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Shan J, Cheng L, Li X, Liu W, Liu Z, Chai Y, Yu Y, Wang X, Wen G. End-tail soaking strategy toward robust and biomimetic sandwich-layered hydrogels for full-thickness bone regeneration. Bioact Mater 2025; 49:486-501. [PMID: 40206197 PMCID: PMC11979482 DOI: 10.1016/j.bioactmat.2025.02.045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 02/10/2025] [Accepted: 02/28/2025] [Indexed: 04/11/2025] Open
Abstract
Despite an increasing number of tissue-engineered scaffolds have been developing for bone regeneration, simple and universal fabrication of biomimetic bone microstructure to repair full-thickness bone defects remains a challenge and an acute clinical demand due to the negligence of microstructural differences within the cortex of cancellous bone. In this work, a biomimetic sandwich-layered PACG-CS@Mn(III) hydrogel (SL hydrogel) was facilely fabricated in an end-tail soaking strategy by simply post-crosslinking of poly(acryloyl 2-glycine)-chitosan (PACG-CS) composite hydrogel using trivalent manganese solutions. Taking the merits of in-situ formation and flexible adjustment of chain entanglements, hydrogen bonds and metal chelate interactions, SL hydrogel with sandwich-like three-layered structures and anisotropic mechanical performance was easily customized through control of the manganese concentration and soaking time in fore-and-aft sides, simulating the structurally and mechanically biomimetic characteristics of cortical and cancellous bone. Furthermore, the produced SL hydrogel also demonstrated favorable biocompatibility and enhanced MnSOD activity via a peroxidase-like reaction, which enabled the excellent radical scavenging efficiency and anti-inflammatory regulation for facilitating the activity, proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). In vivo studies further revealed that these SL hydrogels achieved restrictive pro-vascular regeneration through their stratified structure, thereby promoting the differentiation of osteoblasts. Simultaneously, the mechanical cues of stratified structure could mediate macrophage phenotype transitions in accordance with stem cell-osteoblast differentiation process via the PI3K-AKT pathway, resulting in robust osteogenesis and high-quality bone reconstruction. This facile yet efficient strategy of turning anisotropic hydrogel offers a promising alternative for full-thickness repair of bone defects, which is also significantly imperative to achieve high-performance scaffolds with specific usage requirements and expand their clinic applicability in more complex anisotropic tissues.
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Affiliation(s)
- Jianyang Shan
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, National Center for Orthopaedic Medicine, Shanghai, 200233, China
- Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China
| | - Liang Cheng
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, National Center for Orthopaedic Medicine, Shanghai, 200233, China
| | - Xiang Li
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, National Center for Orthopaedic Medicine, Shanghai, 200233, China
| | - Wenhao Liu
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, National Center for Orthopaedic Medicine, Shanghai, 200233, China
- Shanghai Ocean University, College of Fisheries and Life Science, Shanghai, 201306, China
| | - Zhihua Liu
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, National Center for Orthopaedic Medicine, Shanghai, 200233, China
- Shanghai Ocean University, College of Fisheries and Life Science, Shanghai, 201306, China
| | - Yimin Chai
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, National Center for Orthopaedic Medicine, Shanghai, 200233, China
| | - Yaling Yu
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, National Center for Orthopaedic Medicine, Shanghai, 200233, China
| | - Xing Wang
- Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Gen Wen
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, National Center for Orthopaedic Medicine, Shanghai, 200233, China
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Zhang L, Deng Y, Bai X, Wei X, Ren Y, Chen S, Deng H. Cell therapy for end-stage liver disease: Current state and clinical challenge. Chin Med J (Engl) 2024; 137:2808-2820. [PMID: 39602326 DOI: 10.1097/cm9.0000000000003332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Indexed: 11/29/2024] Open
Abstract
ABSTRACT Liver disease involves a complex interplay of pathological processes, including inflammation, hepatocyte necrosis, and fibrosis. End-stage liver disease (ESLD), such as liver failure and decompensated cirrhosis, has a high mortality rate, and liver transplantation is the only effective treatment. However, to overcome problems such as the shortage of donor livers and complications related to immunosuppression, there is an urgent need for new treatment strategies that need to be developed for patients with ESLD. For instance, hepatocytes derived from donor livers or stem cells can be engrafted and multiplied in the liver, substituting the host hepatocytes and rebuilding the liver parenchyma. Stem cell therapy, especially mesenchymal stem cell therapy, has been widely proved to restore liver function and alleviate liver injury in patients with severe liver disease, which has contributed to the clinical application of cell therapy. In this review, we discussed the types of cells used to treat ESLD and their therapeutic mechanisms. We also summarized the progress of clinical trials around the world and provided a perspective on cell therapy.
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Affiliation(s)
- Lin Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
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Yuan H, Li Y, Kong Z, Peng L, Song J, Hou X, Zhang W, Liu R, Feng T, Zhu C. IL-33-Pretreated Mesenchymal Stem Cells Attenuate Acute Liver Failure by Improving Homing and Polarizing M2 Macrophages. Stem Cells Int 2024; 2024:1273099. [PMID: 39478979 PMCID: PMC11524710 DOI: 10.1155/2024/1273099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 07/05/2024] [Accepted: 09/18/2024] [Indexed: 11/02/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are highly effective in the treatment of acute liver failure (ALF). The efficacy of MSCs is closely related to the inflammatory environment. Therefore, we investigated the functional changes of MSCs in response to interleukin-33 (IL-33) stimulation. The results showed that bone marrow mesenchymal stem cells (BMSCs) pretreated with IL-33 had increased CCR2 expression, targeted CCL2 in the injured liver tissue, and improved the migration ability. Under LPS stimulation, the NF-κB pathway of BMDM was activated, and its phenotype polarized to the M1-type, while BMSCs pretreated with IL-33 inhibited the NF-κB pathway and enhanced M2 macrophage polarization. The M2-type macrophages could further inhibit hepatocytes inflammation, reduce hepatocytes apoptosis, and promote hepatocytes repair. These results suggest that IL-33 can enhance the efficacy of BMSCs in ALF and provide a new strategy for cell therapy of liver diseases.
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Affiliation(s)
- Hui Yuan
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yuwen Li
- Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zihao Kong
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Linya Peng
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jiali Song
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaoxue Hou
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wen Zhang
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Rui Liu
- Department of Infectious and Tropical Diseases, The Second Affiliated Hospital, NHC Key Laboratory of Tropical Disease Control, Hainan Medical University, Haikou, China
| | - Tiantong Feng
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chuanlong Zhu
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department of Infectious and Tropical Diseases, The Second Affiliated Hospital, NHC Key Laboratory of Tropical Disease Control, Hainan Medical University, Haikou, China
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Zhang WB, Chen ZX, Liu Z, Qian XY, Ge YZ, Zhang HY, Xu WT, Shan LT, Zhao DB. PBMC-mediated modulation of macrophage polarization in RAW264.7 cells through STAT1/STAT6 signaling cascades. Int Immunopharmacol 2024; 138:112651. [PMID: 38986303 DOI: 10.1016/j.intimp.2024.112651] [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: 05/29/2024] [Revised: 06/30/2024] [Accepted: 07/05/2024] [Indexed: 07/12/2024]
Abstract
Peripheral blood mononuclear cells (PBMC), sourced autologously, offer numerous advantages when procured: easier acquisition process, no in vitro amplification needed, decreased intervention and overall increased acceptability make PBMC an attractive candidate for cell therapy treatment. However, the exact mechanism by which PBMC treat diseases remains poorly understood. Immune imbalance is the pathological basis of many diseases, with macrophages playing a crucial role in this process. However, research on the role and mechanisms of PBMC in regulating macrophages remains scarce. This study employed an in vitro co-culture model of PBMC and RAW264.7 macrophages to explore the role and mechanisms of PBMC in regulating macrophages. The results showed that the co-culturing led to decreased expression of inflammatory cytokines and increased expression of anti-inflammatory cytokines in RAW264.7 or in the culture supernatant. Additionally, the pro-inflammatory, tissue matrix-degrading M1 macrophages decreased, while the anti-inflammatory, matrix-synthesizing, regenerative M2 macrophages increased in both RAW264.7 and monocytes within PBMC. Moreover, co-cultured macrophages exhibited a significantly decreased p-STAT1/STAT1 ratio, while the p-STAT6/STAT6 ratio significantly increased. This suggests that PBMC may inhibit M1 macrophage polarization by blocking STAT1 signaling cascades and may promote M2 macrophage polarization through the activation of STAT6 signaling cascades. Overall, this study sheds light on the role and mechanism of PBMC in regulating macrophages. Moreover, it was found that monocytes within co-cultured PBMC differentiated into M2 macrophages in the presence of macrophages. This finding provides experimental evidence for the use of PBMC in treating inflammatory diseases, especially macrophage-depleting inflammatory diseases such as osteoarthritis.
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Affiliation(s)
- Wen-Bo Zhang
- Department of Rheumatology and Immunology, Changhai Hospital, Naval Medical University, Shanghai 200433, China
| | - Zu-Xiang Chen
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China
| | - Zhen Liu
- Department of Anatomy, Naval Medical University, Shanghai 200433, China
| | - Xin-Yu Qian
- Department of Rheumatology and Immunology, Changhai Hospital, Naval Medical University, Shanghai 200433, China
| | - Yan-Zhi Ge
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China
| | - Hai-Yan Zhang
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China
| | - Wen-Ting Xu
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China
| | - Le-Tian Shan
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China.
| | - Dong-Bao Zhao
- Department of Rheumatology and Immunology, Changhai Hospital, Naval Medical University, Shanghai 200433, China.
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Tian L, Chen J, Yang M, Chen L, Qiu J, Jiang Y, Tan X, Qian Q, Liang X, Dou X. Xiezhuo Tiaozhi formula inhibits macrophage pyroptosis in the non-alcoholic fatty liver disease by targeting the SIRT1 pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 131:155776. [PMID: 38851104 DOI: 10.1016/j.phymed.2024.155776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 05/12/2024] [Accepted: 05/22/2024] [Indexed: 06/10/2024]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a challenging disease to interfere with and represents a potential long-term risk factor for hepatic fibrosis and liver cancer. The Xiezhuo Tiaozhi (XZTZ) formula, a water extract from crude herbs, has been widely used as an anti-NAFLD agent through clinical observation. However, the underlying pharmacological mechanisms of the XZTZ formula and its impact on the potential pathways against NAFLD have not been elucidated. PURPOSE Our study aims to investigate the pharmacological effects and underlying regulatory mechanisms of the XZTZ formula to treat NAFLD. METHODS The possible active components and pharmacological mechanisms of the XZTZ formula against NAFLD were identified using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) and molecular docking. To further explore the potential mechanisms, forty-eight 6-week-old male C57BL/6 J mice were given individual attention with high-fat and high-sugar diet (HFHSD) or relevant control (Ctrl) diets for 16 weeks to successfully construct a NAFLD mouse model. Subsequently, the levels of serum biochemicals, pathological changes in the liver, and pyroptosis levels were assessed in mice to investigate the therapeutic effects of the XZTZ formula. Further, LPS-induced RAW264.7 cells and Immortalized Mouse Kupffer cells (ImKC) were used to verify the potential mechanisms of the XZTZ formula against NAFLD in vitro. RESULTS We identified 7 chemical compounds and 2 potential therapeutic targets as plausible therapeutic points for the treatment of NAFLD using the XZTZ formula. Subsequent histopathological analysis revealed marked hepatic steatosis and lipid accumulation in the HFHSD mice liver, while conditions were effectively ameliorated by administration of the XZTZ formula. Additionally, our work demonstrated that the XZTZ formula could attenuate M1 polarization, promote M2 polarization, and suppress pyroptosis via the SIRT1 pathway in tissue samples. Moreover, validation performed through LPS-induced RAW264.7 and ImKC cells by showing that silencing SIRT1 weaken the effects of the XZTZ formula on relative pyroptosis affirmed that its role was associated with the SIRT1 pathway in macrophage. CONCLUSION These findings suggest that the XZTZ formula alleviated hepatic steatosis and lipid accumulation in NAFLD mice. These ameliorations are associated with mechanisms involving the attenuation of M1 polarization, promotion of M2 polarization, and anti-pyroptosis effects through the SIRT1 pathway.
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Affiliation(s)
- Lulu Tian
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jing Chen
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Meiqi Yang
- Liaoning University of Traditional Chinese Medicine Xinglin College, Shenyang, Liaoning, China
| | - Lin Chen
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jiannan Qiu
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yuwei Jiang
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Xiaolong Tan
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Qianyu Qian
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Xiao Liang
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
| | - Xiaobing Dou
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
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Ganguly K, Luthfikasari R, Randhawa A, Dutta SD, Patil TV, Acharya R, Lim KT. Stimuli-Mediated Macrophage Switching, Unraveling the Dynamics at the Nanoplatforms-Macrophage Interface. Adv Healthc Mater 2024; 13:e2400581. [PMID: 38637323 DOI: 10.1002/adhm.202400581] [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: 02/15/2024] [Revised: 04/01/2024] [Indexed: 04/20/2024]
Abstract
Macrophages play an essential role in immunotherapy and tissue regeneration owing to their remarkable plasticity and diverse functions. Recent bioengineering developments have focused on using external physical stimuli such as electric and magnetic fields, temperature, and compressive stress, among others, on micro/nanostructures to induce macrophage polarization, thereby increasing their therapeutic potential. However, it is difficult to find a concise review of the interaction between physical stimuli, advanced micro/nanostructures, and macrophage polarization. This review examines the present research on physical stimuli-induced macrophage polarization on micro/nanoplatforms, emphasizing the synergistic role of fabricated structure and stimulation for advanced immunotherapy and tissue regeneration. A concise overview of the research advancements investigating the impact of physical stimuli, including electric fields, magnetic fields, compressive forces, fluid shear stress, photothermal stimuli, and multiple stimulations on the polarization of macrophages within complex engineered structures, is provided. The prospective implications of these strategies in regenerative medicine and immunotherapeutic approaches are highlighted. This review will aid in creating stimuli-responsive platforms for immunomodulation and tissue regeneration.
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Affiliation(s)
- Keya Ganguly
- Department of Biosystems Engineering, Kangwon National University, Chuncheon, 24341, Republic of Korea
- Institute of Forest Science, Kangwon National University, Chuncheon, 24341, Republic of Korea
| | - Rachmi Luthfikasari
- Department of Biosystems Engineering, Kangwon National University, Chuncheon, 24341, Republic of Korea
| | - Aayushi Randhawa
- Department of Biosystems Engineering, Kangwon National University, Chuncheon, 24341, Republic of Korea
- Interdisciplinary Program in Smart Agriculture, Kangwon National University, Chuncheon, 24341, Republic of Korea
| | - Sayan Deb Dutta
- Department of Biosystems Engineering, Kangwon National University, Chuncheon, 24341, Republic of Korea
| | - Tejal V Patil
- Department of Biosystems Engineering, Kangwon National University, Chuncheon, 24341, Republic of Korea
- Interdisciplinary Program in Smart Agriculture, Kangwon National University, Chuncheon, 24341, Republic of Korea
| | - Rumi Acharya
- Department of Biosystems Engineering, Kangwon National University, Chuncheon, 24341, Republic of Korea
- Interdisciplinary Program in Smart Agriculture, Kangwon National University, Chuncheon, 24341, Republic of Korea
| | - Ki-Taek Lim
- Department of Biosystems Engineering, Kangwon National University, Chuncheon, 24341, Republic of Korea
- Interdisciplinary Program in Smart Agriculture, Kangwon National University, Chuncheon, 24341, Republic of Korea
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Ramos Solis N, Cannon A, Dilday T, Abt M, Oblak AL, Soloff AC, Kaplan MH, Yeh ES. HUNK as a key regulator of tumor-associated macrophages in triple negative breast cancer. Oncoimmunology 2024; 13:2364382. [PMID: 38846083 PMCID: PMC11155704 DOI: 10.1080/2162402x.2024.2364382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 05/30/2024] [Accepted: 05/31/2024] [Indexed: 06/09/2024] Open
Abstract
Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC tumors are not sensitive to endocrine therapy, and standardized TNBC treatment regimens are lacking. TNBC is a more immunogenic subtype of breast cancer, making it more responsive to immunotherapy intervention. Tumor-associated macrophages (TAMs) constitute one of the most abundant immune cell populations in TNBC tumors and contribute to cancer metastasis. This study examines the role of the protein kinase HUNK in tumor immunity. Gene expression analysis using NanoString's nCounter PanCancer Immune Profiling panel identified that targeting HUNK is associated with changes in the IL-4/IL-4 R cytokine signaling pathway. Experimental analysis shows that HUNK kinase activity regulates IL-4 production in mammary tumor cells, and this regulation is dependent on STAT3. In addition, HUNK-dependent regulation of IL-4 secreted from tumor cells induces polarization of macrophages into an M2-like phenotype associated with TAMs. In return, IL-4 induces cancer metastasis and macrophages to produce epidermal growth factor. These findings delineate a paracrine signaling exchange between tumor cells and TAMs regulated by HUNK and dependent on IL-4/IL-4 R. This highlights the potential of HUNK as a target for reducing TNBC metastasis through modulation of the TAM population.
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Affiliation(s)
- Nicole Ramos Solis
- Department of Pharmacology and Toxicology, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
- Simon Comprehensive Cancer Center, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
| | - Anthony Cannon
- Department of Microbiology and Immunology, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
| | - Tinslee Dilday
- Department of Pharmacology and Toxicology, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
- Simon Comprehensive Cancer Center, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
| | - Melissa Abt
- Department of Pharmacology and Toxicology, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
| | - Adrian L. Oblak
- Department of Radiology and Imaging Sciences, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
| | - Adam C. Soloff
- Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Mark H. Kaplan
- Simon Comprehensive Cancer Center, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
- Department of Microbiology and Immunology, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
| | - Elizabeth S. Yeh
- Department of Pharmacology and Toxicology, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
- Simon Comprehensive Cancer Center, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
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Soufihasanabad S, Mahmoudi M, Taghavi-Farahabadi M, Mirsanei Z, Mahmoudi Lamouki R, Mirza Abdalla JK, Babaei E, Hashemi SM. In vivo polarization of M2 macrophages by mesenchymal stem cell-derived extracellular vesicles: A novel approach to macrophage polarization and its potential in treating inflammatory diseases. Med Hypotheses 2024; 187:111353. [DOI: 10.1016/j.mehy.2024.111353] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Pignatti E, Maccaferri M, Pisciotta A, Carnevale G, Salvarani C. A comprehensive review on the role of mesenchymal stromal/stem cells in the management of rheumatoid arthritis. Expert Rev Clin Immunol 2024; 20:463-484. [PMID: 38163928 DOI: 10.1080/1744666x.2023.2299729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 12/21/2023] [Indexed: 01/03/2024]
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease with systemic manifestations. Although the success of immune modulatory drug therapy is considerable, about 40% of patients do not respond to treatment. Mesenchymal stromal/stem cells (MSCs) have been demonstrated to have therapeutic potential for inflammatory diseases. AREAS COVERED This review provides an update on RA disease and on pre-clinical and clinical studies using MSCs from bone marrow, umbilical cord, adipose tissue, and dental pulp, to regulate the immune response. Moreover, the clinical use, safety, limitations, and future perspective of MSCs in RA are discussed. Using the PubMed database and ClincalTrials.gov, peer-reviewed full-text papers, abstracts and clinical trials were identified from 1985 through to April 2023. EXPERT OPINION MSCs demonstrated a satisfactory safety profile and potential for clinical efficacy. However, it is mandatory to deepen the investigations on how MSCs affect the proinflammatory deregulated RA patients' cells. MSCs are potentially good candidates for severe RA patients not responding to conventional therapies but a long-term follow-up after stem cells treatment and standardized protocols are needed. Future research should focus on well-designed multicenter randomized clinical trials with adequate sample sizes and properly selected patients satisfying RA criteria for a valid efficacy evaluation.
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Affiliation(s)
- Elisa Pignatti
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Monia Maccaferri
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Alessandra Pisciotta
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Gianluca Carnevale
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Carlo Salvarani
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
- Rheumatology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
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Wang YJ, Xu QY, Ye WM, Yi DY, Zheng XQ, Xie L, Lin LR, Lin Y, Yang TC. Treponema pallidum Promotes the Polarization of M2 Subtype Macrophages to M1 Subtype Mediating the Apoptosis and Inhibiting the Angiogenesis of Human Umbilical Vein Endothelial Cells. ACS Infect Dis 2023; 9:2548-2559. [PMID: 37983134 DOI: 10.1021/acsinfecdis.3c00401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2023]
Abstract
M2 macrophages were related to local immune homeostasis and maternal-fetal tolerance in normal pregnancy; whether M2 macrophages can respond to the stimulation of Treponema pallidum to mediate placental vascular inflammation injury is unclear. In this study, M2 macrophages were constructed to investigate the impact of T. pallidum on macrophage polarization and the underlying signaling pathway involved in this process, and the influence of macrophage polarization triggered by T. pallidum on the apoptosis and angiogenesis of human umbilical vein endothelial cells (HUVEC) was also explored. The results showed that M2 macrophage markers (CD206 and PPARγ) and anti-inflammatory factors (TGFβ and CCL18) were decreased, while M1 macrophage marker CD80 and inflammatory cytokines (IL1β and TNFα) were increased when M2 macrophages were treated with T. pallidum, indicating that T. pallidum promoted the polarization of M2 subtype macrophages to the M1 subtype. Moreover, T. pallidum-induced M1 macrophage polarization was found to be significantly correlated with the activation of Janus kinase 1 (JAK1) and signal transducer and activator of transcription 1 (STAT1). In addition, T. pallidum-induced M1 macrophages were found to promote apoptosis and inhibit the angiogenesis of HUVECs, and JAK1 or STAT1 inhibitors could weaken the apoptosis rate and promote the angiogenesis of HUVECs. These findings revealed that T. pallidum promoted the polarization of M2 macrophages to the M1 subtype through the JAK1-STAT1 signal pathway mediating the apoptosis and inhibiting angiogenesis of HUVECs, which may provide a possible mechanism for T. pallidum-induced adverse pregnancy outcomes.
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Affiliation(s)
- Yong-Jing Wang
- Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China
- Guangyuan Hospital of Traditional Chinese Medicine, Guangyuan 628000, China
| | - Qiu-Yan Xu
- Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China
| | - Wei-Ming Ye
- Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China
| | - Dong-Yu Yi
- Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China
| | - Xin-Qi Zheng
- Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China
| | - Lin Xie
- Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China
| | - Li-Rong Lin
- Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China
- Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen 361004, China
| | - Yu Lin
- Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China
- Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen 361004, China
| | - Tian-Ci Yang
- Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China
- Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen 361004, China
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Liu M, Lu F, Feng J. Therapeutic potential of adipose tissue derivatives in skin photoaging. Regen Med 2023; 18:869-883. [PMID: 37743749 DOI: 10.2217/rme-2023-0098] [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] [Indexed: 09/26/2023] Open
Abstract
Photoaging, the primary cause of exogenous skin aging and predominantly caused by ultraviolet radiation, is an essential type of skin aging characterized by chronic skin inflammation. Recent studies have shown that oxidative stress, inflammation, skin barrier homeostasis, collagen denaturation and pigmentation are the main contributors to it. As a composite tissue rich in matrix and vascular components, adipose tissue derivatives have been recently gaining attention as potential therapeutic agents for various human diseases with fat-processing technology upgrades. This review analyzes both 'minimally treated' and 'nonminimally treated' fat derivatives to give an overview of the preclinical and clinical relevance of adipose tissue derivatives for antiphotoaging application, highlighting their good clinical prospects as well as discussing their safety and potential risks.
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Affiliation(s)
- Meiqi Liu
- Department of Plastic & Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, Guangdong 510515, PR China
| | - Feng Lu
- Department of Plastic & Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, Guangdong 510515, PR China
| | - Jingwei Feng
- Department of Plastic & Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, Guangdong 510515, PR China
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12
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Xu A, Yang Y, Shao Y, Jiang M, Sun Y, Feng B. FHL2 regulates microglia M1/M2 polarization after spinal cord injury via PARP14-depended STAT1/6 pathway. Int Immunopharmacol 2023; 124:110853. [PMID: 37708708 DOI: 10.1016/j.intimp.2023.110853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 08/21/2023] [Accepted: 08/21/2023] [Indexed: 09/16/2023]
Abstract
Neuronal apoptosis and inflammation exacerbate the secondary injury after spinal cord injury (SCI). Four and a half domains 2 (FHL2) is a multifunctional scaffold protein with tissue- and cell-type specific effects on the regulation of inflammation, but its role in SCI remains unclear. The T10 mouse spinal cord contusion model was established, and the mice were immediately injected with lentiviruses carrying FHL2 shRNA after SCI. The results showed that FHL2 expression was increased following SCI, and then gradually decreased. Moreover, FHL2 depletion aggravated functional impairment, neuronal necrosis, and enlarged lesion cavity areas in the injured spinal cord. FHL2 deficiency facilitated neuronal apoptosis by elevating cleaved caspase 3/9 expression, neuroinflammation by regulating microglia polarization, and bone loss. Indeed, FHL2 deficiency increased the secretion of TNF-α and IL-6, M1 microglia polarization, and the activation of STAT1 pathway but decreased the secretion of IL-10 and IL-4, M2 microglia polarization, and the activation of the STAT6 pathway in the spinal cord. In vitro, FHL2 silencing promoted LPS + IFN-γ-induced microglia M1 polarization through activating the STAT1 pathway and alleviated IL-4-induced microglia M2 polarization via inhibiting the STAT6 pathway. FHL2 positively regulated the expression of poly (ADP-ribose) polymerase family member 14 (PARP14) by promoting its transcription. PARP14 overexpression inhibited FHL2 silencing-induced microglia M1 polarization and relieved the inhibitory effect of FHL2 silencing on microglia M2 polarization. Collectively, the study suggests that FHL2 reduces the microglia M1/M2 polarization-mediated inflammation via PARP14-dependent STAT1/6 pathway and thereby improves functional recovery after SCI.
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Affiliation(s)
- Aihua Xu
- Department of Rehabilitation Medicine, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yang Yang
- Department of Rehabilitation Medicine, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yang Shao
- Department of Rehabilitation Medicine, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Manyu Jiang
- Department of Rehabilitation Medicine, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yongxin Sun
- Department of Rehabilitation Medicine, The First Hospital of China Medical University, Shenyang, Liaoning, China.
| | - Bo Feng
- Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang, Liaoning, China.
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13
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Xie D, Ouyang S. The role and mechanisms of macrophage polarization and hepatocyte pyroptosis in acute liver failure. Front Immunol 2023; 14:1279264. [PMID: 37954583 PMCID: PMC10639160 DOI: 10.3389/fimmu.2023.1279264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 10/16/2023] [Indexed: 11/14/2023] Open
Abstract
Acute liver failure (ALF) is a severe liver disease caused by disruptions in the body's immune microenvironment. In the early stages of ALF, Kupffer cells (KCs) become depleted and recruit monocytes derived from the bone marrow or abdomen to replace the depleted macrophages entering the liver. These monocytes differentiate into mature macrophages, which are activated in the immune microenvironment of the liver and polarized to perform various functions. Macrophage polarization can occur in two directions: pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages. Controlling the ratio and direction of M1 and M2 in ALF can help reduce liver injury. However, the liver damage caused by pyroptosis should not be underestimated, as it is a caspase-dependent form of cell death. Inhibiting pyroptosis has been shown to effectively reduce liver damage induced by ALF. Furthermore, macrophage polarization and pyroptosis share common binding sites, signaling pathways, and outcomes. In the review, we describe the role of macrophage polarization and pyroptosis in the pathogenesis of ALF. Additionally, we preliminarily explore the relationship between macrophage polarization and pyroptosis, as well as their effects on ALF.
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Affiliation(s)
| | - Shi Ouyang
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, Department of Infectious Diseases, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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14
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Gong L, Sun X, Jia M. New gene signature from the dominant infiltration immune cell type in osteosarcoma predicts overall survival. Sci Rep 2023; 13:18271. [PMID: 37880378 PMCID: PMC10600156 DOI: 10.1038/s41598-023-45566-6] [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: 03/09/2023] [Accepted: 10/20/2023] [Indexed: 10/27/2023] Open
Abstract
The immune microenvironment of osteosarcoma (OS) has been reported to play an important role in disease progression and prognosis. However, owing to tumor heterogeneity, it is not ideal to predict OS prognosis by examining only infiltrating immune cells. This work aimed to build a prognostic gene signature based on similarities in the immune microenvironments of OS patients. Public datasets were used to examine the correlated genes, and the most consistent dominant infiltrating immune cell type was identified. The LASSO Cox regression model was used to establish a multiple-gene risk prediction signature. A nine-gene prognostic signature was generated from the correlated genes for M0 macrophages and then proven to be effective and reliable in validation cohorts. Signature comparison indicated the priority of the signature. Multivariate Cox regression models indicated that the signature risk score is an independent prognostic factor for OS patients regardless of the Huvos grade in all datasets. In addition, the results of the association between the signature risk score and chemotherapy sensitivity also showed that there was no significant difference in the sensitivity of any drugs between the low- and high-risk groups. A GSEA of GO and KEGG pathways found that antigen processing- and presentation-related biological functions and olfactory transduction receptor signaling pathways have important roles in signature functioning. Our findings showed that M0 macrophages were the dominant infiltrating immune cell type in OS and that the new gene signature is a promising prognostic model for OS patients.
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Affiliation(s)
- Liping Gong
- Department of Academic Research, The Secondary Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, China
| | - Xifeng Sun
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, China
| | - Ming Jia
- Department of Cancer Center, The Secondary Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, China.
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15
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Chen Y, Yang L, Li X. Advances in Mesenchymal stem cells regulating macrophage polarization and treatment of sepsis-induced liver injury. Front Immunol 2023; 14:1238972. [PMID: 37954578 PMCID: PMC10634316 DOI: 10.3389/fimmu.2023.1238972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Accepted: 10/17/2023] [Indexed: 11/14/2023] Open
Abstract
Sepsis is a syndrome of dysregulated host response caused by infection, which leads to life-threatening organ dysfunction. It is a familiar reason of death in critically ill patients. Liver injury frequently occurs in septic patients, yet the development of targeted and effective treatment strategies remains a pressing challenge. Macrophages are essential parts of immunity system. M1 macrophages drive inflammation, whereas M2 macrophages possess anti-inflammatory properties and contribute to tissue repair processes. Mesenchymal stem cells (MSCs), known for their remarkable attributes including homing capabilities, immunomodulation, anti-inflammatory effects, and tissue regeneration potential, hold promise in enhancing the prognosis of sepsis-induced liver injury by harmonizing the delicate balance of M1/M2 macrophage polarization. This review discusses the mechanisms by which MSCs regulate macrophage polarization, alongside the signaling pathways involved, providing an idea for innovative directions in the treatment of sepsis-induced liver injury.
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Affiliation(s)
- Yuhao Chen
- Department of Emergency Medicine, West China Second Hospital of Sichuan University, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Sichuan, China
| | - Lihong Yang
- Department of Emergency Medicine, West China Second Hospital of Sichuan University, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Sichuan, China
| | - Xihong Li
- Department of Emergency Medicine, West China Second Hospital of Sichuan University, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Sichuan, China
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16
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Wang YH, Chen EQ. Mesenchymal Stem Cell Therapy in Acute Liver Failure. Gut Liver 2023; 17:674-683. [PMID: 36843422 PMCID: PMC10502502 DOI: 10.5009/gnl220417] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 11/04/2022] [Accepted: 11/18/2022] [Indexed: 02/28/2023] Open
Abstract
Acute liver failure (ALF) is a severe liver disease syndrome with rapid deterioration and high mortality. Liver transplantation is the most effective treatment, but the lack of donor livers and the high cost of transplantation limit its broad application. In recent years, there has been no breakthrough in the treatment of ALF, and the application of stem cells in the treatment of ALF is a crucial research field. Mesenchymal stem cells (MSCs) are widely used in disease treatment research due to their abundant sources, low immunogenicity, and no ethical restrictions. Although MSCs are effective for treating ALF, the application of MSCs to ALF needs to be further studied and optimized. In this review, we discuss the potential mechanisms of MSCs therapy for ALF, summarize some methods to enhance the efficacy of MSCs, and explore optimal approaches for MSC transplantation.
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Affiliation(s)
- Yong-Hong Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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17
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Huai Q, Zhu C, Zhang X, Dai H, Li X, Wang H. Mesenchymal stromal/stem cells and their extracellular vesicles in liver diseases: insights on their immunomodulatory roles and clinical applications. Cell Biosci 2023; 13:162. [PMID: 37670393 PMCID: PMC10478279 DOI: 10.1186/s13578-023-01122-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 08/30/2023] [Indexed: 09/07/2023] Open
Abstract
Liver disease is a leading cause of mortality and morbidity that is rising globally. Liver dysfunctions are classified into acute and chronic diseases. Various insults, including viral infections, alcohol or drug abuse, and metabolic overload, may cause chronic inflammation and fibrosis, leading to irreversible liver dysfunction. Up to now, liver transplantation could be the last resort for patients with end-stage liver disease. However, liver transplantation still faces unavoidable difficulties. Mesenchymal stromal/stem cells (MSCs) with their broad ranging anti-inflammatory and immunomodulatory properties can be effectively used for treating liver diseases but without the limitation that are associated with liver transplantation. In this review, we summarize and discuss recent advances in the characteristics of MSCs and the potential action mechanisms of MSCs-based cell therapies for liver diseases. We also draw attention to strategies to potentiate the therapeutic properties of MSCs through pre-treatments or gene modifications. Finally, we discuss progress toward clinical application of MSCs or their extracellular vesicles in liver diseases.
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Affiliation(s)
- Qian Huai
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Cheng Zhu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Xu Zhang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Hanren Dai
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Xiaolei Li
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032, China.
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18
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Khan MJ, Singh P, Jha P, Nayek A, Malik MZ, Bagler G, Kumar B, Ponnusamy K, Ali S, Chopra M, Dohare R, Singh IK, Syed MA. Investigating the link between miR-34a-5p and TLR6 signaling in sepsis-induced ARDS. 3 Biotech 2023; 13:282. [PMID: 37496978 PMCID: PMC10366072 DOI: 10.1007/s13205-023-03700-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 05/10/2023] [Indexed: 07/28/2023] Open
Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are lung complications diagnosed by impaired gaseous exchanges leading to mortality. From the diverse etiologies, sepsis is a prominent contributor to ALI/ARDS. In the present study, we retrieved sepsis-induced ARDS mRNA expression profile and identified 883 differentially expressed genes (DEGs). Next, we established an ARDS-specific weighted gene co-expression network (WGCN) and picked the blue module as our hub module based on highly correlated network properties. Later we subjected all hub module DEGs to form an ARDS-specific 3-node feed-forward loop (FFL) whose highest-order subnetwork motif revealed one TF (STAT6), one miRNA (miR-34a-5p), and one mRNA (TLR6). Thereafter, we screened a natural product library and identified three lead molecules that showed promising binding affinity against TLR6. We then performed molecular dynamics simulations to evaluate the stability and binding free energy of the TLR6-lead molecule complexes. Our results suggest these lead molecules may be potential therapeutic candidates for treating sepsis-induced ALI/ARDS. In-silico studies on clinical datasets for sepsis-induced ARDS indicate a possible positive interaction between miR-34a and TLR6 and an antagonizing effect on STAT6 to promote inflammation. Also, the translational study on septic mice lungs by IHC staining reveals a hike in the expression of TLR6. We report here that miR-34a actively augments the effect of sepsis on lung epithelial cell apoptosis. This study suggests that miR-34a promotes TLR6 to heighten inflammation in sepsis-induced ALI/ARDS. Supplementary Information The online version contains supplementary material available at 10.1007/s13205-023-03700-1.
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Affiliation(s)
- Mohd Junaid Khan
- Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi, 110025 India
| | - Prithvi Singh
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025 India
| | - Prakash Jha
- Laboratory of Molecular Modeling and Anticancer Drug Development, Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, New Delhi, 110007 India
| | - Arnab Nayek
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029 India
| | - Md. Zubbair Malik
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman, 15462 Kuwait City, Kuwait
| | - Ganesh Bagler
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, 110020 India
| | - Bhupender Kumar
- Department of Microbiology, Swami Shraddhanand College, University of Delhi, New Delhi, 110036 India
| | - Kalaiarasan Ponnusamy
- Biotechnology and Viral Hepatitis Division, National Centre for Disease Control, Sham Nath Marg, New Delhi, 110054 India
| | - Shakir Ali
- Department of Biochemistry, School of Chemical and Life Sciences Jamia Hamdard, New Delhi, 110062 India
| | - Madhu Chopra
- Laboratory of Molecular Modeling and Anticancer Drug Development, Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, New Delhi, 110007 India
| | - Ravins Dohare
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025 India
| | - Indrakant Kumar Singh
- Molecular Biology Research Lab, Department of Zoology, Deshbandhu College, University of Delhi, Kalkaji, New Delhi, 110019 India
- DBC i4 Center, Deshbandhu College, University of Delhi, Kalkaji, New Delhi, 110019 India
| | - Mansoor Ali Syed
- Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi, 110025 India
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Li Y, Guo J, Zhang H, Li Z, Ren Y, Jiang Y, Liu X, Hu X. LILRB4 regulates the function of decidual MDSCs via the SHP-2/STAT6 pathway during Toxoplasma gondii infection. Parasit Vectors 2023; 16:237. [PMID: 37461040 PMCID: PMC10353217 DOI: 10.1186/s13071-023-05856-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 06/30/2023] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND Toxoplasma gondii infection can cause adverse pregnancy outcomes, such as recurrent abortion, fetal growth restriction and infants with malformations, among others. Decidual myeloid-derived suppressor cells (dMDSCs) are a novel immunosuppressive cell type at the fetal-maternal interface which play an important role in sustaining normal pregnancy that is related to their high expression of the inhibitory molecule leukocyte immunoglobulin-like receptor B4 (LILRB4). It has been reported that the expression of LILRB4 is downregulated on decidual macrophages after T. gondii infection, but it remains unknown whether T. gondii infection can induce dMDSC dysfunction resulting from the change in LILRB4 expression. METHODS LILRB4-deficient (LILRB4-/-) pregnant mice infected with T. gondii with associated adverse pregnancy outcomes, and anti-LILRB4 neutralized antibodies-treated infected human dMDSCs were used in vivo and in vitro experiments, respectively. The aim was to investigate the effect of LILRB4 expression on dMDSC dysfunction induced by T. gondii infection. RESULTS Toxoplasma gondii infection was observed to reduce STAT3 phosphorylation, resulting in decreased LILRB4 expression on dMDSCs. The levels of the main functional molecules (arginase-1 [Arg-1], interleukin-10 [IL-10]) and main signaling molecules (phosphorylated Src-homology 2 domain-containing protein tyrosine phosphatase [p-SHP2], phosphorylated signal transducer and activator of transcription 6 [p-STAT6]) in dMDSCs were all significantly reduced in human and mouse dMDSCs due to the decrease of LILRB4 expression induced by T. gondii infection. SHP-2 was found to directly bind to STAT6 and STAT6 to bind to the promoter of the Arg-1 and IL-10 genes during T. gondii infection. CONCLUSIONS The downregulation of LILRB4 expression on dMDSCs induced by T. gondii infection could regulate the expression of Arg-1 and IL-10 via the SHP-2/STAT6 pathway, resulting in the dysfunction of dMDSCs, which might contribute to adverse outcomes during pregnancy by T. gondii infection.
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Affiliation(s)
- Yuantao Li
- Department of Gynecology and Obstetrics, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong, People's Republic of China
| | - Jingjing Guo
- Department of Gynecology and Obstetrics, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong, People's Republic of China
| | - Haixia Zhang
- Department of Immunology, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Zhidan Li
- Department of Immunology, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Yushan Ren
- Department of Immunology, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Yuzhu Jiang
- Department of Immunology, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Xianbing Liu
- Department of Immunology, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Xuemei Hu
- Department of Immunology, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China.
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20
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Chen J, Ma H, Meng Y, Liu Q, Wang Y, Lin Y, Yang D, Yao W, Wang Y, He X, Li P. Analysis of the mechanism underlying diabetic wound healing acceleration by Calycosin-7-glycoside using network pharmacology and molecular docking. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 114:154773. [PMID: 36990011 DOI: 10.1016/j.phymed.2023.154773] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/27/2023] [Accepted: 03/14/2023] [Indexed: 06/19/2023]
Abstract
BACKGROUND Diabetic wounds represent a severe clinical challenge in which impaired M2 macrophage polarization and continuous macrophage glycolysis play crucial roles. Calycosin-7-glucoside (CG) is an isoflavone component in Astragali Radix (AR), which has become a research focus for treating diabetic wounds following reports indicating that it has anti-inflammatory effects. However, the mechanism through which CG can treat diabetic wounds is yet to be deciphered. PURPOSE This study aimed to evaluate the therapeutic effect of CG on diabetic wounds and its underlying mechanism. METHODS The potential mechanism underlying the treatment of diabetic wounds by CG was screened using bioinformatics. The therapeutic effects of CG were then investigated using a db/db diabetic wound model. Moreover, an LPS- and IFN-γ-induced RAW264.7 cell inflammation model was used to elucidate the mechanism underlying the therapeutic effects of CG against diabetic wounds. RESULTS Network pharmacology predicted that the AMPK pathway could be the main target through which CG treats diabetic wounds. In db/db diabetic mice, CG could accelerate wound healing and promote granulation tissue regeneration. Protein chip technology revealed that CG increased the production of M-CSF, G-CSF, GM-CSF, IL-10, IL-13, and IL-4 but not that of MCP-1, IL-1β, IL-1α, TNF-α, and TNF-RII. Moreover, CG elevated the proportion of Ly6CLo/- anti-inflammatory monocytes in peripheral blood and M2 macrophages in the wound. The ELISA and flow cytometry analyses revealed that CG enhanced the levels of IL-10, VEGF, CD206, and Arg-1 expression whereas it considerably reduced the levels of IL-1, IL-6, IL-12, TNF-α, CD86, and iNOS expression. Meanwhile, CG increased the macrophage mitochondrial membrane potential and decreased the mitochondrial ADP/ATP ratio and glycolysis rate of M1 macrophages through the ROS/AMPK/STAT6 pathway. CONCLUSIONS The network pharmacology and molecular dockin identified the AMPK pathway as a critical pathway for treating diabetic wounds using topical CG application. CG was found to promote anti-inflammatory monocyte recruitment and decrease the mitochondrial glycolysis rate to induce M2 macrophage polarization via the ROS/AMPK/STAT6 pathway. These results suggest that CG might be a promising therapeutic agent for diabetic wounds.
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Affiliation(s)
- Jia Chen
- Beijing University of Chinese Medicine, Beijing 100105, China; Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Huike Ma
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Yujiao Meng
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Qingwu Liu
- Beijing University of Chinese Medicine, Beijing 100105, China; Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Yan Wang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Yan Lin
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Danyang Yang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Wentao Yao
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Yazhuo Wang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Xiujuan He
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China.
| | - Ping Li
- Beijing University of Chinese Medicine, Beijing 100105, China; Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China.
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21
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Yang Y, Zhao N, Wang R, Zhan Z, Guo S, Song H, Wiemer EAC, Ben J, Ma J. Macrophage MVP regulates fracture repair by promoting M2 polarization via JAK2-STAT6 pathway. Int Immunopharmacol 2023; 120:110313. [PMID: 37267856 DOI: 10.1016/j.intimp.2023.110313] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 04/19/2023] [Accepted: 05/07/2023] [Indexed: 06/04/2023]
Abstract
OBJECTIVE Major vault protein (MVP) is vital in various macrophage-related inflammatory diseases. However, the effects of MVP on macrophage polarization during fracture repair are still unknown. METHODS We used Mvpflox/floxLyz2-Cre mice (myeloid-specific MVP gene knockout, abbreviated as MacKO) and Mvpflox/flox (abbreviated as MacWT) mice to compare their fracture healing phenotype. Next, we traced the changes in macrophage immune status in vivo and in vitro. We further explored the effects of MVP on osteogenesis and osteoclastogenesis. Finally, we re-expressed MVP in MacKO mice to confirm the role of MVP in fracture healing. RESULTS The lack of MVP in macrophages impaired their transition from a pro-inflammatory to an anti-inflammatory phenotype during fracture repair. The increased secretion of pro-inflammatory cytokines by macrophages promoted their osteoclastic differentiation and impaired BMSC osteogenic differentiation, ultimately leading to impaired fracture repair in MacKO mice. Last, adeno-associated virus (AAV)-Mvp tibial injection significantly promoted fracture repair in MacKO mice. CONCLUSIONS Our findings showed MVP has a previously unknown immunomodulatory role in macrophages during fracture repair. Targeting macrophage MVP may represent a novel therapeutic method for fracture treatment.
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Affiliation(s)
- Yan Yang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China; Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Na Zhao
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China; Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Ruobing Wang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China; Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Zhuorong Zhan
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China; Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Shuyu Guo
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China; Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Haiyang Song
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China; Department of General Dentistry, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Erik A C Wiemer
- Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, the Netherlands
| | - Jingjing Ben
- Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, China
| | - Junqing Ma
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China; Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
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Cui XY, Jiang XD, Li WH, Zhang R, You HJ, Tang ZQ, Ma Y, Yang Z, Che NC, Liu WL. Investigation of effective components and action mechanism of Yiguanjian in treatment of liver fibrosis based on network pharmacology. Shijie Huaren Xiaohua Zazhi 2023; 31:256-267. [DOI: 10.11569/wcjd.v31.i7.256] [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] [Indexed: 04/07/2023] Open
Abstract
BACKGROUND Traditional Chinese medicine compounds are characterized by the comprehensive adjustment of multiple components and show unique advantages in the prevention and treatment of liver fibrosis. Yiguanjian (YGJ) is a famous prescription for nourishing Yin to soothe the liver, which can improve the symptoms of liver fibrosis, and understanding its anti-liver fibrosis mechanism can promote its development and use.
AIM To explore the mechanism of YGJ in the treatment of liver fibrosis through network pharmacology and to experi-mentally validate the initial results obtained.
METHODS Components of YGJ and potentially targeted proteins were downloaded from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. The targets of liver fibrosis were accessed from GeneCard and OMIM databases. STRING database was utilized to construct a protein-protein interaction (PPI) network based on the components of YGJ and the targets of liver fibrosis. The PPI network was subjected to random walk with restart (RWR) to obtain key genes, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed based on the DAVID database. For animal experimental validation, eighteen SD rats were randomly assigned to a normal group, a model group, and a YGJ group. The rats in the model group and YGJ group were intraperitoneally injected with 50% CCl4 olive oil solution for 6 wk to induce liver fibrosis, and rats in the normal group were intraperitoneally injected with the same amount of olive oil solution. Then, the rats of the YGJ group were given YGJ decoction (6.67 g/kg) daily for 4 weeks. Meanwhile, rats in the other groups were given distilled water. Blood and liver samples were collected, and the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum of rats were detected with an automated analyzer. Pathological changes in liver tissue were observed by hematoxylin-eosin (HE) and Masson staining. Western blot and qRT-PCR were used to detect the expression of key proteins and genes in the liver.
RESULTS A total of 52 components and 186 potential targets of YGJ were obtained, and 1080 targets of liver fibrosis were screened. The top 10 genes with the high-affinity scores to the drug targets were STAT6, SRC, MAPK3, STX1A, EP300, STAT3, PLG, CTNNB1, CDKN1B, and CANX. The top 50 genes were mainly enriched in response to PI3K- Akt signaling pathway and FoxO signaling pathway, etc. In CCl4-induced liver fibrosis rats, YGJ decoction could significantly improve liver lesions and reduce fibrosis. YGJ decoction could reduce α-SMA expression, promote the expression of phosphorylated STAT6, increase the protein expression of PPAR-γ and CD163 and the mRNA expression of Arg-1, CD206, and CD163, and inhibit the gene expression of IL-6.
CONCLUSION The therapeutic effect of YGJ decoction for liver fibrosis involves multiple components and multiple pathways, including the STAT6/PPAR-γ pathway.
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Peckert-Maier K, Langguth P, Strack A, Stich L, Mühl-Zürbes P, Kuhnt C, Drassner C, Zinser E, Wrage M, Mattner J, Steinkasserer A, Royzman D, Wild AB. CD83 expressed by macrophages is an important immune checkpoint molecule for the resolution of inflammation. Front Immunol 2023; 14:1085742. [PMID: 36875129 PMCID: PMC9975560 DOI: 10.3389/fimmu.2023.1085742] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 02/03/2023] [Indexed: 02/17/2023] Open
Abstract
Excessive macrophage (Mφ) activation results in chronic inflammatory responses or autoimmune diseases. Therefore, identification of novel immune checkpoints on Mφ, which contribute to resolution of inflammation, is crucial for the development of new therapeutic agents. Herein, we identify CD83 as a marker for IL-4 stimulated pro-resolving alternatively activated Mφ (AAM). Using a conditional KO mouse (cKO), we show that CD83 is important for the phenotype and function of pro-resolving Mφ. CD83-deletion in IL-4 stimulated Mφ results in decreased levels of inhibitory receptors, such as CD200R and MSR-1, which correlates with a reduced phagocytic capacity. In addition, CD83-deficient Mφ upon IL-4 stimulation, show an altered STAT-6 phosphorylation pattern, which is characterized by reduced pSTAT-6 levels and expression of the target gene Gata3. Concomitantly, functional studies in IL-4 stimulated CD83 KO Mφ reveal an increased production of pro-inflammatory mediators, such as TNF-α, IL-6, CXCL1 and G-CSF. Furthermore, we show that CD83-deficient Mφ have enhanced capacities to stimulate the proliferation of allo-reactive T cells, which was accompanied by reduced frequencies of Tregs. In addition, we show that CD83 expressed by Mφ is important to limit the inflammatory phase using a full-thickness excision wound healing model, since inflammatory transcripts (e.g. Cxcl1, Il6) were increased, whilst resolving transcripts (e.g. Ym1, Cd200r, Msr-1) were decreased in wounds at day 3 after wound infliction, which reflects the CD83 resolving function on Mφ also in vivo. Consequently, this enhanced inflammatory milieu led to an altered tissue reconstitution after wound infliction. Thus, our data provide evidence that CD83 acts as a gatekeeper for the phenotype and function of pro-resolving Mφ.
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Affiliation(s)
- Katrin Peckert-Maier
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Pia Langguth
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Astrid Strack
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Lena Stich
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Petra Mühl-Zürbes
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Christine Kuhnt
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Christina Drassner
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Elisabeth Zinser
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Marius Wrage
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitäts-klinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Jochen Mattner
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitäts-klinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Alexander Steinkasserer
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Dmytro Royzman
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
| | - Andreas B. Wild
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich–Alexander Universität Erlangen–Nürnberg, Erlangen, Germany
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STAT6 inhibits ferroptosis and alleviates acute lung injury via regulating P53/SLC7A11 pathway. Cell Death Dis 2022; 13:530. [PMID: 35668064 PMCID: PMC9169029 DOI: 10.1038/s41419-022-04971-x] [Citation(s) in RCA: 99] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 05/16/2022] [Accepted: 05/25/2022] [Indexed: 01/21/2023]
Abstract
Compelling evidences have revealed the emerging role of ferroptosis in the pathophysiological process of acute lung injury (ALI), but its modulation is not clear. Here, we identified that STAT6 acted as a critical regulator of epithelium ferroptosis during ALI. Firstly, STAT6 expression and activity were increased in the ALI mice models caused by crystalline silica (CS), LPS and X-ray exposure. Followed by confirming the contribution of ferroptosis in the above ALI with ferrostatin-1 and deferoxamine intervention, bioinformatic analyses revealed that STAT6 expression was negatively correlated with ferroptosis. Consistently, lung epithelium-specific depletion of STAT6 in mice or STAT6 knockdown in cultured epithelial cells exacerbated ferroptosis in the above ALI. While overexpression of STAT6 in lung epithelial cells attenuated the ferroptosis. Mechanistically, SLC7A11 is a typical ferroptosis-related gene and negatively regulated by P53. CREB-binding protein (CBP) is a critical acetyltransferase of P53 acetylation, showing valuable regulation on targets' transcription. Herein, we found that STAT6 negatively regulates ferroptosis through competitively binding with CBP, which inhibits P53 acetylation and transcriptionally restores SLC7A11 expression. Finally, pulmonary-specific STAT6 overexpression decreased the ferroptosis and attenuated CS and LPS induced lung injury. Our findings revealed that STAT6 is a pivotal regulator of ferroptosis, which may be a potential therapeutic target for the treatment of acute lung injury.
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25
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Ko GR, Lee JS. Engineering of Immune Microenvironment for Enhanced Tissue Remodeling. Tissue Eng Regen Med 2022; 19:221-236. [PMID: 35041181 PMCID: PMC8971302 DOI: 10.1007/s13770-021-00419-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 11/30/2021] [Accepted: 12/14/2021] [Indexed: 01/21/2023] Open
Abstract
The capability to restore the structure and function of tissues damaged by fatal diseases and trauma is essential for living organisms. Various tissue engineering approaches have been applied in lesions to enhance tissue regeneration after injuries and diseases in living organisms. However, unforeseen immune reactions by the treatments interfere with successful healing and reduce the therapeutic efficacy of the strategies. The immune system is known to play essential roles in the regulation of the microenvironment and recruitment of cells that directly or indirectly participate in tissue remodeling in defects. Accordingly, regenerative immune engineering has emerged as a novel approach toward efficiently inducing regeneration using engineering techniques that modulate the immune system. It is aimed at providing a favorable immune microenvironment based on the controlled balance between pro-inflammation and anti-inflammation. In this review, we introduce recent developments in immune engineering therapeutics based on various cell types and biomaterials. These developments could potentially overcome the therapeutic limitations of tissue remodeling.
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Affiliation(s)
- Ga Ryang Ko
- Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan University (SKKU), Suwon, 16419, Republic of Korea
- Department of Biomedical Engineering, Sungkyunkwan University (SKKU), Suwon, 16419, Republic of Korea
| | - Jung Seung Lee
- Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan University (SKKU), Suwon, 16419, Republic of Korea.
- Department of Biomedical Engineering, Sungkyunkwan University (SKKU), Suwon, 16419, Republic of Korea.
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26
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Wang Y, Li C, Wan Y, Qi M, Chen Q, Sun Y, Sun X, Fang J, Fu L, Xu L, Dong B, Wang L. Quercetin-Loaded Ceria Nanocomposite Potentiate Dual-Directional Immunoregulation via Macrophage Polarization against Periodontal Inflammation. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2021; 17:e2101505. [PMID: 34499411 DOI: 10.1002/smll.202101505] [Citation(s) in RCA: 107] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 07/13/2021] [Indexed: 05/22/2023]
Abstract
Macrophage polarization toward M1 phenotype (pro-inflammation) is closely associated with the destructive phase of periodontal inflammation. Nanoceria is verified to inhibit M1 polarization of macrophages by the favorable ability of reactive oxygen species (ROS) scavenging. However, the function of nanoceria on macrophage polarization toward M2 phenotype (anti-inflammation) in reparative phase of periodontal inflammation is quite limited. In this work, by introducing an antioxidant drug quercetin onto nano-octahedral ceria, synergistic and intense regulation of host immunity against periodontal disease is realized. Such nanocomposite can control the phenotypic switch of macrophages by not only inhibition of M1 polarization for suppressing the damage in the destructive phase but also promotion of M2 polarization for regenerating the surrounding tissues in reparative phase of periodontal disease. As-prepared nanocomposite can effectively increase the M2/M1 ratio of macrophage polarization in inflammatory cellular models by lipopolysaccharide stimulation. More importantly, the nanocomposite also exerts an improved therapeutic potential against local inflammation by significant downregulation of pro-inflammatory cytokines and upregulation of anti-inflammatory cytokines in an animal model with periodontal inflammation. Therefore, this newly developed nanomedicine is efficient in ROS scavenging and driving pro-inflammatory macrophages to the anti-inflammatory phenotype to eliminate inflammation, thereby providing a promising candidate for treating periodontal inflammation.
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Affiliation(s)
- Yu Wang
- Department of Prosthodontics, Jilin Provincial Key Laboratory of Sciences and Technology of Stomatology Nanoengineering, School of Dentistry, Jilin University, Changchun, 130021, China
| | - Chunyan Li
- Department of Prosthodontics, Jilin Provincial Key Laboratory of Sciences and Technology of Stomatology Nanoengineering, School of Dentistry, Jilin University, Changchun, 130021, China
| | - Yao Wan
- Department of Oral Implantology, School of Dentistry, Jilin University, Changchun, 130021, China
| | - Manlin Qi
- Department of Oral Implantology, School of Dentistry, Jilin University, Changchun, 130021, China
| | - Qiuhan Chen
- Department of Prosthodontics, Jilin Provincial Key Laboratory of Sciences and Technology of Stomatology Nanoengineering, School of Dentistry, Jilin University, Changchun, 130021, China
| | - Yue Sun
- Department of Oral Implantology, School of Dentistry, Jilin University, Changchun, 130021, China
| | - Xiaolin Sun
- Department of Oral Implantology, School of Dentistry, Jilin University, Changchun, 130021, China
| | - Jiao Fang
- Department of Oral Implantology, School of Dentistry, Jilin University, Changchun, 130021, China
| | - Li Fu
- Department of Oral Implantology, School of Dentistry, Jilin University, Changchun, 130021, China
| | - Lin Xu
- State Key Laboratory on Integrated Optoelectronics, College of Electronic Science and Engineering, Jilin University, Changchun, 130012, China
| | - Biao Dong
- State Key Laboratory on Integrated Optoelectronics, College of Electronic Science and Engineering, Jilin University, Changchun, 130012, China
| | - Lin Wang
- Department of Oral Implantology, School of Dentistry, Jilin University, Changchun, 130021, China
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Lu D, Xu Y, Liu Q, Zhang Q. Mesenchymal Stem Cell-Macrophage Crosstalk and Maintenance of Inflammatory Microenvironment Homeostasis. Front Cell Dev Biol 2021; 9:681171. [PMID: 34249933 PMCID: PMC8267370 DOI: 10.3389/fcell.2021.681171] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 05/28/2021] [Indexed: 12/13/2022] Open
Abstract
Macrophages are involved in almost every aspect of biological systems and include development, homeostasis and repair. Mesenchymal stem cells (MSCs) have good clinical application prospects due to their ability to regulate adaptive and innate immune cells, particularly macrophages, and they have been used successfully for many immune disorders, including inflammatory bowel disease (IBD), acute lung injury, and wound healing, which have been reported as macrophage-mediated disorders. In the present review, we focus on the interaction between MSCs and macrophages and summarize their methods of interaction and communication, such as cell-to-cell contact, soluble factor secretion, and organelle transfer. In addition, we discuss the roles of MSC-macrophage crosstalk in the development of disease and maintenance of homeostasis of inflammatory microenvironments. Finally, we provide optimal strategies for applications in immune-related disease treatments.
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Affiliation(s)
- Di Lu
- The Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yan Xu
- The Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qiuli Liu
- The Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qi Zhang
- The Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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28
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Bai Y, Cui X, Gao X, Liu C, Lv X, Zheng S. Poly (I: C) inhibits reticuloendothelial virus replication in chicken macrophage-like cells through the activation of toll-like receptor-3 signaling. Mol Immunol 2021; 136:110-117. [PMID: 34098343 DOI: 10.1016/j.molimm.2021.05.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/16/2021] [Accepted: 05/24/2021] [Indexed: 10/21/2022]
Abstract
Reticuloendothelial virus (REV) is widely found in many domestic poultry areas and results in severe immunosuppression of infected chickens. This increases the susceptibility to other pathogens, which causes economic losses to the poultry industry. The aim of our study was to determine whether polyinosinic-polycytidylic acid [Poly (I: C)] treatment could inhibit REV replication in chicken macrophage-like cell line, HD11. We found that Poly (I: C) treatment could markedly inhibit REV replication in HD11 from 24 to 48 h post infection (hpi). Additionally, Poly (I: C) treatment could switch HD11 from an inactive type into M1-like polarization from 24 to 48 hpi. Furthermore, Poly (I: C) treatment promoted interferon-β secretion from HD11 post REV infection. Moreover, Toll-like receptor-3 (TLR-3) mRNA and protein levels in HD11 treated with Poly (I: C) were markedly increased compared to those of HD11 not treated with Poly (I: C). The above results suggested that Poly (I: C) treatment switches HD11 into M1-like polarization to secret more interferon-β and activate TLR-3 signaling, which contributes to block REV replication. Our findings provide a theoretical reference for further studying the underlying pathogenic mechanism of REV and Poly (I: C) as a potential therapeutic intervention against REV infection.
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Affiliation(s)
- Yu Bai
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Department of Veterinary Pathophysiology, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China; Department of Veterinary Pathophysiology, College of Animal Medicine, China Agricultural University, Beijing, 100193, China
| | - Xinhua Cui
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Department of Veterinary Pathophysiology, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Xueli Gao
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Department of Veterinary Pathophysiology, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Chaonan Liu
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Department of Veterinary Pathophysiology, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Xiaoping Lv
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Department of Veterinary Pathophysiology, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Shimin Zheng
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Department of Veterinary Pathophysiology, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China.
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29
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Yeo GEC, Ng MH, Nordin FB, Law JX. Potential of Mesenchymal Stem Cells in the Rejuvenation of the Aging Immune System. Int J Mol Sci 2021; 22:5749. [PMID: 34072224 PMCID: PMC8198707 DOI: 10.3390/ijms22115749] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/22/2021] [Accepted: 05/24/2021] [Indexed: 12/14/2022] Open
Abstract
Rapid growth of the geriatric population has been made possible with advancements in pharmaceutical and health sciences. Hence, age-associated diseases are becoming more common. Aging encompasses deterioration of the immune system, known as immunosenescence. Dysregulation of the immune cell production, differentiation, and functioning lead to a chronic subclinical inflammatory state termed inflammaging. The hallmarks of the aging immune system are decreased naïve cells, increased memory cells, and increased serum levels of pro-inflammatory cytokines. Mesenchymal stem cell (MSC) transplantation is a promising solution to halt immunosenescence as the cells have excellent immunomodulatory functions and low immunogenicity. This review compiles the present knowledge of the causes and changes of the aging immune system and the potential of MSC transplantation as a regenerative therapy for immunosenescence.
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Affiliation(s)
| | | | | | - Jia Xian Law
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Cheras 56000, Malaysia; (G.E.C.Y.); (M.H.N.); (F.B.N.)
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