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Song HM, Li ZW, Huang Q, Wu CG, Li MH, Shen JK. A diagnostic signatures for intervertebral disc degeneration using TNFAIP6 and COL6A2 based on single-cell RNA-seq and bulk RNA-seq analyses. Ann Med 2025; 57:2443568. [PMID: 39704340 DOI: 10.1080/07853890.2024.2443568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 04/01/2024] [Accepted: 09/17/2024] [Indexed: 12/21/2024] Open
Abstract
OBJECTIVES Intervertebral disc degeneration (IVDD) is a prevalent degenerative condition associated with a high incidence rate of low back pain and disability. This study aimed to identify potential biomarkers and signaling pathways associated with IVDD. METHODS Biomarkers were discerned through bulk-RNA and single-cell RNA sequencing (scRNA-Seq) investigations of IVDD cases from the Gene Expression Omnibus (GEO) database. Following this, two central genes were identified. Furthermore, gene set enrichment analysis (GSEA) and receiver operating characteristic (ROC) curve analysis were conducted. The transcriptional factor (TF) derived from nucleus pulposus (NP) cells was examined through the DoRothEA R package. RT-qPCR and IHC techniques were employed to confirm the expression of the two hub genes and their associated genes in tissue samples. RESULTS The proteins Tumor necrosis factor-inducible gene 6 protein (TNFAIP6) and collagen VI-α2 (COL6A2) were frequently analyzed using a combination of DEGs from datasets GSE70362, GSE124272, and scRNA-seq. Examination of gene expression across multiple datasets indicated significant differences in TNFAIP6 and COL6A2 levels in IVDD compared to control or normal groups (p < 0.05). These two central genes demonstrated strong diagnostic utility in the training cohort and reliable predictive value in the validation datasets. Our study verified the potential role of ZEB2 as a TF in regulating two key genes associated with IVDD. Furthermore, qPCR and IHC confirmed elevated expression levels of the hub genes and transcription factor. CONCLUSION We identified biomarkers, specifically TNFAIP6 and COL6A2, that have the potential to predict disease activity and aid in the diagnosis of IVDD.
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Affiliation(s)
- Hong-Mei Song
- Department of Radiology, The Second Affiliated Hospital of Soochow University, Suzhou, China
- Department of Interventional Radiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zuo-Wei Li
- Department of Urological Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qin Huang
- Department of Pathology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chun-Gen Wu
- Department of Interventional Radiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ming-Hua Li
- Department of Interventional Radiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun-Kang Shen
- Department of Radiology, The Second Affiliated Hospital of Soochow University, Suzhou, China
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Cheng X, Li YL, Wang H, Zhang RJ, Fan KY, Qi XT, Zheng GP, Dong HL. Mesenchymal stem cell therapy in atherosclerosis: A bibliometric and visual analysis. World J Stem Cells 2024; 16:1062-1085. [PMID: 39734478 PMCID: PMC11669984 DOI: 10.4252/wjsc.v16.i12.1062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 10/15/2024] [Accepted: 11/18/2024] [Indexed: 12/13/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are capable of self-renewal and differentiation, and extensive studies have demonstrated their therapeutic potential in atherosclerosis (AS). AIM To conduct a bibliometric analysis of studies on the use of MSC therapy for AS over the past two decades, assess key trends and provide insights for future research directions. METHODS We systematically searched the Web of Science Core Collection database for articles published between 1999 and 2023, yielding a total of 556 articles. Visual representation and bibliometric analysis of information and trends were facilitated using CiteSpace, the R package 'bibliometrix' and VOSviewer. RESULTS The analyzed articles were predominantly from 52 countries/regions, with prominent contributions from China and the United States. A cohort of 3057 authors contributed to these publications, with the works of Libby P distinguished by their influence and citation count. Int J Mol Sci has emerged as the journal with the highest publication volume, prominently disseminating influential papers and identifying citation outbreaks. Furthermore, our analysis identified current research hotspots within the field, focusing on vascular progenitor cells, inflammatory mechanisms, and extracellular vesicles. Emerging research frontiers, such as extracellular vesicles and oxidative stress, have been highlighted as areas of burgeoning interest. Finally, we offer perspectives on the status of research and future directions of MSC therapy in AS. CONCLUSION This comprehensive analysis provides valuable insights for advancing scientific research on MSC therapy for AS. By elucidating pivotal trends and research directions, this study aimed to foster innovation and promote the progress of disciplines in this field, thereby contributing to advancing scientific knowledge and clinical practice.
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Affiliation(s)
- Xing Cheng
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
| | - Ya-Ling Li
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
| | - Heng Wang
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney 2145, New South Wales, Australia
| | - Rui-Jing Zhang
- Department of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
| | - Ke-Yi Fan
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
| | - Xiao-Tong Qi
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
| | - Guo-Ping Zheng
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney 2145, New South Wales, Australia
| | - Hong-Lin Dong
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China.
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Lee WJ, Cho KJ, Kim GW. Mitigation of Atherosclerotic Vascular Damage and Cognitive Improvement Through Mesenchymal Stem Cells in an Alzheimer's Disease Mouse Model. Int J Mol Sci 2024; 25:13210. [PMID: 39684920 DOI: 10.3390/ijms252313210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 12/05/2024] [Accepted: 12/05/2024] [Indexed: 12/18/2024] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive memory loss and other cognitive disturbances. Patients with AD can be vulnerable to vascular damage, and damaged vessels can lead to cognitive impairment. Mesenchymal stem cell (MSC) treatment has shown potential in ameliorating AD pathogenesis, but its effect on vascular function remains unclear. This study aimed to improve cognitive function by alleviating atherosclerosis-induced vessel damage using MSCs in mice with a genetic AD background. In this study, a 5xFAD mouse model of AD was used, and atherosclerotic vessel damage was induced by high-fat diets (HFDs). MSCs were injected into the tail vein along with mannitol in 5xFAD mice on an HFD. MSCs were detected in the brain, and vascular damage was improved following MSC treatment. Behavioral tests showed that MSCs enhanced cognitive function, as measured by the Y-maze and passive avoidance tests. Additionally, muscle strength measured by the rotarod test was also increased by MSCs in AD mice with vessel damage induced by HFDs. Overall, our results suggest that stem cells can alleviate vascular damage caused by metabolic diseases, including HFDs, and vascular disease in individuals carrying the AD gene. Consequently, this alleviates cognitive decline related to vascular dementia symptoms.
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Affiliation(s)
- Woong Jin Lee
- Department of Neurology, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea
| | - Kyoung Joo Cho
- Department of Life Science, Kyonggi University, Suwon 16227, Republic of Korea
| | - Gyung Whan Kim
- Department of Neurology, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea
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Ma Y, Gu T, He S, He S, Jiang Z. Development of stem cell therapy for atherosclerosis. Mol Cell Biochem 2024; 479:779-791. [PMID: 37178375 DOI: 10.1007/s11010-023-04762-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 05/05/2023] [Indexed: 05/15/2023]
Abstract
Cardiovascular disease (CVD) has a high incidence and low cure rate worldwide, and atherosclerosis (AS) is the main factor inducing cardiovascular disease, of which lipid deposition in the vessel wall is the main marker of AS. Currently, although statins can be used to lower lipids and low-density lipoprotein (LDL) in AS, the cure rate for AS remains low. Therefore, there is an urgent need to develop new therapeutic approaches, and stem cells are now widely studied, while stem cells are a class of cell types that always maintain the ability to differentiate and can differentiate to form other cells and tissues, and stem cell transplantation techniques have shown efficacy in the treatment of other diseases. With the establishment of cellular therapies and continued research in stem cell technology, stem cells are also being used to address the problem of AS. In this paper, we focus on recent research advances in stem cell therapy for AS and briefly summarize the relevant factors that induce the formation of AS. We mainly discuss the efficacy and application prospects of mesenchymal stem cells (MSCs) for the treatment of AS, in addition to the partial role and potential of exosomes in the treatment of AS. Further, provide new ideas for the clinical application of stem cells.
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Affiliation(s)
- Yun Ma
- Institute of Biochemistry and Molecular Biology, Hengyang Medical College, University of South China, Hengyang, 421001, Hunan, China
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hengyang Medical School, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, University of South China, Hengyang, 421001, Hunan, China
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Tianhe Gu
- Institute of Biochemistry and Molecular Biology, Hengyang Medical College, University of South China, Hengyang, 421001, Hunan, China
| | - Siqi He
- Institute of Biochemistry and Molecular Biology, Hengyang Medical College, University of South China, Hengyang, 421001, Hunan, China
| | - Shuya He
- Institute of Biochemistry and Molecular Biology, Hengyang Medical College, University of South China, Hengyang, 421001, Hunan, China
| | - Zhisheng Jiang
- Institute of Biochemistry and Molecular Biology, Hengyang Medical College, University of South China, Hengyang, 421001, Hunan, China.
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hengyang Medical School, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, University of South China, Hengyang, 421001, Hunan, China.
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Zhang L, Wu X, Hong L. Endothelial Reprogramming in Atherosclerosis. Bioengineering (Basel) 2024; 11:325. [PMID: 38671747 PMCID: PMC11048243 DOI: 10.3390/bioengineering11040325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 03/22/2024] [Accepted: 03/25/2024] [Indexed: 04/28/2024] Open
Abstract
Atherosclerosis (AS) is a severe vascular disease that results in millions of cases of mortality each year. The development of atherosclerosis is associated with vascular structural lesions, characterized by the accumulation of immune cells, mesenchymal cells, lipids, and an extracellular matrix at the intimal resulting in the formation of an atheromatous plaque. AS involves complex interactions among various cell types, including macrophages, endothelial cells (ECs), and smooth muscle cells (SMCs). Endothelial dysfunction plays an essential role in the initiation and progression of AS. Endothelial dysfunction can encompass a constellation of various non-adaptive dynamic alterations of biology and function, termed "endothelial reprogramming". This phenomenon involves transitioning from a quiescent, anti-inflammatory state to a pro-inflammatory and proatherogenic state and alterations in endothelial cell identity, such as endothelial to mesenchymal transition (EndMT) and endothelial-to-immune cell-like transition (EndIT). Targeting these processes to restore endothelial balance and prevent cell identity shifts, alongside modulating epigenetic factors, can attenuate atherosclerosis progression. In the present review, we discuss the role of endothelial cells in AS and summarize studies in endothelial reprogramming associated with the pathogenesis of AS.
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Affiliation(s)
- Lu Zhang
- Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Xin Wu
- Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Liang Hong
- Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
- Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL 60612, USA
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA
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Huerta CT, Zhang L, Ortiz YY, Li Y, Zeynaloo E, Dikici E, Siahaan TJ, Deo SK, Daunert S, Liu ZJ, Velazquez OC. Directing Cell Delivery to Murine Atherosclerotic Aortic Lesions via Targeting Inflamed Circulatory Interface using Nanocarriers. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.02.578719. [PMID: 38370711 PMCID: PMC10871190 DOI: 10.1101/2024.02.02.578719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/20/2024]
Abstract
Stem cell therapy holds significant potential for many inflammatory diseases and regenerative medicine applications. However, delivery of therapeutic cells to specific disease sites after systemic administration without indiscriminate trafficking to other non-target tissues is a major limitation of current cell therapies. Here, we describe a novel nanocarrier-directed targeted cell delivery system that enables cell surface coating with dendrimer nanocarriers containing adhesion moieties to serve as a global positioning system "GPS" to guide circulating cells to targeted lesions and mediate the anchoring of cells at the inflammation site. By exploiting cell surface ligands/receptors selectively and/or molecular moieties that are highly expressed on activated endothelium in pathologic disease states, nanocarrier-coated cells containing the counterpart binding receptors/ligands can be enabled to specifically traffic to and dock at vasculature within target lesions. We demonstrate the efficacy of the I-domain fragment of LFA-1 ( id LFA-1) complexed to modified nanocarriers to facilitate homing of mesenchymal stem cells (MSCs) to inflamed luminal endothelial cells on which ICAM-1 is highly expressed in a murine model of aortic atherosclerosis. Our method can overcome challenges imposed by the high velocity and dynamic circulatory flow of the aorta to successfully deliver MSCs to atherosclerotic regions and allow for docking of the potentially therapeutic and immunomodulating cells. This targeted cell-delivery platform can be tailored for selective systemic delivery of various types of therapeutic cells to different disease areas.
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Pan Q, Chen C, Yang YJ. Top Five Stories of the Cellular Landscape and Therapies of Atherosclerosis: Current Knowledge and Future Perspectives. Curr Med Sci 2024; 44:1-27. [PMID: 38057537 DOI: 10.1007/s11596-023-2818-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 10/22/2023] [Indexed: 12/08/2023]
Abstract
Atherosclerosis (AS) is characterized by impairment and apoptosis of endothelial cells, continuous systemic and focal inflammation and dysfunction of vascular smooth muscle cells, which is documented as the traditional cellular paradigm. However, the mechanisms appear much more complicated than we thought since a bulk of studies on efferocytosis, transdifferentiation and novel cell death forms such as ferroptosis, pyroptosis, and extracellular trap were reported. Discovery of novel pathological cellular landscapes provides a large number of therapeutic targets. On the other side, the unsatisfactory therapeutic effects of current treatment with lipid-lowering drugs as the cornerstone also restricts the efforts to reduce global AS burden. Stem cell- or nanoparticle-based strategies spurred a lot of attention due to the attractive therapeutic effects and minimized adverse effects. Given the complexity of pathological changes of AS, attempts to develop an almighty medicine based on single mechanisms could be theoretically challenging. In this review, the top stories in the cellular landscapes during the initiation and progression of AS and the therapies were summarized in an integrated perspective to facilitate efforts to develop a multi-targets strategy and fill the gap between mechanism research and clinical translation. The future challenges and improvements were also discussed.
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Affiliation(s)
- Qi Pan
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100037, China
| | - Cheng Chen
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100037, China
| | - Yue-Jin Yang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100037, China.
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8
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Yu M, Cheng X. Editorial Commentary: Top Five Stories of the Cellular Landscape and Therapies of Atherosclerosis: Current Knowledge and Future Perspectives. Curr Med Sci 2024; 44:241-243. [PMID: 38277018 DOI: 10.1007/s11596-023-2825-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2024]
Affiliation(s)
- Miao Yu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiang Cheng
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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9
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Kwon HY, Yoon Y, Hong JE, Rhee KJ, Sohn JH, Jung PY, Kim MY, Baik SK, Ryu H, Eom YW. Role of TGF-β and p38 MAPK in TSG-6 Expression in Adipose Tissue-Derived Stem Cells In Vitro and In Vivo. Int J Mol Sci 2023; 25:477. [PMID: 38203646 PMCID: PMC10778696 DOI: 10.3390/ijms25010477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 12/26/2023] [Accepted: 12/28/2023] [Indexed: 01/12/2024] Open
Abstract
Mesenchymal stem cells (MSCs) regulate immune cell activity by expressing tumor necrosis factor-α (TNF-α)-stimulated gene 6 (TSG-6) in inflammatory environments; however, whether anti-inflammatory responses affect TSG-6 expression in MSCs is not well understood. Therefore, we investigated whether transforming growth factor-β (TGF-β) regulates TSG-6 expression in adipose tissue-derived stem cells (ASCs) and whether effective immunosuppression can be achieved using ASCs and TGF-β signaling inhibitor A83-01. TGF-β significantly decreased TSG-6 expression in ASCs, but A83-01 and the p38 inhibitor SB202190 significantly increased it. However, in septic C57BL/6 mice, A83-01 further reduced the survival rate of the lipopolysaccharide (LPS)-treated group and ASC transplantation did not improve the severity induced by LPS. ASC transplantation alleviated the severity of sepsis induced by LPS+A83-01. In co-culture of macrophages and ASCs, A83-01 decreased TSG-6 expression whereas A83-01 and SB202190 reduced Cox-2 and IDO-2 expression in ASCs. These results suggest that TSG-6 expression in ASCs can be regulated by high concentrations of pro-inflammatory cytokines in vitro and in vivo, and that A83-01 and SB202190 can reduce the expression of immunomodulators in ASCs. Therefore, our data suggest that co-treatment of ASCs with TGF-β or p38 inhibitors is not adequate to modulate inflammation.
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Affiliation(s)
- Hye Youn Kwon
- Department of Surgery, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea; (H.Y.K.); (P.Y.J.)
| | - Yongdae Yoon
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea; (Y.Y.); (M.Y.K.); (S.K.B.)
| | - Ju-Eun Hong
- Department of Biomedical Laboratory Science, College of Software and Digital Healthcare Convergence, Yonsei University Mirae Campus, Wonju 26493, Republic of Korea; (J.-E.H.); (K.-J.R.)
| | - Ki-Jong Rhee
- Department of Biomedical Laboratory Science, College of Software and Digital Healthcare Convergence, Yonsei University Mirae Campus, Wonju 26493, Republic of Korea; (J.-E.H.); (K.-J.R.)
| | - Joon Hyung Sohn
- Department of Convergence Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea;
| | - Pil Young Jung
- Department of Surgery, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea; (H.Y.K.); (P.Y.J.)
| | - Moon Young Kim
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea; (Y.Y.); (M.Y.K.); (S.K.B.)
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
| | - Soon Koo Baik
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea; (Y.Y.); (M.Y.K.); (S.K.B.)
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
| | - Hoon Ryu
- Department of Surgery, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea; (H.Y.K.); (P.Y.J.)
| | - Young Woo Eom
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea; (Y.Y.); (M.Y.K.); (S.K.B.)
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Sekenova A, Li Y, Issabekova A, Saparov A, Ogay V. TNF-α Preconditioning Improves the Therapeutic Efficacy of Mesenchymal Stem Cells in an Experimental Model of Atherosclerosis. Cells 2023; 12:2262. [PMID: 37759485 PMCID: PMC10526914 DOI: 10.3390/cells12182262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 08/15/2023] [Accepted: 08/17/2023] [Indexed: 09/29/2023] Open
Abstract
Atherosclerosis (AS) is an inflammatory disease involving multiple factors in its initiation and development. In recent years, the potential application of mesenchymal stem cells (MSCs) for treating AS has been investigated. This study examined the effect of TNF-α preconditioning on MSCs' therapeutic efficacy in treating AS in ApoE KO mice. TNF-α-treated MSCs were administered to high-fat diet-treated ApoE KO mice. Cytokine and serum lipid levels were measured before and after treatment. Cryosections of the atherosclerotic aorta were stained with Oil-Red-O, and the relative areas of atherosclerotic lesions were measured. The level of Tregs were increased in TNF-α-MSC-treated animals compared to the MSCs group. In addition, the systemic administration of TNF-α-MSCs to ApoE KO mice reduced the level of proinflammatory cytokines such as TNF-α and IFN-γ and increased the level of the immunosuppressive IL-10 in the blood serum. Total cholesterol and LDL levels were decreased, and HDL levels were increased in the TNF-α-MSCs group of ApoE KO mice. A histological analysis showed that TNF-α-MSCs decreased the size of the atherosclerotic lesion in the aorta of ApoE KO mice by 38%, although there was no significant difference when compared with untreated MSCs. Thus, our data demonstrate that TNF-α-MSCs are more effective at treating AS than untreated MSCs.
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Affiliation(s)
- Aliya Sekenova
- Laboratory of Stem Cells, National Center for Biotechnology, Astana 010000, Kazakhstan
| | - Yelena Li
- Laboratory of Stem Cells, National Center for Biotechnology, Astana 010000, Kazakhstan
| | - Assel Issabekova
- Laboratory of Stem Cells, National Center for Biotechnology, Astana 010000, Kazakhstan
| | - Arman Saparov
- Department of Medicine, School of Medicine, Nazarbayev University, Astana 010000, Kazakhstan
| | - Vyacheslav Ogay
- Laboratory of Stem Cells, National Center for Biotechnology, Astana 010000, Kazakhstan
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11
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Li Y, Shi G, Liang W, Shang H, Li H, Han Y, Zhao W, Bai L, Qin C. Allogeneic Adipose-Derived Mesenchymal Stem Cell Transplantation Alleviates Atherosclerotic Plaque by Inhibiting Ox-LDL Uptake, Inflammatory Reaction and Endothelial Damage in Rabbits. Cells 2023; 12:1936. [PMID: 37566014 PMCID: PMC10417209 DOI: 10.3390/cells12151936] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 07/15/2023] [Accepted: 07/19/2023] [Indexed: 08/12/2023] Open
Abstract
Atherosclerosis (AS) is a chronic inflammatory disease of arteries fueled by lipids. It is a major cause of cardiovascular morbidity and mortality. Mesenchymal stem cells have been used for the treatment of atherosclerotic lesions. Adipose-derived stem cells (ADSCs) have been shown to regulate the activation state of macrophages and exhibit anti-inflammatory capabilities. However, the effect of allogeneic ADSCs in the treatment of AS have not been investigated. In this study, the early treatment effect and preliminary mechanism analysis of allogeneic rabbit ADSCs intravenous transplantation were investigated in a high-fat diet rabbit model. The polarization mechanism of rabbit ADSCs on the macrophage was further analyzed in vitro. Compared with the model group, blood lipid levels declined, the plaque area, oxidized low-density lipoprotein (ox-LDL) uptake, scavenger receptor A1 and cluster of differentiation (CD) 36 levels were all significantly reduced, and the accumulation of inflammatory M1 macrophages, apoptosis, interleukin (IL)-6 and tumor necrosis factor (TNF)-α expression were decreased. The endothelial cells (CD31), M2 macrophages, IL-10 and the transforming growth factor (TGF)-β levels increased. In vitro, ADSCs can promote the M1 macrophage phenotypic switch toward the M2 macrophage through their secreted exosomes, and the main mechanism includes increasing arginase 1 expression and IL-10 secretion, declining inducible nitric oxide synthase (iNOS) expression and TNF-α secretion, and activating the STAT6 pathway. Therefore, allogeneic rabbit ADSC transplantation can transmigrate to the aortic atherosclerotic plaques and show a good effect in lowering blood lipids and alleviating atherosclerotic plaque in the early stage of AS by inhibiting ox-LDL uptake, inflammatory response, and endothelial damage.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Chuan Qin
- NHC Key Laboratory of Human Diseases Comparative Medicine, National Human Diseases Animal Model Resource Center, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Medical Laboratory Animal Science, Chinese Academy of Medical Science (CAMS) & Comparative Medicine Centre, Peking Union Medical College (PUMC), Beijing 100021, China
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12
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Zou D, Yang P, Liu J, Dai F, Xiao Y, Zhao A, Huang N. Constructing Mal-Efferocytic Macrophage Model and Its Atherosclerotic Spheroids and Rat Model for Therapeutic Evaluation. Adv Biol (Weinh) 2023; 7:e2200277. [PMID: 36721069 DOI: 10.1002/adbi.202200277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/27/2022] [Indexed: 02/02/2023]
Abstract
Efferocytosis, responsible for apoptotic cell clearance, is an essential factor against atherosclerosis. It is reported that efferocytosis is severely impaired in fibroatheroma, especially in vulnerable thin cap fibroatheroma. However, there is a shortage of studies on efferocytosis defects in cell and animal models. Here, the impacts of oxidized low density lipoprotein (ox-LDL) and glut 1 inhibitor (STF31) on efferocytosis of macrophages are studied, and an evaluation system is constructed. Through regulating the cell ratios and stimulus, three types of atherosclerotic spheroids are fabricated, and a necrotic core emerges with surrounding apoptotic cells. Rat models present a similar phenomenon in that substantial apoptotic cells are uncleared in time in vulnerable plaque, and the model period is shortened to 7 weeks. Mechanism studies reveal that ox-LDL, through mRNA and miRNA modulation, downregulates efferocytosis receptor (PPARγ/LXRα/MerTK), internalization molecule (SLC29a1), and upregulates the competitive receptor CD300a that inhibits efferocytosis receptor-ligand binding process. The foam cell differentiation has also confirmed that CD36 and Lp-PLA2 levels are significantly elevated, and macrophages present an interesting transition into prothrombic phenotype. Collectively, the atherosclerotic models featured by efferocytosis defect provide a comprehensive platform to evaluate the efficacy of medicine and biomaterials for atherosclerosis treatment.
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Affiliation(s)
- Dan Zou
- Key Laboratory for Advanced Technologies of Materials, Ministry of Education, Chengdu, 610031, P. R. China
- School of Material Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, P. R. China
| | - Ping Yang
- Key Laboratory for Advanced Technologies of Materials, Ministry of Education, Chengdu, 610031, P. R. China
- School of Material Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, P. R. China
| | - Jianan Liu
- Key Laboratory for Advanced Technologies of Materials, Ministry of Education, Chengdu, 610031, P. R. China
- School of Material Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, P. R. China
| | - Fanfan Dai
- Key Laboratory for Advanced Technologies of Materials, Ministry of Education, Chengdu, 610031, P. R. China
- School of Material Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, P. R. China
| | - Yangyang Xiao
- Key Laboratory for Advanced Technologies of Materials, Ministry of Education, Chengdu, 610031, P. R. China
- School of Material Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, P. R. China
| | - Ansha Zhao
- Key Laboratory for Advanced Technologies of Materials, Ministry of Education, Chengdu, 610031, P. R. China
- School of Material Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, P. R. China
| | - Nan Huang
- Key Laboratory for Advanced Technologies of Materials, Ministry of Education, Chengdu, 610031, P. R. China
- School of Material Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, P. R. China
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13
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Egea V, Megens RTA, Santovito D, Wantha S, Brandl R, Siess W, Khani S, Soehnlein O, Bartelt A, Weber C, Ries C. Properties and fate of human mesenchymal stem cells upon miRNA let-7f-promoted recruitment to atherosclerotic plaques. Cardiovasc Res 2023; 119:155-166. [PMID: 35238350 PMCID: PMC10022860 DOI: 10.1093/cvr/cvac022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 02/28/2022] [Indexed: 11/12/2022] Open
Abstract
AIMS Atherosclerosis is a chronic inflammatory disease of the arteries leading to the formation of atheromatous plaques. Human mesenchymal stem cells (hMSCs) are recruited from the circulation into plaques where in response to their environment they adopt a phenotype with immunomodulatory properties. However, the mechanisms underlying hMSC function in these processes are unclear. Recently, we described that miRNA let-7f controls hMSC invasion guided by inflammatory cytokines and chemokines. Here, we investigated the role of let-7f in hMSC tropism to human atheromas and the effects of the plaque microenvironment on cell fate and release of soluble factors. METHODS AND RESULTS Incubation of hMSCs with LL-37, an antimicrobial peptide abundantly found in plaques, increased biosynthesis of let-7f and N-formyl peptide receptor 2 (FPR2), enabling chemotactic invasion of the cells towards LL-37, as determined by qRT-PCR, flow cytometry, and cell invasion assay analysis. In an Apoe-/- mouse model of atherosclerosis, circulating hMSCs preferentially adhered to athero-prone endothelium. This property was facilitated by elevated levels of let-7f in the hMSCs, as assayed by ex vivo artery perfusion and two-photon laser scanning microscopy. Exposure of hMSCs to homogenized human atheromatous plaque material considerably induced the production of various cytokines, chemokines, matrix metalloproteinases, and tissue inhibitors of metalloproteinases, as studied by PCR array and western blot analysis. Moreover, exposure to human plaque extracts elicited differentiation of hMSCs into cells of the myogenic lineage, suggesting a potentially plaque-stabilizing effect. CONCLUSIONS Our findings indicate that let-7f promotes hMSC tropism towards atheromas through the LL-37/FPR2 axis and demonstrate that hMSCs upon contact with human plaque environment develop a potentially athero-protective signature impacting the pathophysiology of atherosclerosis.
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Affiliation(s)
- Virginia Egea
- Corresponding authors. Tel: +49-89-4400-55310, E-mail: (C.R.); Tel: +49-89-4400-43902, E-mail: (V.E.)
| | - Remco Theodorus Adrianus Megens
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University of Munich, Munich, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
- Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands
| | - Donato Santovito
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University of Munich, Munich, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
- Institute for Genetic and Biomedical Research (IRGB), UoS of Milan, National Research Council (CNR), Milan, Italy
| | - Sarawuth Wantha
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Richard Brandl
- St. Mary’s Square Institute for Vascular Surgery and Phlebology, Munich, Germany
| | - Wolfgang Siess
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Sajjad Khani
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Oliver Soehnlein
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University of Munich, Munich, Germany
- Department of Physiology and Pharmacology (FyFa), Karolinska Institutet, Stockholm, Sweden
- Institute for Experimental Pathology (ExPat), Center for Molecular Biology of Inflammation (ZMBE), Westfaelische Wilhelms-University of Muenster, Muenster, Germany
| | - Alexander Bartelt
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University of Munich, Munich, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
- Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany
- Department of Molecular Metabolism, Sabri Ülker Center for Metabolic Research, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA
| | - Christian Weber
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University of Munich, Munich, Germany
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Christian Ries
- Corresponding authors. Tel: +49-89-4400-55310, E-mail: (C.R.); Tel: +49-89-4400-43902, E-mail: (V.E.)
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14
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Mesples AD, Cox DC, Lundy HD, Antonio-Collie S, Diggis CW, Lakey JR. Monitoring of Autoantibodies Following Autologous Hematopoietic Stem Cell Transplantation in 6 Children with Recently Diagnosed Type 1 Diabetes Mellitus. Med Sci Monit 2023; 29:e938979. [PMID: 36659834 PMCID: PMC9872439 DOI: 10.12659/msm.938979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Bone marrow stem cells have been shown to be a promising therapeutic strategy for autoimmune diseases. This study aimed to assess the safety and efficacy of autologous hematopoietic stem cell (ABMSC) transplantation without immunoablation used to suppress the autoimmune reaction in 6 children with newly diagnosed autoimmune diabetes mellitus. We monitored the levels of islet cell antibodies (ICA), antibodies against islet antigen-related tyrosine phosphatase 2 (IA2), glutamic acid-decarboxylase (GAD) antibodies, and anti-insulin antibodies (AIA). MATERIAL AND METHODS Between 2018 and 2022, 6 children (age 6-10 years, average 8 years) recently diagnosed with type 1 diabetes mellitus with the presence of ICA, IA2, GAD, AIA and ketoacidosis, were treated with an ABMSC stimulated with Filgrastim, granulocyte colony-stimulating factor (G-CSF), 10 ug/kg/day for 4 days. Bone marrow was harvested on day 5, collected by puncture and identified as mononuclear cells >180×10⁶/kg, CD34+ >0.22%, and transplanted by intravenous (i.v.) infusion. Patients were monitored with ICA, IA2, GAD, AIA, C-peptide, blood glucose, and glycosylated hemoglobin A1c (HbA1C) 6 months after the procedure. RESULTS At 6-month follow-up, we observed a negative value of the ICA, which was previously positive (P<0.001). The IA2 (p=0.037) and GAD (P=0.377) antibodies decreased slowly but were significantly lower. AIA remained high. A decrease in blood glucose and HbA1C levels was observed (P<0.001). No complications occurred during follow-up. CONCLUSIONS Autologous hematopoietic stem cell transplantation without immunoablation was safe and effective in significantly decreasing the production and effect of autoantibodies against ICA, GAD, and IA2, as well as decreasing blood sugar levels and HbA1c.
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Affiliation(s)
| | - Desiree C.T. Cox
- National Stem Cells Ethics Committee (NSCEC), Ministry of Health, Nassau, Bahamas,Biotech, BioPep, Denver, CO, USA
| | - Harriet D. Lundy
- Regenerative Medicine Program, Doctors Hospital Health System, Nassau, Bahamas
| | | | - Charles W. Diggis
- Regenerative Medicine Program, Doctors Hospital Health System, Nassau, Bahamas
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15
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La Russa D, Di Santo C, Lizasoain I, Moraga A, Bagetta G, Amantea D. Tumor Necrosis Factor (TNF)-α-Stimulated Gene 6 (TSG-6): A Promising Immunomodulatory Target in Acute Neurodegenerative Diseases. Int J Mol Sci 2023; 24:ijms24021162. [PMID: 36674674 PMCID: PMC9865344 DOI: 10.3390/ijms24021162] [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: 12/05/2022] [Revised: 12/26/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
Tumor necrosis factor (TNF)-α-stimulated gene 6 (TSG-6), the first soluble chemokine-binding protein to be identified in mammals, inhibits chemotaxis and transendothelial migration of neutrophils and attenuates the inflammatory response of dendritic cells, macrophages, monocytes, and T cells. This immunoregulatory protein is a pivotal mediator of the therapeutic efficacy of mesenchymal stem/stromal cells (MSC) in diverse pathological conditions, including neuroinflammation. However, TSG-6 is also constitutively expressed in some tissues, such as the brain and spinal cord, and is generally upregulated in response to inflammation in monocytes/macrophages, dendritic cells, astrocytes, vascular smooth muscle cells and fibroblasts. Due to its ability to modulate sterile inflammation, TSG-6 exerts protective effects in diverse degenerative and inflammatory diseases, including brain disorders. Emerging evidence provides insights into the potential use of TSG-6 as a peripheral diagnostic and/or prognostic biomarker, especially in the context of ischemic stroke, whereby the pathobiological relevance of this protein has also been demonstrated in patients. Thus, in this review, we will discuss the most recent data on the involvement of TSG-6 in neurodegenerative diseases, particularly focusing on relevant anti-inflammatory and immunomodulatory functions. Furthermore, we will examine evidence suggesting novel therapeutic opportunities that can be afforded by modulating TSG-6-related pathways in neuropathological contexts and, most notably, in stroke.
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Affiliation(s)
- Daniele La Russa
- Section of Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy
| | - Chiara Di Santo
- Section of Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy
| | - Ignacio Lizasoain
- Unidad de Investigación Neurovascular, Departamento de Farmacología y Toxicología, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid, and Instituto de Investigación Hospital 12 de Octubre (Imas12), 28040 Madrid, Spain
| | - Ana Moraga
- Unidad de Investigación Neurovascular, Departamento de Farmacología y Toxicología, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid, and Instituto de Investigación Hospital 12 de Octubre (Imas12), 28040 Madrid, Spain
| | - Giacinto Bagetta
- Section of Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy
| | - Diana Amantea
- Section of Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy
- Correspondence:
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16
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Papastamos C, Antonopoulos AS, Simantiris S, Koumallos N, Theofilis P, Sagris M, Tsioufis K, Androulakis E, Tousoulis D. Stem Cell-based Therapies in Cardiovascular Diseases: From Pathophysiology to Clinical Outcomes. Curr Pharm Des 2023; 29:2795-2801. [PMID: 37641986 DOI: 10.2174/1381612829666230828102130] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 06/18/2023] [Accepted: 07/19/2023] [Indexed: 08/31/2023]
Abstract
Over 20 years of intensified research in the field of stem cells brought about unprecedented possibilities in treating heart diseases. The investigators were initially fascinated by the idea of regenerating the lost myocardium and replacing it with new functional cardiomyocytes, but this was extremely challenging. However, the multifactorial effects of stem cell-based therapies beyond mere cardiomyocyte generation, caused by paracrine signaling, would open up new possibilities in treating cardiovascular diseases. To date, there is a strong body of evidence that the anti-inflammatory, anti-apoptotic, and immunomodulatory effects of stem cell therapy may alleviate atherosclerosis progression. In the present review, our objective is to provide a brief overview of the stem cell-based therapeutic options. We aim to delineate the pathophysiological mechanisms of their beneficial effects in cardiovascular diseases especially in coronary artery disease and to highlight some conclusions from important clinical studies in the field of regenerative medicine in cardiovascular diseases and how we could further move onwards.
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Affiliation(s)
- Charalampos Papastamos
- 1st Cardiology Department, Hippokration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Alexios S Antonopoulos
- 1st Cardiology Department, Hippokration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Spyridon Simantiris
- 1st Cardiology Department, Hippokration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Nikolaos Koumallos
- 1st Cardiology Department, Hippokration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Theofilis
- 1st Cardiology Department, Hippokration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Marios Sagris
- 1st Cardiology Department, Hippokration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantinos Tsioufis
- 1st Cardiology Department, Hippokration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Dimitris Tousoulis
- 1st Cardiology Department, Hippokration General Hospital, National and Kapodistrian University of Athens, Athens, Greece
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17
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Goh WX, Kok YY, Wong CY. Comparison of Cell-based and Nanoparticle-based Therapeutics in Treating Atherosclerosis. Curr Pharm Des 2023; 29:2827-2840. [PMID: 37936453 DOI: 10.2174/0113816128272185231024115046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 09/06/2023] [Accepted: 09/14/2023] [Indexed: 11/09/2023]
Abstract
Today, cardiovascular diseases are among the biggest public health threats worldwide. Atherosclerosis, a chronic inflammatory disease with complex aetiology and pathogenesis, predispose many of these conditions, including the high mortality rate-causing ischaemic heart disease and stroke. Nevertheless, despite the alarming prevalence and absolute death rate, established treatments for atherosclerosis are unsatisfactory in terms of efficacy, safety, and patient acceptance. The rapid advancement of technologies in healthcare research has paved new treatment approaches, namely cell-based and nanoparticle-based therapies, to overcome the limitations of conventional therapeutics. This paper examines the different facets of each approach, discusses their principles, strengths, and weaknesses, analyses the main targeted pathways and their contradictions, provides insights on current trends as well as highlights any unique mechanisms taken in recent years to combat the progression of atherosclerosis.
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Affiliation(s)
- Wen Xi Goh
- Division of Applied Biomedical Science and Biotechnology, School of Health Sciences, International Medical University, Kuala Lumpur, Malaysia
| | - Yih Yih Kok
- Division of Applied Biomedical Science and Biotechnology, School of Health Sciences, International Medical University, Kuala Lumpur, Malaysia
| | - Chiew Yen Wong
- Division of Applied Biomedical Science and Biotechnology, School of Health Sciences, International Medical University, Kuala Lumpur, Malaysia
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18
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Huang L, Fang H, Zhang T, Hu B, Liu S, Lv F, Zeng Z, Liu H, Zhou W, Wang X. Drug-loaded balloon with built-in NIR controlled tip-separable microneedles for long-effective arteriosclerosis treatment. Bioact Mater 2022; 23:526-538. [PMID: 36514389 PMCID: PMC9730155 DOI: 10.1016/j.bioactmat.2022.11.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 10/24/2022] [Accepted: 11/22/2022] [Indexed: 12/12/2022] Open
Abstract
Drug-eluting balloon (DEB) angioplasty has emerged as an effective treatment for cardiovascular and cerebrovascular diseases. However, distal embolism and late lumen restenosis could be caused by drug loss during DEB handling and rapid drug metabolization. Here, a drug-loaded balloon equipped with tip-separable microneedles on the balloon surface (MNDLB) was developed. Inbuilt near-infrared (NIR) ring laser inside the catheter inner shaft was introduced to activate the biodegradable microneedle tips for the first time. The drug-loaded tips thus could be embedded in the vasculature and then released antiproliferative drug - paclitaxel slowly via polymer degradation for more than half a year. A significant increase in drug delivery efficiency and superior therapeutic effectiveness compared with the standard DEB were demonstrated using an atherosclerosis rabbit model.
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Affiliation(s)
- Li Huang
- Department of Vascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, 330006, PR China,The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, 330088, PR China
| | - Huaqiang Fang
- Department of Vascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, 330006, PR China
| | - Teng Zhang
- Department of Vascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, 330006, PR China
| | - Binbin Hu
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, 330088, PR China
| | - Shichen Liu
- Department of Vascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, 330006, PR China
| | - Fanzhen Lv
- Department of Vascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, 330006, PR China
| | - Zhaoxia Zeng
- Department of Radiology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, 330006, PR China
| | - Huijie Liu
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, 330088, PR China
| | - Weimin Zhou
- Department of Vascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, 330006, PR China,Corresponding author.
| | - Xiaolei Wang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, 330088, PR China,School of Chemistry and Chemical Engineering, Nanchang University, Nanchang, Jiangxi, 330088, PR China,Corresponding author. The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, 330088, PR China.
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19
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Lin D, Li W, Zhang N, Cai M. Identification of TNFAIP6 as a hub gene associated with the progression of glioblastoma by weighted gene co-expression network analysis. IET Syst Biol 2022; 16:145-156. [PMID: 35766985 PMCID: PMC9469790 DOI: 10.1049/syb2.12046] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 05/29/2022] [Accepted: 06/08/2022] [Indexed: 11/19/2022] Open
Abstract
This study aims to discover the genetic modules that distinguish glioblastoma multiforme (GBM) from low‐grade glioma (LGG) and identify hub genes. A co‐expression network is constructed using the expression profiles of 28 GBM and LGG patients from the Gene Expression Omnibus database. The authors performed gene ontology (GO) and Kyoto encyclopaedia of genes and genomes (KEGG) analysis on these genes. The maximal clique centrality method was used to identify hub genes. Online tools were employed to confirm the link between hub gene expression and overall patient survival rate. The top 5000 genes with major variance were classified into 18 co‐expression gene modules. GO analysis indicated that abnormal changes in ‘cell migration’ and ‘collagen metabolic process’ were involved in the development of GBM. KEGG analysis suggested that ‘focal adhesion’ and ‘p53 signalling pathway’ regulate the tumour progression. TNFAIP6 was identified as a hub gene, and the expression of TNFAIP6 was increased with the elevation of pathological grade. Survival analysis indicated that the higher the expression of TNFAIP6, the shorter the survival time of patients. The authors identified TNFAIP6 as the hub gene in the progression of GBM, and its high expression indicates the poor prognosis of the patients.
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Affiliation(s)
- Dongdong Lin
- Department of Neurosurgery, The Second Affiliated Hospital-Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wei Li
- Department of Neurosurgery, The Second Affiliated Hospital-Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Nu Zhang
- Department of Neurosurgery, The Second Affiliated Hospital-Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ming Cai
- Department of Neurosurgery, The Second Affiliated Hospital-Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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20
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S S, Dahal S, Bastola S, Dayal S, Yau J, Ramamurthi A. Stem Cell Based Approaches to Modulate the Matrix Milieu in Vascular Disorders. Front Cardiovasc Med 2022; 9:879977. [PMID: 35783852 PMCID: PMC9242410 DOI: 10.3389/fcvm.2022.879977] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 05/20/2022] [Indexed: 12/12/2022] Open
Abstract
The extracellular matrix (ECM) represents a complex and dynamic framework for cells, characterized by tissue-specific biophysical, mechanical, and biochemical properties. ECM components in vascular tissues provide structural support to vascular cells and modulate their function through interaction with specific cell-surface receptors. ECM–cell interactions, together with neurotransmitters, cytokines, hormones and mechanical forces imposed by blood flow, modulate the structural organization of the vascular wall. Changes in the ECM microenvironment, as in post-injury degradation or remodeling, lead to both altered tissue function and exacerbation of vascular pathologies. Regeneration and repair of the ECM are thus critical toward reinstating vascular homeostasis. The self-renewal and transdifferentiating potential of stem cells (SCs) into other cell lineages represents a potentially useful approach in regenerative medicine, and SC-based approaches hold great promise in the development of novel therapeutics toward ECM repair. Certain adult SCs, including mesenchymal stem cells (MSCs), possess a broader plasticity and differentiation potential, and thus represent a viable option for SC-based therapeutics. However, there are significant challenges to SC therapies including, but not limited to cell processing and scaleup, quality control, phenotypic integrity in a disease milieu in vivo, and inefficient delivery to the site of tissue injury. SC-derived or -inspired strategies as a putative surrogate for conventional cell therapy are thus gaining momentum. In this article, we review current knowledge on the patho-mechanistic roles of ECM components in common vascular disorders and the prospects of developing adult SC based/inspired therapies to modulate the vascular tissue environment and reinstate vessel homeostasis in these disorders.
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21
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Qu Y, Yang F, Meng F, Chen X, Zhang Q, Yu T, Wen S, Pan Y. Plasma Concentration of Tumor Necrosis Factor-Stimulated Gene-6 as a Novel Diagnostic and 3-Month Prognostic Indicator in Non-Cardioembolic Acute Ischemic Stroke. Front Immunol 2022; 13:713379. [PMID: 35222359 PMCID: PMC8868935 DOI: 10.3389/fimmu.2022.713379] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 01/05/2022] [Indexed: 11/29/2022] Open
Abstract
Background Tumor necrosis factor-stimulated gene-6 (TSG-6) is a multifunctional, anti-inflammatory, and protective protein, while the association between TSG-6 and acute ischemic stroke (AIS) remains unclear in humans. This study aims to investigate the potential diagnostic and short-term prognosis predictive values of TSG-6 in non-cardioembolic AIS. Methods A total of 134 non-cardioembolic AIS patients within 24 h after AIS onset and 40 control subjects were recruited. Using an AIS dataset from the Gene Expression Omnibus database and setting the median expression level of TNFAIP6 as the cutoff point, data were divided into TNFAIP6-high and TNFAIP6-low expression groups. Differently expressed genes (DEGs) were extracted to perform gene enrichment analysis and protein–protein interaction (PPI) network. Baseline data were analyzed in a four-group comparison plotted as plasma TSG-6 concentration median and 25th/75th percentiles. The correlative factors of 3-month outcome were evaluated by logistic regression. TSG-6 concentrations and TSG-6-to-interleukin-8 ratios were compared in a block design. A receiver-operating characteristic curve was used to analyze the detective value of TSG-6 and 3-month prognosis predictive values of TSG-6 and TSG-6-to-interleukin-8 ratio. Results Non-cardioembolic AIS patients had significantly higher plasma TSG-6 levels than control subjects (P < 0.0001). The large-artery atherosclerosis group had significantly higher TSG-6 levels than the small-artery occlusion group (P = 0.0184). Seven hundred and eighty-two DEGs might be both AIS-related and TNFAIP6-correlated genes, and 17 targets were deemed AIS-related being closely relevant to TNFAIP6. Interleukin-8 was selected for further study. The National Institutes of Health Stroke Scale and the Acute Stroke Registry and Analysis of Lausanne scores at admission, lesion volume, neutrophil count, neutrophil-to-lymphocyte ratio, and interleukin-8 level were positively correlated with TSG-6 level, respectively (P < 0.0001). The unfavorable outcome group had meaningfully higher TSG-6 levels (P < 0.0001) and lower TSG-6-to-interleukin-8 ratios (P < 0.0001) than the favorable outcome group. After adjusting for confounding variables, elevated TSG-6 levels remained independently associated with 3-month poor prognosis of non-cardioembolic AIS (P = 0.017). In non-cardioembolic AIS, the cutoff values of TSG-6 concentration for detection and 3-month prognosis prediction and the TSG-6-to-interleukin-8 ratio for the 3-month prognosis prediction were 8.13 ng/ml [AUC, 0.774 (0.686–0.861); P < 0.0001], 10.21 ng/ml [AUC, 0.795 (0.702–0.887); P < 0.0001], and 1.505 [AUC, 0.873 (0.795–0.951); P < 0.0001]. Conclusions Plasma TSG-6 concentration was a novel indicator for non-cardioembolic AIS diagnosis and 3-month prognosis. Elevated TSG-6-to-interleukin-8 ratio might suggest a 3-month favorable outcome.
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Affiliation(s)
- Yewei Qu
- Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Fan Yang
- Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Fanwei Meng
- Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xi Chen
- Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qingqing Zhang
- Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Tian Yu
- Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shirong Wen
- Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yujun Pan
- Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
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22
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Tao J, Cao X, Yu B, Qu A. Vascular Stem/Progenitor Cells in Vessel Injury and Repair. Front Cardiovasc Med 2022; 9:845070. [PMID: 35224067 PMCID: PMC8866648 DOI: 10.3389/fcvm.2022.845070] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 01/17/2022] [Indexed: 11/13/2022] Open
Abstract
Vascular repair upon vessel injury is essential for the maintenance of arterial homeostasis and function. Stem/progenitor cells were demonstrated to play a crucial role in regeneration and replenishment of damaged vascular cells during vascular repair. Previous studies revealed that myeloid stem/progenitor cells were the main sources of tissue regeneration after vascular injury. However, accumulating evidences from developing lineage tracing studies indicate that various populations of vessel-resident stem/progenitor cells play specific roles in different process of vessel injury and repair. In response to shear stress, inflammation, or other risk factors-induced vascular injury, these vascular stem/progenitor cells can be activated and consequently differentiate into different types of vascular wall cells to participate in vascular repair. In this review, mechanisms that contribute to stem/progenitor cell differentiation and vascular repair are described. Targeting these mechanisms has potential to improve outcome of diseases that are characterized by vascular injury, such as atherosclerosis, hypertension, restenosis, and aortic aneurysm/dissection. Future studies on potential stem cell-based therapy are also highlighted.
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Affiliation(s)
- Jiaping Tao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
- The Key Laboratory of Cardiovascular Remodeling-Related Diseases, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Metabolic Disorder-Related Cardiovascular Diseases, Beijing, China
| | - Xuejie Cao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
- The Key Laboratory of Cardiovascular Remodeling-Related Diseases, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Metabolic Disorder-Related Cardiovascular Diseases, Beijing, China
| | - Baoqi Yu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
- The Key Laboratory of Cardiovascular Remodeling-Related Diseases, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Metabolic Disorder-Related Cardiovascular Diseases, Beijing, China
- *Correspondence: Baoqi Yu
| | - Aijuan Qu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
- The Key Laboratory of Cardiovascular Remodeling-Related Diseases, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Metabolic Disorder-Related Cardiovascular Diseases, Beijing, China
- Aijuan Qu
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23
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Wang Y, Qi Z, Yan Z, Ji N, Yang X, Gao D, Hu L, Lv H, Zhang J, Li M. Mesenchymal Stem Cell Immunomodulation: A Novel Intervention Mechanism in Cardiovascular Disease. Front Cell Dev Biol 2022; 9:742088. [PMID: 35096808 PMCID: PMC8790228 DOI: 10.3389/fcell.2021.742088] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 12/14/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are the member of multipotency stem cells, which possess the capacity for self-renewal and multi-directional differentiation, and have several characteristics, including multi-lineage differentiation potential and immune regulation, which make them a promising source for cell therapy in inflammation, immune diseases, and organ transplantation. In recent years, MSCs have been described as a novel therapeutic strategy for the treatment of cardiovascular diseases because they are potent modulators of immune system with the ability to modulating immune cell subsets, coordinating local and systemic innate and adaptive immune responses, thereby enabling the formation of a stable inflammatory microenvironment in damaged cardiac tissues. In this review, the immunoregulatory characteristics and potential mechanisms of MSCs are sorted out, the effect of these MSCs on immune cells is emphasized, and finally the application of this mechanism in the treatment of cardiovascular diseases is described to provide help for clinical application.
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Affiliation(s)
- Yueyao Wang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Zhongwen Qi
- Institute of Gerontology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhipeng Yan
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Nan Ji
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiaoya Yang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Dongjie Gao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Leilei Hu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hao Lv
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Junping Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Meng Li
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
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24
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Comprehensive Analysis to Identify Key Genes Involved in Advanced Atherosclerosis. DISEASE MARKERS 2021; 2021:4026604. [PMID: 34925641 PMCID: PMC8683248 DOI: 10.1155/2021/4026604] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 11/13/2021] [Indexed: 02/06/2023]
Abstract
Background The study was aimed at finding accurate and effective therapeutic targets and deepening our understanding of the mechanisms of advanced atherosclerosis (AA). Methods We downloaded the gene expression datasets GSE28829, GSE120521, and GSE43292 from Gene Expression Omnibus. Weighted gene coexpression network analysis (WGCNA) was performed for GSE28829, and functional enrichment analysis and protein–protein interaction network analysis were conducted on the key module. Significant genes in the key module were analyzed by molecular complex detection, and genes in the most important subnetwork were defined as hub genes. Multiple dataset analyses for hub genes were conducted. Genes that overlapped between hub genes and differentially expressed genes (DEGs) of GSE28829 and GSE120521 were defined as key genes. Further validation for key genes was performed using GSE28829 and GSE43292. Gene set enrichment analysis (GSEA) was applied to key genes. Results A total of 77 significant genes in the key module of GSE28829 were screened out that were mainly associated with inflammation and immunity. The subnetwork was obtained from significant genes, and 18 genes in this module were defined as hub genes, which were related to immunity and expressed in multiple diseases, particularly systemic lupus erythematosus. Some hub genes were regulated by SPI1 and associated with the blood, spleen, and lung. After overlapping with DEGs of GSE28829 and GSE120521, a total of 10 genes (HCK, ITGAM, CTSS, TYROBP, LAPTM5, FCER1G, ITGB2, NCF2, AIF1, and CD86) were identified as key genes. All key genes were validated and evaluated successfully and were related to immune response pathways. Conclusion Our study suggests that the key genes related to immune and inflammatory responses are involved in the development of AA. This may deepen our understanding of the mechanisms of and provide valuable therapeutic targets for AA.
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25
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Chang YJ, Wang KC. Therapeutic perspectives of extracellular vesicles and extracellular microRNAs in atherosclerosis. CURRENT TOPICS IN MEMBRANES 2021; 87:255-277. [PMID: 34696887 DOI: 10.1016/bs.ctm.2021.08.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Extracellular signaling molecules, such as growth factors, cytokines, and hormones, regulate cell behaviors and fate through endocrine, paracrine, and autocrine actions and play essential roles in maintaining tissue homeostasis. MicroRNAs, an important class of posttranscriptional modulators, could stably present in extracellular space and body fluids and participate in intercellular communication in health and diseases. Indeed, recent studies demonstrated that microRNAs could be secreted through vesicular and non-vesicular routes, transported in body fluids, and then transmitted to recipient cells to regulate target gene expression and signaling events. Over the past decade, a great deal of effort has been made to investigate the functional roles of extracellular vesicles and extracellular microRNAs in pathological conditions. Emerging evidence suggests that altered levels of extracellular vesicles and extracellular microRNAs in body fluids, as part of the cellular responses to atherogenic factors, are associated with the development of atherosclerosis. This review article provides a brief overview of extracellular vesicles and perspectives of their applications as therapeutic tools for cardiovascular pathologies. In addition, we highlight the role of extracellular microRNAs in atherogenesis and offer a summary of circulating microRNAs in liquid biopsies associated with atherosclerosis.
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Affiliation(s)
- Ya-Ju Chang
- Department of Family Medicine and Public Health, School of Medicine, University of California San Diego, La Jolla, CA, United States
| | - Kuei-Chun Wang
- School of Biological and Health Systems Engineering, Ira A. Fulton Schools of Engineering, Arizona State University, Tempe, AZ, United States.
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26
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Li Y, Shi G, Han Y, Shang H, Li H, Liang W, Zhao W, Bai L, Qin C. Therapeutic potential of human umbilical cord mesenchymal stem cells on aortic atherosclerotic plaque in a high-fat diet rabbit model. Stem Cell Res Ther 2021; 12:407. [PMID: 34266502 PMCID: PMC8281645 DOI: 10.1186/s13287-021-02490-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 07/04/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Atherosclerosis (AS) is a complex disease caused in part by dyslipidemia and chronic inflammation. AS is associated with serious cardiovascular disease and remains the leading cause of mortality worldwide. Mesenchymal stem cells (MSCs) have evolved as an attractive therapeutic agent in various diseases including AS. Human umbilical cord MSCs (UCSCs) have been used in cell therapy trials due to their ability to differentiate and proliferate. The present study aimed to investigate the effect of UCSCs treatment on atherosclerotic plaque formation and the progression of lesions in a high-fat diet rabbit model. METHODS Rabbits were fed a high-fat diet and then randomly divided into three groups: control, model, and treatment groups. Rabbits in the treatment group were injected with UCSCs (6 × 106 in 500 μL phosphate buffered saline) after 1 month of high-fat diet, once every 2 weeks, for 3 months. The model group was given PBS only. We analyzed serum biomarkers, used ultrasound and histopathology to detect arterial plaques and laser Doppler imaging to measure peripheral blood vessel blood filling, and analyzed the intestinal flora and metabolism. RESULTS Histological analysis showed that the aortic plaque area was significantly reduced in the treatment group. We also found a significant decrease in macrophage accumulation and apoptosis, an increase in expression of scavenger receptors CD36 and SRA1, a decrease in uptake of modified low-density protein (ox-LDL), and a decrease in levels of pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α following UCSCs treatment. We also found that anti-inflammatory cytokines IL-10 and transforming growth factor (TGF)-β expression increased in the aorta atherosclerotic plaque of the treatment group. UCSCs treatment improved the early peripheral blood filling, reduced the serum lipid level, and inhibited inflammation progression by regulating the intestinal flora dysbiosis caused by the high-fat diet. More specifically, levels of the microbiota-dependent metabolite trimethylamine-N-oxide (TMAO) were down-regulated in the treatment group. CONCLUSIONS UCSCs treatment alleviated atherosclerotic plaque burden by reducing inflammation, regulating the intestinal flora and TMAO levels, and repairing the damaged endothelium.
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Affiliation(s)
- Yanhong Li
- Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health; Institute of Medical Laboratory Animal Science, CAMS&PUMC; Key Laboratory of Human Diseases Animal Models, State Administration of Traditional Chinese Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Beijing, 100021, China
| | - Guiying Shi
- Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health; Institute of Medical Laboratory Animal Science, CAMS&PUMC; Key Laboratory of Human Diseases Animal Models, State Administration of Traditional Chinese Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Beijing, 100021, China
| | - Yunlin Han
- Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health; Institute of Medical Laboratory Animal Science, CAMS&PUMC; Key Laboratory of Human Diseases Animal Models, State Administration of Traditional Chinese Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Beijing, 100021, China
| | - Haiquan Shang
- Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health; Institute of Medical Laboratory Animal Science, CAMS&PUMC; Key Laboratory of Human Diseases Animal Models, State Administration of Traditional Chinese Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Beijing, 100021, China
| | - Huiwu Li
- Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health; Institute of Medical Laboratory Animal Science, CAMS&PUMC; Key Laboratory of Human Diseases Animal Models, State Administration of Traditional Chinese Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Beijing, 100021, China
| | - Wei Liang
- Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health; Institute of Medical Laboratory Animal Science, CAMS&PUMC; Key Laboratory of Human Diseases Animal Models, State Administration of Traditional Chinese Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Beijing, 100021, China
| | - Wenjie Zhao
- Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health; Institute of Medical Laboratory Animal Science, CAMS&PUMC; Key Laboratory of Human Diseases Animal Models, State Administration of Traditional Chinese Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Beijing, 100021, China
| | - Lin Bai
- Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health; Institute of Medical Laboratory Animal Science, CAMS&PUMC; Key Laboratory of Human Diseases Animal Models, State Administration of Traditional Chinese Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Beijing, 100021, China
| | - Chuan Qin
- Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health; Institute of Medical Laboratory Animal Science, CAMS&PUMC; Key Laboratory of Human Diseases Animal Models, State Administration of Traditional Chinese Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Beijing, 100021, China.
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27
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Kirwin T, Gomes A, Amin R, Sufi A, Goswami S, Wang B. Mechanisms underlying the therapeutic potential of mesenchymal stem cells in atherosclerosis. Regen Med 2021; 16:669-682. [PMID: 34189963 DOI: 10.2217/rme-2021-0024] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Atherosclerosis is a chronic inflammatory condition resulting in the formation of fibrofatty plaques within the intimal layer of arterial walls. The identification of resident stem cells in the vascular wall has led to significant investigation into their contributions to health and disease, as well as their therapeutic potential. Of these, mesenchymal stem cells (MSCs) are the most widely studied in human clinical trials, which have demonstrated a modulatory role in vascular physiology and disease. This review highlights the most recent knowledge surrounding the cell biology of MSCs, including their origin, identification markers and differentiation potential. The limitations concerning the implementation of MSC therapy are considered and novel solutions to overcome these are proposed.
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Affiliation(s)
- Thomas Kirwin
- Department of Medicine, Imperial College London, SW7 2BU, UK.,College of Medical & Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Ana Gomes
- Department of Medicine, Imperial College London, SW7 2BU, UK
| | - Ravi Amin
- Department of Medicine, Imperial College London, SW7 2BU, UK
| | - Annam Sufi
- Department of Medicine, Imperial College London, SW7 2BU, UK.,GKT School of Medical Education, King's College London, London, SE1 1UL, UK
| | - Sahil Goswami
- Department of Medicine, Imperial College London, SW7 2BU, UK.,Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, E1 2AD, UK
| | - Brian Wang
- Department of Medicine, Imperial College London, SW7 2BU, UK
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28
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Maqbool M, Algraittee SJR, Boroojerdi MH, Sarmadi VH, John CM, Vidyadaran S, Ramasamy R. Human mesenchymal stem cells inhibit the differentiation and effector functions of monocytes. Innate Immun 2021; 26:424-434. [PMID: 32635840 PMCID: PMC7903531 DOI: 10.1177/1753425919899132] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Although monocytes represent an essential part of the host defence system, their accumulation and prolonged stimulation could be detrimental and may aggravate chronic inflammatory diseases. The present study has explored the less-understood immunomodulatory effects of mesenchymal stem cells on monocyte functions. Isolated purified human monocytes were co-cultured with human umbilical cord-derived mesenchymal stem cells under appropriate culture conditions to assess monocytes' vital functions. Based on the surface marker analysis, mesenchymal stem cells halted monocyte differentiation into dendritic cells and macrophages and reduced their phagocytosis functions, which rendered an inability to stimulate T-cell proliferation. The present study confers that mesenchymal stem cells exerted potent immunosuppressive activity on monocyte functions such as differentiation, phagocytosis and Ag presentation; hence, they promise a potential therapeutic role in down-regulating the unwanted monocyte-mediated immune responses in the context of chronic inflammatory diseases.
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Affiliation(s)
- Maryam Maqbool
- Department of Pathology, University Putra Malaysia, Malaysia.,Faculty of Medicine and Health Sciences, University Putra Malaysia, Malaysia
| | - Satar Jabbar Rahi Algraittee
- Department of Pathology, University Putra Malaysia, Malaysia.,Faculty of Medicine and Health Sciences, University Putra Malaysia, Malaysia.,Department of Medical Microbiology, University of Kerbala, Iraq
| | - Mohadese Hashem Boroojerdi
- Department of Pathology, University Putra Malaysia, Malaysia.,Faculty of Medicine and Health Sciences, University Putra Malaysia, Malaysia
| | - Vahid Hosseinpour Sarmadi
- Department of Pathology, University Putra Malaysia, Malaysia.,Faculty of Medicine and Health Sciences, University Putra Malaysia, Malaysia
| | - Cini Mathew John
- Department of Pathology, University Putra Malaysia, Malaysia.,Department of Pharmacology and Chemistry, University Teknologi MARA, Malaysia.,Department of Physiology and Pharmacology, University of Calgary, Canada
| | | | - Rajesh Ramasamy
- Department of Pathology, University Putra Malaysia, Malaysia.,Faculty of Medicine and Health Sciences, University Putra Malaysia, Malaysia
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29
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Wei B, Chen Y, Zhou W, Li X, Shi L, Liao S. Interleukin IL-5 alleviates sepsis-induced acute lung injury by regulating the immune response in rats. Bioengineered 2021; 12:2132-2139. [PMID: 34057015 PMCID: PMC8806508 DOI: 10.1080/21655979.2021.1930746] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
To study the effect of IL-5 on the immune response and lung injury in rats with sepsis. We constructed a rat model of sepsis by cecal ligation and puncture (CLP). The rats were randomly divided into the control group, the sham group, the CLP group and the IL-5 group, with 6 rats in each group. With the induction of CLP, the lung tissue of rats was severely injured, and the water content of lung tissue was significantly increased. Moreover, the ratio of CD4+/CD8+ was significantly decreased and Th1/Th2 was significantly increased in the peripheral blood. The content of IL-6, TNF-α, and HMGB1 was found to be increased in the CLP group. However, with the injection of IL-5, the degree of lung tissue injury in CLP rats was alleviated and the water content of lung tissue was significantly reduced. The ratio of CD4+/CD8+ was increased and Th1/Th2 was significantly down-regulated in the peripheral blood and the levels of IL-6, TNF-α, and HMGB1 in serum were significantly decreased. In conclusion, IL-5 can alleviate lung injury by regulating the immune response and inhibiting the systemic inflammatory response induced by sepsis.
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Affiliation(s)
- Beichun Wei
- Department of Emergency, Nanfang Hospital, Southern Medical University, Guangdong, China
| | - Yu Chen
- Department of Anesthesiology, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Wangmei Zhou
- Department of Emergency, Nanfang Hospital, Southern Medical University, Guangdong, China
| | - Xu Li
- Department of Emergency, Nanfang Hospital, Southern Medical University, Guangdong, China
| | - Lei Shi
- Department of Burns and Plastic Surgery, The Hospital Affiliated to Jiangsu Universitity, Jiangsu, China
| | - Shengwu Liao
- School of Public Health, Southern Medical University, Guangdong, China
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30
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Ohta H, Liu X, Maeda M. Autologous adipose mesenchymal stem cell administration in arteriosclerosis and potential for anti-aging application: a retrospective cohort study. Stem Cell Res Ther 2020; 11:538. [PMID: 33308301 PMCID: PMC7733281 DOI: 10.1186/s13287-020-02067-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 10/21/2020] [Indexed: 12/18/2022] Open
Abstract
Objective Arteriosclerosis is an age-related disease and a leading cause of cardiovascular disease. In animal experiments, mesenchymal stem cells and its culture-conditioned medium have been shown to be promising tools for prevention or treatment of arteriosclerosis. On the basis of these evidences, we aimed to assess whether administration of autologous adipose-derived mesenchymal stem cells (Ad-MSC) is safe and effective for treatment of arteriosclerosis. Methods We retrospectively reviewed clinical records of patients with arteriosclerosis who had received autologous Ad-MSC administration at our clinic. Patients’ characteristics were recorded and data on lipid profile, intimal-media thickness (IMT), cardio-ankle vascular index (CAVI), and ankle-brachial index (ABI) before and after Ad-MSC administration were collected and compared. Results Treatment with Ad-MSC significantly improved HDL, LDL, and remnant-like particle (RLP) cholesterol levels. No adverse effect or toxicity was observed in relation to the treatment. Of the patients with abnormal HDL values before treatment, the vast majority showed improvement in the values. Overall, the measurements after treatment were significantly increased compared with those before treatment (p < 0.01). In addition, decreases in LDL cholesterol and RLP levels were observed after treatment in patients who had abnormal LDL cholesterol or RLP levels before treatment. The majority of patients with pre-treatment abnormal CAVI values had improved values after treatment. In patients with available IMT values, a significant decrease in the IMT values was found after therapy (p < 0.01). All patients with borderline arteriosclerosis disease had improved laboratory findings after treatment. In general, post-treatment values were significantly decreased as compared with pre-treatment values. Of the patients with normal ABI values before treatment at the same time as CAVI, the vast majority remained normal after treatment. Conclusions These findings suggest that Ad-MSC administration is safe and effective in patients developing arteriosclerosis, thereby providing an attractive tool for anti-aging application.
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Affiliation(s)
- Hiroki Ohta
- Regenerative Medicine, Sun Field Clinic, TIME24 Building 1F 2-4-32 Aomi, Koto-ku, Tokyo, 135-0064, Japan.
| | - Xiaolan Liu
- Regenerative Medicine, Sun Field Clinic, TIME24 Building 1F 2-4-32 Aomi, Koto-ku, Tokyo, 135-0064, Japan
| | - Miho Maeda
- Regenerative Medicine, Sun Field Clinic, TIME24 Building 1F 2-4-32 Aomi, Koto-ku, Tokyo, 135-0064, Japan
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31
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Shafi O. Switching of vascular cells towards atherogenesis, and other factors contributing to atherosclerosis: a systematic review. Thromb J 2020; 18:28. [PMID: 33132762 PMCID: PMC7592591 DOI: 10.1186/s12959-020-00240-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 09/23/2020] [Indexed: 12/17/2022] Open
Abstract
Background Onset, development and progression of atherosclerosis are complex multistep processes. Many aspects of atherogenesis are not yet properly known. This study investigates the changes in vasculature that contribute to switching of vascular cells towards atherogenesis, focusing mainly on ageing. Methods Databases including PubMed, MEDLINE and Google Scholar were searched for published articles without any date restrictions, involving atherogenesis, vascular homeostasis, aging, gene expression, signaling pathways, angiogenesis, vascular development, vascular cell differentiation and maintenance, vascular stem cells, endothelial and vascular smooth muscle cells. Results Atherogenesis is a complex multistep process that unfolds in a sequence. It is caused by alterations in: epigenetics and genetics, signaling pathways, cell circuitry, genome stability, heterotypic interactions between multiple cell types and pathologic alterations in vascular microenvironment. Such alterations involve pathological changes in: Shh, Wnt, NOTCH signaling pathways, TGF beta, VEGF, FGF, IGF 1, HGF, AKT/PI3K/ mTOR pathways, EGF, FOXO, CREB, PTEN, several apoptotic pathways, ET - 1, NF-κB, TNF alpha, angiopoietin, EGFR, Bcl - 2, NGF, BDNF, neurotrophins, growth factors, several signaling proteins, MAPK, IFN, TFs, NOs, serum cholesterol, LDL, ephrin, its receptor pathway, HoxA5, Klf3, Klf4, BMPs, TGFs and others.This disruption in vascular homeostasis at cellular, genetic and epigenetic level is involved in switching of the vascular cells towards atherogenesis. All these factors working in pathologic manner, contribute to the development and progression of atherosclerosis. Conclusion The development of atherosclerosis involves the switching of gene expression towards pro-atherogenic genes. This happens because of pathologic alterations in vascular homeostasis. When pathologic alterations in epigenetics, genetics, regulatory genes, microenvironment and vascular cell biology accumulate beyond a specific threshold, then the disease begins to express itself phenotypically. The process of biological ageing is one of the most significant factors in this aspect as it is also involved in the decline in homeostasis, maintenance and integrity.The process of atherogenesis unfolds sequentially (step by step) in an interconnected loop of pathologic changes in vascular biology. Such changes are involved in 'switching' of vascular cells towards atherosclerosis.
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Affiliation(s)
- Ovais Shafi
- Sindh Medical College - Dow University of Health Sciences, Karachi, Pakistan
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High Dose of Intravenous Allogeneic Umbilical Cord-Derived Mesenchymal Stem Cells (CLV-100) Infusion Displays Better Immunomodulatory Effect among Healthy Volunteers: A Phase 1 Clinical Study. Stem Cells Int 2020; 2020:8877003. [PMID: 33061992 PMCID: PMC7539086 DOI: 10.1155/2020/8877003] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/18/2020] [Accepted: 07/11/2020] [Indexed: 12/13/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) express growth factors and other cytokines that stimulate repair and control the immune response. MSCs are also immunoprivileged with low risk of rejection. Umbilical cord-derived MSCs (UCMSCs) are particularly attractive as an off-the-shelf allogeneic treatment in emergency medical conditions. We aim to determine the safety and efficacy of intravenous allogeneic infusion of UCMSCs (CLV-100) by Cytopeutics® (Selangor, Malaysia) in healthy volunteers, and to determine the effective dose at which an immunomodulatory effect is observed. Methodology. Umbilical cord samples were collected after delivery of full-term, healthy babies with written consent from both parents. All 3 generations (newborn, parents, and grandparents) were screened for genetic mutations, infections, cancers, and other inherited diseases. Samples were transferred to a certified Good Manufacturing Practice laboratory for processing. Subjects were infused with either low dose (LD, 65 million cells) or high dose (HD, 130 million cells) of CLV-100 and followed up for 6 months. We measured cytokines using ELISA including anti-inflammatory cytokines interleukin 1 receptor antagonist (IL-1RA), interleukin 10 (IL-10), pro-/anti-inflammatory cytokine interleukin 6 (IL-6), and the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α). Results 11 healthy subjects (LD, n = 5; HD, n = 6; mean age of 55 ± 13 years) were recruited. All subjects tolerated the CLV-100 infusion well with no adverse reaction throughout the study especially in vital parameters and routine blood tests. At 6 months, the HD group had significantly higher levels of anti-inflammatory markers IL1-RA (705 ± 160 vs. 306 ± 36 pg/mL; p = 0.02) and IL-10 (321 ± 27 vs. 251 ± 28 pg/mL; p = 0.02); and lower levels of proinflammatory marker TNF-α (74 ± 23 vs. 115 ± 15 pg/mL; p = 0.04) compared to LD group. Conclusion Allogeneic UCMSCs CLV-100 infusion is safe and well-tolerated in low and high doses. Anti-inflammatory effect is observed with a high-dose infusion.
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Eissa M, Elarabany N, Hyder A. In vitro efficacy of liver microenvironment in bone marrow mesenchymal stem cell differentiation. In Vitro Cell Dev Biol Anim 2020; 56:341-348. [PMID: 32270392 DOI: 10.1007/s11626-020-00436-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Accepted: 02/08/2020] [Indexed: 12/31/2022]
Abstract
Bone marrow-derived mesenchymal stem cells (BM-MSCs) represent an interesting alternative to liver or hepatocyte transplantation to treat liver injuries. Many studies have reported that MSCs can treat several diseases, including liver damage, just by injection into the bloodstream, without evidence of differentiation. The improvements were attributed to the organotrophic factors, low immunogenicity, immunomodulatory, and anti-inflammatory effects of MSCs, rather than their differentiation. The aim of the present study was to answer the question of whether the presence of BM-MSCs in the hepatic microenvironment will lead to their differentiation to functional hepatocyte-like cells. The hepatic microenvironment was mimicked in vitro by culture for 21 d with liver extract. The resulted cells expressed marker genes of the hepatic lineage including AFP, CK18, and Hnf4a. Functionally, they were able to detoxify ammonia into urea, to store glycogen as observed by PAS staining, and to synthesize glucose from pyruvate/lactate mixture. Phenotypically, the expression of MSC surface markers CD90 and CD105 decreased by differentiation. This evidenced differentiation into hepatocyte-like cells was accompanied by a downregulation of the stem cell marker genes sox2 and Nanog and the cell cycle regulatory genes ANAPC2, CDC2, Cyclin A1, and ABL1. The present results suggest a clear differentiation of BM-MSCs into functional hepatocyte-like cells by the extracted liver microenvironment. This differentiation is confirmed by a decrease in the stemness and mitotic activities. Tracking transplanted BM-MSCs and proving their in vivo differentiation remains to be elucidated.
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Affiliation(s)
- Manar Eissa
- Faculty of Science, Damietta University, New Damietta, 34517, Egypt
| | - Naglaa Elarabany
- Faculty of Science, Damietta University, New Damietta, 34517, Egypt
| | - Ayman Hyder
- Faculty of Science, Damietta University, New Damietta, 34517, Egypt.
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Chen L, Qin L, Liu X, Meng X. CTRP3 Alleviates Ox-LDL-Induced Inflammatory Response and Endothelial Dysfunction in Mouse Aortic Endothelial Cells by Activating the PI3K/Akt/eNOS Pathway. Inflammation 2020; 42:1350-1359. [PMID: 30887395 DOI: 10.1007/s10753-019-00996-1] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
C1q/tumor necrosis factor-related protein-3 (CTRP3) is a novel, certified, adipokine that beneficially regulates metabolism and inflammation in the cardiovascular system. Atherosclerotic plaque rupturing and secondary thrombosis cause vascular disorders, such as myocardial infarction and unstable angina. However, the underlying role of CTRP3 in atherosclerosis remains unclear. In this study, we aimed to elucidate whether and how CTRP3 ameliorates inflammation and endothelial dysfunction caused by oxidized low-density lipoprotein (ox-LDL). We first confirmed that CTRP3 expression was inhibited in ApoE-/- mice, compared to normal mice. Then, pcDNA-CTRP3 and siCTRP3 were transfected into mouse aortic endothelial cells after ox-LDL stimulation, and we observed that enhanced CTRP3 remarkably downregulated CRP, TNF-α, IL-6, CD40, and CD40L. We also observed that overexpression of CTRP3 elevated cell activity and decreased lactated hydrogenase release, accompanied by a marked reduction in cell apoptosis induced by ox-LDL. Meanwhile, overexpressed CTRP3 caused a decrease in Ang II, ICAM-1, and VCAM-1 expression, and it restored the balance between ET-1 and NO. Mechanism analysis confirmed that incremental CTRP3 upregulated p-PI3K, p-Akt, and p-eNOS expression, indicating that CTRP3 facilitated activation of the PI3K/Akt/eNOS pathway. On the contrary, siCTRP3 exerted the opposite effect to this activation. Blocking these pathways using LY294002 or L-NAME attenuated the protective role of CTRP3. Overall, these results suggest that CTRP3 can efficiently inhibit the inflammatory response and endothelial dysfunction induced by ox-LDL in mouse aortic endothelial cells, perhaps by activating the PI3K/Akt/eNOS pathway, indicating a promising strategy against atherosclerosis.
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Affiliation(s)
- Lei Chen
- Department of Critical Care Medicine, Gansu Provincial Hospital of TCM, No. 418, Guazhou Road, Qilihe District, Lanzhou City, 730050, Gansu, People's Republic of China.
| | - Lijun Qin
- Department of Cardiology, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, People's Republic of China
| | - Xin Liu
- Department of Rheumatic Osteopathology, Gansu Provincial Hospital of TCM, Lanzhou, 730050, Gansu, People's Republic of China
| | - Xiangyun Meng
- Central Laboratory, Gansu Provincial Hospital of TCM, Lanzhou, 730050, Gansu, People's Republic of China
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Colmegna I, Stochaj U. MSC - targets for atherosclerosis therapy. Aging (Albany NY) 2019; 11:285-286. [PMID: 30591619 PMCID: PMC6366979 DOI: 10.18632/aging.101735] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 12/17/2018] [Indexed: 12/12/2022]
Affiliation(s)
- Ines Colmegna
- Division of Rheumatology, Department of Medicine, McGill University, Montreal, QC, Canada
| | - Ursula Stochaj
- Department of Physiology, McGill University, Montreal, QC, Canada
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Mahdavi Gorabi A, Banach M, Reiner Ž, Pirro M, Hajighasemi S, Johnston TP, Sahebkar A. The Role of Mesenchymal Stem Cells in Atherosclerosis: Prospects for Therapy via the Modulation of Inflammatory Milieu. J Clin Med 2019; 8:E1413. [PMID: 31500373 PMCID: PMC6780166 DOI: 10.3390/jcm8091413] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 09/02/2019] [Accepted: 09/04/2019] [Indexed: 12/24/2022] Open
Abstract
Atherosclerosis is a chronic, inflammatory disease that mainly affects the arterial intima. The disease is more prevalent in middle-age and older individuals with one or more cardiovascular risk factors, including dyslipidemia, hypertension, diabetes, smoking, obesity, and others. The beginning and development of atherosclerosis has been associated with several immune components, including infiltration of inflammatory cells, monocyte/macrophage-derived foam cells, and inflammatory cytokines and chemokines. Mesenchymal stem cells (MSCs) originate from several tissue sources of the body and have self-renewal and multipotent differentiation characteristics. They also have immunomodulatory and anti-inflammatory properties. Recently, it was shown that MSCs have a regulatory role in plasma lipid levels. In addition, MSCs have shown to have promising potential in terms of treatment strategies for several diseases, including those with an inflammatory component. In this regard, transplantation of MSCs to patients with atherosclerosis has been proposed as a novel strategy in the treatment of this disease. In this review, we summarize the current advancements regarding MSCs for the treatment of atherosclerosis.
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Affiliation(s)
- Armita Mahdavi Gorabi
- Department of Basic and Clinical Research, Tehran Heart Center, Tehran University of Medical Sciences, Tehran 1411713138, Iran
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, 90-549 Lodz, Poland
- Polish Mother's Memorial Hospital Research Institute (PMMHRI), 93-338 Lodz, Poland
| | - Željko Reiner
- Department of Internal medicine, University Hospital Center Zagreb, Kišpatićeva 12, Zagreb 1000, Croatia
| | - Matteo Pirro
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, 06123 Perugia, Italy
| | - Saeideh Hajighasemi
- Department of Medical Biotechnology, Faculty of Paramedicine, Qazvin University of Medical Sciences, Qazvin 1531534199, Iran
| | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64110, USA
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad 91778-99191, Iran.
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad 91778-99191, Iran.
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 91778-99191, Iran.
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Bolte J, Vater C, Culla AC, Ahlfeld T, Nowotny J, Kasten P, Disch AC, Goodman SB, Gelinsky M, Stiehler M, Zwingenberger S. Two-step stem cell therapy improves bone regeneration compared to concentrated bone marrow therapy. J Orthop Res 2019; 37:1318-1328. [PMID: 30628121 DOI: 10.1002/jor.24215] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 12/26/2018] [Indexed: 02/04/2023]
Abstract
Adult stem cells are a promising tool to positively influence bone regeneration. Concentrated bone marrow therapy entails isolating osteoprogenitor cells during surgery with, however, only low cells yield. Two step stem cell therapy requires an additional harvesting procedure but generates high numbers of progenitor cells that facilitate osteogenic pre-differentiation. To further improve bone regeneration, stem cell therapy can be combined with growth factors from platelet rich plasma (PRP) or its lysate (PL) to potentially fostering vascularization. The aim of this study was to investigate the effects of bone marrow concentrate (BMC), osteogenic pre-differentiation of mesenchymal stromal cells (MSCs), and PL on bone regeneration and vascularization. Bone marrow from four different healthy human donors was used for either generation of BMC or for isolation of MSCs. Seventy-two mice were randomized to six groups (Control, PL, BMC, BMC + PL, pre-differentiated MSCs, pre-differentiated MSCs + PL). The influence of PL, BMC, and pre-differentiated MSCs was investigated systematically in a 2 mm femoral bone defect model. After a 6-week follow-up, the pre-differentiated MSCs + PL group showed the highest bone volume, highest grade of histological defect healing and highest number of bridged defects with measurable biomechanical stiffness. Using expanded and osteogenically pre-differentiated MSCs for treatment of a critical-size bone defect was favorable with regards to bone regeneration compared to treatment with cells from BMC. The addition of PL alone had no significant influence; therefore the role of PL for bone regeneration remains unclear. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1318-1328, 2019.
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Affiliation(s)
- Julia Bolte
- University Center of Orthopaedics and Traumatology, University Medicine Carl Gustav Carus Dresden, Fetscherstraße 74, TU Dresden 01307, Dresden, Germany
- Center for Translational Bone, Joint and Soft Tissue Research, University Medicine Carl Gustav Carus Dresden, TU Dresden, Dresden, Germany
| | - Corina Vater
- University Center of Orthopaedics and Traumatology, University Medicine Carl Gustav Carus Dresden, Fetscherstraße 74, TU Dresden 01307, Dresden, Germany
- Center for Translational Bone, Joint and Soft Tissue Research, University Medicine Carl Gustav Carus Dresden, TU Dresden, Dresden, Germany
| | - Anna Carla Culla
- University Center of Orthopaedics and Traumatology, University Medicine Carl Gustav Carus Dresden, Fetscherstraße 74, TU Dresden 01307, Dresden, Germany
- Center for Translational Bone, Joint and Soft Tissue Research, University Medicine Carl Gustav Carus Dresden, TU Dresden, Dresden, Germany
| | - Tilman Ahlfeld
- Center for Translational Bone, Joint and Soft Tissue Research, University Medicine Carl Gustav Carus Dresden, TU Dresden, Dresden, Germany
| | - Jörg Nowotny
- University Center of Orthopaedics and Traumatology, University Medicine Carl Gustav Carus Dresden, Fetscherstraße 74, TU Dresden 01307, Dresden, Germany
| | - Philip Kasten
- Orthopädisch Chirurgisches Centrum, Tübingen, Germany
| | - Alexander C Disch
- University Center of Orthopaedics and Traumatology, University Medicine Carl Gustav Carus Dresden, Fetscherstraße 74, TU Dresden 01307, Dresden, Germany
| | - Stuart B Goodman
- Department of Orthopaedic Surgery, Stanford University, Stanford, California
| | - Michael Gelinsky
- Center for Translational Bone, Joint and Soft Tissue Research, University Medicine Carl Gustav Carus Dresden, TU Dresden, Dresden, Germany
| | - Maik Stiehler
- University Center of Orthopaedics and Traumatology, University Medicine Carl Gustav Carus Dresden, Fetscherstraße 74, TU Dresden 01307, Dresden, Germany
- Center for Translational Bone, Joint and Soft Tissue Research, University Medicine Carl Gustav Carus Dresden, TU Dresden, Dresden, Germany
| | - Stefan Zwingenberger
- University Center of Orthopaedics and Traumatology, University Medicine Carl Gustav Carus Dresden, Fetscherstraße 74, TU Dresden 01307, Dresden, Germany
- Center for Translational Bone, Joint and Soft Tissue Research, University Medicine Carl Gustav Carus Dresden, TU Dresden, Dresden, Germany
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Effects of Cervical Rotatory Manipulation (CRM) on Carotid Atherosclerosis Plaque in Vulnerability: A Histological and Immunohistochemical Study Using Animal Model. BIOMED RESEARCH INTERNATIONAL 2019; 2019:3793840. [PMID: 30863777 PMCID: PMC6378770 DOI: 10.1155/2019/3793840] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 12/22/2018] [Accepted: 01/10/2019] [Indexed: 11/17/2022]
Abstract
Background The safety of cervical rotatory manipulation (CRM) is still controversial, especially in patients with carotid artery atherosclerosis (CAS). The study aimed to investigate the effects of CRM on carotid plaques in vulnerability. Methods 50 rabbits were randomly divided into four groups: model rabbits with CRM [CAS-CRM (n=15)]; model rabbits without CRM [CAS (n=15)]; normal rabbits with CRM [Normal-CRM (n=10)]; and Blank-control group (n=10). CAS disease models were induced by carotid artery balloon injury combined with a high-fat diet for 12 weeks. Then, CRM technique was performed in CAS-CRM and Normal-CRM groups for 3 weeks. In the end, determination of serum level of hs-CRP and Lp-PLA2, histological analysis under HE and Masson trichromic staining, and immunohistochemical analysis with CD34 and CD68 antibody were completed in order. Results Carotid stenosis rates on successful model rabbits ranged from 70% to 98%. The CAS-CRM group had an increased level of hs-CRP (P<0.05), in comparison with the CAS group, whereas effects were not significant between the Normal-CRM group and Blank-control group. In comparison with the CAS group, the positive expression of CD34 and CD68 in the CAS-CRM group increased significantly (P<0.05). Conclusion CRM therapy may increase the vulnerability of carotid plaque in rabbits with severe CAS.
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Li W, Huang H, Li L, Wang L, Li Y, Wang Y, Guo S, Li L, Wang D, He Y, Chen L. The Pathogenesis of Atherosclerosis Based on Human Signaling Networks and Stem Cell Expression Data. Int J Biol Sci 2018; 14:1678-1685. [PMID: 30416382 PMCID: PMC6216023 DOI: 10.7150/ijbs.27896] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 08/01/2018] [Indexed: 02/07/2023] Open
Abstract
Atherosclerosis is a common and complex disease, whose morbidity increased significantly. Here, an integrated approach was proposed to elucidate systematically the pathogenesis of atherosclerosis from a systems biology point of view. Two weighted human signaling networks were constructed based on atherosclerosis related gene expression data of stem cells. Then, 37 candidate Atherosclerosis-risk Modules were detected using four kinds of permutation tests. Five Atherosclerosis-risk Modules (three Absent Modules and two Emerging Modules) enriched in functions significantly associated with disease genes were identified and verified to be associated with the maintenance of normal biological process and the pathogenesis and development of atherosclerosis. Especially for Atherosclerosis-risk Emerging Module P96, it could distinguish between normal and disease samples by Supporting Vector Machine with the average expression value of the module as classification feature. These identified modules and their genes may act as potential atherosclerosis biomarkers. Our study would shed light on the signal transduction of atherosclerosis, and provide new insights to its pathogenesis from the perspective of stem cells.
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Affiliation(s)
- Wan Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China
| | - Hao Huang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China
| | - Lei Li
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Li Wang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China
| | - Yong Li
- Dean's Office, Harbin Medical University, Harbin, Heilongjiang, China
| | - Yahui Wang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China
| | - Shanshan Guo
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China
| | - Liansheng Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China
| | - Donghua Wang
- Department of general surgery, General Hospital of Heilongjiang Province Land Reclamation Bureau, 150088, Harbin, China
| | - Yuehan He
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China
| | - Lina Chen
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China
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StemBell therapy stabilizes atherosclerotic plaques after myocardial infarction. Cytotherapy 2018; 20:1143-1154. [DOI: 10.1016/j.jcyt.2018.05.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 05/11/2018] [Accepted: 05/14/2018] [Indexed: 01/10/2023]
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Gomes FLT, Maranhão RC, Tavares ER, Carvalho PO, Higuchi ML, Mattos FR, Pitta FG, Hatab SA, Kalil-Filho R, Serrano CV. Regression of Atherosclerotic Plaques of Cholesterol-Fed Rabbits by Combined Chemotherapy With Paclitaxel and Methotrexate Carried in Lipid Core Nanoparticles. J Cardiovasc Pharmacol Ther 2018; 23:561-569. [PMID: 29779420 DOI: 10.1177/1074248418778836] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
In previous studies, it was demonstrated that lipid core nanoparticles (LDE) resemble the low-density lipoprotein structure and carrying the antiproliferative agent paclitaxel (PTX) strongly reduced atherosclerosis lesions induced in rabbits by cholesterol feeding. Currently, the aim was to verify whether combining LDE-PTX treatment with methotrexate (MTX) associated with LDE (LDE-MTX) could accelerate the atherosclerosis regression attained with single LDE-PTX treatment, after withdrawing the cholesterol feeding. Thirty-eight rabbits were fed 1% cholesterol chow for 8 weeks. Six of these rabbits were then euthanized for analyses of the aorta (controls). In the remaining rabbits, cholesterol feeding was withdrawn, and those 32 animals were allocated to 3 groups submitted to different 8-week intravenous treatments, all once/week: LDE-PTX (n = 10; 4 mg/kg), LDE-PTX + LDE-MTX (n = 11; 4 mg/kg), and LDE-alone (n = 11). Rabbits were then euthanized and aortas were excised for morphometric, immunohistochemical, and gene expression analyses. After cholesterol feeding withdrawal, in comparison with LDE-alone group, both LDE-PTX and LDE-PTX + LDE-MTX treatments had the ability to increase the regression of plaque areas: -49% in LDE-PTX and -59% for LDE-PTX + LDE-MTX. However, only LDE-PTX + LDE-MTX treatment elicited reduction in the intima area, estimated in -57%. Macrophage presence in aortic lesions was reduced 48% by LDE-PTX and 43% by LDE-PTX + LDE-MTX treatment. Matrix metalloproteinase 9 was reduced by either LDE-PTX (74%) or LDE-PTX + LDE-MTX (78%). Tumor necrosis factor α gene expression was reduced 65% by LDE-PTX and 79% by LDE-PTX + LDE-MTX. In conclusion, treatment with LDE-PTX indeed accelerated plaque reduction after cholesterol feeding; LDE-PTX + LDE-MTX further increased this effect, without any observed toxicity. These results pave the way for the use of combined chemotherapy to achieve stronger effects on aggravated, highly inflamed atherosclerotic lesions.
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Affiliation(s)
- Fernando L T Gomes
- 1 Heart Institute (InCor) of the Medical School Hospital University of São Paulo, São Paulo, Brazil.,2 Hospital Cassiano Antônio de Moraes, Federal University of Espírito Santo, Espírito Santo, Brazil
| | - Raul C Maranhão
- 1 Heart Institute (InCor) of the Medical School Hospital University of São Paulo, São Paulo, Brazil.,3 Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Elaine R Tavares
- 1 Heart Institute (InCor) of the Medical School Hospital University of São Paulo, São Paulo, Brazil
| | - Priscila O Carvalho
- 1 Heart Institute (InCor) of the Medical School Hospital University of São Paulo, São Paulo, Brazil
| | - Maria L Higuchi
- 1 Heart Institute (InCor) of the Medical School Hospital University of São Paulo, São Paulo, Brazil
| | - Fernando R Mattos
- 1 Heart Institute (InCor) of the Medical School Hospital University of São Paulo, São Paulo, Brazil
| | - Fabio G Pitta
- 1 Heart Institute (InCor) of the Medical School Hospital University of São Paulo, São Paulo, Brazil
| | - Sergio A Hatab
- 2 Hospital Cassiano Antônio de Moraes, Federal University of Espírito Santo, Espírito Santo, Brazil
| | - Roberto Kalil-Filho
- 1 Heart Institute (InCor) of the Medical School Hospital University of São Paulo, São Paulo, Brazil
| | - Carlos V Serrano
- 1 Heart Institute (InCor) of the Medical School Hospital University of São Paulo, São Paulo, Brazil
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Zhang X, Huang F, Li W, Dang JL, Yuan J, Wang J, Zeng DL, Sun CX, Liu YY, Ao Q, Tan H, Su W, Qian X, Olsen N, Zheng SG. Human Gingiva-Derived Mesenchymal Stem Cells Modulate Monocytes/Macrophages and Alleviate Atherosclerosis. Front Immunol 2018; 9:878. [PMID: 29760701 PMCID: PMC5937358 DOI: 10.3389/fimmu.2018.00878] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2018] [Accepted: 04/09/2018] [Indexed: 12/15/2022] Open
Abstract
Atherosclerosis is the major cause of cardiovascular diseases. Current evidences indicate that inflammation is involved in the pathogenesis of atherosclerosis. Human gingiva-derived mesenchymal stem cells (GMSC) have shown anti-inflammatory and immunomodulatory effects on autoimmune and inflammatory diseases. However, the function of GMSC in controlling atherosclerosis is far from clear. The present study is aimed to elucidate the role of GMSC in atherosclerosis, examining the inhibition of GMSC on macrophage foam cell formation, and further determining whether GMSC could affect the polarization and activation of macrophages under different conditions. The results show that infusion of GMSC to AopE−/− mice significantly reduced the frequency of inflammatory monocytes/macrophages and decreased the plaque size and lipid deposition. Additionally, GMSC treatment markedly inhibited macrophage foam cell formation and reduced inflammatory macrophage activation, converting inflammatory macrophages to anti-inflammatory macrophages in vitro. Thus, our study has revealed a significant role of GMSC on modulating inflammatory monocytes/macrophages and alleviating atherosclerosis.
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Affiliation(s)
- Ximei Zhang
- Center for Clinic Immunology, Third Affiliated Hospital at Sun Yat-sen University, Guangzhou, China.,Division of Cardiology, Third Affiliated Hospital at Sun Yat-sen University, Guangzhou, China
| | - Feng Huang
- Center for Clinic Immunology, Third Affiliated Hospital at Sun Yat-sen University, Guangzhou, China
| | - Weixuan Li
- Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Jun-Long Dang
- Center for Clinic Immunology, Third Affiliated Hospital at Sun Yat-sen University, Guangzhou, China
| | - Jia Yuan
- Division of Stomatology, Third Affiliated Hospital at Sun Yat-sen University, Guangzhou, China
| | - Julie Wang
- Division of Rheumatology, Penn State Milton S. Hershey Medical Center, Hershey, PA, United States
| | - Dong-Lan Zeng
- Center for Clinic Immunology, Third Affiliated Hospital at Sun Yat-sen University, Guangzhou, China
| | - Can-Xing Sun
- Center for Clinic Immunology, Third Affiliated Hospital at Sun Yat-sen University, Guangzhou, China
| | - Yan-Ying Liu
- Division of Rheumatology, Peking University People's Hospital, Beijing, China
| | - Qian Ao
- Department of Regeneration, Chinese Medical University, Shenyang, China
| | - Hongmei Tan
- Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Wenru Su
- Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Xiaoxian Qian
- Division of Cardiology, Third Affiliated Hospital at Sun Yat-sen University, Guangzhou, China
| | - Nancy Olsen
- Division of Rheumatology, Penn State Milton S. Hershey Medical Center, Hershey, PA, United States
| | - Song Guo Zheng
- Division of Rheumatology, Penn State Milton S. Hershey Medical Center, Hershey, PA, United States
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Watanabe R, Sato Y, Ozawa N, Takahashi Y, Koba S, Watanabe T. Emerging Roles of Tumor Necrosis Factor-Stimulated Gene-6 in the Pathophysiology and Treatment of Atherosclerosis. Int J Mol Sci 2018; 19:E465. [PMID: 29401724 PMCID: PMC5855687 DOI: 10.3390/ijms19020465] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 01/22/2018] [Accepted: 01/30/2018] [Indexed: 02/06/2023] Open
Abstract
Tumor necrosis factor-stimulated gene-6 (TSG-6) is a 35-kDa glycoprotein that has been shown to exert anti-inflammatory effects in experimental models of arthritis, acute myocardial infarction, and acute cerebral infarction. Several lines of evidence have shed light on the pathophysiological roles of TSG-6 in atherosclerosis. TSG-6 suppresses inflammatory responses of endothelial cells, neutrophils, and macrophages as well as macrophage foam cell formation and vascular smooth muscle cell (VSMC) migration and proliferation. Exogenous TSG-6 infusion and endogenous TSG-6 attenuation with a neutralizing antibody for four weeks retards and accelerates, respectively, the development of aortic atherosclerotic lesions in ApoE-deficient mice. TSG-6 also decreases the macrophage/VSMC ratio (a marker of plaque instability) and promotes collagen fibers in atheromatous plaques. In patients with coronary artery disease (CAD), plasma TSG-6 levels are increased and TSG-6 is abundantly expressed in the fibrous cap within coronary atheromatous plaques, indicating that TSG-6 increases to counteract the progression of atherosclerosis and stabilize the plaque. These findings indicate that endogenous TSG-6 enhancement and exogenous TSG-6 replacement treatments are expected to emerge as new lines of therapy against atherosclerosis and related CAD. Therefore, this review provides support for the clinical utility of TSG-6 in the diagnosis and treatment of atherosclerotic cardiovascular diseases.
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Affiliation(s)
- Rena Watanabe
- Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji-City, Tokyo 192-0392, Japan.
| | - Yuki Sato
- Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji-City, Tokyo 192-0392, Japan.
| | - Nana Ozawa
- Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji-City, Tokyo 192-0392, Japan.
| | - Yui Takahashi
- Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji-City, Tokyo 192-0392, Japan.
| | - Shinji Koba
- Division of Cardiology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan.
| | - Takuya Watanabe
- Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji-City, Tokyo 192-0392, Japan.
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Comparisons of the therapeutic effects of three different routes of bone marrow mesenchymal stem cell transplantation in cerebral ischemic rats. Brain Res 2017; 1680:143-154. [PMID: 29274877 DOI: 10.1016/j.brainres.2017.12.017] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 12/12/2017] [Accepted: 12/13/2017] [Indexed: 01/19/2023]
Abstract
Bone marrow mesenchymal stem cells (BMSCs) are mainly administered via three routes: intra-arterial, intravenous and intracerebral. It has been reported that BMSC administration via each route ameliorates the functional deficits after cerebral ischemia. However, there have been no comparisons of the therapeutic benefits of BMSC administration through different delivery routes. In this study, we injected BMSCs into a rat model of transient middle cerebral artery occlusion (MCAO) through the intra-arterial, intravenous, or intracerebral route at day 7 after MCAO. Control animals received only the vehicle. Neurological function was assessed at post-ischemic days (PIDs) 1, 7, 14, 21, 28 and 35 using behavioral tests (modified Neurological Severity Score (mNSS) and the adhesive removal test). At PID 35, the rat brain tissues were processed for histochemical and immunohistochemical staining. Our results showed that BMSC transplantation via the intra-arterial, intravenous, and intracerebral routes induced greater improvement in neurological functions than the control treatments; furthermore, the intra-arterial route showed the greatest degree and speed of neurological functional recovery. Moreover, BMSCs treatment through each route enhanced reconstruction of axonal myelination in the area of the corpus callosum on the infarct side of the cerebral hemisphere, increased the expression of SYN and Ki-67, and decreased the expression of Nogo-A in the brain. These effects were more apparent in the intra-arterial group than in the intravenous and intracerebral groups. These data suggest that BMSCs transplantation, especially through intra-arterial delivery, can effectively improve neurological function intra-arterial. The underlying mechanism may include the promotion of synaptogenesis, endogenous cell proliferation, and axonal regeneration.
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Hamidian Jahromi S, Li Y, Davies JE. Effect of Tumor Necrosis Factor Alpha Dose and Exposure Time on Tumor Necrosis Factor-Induced Gene-6 Activation by Neonatal and Adult Mesenchymal Stromal Cells. Stem Cells Dev 2017; 27:44-54. [PMID: 29121823 DOI: 10.1089/scd.2017.0179] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Tumor necrosis factor alpha (TNF-α) induced protein 6 is a major anti-inflammatory mediator released by activated mesenchymal stromal cells (MSCs). Neonatal MSCs are considered more metabolically active than cells derived from adult tissues, and potentially less heterogeneous. We hypothesized that a TNF-α-activated neonatal MSC population [human umbilical cord perivascular cells (HUCPVCs)] would show an enhanced level of TSG-6 activation compared with adult bone marrow MSCs (BMMSCs). Thus, we stimulated HUCPVCs, and both human BMMSCs (hBMMSCs) and mouse BMMSCs (mBMMSCs) with 1, 10, 50, and 100 ng/mL of recombinant TNF-α over various exposure times. Supernatant, and total RNA, of the cells were collected for measurement of both TSG-6 RNA expression, and secreted TSG-6 protein. To compare gene levels, quantification was done by normalizing the expression levels of TSG-6 to the geometric mean of the three most stable reference genes, out of a cohort of 30 tested genes, using the Pfaffl method. We found that HUCPVCs exhibited both an enhanced and more rapid response to low dose (1 ng/mL) TNF-α exposure resulting in ∼11.5-fold increase in TSG-6 expression within the first 30 min. In contrast, hBMMSCs showed 2-fold increase by 1 h that increased to 9.5-fold with a higher (50 ng/mL) TNF-α exposure for the same time. mBMMSCs showed a two-fold increase after 24 h that was independent of TNF-α concentration. Thus, although TSG-6 expression level varied among donors, both hMSC populations exhibited enhanced TSG-6 upregulation, upon TNF-α stimulation, compared with mBMMSCs. In conclusion, HUCPVCs showed higher sensitivity, and a prompter response to TNF-α stimulation compared with hBMMSCs. Thus, neonatal MSCs may be a stronger candidate population than those derived from adult bone marrow to treat inflammatory diseases.
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Affiliation(s)
- Shiva Hamidian Jahromi
- 1 Institute of Biomaterials and Biomedical Engineering, University of Toronto , Toronto, Ontario, Canada .,2 Faculty of Dentistry, University of Toronto , Toronto, Ontario, Canada
| | - Yunqing Li
- 1 Institute of Biomaterials and Biomedical Engineering, University of Toronto , Toronto, Ontario, Canada
| | - John E Davies
- 1 Institute of Biomaterials and Biomedical Engineering, University of Toronto , Toronto, Ontario, Canada .,2 Faculty of Dentistry, University of Toronto , Toronto, Ontario, Canada
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Wang SK, Xie J, Green LA, McCready RA, Motaganahalli RL, Fajardo A, Babbey CC, Murphy MP. TSG-6 is highly expressed in human abdominal aortic aneurysms. J Surg Res 2017; 220:311-319. [PMID: 29180197 PMCID: PMC5864112 DOI: 10.1016/j.jss.2017.06.078] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 06/19/2017] [Accepted: 06/28/2017] [Indexed: 12/28/2022]
Abstract
BACKGROUND The formation of abdominal aortic aneurysms (AAA) is characterized by a dominance of proinflammatory forces that result in smooth muscle cell apoptosis, extracellular matrix degradation, and progressive diameter expansion. Additional defects in the antiinflammatory response may also play a role but have yet to be fully characterized. TSG-6 (TNF-stimulated gene-6) is a potent antiinflammatory protein involved in extracellular matrix stabilization and cell migration active in many pathological conditions. Here, we describe its role in AAA formation. METHODS Blood and/or aortic tissue samples were collected from organ donors, subjects undergoing elective AAA screening, and open surgical AAA repair. Aortic specimens collected were preserved for IHC or immediately assayed after tissue homogenization. Protein concentrations in tissue and plasma were assayed by ELISA. All immune cell populations were assayed using FACS. In vitro, macrophage polarization from monocytes was performed with young, healthy donor PBMCs. RESULTS TSG-6 was found to be abnormally elevated in both the plasma and aortic wall of patients with AAA compared with healthy and risk-factor matched non-AAA donors. We observed the highest tissue concentration of TSG-6 in the less-diseased proximal and distal shoulders compared with the central aspect of the aneurysm. IHC localized most TSG-6 to the tunica media with minor expression in the tunica adventitia of the aortic wall. Higher concentrations of both M1 and M2 macrophages where also observed, however M1/M2 ratios were unchanged from healthy controls. We observed no difference in M1/M2 ratios in the peripheral blood of risk-factor matched non-AAA and AAA patients. Interesting, TSG-6 inhibited the polarization of the antiinflammatory M2 phenotype in vitro. CONCLUSIONS AAA formation results from an imbalance of inflammatory forces causing aortic wall infiltration of mononuclear cells leading to the vessel breakdown. In the AAA condition, we report an elevation of TSG-6 expression in both the aortic wall and the peripheral circulation.
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Affiliation(s)
- S Keisin Wang
- Indiana University School of Medicine, Richard Roudebush Veteran Affairs Medical Center, Department of Surgery, Division of Vascular Surgery and Center for Aortic Disease, Indianapolis, Indiana
| | - Jie Xie
- Indiana University School of Medicine, Richard Roudebush Veteran Affairs Medical Center, Department of Surgery, Division of Vascular Surgery and Center for Aortic Disease, Indianapolis, Indiana
| | - Linden A Green
- Indiana University School of Medicine, Richard Roudebush Veteran Affairs Medical Center, Department of Surgery, Division of Vascular Surgery and Center for Aortic Disease, Indianapolis, Indiana
| | - Robert A McCready
- Indiana University School of Medicine, Richard Roudebush Veteran Affairs Medical Center, Department of Surgery, Division of Vascular Surgery and Center for Aortic Disease, Indianapolis, Indiana
| | - Raghu L Motaganahalli
- Indiana University School of Medicine, Richard Roudebush Veteran Affairs Medical Center, Department of Surgery, Division of Vascular Surgery and Center for Aortic Disease, Indianapolis, Indiana
| | - Andres Fajardo
- Indiana University School of Medicine, Richard Roudebush Veteran Affairs Medical Center, Department of Surgery, Division of Vascular Surgery and Center for Aortic Disease, Indianapolis, Indiana
| | - Clifford C Babbey
- Indiana University School of Medicine, Richard Roudebush Veteran Affairs Medical Center, Department of Surgery, Division of Vascular Surgery and Center for Aortic Disease, Indianapolis, Indiana
| | - Michael P Murphy
- Indiana University School of Medicine, Richard Roudebush Veteran Affairs Medical Center, Department of Surgery, Division of Vascular Surgery and Center for Aortic Disease, Indianapolis, Indiana.
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Kizilay Mancini O, Lora M, Cuillerier A, Shum-Tim D, Hamdy R, Burelle Y, Servant MJ, Stochaj U, Colmegna I. Mitochondrial Oxidative Stress Reduces the Immunopotency of Mesenchymal Stromal Cells in Adults With Coronary Artery Disease. Circ Res 2017; 122:255-266. [PMID: 29113965 DOI: 10.1161/circresaha.117.311400] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Revised: 10/31/2017] [Accepted: 11/06/2017] [Indexed: 12/25/2022]
Abstract
RATIONALE Mesenchymal stromal cells (MSCs) are promising therapeutic strategies for coronary artery disease; however, donor-related variability in cell quality is a main cause of discrepancies in preclinical studies. In vitro, MSCs from individuals with coronary artery disease have reduced ability to suppress activated T-cells. The mechanisms underlying the altered immunomodulatory capacity of MSCs in the context of atherosclerosis remain elusive. OBJECTIVE The aim of this study was to assess the role of mitochondrial dysfunction in the impaired immunomodulatory properties of MSCs from patients with atherosclerosis. METHODS AND RESULTS Adipose tissue-derived MSCs were isolated from atherosclerotic (n=38) and nonatherosclerotic (n=42) donors. MSCs:CD4+T-cell suppression was assessed in allogeneic coculture systems. Compared with nonatherosclerotic-MSCs, atherosclerotic-MSCs displayed higher levels of both intracellular (P=0.006) and mitochondrial (P=0.03) reactive oxygen species reflecting altered mitochondrial function. The increased mitochondrial reactive oxygen species levels of atherosclerotic-MSCs promoted a phenotypic switch characterized by enhanced glycolysis and an altered cytokine secretion (interleukin-6 P<0.0001, interleukin-8/C-X-C motif chemokine ligand 8 P=0.04, and monocyte chemoattractant protein-1/chemokine ligand 2 P=0.01). Furthermore, treatment of atherosclerotic-MSCs with the reactive oxygen species scavenger N-acetyl-l-cysteine reduced the levels of interleukin-6, interleukin-8/C-X-C motif chemokine ligand 8, and monocyte chemoattractant protein-1/chemokine ligand 2 in the MSC secretome and improved MSCs immunosuppressive capacity (P=0.03). CONCLUSIONS An impaired mitochondrial function of atherosclerotic-MSCs underlies their altered secretome and reduced immunopotency. Interventions aimed at restoring the mitochondrial function of atherosclerotic-MSCs improve their in vitro immunosuppressive ability and may translate into enhanced therapeutic efficiency.
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Affiliation(s)
- Ozge Kizilay Mancini
- From the Department of Anatomy and Cell Biology (O.K.M.), Department of Physiology (U.S.), Divisions of Cardiac Surgery and Surgical Research, Department of Surgery (D.S.T.), Division of Rheumatology, Department of Medicine (I.C., M.L.) McGill University, Montreal, Quebec, Canada; Shriners Hospital for Children (R.H.); Department of Cellular and Molecular Medicine, Faculty of Medicine (A.C., Y.B.), University of Ottawa, Ontario, Canada; and Faculty of Pharmacy (M.J.S.), University of Montreal, Quebec, Canada
| | - Maximilien Lora
- From the Department of Anatomy and Cell Biology (O.K.M.), Department of Physiology (U.S.), Divisions of Cardiac Surgery and Surgical Research, Department of Surgery (D.S.T.), Division of Rheumatology, Department of Medicine (I.C., M.L.) McGill University, Montreal, Quebec, Canada; Shriners Hospital for Children (R.H.); Department of Cellular and Molecular Medicine, Faculty of Medicine (A.C., Y.B.), University of Ottawa, Ontario, Canada; and Faculty of Pharmacy (M.J.S.), University of Montreal, Quebec, Canada
| | - Alexanne Cuillerier
- From the Department of Anatomy and Cell Biology (O.K.M.), Department of Physiology (U.S.), Divisions of Cardiac Surgery and Surgical Research, Department of Surgery (D.S.T.), Division of Rheumatology, Department of Medicine (I.C., M.L.) McGill University, Montreal, Quebec, Canada; Shriners Hospital for Children (R.H.); Department of Cellular and Molecular Medicine, Faculty of Medicine (A.C., Y.B.), University of Ottawa, Ontario, Canada; and Faculty of Pharmacy (M.J.S.), University of Montreal, Quebec, Canada
| | - Dominique Shum-Tim
- From the Department of Anatomy and Cell Biology (O.K.M.), Department of Physiology (U.S.), Divisions of Cardiac Surgery and Surgical Research, Department of Surgery (D.S.T.), Division of Rheumatology, Department of Medicine (I.C., M.L.) McGill University, Montreal, Quebec, Canada; Shriners Hospital for Children (R.H.); Department of Cellular and Molecular Medicine, Faculty of Medicine (A.C., Y.B.), University of Ottawa, Ontario, Canada; and Faculty of Pharmacy (M.J.S.), University of Montreal, Quebec, Canada
| | - Reggie Hamdy
- From the Department of Anatomy and Cell Biology (O.K.M.), Department of Physiology (U.S.), Divisions of Cardiac Surgery and Surgical Research, Department of Surgery (D.S.T.), Division of Rheumatology, Department of Medicine (I.C., M.L.) McGill University, Montreal, Quebec, Canada; Shriners Hospital for Children (R.H.); Department of Cellular and Molecular Medicine, Faculty of Medicine (A.C., Y.B.), University of Ottawa, Ontario, Canada; and Faculty of Pharmacy (M.J.S.), University of Montreal, Quebec, Canada
| | - Yan Burelle
- From the Department of Anatomy and Cell Biology (O.K.M.), Department of Physiology (U.S.), Divisions of Cardiac Surgery and Surgical Research, Department of Surgery (D.S.T.), Division of Rheumatology, Department of Medicine (I.C., M.L.) McGill University, Montreal, Quebec, Canada; Shriners Hospital for Children (R.H.); Department of Cellular and Molecular Medicine, Faculty of Medicine (A.C., Y.B.), University of Ottawa, Ontario, Canada; and Faculty of Pharmacy (M.J.S.), University of Montreal, Quebec, Canada
| | - Marc J Servant
- From the Department of Anatomy and Cell Biology (O.K.M.), Department of Physiology (U.S.), Divisions of Cardiac Surgery and Surgical Research, Department of Surgery (D.S.T.), Division of Rheumatology, Department of Medicine (I.C., M.L.) McGill University, Montreal, Quebec, Canada; Shriners Hospital for Children (R.H.); Department of Cellular and Molecular Medicine, Faculty of Medicine (A.C., Y.B.), University of Ottawa, Ontario, Canada; and Faculty of Pharmacy (M.J.S.), University of Montreal, Quebec, Canada
| | - Ursula Stochaj
- From the Department of Anatomy and Cell Biology (O.K.M.), Department of Physiology (U.S.), Divisions of Cardiac Surgery and Surgical Research, Department of Surgery (D.S.T.), Division of Rheumatology, Department of Medicine (I.C., M.L.) McGill University, Montreal, Quebec, Canada; Shriners Hospital for Children (R.H.); Department of Cellular and Molecular Medicine, Faculty of Medicine (A.C., Y.B.), University of Ottawa, Ontario, Canada; and Faculty of Pharmacy (M.J.S.), University of Montreal, Quebec, Canada
| | - Inés Colmegna
- From the Department of Anatomy and Cell Biology (O.K.M.), Department of Physiology (U.S.), Divisions of Cardiac Surgery and Surgical Research, Department of Surgery (D.S.T.), Division of Rheumatology, Department of Medicine (I.C., M.L.) McGill University, Montreal, Quebec, Canada; Shriners Hospital for Children (R.H.); Department of Cellular and Molecular Medicine, Faculty of Medicine (A.C., Y.B.), University of Ottawa, Ontario, Canada; and Faculty of Pharmacy (M.J.S.), University of Montreal, Quebec, Canada.
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Shu JE, Ying ML, Chen XR, Hua JJ, Fu JT, Xia XM, Pan YH, Jiang Y. Prognostic value of high-resolution magnetic resonance imaging in evaluating carotid atherosclerotic plaque in patients with ischemic stroke. Medicine (Baltimore) 2017; 96:e8515. [PMID: 29137053 PMCID: PMC5690746 DOI: 10.1097/md.0000000000008515] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Ischemic stroke (IS) is a devastating occurrence affecting millions worldwide. This study aimed to evaluate the prognostic value of high-resolution magnetic resonance imaging (HRMRI) in assessing carotid atherosclerotic plaque in IS patients. METHODS Between January 2013 and March 2015, 338 IS patients were recruited for the investigative purposes of the study. All participants of the study underwent an HRMRI inspection procedure after being admitted into the hospital. During this study, we systematically analyzed and measured various types of fibrous caps, lipid compositions, and plaque lipid ratios. Univariate and multivariate logistic regression analyses were performed for predicting prognosis of IS patients. A receiver-operating characteristic (ROC) curve was employed to determine the accuracy of the IS prognosis. RESULTS The percentage of type I fibrous caps exhibited significant decrease, while the percentage of type III fibrous caps, lipid compositions, and lipid ratios all displayed increase. The results of the univariate analysis indicated that age, hypertension, hyperlipidemia, treatment regimens, fibrous cap type, plaque type, lipid composition, and lipid ratio shared a correlation in regards to the poor prognosis of IS patients. Multivariate logistic regression analysis demonstrated that the prognosis of IS patients was not necessarily dependent on fibrous cap type, plaque type, or age. ROC curves revealed that the HRMRI possessed a strong predicative ability in relation to the identification of the prognosis of IS patients through factors such as type of plaque and fibrous caps determination. CONCLUSION Our study conclusively intimated the promise of HRMRI as an evaluative tool for the determination of carotid atherosclerotic plaques in patients with IS.
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Mistriotis P, Andreadis ST. Vascular aging: Molecular mechanisms and potential treatments for vascular rejuvenation. Ageing Res Rev 2017; 37:94-116. [PMID: 28579130 DOI: 10.1016/j.arr.2017.05.006] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2017] [Revised: 05/22/2017] [Accepted: 05/25/2017] [Indexed: 12/14/2022]
Abstract
Aging is the main risk factor contributing to vascular dysfunction and the progression of vascular diseases. In this review, we discuss the causes and mechanisms of vascular aging at the tissue and cellular level. We focus on Endothelial Cell (EC) and Smooth Muscle Cell (SMC) aging due to their critical role in mediating the defective vascular phenotype. We elaborate on two categories that contribute to cellular dysfunction: cell extrinsic and intrinsic factors. Extrinsic factors reflect systemic or environmental changes which alter EC and SMC homeostasis compromising vascular function. Intrinsic factors induce EC and SMC transformation resulting in cellular senescence. Replenishing or rejuvenating the aged/dysfunctional vascular cells is critical to the effective repair of the vasculature. As such, this review also elaborates on recent findings which indicate that stem cell and gene therapies may restore the impaired vascular cell function, reverse vascular aging, and prolong lifespan.
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Affiliation(s)
- Panagiotis Mistriotis
- Bioengineering Laboratory, Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Amherst, NY 14260-4200, USA
| | - Stelios T Andreadis
- Bioengineering Laboratory, Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Amherst, NY 14260-4200, USA; Department of Biomedical Engineering, University at Buffalo, The State University of New York, Amherst, NY 14260-4200, USA; Center of Excellence in Bioinformatics and Life Sciences, Buffalo, NY 14203, USA.
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Li F, Guo X, Chen SY. Function and Therapeutic Potential of Mesenchymal Stem Cells in Atherosclerosis. Front Cardiovasc Med 2017; 4:32. [PMID: 28589127 PMCID: PMC5438961 DOI: 10.3389/fcvm.2017.00032] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 05/01/2017] [Indexed: 12/24/2022] Open
Abstract
Atherosclerosis is a complicated disorder and largely attributable to dyslipidaemia and chronic inflammation. Despite therapeutic advances over past decades, atherosclerosis remains the leading cause of mortality worldwide. Due to their capability of immunomodulation and tissue regeneration, mesenchymal stem cells (MSCs) have evolved as an attractive therapeutic agent in various diseases including atherosclerosis. Accumulating evidences support the protective role of MSCs in all stages of atherosclerosis. In this review, we highlight the current understanding of MSCs including their characteristics such as molecular markers, tissue distribution, migratory property, immune-modulatory competence, etc. We also summarize MSC functions in animal models of atherosclerosis. MSC transplantation is able to modulate cytokine and chemokine secretion, reduce endothelial dysfunction, promote regulatory T cell function, decrease dyslipidemia, and stabilize vulnerable plaques during atherosclerosis development. In addition, MSCs may migrate to lesions where they develop into functional cells during atherosclerosis formation. Finally, the perspectives of MSCs in clinical atherosclerosis therapy are discussed.
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Affiliation(s)
- Feifei Li
- Department of Physiology & Pharmacology, University of Georgia, Athens, GA, USA.,The Department of Cardiovascular Surgery, Union Hospital, Wuhan, China
| | - Xia Guo
- Department of Physiology & Pharmacology, University of Georgia, Athens, GA, USA
| | - Shi-You Chen
- Department of Physiology & Pharmacology, University of Georgia, Athens, GA, USA
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