2022] [Indexed: 11/13/2022] Open
Abstract
Stem cell-based therapy is a promising option for repair of injured tissue. Stem cells have homing characteristics and can be mobilized to the injury sites following activation, under the regulation of the SDF-1/CXCR4 axis. However, a sufficient level of stem cell aggregation and retention is essential for ensuring favorable repair outcomes. Problems related to stem cell delivery/recruitment efficiency and retention in the injury site are among the main challenges faced during in vivo studies on stem cell therapy. In this study, we designed an SDF-1(alpha) magnetic nanoparticle delivery system for stem cell recruitment. We expressed and purified a biotin-labeled SDF-1(alpha) protein and immobilized it on streptavidin-modified magnetic nanoparticles (MNP) through the streptavidin-biotin linkage, with an efficiency of approximately 14%. The physicochemical properties of the SDF-MNP in glycerol buffer were similar to those of the streptavidin-modified MNP. Further evidence suggested that SDF-MNP barely show cytotoxicity even at a concentration of 125 µg/ml MNP and have a promising chemotaxis effect on mesenchymal stem cells in vitro and in vivo. Our study provides a strategy for the assembly of magnetic nanoparticle carrier systems for protein factors, as well as preliminary evidence for the application of SDF-MNP in stem cell-based therapy for the regeneration of injured bone tissue.
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Affiliation(s)
- Xu Wang
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China
- The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China
| | - XinXin Han
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Yi Qiu
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Jianbo Sun
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
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Kim SY, Yoon TH, Na J, Yi SJ, Jin Y, Kim M, Oh TH, Chung TW. Mesenchymal Stem Cells and Extracellular Vesicles Derived from Canine Adipose Tissue Ameliorates Inflammation, Skin Barrier Function and Pruritus by Reducing JAK/STAT Signaling in Atopic Dermatitis. Int J Mol Sci 2022; 23:ijms23094868. [PMID: 35563259 PMCID: PMC9101369 DOI: 10.3390/ijms23094868] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/22/2022] [Accepted: 04/25/2022] [Indexed: 02/01/2023] Open
Abstract
Canine atopic dermatitis (AD) is a common chronic inflammatory skin disorder resulting from imbalance between T lymphocytes. Current canine AD treatments use immunomodulatory drugs, but some of the dogs have limitations that do not respond to standard treatment, or relapse after a period of time. Thus, the purpose of this study was to evaluate the immunomodulatory effect of mesenchymal stem cells derived from canine adipose tissue (cASCs) and cASCs-derived extracellular vesicles (cASC-EVs) on AD. First, we isolated and characterized cASCs and cASCs-EVs to use for the improvement of canine atopic dermatitis. Here, we investigated the effect of cASCs or cASC-EVs on DNCB-induced AD in mice, before using for canine AD. Interestingly, we found that cASCs and cASC-EVs improved AD-like dermatitis, and markedly decreased levels of serum IgE, (49.6%, p = 0.002 and 32.1%, p = 0.016 respectively) epidermal inflammatory cytokines and chemokines, such as IL-4 (32%, p = 0.197 and 44%, p = 0.094 respectively), IL-13 (47.4%, p = 0.163, and 50.0%, p = 0.039 respectively), IL-31 (64.3%, p = 0.030 and 76.2%, p = 0.016 respectively), RANTES (66.7%, p = 0.002 and 55.6%, p = 0.007) and TARC (64%, p = 0.016 and 86%, p = 0.010 respectively). In addition, cASCs or cASC-EVs promoted skin barrier repair by restoring transepidermal water loss, enhancing stratum corneum hydration and upregulating the expression levels of epidermal differentiation proteins. Moreover, cASCs or cASC-EVs reduced IL-31/TRPA1-mediated pruritus and activation of JAK/STAT signaling pathway. Taken together, these results suggest the potential of cASCs or cASC-EVs for the treatment of chronic inflammation and damaged skin barrier in AD or canine AD.
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Affiliation(s)
- Sung Youl Kim
- GNG CELL Co., Ltd., R&D Center, 122 Unjung-ro, Bundang-gu, Seongnam-si 13466, Korea; (S.Y.K.); (T.H.Y.)
| | - Tae Hong Yoon
- GNG CELL Co., Ltd., R&D Center, 122 Unjung-ro, Bundang-gu, Seongnam-si 13466, Korea; (S.Y.K.); (T.H.Y.)
| | - Jungtae Na
- Department of Life Science, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 04107, Korea;
| | - Seong Joon Yi
- Department of Veterinary Anatomy, College of Veterinary Medicine, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Korea;
| | - Yunseok Jin
- Department of Veterinary Internal Medicine, College of Veterinary Medicine, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Korea; (Y.J.); (M.K.)
| | - Minji Kim
- Department of Veterinary Internal Medicine, College of Veterinary Medicine, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Korea; (Y.J.); (M.K.)
| | - Tae-Ho Oh
- Department of Veterinary Internal Medicine, College of Veterinary Medicine, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Korea; (Y.J.); (M.K.)
- Correspondence: (T.-H.O.); (T.-W.C.)
| | - Tae-Wook Chung
- JIN BioCell Co., Ltd., R&D Center, #101-103, National Clinical Research Center for Korean Medicine, Pusan National University Korean Medicine Hospital, 20 Geumo-ro, Mulgeum-eup, Yangsan-si 50612, Korea
- Correspondence: (T.-H.O.); (T.-W.C.)
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Peng YQ, Wu ZC, Xu ZB, Fang SB, Chen DH, Zhang HY, Liu XQ, He BX, Chen D, Akdis CA, Fu QL. Mesenchymal stromal cells-derived small extracellular vesicles modulate DC function to suppress Th2 responses via IL-10 in patients with allergic rhinitis. Eur J Immunol 2022; 52:1129-1140. [PMID: 35415925 PMCID: PMC9545324 DOI: 10.1002/eji.202149497] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 02/01/2022] [Accepted: 04/11/2022] [Indexed: 12/02/2022]
Abstract
Mesenchymal stromal cells (MSCs) are well known for their immunoregulatory roles on allergic inflammation particularly by acting on T cells, B cells, and dendritic cells (DCs). MSC‐derived small extracellular vesicles (MSC‐sEV) are increasingly considered as one of the main factors for the effects of MSCs on immune responses. However, the effects of MSC‐sEV on DCs in allergic diseases remain unclear.
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Affiliation(s)
- Ya-Qi Peng
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Otolaryngology-Head and Neck Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Zi-Cong Wu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhi-Bin Xu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shu-Bin Fang
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - De-Hua Chen
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hong-Yu Zhang
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiao-Qing Liu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Bi-Xin He
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dong Chen
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Cezmi A Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.,Christine Kühne - Center for Research and Education (CK-CARE), Davos, Switzerland
| | - Qing-Ling Fu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
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Zhang L, Ma XJN, Fei YY, Han HT, Xu J, Cheng L, Li X. Stem cell therapy in liver regeneration: Focus on mesenchymal stem cells and induced pluripotent stem cells. Pharmacol Ther 2022; 232:108004. [PMID: 34597754 DOI: 10.1016/j.pharmthera.2021.108004] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 08/11/2021] [Accepted: 09/23/2021] [Indexed: 02/07/2023]
Abstract
The liver has the ability to repair itself after injury; however, a variety of pathological changes in the liver can affect its ability to regenerate, and this could lead to liver failure. Mesenchymal stem cells (MSCs) are considered a good source of cells for regenerative medicine, as they regulate liver regeneration through different mechanisms, and their efficacy has been demonstrated by many animal experiments and clinical studies. Induced pluripotent stem cells, another good source of MSCs, have also made great progress in the establishment of organoids, such as liver disease models, and in drug screening. Owing to the recent developments in MSCs and induced pluripotent stem cells, combined with emerging technologies including graphene, nano-biomaterials, and gene editing, precision medicine and individualized clinical treatment may be realized in the near future.
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Affiliation(s)
- Lu Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China; The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Xiao-Jing-Nan Ma
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Yuan-Yuan Fei
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China
| | - Heng-Tong Han
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Jun Xu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Lu Cheng
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China
| | - Xun Li
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China; Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Hepatopancreatobiliary Surgery Institute of Gansu Province, Lanzhou 730000, PR China; The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China.
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Brown SV, Dewitt S, Clayton A, Waddington RJ. Identifying the Efficacy of Extracellular Vesicles in Osteogenic Differentiation: An EV-Lution in Regenerative Medicine. FRONTIERS IN DENTAL MEDICINE 2022. [DOI: 10.3389/fdmed.2022.849724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) have long been the focus for regenerative medicine and the restoration of damaged or aging cells throughout the body. However, the efficacy of MSCs in cell-based therapy still remains unpredictable and carries with it enumerable risks. It is estimated that only 3-10% of MSCs survive transplantation, and there remains undefined and highly variable heterogeneous biological potency within these administered cell populations. The mode of action points to secreted factors produced by MSCs rather than the reliance on engraftment. Hence harnessing such secreted elements as a replacement for live-cell therapies is attractive. Extracellular vesicles (EVs) are heterogenous lipid bounded structures, secreted by cells. They comprise a complex repertoire of molecules including RNA, proteins and other factors that facilitate cell-to-cell communication. Described as protected signaling centers, EVs can modify the cellular activity of recipient cells and are emerging as a credible alternative to cell-based therapies. EV therapeutics demonstrate beneficial roles for wound healing by preventing apoptosis, moderating immune responses, and stimulating angiogenesis, in addition to promoting cell proliferation and differentiation required for tissue matrix synthesis. Significantly, EVs maintain their signaling function following transplantation, circumventing the issues related to cell-based therapies. However, EV research is still in its infancy in terms of their utility as medicinal agents, with many questions still surrounding mechanistic understanding, optimal sourcing, and isolation of EVs for regenerative medicine. This review will consider the efficacy of using cell-derived EVs compared to traditional cell-based therapies for bone repair and regeneration. We discuss the factors to consider in developing productive lines of inquiry and establishment of standardized protocols so that EVs can be harnessed from optimal secretome production, to deliver reproducible and effective therapies.
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Fructus Amomi extract attenuates nasal inflammation by restoring Th1/Th2 balance and downregulation of NF-kBphosphorylation in OVA-induced allergic rhinitis. Biosci Rep 2022; 42:231000. [PMID: 35274678 PMCID: PMC8935377 DOI: 10.1042/bsr20212681] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 03/04/2022] [Accepted: 03/09/2022] [Indexed: 11/29/2022] Open
Abstract
Fructus Amomi Cardamomi (FA) is the mature fruit of Amomum villosum Lour (family Zingiberaceae) and is commonly used in Chinese traditional medicine to treat various gastrointestinal disorders. FA’s possible benefits as an allergic rhinitis (AR) treatment, however, have not been examined. We used an ovalbumin (OVA)-induced AR mouse model to identify any anti-allergic effects associated with the administration of 200 mg/kg FA or dexamethasone (Dex) 2.5 mg/kg by oral administration. The results of our testing confirm that FA ameliorated nasal symptoms and alleviated nasal epithelium swelling, reduced the goblet cell hyperplasia and eosinophil cell infiltration in the nasal epithelium, and inhibited lung tissue inflammation and Dex as well. Significantly decreased Th2 cytokine (interleukin (IL)-1β, IL-4, and IL-5) expression, and a correspondingly significant increase in Th1 cytokine (IL-12, interferon (IFN)-γ) production, was observed in nasal lavage fluid (NALF) taken from mice that received FA or Dex treatment. FA also reduced the presence of OVA-specific immunoglobulin (Ig) E, OVA-specific IgG1, and histamine levels in serum, and inhibited mast cell degranulation in vitro. In addition, these effects were involved with the reduction in NF-κB phosphorylation. These results suggest that FA restores Th1/Th2 balance and inhibits NF-κB phosphorylation and mast cell degranulation, thereby achieving a notable anti-inflammatory effect. Accordingly, it has the potential to be used as an efficacious therapeutic treatment for AR.
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Treatment of Chronic Kidney Disease with Extracellular Vesicles from Mesenchymal Stem Cells and CD133 + Expanded Cells: A Comparative Preclinical Analysis. Int J Mol Sci 2022; 23:ijms23052521. [PMID: 35269664 PMCID: PMC8910174 DOI: 10.3390/ijms23052521] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 02/16/2022] [Accepted: 02/17/2022] [Indexed: 01/06/2023] Open
Abstract
Chronic kidney disease (CKD) is characterized by structural abnormalities and the progressive loss of kidney function. Extracellular vesicles (EVs) from human umbilical cord tissue (hUCT)-derived mesenchymal stem cells (MSCs) and expanded human umbilical cord blood (hUCB)-derived CD133+ cells (eCD133+) maintain the characteristics of the parent cells, providing a new form of cell-free treatment. We evaluated the effects of EVs from hUCT-derived MSCs and hUCB-derived CD133+ cells on rats with CDK induced by an adenine-enriched diet. EVs were isolated by ultracentrifugation and characterized by nanoparticle tracking analysis (NTA) and electron microscopy. The animals were randomized and divided into the MSC-EV group, eEPC-EV group and control group. Infusions occurred on the seventh and 14th days after CKD induction. Evaluations of kidney function were carried out by biochemical and histological analyses. Intense labeling of the α-SMA protein was observed when comparing the control with MSC-EVs. In both groups treated with EVs, a significant increase in serum albumin was observed, and the increase in cystatin C was inhibited. The results indicated improvements in renal function in CKD, demonstrating the therapeutic potential of EVs derived from MSCs and eCD133+ cells and suggesting the possibility that in the future, more than one type of EV will be used concurrently.
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36
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Lee DG, Lee YJ, Park SH, Park HR, Kang H, Kim JE. Preventive Effects of a Human Hematopoietic Mesenchymal Stem Cell (hHMSC) Therapy in Ovalbumin-Induced Food Allergy. Biomedicines 2022; 10:511. [PMID: 35203718 PMCID: PMC8962321 DOI: 10.3390/biomedicines10020511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/02/2022] [Accepted: 02/17/2022] [Indexed: 11/23/2022] Open
Abstract
No effective therapeutic strategies have been developed against food allergies. Immunomodulation during early infant period could prevent the development of food allergies. We investigated the preventive effects of human hematopoietic mesenchymal stem cells (hHMSCs) in mice with ovalbumin (OVA)-induced food allergy. BALB/c mice with OVA-induced food allergy were divided into 3 groups, and each group was treated with hHMSCs or hHMSC culture medium (hHMSC-CM) or saline. Ear thickness, allergy score, rectal temperature, and diarrhea occurrence were checked. Total IgE, OVA-specific IgE, and mucosal mast cell protease-1 (mMCP-1) were measured by ELISA. Other allergic parameters were analyzed using histology specimens, RT-PCR, and flow cytometry. Treatment with hHMSCs or hHMSC-CM significantly suppressed the frequency of anaphylactic response and rectal temperature decline, reduced diarrhea, total IgE, OVA-specific IgE, and mMCP-1. While the treatment decreased the level of Th2 cytokines, it enhanced IL-10 and TGF-β1 mRNA. Exposure to hHMSC or hHMSC-CM did not generate regulatory T cells, but reduced mast cells. The immunomodulatory effect on the Th2 cytokines was greater in hHMSC-CM than in hHMSCs. hHMSC treatment may be a promising preventive intervention against food allergy. Further studies are needed to elucidate the key substances released from hHMSC to induce immune tolerance.
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Affiliation(s)
| | | | | | | | | | - Jung-Eun Kim
- Department of Dermatology, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Korea; (D.-G.L.); (Y.-J.L.); (S.-H.P.); (H.-R.P.); (H.K.)
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37
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Shan L, Liu S, Zhang Q, Zhou Q, Shang Y. Human bone marrow-mesenchymal stem cell-derived exosomal microRNA-188 reduces bronchial smooth muscle cell proliferation in asthma through suppressing the JARID2/Wnt/β-catenin axis. Cell Cycle 2022; 21:352-367. [PMID: 34974799 PMCID: PMC8855860 DOI: 10.1080/15384101.2021.2020432] [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: 01/04/2023] Open
Abstract
The functions of exosomes in allergic diseases including asthma have aroused increasing concerns. This paper focuses on the effects of exosomes derived from human bone marrow-mesenchymal stem cells (hBM-MSCs) on the proliferation of bronchial smooth muscle cells in asthma and the mechanism involved. Exosomes were extracted from hBM-MSCs and identified. Human BSMCs were induced with transforming growth factor (TGF)-β1 to mimic an asthma-like condition in vitro and then treated with exosomes. A mouse model with asthma was induced by ovalbumin (OVA) and treated with exosomes for in vivo study. The hBM-MSC-derived exosomes significantly reduced the abnormal proliferation and migration of TGF-β1-treated BSMCs. microRNA (miR)-188 was the most enriched miRNA in exosomes according the microarray analysis, and JARID2 was identified as a mRNA target of miR-188. Either downregulation of miR-188 or upregulation of JARID2 blocked the protective effects of exosomes on BSMCs. JARID2 activated the Wnt/β-catenin signaling pathway. In the asthmatic mice, hBM-MSC-derived exosomes reduced inflammatory cell infiltration, mucus production, and collagen deposition in mouse lung tissues. In conclusion, this study suggestes that hBM-MSC-derived exosomes suppress proliferation of BSMCs and lung injury in asthmatic mice through the miR-188/JARID2/Wnt/β-catenin axis. This study may provide novel insights into asthma management.
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Affiliation(s)
- Lishen Shan
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, P.R. China
| | - Si Liu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, P.R. China
| | - Qinzhen Zhang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, P.R. China
| | - Qianlan Zhou
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, P.R. China
| | - Yunxiao Shang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, P.R. China,CONTACT Yunxiao Shang Department of Pediatrics, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Heping District, Shenyang110004, Liaoning, P.R. China
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Li CQ, Sun QX, Xu SY, Li LD, Xiao H, Zhang QN. Nebulized Mycobacterium vaccae protects against asthma by attenuating the imbalance of IRF4/IRF8 expression in dendritic cells. Asian Pac J Trop Biomed 2022. [DOI: 10.4103/2221-1691.363878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
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39
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Kim EY, Kim HS, Hong KS, Chung HM, Park SP, Noh G. Mesenchymal stem/stromal cell therapy in atopic dermatitis and chronic urticaria: immunological and clinical viewpoints. Stem Cell Res Ther 2021; 12:539. [PMID: 34635172 PMCID: PMC8503727 DOI: 10.1186/s13287-021-02583-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 08/30/2021] [Indexed: 12/29/2022] Open
Abstract
Allergic diseases are immune-mediated diseases. Allergies share a common immunopathogenesis, with specific differences according to the specific disease. Mesenchymal stem/stromal cells (MSCs) have been applied to people suffering from allergic and many other diseases. In this review, the immunologic roles of MSCs are systemically reviewed according to disease immunopathogenesis from a clinical viewpoint. MSCs seem to be a promising therapeutic modality not only as symptomatic treatments but also as causative and even preventive treatments for allergic diseases, including atopic dermatitis and chronic urticaria.
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Affiliation(s)
| | - Hyuk Soon Kim
- Department of Biomedical Sciences, College of Natural Science, The Graduate School of Dong-A University, Busan, Korea.,Department of Health Sciences, The Graduate School of Dong-A University, Busan, Korea
| | | | - Hyung-Min Chung
- Miraecellbio Co., Ltd., Seoul, Korea.,Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul, Korea
| | - Se-Pill Park
- Miraecellbio Co., Ltd., Seoul, Korea. .,Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, Jeju, 63243, Korea.
| | - Geunwoong Noh
- Department of Allergy, Allergy and Clinical Immunology Center, Cheju Halla General Hospital, Doreongno 65, Jeju-si, 63127, Jeju Special Self-Governing Province, Korea.
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Mesenchymal Stem Cells in the Treatment of COVID-19, a Promising Future. Cells 2021; 10:cells10102588. [PMID: 34685567 PMCID: PMC8533906 DOI: 10.3390/cells10102588] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/11/2021] [Accepted: 09/17/2021] [Indexed: 12/20/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in virtually all tissues; they have a potent self-renewal capacity and can differentiate into multiple cell types. They also affect the ambient tissue by the paracrine secretion of numerous factors in vivo, including the induction of other stem cells’ differentiation. In vitro, the culture media supernatant is named secretome and contains soluble molecules and extracellular vesicles that retain potent biological function in tissue regeneration. MSCs are considered safe for human treatment; their use does not involve ethical issues, as embryonic stem cells do not require genetic manipulation as induced pluripotent stem cells, and after intravenous injection, they are mainly found in the lugs. Therefore, these cells are currently being tested in various preclinical and clinical trials for several diseases, including COVID-19. Several affected COVID-19 patients develop induced acute respiratory distress syndrome (ARDS) associated with an uncontrolled inflammatory response. This condition causes extensive damage to the lungs and may leave serious post-COVID-19 sequelae. As the disease may cause systemic alterations, such as thromboembolism and compromised renal and cardiac function, the intravenous injection of MSCs may be a therapeutic alternative against multiple pathological manifestations. In this work, we reviewed the literature about MSCs biology, focusing on their function in pulmonary regeneration and their use in COVID-19 treatment.
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Pluripotent-derived Mesenchymal Stem/stromal Cells: an Overview of the Derivation Protocol Efficacies and the Differences Among the Derived Cells. Stem Cell Rev Rep 2021; 18:94-125. [PMID: 34545529 DOI: 10.1007/s12015-021-10258-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2021] [Indexed: 10/20/2022]
Abstract
Mesenchymal stem/stromal cells (MSCs) are remarkable tools for regenerative medicine. Therapeutic approaches using these cells can promote increased activity and viability in several cell types through diverse mechanisms such as paracrine and immunomodulatory activities, contributing substantially to tissue regeneration and functional recovery. However, biological samples of human MSCs, usually obtained from adult tissues, often exhibit variable behavior during in vitro culture, especially with respect to cell population heterogeneity, replicative senescence, and consequent loss of functionality. Accordingly, it is necessary to establish standard protocols to generate high-quality, stable cell cultures, for example, by using pluripotent stem cells (PSCs) in derivation protocols of MSC-like cells since PSCs maintain their characteristics consistently during culture. However, the available protocols seem to generate distinct populations of PSC-derivedMSCs (PSC-MSCs) with peculiar attributes, which do not always resemble bona fide primary MSCs. The present review addresses the developmental basis behind some of these derivation protocols, exposing the differences among them and discussing the functional properties of PSC-MSCs, shedding light on elements that may help determine standard characterizations and criteria to evaluate and define these cells.
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Liao C, Han Y, Chen Z, Baigude H. The extract of black cumin, licorice, anise, and black tea alleviates OVA-induced allergic rhinitis in mouse via balancing activity of helper T cells in lung. Allergy Asthma Clin Immunol 2021; 17:87. [PMID: 34493326 PMCID: PMC8424864 DOI: 10.1186/s13223-021-00587-6] [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: 01/05/2021] [Accepted: 08/16/2021] [Indexed: 11/16/2022] Open
Abstract
Background A formulation of black cumin (Nigella sativa L.), licorice (Glycyrrhiza glabra L.), anise (Pimpinella anisum L.) and tea (Camellia sinensis (L.) Kuntze) (denoted BLAB tea) is traditionally used to relief allergy reaction including allergic rhinitis. However, little is known about its underlining mechanism of anti-allergic effects. Methods To investigate the anti-allergenic mechanism of BLAB tea, we treated ovalbumin (OVA)-induced allergic rhinitis (AR) model of mice with BLAB tea, and elucidated its possible mechanism of action. Mice in the control group were treated with phosphate-buffered saline only. Subsequently, the infiltration of different inflammatory cells was measured. In addition, histopathological changes in the nasal mucosa, and the levels of allergen-specific cytokines and OVA-specific immunoglobulins were measured. Results The aqueous extract of BLAB significantly alleviated the nasal symptoms and reduced the accumulation of inflammatory cells in the nasal mucosa and nasal lavage fluid of AR model of mice. Conclusion The aqueous extract of BLAB induced the production of Th1 and Treg cytokines and inhibited the release of Th2 cytokines and histamine in nasal mucosa and serum of mice while decreasing the serum levels of OVA-specific IgE, IgG1, and IgG2a. These results suggest the potential of the aqueous extract of BLAB as a treatment option for allergic diseases. Supplementary Information The online version contains supplementary material available at 10.1186/s13223-021-00587-6.
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Affiliation(s)
- Chengsong Liao
- Xilingol Institute of Bioengineering, Xilingol Vocational College, 11 Mingantu Road, Xilinhot, 026000, Inner Mongolia, People's Republic of China.
| | - Yangyang Han
- Xilingol Institute of Bioengineering, Xilingol Vocational College, 11 Mingantu Road, Xilinhot, 026000, Inner Mongolia, People's Republic of China
| | - Zhijing Chen
- Xilingol Institute of Bioengineering, Xilingol Vocational College, 11 Mingantu Road, Xilinhot, 026000, Inner Mongolia, People's Republic of China
| | - Huricha Baigude
- School of Chemistry & Chemical Engineering, Inner Mongolia University, 235 Daxue West Road, Hohhot, 010021, Inner Mongolia, People's Republic of China.
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43
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Wang M, Zhou T, Zhang Z, Liu H, Zheng Z, Xie H. Current therapeutic strategies for respiratory diseases using mesenchymal stem cells. MedComm (Beijing) 2021; 2:351-380. [PMID: 34766151 PMCID: PMC8554668 DOI: 10.1002/mco2.74] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 03/15/2021] [Accepted: 03/18/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) have a great potential to proliferate, undergo multi-directional differentiation, and exert immunoregulatory effects. There is already much enthusiasm for their therapeutic potentials for respiratory inflammatory diseases. Although the mechanism of MSCs-based therapy has been well explored, only a few articles have summarized the key advances in this field. We hereby provide a review over the latest progresses made on the MSCs-based therapies for four types of inflammatory respiratory diseases, including idiopathic pulmonary fibrosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, and asthma, and the uncovery of their underlying mechanisms from the perspective of biological characteristics and functions. Furthermore, we have also discussed the advantages and disadvantages of the MSCs-based therapies and prospects for their optimization.
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Affiliation(s)
- Ming‐yao Wang
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Ting‐yue Zhou
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Zhi‐dong Zhang
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Hao‐yang Liu
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Zhi‐yao Zheng
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Hui‐qi Xie
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
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44
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Shin JW, Ryu S, Ham J, Jung K, Lee S, Chung DH, Kang HR, Kim HY. Mesenchymal Stem Cells Suppress Severe Asthma by Directly Regulating Th2 Cells and Type 2 Innate Lymphoid Cells. Mol Cells 2021; 44:580-590. [PMID: 34462397 PMCID: PMC8424137 DOI: 10.14348/molcells.2021.0101] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/25/2021] [Accepted: 05/27/2021] [Indexed: 12/19/2022] Open
Abstract
Patients with severe asthma have unmet clinical needs for effective and safe therapies. One possibility may be mesenchymal stem cell (MSC) therapy, which can improve asthma in murine models. However, it remains unclear how MSCs exert their beneficial effects in asthma. Here, we examined the effect of human umbilical cord blood-derived MSCs (hUC-MSC) on two mouse models of severe asthma, namely, Alternaria alternata-induced and house dust mite (HDM)/diesel exhaust particle (DEP)-induced asthma. hUC-MSC treatment attenuated lung type 2 (Th2 and type 2 innate lymphoid cell) inflammation in both models. However, these effects were only observed with particular treatment routes and timings. In vitro co-culture showed that hUC-MSC directly downregulated the interleukin (IL)-5 and IL-13 production of differentiated mouse Th2 cells and peripheral blood mononuclear cells from asthma patients. Thus, these results showed that hUC-MSC treatment can ameliorate asthma by suppressing the asthmogenic cytokine production of effector cells. However, the successful clinical application of MSCs in the future is likely to require careful optimization of the route, dosage, and timing.
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Affiliation(s)
- Jae Woo Shin
- Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Seungwon Ryu
- Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Jongho Ham
- Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Keehoon Jung
- Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Korea
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 03080, Korea
| | - Sangho Lee
- Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Korea
- Biomedical Institute for Convergence at SKKU, Sungkyunkwan University, Suwon 16419, Korea
| | - Doo Hyun Chung
- Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Korea
- Laboratory of Immune Regulation, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Hye-Ryun Kang
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 03080, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Hye Young Kim
- Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 03080, Korea
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45
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Goldsteen PA, Yoseif C, Dolga AM, Gosens R. Human pluripotent stem cells for the modelling and treatment of respiratory diseases. Eur Respir Rev 2021; 30:30/161/210042. [PMID: 34348980 PMCID: PMC9488746 DOI: 10.1183/16000617.0042-2021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 05/26/2021] [Indexed: 01/17/2023] Open
Abstract
Respiratory diseases are among the leading causes of morbidity and mortality worldwide, representing a major unmet medical need. New chemical entities rarely make it into the clinic to treat respiratory diseases, which is partially due to a lack of adequate predictive disease models and the limited availability of human lung tissues to model respiratory disease. Human pluripotent stem cells (hPSCs) may help fill this gap by serving as a scalable human in vitro model. In addition, human in vitro models of rare genetic mutations can be generated using hPSCs. hPSC-derived epithelial cells and organoids have already shown great potential for the understanding of disease mechanisms, for finding new potential targets by using high-throughput screening platforms, and for personalised treatments. These potentials can also be applied to other hPSC-derived lung cell types in the future. In this review, we will discuss how hPSCs have brought, and may continue to bring, major changes to the field of respiratory diseases by understanding the molecular mechanisms of the pathology and by finding efficient therapeutics. Human pluripotent stem cells may help to develop animal-free, fully human in vitro models to advance our understanding of disease mechanisms, for finding new potential targets by using high-throughput screening platforms, and for personalised treatments.https://bit.ly/3cahaqz
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Affiliation(s)
- Pien A Goldsteen
- Dept of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands .,GRIAC Research Institute, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Christina Yoseif
- Dept of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands
| | - Amalia M Dolga
- Dept of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands.,GRIAC Research Institute, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Reinoud Gosens
- Dept of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands.,GRIAC Research Institute, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
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46
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Kaboodkhani R, Mehrabani D, Karimi-Busheri F. Achievements and Challenges in Transplantation of Mesenchymal Stem Cells in Otorhinolaryngology. J Clin Med 2021; 10:2940. [PMID: 34209041 PMCID: PMC8267672 DOI: 10.3390/jcm10132940] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/25/2021] [Accepted: 06/28/2021] [Indexed: 12/15/2022] Open
Abstract
Otorhinolaryngology enrolls head and neck surgery in various tissues such as ear, nose, and throat (ENT) that govern different activities such as hearing, breathing, smelling, production of vocal sounds, the balance, deglutition, facial animation, air filtration and humidification, and articulation during speech, while absence of these functions can lead to high morbidity and even mortality. Conventional therapies for head and neck damaged tissues include grafts, transplants, and artificial materials, but grafts have limited availability and cause morbidity in the donor site. To improve these limitations, regenerative medicine, as a novel and rapidly growing field, has opened a new therapeutic window in otorhinolaryngology by using cell transplantation to target the healing and replacement of injured tissues. There is a high risk of rejection and tumor formation for transplantation of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs); mesenchymal stem cells (MSCs) lack these drawbacks. They have easy expansion and antiapoptotic properties with a wide range of healing and aesthetic functions that make them a novel candidate in otorhinolaryngology for craniofacial defects and diseases and hold immense promise for bone tissue healing; even the tissue sources and types of MSCs, the method of cell introduction and their preparation quality can influence the final outcome in the injured tissue. In this review, we demonstrated the anti-inflammatory and immunomodulatory properties of MSCs, from different sources, to be safely used for cell-based therapies in otorhinolaryngology, while their achievements and challenges have been described too.
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Affiliation(s)
- Reza Kaboodkhani
- Otorhinolaryngology Research Center, Department of Otorhinolaryngology, School of Medicine, Shiraz University of Medical Sciences, Shiraz 71936-36981, Iran;
| | - Davood Mehrabani
- Stem Cell Technology Research Center, Shiraz University of Medical Sciences, Shiraz 71348-14336, Iran
- Burn and Wound Healing Research Center, Shiraz University of Medical Sciences, Shiraz 71987-74731, Iran
- Comparative and Experimental Medicine Center, Shiraz University of Medical Sciences, Shiraz 71348-14336, Iran
- Li Ka Shing Center for Health Research and Innovation, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Feridoun Karimi-Busheri
- Department of Oncology, Faculty of Medicine, University of Alberta, Edmonton, AB T6G 1Z2, Canada
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47
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Atkinson SP. A preview of selected articles. Stem Cells Transl Med 2021. [PMCID: PMC8133349 DOI: 10.1002/sctm.21-0133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
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48
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Tang H, Han X, Li T, Feng Y, Sun J. Protective effect of miR-138-5p inhibition modified human mesenchymal stem cell on ovalbumin-induced allergic rhinitis and asthma syndrome. J Cell Mol Med 2021; 25:5038-5049. [PMID: 33973707 PMCID: PMC8178307 DOI: 10.1111/jcmm.16473] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 02/09/2021] [Accepted: 02/26/2021] [Indexed: 12/11/2022] Open
Abstract
The objective of the study is to evaluate the protective effects of human mesenchymal stem cells (hMSCs) modified with miR‐138‐5p inhibitor against the allergic rhinitis and asthma syndrome (ARAS). MiR‐138‐5p or negative control was transfected into hMSCs, and fluorescence‐activated cell sorting was used to evaluate hMSC surface markers. Quantitative real‐time PCR (qRT‐PCR) was used to evaluate miR‐138‐5p, SIRT1, caspase‐3, IL‐6, IL‐1β and TNF‐α levels after TNF‐α and IL‐6 stimulations. hMSCs with or without miR‐138‐5p inhibition was intranasally administered into ARAS mice (n = 10 each group), followed by monitoring sneezing and nasal rubbing events to evaluate the allergic symptoms. Histamine, ovalbumin‐specific IgE, IgG2a, IgG1 and LTC4 release were monitored in the serum and nasal lavage fluid using enzyme‐linked immunosorbent assay. Expression of SIRT1 and HMGB1/TLR4 pathway in nasal mucosa was assessed. After miR‐138‐5p inhibitor transfection, the hMSC lineage was preserved. Binding between SIRT1 and miR‐138‐4p was observed, and miR‐138‐5p inhibition led to upregulation of SIRT1. Inhibition of miR‐138‐5p led to attenuated inflammatory responses of hMSCs upon TNF‐α and IL‐6 stimulation, and allergic symptoms in mice, as well as histamine and ovalbumin‐specific IgG release. hMSCs with miR‐138‐5p inhibition showed characteristics of activated SIRT1 and inhibited HMGB1/TLR4 pathway. Inhibition of miR‐138‐5p in hMSCs enhanced its effects in attenuating inflammatory responses and allergic reaction in the ARAS model, which is presumably regulated by SIRT1 and the HMGB1/TLR4 pathway.
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Affiliation(s)
- Huaping Tang
- Department of Respiratory Medicine, Qingdao Municipal Hospital, Qingdao, China
| | - Xiaolei Han
- Health Office, Qingdao Municipal Hospital, Qingdao, China
| | - Tingtian Li
- Department of Respiratory Medicine, Qingdao Municipal Hospital, Qingdao, China
| | - Yan Feng
- Department of Respiratory Medicine, Qingdao Municipal Hospital, Qingdao, China
| | - Jie Sun
- Department of International Clinic, Qingdao Municipal Hospital, Qingdao, China
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49
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Tong Y, Zuo J, Yue D. Application Prospects of Mesenchymal Stem Cell Therapy for Bronchopulmonary Dysplasia and the Challenges Encountered. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9983664. [PMID: 33997051 PMCID: PMC8110410 DOI: 10.1155/2021/9983664] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/27/2021] [Accepted: 04/29/2021] [Indexed: 01/01/2023]
Abstract
Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in premature babies, especially affecting those with very low or extremely low birth weights. Survivors experience adverse lung and neurological defects including cognitive dysfunction. This impacts the prognosis of children with BPD and may result in developmental delays. The currently available options for the treatment of BPD are limited owing to low efficacy or several side effects; therefore, there is a lack of effective treatments for BPD. The treatment for BPD must help in the repair of damaged lung tissue and promote further growth of the lung tissue. In recent years, the emergence of stem cell therapy, especially mesenchymal stem cell (MSC) therapy, has improved the treatment of BPD to a great extent. This article briefly reviews the advantages, research progress, and challenges faced with the use of MSCs in the treatment of BPD. Stem cell therapy is beneficial as it repairs damaged tissues by reducing inflammation, fibrosis, and by acting against oxidative stress damage. Experimental trials have also proven that MSCs provide a promising avenue for BPD treatment. However, there are challenges such as the possibility of MSCs contributing to tumorous growths, the presence of heterogeneous cell populations resulting in variable efficacy, and the ethical considerations regarding the use of this treatment in humans. Therefore, more research must be conducted to determine whether MSC therapy can be approved as a treatment option for BPD.
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Affiliation(s)
- Yajie Tong
- Department of Pediatrics, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004 Liaoning, China
| | - Jingye Zuo
- Department of Pediatrics, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004 Liaoning, China
| | - Dongmei Yue
- Department of Pediatrics, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004 Liaoning, China
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50
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Fan X, Xu ZB, Li CL, Zhang HY, Peng YQ, He BX, Liu XQ, Chen DH, Chen D, Akdis CA, Fu QL. Mesenchymal stem cells regulate type 2 innate lymphoid cells via regulatory T cells through ICOS-ICOSL interaction. STEM CELLS (DAYTON, OHIO) 2021; 39:975-987. [PMID: 33662168 PMCID: PMC8360040 DOI: 10.1002/stem.3369] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 01/19/2021] [Accepted: 02/03/2021] [Indexed: 11/10/2022]
Abstract
Group 2 innate lymphoid cells (ILC2s) are recognized as key controllers and effectors of type 2 inflammation. Mesenchymal stem cells (MSCs) have been shown to alleviate type 2 inflammation by modulating T lymphocyte subsets and decreasing TH 2 cytokine levels. However, the effects of MSCs on ILC2s have not been investigated. In this study, we investigated the potential immunomodulatory effects of MSCs on ILC2s in peripheral blood mononuclear cells (PBMCs) from allergic rhinitis patients and healthy subjects. We further investigated the mechanisms involved in the MSC modulation using isolated lineage negative (Lin- ) cells. PBMCs and Lin- cells were cocultured with induced pluripotent stem cell-derived MSCs (iPSC-MSCs) under the stimulation of epithelial cytokines IL-25 and IL-33. And the ILC2 levels and functions were examined and the possible mechanisms were investigated based on regulatory T (Treg) cells and ICOS-ICOSL pathway. iPSC-MSCs successfully decreased the high levels of IL-13, IL-9, and IL-5 in PBMCs in response to IL-25, IL-33, and the high percentages of IL-13+ ILC2s and IL-9+ ILC2s in response to epithelial cytokines were significantly reversed after the treatment of iPSC-MSCs. However, iPSC-MSCs were found directly to enhance ILC2 levels and functions via ICOS-ICOSL interaction in Lin- cells and pure ILC2s. iPSC-MSCs exerted their inhibitory effects on ILC2s via activating Treg cells through ICOS-ICOSL interaction. The MSC-induced Treg cells then suppressed ILC2s by secreting IL-10 in the coculture system. This study revealed that human MSCs suppressed ILC2s via Treg cells through ICOS-ICOSL interaction, which provides further insight to regulate ILC2s in inflammatory disorders.
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Affiliation(s)
- Xingliang Fan
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Zhi-Bin Xu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Cheng-Lin Li
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.,Center for Clinical Medicine Innovation, ShenZhen Hospital of Southern Medical University, Guangdong, People's Republic of China
| | - Hong-Yu Zhang
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Ya-Qi Peng
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Bi-Xin He
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Xiao-Qing Liu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - De-Hua Chen
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Dong Chen
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Cezmi A Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.,Christine Kühne-Center for Research and Education (CK-CARE), Davos, Switzerland
| | - Qing-Ling Fu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.,Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
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