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Tariq H, Bukhari SZ, An R, Dong J, Ihsan A, Younis MR. Stem cell-derived exosome delivery systems for treating atherosclerosis: The new frontier of stem cell therapy. Mater Today Bio 2025; 30:101440. [PMID: 39866781 PMCID: PMC11758955 DOI: 10.1016/j.mtbio.2024.101440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 12/14/2024] [Accepted: 12/30/2024] [Indexed: 01/28/2025] Open
Abstract
Cardiovascular diseases (CVDs) are a leading cause of mortality worldwide. As a chronic inflammatory disease with a complicated pathophysiology marked by abnormal lipid metabolism and arterial plaque formation, atherosclerosis is a major contributor to CVDs and can induce abrupt cardiac events. The discovery of exosomes' role in intercellular communication has sparked a great deal of interest in them recently. Exosomes are involved in strategic phases of the onset and development of atherosclerosis because they have been identified to control pathophysiologic pathways including inflammation, angiogenesis, or senescence. This review investigates the potential role of stem cell-derived exosomes in atherosclerosis management. We briefly introduced atherosclerosis and stem cell therapy including stem cell-derived exosomes. The biogenesis of exosomes along with their secretion and isolation have been elaborated. The design engineering of exosomes has been summarized to present how drug loading and surface modification with targeting ligands can improve the therapeutic and targeting capacity of exosomes, demonstrating atheroprotective action. Moreover, the mechanism of action (endothelial dysfunction, reduction of dyslipidemia, macrophage polarization, vascular calcification, and angiogenesis) of drug-loaded exosomes to treat atherosclerosis has been discussed in detail. In the end, a comparative and balanced viewpoint has been given regarding the current challenges and potential solutions to advance exosome engineering for cardiovascular therapeutic applications.
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Affiliation(s)
- Hassan Tariq
- Department of Molecular, Cell and Developmental Biology, University of California - Los Angeles, Los Angeles, CA, 90095, USA
| | - Syeda Zunaira Bukhari
- National Institute for Biotechnology and Genetic Engineering College, Pakistan Institute of Engineering and Applied Sciences (NIBGE-C, PIEAS), Faisalabad, Pakistan
| | - Ruibing An
- Institute of Optical Functional Materials for Biomedical Imaging, School of Chemistry and Pharmaceutical Engineering, Shandong First Medical University & Shandong Academy of Medical Science, Taian, Shandong, 271016, PR China
| | - Jian Dong
- Institute of Optical Functional Materials for Biomedical Imaging, School of Chemistry and Pharmaceutical Engineering, Shandong First Medical University & Shandong Academy of Medical Science, Taian, Shandong, 271016, PR China
| | - Ayesha Ihsan
- National Institute for Biotechnology and Genetic Engineering College, Pakistan Institute of Engineering and Applied Sciences (NIBGE-C, PIEAS), Faisalabad, Pakistan
| | - Muhammad Rizwan Younis
- Institute of Optical Functional Materials for Biomedical Imaging, School of Chemistry and Pharmaceutical Engineering, Shandong First Medical University & Shandong Academy of Medical Science, Taian, Shandong, 271016, PR China
- Department of Chemical and Biomolecular Engineering, University of California - Los Angeles, Los Angeles, CA, 90095, USA
- Department of Molecular, Cell and Developmental Biology, University of California - Los Angeles, Los Angeles, CA, 90095, USA
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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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Galhom RA, Ali SNS, El-Fark MMO, Ali MHM, Hussein HH. Assessment of therapeutic efficacy of adipose tissue-derived mesenchymal stem cells administration in hyperlipidemia-induced aortic atherosclerosis in adult male albino rats. Tissue Cell 2024; 90:102498. [PMID: 39079452 DOI: 10.1016/j.tice.2024.102498] [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: 06/20/2024] [Revised: 07/21/2024] [Accepted: 07/24/2024] [Indexed: 09/03/2024]
Abstract
Atherosclerosis (AS) is a common disease seriously detrimental to human health. AS is a chronic progressive disease related to inflammatory reactions. The present study aimed to characterize and evaluate the effects of adipose tissue stem cells (ADSCs) in high-fat diet-induced atherosclerosis in a rat model. The present study comprises thirty-six rats and they were divided into three groups: the control group, the high-fat diet (HFD) group; which received a high-fat diet, and the high-fat diet + stem cells (HFD+SC) group; which was fed with a high-fat diet along with the administration of intravenous ADSCs. Food was given to the animals for 20 weeks to establish dyslipidemia models. After 20 weeks, animals were sacrificed by cervical dislocation; blood was collected to measure total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL); aortae were collected to detect morphologic changes. Rats of the HFD group showed a significant increase in body weight (B.Wt), altered lipid profile increased expression of inducible nitric oxide synthase (iNOS), and decreased expression of endothelial nitric oxide synthase (eNOS). However, in HFD+SC there was a significant decrease in body weight gain and an improvement in lipid profile. Histopathological and ultrastructural variations observed in the aorta of the HFD group when treated with ADSCs showed preserved normal histological architecture and reduced atherosclerosis compared with the HFD group. This was evidenced by laboratory, histological, immunohistochemical, and morphometric studies. Thus, ADSCs reduced TC, TG, and LDL, reduced the expression of iNOS, and increased the expression of eNOS. The high-fat diet was likely to cause damage to the wall of blood vessels. Systemically transplanted ADSCs could home to the aorta, and further protect the aorta from HFD-induced damage.
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Affiliation(s)
- Rania A Galhom
- Department of Human Anatomy and Embryology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt; Department of Human Anatomy and Embryology, Faculty of Medicine, Badr University in Cairo (BUC), Egypt.
| | - Saleh Nasser Saleh Ali
- Department of Human Anatomy and Embryology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt; Department of Human Anatomy and Embryology, Faculty of Medicine and Health Sciences, Thamar University, Thamar, Yemen.
| | - Magdy Mohamed Omar El-Fark
- Department of Human Anatomy and Embryology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
| | - Mona Hassan Mohammed Ali
- Department of Human Anatomy and Embryology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
| | - Hoda Hassan Hussein
- Department of Human Anatomy and Embryology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
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Korn A, Simsek S, Fiet MD, Waas IS, Niessen HW, Krijnen PA. Application of adipose tissue-derived stem cell therapy with a clinically relevant dose does not significantly affect atherosclerotic plaque characteristics in a streptozotocin-induced hyperglycaemia mouse model. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY PLUS 2024; 9:100083. [PMID: 39803590 PMCID: PMC11708420 DOI: 10.1016/j.jmccpl.2024.100083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 07/08/2024] [Indexed: 01/16/2025]
Abstract
Aims Diabetes mellitus (DM) induces increased inflammation of atherosclerotic plaques, resulting in elevated plaque instability. Mesenchymal stem cell (MSC) therapy was shown to decrease plaque size and increase stability in non-DM animal models. We now studied the effect of MSC therapy in a streptozotocin-induced hyperglycaemia mouse model using a clinically relevant dose of adipose tissue-derived MSCs (ASCs). Methods Hyperglycaemia was induced in male C57BL/6 ApoE-/- mice (n=24) via intraperitoneal streptozotocin (STZ) injection (0.05 mg/g bodyweight) for 5 consecutive days. 16 weeks after the first STZ injection, the mice received either 100,000 ASCs (n=9) or vehicle (n=14) intravenously. The effects of ASC treatment on the size and stability of aortic root atherosclerotic plaques were determined 4 weeks post-treatment via (immuno)histochemical analyses. Furthermore, plasma monocyte subsets within 3 days pre- and 3 days post-treatment, and 4 weeks post-treatment, were studied. Results ASC treatment did not significantly affect atherosclerotic plaque size or intra-plaque inflammation. Although ASC-treated mice had a higher percentage of intra-plaque fibrosis (42.5±3.3%) compared to vehicle-treated mice (37.6±6.8%, p=0.07), this did not reach significance. Additionally, although differences in the percentages of circulating pro- and anti-inflammatory monocytes were observed after ASC treatment compared to pre-treatment (p=0.005), their levels did not differ significantly at any time point compared to vehicle-treated mice. Conclusions ASC treatment with a clinically relevant dose did not significantly affect atherosclerotic plaque size or intra-plaque inflammation in a hyperglycaemia mouse model. Despite a borderline significant improvement in intraplaque fibrotic content, the potential of ASC treatment on atherosclerotic plaque stability in a diabetic environment remains to be determined.
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Affiliation(s)
- Amber Korn
- Department of Pathology, Amsterdam University Medical Centres (AUMC), Location VUmc, Amsterdam, the Netherlands
- Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
| | - Suat Simsek
- Department of Internal Medicine, Northwest Clinics, Alkmaar, the Netherlands
- Department of Internal Medicine, AUMC, Location VUmc, Amsterdam, the Netherlands
| | - Mitchell D. Fiet
- Department of Pathology, Amsterdam University Medical Centres (AUMC), Location VUmc, Amsterdam, the Netherlands
- Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
| | | | - Hans W.M. Niessen
- Department of Pathology, Amsterdam University Medical Centres (AUMC), Location VUmc, Amsterdam, the Netherlands
- Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
- Department of Cardiac Surgery, AUMC, Location VUmc, Amsterdam, the Netherlands
| | - Paul A.J. Krijnen
- Department of Pathology, Amsterdam University Medical Centres (AUMC), Location VUmc, Amsterdam, the Netherlands
- Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
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Wang Z, Zhang G, Hu S, Fu M, Zhang P, Zhang K, Hao L, Chen S. Research progress on the protective effect of hormones and hormone drugs in myocardial ischemia-reperfusion injury. Biomed Pharmacother 2024; 176:116764. [PMID: 38805965 DOI: 10.1016/j.biopha.2024.116764] [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: 02/21/2024] [Revised: 05/05/2024] [Accepted: 05/17/2024] [Indexed: 05/30/2024] Open
Abstract
Ischemic heart disease (IHD) is a condition where the heart muscle does not receive enough blood flow, leading to cardiac dysfunction. Restoring blood flow to the coronary artery is an effective clinical therapy for myocardial ischemia. This strategy helps lower the size of the myocardial infarction and improves the prognosis of patients. Nevertheless, if the disrupted blood flow to the heart muscle is restored within a specific timeframe, it leads to more severe harm to the previously deprived heart tissue. This condition is referred to as myocardial ischemia/reperfusion injury (MIRI). Until now, there is a dearth of efficacious strategies to prevent and manage MIRI. Hormones are specialized substances that are produced directly into the circulation by endocrine organs or tissues in humans and animals, and they have particular effects on the body. Hormonal medications utilize human or animal hormones as their active components, encompassing sex hormones, adrenaline medications, thyroid hormone medications, and others. While several studies have examined the preventive properties of different endocrine hormones, such as estrogen and hormone analogs, on myocardial injury caused by ischemia-reperfusion, there are other hormone analogs whose mechanisms of action remain unexplained and whose safety cannot be assured. The current study is on hormones and hormone medications, elucidating the mechanism of hormone pharmaceuticals and emphasizing the cardioprotective effects of different endocrine hormones. It aims to provide guidance for the therapeutic use of drugs and offer direction for the examination of MIRI in clinical therapy.
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Affiliation(s)
- Zhongyi Wang
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China
| | - Gaojiang Zhang
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China
| | - Shan Hu
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China
| | - Meilin Fu
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China
| | - Pingyuan Zhang
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China
| | - Kuo Zhang
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China
| | - Liying Hao
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China.
| | - Sichong Chen
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China.
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Duan H, Tao N, Lv L, Yan KX, You YG, Mao Z, Wang CY, Li X, Jin JY, Wu CT, Wang H. Hepatocyte growth factor enhances the ability of dental pulp stem cells to ameliorate atherosclerosis in apolipoprotein E-knockout mice. World J Stem Cells 2024; 16:575-590. [PMID: 38817328 PMCID: PMC11135256 DOI: 10.4252/wjsc.v16.i5.575] [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: 01/18/2024] [Revised: 03/18/2024] [Accepted: 04/09/2024] [Indexed: 05/24/2024] Open
Abstract
BACKGROUND Atherosclerosis (AS), a chronic inflammatory disease of blood vessels, is a major contributor to cardiovascular disease. Dental pulp stem cells (DPSCs) are capable of exerting immunomodulatory and anti-inflammatory effects by secreting cytokines and exosomes and are widely used to treat autoimmune and inflammation-related diseases. Hepatocyte growth factor (HGF) is a pleiotropic cytokine that plays a key role in many inflammatory and autoimmune diseases. AIM To modify DPSCs with HGF (DPSC-HGF) and evaluate the therapeutic effect of DPSC-HGF on AS using an apolipoprotein E-knockout (ApoE-/-) mouse model and an in vitro cellular model. METHODS ApoE-/- mice were fed with a high-fat diet (HFD) for 12 wk and injected with DPSC-HGF or Ad-Null modified DPSCs (DPSC-Null) through tail vein at weeks 4, 7, and 11, respectively, and the therapeutic efficacy and mechanisms were analyzed by histopathology, flow cytometry, lipid and glucose measurements, real-time reverse transcription polymerase chain reaction (RT-PCR), and enzyme-linked immunosorbent assay at the different time points of the experiment. An in vitro inflammatory cell model was established by using RAW264.7 cells and human aortic endothelial cells (HAOECs), and indirect co-cultured with supernatant of DPSC-Null (DPSC-Null-CM) or DPSC-HGF-CM, and the effect and mechanisms were analyzed by flow cytometry, RT-PCR and western blot. Nuclear factor-κB (NF-κB) activators and inhibitors were also used to validate the related signaling pathways. RESULTS DPSC-Null and DPSC-HGF treatments decreased the area of atherosclerotic plaques and reduced the expression of inflammatory factors, and the percentage of macrophages in the aorta, and DPSC-HGF treatment had more pronounced effects. DPSCs treatment had no effect on serum lipoprotein levels. The FACS results showed that DPSCs treatment reduced the percentages of monocytes, neutrophils, and M1 macrophages in the peripheral blood and spleen. DPSC-Null-CM and DPSC-HGF-CM reduced adhesion molecule expression in tumor necrosis factor-α stimulated HAOECs and regulated M1 polarization and inflammatory factor expression in lipopolysaccharide-induced RAW264.7 cells by inhibiting the NF-κB signaling pathway. CONCLUSION This study suggested that DPSC-HGF could more effectively ameliorate AS in ApoE-/- mice on a HFD, and could be of greater value in stem cell-based treatments for AS.
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Affiliation(s)
- Han Duan
- School of Life Sciences, Hebei University, Baoding 071002, Hebei Province, China
| | - Ning Tao
- Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Lin Lv
- Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Kai-Xin Yan
- Department of Cardiology, The Sixth Medical Centre, Chinese People's Liberation Army General Hospital, Beijing 100037, China
| | - Yong-Gang You
- Department of Orthopaedics, The Fourth Medical Centre, Chinese People's Liberation Army General Hospital, Beijing 100853, China
| | - Zhuang Mao
- Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Chang-Yao Wang
- School of Life Sciences, Hebei University, Baoding 071002, Hebei Province, China
| | - Xue Li
- Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Jia-Yan Jin
- Third Cadet Regiment, School of Basic Medical Science, Air Force Medical University, Xi'an 710032, Shaanxi Province, China
| | - Chu-Tse Wu
- Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Hua Wang
- School of Life Sciences, Hebei University, Baoding 071002, Hebei Province, China
- Beijing Institute of Radiation Medicine, Beijing 100850, China.
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Zhang N, Luo Y, Shao J, Sun H, Ma K, Gao X. Exosomal long non-coding RNA AU020206 alleviates macrophage pyroptosis in atherosclerosis by suppressing CEBPB-mediated NLRP3 transcription. Exp Cell Res 2024; 438:114054. [PMID: 38657723 DOI: 10.1016/j.yexcr.2024.114054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 04/19/2024] [Accepted: 04/20/2024] [Indexed: 04/26/2024]
Abstract
Recent studies have suggested exosomes (EXO) as potential therapeutic tools for cardiovascular diseases, including atherosclerosis (AS). This study investigates the function of bone marrow stem cell (BMSC)-derived exosomes (EXO) on macrophage pyroptosis in AS and explores the associated mechanism. BMSC-EXO were isolated from healthy mice and identified. RAW264.7 cells (mouse macrophages) were exposed to oxLDL to simulate an AS condition. BMSC-EXO treatment enhanced viability and reduced lactate dehydrogenase release of macrophages. An animal model of AS was established using ApoE-/- mice. BMSC-EXO treatment suppressed plaque formation as well as macrophage and lipid infiltration in mouse aortic tissues. Moreover, BMSC-EXO decreased concentrations of pyroptosis-related markers interleukin (IL)-1β, IL-18, cleaved-caspase-1 and gasdermin D in vitro and in vivo. Long non-coding RNA AU020206 was carried by the BMSC-EXO, and it bound to CCAAT enhancer binding protein beta (CEBPB) to block CEBPB-mediated transcriptional activation of NLR family pyrin domain containing 3 (NLRP3). Functional assays revealed that silencing of AU020206 aggravated macrophage pyroptosis and exacerbated AS symptoms in mice. These exacerbations were blocked upon CEBPB silencing but then restored after NLRP3 overexpression. In conclusion, this study demonstrates that AU020206 delivered by BMSC-EXO alleviates macrophage pyroptosis in AS by blocking CEBPB-mediated transcriptional activation of NLRP3.
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Affiliation(s)
- Nan Zhang
- Department of Vascular Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, PR China
| | - Yuxin Luo
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, PR China
| | - Jiawei Shao
- Department of Vascular Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, PR China
| | - Huanhuan Sun
- Department of Vascular Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, PR China
| | - Kai Ma
- Department of Vascular Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, PR China
| | - Xiang Gao
- Department of Vascular Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, PR China.
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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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Bakinowska E, Kiełbowski K, Boboryko D, Bratborska AW, Olejnik-Wojciechowska J, Rusiński M, Pawlik A. The Role of Stem Cells in the Treatment of Cardiovascular Diseases. Int J Mol Sci 2024; 25:3901. [PMID: 38612710 PMCID: PMC11011548 DOI: 10.3390/ijms25073901] [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: 02/11/2024] [Revised: 03/28/2024] [Accepted: 03/29/2024] [Indexed: 04/14/2024] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of death and include several vascular and cardiac disorders, such as atherosclerosis, coronary artery disease, cardiomyopathies, and heart failure. Multiple treatment strategies exist for CVDs, but there is a need for regenerative treatment of damaged heart. Stem cells are a broad variety of cells with a great differentiation potential that have regenerative and immunomodulatory properties. Multiple studies have evaluated the efficacy of stem cells in CVDs, such as mesenchymal stem cells and induced pluripotent stem cell-derived cardiomyocytes. These studies have demonstrated that stem cells can improve the left ventricle ejection fraction, reduce fibrosis, and decrease infarct size. Other studies have investigated potential methods to improve the survival, engraftment, and functionality of stem cells in the treatment of CVDs. The aim of the present review is to summarize the current evidence on the role of stem cells in the treatment of CVDs, and how to improve their efficacy.
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Affiliation(s)
- Estera Bakinowska
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (E.B.); (K.K.); (D.B.); (J.O.-W.); (M.R.)
| | - Kajetan Kiełbowski
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (E.B.); (K.K.); (D.B.); (J.O.-W.); (M.R.)
| | - Dominika Boboryko
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (E.B.); (K.K.); (D.B.); (J.O.-W.); (M.R.)
| | | | - Joanna Olejnik-Wojciechowska
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (E.B.); (K.K.); (D.B.); (J.O.-W.); (M.R.)
| | - Marcin Rusiński
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (E.B.); (K.K.); (D.B.); (J.O.-W.); (M.R.)
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (E.B.); (K.K.); (D.B.); (J.O.-W.); (M.R.)
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Egea V. Caught in action: how MSCs modulate atherosclerotic plaque. Front Cell Dev Biol 2024; 12:1379091. [PMID: 38601079 PMCID: PMC11004314 DOI: 10.3389/fcell.2024.1379091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 03/15/2024] [Indexed: 04/12/2024] Open
Abstract
Atherosclerosis (AS) is a medical condition marked by the stiffening and constriction of the arteries. This is caused by the accumulation of plaque, a substance made up of fat, cholesterol, calcium, and other elements present in the blood. Over time, this plaque solidifies and constricts the arteries, restricting the circulation of oxygen-rich blood to the organs and other body parts. The onset and progression of AS involve a continuous inflammatory response, including the infiltration of inflammatory cells, foam cells derived from monocytes/macrophages, and inflammatory cytokines and chemokines. Mesenchymal stromal cells (MSCs), a type of multipotent stem cells originating from various body tissues, have recently been demonstrated to have a protective and regulatory role in diseases involving inflammation. Consequently, the transplantation of MSCs is being proposed as a novel therapeutic strategy for atherosclerosis treatment. This mini-review intends to provide a summary of the regulatory effects of MSCs at the plaque site to lay the groundwork for therapeutic interventions.
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Affiliation(s)
- Virginia Egea
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
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11
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Mao J, Qian S, Zhao Q, Zhao B, Lu B, Zhang L, Mao X, Zhang Y, Cui W, Sun X. Balancing macrophage polarization via stem cell-derived apoptotic bodies for diabetic wound healing. MED 2024; 5:148-168.e8. [PMID: 38340709 DOI: 10.1016/j.medj.2024.01.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 10/18/2023] [Accepted: 01/15/2024] [Indexed: 02/12/2024]
Abstract
BACKGROUND Adipose tissue-derived stem cell-derived apoptotic bodies (ADSC-ABs) have shown great potential for immunomodulation and regeneration, particularly in diabetic wound therapy. However, their local application has been limited by unclear regulatory mechanisms, rapid clearance, and short tissue retention times. METHODS We analyzed the key role molecules and regulatory pathways of ADSC-ABs in regulating inflammatory macrophages by mRNA sequencing and microRNA (miRNA) sequencing and then verified them by gene knockdown. To prevent rapid clearance, we employed microfluidics technology to prepare methacrylate-anhydride gelatin (GelMA) microspheres (GMS) for controlled release of ABs. Finally, we evaluated the effectiveness of ADSC-AB-laden GMSs (ABs@GMSs) in a diabetic rat wound model. FINDINGS Our results demonstrated that ADSC-ABs effectively balanced macrophage inflammatory polarization through the janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, mediated by miR-20a-5p. Furthermore, we showed that AB@GMSs had good biocompatibility, significantly delayed local clearance of ABs, and ameliorated diabetic wound inflammation and promoted vascularization, thus facilitating its healing. CONCLUSIONS Our study reveals the regulatory mechanism of ADSC-ABs in balancing macrophage inflammatory polarization and highlightsthe importance of delaying their local clearance by GMSs. These findings have important implications for the development of novel therapies for diabetic wound healing. FUNDING This research was supported by the National Key Research and Development Program of China (2020YFA0908200), National Natural Science Foundation of China (82272263, 82002053, 32000937, and 82202467), Shanghai "Rising Stars of Medical Talents" Youth Development Program (22MC1940300), Shanghai Municipal Health Commission (20204Y0354), and Shanghai Science and Technology Development Funds (22YF1421400).
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Affiliation(s)
- Jiayi Mao
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai 200011, P.R. China
| | - Shutong Qian
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai 200011, P.R. China
| | - Qiuyu Zhao
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai 200011, P.R. China
| | - Binfan Zhao
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai 200011, P.R. China
| | - Bolun Lu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai 200011, P.R. China
| | - Liucheng Zhang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai 200011, P.R. China
| | - Xiyuan Mao
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai 200011, P.R. China
| | - Yuguang Zhang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai 200011, P.R. China.
| | - Wenguo Cui
- Department of Orthopedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, P.R. China.
| | - Xiaoming Sun
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai 200011, P.R. China.
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12
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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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13
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Sun S, Liu F, Fan F, Chen N, Pan X, Wei Z, Zhang Y. Exploring the mechanism of atherosclerosis and the intervention of traditional Chinese medicine combined with mesenchymal stem cells based on inflammatory targets. Heliyon 2023; 9:e22005. [PMID: 38045166 PMCID: PMC10692769 DOI: 10.1016/j.heliyon.2023.e22005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 11/01/2023] [Accepted: 11/01/2023] [Indexed: 12/05/2023] Open
Abstract
Atherosclerosis (AS) is a chronic inflammatory vascular disease, which is the common pathological basis of cardiovascular and cerebrovascular diseases. The immune inflammatory response throughout the course of AS has been evidenced by studies, in which a large number of immune cells and inflammatory factors play a crucial role in the pathogenesis of AS. The inflammation related to AS is mainly mediated by inflammatory cytokines (IL-1β, IL-6, IL-18, TNF-α, hs-CRP, SAA), inflammatory enzymes (Lp-PLA2, sPLA2-IIA, MMPs), and inflammatory signaling pathways (P38 MAPK signaling pathway, NF-κB signaling pathway, TLR2/4 signaling pathway). It is involved in the pathophysiological process of AS, and the degree of inflammation measured by it can be used to evaluate the risk of progression of AS plaque instability. In recent years, traditional Chinese medicine (TCM) has shown the advantage of minimal side effects in immune regulation and has made some progress in the prevention and treatment of AS. Mesenchymal stem cells (MSCs), as self-renewal, highly differentiated, and pluripotent stem cells with anti-inflammatory properties and immune regulation, have been widely used for AS treatment. They also play an important inflammation-immune regulatory function in AS. Notably, in terms of regulating immune cells and inflammatory factors, compared with TCM and its compound, the combination therapy has obvious anti-inflammatory advantages over the use of MSCs alone. It is an important means to further improve the efficacy of AS and provides a new way for the prevention and treatment of AS.
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Affiliation(s)
- Shibiao Sun
- Henan University of Chinese Medicine, Zhengzhou 450000, China
| | - Feixiang Liu
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China
| | - Feiyan Fan
- Henan University of Chinese Medicine, Zhengzhou 450000, China
| | - Na Chen
- Henan University of Chinese Medicine, Zhengzhou 450000, China
| | - Xiaolong Pan
- Henan University of Chinese Medicine, Zhengzhou 450000, China
| | - Zhihui Wei
- Henan University of Chinese Medicine, Zhengzhou 450000, China
| | - Yunke Zhang
- Henan University of Chinese Medicine, Zhengzhou 450000, China
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China
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Hu HJ, Xiao XR, Li T, Liu DM, Geng X, Han M, Cui W. Integrin beta 3-overexpressing mesenchymal stromal cells display enhanced homing and can reduce atherosclerotic plaque. World J Stem Cells 2023; 15:931-946. [PMID: 37900938 PMCID: PMC10600744 DOI: 10.4252/wjsc.v15.i9.931] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/22/2023] [Accepted: 08/23/2023] [Indexed: 09/25/2023] Open
Abstract
BACKGROUND Umbilical cord (UC) mesenchymal stem cell (MSC) transplantation is a potential therapeutic intervention for atherosclerotic vascular disease. Integrin beta 3 (ITGB3) promotes cell migration in several cell types. However, whether ITGB-modified MSCs can migrate to plaque sites in vivo and play an anti-atherosclerotic role remains unclear. AIM To investigate whether ITGB3-overexpressing MSCs (MSCsITGB3) would exhibit improved homing efficacy in atherosclerosis. METHODS UC MSCs were isolated and expanded. Lentiviral vectors encoding ITGB3 or green fluorescent protein (GFP) as control were transfected into MSCs. Sixty male apolipoprotein E-/- mice were acquired from Beijing Vital River Lab Animal Technology Co., Ltd and fed with a high-fat diet (HFD) for 12 wk to induce the formation of atherosclerotic lesions. These HFD-fed mice were randomly separated into three clusters. GFP-labeled MSCs (MSCsGFP) or MSCsITGB3 were transplanted into the mice intravenously via the tail vein. Immunofluorescence staining, Oil red O staining, histological analyses, western blotting, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction were used for the analyses. RESULTS ITGB3 modified MSCs successfully differentiated into the "osteocyte" and "adipocyte" phenotypes and were characterized by positive expression (> 91.3%) of CD29, CD73, and CD105 and negative expression (< 1.35%) of CD34 and Human Leukocyte Antigen-DR. In a transwell assay, MSCsITGB3 showed significantly faster migration than MSCsGFP. ITGB3 overexpression had no effects on MSC viability, differentiation, and secretion. Immunofluorescence staining revealed that ITGB3 overexpression substantially enhanced the homing of MSCs to plaque sites. Oil red O staining and histological analyses further confirmed the therapeutic effects of MSCsITGB3, significantly reducing the plaque area. Enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction revealed that MSCITGB3 transplantation considerably decreased the inflammatory response in pathological tissues by improving the dynamic equilibrium of pro- and anti-inflammatory cytokines. CONCLUSION These results showed that ITGB3 overexpression enhanced the MSC homing ability, providing a potential approach for MSC delivery to plaque sites, thereby optimizing their therapeutic effects.
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Affiliation(s)
- Hai-Juan Hu
- First Division, Department of Cardiology, The Second Hospital of Hebei Medical University and Institute of Cardiocerebrovascular Disease of Hebei Province, Shijiazhuang 050000, Hebei Province, China
| | - Xue-Ru Xiao
- Department of Obstetrics, Shijiazhuang People's Hospital, Shijiazhuang 050030, Hebei Province, China
| | - Tong Li
- First Division, Department of Cardiology, The Second Hospital of Hebei Medical University and Institute of Cardiocerebrovascular Disease of Hebei Province, Shijiazhuang 050000, Hebei Province, China
| | - De-Min Liu
- First Division, Department of Cardiology, The Second Hospital of Hebei Medical University and Institute of Cardiocerebrovascular Disease of Hebei Province, Shijiazhuang 050000, Hebei Province, China
| | - Xue Geng
- First Division, Department of Cardiology, The Second Hospital of Hebei Medical University and Institute of Cardiocerebrovascular Disease of Hebei Province, Shijiazhuang 050000, Hebei Province, China
| | - Mei Han
- Key Laboratory of Medical Biotechnology of Hebei Province, Department of Biochemistry and Molecular Biology, College of Basic Medicine, Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang 050017, Hebei Province, China
| | - Wei Cui
- First Division, Department of Cardiology, The Second Hospital of Hebei Medical University and Institute of Cardiocerebrovascular Disease of Hebei Province, Shijiazhuang 050000, Hebei Province, China.
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15
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Wang Y, Gao T, Wang B. Application of mesenchymal stem cells for anti-senescence and clinical challenges. Stem Cell Res Ther 2023; 14:260. [PMID: 37726805 PMCID: PMC10510299 DOI: 10.1186/s13287-023-03497-z] [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] [Accepted: 09/13/2023] [Indexed: 09/21/2023] Open
Abstract
Senescence is a hot topic nowadays, which shows the accumulation of senescent cells and inflammatory factors, leading to the occurrence of various senescence-related diseases. Although some methods have been identified to partly delay senescence, such as strengthening exercise, restricting diet, and some drugs, these only slow down the process of senescence and cannot fundamentally delay or even reverse senescence. Stem cell-based therapy is expected to be a potential effective way to alleviate or cure senescence-related disorders in the coming future. Mesenchymal stromal cells (MSCs) are the most widely used cell type in treating various diseases due to their potentials of self-replication and multidirectional differentiation, paracrine action, and immunoregulatory effects. Some biological characteristics of MSCs can be well targeted at the pathological features of aging. Therefore, MSC-based therapy is also a promising strategy to combat senescence-related diseases. Here we review the recent progresses of MSC-based therapies in the research of age-related diseases and the challenges in clinical application, proving further insight and reference for broad application prospects of MSCs in effectively combating senesce in the future.
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Affiliation(s)
- Yaping Wang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People's Republic of China
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China
| | - Tianyun Gao
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People's Republic of China
| | - Bin Wang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People's Republic of China.
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16
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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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17
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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: 7] [Impact Index Per Article: 3.5] [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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18
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Cortés-Morales VA, Chávez-Sánchez L, Rocha-Zavaleta L, Espíndola-Garibay S, Monroy-García A, Castro-Manrreza ME, Fajardo-Orduña GR, Apresa-García T, Gutiérrez-de la Barrera M, Mayani H, Montesinos JJ. Mesenchymal Stem/Stromal Cells Derived from Cervical Cancer Promote M2 Macrophage Polarization. Cells 2023; 12:cells12071047. [PMID: 37048119 PMCID: PMC10093665 DOI: 10.3390/cells12071047] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 03/17/2023] [Accepted: 03/23/2023] [Indexed: 04/03/2023] Open
Abstract
Macrophages with the M2 phenotype promote tumor development through the immunosuppression of antitumor immunity. We previously demonstrated the presence of mesenchymal stem/stromal cells (MSCs) in cervical cancer (CeCa-MSCs), suggesting an immune protective capacity in tumors, but to date, their effect in modulating macrophage polarization remains unknown. In this study, we compared the capacities of MSCs from normal cervix (NCx) and CeCa to promote M2 macrophage polarization in a coculture system. Our results demonstrated that CeCa-MSCs, in contrast to NCx-MSCs, significantly decreased M1 macrophage cell surface marker expression (HLA-DR, CD80, CD86) and increased M2 macrophage expression (CD14, CD163, CD206, Arg1) in cytokine-induced CD14+ monocytes toward M1- or M2-polarized macrophages. Interestingly, compared with NCx-MSCs, in M2 macrophages generated from CeCa-MSC cocultures, we observed an increase in the percentage of phagocytic cells, in the intracellular production of IL-10 and IDO, the capacity to decrease T cell proliferation and for the generation of CD4+CD25+FoxP3+ Tregs. Importantly, this capacity to promote M2 macrophage polarization was correlated with the intracellular expression of macrophage colony-stimulating factor (M-CSF) and upregulation of IL-10 in CeCa-MSCs. Furthermore, the presence of M2 macrophages was correlated with the increased production of IL-10 and IL-1RA anti-inflammatory molecules. Our in vitro results indicate that CeCa-MSCs, in contrast to NCx-MSCs, display an increased M2-macrophage polarization potential and suggest a role of CeCa-MSCs in antitumor immunity.
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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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Zhang X, Ren Z, Jiang Z. EndMT-derived mesenchymal stem cells: a new therapeutic target to atherosclerosis treatment. Mol Cell Biochem 2022; 478:755-765. [PMID: 36083511 DOI: 10.1007/s11010-022-04544-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 08/12/2022] [Indexed: 11/28/2022]
Abstract
Cardiovascular diseases, such as coronary artery disease and stroke, are the main threats to human health worldwide. Atherosclerosis, a chronic inflammatory disorder, plays a role as an initiator of all of the above-mentioned diseases. Cell therapy for diseases has attracted widespread attention. Mesenchymal stem cells (MSCs) are a type of stem cell that still exist in adults and have the characteristics of self-renewal ability, pluripotent differentiation potential, immunomodulation, tissue regeneration, anti-inflammation and low immunogenicity. In light of the properties of MSCs, some researchers have begun to target MSCs to create a possible way to alleviate atherosclerosis. Most of these studies are focused on MSC transplantation, injecting MSCs to modulate macrophages, the key inflammatory cell in atherosclerosis plaque. According to recent studies, researchers found that endothelial-to-mesenchymal transition (EndMT) has something to do with atherosclerosis development. A new cell type MSC might also appear during the EndMT process. In this article, we summarize the characteristics of MSCs, the latest progress of MSC research and its application prospects, and in view of the process of EndMT occurring in atherosclerosis, we propose some new ideas for the treatment of atherosclerosis by targeting MSCs.
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Affiliation(s)
- Xiaofan Zhang
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Zhong Ren
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Zhisheng Jiang
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, Hengyang Medical School, University of South China, Hengyang, 421001, China.
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Yao G, Qi J, Li X, Tang X, Li W, Chen W, Xia N, Wang S, Sun L. Mesenchymal stem cell transplantation alleviated atherosclerosis in systemic lupus erythematosus through reducing MDSCs. Stem Cell Res Ther 2022; 13:328. [PMID: 35850768 PMCID: PMC9290280 DOI: 10.1186/s13287-022-03002-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 05/19/2022] [Indexed: 12/02/2022] Open
Abstract
Objective The mechanism by which mesenchymal stem cell (MSC) transplantation alleviates atherosclerosis in systemic lupus erythematosus (SLE) remains elusive. In this study, we aim to explore the efficacy and mechanism of MSC in ameliorating atherosclerosis in SLE. Methods ApoE−/− and Fas−/− mice on the B6 background were cross-bred to generate SLE mice with atherosclerosis. Myeloid-derived suppressor cells (MDSCs) were sorted and quantified. The apoE−/−Fas−/− mice were either treated with anti-Gr antibody or injected with MDSCs. The lupus-like autoimmunity and atherosclerotic lesions were evaluated. Furthermore, the apoE−/−Fas−/− mice were transplanted with MSCs and lupus-like autoimmunity and atherosclerotic lesions were assessed. Results MDSCs in peripheral blood, spleen, draining lymph nodes increased in apoE−/−Fas−/− mice compared with B6 mice. Moreover, the adoptive transfer of MDSCs aggravated both atherosclerosis and SLE pathologies, whereas depleting MDSCs ameliorated those pathologies in apoE−/−Fas−/− mice. MSC transplantation in apoE−/−Fas−/− mice decreased the percentage of MDSCs, alleviated the typical atherosclerotic lesions, including atherosclerotic lesions in aortae and liver, and reduced serum cholesterol, triglyceride and low-density lipoprotein levels. MSC transplantation also reduced SLE pathologies, including splenomegaly, glomerular lesions, anti-dsDNA antibody in serum, urine protein and serum creatinine. Moreover, MSC transplantation regulated the generation and function of MDSCs through secreting prostaglandin E 2 (PGE2). Conclusion Taken together, these results indicated that the increased MDSCs contributed to atherosclerosis in SLE. MSC transplantation ameliorated the atherosclerosis and SLE through reducing MDSCs by secreting PGE2. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03002-y.
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Affiliation(s)
- Genhong Yao
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Jingjing Qi
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China.,Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Xiaojing Li
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Xiaojun Tang
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Wenchao Li
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Weiwei Chen
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Nan Xia
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Shiying Wang
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China.
| | - Lingyun Sun
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China.
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22
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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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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: 20] [Impact Index Per Article: 6.7] [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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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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25
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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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26
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Lu D, Xu Y, Liu Q, Zhang Q. Mesenchymal Stem Cell-Macrophage Crosstalk and Maintenance of Inflammatory Microenvironment Homeostasis. Front Cell Dev Biol 2021; 9:681171. [PMID: 34249933 PMCID: PMC8267370 DOI: 10.3389/fcell.2021.681171] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 05/28/2021] [Indexed: 12/13/2022] Open
Abstract
Macrophages are involved in almost every aspect of biological systems and include development, homeostasis and repair. Mesenchymal stem cells (MSCs) have good clinical application prospects due to their ability to regulate adaptive and innate immune cells, particularly macrophages, and they have been used successfully for many immune disorders, including inflammatory bowel disease (IBD), acute lung injury, and wound healing, which have been reported as macrophage-mediated disorders. In the present review, we focus on the interaction between MSCs and macrophages and summarize their methods of interaction and communication, such as cell-to-cell contact, soluble factor secretion, and organelle transfer. In addition, we discuss the roles of MSC-macrophage crosstalk in the development of disease and maintenance of homeostasis of inflammatory microenvironments. Finally, we provide optimal strategies for applications in immune-related disease treatments.
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Affiliation(s)
- Di Lu
- The Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yan Xu
- The Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qiuli Liu
- The Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qi Zhang
- The Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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27
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Lin F, Zhang S, Liu X, Wu M. RETRACTED: Mouse bone marrow derived mesenchymal stem cells-secreted exosomal microRNA-125b-5p suppresses atherosclerotic plaque formation via inhibiting Map4k4. Life Sci 2021; 274:119249. [PMID: 33652034 DOI: 10.1016/j.lfs.2021.119249] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 01/16/2021] [Accepted: 01/25/2021] [Indexed: 02/08/2023]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. Concern was raised about the reliability of the Western blot results in Figs. 2D and 4E, which appear to have the same eyebrow shaped phenotype as many other publications tabulated here (https://docs.google.com/spreadsheets/d/149EjFXVxpwkBXYJOnOHb6RhAqT4a2llhj9LM60MBffM/edit#gid=0). The journal requested the corresponding author comment on these concerns and provide the raw data. However the authors were not able to satisfactorily fulfil this request and therefore the Editor-in-Chief decided to retract the article.
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Affiliation(s)
- Feng Lin
- Department of Cardiology, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen 518000, Guangdong, China.
| | - Suihao Zhang
- Department of Cardiology, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen 518000, Guangdong, China
| | - Xia Liu
- Department of Cardiology, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen 518000, Guangdong, China
| | - Meishan Wu
- Department of Cardiology, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen 518000, Guangdong, China
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28
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Tsai SCS, Lin FCF, Chang KH, Li MC, Chou RH, Huang MY, Chen YC, Kao CY, Cheng CC, Lin HC, Hsu YC. The intravenous administration of skin-derived mesenchymal stem cells ameliorates hearing loss and preserves cochlear hair cells in cisplatin-injected mice: SMSCs ameliorate hearing loss and preserve outer hair cells in mice. Hear Res 2021; 413:108254. [PMID: 34020824 DOI: 10.1016/j.heares.2021.108254] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 03/12/2021] [Accepted: 04/13/2021] [Indexed: 12/21/2022]
Abstract
Mesenchymal stem cells (MSCs) can be isolated from different tissue origins, such as the bone marrow, the placenta, the umbilical cord, adipose tissues, and skin tissues. MSCs can secrete anti-inflammatory molecules and growth factors for tissue repair and remodeling. However, the ability of skin-derived MSCs (SMSCs) to repair cochlear damage and ameliorate hearing loss remains unclear. Cisplatin is a commonly used chemotherapeutic agent that has the side effect of ototoxicity due to inflammation and oxidative stress. This study investigated the effects of SMSCs on cisplatin-induced hearing loss in mice. Two independent experiments were designed for modeling cisplatin-induced hearing loss in mice, one for chronic toxicity (4 mg/kg intraperitoneal [IP] injection once per day for 5 consecutive days) and the other for acute toxicity (25 mg/kg IP injection once on day one). Three days after cisplatin injection, 1 × 106 or 3 × 106 SMSCs were injected through the tail vein. Data on auditory brain responses suggested that SMSCs could significantly reduce the hearing threshold of cisplatin-injected mice. Furthermore, immunohistochemical staining data suggested that SMSCs could significantly ameliorate the loss of cochlear hair cells, TUNEL-positive cells and cleaved caspase 3-positive cells in cisplatin-injected mice. Neuropathological gene analyses revealed that SMSCs treatment could downregulate the expression of cochlear genes involved in apoptosis, autophagy, chromatin modification, disease association, matrix remodeling, oxidative stress, tissue integrity, transcription, and splicing and unfolded protein responses. Additionally, SMSCs treatment could upregulate the expression of cochlear genes affecting the axon and dendrite structures, cytokines, trophic factors, the neuronal skeleton and those involved in carbohydrate metabolism, growth factor signaling, myelination, neural connectivity, neural transmitter release, neural transmitter response and reuptake, neural transmitter synthesis and storage, and vesicle trafficking. Results from TUNEL and caspase 3 staining further confirmed that cisplatin-induced apoptosis in cochlear tissues of cisplatin-injected mice could be reduced by SMSCs treatment. In conclusion, the evidence of the effects of SMSCs in favor of ameliorating ototoxicity-induced hearing loss suggests a potential clinical application.
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Affiliation(s)
- Stella Chin-Shaw Tsai
- Department of Otolaryngology, Tungs' Taichung Metroharbor Hospital, Taichung, Taiwan
| | | | - Kuang-Hsi Chang
- Department of Medical Research, Tungs' Taichung Metroharbor Hospital, Taichung, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; General Education Center, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan
| | - Min-Chih Li
- Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taiwan
| | - Ruey-Hwang Chou
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan; Department of Biotechnology, Asia University, Taichung, Taiwan
| | - Mei-Yue Huang
- Maria Von Med-Biotechnology Co. Ltd., Taipei, Taiwan
| | | | - Chien-Yu Kao
- Medical and Pharmaceutical Industry Technology and Development Center, Taipei, Taiwan
| | - Ching-Chang Cheng
- Laboratory Animal Service Center, Office of Research and Development, China Medical University, Taiwan
| | - Hung-Ching Lin
- Department of Audiology and Speech-Language Pathology, Mackay Medical College, New Taipei City, Taiwan; Department of Otolaryngology, Mackay Memorial Hospital, Taipei, Taiwan
| | - Yi-Chao Hsu
- Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taiwan; Department of Audiology and Speech-Language Pathology, Mackay Medical College, New Taipei City, Taiwan.
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29
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Hasgur S, Desbourdes L, Relation T, Overholt KM, Stanek JR, Guess AJ, Yu M, Patel P, Roback L, Dominici M, Otsuru S, Horwitz EM. Splenic macrophage phagocytosis of intravenously infused mesenchymal stromal cells attenuates tumor localization. Cytotherapy 2021; 23:411-422. [PMID: 33781710 DOI: 10.1016/j.jcyt.2020.04.102] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 04/17/2020] [Accepted: 04/28/2020] [Indexed: 12/13/2022]
Abstract
Mesenchymal stromal cells (MSCs) possess remarkable tumor tropism, making them ideal vehicles to deliver tumor-targeted therapeutic agents; however, their value in clinical medicine has yet to be realized. A barrier to clinical utilization is that only a small fraction of infused MSCs ultimately localize to the tumor. In an effort to overcome this obstacle, we sought to enhance MSC trafficking by focusing on the factors that govern MSC arrival within the tumor microenvironment. Our findings show that MSC chemoattraction is only present in select tumors, including osteosarcoma, and that the chemotactic potency among similar tumors varies substantially. Using an osteosarcoma xenograft model, we show that human MSCs traffic to the tumor within several hours of infusion. After arrival, MSCs are observed to localize in clusters near blood vessels and MSC-associated bioluminescence signal intensity is increased, suggesting that the seeded cells expand after engraftment. However, our studies reveal that a significant portion of MSCs are eliminated en route by splenic macrophage phagocytosis, effectively limiting the number of cells available for tumor engraftment. To increase MSC survival, we transiently depleted macrophages with liposomal clodronate, which resulted in increased tumor localization without substantial reduction in tumor-associated macrophages. Our data suggest that transient macrophage depletion will significantly increase the number of MSCs in the spleen and thus improve MSC localization within a tumor, theoretically increasing the effective dose of an anti-cancer agent. This strategy may subsequently improve the clinical efficacy of MSCs as vehicles for the tumor-directed delivery of therapeutic agents.
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Affiliation(s)
- Suheyla Hasgur
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Laura Desbourdes
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Theresa Relation
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Kathleen M Overholt
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Joseph R Stanek
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Adam J Guess
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Minjun Yu
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Pratik Patel
- Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Linda Roback
- Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Massimo Dominici
- Department of Medical and Surgical Sciences of Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Satoru Otsuru
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Edwin M Horwitz
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA; Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA.
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30
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Zha K, Li X, Tian G, Yang Z, Sun Z, Yang Y, Wei F, Huang B, Jiang S, Li H, Sui X, Liu S, Guo Q. Evaluation of CD49f as a novel surface marker to identify functional adipose-derived mesenchymal stem cell subset. Cell Prolif 2021; 54:e13017. [PMID: 33704842 PMCID: PMC8088464 DOI: 10.1111/cpr.13017] [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] [Received: 10/26/2020] [Revised: 02/07/2021] [Accepted: 02/16/2021] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES CD49f is expressed on a variety of stem cells and has certain effects on their cytological functions, such as proliferation and differentiation potential. However, whether CD49f is expressed on the surface of adipose tissue-derived mesenchymal stem cells (ADSCs) and its effect on ADSCs has not been clarified. MATERIALS AND METHODS The effects of in vitro culture passage and inflammatory factor treatment on CD49f expression and the adhesion ability of ADSCs from mice and rats were investigated. CD49f+ cells were selected from rat ADSCs (rADSCs) by magnetic-activated cell sorting (MACS), and the cellular functions of CD49f+ ADSCs and unsorted ADSCs, including their clonogenic, proliferation, adipogenic and osteogenic differentiation, migration and anti-apoptotic capacities, were compared. RESULTS CD49f expression and the adhesion ability of ADSCs decreased with increasing in vitro culture passage number. TNF-α and IFN-γ treatment decreased CD49f expression but increased the adhesion ability of ADSCs. After CD49f was blocked with an anti-CD49f antibody, the adhesion ability of ADSCs was decreased. No significant difference in clonogenic activity was observed between unsorted ADSCs and CD49f+ ADSCs. CD49f+ ADSCs had greater proliferation, adipogenic and osteogenic differentiation, migration and anti-apoptotic capacities than unsorted ADSCs. CONCLUSION In the current study, the expression of CD49f on ADSCs was identified for the first time. The expression of CD49f on ADSCs was influenced by in vitro culture passage number and inflammatory factor treatment. Compared with unsorted ADSCs, CD49f + ADSCs exhibited superior cellular functions, thus may have great application value in mesenchymal stem cell (MSC)-based therapies.
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Affiliation(s)
- Kangkang Zha
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Xu Li
- Musculoskeletal Research Laboratory, Department of Orthopedics and Traumatology, Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Guangzhao Tian
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Zhen Yang
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Zhiqiang Sun
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Yu Yang
- The Second People's Hospital of Guiyang, Guiyang, China
| | - Fu Wei
- Department of Orthopedics, The First Affiliated Hospital of University of South China, Hengyang, China
| | - Bo Huang
- Department of Bone and Joint Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Shuangpeng Jiang
- Department of Orthopedics, The First Hospital of China Medical University, Shenyang, China
| | - Hao Li
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Xiang Sui
- School of Medicine, Nankai University, Tianjin, China
| | - Shuyun Liu
- School of Medicine, Nankai University, Tianjin, China
| | - Quanyi Guo
- School of Medicine, Nankai University, Tianjin, China
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31
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Xi W, Chen W, Sun W, Li X, Suo Z, Jiang G, Gao P, Li Q. Mitochondrial activity regulates the differentiation of skin-derived mesenchymal stem cells into brown adipocytes to contribute to hypertension. Stem Cell Res Ther 2021; 12:167. [PMID: 33691786 PMCID: PMC7945215 DOI: 10.1186/s13287-021-02169-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 01/14/2021] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Brown adipocytes (BAs) are major components of brown adipose tissue (BAT), which is involved in blood pressure regulation. BAs are derived from multiple progenitors, including PDGFRα+ adipose-derived stem cells (ASCs). Skin-derived mesenchymal stem cells (S-MSCs) have the capacity to differentiate into adipocytes; however, their ability to differentiate into BAs remains unexplored. We aim to study the ability and regulatory mechanism of the differentiation of S-MSCs into BAs and the direct role of BAT in blood pressure regulation. METHODS Protein expression was measured by flow cytometry or Western blotting, and gene mRNA levels were quantified by real-time quantitative PCR (RT-PCR). To induce the differentiation of S-MSCs into BAs, S-MSCs were stimulated with a brown adipogenic cocktail comprising insulin, IBMX, dexamethasone, triiodothyronine (T3), and rosiglitazone for the indicated periods. The oxygen consumption rate (OCR) was measured with an XF24 Extracellular Flux Analyzer. Mitochondrial mass was determined by flow cytometry and fluorescence staining. Hypertension was induced in WT mice by infusion of angiotensin II (Ang II), and systolic blood pressure (SBP) was measured using a tail cuff. Interscapular brown adipose tissue (iBAT)-deficient mice were generated by surgical removal of the iBAT depot, after which the animals were allowed to recover for 6 days. Aortic, iBAT, and heart tissue sections were analyzed by hematoxylin and eosin (HE) staining. RESULTS We found that in vitro, S-MSCs isolated from the mouse dermis expressed the stem cell markers CD90/105 and PDGFRα and readily differentiated into BAs. Mitochondrial biogenesis and oxygen consumption were markedly increased during differentiation of S-MSCs into BAs. In vivo, iBAT was converted to white adipose tissue (WAT) in Ang II-induced hypertensive mice. We assessed the direct role of BAT in blood pressure (BP) regulation by using iBAT-deficient mice (generated by surgical removal of iBAT) and C57BL/6 (wild-type (WT)) mice and found that Ang II-induced BP elevation and vascular damage were markedly aggravated in iBAT-deficient mice compared with WT mice. CONCLUSIONS This study demonstrates that PDGFRα+ S-MSCs are able to differentiate into BAs and that this differentiation is regulated by mitochondrial activity. We also show that BAT plays a direct role in ameliorating Ang II-induced hypertension. The therapeutic potential of BAT for the prevention of hypertension-induced organ remodeling thus warrants further investigation.
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Affiliation(s)
- Wenda Xi
- The Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China
| | - Wendong Chen
- The Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China
| | - Weihong Sun
- Department of Digestion, Huaihe Hospital of Henan University, Kaifeng, 475000, China
| | - Xiangxiao Li
- The Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China
| | - Zhimin Suo
- Department of Digestion, Huaihe Hospital of Henan University, Kaifeng, 475000, China
| | - Gonghao Jiang
- The Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China
| | - Pingjin Gao
- The Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China
| | - Qun Li
- The Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China.
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32
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Dabrowska S, Andrzejewska A, Janowski M, Lukomska B. Immunomodulatory and Regenerative Effects of Mesenchymal Stem Cells and Extracellular Vesicles: Therapeutic Outlook for Inflammatory and Degenerative Diseases. Front Immunol 2021; 11:591065. [PMID: 33613514 PMCID: PMC7893976 DOI: 10.3389/fimmu.2020.591065] [Citation(s) in RCA: 131] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 12/21/2020] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are non-hematopoietic, multipotent stem cells derived from mesoderm, which can be easily isolated from many sources such as bone marrow, umbilical cord or adipose tissue. MSCs provide support for hematopoietic stem cells and have an ability to differentiate into multiple cell lines. Moreover, they have proangiogenic, protective and immunomodulatory properties. MSCs have the capacity to modulate both innate and adaptive immune responses, which accompany many diseases, by inhibiting pro-inflammatory reactions and stimulating anti-inflammatory activity. Recent findings revealed that the positive effect of MSCs is at least partly associated with the production of extracellular vesicles (EVs). EVs are small membrane structures, containing proteins, lipids and nuclei acids, which take part in intra-cellular communication. Many studies indicate that EVs contain protective and pro-regenerative properties and can modulate an immune response that is activated in various diseases such as CNS diseases, myocardial infarction, liver injury, lung diseases, ulcerative colitis or kidney injury. Thus, EVs have similar functions as their cells of origin and since they do not carry the risk of cell transplantation, such as tumor formation or small vessel blockage, they can be considered a potential therapeutic tool for cell-free therapy.
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Affiliation(s)
- Sylwia Dabrowska
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland
| | - Anna Andrzejewska
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland
| | - Miroslaw Janowski
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland.,University of Maryland School of Medicine, Baltimore, MD, United States.,Center for Advanced Imaging Research, Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Barbara Lukomska
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland
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33
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Dumitrescu M, Vacaru AM, Trusca VG, Fenyo IM, Ionita R, Gafencu AV. K2 Transfection System Boosts the Adenoviral Transduction of Murine Mesenchymal Stromal Cells. Int J Mol Sci 2021; 22:E598. [PMID: 33435318 PMCID: PMC7826527 DOI: 10.3390/ijms22020598] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 12/30/2020] [Accepted: 01/05/2021] [Indexed: 12/11/2022] Open
Abstract
Adenoviral vectors are important vehicles for delivering therapeutic genes into mammalian cells. However, the yield of the adenoviral transduction of murine mesenchymal stromal cells (MSC) is low. Here, we aimed to improve the adenoviral transduction efficiency of bone marrow-derived MSC. Our data showed that among all the potential transduction boosters that we tested, the K2 Transfection System (K2TS) greatly increased the transduction efficiency. After optimization of both K2TS components, the yield of the adenoviral transduction increased from 18% to 96% for non-obese diabetic (NOD)-derived MSC, from 30% to 86% for C57BL/6-derived MSC, and from 0.6% to 63% for BALB/c-derived MSC, when 250 transduction units/cell were used. We found that MSC derived from these mouse strains expressed different levels of the coxsackievirus and adenovirus receptors (MSC from C57BL/6≥NOD>>>BALB/c). K2TS did not increase the level of the receptor expression, but desensitized the cells to foreign DNA and facilitated the virus entry into the cell. The expression of Stem cells antigen-1 (Sca-1) and 5'-nucleotidase (CD73) MSC markers, the adipogenic and osteogenic differentiation potential, and the immunosuppressive capacity were preserved after the adenoviral transduction of MSC in the presence of the K2TS. In conclusion, K2TS significantly enhanced the adenoviral transduction of MSC, without interfering with their main characteristics and properties.
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Affiliation(s)
| | | | | | | | | | - Anca Violeta Gafencu
- Institute of Cellular Biology and Pathology “N. Simionescu”, 8, B.P. Hasdeu Street, 050568 Bucharest, Romania; (M.D.); (A.M.V.); (V.G.T.); (I.M.F.); (R.I.)
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34
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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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35
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Stevens HY, Bowles AC, Yeago C, Roy K. Molecular Crosstalk Between Macrophages and Mesenchymal Stromal Cells. Front Cell Dev Biol 2020; 8:600160. [PMID: 33363157 PMCID: PMC7755599 DOI: 10.3389/fcell.2020.600160] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 11/05/2020] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) have been widely investigated for regenerative medicine applications, from treating various inflammatory diseases as a cell therapy to generating engineered tissue constructs. Numerous studies have evaluated the potential effects of MSCs following therapeutic administration. By responding to their surrounding microenvironment, MSCs may mediate immunomodulatory effects through various mechanisms that directly (i.e., contact-dependent) or indirectly (i.e., paracrine activity) alter the physiology of endogenous cells in various disease pathologies. More specifically, a pivotal crosstalk between MSCs and tissue-resident macrophages and monocytes (TMφ) has been elucidated using in vitro and in vivo preclinical studies. An improved understanding of this crosstalk could help elucidate potential mechanisms of action (MOAs) of therapeutically administered MSCs. TMφ, by nature of their remarkable functional plasticity and prevalence within the body, are uniquely positioned as critical modulators of the immune system - not only in maintaining homeostasis but also during pathogenesis. This has prompted further exploration into the cellular and molecular alterations to TMφ mediated by MSCs. In vitro assays and in vivo preclinical trials have identified key interactions mediated by MSCs that polarize the responses of TMφ from a pro-inflammatory (i.e., classical activation) to a more anti-inflammatory/reparative (i.e., alternative activation) phenotype and function. In this review, we describe physiological and pathological TMφ functions in response to various stimuli and discuss the evidence that suggest specific mechanisms through which MSCs may modulate TMφ phenotypes and functions, including paracrine interactions (e.g., secretome and extracellular vesicles), nanotube-mediated intercellular exchange, bioenergetics, and engulfment by macrophages. Continued efforts to elucidate this pivotal crosstalk may offer an improved understanding of the immunomodulatory capacity of MSCs and inform the development and testing of potential MOAs to support the therapeutic use of MSCs and MSC-derived products in various diseases.
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Affiliation(s)
- Hazel Y. Stevens
- Marcus Center for Therapeutic Cell Characterization and Manufacturing, Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, United States
| | - Annie C. Bowles
- Marcus Center for Therapeutic Cell Characterization and Manufacturing, Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, United States
| | - Carolyn Yeago
- Marcus Center for Therapeutic Cell Characterization and Manufacturing, Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, United States
- NSF Engineering Research Center (ERC) for Cell Manufacturing Technologies (CMaT), Georgia Institute of Technology, Atlanta, GA, United States
| | - Krishnendu Roy
- Marcus Center for Therapeutic Cell Characterization and Manufacturing, Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, United States
- NSF Engineering Research Center (ERC) for Cell Manufacturing Technologies (CMaT), Georgia Institute of Technology, Atlanta, GA, United States
- The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, Atlanta, GA, United States
- Center for ImmunoEngineering, Georgia Institute of Technology, Atlanta, GA, United States
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36
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Zhang B, Zhao N, Zhang J, Liu Y, Zhu D, Kong Y. Mesenchymal stem cells rejuvenate cardiac muscle through regulating macrophage polarization. Aging (Albany NY) 2020; 11:3900-3908. [PMID: 31212255 PMCID: PMC6628986 DOI: 10.18632/aging.102009] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Accepted: 05/29/2019] [Indexed: 12/13/2022]
Abstract
We have shown that the effects of transplantation of CD146+ mesenchymal stem cells (MSCs) on myocardial regeneration after myocardial infarction (MI) exceeds the effects of transplantation of MSCs, likely resulting from reduction of aging-associated cellular reactive oxygen species in injured cardiac muscle cells (CMCs). Since the role of macrophages in the MSC-mediated recovery of heart function after MI remains unclear, this question was thus addressed in the current study. We found that transplantation of MSCs did not alter the total number of the macrophages in the injured heart, but induced their polarization towards a M2-phenotype. Moreover, administration of tumor necrosis factor alpha (TNFα) into MSC-transplanted mice, which prevented M2-polarization of macrophages, abolished the effects of MSCs on recovery of heart function and on the reduction of infarcted cardiac tissue. Thus, our data suggest that MSCs may rejuvenate CMCs after ischemic injury at least partially through induction of M2-polarization of macrophages.
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Affiliation(s)
- Busheng Zhang
- Department of Cardiac Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Naishi Zhao
- Department of Cardiac Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Jing Zhang
- Department of Cardiac Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Yu Liu
- Department of Cardiac Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China
| | - Dan Zhu
- Department of Cardiac Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Ye Kong
- Department of Cardiac Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
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37
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Takafuji Y, Hori M, Mizuno T, Harada-Shiba M. Humoral factors secreted from adipose tissue-derived mesenchymal stem cells ameliorate atherosclerosis in Ldlr-/- mice. Cardiovasc Res 2020; 115:1041-1051. [PMID: 30388208 DOI: 10.1093/cvr/cvy271] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 04/09/2018] [Accepted: 10/31/2018] [Indexed: 01/01/2023] Open
Abstract
AIMS Atherosclerosis is a chronic inflammatory disease of the vasculature. Mesenchymal stem cells (MSCs) exert immunomodulatory and immunosuppressive effects by secreting humoral factors; however, the intravascular MSC administration presents a risk of vascular occlusion. Here, we investigated both the effect of conditioned medium from cultured MSCs (MSC-CM) on atherosclerosis and the underlying mechanism. METHODS AND RESULTS Low-density lipoprotein receptor-deficient (Ldlr-/-) mice were fed a high-fat diet and received intravenous injections of either MSC-CM from adipose tissue-derived MSCs or control medium 2×/week for 13 weeks. MSC-CM treatment decreased the atherosclerotic plaque area in the aorta and aortic root of Ldlr-/- mice by 41% and 30%, respectively, with no change in serum lipoprotein levels. Histopathologically, the MSC-CM treatment decreased the expression of cell adhesion molecules (CAMs) and the accumulation of macrophages on the vascular walls. Extracellular vesicles (EVs) and supernatant (MSC-CM supernatant) were separated from the MSC-CM by ultracentrifugation. In tumour necrosis factor-α stimulated human aortic endothelial cells (HAOECs), both the MSC EVs and MSC-CM supernatant decreased CAM expression by inhibiting the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NFκB) pathways. In macrophages, the MSC-CM supernatant decreased the lipopolysaccharide-induced increases in M1 marker expression by inhibiting both the MAPK and NFκB pathways and increased the expression of M2 markers by activating the signal transducer and activator of transcription 3 pathway. In co-culture, inflamed HAOECs pretreated with MSC-CM supernatant and MSC EVs exhibited decreased monocyte adhesion to HAOECs. In addition, the neutralization of hepatocyte growth factor (HGF) in MSC-CM or MSC-CM supernatant attenuated their abilities to suppress monocyte adhesion to HAOECs in co-culture. CONCLUSION MSC-CM ameliorated atherosclerosis in Ldlr-/- mice and suppressed CAM expression and macrophage accumulation in the vascular walls. Humoral factors, including HGF and EVs from MSCs, hold promise as therapeutic agents to reduce the residual risk of coronary artery diseases.
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Affiliation(s)
- Yoshimasa Takafuji
- Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka, Japan
| | - Mika Hori
- Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka, Japan
| | - Toshihide Mizuno
- Department of Artificial Organs, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka, Japan
| | - Mariko Harada-Shiba
- Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka, Japan
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38
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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; 8:1413. [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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39
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Maguire G. The Safe and Efficacious Use of Secretome From Fibroblasts and Adipose-derived (but not Bone Marrow-derived) Mesenchymal Stem Cells for Skin Therapeutics. THE JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY 2019; 12:E57-E69. [PMID: 31531174 PMCID: PMC6715117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Stem cell-based products are rapidly emerging in the marketplace as topical skin care and wound care products. Confusion is prevalent among healthcare providers and end-users about these products. Adipose-derived stem cells, fibroblasts, platelets, and bone marrow-derived stem cells are the most common cells used for stem cell therapeutic development, medical procedures, and skin care products. In this review, the significant advantages of adipose-derived stem cells and fibroblasts in terms of safety and efficacy are highlighted and compared to relatively risky platelets and bone marrow stem cells.
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Affiliation(s)
- Greg Maguire
- Dr. Maguire is with NeoGenesis, Inc. in San Diego, California
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40
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Wei X, Sun G, Zhao X, Wu Q, Chen L, Xu Y, Pang X, Qi G. Human amnion mesenchymal stem cells attenuate atherosclerosis by modulating macrophage function to reduce immune response. Int J Mol Med 2019; 44:1425-1435. [PMID: 31364743 PMCID: PMC6713407 DOI: 10.3892/ijmm.2019.4286] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 06/28/2019] [Indexed: 01/05/2023] Open
Abstract
Mesenchymal stem cells (MSCs) show immunosuppressive activities and alleviate atherosclerosis (AS) formation in apolipoprotein E-knockout (apoE-KO) mice. Human amnion mesenchymal stem cells (hAMSCs), a particular population of mesenchymal stem cells, have been shown to have immunomodulatory abilities. The present study investigated the effects of hAMSCs treatment on early atherosclerotic plaque formation and the progression of established lesion in apoE-KO mice. In total, 36 mice were fed with a high-fat diet. Mice were subjected to hAMSCs-injection treatment simultaneously with high-fat diet (early treatment) or after 8 weeks of high-fat diet (delayed treatment). In each treatment, mice were divided into three groups: i) hAMSCs group with hAMSCs treatment; ii) PBS group injected with PBS; and iii) control group without injection. Histological results showed that the plaque area in the aortic arch of mice was significantly reduced after hAMSCs treatment in the early and delayed treatment groups. In addition, immunohistochemical analysis suggested that the accumulation of macrophages was significantly decreased after hAMSCs treatment. Similarly, the release of the pro-inflammatory cytokine tumor necrosis factor-α was also decreased, whereas the release of the anti-inflammatory cytokine interleukin-10 was increased. In addition, hAMSCs treatment suppressed the phosphorylation of p65 and inhibitor of κB-α, suggesting that NF-κB pathway was involved in the hAMSCs-mediated suppression of immune response. In conclusion, hAMSCs treatment was effective in reducing immune response, which is the one of the major causes of AS, eventually leading to a significant reduction in size of athero-sclerotic lesions.
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Affiliation(s)
- Xiufang Wei
- Department of Geriatric Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Guang Sun
- Department of Geriatric Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Xiaoxue Zhao
- Department of Cardiology, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning 110024, P.R. China
| | - Qianqian Wu
- Department of Geriatric Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Ling Chen
- Department of Geriatric Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Yichi Xu
- Department of Geriatric Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Xining Pang
- Department of Stem Cells and Regenerative Medicine, National Health Commission of China and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Guoxian Qi
- Department of Geriatric Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
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Li X, Sun W, Xi W, Shen W, Wei T, Chen W, Gao P, Li Q. Transplantation of skin mesenchymal stem cells attenuated AngII-induced hypertension and vascular injury. Biochem Biophys Res Commun 2018; 497:1068-1075. [DOI: 10.1016/j.bbrc.2018.02.180] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 02/23/2018] [Indexed: 12/28/2022]
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Shi H, Liang M, Chen W, Sun X, Wang X, Li C, Yang Y, Yang Z, Zeng W. Human induced pluripotent stem cell‑derived mesenchymal stem cells alleviate atherosclerosis by modulating inflammatory responses. Mol Med Rep 2017; 17:1461-1468. [PMID: 29257199 PMCID: PMC5780084 DOI: 10.3892/mmr.2017.8075] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2016] [Accepted: 06/13/2017] [Indexed: 01/22/2023] Open
Abstract
The transplantation of mesenchymal stem cells (MSCs) has been a reported method for alleviating atherosclerosis (AS). Because the availability of bone marrow‑derived MSCs (BM‑MSCs) is limited, the authors used this study to explore the use of a new type of MSC, human induced pluripotent stem cell‑derived MSCs (iPSC‑MSCs), to evaluate whether these cells could alleviate AS. iPSC‑MSCs were intravenously administered to ApoE knock out mice fed on a high‑fat diet (HFD) for 12 weeks. It was reported that systematically administering iPSC‑MSCs clearly reduced the size of plaques. In addition, the numbers of macrophages and lipids in plaques were lower in the HFD + iPSC‑MSCs group than in the HFD group. Furthermore, iPSC‑MSCs attenuated AS‑associated inflammation by decreasing the levels of inflammatory cytokines, such as tumor necrosis factor‑α and interleukin‑6, in serum. In addition, the expression of Notch1 was higher in the HFD group, and injecting iPSC‑MSCs reversed this effect. In conclusion, the current study provides the first evidence indicating that iPSC‑MSCs may be a new optional MSC‑based strategy for treating AS.
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Affiliation(s)
- Hui Shi
- Department of Cardiology, Heart Center, The First Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Meiling Liang
- Department of Cardiology, Sun Yat‑sen Cardiovascular Hospital of Shenzhen, Shenzhen, Guangdong 510080, P.R. China
| | - Weiyan Chen
- Department of Intensive Care Unit, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510080, P.R. China
| | - Xiuting Sun
- Department of Cardiology, Heart Center, The First Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Xiang Wang
- Department of Cardiology, Laiwu People's Hospital, Laiwu, Shandong 271100, P.R. China
| | - Chenghsun Li
- Department of Cardiology, Heart Center, The First Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Yiying Yang
- Department of Cardiology, Heart Center, The First Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Zhisheng Yang
- Department of Cardiology, Heart Center, The First Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Wutao Zeng
- Department of Cardiology, Heart Center, The First Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
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Parga JA, García-Garrote M, Martínez S, Raya Á, Labandeira-García JL, Rodríguez-Pallares J. Prostaglandin EP2 Receptors Mediate Mesenchymal Stromal Cell-Neuroprotective Effects on Dopaminergic Neurons. Mol Neurobiol 2017; 55:4763-4776. [DOI: 10.1007/s12035-017-0681-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 06/29/2017] [Indexed: 12/20/2022]
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Crosstalk with Inflammatory Macrophages Shapes the Regulatory Properties of Multipotent Adult Progenitor Cells. Stem Cells Int 2017; 2017:2353240. [PMID: 28785285 PMCID: PMC5529661 DOI: 10.1155/2017/2353240] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 05/27/2017] [Accepted: 06/12/2017] [Indexed: 01/25/2023] Open
Abstract
Macrophages and microglia are key effector cells in immune-mediated neuroinflammatory disorders. Driving myeloid cells towards an anti-inflammatory, tissue repair-promoting phenotype is considered a promising strategy to halt neuroinflammation and promote central nervous system (CNS) repair. In this study, we defined the impact of multipotent adult progenitor cells (MAPC), a stem cell population sharing common mesodermal origin with mesenchymal stem cells (MSCs), on the phenotype of macrophages and the reciprocal interactions between these two cell types. We show that MAPC suppress the secretion of tumor necrosis factor alpha (TNF-α) by inflammatory macrophages partially through a cyclooxygenase 2- (COX-2-) dependent mechanism. In turn, we demonstrate that inflammatory macrophages trigger the immunomodulatory properties of MAPC, including an increased expression of immunomodulatory mediators (e.g., inducible nitric oxide synthase (iNOS) and COX-2), chemokines, and chemokine receptors. Macrophage-primed MAPC secrete soluble factors that suppress TNF-α release by macrophages. Moreover, the MAPC secretome suppresses the antigen-specific proliferation of autoreactive T cells and the T cell stimulatory capacity of macrophages. Finally, MAPC increase their motility towards secreted factors of activated macrophages. Collectively, these in vitro findings reveal intimate reciprocal interactions between MAPC and inflammatory macrophages, which are of importance in the design of MAPC-based therapeutic strategies for neuroinflammatory disorders in which myeloid cells play a crucial role.
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Crosstalk between mesenchymal stem cells and macrophages in inflammatory bowel disease and associated colorectal cancer. Contemp Oncol (Pozn) 2017; 21:91-97. [PMID: 28947877 PMCID: PMC5611497 DOI: 10.5114/wo.2017.68616] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 05/17/2017] [Indexed: 12/19/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are attractive seed cells for immunotherapy, tissue engineering and regenerative medicine due to their self-renewal and multidirectional differentiation abilities, diverse immunoregulatory functions and ease of isolation from a wide range of tissues. MSCs exert their immunoregulatory effect on immune cells via cell-to-cell contact and paracrine mechanisms. In turn, MSCs can also be modulated by immune cells. Macrophages are constantly present in the mucosa of the intestinal tract of mammals and play an important role in the development and progression of inflammatory bowel disease (IBD), a chronic and recurrent inflammatory disease of the gastrointestinal tract characterized by idiopathic mucosal inflammation. The increased morbidity and mortality of IBD have made it a disease hard to cure in the clinic. MSCs have emerged as an important tool for IBD therapy due to their abilities to differentiate into enterocyte-like cells and regulate inflammatory cells, especially macrophages. In this review, we discuss the recent advances in the interaction between MSCs and macrophages in diseases, with an emphasis on IBD. We propose that an optimized MSC-based therapy would provide a novel strategy for the treatment of IBD and the prevention of IBD-associated colorectal cancer (CRC).
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Yin Y, Wu RX, He XT, Xu XY, Wang J, Chen FM. Influences of age-related changes in mesenchymal stem cells on macrophages during in-vitro culture. Stem Cell Res Ther 2017; 8:153. [PMID: 28646912 PMCID: PMC5483296 DOI: 10.1186/s13287-017-0608-0] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Accepted: 06/08/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have been widely used in cytotherapy and tissue engineering due to their immunosuppressive ability and regenerative potential. Recently, the immunomodulatory influence of MSCs has been gaining increasing attention because their functional roles in modulating immune responses likely have high clinical significance. METHODS In this study, we investigated the influence of MSCs on macrophages (Mφs) in in-vitro cell culture systems. Given evidence that aged MSCs are functionally compromised, bone marrow-derived MSCs (BMSCs) isolated from both young and aged mice (YMSCs and AMSCs) were evaluated and contrasted. RESULTS We found that YMSCs exhibited greater proliferative and osteo-differentiation potential compared to AMSCs. When cocultured with RAW264.7 cells (an Mφ cell line), both YMSCs and AMSCs coaxed polarization of Mφs toward an M2 phenotype and induced secretion of anti-inflammatory and immunomodulatory cytokines. Compared to AMSCs, YMSCs exhibited a more potent immunomodulatory effect. While Mφs cocultured with either YMSCs or AMSCs displayed similar phagocytic ability, AMSC coculture was found to enhance Mφ migration in Transwell systems. When BMSCs were prestimulated with interferon gamma before coculture with RAW264.7 cells, their regulatory effects on Mφs appeared to be modified. Here, compared to stimulated AMSCs, stimulated YMSCs also exhibited enhanced cellular influence on cocultured RAW264.7 cells. CONCLUSIONS Our data suggest that BMSCs exert an age-related regulatory effect on Mφs with respect to their phenotype and functions but an optimized stimulation to enhance MSC immunomodulation is in need of further investigation.
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Affiliation(s)
- Yuan Yin
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, Department of Periodontology, School of Stomatology, Fourth Military Medical University, 145th West Changle Road, Xi’an, 710032 People’s Republic of China
| | - Rui-Xin Wu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, Department of Periodontology, School of Stomatology, Fourth Military Medical University, 145th West Changle Road, Xi’an, 710032 People’s Republic of China
| | - Xiao-Tao He
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, Department of Periodontology, School of Stomatology, Fourth Military Medical University, 145th West Changle Road, Xi’an, 710032 People’s Republic of China
| | - Xin-Yue Xu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, Department of Periodontology, School of Stomatology, Fourth Military Medical University, 145th West Changle Road, Xi’an, 710032 People’s Republic of China
| | - Jia Wang
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, Department of Periodontology, School of Stomatology, Fourth Military Medical University, 145th West Changle Road, Xi’an, 710032 People’s Republic of China
| | - Fa-Ming Chen
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, Department of Periodontology, School of Stomatology, Fourth Military Medical University, 145th West Changle Road, Xi’an, 710032 People’s Republic of China
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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: 58] [Impact Index Per Article: 7.3] [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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Zhang X, Huang F, Chen Y, Qian X, Zheng SG. Progress and prospect of mesenchymal stem cell-based therapy in atherosclerosis. Am J Transl Res 2016; 8:4017-4024. [PMID: 27829989 PMCID: PMC5095298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 09/15/2016] [Indexed: 06/06/2023]
Abstract
Atherosclerosis is a chronic inflammatory disease of the arterial intima, occurring usually in the aged populations who are suffering from hypertension, dyslipidemia and diabetes for a long time. Research on atherosclerosis has shown that macrophage foam cell formation, inflammation, dyslipidemia and immune cells infiltration are all involved in regulating the onset and progression of atherosclerosis. Mesenchymal stem cells (MSCs) originated from different kinds of tissue are a group of cells possessing well-established self-renewal and multipotent differentiation properties as well as immunomodulatory and anti-inflammatory roles. Recent studies have displayed their dyslipidemia regulation functions. Transplantation of MSCs to atherosclerotic patients might be a new multifactorial therapeutic strategy to improve atherosclerosis. This review updates the advancement on MSCs and atherosclerosis.
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Affiliation(s)
- Ximei Zhang
- Division of Cardiology, Third Affiliated Hospital at Sun Yat-sen UniversityGuangzhou 510630, Guangdong, China
- Center for Clinic Immunology, Third Affiliated Hospital at Sun Yat-sen UniversityGuangzhou 4510630, Guangdong, China
| | - Feng Huang
- Center for Clinic Immunology, Third Affiliated Hospital at Sun Yat-sen UniversityGuangzhou 4510630, Guangdong, China
| | - Yanming Chen
- Division of Endocrinology, Third Affiliated Hospital at Sun Yat-sen UniversityGuangzhou 510630, Guangdong, China
| | - Xiaoxian Qian
- Division of Cardiology, Third Affiliated Hospital at Sun Yat-sen UniversityGuangzhou 510630, Guangdong, China
- Center for Clinic Immunology, Third Affiliated Hospital at Sun Yat-sen UniversityGuangzhou 4510630, Guangdong, China
- Institute Integrated Traditional Chinese and Western Medicine, Sun Yat-sen UniversityGuangzhou 510630, Guangdong, China
| | - Song Guo Zheng
- Center for Clinic Immunology, Third Affiliated Hospital at Sun Yat-sen UniversityGuangzhou 4510630, Guangdong, China
- Division of Rheumatology, Penn State Milton S. Hershey Medical CenterHershey, PA 17033, USA
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Qun L, Wenda X, Weihong S, Jianyang M, Wei C, Fangzhou L, Zhenyao X, Pingjin G. miRNA-27b modulates endothelial cell angiogenesis by directly targeting Naa15 in atherogenesis. Atherosclerosis 2016; 254:184-192. [PMID: 27755984 DOI: 10.1016/j.atherosclerosis.2016.10.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Revised: 09/06/2016] [Accepted: 10/04/2016] [Indexed: 01/23/2023]
Abstract
BACKGROUND AND AIMS The CCL20/CCR6 axis has been shown to play a vital role in the pathogenesis of atherosclerosis (AS). However, the regulatory mechanism remains unclear. Here, we studied the miRNA-mediated epigenetic regulation of the CCL20/CCR6 axis in atherogenesis. METHODS CCR6+/+ApoE-/- and CCR6-/-ApoE-/- mice were fed a high-fat diet for 24 weeks. Plaque size was evaluated via ultrasound biomicroscope and hematoxylin and eosin. Protein expression were measured by Western blotting or immunofluorescence/immunohistochemistry or ELISA, and gene mRNA levels were detected by RT-PCR. Seven hundred and sixty miRNAs were screened via miRNA profiling. miRNA-27b target genes were predicted using software and verified with a dual luciferase reporter assay. The tube formation of mouse aortic endothelial cells (MAECs) was performed on Matrigel. RESULTS In contrast to wild-type ApoE-/- mice, CCR6 deficiency led to a significantly decreased plaque size, CD31, CCR6, CCL20 expression and number of CCL20+ macrophages in atherosclerotic plaques. Stimulation of mouse primary peritoneal macrophages (MPPMs) resulted in increased IL-23 release. miRNA-27b was the most highly expressed (5.19-fold increase) miRNA among the 760 miRNAs screened in the vessel. Naa15 was verified as miRNA-27b target gene, which was diminished in the plaques. Transfection of siRNA Naa15 or miRNA-27b mimic into MAECs caused an increase tube formation. CONCLUSIONS CCR6 deletion effectively ameliorates atherosclerosis progression by reducing macrophage accumulation, resulting in reduced secretion of CCL20 and IL-23. Mechanistically, the decreased miRNA-27b regulates the activity of the CCL20/CCR6 axis by targeting Naa15, and promotes plaque stability in atherosclerosis.
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Affiliation(s)
- Li Qun
- The State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Key Laboratory of Stem Cell Biology and Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Xi Wenda
- The State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Sun Weihong
- Key Laboratory of Stem Cell Biology and Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ma Jianyang
- Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, 20001, China
| | - Cai Wei
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Lou Fangzhou
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xu Zhenyao
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Gao Pingjin
- The State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Key Laboratory of Stem Cell Biology and Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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Papageorgiou N, Zacharia E, Briasoulis A, Charakida M, Tousoulis D. Celecoxib for the treatment of atherosclerosis. Expert Opin Investig Drugs 2016; 25:619-633. [PMID: 26940257 DOI: 10.1517/13543784.2016.1161756] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION It is widely accepted that inflammation plays a pivotal role in the progression of atherosclerosis. Anti-inflammatory drugs and especially selective cyclooxygenase-2 (COX-2) inhibitors have attracted a keen interest. AREAS COVERED In the present drug evaluation article, the authors elucidate the role of celecoxib, a selective COX-2 inhibitor, in the treatment of atherosclerosis. They discuss the atherogenic properties of the COX-2 enzyme. In addition, they address the studies that support an atheroprotective role of celecoxib. Moreover, they provide a review of the literature on the role of COX-2 inhibitors in increasing the rate of major adverse cardiovascular events. Finally, they discuss the emerging evidence that supports celecoxib as an adjuvant or neo-adjuvant therapy to percutaneous coronary intervention (PCI). EXPERT OPINION Several studies have demonstrated a beneficial effect of celecoxib on the progression of atherosclerosis. Nevertheless, this evidence is mainly derived from preliminary data, while a substantial number of clinical studies have raised concerns regarding the cardiovascular safety of COX-2 inhibitors. Interestingly, recent clinical studies have supported the advantages of short-term celecoxib administration in patients undergoing PCI. However, many more large scale clinical trials are required to assess the long-term safety and efficacy of celecoxib administration in patients with cardiovascular disease.
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Affiliation(s)
| | - Effimia Zacharia
- b 1st Department of Cardiology, Hippokration Hospital , University of Athens , Athens , Greece
| | - Alexandros Briasoulis
- c Division of Cardiology , Wayne State University/Detroit Medical Center , Detroit , MI , USA
| | - Marietta Charakida
- d Vascular Physiology Unit, Institute of Cardiovascular Science , University College London , London , UK
| | - Dimitris Tousoulis
- b 1st Department of Cardiology, Hippokration Hospital , University of Athens , Athens , Greece
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