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Ge Z, Qiu C, Zhou J, Yang Z, Jiang T, Yuan W, Yu L, Li J. Proteomic analysis of human Wharton's jelly mesenchymal stem/stromal cells and human amniotic epithelial stem cells: a comparison of therapeutic potential. Sci Rep 2024; 14:28061. [PMID: 39543366 PMCID: PMC11564572 DOI: 10.1038/s41598-024-79063-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 11/06/2024] [Indexed: 11/17/2024] Open
Abstract
Perinatal stem cells have prominent applications in cell therapy and regenerative medicine. Among them, human Wharton's jelly mesenchymal stem/stromal cells (hWJMSCs) and human amniotic epithelial stem cells (hAESCs) have been widely used. However, the distinction in the therapeutic potential of hWJMSCs and hAESCs is poorly understood. In this study, we reported the phenotypic differences between these two distinct cell types and provided the first systematic comparison of their therapeutic potential in terms of immunomodulation, extracellular matrix (ECM) remodelling, angiogenesis and antioxidative stress using proteomics. The results revealed that the two cell types presented different protein expression profiles and were both promising candidates for cell therapy. Both types of cells demonstrated angiogenic and antifibrotic potential, whereas hAESCs presented superior immunological tolerance and antioxidant properties, which were supported by a series of relevant in vitro assays. Our study provides clues for the selection of appropriate cell types for diverse indications in cell therapy, which contributes to the advancement of their clinical translation and application.
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Affiliation(s)
- Zhen Ge
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 310013, Zhejiang, China
| | - Chen Qiu
- Zhejiang Key Laboratory of Cardiovascular Intervention and Precision Medicine of Sir Run Run Shaw Hospital, Zhejiang University-Lishui Joint Innovation Center for Life and Health, Zhejiang University, Hangzhou, 310058, China
- College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, Joint Research Centre for Engineering Biology, Zhejiang University-University of Edinburgh Institute, Zhejiang University, Haining, 314400, China
| | - Jiayi Zhou
- Zhejiang Key Laboratory of Cardiovascular Intervention and Precision Medicine of Sir Run Run Shaw Hospital, Zhejiang University-Lishui Joint Innovation Center for Life and Health, Zhejiang University, Hangzhou, 310058, China
- College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, Joint Research Centre for Engineering Biology, Zhejiang University-University of Edinburgh Institute, Zhejiang University, Haining, 314400, China
| | - Zhuoheng Yang
- Zhejiang Key Laboratory of Cardiovascular Intervention and Precision Medicine of Sir Run Run Shaw Hospital, Zhejiang University-Lishui Joint Innovation Center for Life and Health, Zhejiang University, Hangzhou, 310058, China
- College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, Joint Research Centre for Engineering Biology, Zhejiang University-University of Edinburgh Institute, Zhejiang University, Haining, 314400, China
| | - Tuoying Jiang
- Zhejiang Key Laboratory of Cardiovascular Intervention and Precision Medicine of Sir Run Run Shaw Hospital, Zhejiang University-Lishui Joint Innovation Center for Life and Health, Zhejiang University, Hangzhou, 310058, China
- College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, Joint Research Centre for Engineering Biology, Zhejiang University-University of Edinburgh Institute, Zhejiang University, Haining, 314400, China
| | - Weixin Yuan
- College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, Joint Research Centre for Engineering Biology, Zhejiang University-University of Edinburgh Institute, Zhejiang University, Haining, 314400, China
| | - Luyang Yu
- Zhejiang Key Laboratory of Cardiovascular Intervention and Precision Medicine of Sir Run Run Shaw Hospital, Zhejiang University-Lishui Joint Innovation Center for Life and Health, Zhejiang University, Hangzhou, 310058, China.
- College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, Joint Research Centre for Engineering Biology, Zhejiang University-University of Edinburgh Institute, Zhejiang University, Haining, 314400, China.
| | - Jinying Li
- Zhejiang Key Laboratory of Cardiovascular Intervention and Precision Medicine of Sir Run Run Shaw Hospital, Zhejiang University-Lishui Joint Innovation Center for Life and Health, Zhejiang University, Hangzhou, 310058, China.
- College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, Joint Research Centre for Engineering Biology, Zhejiang University-University of Edinburgh Institute, Zhejiang University, Haining, 314400, China.
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Wei S, Li M, Wang Q, Zhao Y, Du F, Chen Y, Deng S, Shen J, Wu K, Yang J, Sun Y, Gu L, Li X, Li W, Chen M, Ling X, Yu L, Xiao Z, Dong L, Wu X. Mesenchymal Stromal Cells: New Generation Treatment of Inflammatory Bowel Disease. J Inflamm Res 2024; 17:3307-3334. [PMID: 38800593 PMCID: PMC11128225 DOI: 10.2147/jir.s458103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 05/09/2024] [Indexed: 05/29/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, which has a high recurrence rate and is incurable due to a lack of effective treatment. Mesenchymal stromal cells (MSCs) are a class of pluripotent stem cells that have recently received a lot of attention due to their strong self-renewal ability and immunomodulatory effects, and a large number of experimental and clinical models have confirmed the positive therapeutic effect of MSCs on IBD. In preclinical studies, MSC treatment for IBD relies on MSCs paracrine effects, cell-to-cell contact, and its mediated mitochondrial transfer for immune regulation. It also plays a therapeutic role in restoring the intestinal mucosal barrier through the homing effect, regulation of the intestinal microbiome, and repair of intestinal epithelial cells. In the latest clinical trials, the safety and efficacy of MSCs in the treatment of IBD have been confirmed by transfusion of autologous or allogeneic bone marrow, umbilical cord, and adipose MSCs, as well as their derived extracellular vesicles. However, regarding the stable and effective clinical use of MSCs, several concerns emerge, including the cell sources, clinical management (dose, route and frequency of administration, and pretreatment of MSCs) and adverse reactions. This article comprehensively summarizes the effects and mechanisms of MSCs in the treatment of IBD and its advantages over conventional drugs, as well as the latest clinical trial progress of MSCs in the treatment of IBD. The current challenges and future directions are also discussed. This review would add knowledge into the understanding of IBD treatment by applying MSCs.
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Affiliation(s)
- Shulin Wei
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Mingxing Li
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Qin Wang
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Yueshui Zhao
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Fukuan Du
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Yu Chen
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Shuai Deng
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Jing Shen
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Ke Wu
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Jiayue Yang
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Yuhong Sun
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Li Gu
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Xiaobing Li
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Wanping Li
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Meijuan Chen
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Xiao Ling
- Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China
| | - Lei Yu
- Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China
| | - Zhangang Xiao
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Lishu Dong
- Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China
| | - Xu Wu
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
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Hu J, Fu S, Zhan Z, Zhang J. Advancements in dual-target inhibitors of PI3K for tumor therapy: Clinical progress, development strategies, prospects. Eur J Med Chem 2024; 265:116109. [PMID: 38183777 DOI: 10.1016/j.ejmech.2023.116109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 12/24/2023] [Accepted: 12/28/2023] [Indexed: 01/08/2024]
Abstract
Phosphoinositide 3-kinases (PI3Ks) modify lipids by the phosphorylation of inositol phospholipids at the 3'-OH position, thereby participating in signal transduction and exerting effects on various physiological processes such as cell growth, metabolism, and organism development. PI3K activation also drives cancer cell growth, survival, and metabolism, with genetic dysregulation of this pathway observed in diverse human cancers. Therefore, this target is considered a promising potential therapeutic target for various types of cancer. Currently, several selective PI3K inhibitors and one dual-target PI3K inhibitor have been approved and launched on the market. However, the majority of these inhibitors have faced revocation or voluntary withdrawal of indications due to concerns regarding their adverse effects. This article provides a comprehensive review of the structure and biological functions, and clinical status of PI3K inhibitors, with a specific emphasis on the development strategies and structure-activity relationships of dual-target PI3K inhibitors. The findings offer valuable insights and future directions for the development of highly promising dual-target drugs targeting PI3K.
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Affiliation(s)
- Jiarui Hu
- Department of Neurology, Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Siyu Fu
- Department of Neurology, Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Zixuan Zhan
- Department of Neurology, Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Jifa Zhang
- Department of Neurology, Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
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Yang LF, He JD, Jiang WQ, Wang XD, Yang XC, Liang Z, Zhou YK. Interferon-gamma Treatment of Human Umbilical Cord Mesenchymal Stem Cells can Significantly Reduce Damage Associated with Diabetic Peripheral Neuropathy in Mice. Curr Stem Cell Res Ther 2024; 19:1129-1141. [PMID: 37644749 DOI: 10.2174/1574888x19666230829155046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 07/17/2023] [Accepted: 07/24/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND Diabetic peripheral neuropathy causes significant pain to patients. Umbilical cord mesenchymal stem cells have been shown to be useful in the treatment of diabetes and its complications. The aim of this study was to investigate whether human umbilical cord mesenchymal stem cells treated with interferon-gamma can ameliorate nerve injury associated with diabetes better than human umbilical cord mesenchymal stem cells without interferon-gamma treatment. METHODS Human umbilical cord mesenchymal stem cells were assessed for adipogenic differentiation, osteogenic differentiation, and proliferation ability. Vonfry and a hot disc pain tester were used to evaluate tactile sensation and thermal pain sensation in mice. Hematoxylin-eosin and TUNEL staining were performed to visualize sciatic nerve fiber lesions and Schwann cell apoptosis in diabetic mice. Western blotting was used to detect expression of the apoptosis-related proteins Bax, B-cell lymphoma-2, and caspase-3 in mouse sciatic nerve fibers and Schwann cells. Real-Time Quantitative PCR was used to detect mRNA levels of the C-X-C motif chemokine ligand 1, C-X-C motif chemokine ligand 2, C-X-C motif chemokine ligand 9, and C-X-C motif chemokine ligand 10 in mouse sciatic nerve fibers and Schwann cells. Enzyme-linked immunosorbent assay was used to detect levels of the inflammatory cytokines, interleukin- 1β, interleukin-6, and tumor necrosis factor-α in serum and Schwann cells. RESULTS The adipogenic differentiation capacity, osteogenic differentiation capacity, and proliferation ability of human umbilical cord mesenchymal stem cells were enhanced after interferon-gamma treatment. Real-Time Quantitative PCR revealed that interferon-gamma promoted expression of the adipogenic markers, PPAR-γ and CEBP-α, as well as of the osteogenic markers secreted phosphoprotein 1, bone gamma-carboxyglutamate protein, collagen type I alpha1 chain, and Runt-related transcription factor 2. The results of hematoxylin-eosin and TUNEL staining showed that pathological nerve fiber damage and Schwann cell apoptosis were reduced after the injection of interferon-gamma-treated human umbilical cord mesenchymal stem cells. Expression of the apoptosis-related proteins, caspase-3 and Bax, was significantly reduced, while expression of the anti-apoptotic protein B-cell lymphoma-2 was significantly increased. mRNA levels of the cell chemokines, C-X-C motif chemokine ligand 1, C-X-C motif chemokine ligand 2, C-X-C motif chemokine ligand 9, and C-X-C motif chemokine ligand 10, were significantly reduced, and levels of the inflammatory cytokines, interleukin-1β, interleukin-6, and tumor necrosis factor-α, were decreased. Tactile and thermal pain sensations were improved in diabetic mice. CONCLUSION Interferon-gamma treatment of umbilical cord mesenchymal stem cells enhanced osteogenic differentiation, adipogenic differentiation, and proliferative potential. It can enhance the ability of human umbilical cord mesenchymal stem cells to alleviate damage to diabetic nerve fibers and Schwann cells, in addition to improving the neurological function of diabetic mice.
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Affiliation(s)
- Li-Fen Yang
- Department of Endocrinology and Metabolism, First People's Hospital of Yunnan Province, China
| | - Jun-Dong He
- Department of Endocrinology and Metabolism, First People's Hospital of Yunnan Province, China
- Medical School, Kunming University of Science and Technology, Kunming, 650300, Yunnan Province, People's Republic of China
| | - Wei-Qi Jiang
- The First Clinical Medical College, Kunming Medical University, Kunming, 650050, People's Republic of China
| | - Xiao-Dan Wang
- Kunming Yan'an Hospital Kunming, 650051, People's Republic of China
| | - Xiao-Chun Yang
- Department of Ophthalmology First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, 650032, People's Republic of China
| | - Zhi Liang
- Department of Information Center, First People's Hospital of Yunnan Province, China
| | - Yi-Kun Zhou
- Department of Endocrinology and Metabolism, First People's Hospital of Yunnan Province, China
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Tian CM, Zhang Y, Yang MF, Xu HM, Zhu MZ, Yao J, Wang LS, Liang YJ, Li DF. Stem Cell Therapy in Inflammatory Bowel Disease: A Review of Achievements and Challenges. J Inflamm Res 2023; 16:2089-2119. [PMID: 37215379 PMCID: PMC10199681 DOI: 10.2147/jir.s400447] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 05/03/2023] [Indexed: 05/24/2023] Open
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a group of chronic inflammatory diseases of the gastrointestinal tract. Repeated inflammation can lead to complications, such as intestinal fistula, obstruction, perforation, and bleeding. Unfortunately, achieving durable remission and mucosal healing (MH) with current treatments is difficult. Stem cells (SCs) have the potential to modulate immunity, suppress inflammation, and have anti-apoptotic and pro-angiogenic effects, making them an ideal therapeutic strategy to target chronic inflammation and intestinal damage in IBD. In recent years, hematopoietic stem cells (HSCs) and adult mesenchymal stem cells (MSCs) have shown efficacy in treating IBD. In addition, numerous clinical trials have evaluated the efficiency of MSCs in treating the disease. This review summarizes the current research progress on the safety and efficacy of SC-based therapy for IBD in both preclinical models and clinical trials. We discuss potential mechanisms of SC therapy, including tissue repair, paracrine effects, and the promotion of angiogenesis, immune regulation, and anti-inflammatory effects. We also summarize current SC engineering strategies aimed at enhancing the immunosuppressive and regenerative capabilities of SCs for treating intestinal diseases. Additionally, we highlight current limitations and future perspectives of SC-related therapy for IBD.
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Affiliation(s)
- Cheng-Mei Tian
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
- Department of Emergency, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Yuan Zhang
- Department of Medical Administration, Huizhou Institute of Occupational Diseases Control and Prevention, Huizhou, Guangdong, People’s Republic of China
| | - Mei-Feng Yang
- Department of Hematology, Yantian District People’s Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - Hao-Ming Xu
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, People’s Republic of China
| | - Min-Zheng Zhu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, People’s Republic of China
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Li-Sheng Wang
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Yu-Jie Liang
- Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - De-Feng Li
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
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Silva-Carvalho AÉ, da Silva IGM, Corrêa JR, Saldanha-Araujo F. Regulatory T-Cell Enhancement, Expression of Adhesion Molecules, and Production of Anti-Inflammatory Factors Are Differentially Modulated by Spheroid-Cultured Mesenchymal Stem Cells. Int J Mol Sci 2022; 23:ijms232214349. [PMID: 36430835 PMCID: PMC9695986 DOI: 10.3390/ijms232214349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/14/2022] [Accepted: 11/15/2022] [Indexed: 11/22/2022] Open
Abstract
The culture of mesenchymal stem cells (MSCs) as spheroids promotes a more physiological cellular behavior, as it more accurately reflects the biological microenvironment. Nevertheless, mixed results have been found regarding the immunosuppressive properties of spheroid-cultured MSCs (3D-MSCs), the mechanisms of immunoregulation of 3D-MSCs being scarcely described at this point. In the present study, we constructed spheroids from MSCs and compared their immunosuppressive potential with that of MSCs cultured in monolayer (2D-MSCs). First, we evaluated the ability of 2D-MSCs and 3D-MSCs to control the activation and proliferation of T-cells. Next, we evaluated the percentage of regulatory T-cells (Tregs) after the co-culturing of peripheral blood mononuclear cells (PBMCs) with 2D-MSCs and 3D-MSCs. Finally, we investigated the expression of adhesion molecules, as well as the expressions of several anti-inflammatory transcripts in 2D-MSCs and 3D-MSCs maintained in both inflammatory and non-inflammatory conditions. Interestingly, our data show that several anti-inflammatory genes are up-regulated in 3D-MSCs, and that these cells can control T-cell proliferation. Nevertheless, 2D-MSCs are more efficient in suppressing the immune cell proliferation. Importantly, contrary to what was observed in 3D-MSCs, the expressions of ICAM-1 and VCAM-1 are significantly upregulated in 2D-MSCs exposed to an inflammatory environment. Furthermore, only 2D-MSCs are able to promote the enhancement of Tregs. Taken together, our data clearly show that the immunosuppressive potential of MSCs is significantly impacted by their shape, and highlights the important role of cell-cell adhesion molecules for optimal MSC immunomodulatory function.
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Affiliation(s)
- Amandda Évelin Silva-Carvalho
- Hematology and Stem Cells Laboratory, University of Brasília, Brasilia 70910-900, Brazil
- Molecular Pharmacology Laboratory, University of Brasília, Brasilia 70910-900, Brazil
| | | | - José Raimundo Corrêa
- Microscopy and Microanalysis Laboratory, University of Brasília, Brasilia 70910-900, Brazil
| | - Felipe Saldanha-Araujo
- Hematology and Stem Cells Laboratory, University of Brasília, Brasilia 70910-900, Brazil
- Correspondence: ; Tel./Fax: +55-61-3107-2008
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Xu C, Feng C, Huang P, Li Y, Liu R, Liu C, Han Y, Chen L, Ding Y, Shao C, Shi Y. TNFα and IFNγ rapidly activate PI3K-AKT signaling to drive glycolysis that confers mesenchymal stem cells enhanced anti-inflammatory property. Stem Cell Res Ther 2022; 13:491. [PMID: 36195887 PMCID: PMC9531381 DOI: 10.1186/s13287-022-03178-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 09/17/2022] [Indexed: 12/31/2022] Open
Abstract
Background Mesenchymal stem/stromal cells (MSCs) acquire immunosuppressive capacity only in an inflammatory microenvironment. This can be recapitulated in vitro by treating MSCs with inflammatory cytokines TNFα and IFNγ, which induce indoleamine 2,3-dioxygenase (IDO) and TNF-stimulated gene-6 (TSG-6). However, the signaling pathways downstream of the cytokines remain to be elucidated. Methods Inflammatory bowel disease (IBD) mouse model was established by subjecting mice to dextran sulfate sodium (DSS) in drinking water for 7 days. Human UC-MSCs were pretreated with TNF-α and IFN-γ for 24 h and were then infused intravenously at day 2 of DSS administration. Colon tissues were collected for length measurement and histopathological examination. The serum level of IL-6 in mice was measured by enzyme-linked immunosorbent assay. Real-time PCR and Western blot were used to examine the mRNA level and protein expression. MSCs overexpressing constitutive active AKT or dominant negative AKT were generated and were analyzed. The glycolysis level of the MSCs was measured using Extracellular Flux Analyzer. 2-NBDG was used to monitor the uptake of glucose by MSCs. Results TNFα and IFNγ treatment led to rapid consumption of glucose and metabolic skewing toward glycolysis in MSCs, which was required for the therapeutic efficacy of MSCs on IBD. Blockade of glycolysis in MSCs inhibited the expression of immunomodulatory molecules, IDO and TSG-6, as well as the therapeutic effect on IBD. Moreover, PI3K-AKT signaling axis was rapidly activated and was required for the skewing toward glycolysis induced by TNFα and IFNγ. MSCs expressing dominant negative AKT were compromised in their therapeutic efficacy on IBD. Conclusion The glycolysis-dependent anti-inflammatory property of MSCs conferred by inflammatory cytokines is mediated by PI3K-AKT signaling pathway. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03178-3.
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Affiliation(s)
- Chenchang Xu
- The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.,Department of Interventional Radiology and Vascular Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China
| | - Chao Feng
- The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Peiqing Huang
- The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Yinghong Li
- The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Rui Liu
- The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Chunxiao Liu
- The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Yuyi Han
- The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Lei Chen
- Department of Interventional Radiology and Vascular Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China
| | - Yayun Ding
- The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Changshun Shao
- The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
| | - Yufang Shi
- The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
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8
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Yao M, Chen Z, He X, Long J, Xia X, Li Z, Yang Y, Ao L, Xing W, Lian Q, Liang H, Xu X. Cross talk between glucose metabolism and immunosuppression in IFN-γ-primed mesenchymal stem cells. Life Sci Alliance 2022; 5:e202201493. [PMID: 36260750 PMCID: PMC9463493 DOI: 10.26508/lsa.202201493] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 08/30/2022] [Accepted: 08/30/2022] [Indexed: 11/28/2022] Open
Abstract
The immunosuppressive function "licensed" by IFN-γ is a vital attribute of mesenchymal stem cells (MSCs) widely used in the treatment of inflammatory diseases. However, the mechanism and impact of metabolic reprogramming on MSC immunomodulatory plasticity remain unclear. Here, we explored the mechanism by which glucose metabolism affects the immunomodulatory reprogramming of MSCs "licensed" by IFN-γ. Our data showed that glucose metabolism regulates the immunosuppressive function of human umbilical cord MSCs (hUC-MSCs) challenged by IFN-γ through the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Furthermore, ATP facilitated the cross talk between glucose metabolism and the JAK-STAT system, which stimulates the phosphorylation of JAK2 and STATs, as well as the expression of indoleamine 2, 3-dioxygenase and programmed cell death-1 ligand. Moreover, ATP synergistically enhanced the therapeutic efficacy of IFN-γ-primed hUC-MSCs against acute pneumonia in mice. These results indicate a novel cross talk between the immunosuppressive function, glucose metabolism, and mitochondrial oxidation and provide a novel targeting strategy to enhance the therapeutic efficacies of hUC-MSCs.
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Affiliation(s)
- Mengwei Yao
- Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
- Central Laboratory, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Army Medical University, Chongqing, China
| | - Zhuo Chen
- Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
- Central Laboratory, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China
| | - Xiao He
- PLA Rocket Force Characteristic Medical Center, Beijing, China
| | - Jiaoyue Long
- Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
- Central Laboratory, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China
| | - Xuewei Xia
- Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
- Central Laboratory, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Army Medical University, Chongqing, China
| | - Zhan Li
- Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
- Central Laboratory, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China
| | - Yu Yang
- Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
- Central Laboratory, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China
| | - Luoquan Ao
- Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
- Central Laboratory, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China
| | - Wei Xing
- Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
- Central Laboratory, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China
| | - Qizhou Lian
- HKUMed Laboratory of Cellular Therapeutics, and State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pok Fu Lam, Hong Kong
- Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
- Department of Surgery, The University of Hong Kong Shenzhen Hospital, Shenzhen, China
| | - Huaping Liang
- Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Xiang Xu
- Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
- Central Laboratory, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Army Medical University, Chongqing, China
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9
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Zhou C, Bai XY. Strategies for the induction of anti-inflammatory mesenchymal stem cells and their application in the treatment of immune-related nephropathy. Front Med (Lausanne) 2022; 9:891065. [PMID: 36059816 PMCID: PMC9437354 DOI: 10.3389/fmed.2022.891065] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 07/21/2022] [Indexed: 11/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have potent immunomodulatory functions. Animal studies and clinical trials have demonstrated that MSCs can inhibit immune/inflammatory response in tissues and have good therapeutic effects on a variety of immune-related diseases. However, MSCs currently used for treatment are a mixed, undefined, and heterogeneous cell population, resulting in inconsistent clinical treatment effects. MSCs have dual pro-inflammatory/anti-inflammatory regulatory functions in different environments. In different microenvironments, the immunomodulatory function of MSCs has plasticity; therefore, MSCs can transform into pro-inflammatory MSC1 or anti-inflammatory MSC2 phenotypes. There is an urgent need to elucidate the molecular mechanism that induces the phenotypic transition of MSCs to pro-inflammatory or anti-inflammatory MSCs and to develop technical strategies that can induce the transformation of MSCs to the anti-inflammatory MSC2 phenotype to provide a theoretical basis for the future clinical use of MSCs in the treatment of immune-related nephropathy. In this paper, we summarize the relevant strategies and mechanisms for inducing the transformation of MSCs into the anti-inflammatory MSC2 phenotype and enhancing the immunosuppressive function of MSCs.
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10
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Zhang HM, Yuan S, Meng H, Hou XT, Li J, Xue JC, Li Y, Wang Q, Nan JX, Jin XJ, Zhang QG. Stem Cell-Based Therapies for Inflammatory Bowel Disease. Int J Mol Sci 2022; 23:8494. [PMID: 35955628 PMCID: PMC9368934 DOI: 10.3390/ijms23158494] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 11/23/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic, relapsing disease that severely affects patients' quality of life. The exact cause of IBD is uncertain, but current studies suggest that abnormal activation of the immune system, genetic susceptibility, and altered intestinal flora due to mucosal barrier defects may play an essential role in the pathogenesis of IBD. Unfortunately, IBD is currently difficult to be wholly cured. Thus, more treatment options are needed for different patients. Stem cell therapy, mainly including hematopoietic stem cell therapy and mesenchymal stem cell therapy, has shown the potential to improve the clinical disease activity of patients when conventional treatments are not effective. Stem cell therapy, an emerging therapy for IBD, can alleviate mucosal inflammation through mechanisms such as immunomodulation and colonization repair. Clinical studies have confirmed the effectiveness of stem cell transplantation in refractory IBD and the ability to maintain long-term remission in some patients. However, stem cell therapy is still in the research stage, and its safety and long-term efficacy remain to be further evaluated. This article reviews the upcoming stem cell transplantation methods for clinical application and the results of ongoing clinical trials to provide ideas for the clinical use of stem cell transplantation as a potential treatment for IBD.
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Affiliation(s)
- Hua-Min Zhang
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, China; (H.-M.Z.); (S.Y.); (J.-X.N.)
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
| | - Shuo Yuan
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, China; (H.-M.Z.); (S.Y.); (J.-X.N.)
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
| | - Huan Meng
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
| | - Xiao-Ting Hou
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
| | - Jiao Li
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
- Department of Immunology and Pathogenic Biology, College of Basic Medicine, Yanbian University, Yanji 133002, China
| | - Jia-Chen Xue
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
- Department of Immunology and Pathogenic Biology, College of Basic Medicine, Yanbian University, Yanji 133002, China
| | - You Li
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
| | - Qi Wang
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
| | - Ji-Xing Nan
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, China; (H.-M.Z.); (S.Y.); (J.-X.N.)
| | - Xue-Jun Jin
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, China; (H.-M.Z.); (S.Y.); (J.-X.N.)
| | - Qing-Gao Zhang
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
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11
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The Role of Indoleamine 2, 3-Dioxygenase 1 in Regulating Tumor Microenvironment. Cancers (Basel) 2022; 14:cancers14112756. [PMID: 35681736 PMCID: PMC9179436 DOI: 10.3390/cancers14112756] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/19/2022] [Accepted: 05/27/2022] [Indexed: 02/05/2023] Open
Abstract
Indoleamine 2, 3-dioxygenase 1 (IDO1) is a rate-limiting enzyme that metabolizes an essential amino acid tryptophan (Trp) into kynurenine (Kyn), and it promotes the occurrence of immunosuppressive effects by regulating the consumption of Trp and the accumulation of Kyn in the tumor microenvironment (TME). Recent studies have shown that the main cellular components of TME interact with each other through this pathway to promote the formation of tumor immunosuppressive microenvironment. Here, we review the role of the immunosuppression mechanisms mediated by the IDO1 pathway in tumor growth. We discuss obstacles encountered in using IDO1 as a new tumor immunotherapy target, as well as the current clinical research progress.
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12
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Bone Mesenchymal Stem Cell-Derived Exosome-Enclosed miR-181a Induces CD4+CD25+FOXP3+ Regulatory T Cells via SIRT1/Acetylation-Mediated FOXP3 Stabilization. JOURNAL OF ONCOLOGY 2022; 2022:8890434. [PMID: 35664563 PMCID: PMC9162841 DOI: 10.1155/2022/8890434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/22/2022] [Accepted: 03/24/2022] [Indexed: 11/18/2022]
Abstract
Bone marrow mesenchymal stem cells (BMSCs) have been identified as a potential therapeutic approach to immune-related diseases. Here, we show that BMSC-derived exosomes promote FOXP3 expression and induce the conversion of CD4+ T cells into CD4+CD25+FOXP3+ Treg cells, which is significant for immunosuppressive activity. We found that miR-181a-5p is upregulated in BMSC-derived exosomes and can be transferred to CD4+ T cells. In CD4+ cells, miR-181a directly targets SIRT1 and suppresses its expression. Moreover, downregulated SIRT1 enhances FOXP3 via protein acetylation. In conclusion, our data demonstrated that BMSC-derived exosomal miR-181a is critical in the maintenance of immune tolerance. Furthermore, our results reveal that BMSC-derived exosomal miR-181a induces the production of CD4+CD25+FOXP3+ Treg cells via SIRT1/acetylation/FOXP3.
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13
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Suzdaltseva Y, Goryunov K, Silina E, Manturova N, Stupin V, Kiselev SL. Equilibrium among Inflammatory Factors Determines Human MSC-Mediated Immunosuppressive Effect. Cells 2022; 11:1210. [PMID: 35406773 PMCID: PMC8997511 DOI: 10.3390/cells11071210] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 03/29/2022] [Accepted: 04/02/2022] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are thought to be a promising therapeutic agent due to their multiple paracrine and immunomodulatory properties, providing protection from chronic inflammation and promoting tissue repair. MSCs can regulate the balance of pro-inflammatory and anti-inflammatory factors in inflamed tissues, creating a microenvironment necessary for successful healing; however, their interactions with immune cells are still poorly studied. We examined the temporal and spatial changes in gene regulation and the paracrine milieu accompanying the MSC-mediated immunosuppression effect in mixed cultures with activated peripheral blood mononuclear cells (PBMCs). Our data reveal that the peak of suppression of PBMC proliferation was achieved within 48 h following co-culture with MSCs and subsequently did not undergo a significant change. This effect was accompanied by an increase in COX-2 expression and an induction of IDO synthesis in MSCs. At this point, the expression of IL-1, IL-6, IL-8, IFN-γ, MCP-1, and G-CSF was upregulated in co-cultured cells. On the contrary, we observed a decrease in the concentrations of IL-10, IL-13, IL-5, and MIP-1b in co-culture supernatants compared to intact cultures of activated PBMCs. The regulation of IDO, IL-1, IL-6, and G-CSF production was accomplished with the involvement of direct cell-cell contact between MSCs and PBMCs. These findings provide new insights into the use of potential precondition inducers or their combinations to obtain functionally qualified MSCs for more effective treatment of inflammatory diseases.
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Affiliation(s)
- Yulia Suzdaltseva
- Department of Epigenetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, 119333 Moscow, Russia;
| | - Kirill Goryunov
- Department of Cell Technologies, National Medical Research Center for Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia;
| | - Ekaterina Silina
- Institute of Biodesign and Modeling of Complex Systems, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia;
| | - Natalia Manturova
- Department of Plastic and Reconstructive surgery, Cosmetology and Cell Technologies, Pirogov Russian National Research Medical University, 117997 Moscow, Russia;
| | - Victor Stupin
- Department of Hospital Surgery, Pirogov Russian National Research Medical University, 117997 Moscow, Russia;
| | - Sergey L. Kiselev
- Department of Epigenetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, 119333 Moscow, Russia;
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14
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Han Y, Yang J, Fang J, Zhou Y, Candi E, Wang J, Hua D, Shao C, Shi Y. The secretion profile of mesenchymal stem cells and potential applications in treating human diseases. Signal Transduct Target Ther 2022; 7:92. [PMID: 35314676 PMCID: PMC8935608 DOI: 10.1038/s41392-022-00932-0] [Citation(s) in RCA: 300] [Impact Index Per Article: 100.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 11/18/2021] [Accepted: 02/20/2022] [Indexed: 02/06/2023] Open
Abstract
AbstractMesenchymal stromal/stem cells (MSCs) possess multi-lineage differentiation and self-renewal potentials. MSCs-based therapies have been widely utilized for the treatment of diverse inflammatory diseases, due to the potent immunoregulatory functions of MSCs. An increasing body of evidence indicates that MSCs exert their therapeutic effects largely through their paracrine actions. Growth factors, cytokines, chemokines, extracellular matrix components, and metabolic products were all found to be functional molecules of MSCs in various therapeutic paradigms. These secretory factors contribute to immune modulation, tissue remodeling, and cellular homeostasis during regeneration. In this review, we summarize and discuss recent advances in our understanding of the secretory behavior of MSCs and the intracellular communication that accounts for their potential in treating human diseases.
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15
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Becerra J, Duran I. Inflammation, a common mechanism in frailty and COVID-19, and stem cells as a therapeutic approach. Stem Cells Transl Med 2021; 10:1482-1490. [PMID: 34164948 PMCID: PMC8550702 DOI: 10.1002/sctm.21-0074] [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: 03/02/2021] [Revised: 05/12/2021] [Accepted: 06/06/2021] [Indexed: 12/15/2022] Open
Abstract
As our life expectancy increases, specific medical conditions appear, and new challenges are met in terms of global health. Frailty has become a medical and scientific concept to define pathologies where inflammation, depressed immune system, cellular senescence, and molecular aging converge. But more importantly, frailty is the ultimate cause of death that limits our life span and deteriorates health in an increasing proportion of the world population. The difficulty of tackling this problem is the combination of factors that influence frailty appearance, such as stem cells exhaustion, inflammation, loss of regeneration capability, and impaired immunomodulation. To date, multiple research fields have found mechanisms participating in this health condition, but to make progress, science will need to investigate frailty with an interdisciplinary approach. This article summarizes the current efforts to understand frailty from their processes mediated by inflammation, aging, and stem cells to provide a new perspective that unifies the efforts in producing advanced therapies against medical conditions in the context of frailty. We believe this approach against frailty is particularly relevant to COVID-19, since people in a state of frailty die more frequently due to the hyperinflammatory process associated with this infection.
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Affiliation(s)
- José Becerra
- Department of Cell Biology, Genetics, and PhysiologyFaculty of Sciences, University of Málaga, IBIMAMálagaSpain
- Networking Biomedical Research Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER‐BBN)Andalusian Centre for Nanomedicine and Biotechnology‐BIONANDMálagaSpain
| | - Ivan Duran
- Department of Cell Biology, Genetics, and PhysiologyFaculty of Sciences, University of Málaga, IBIMAMálagaSpain
- Networking Biomedical Research Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER‐BBN)Andalusian Centre for Nanomedicine and Biotechnology‐BIONANDMálagaSpain
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16
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Sharma GP, Frei AC, Narayanan J, Gasperetti T, Veley D, Amjad A, Albano K, Fish BL, Himburg HA. Brain-derived neurotrophic factor promotes immune reconstitution following radiation injury via activation of bone marrow mesenchymal stem cells. PLoS One 2021; 16:e0259042. [PMID: 34695155 PMCID: PMC8544859 DOI: 10.1371/journal.pone.0259042] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 10/11/2021] [Indexed: 11/18/2022] Open
Abstract
Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family which has been extensively studied for its roles in neural development, long-term memory, brain injury, and neurodegenerative diseases. BDNF signaling through tropomyosin receptor kinase B (TrkB) stimulates neuronal cell survival. For this reason, small molecule TrkB agonists are under pre-clinical develoment for the treatment of a range of neurodegenerative diseases and injuries. Our laboratory recently reported BDNF is secreted by pro-regenerative endothelial progenitor cells (EPCs) which support hematopoietic reconstitution following total body irradiation (TBI). Here we report BDNF-TrkB signaling plays a novel regenerative role in bone marrow and thymic regeneration following radiation injury. Exogenous administration of BDNF or TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) following myelosuppressive radiation injury promoted faster recovery of mature blood cells and hematopoietic stem cells capable of multi-lineage reconstitution. BDNF promotes hematopoietic regeneration via activation of PDGFRα+ bone marrow mesenchymal stem cells (MSCs) which increase secretion of hematopoietic cytokines interleukin 6 (IL-6) and leukemia inhibitory factor (LIF) in response to TrkB activation. These data suggest pharmacologic activation of the BDNF pathway with either BDNF or 7,8-DHF may be beneficial for treatment of radiation or chemotherapy induced myelosuppression.
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Affiliation(s)
- Guru Prasad Sharma
- Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Anne C. Frei
- Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Jayashree Narayanan
- Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Tracy Gasperetti
- Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Dana Veley
- Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Asma Amjad
- Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Katherine Albano
- Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Brian L. Fish
- Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Heather A. Himburg
- Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
- Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
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17
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Carty F, Dunbar H, Hawthorne IJ, Ting AE, Stubblefield SR, Van't Hof W, English K. IFN-γ and PPARδ influence the efficacy and retention of multipotent adult progenitor cells in graft vs host disease. Stem Cells Transl Med 2021; 10:1561-1574. [PMID: 34397170 PMCID: PMC8550699 DOI: 10.1002/sctm.21-0008] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 06/29/2021] [Accepted: 07/28/2021] [Indexed: 01/14/2023] Open
Abstract
Cell‐based therapy for the treatment of inflammatory disorders has focused on the application of mesenchymal stromal cells (MSCs) and multipotent adult progenitor cells (MAPCs). Despite the recent positive findings in industry‐sponsored clinical trials of MSCs and MAPCs for graft vs host disease (GvHD), cell therapy is efficacious in some but not all patients, highlighting the need to identify strategies to enhance cell‐based therapeutic efficacy. Here, we demonstrate the capacity for interferon (IFN)‐γ licensing to enhance human MAPC efficacy and retention following early administration in a humanized mouse model of acute GvHD (aGvHD). Activation of the nuclear receptor peroxisome proliferator‐activated receptor delta (PPARδ) negatively influenced the retention and efficacy of human MAPCs as well as IFN‐γ‐licensed MAPCs in the aGvHD model. PPARδ antagonism significantly enhanced the efficacy of human MAPCs when administered early in the humanized aGvHD model. COX‐2 expression in human MAPC was significantly decreased in IFN‐γ licensed MAPCs exposed to a PPARδ agonist. Importantly, MAPC exposure to the PPARδ antagonist in the presence of a COX‐2 inhibitor indomethacin before administration significantly reduced the efficacy of PPARδ antagonized MAPCs in the aGvHD humanized mouse model. This is the first study to demonstrate the importance of PPARδ in human MAPC efficacy in vivo and highlights the importance of understanding the disease microenvironment in which cell‐based therapies are to be administered. In particular, the presence of PPARδ ligands may negatively influence MAPC or MSC therapeutic efficacy.
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Affiliation(s)
- Fiona Carty
- Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland.,Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland
| | - Hazel Dunbar
- Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland.,Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland
| | - Ian J Hawthorne
- Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland.,Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland
| | | | | | - Wouter Van't Hof
- Athersys, Inc, Cleveland, Ohio, USA.,Cleveland Cord Blood Center, Cleveland, Ohio, USA
| | - Karen English
- Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland.,Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland
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18
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Kim J, Kim YS, Park SH. Metformin as a Treatment Strategy for Sjögren's Syndrome. Int J Mol Sci 2021; 22:7231. [PMID: 34281285 PMCID: PMC8269365 DOI: 10.3390/ijms22137231] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 06/25/2021] [Accepted: 06/30/2021] [Indexed: 12/26/2022] Open
Abstract
Sjögren's syndrome (SS), a chronic inflammatory disease involving the salivary and lacrimal glands, presents symptoms of sicca as well as systemic manifestations such as fatigue and musculoskeletal pain. Only a few treatments have been successful in management of SS; thus treatment of the disease is challenging. Metformin is the first-line agent for type 2 diabetes and has anti-inflammatory potential. Its immunomodulatory capacity is exerted via activation of 5' adenosine monophosphate-activated protein kinase (AMPK). Metformin inhibits mitochondrial respiratory chain complex I which leads to change in adenosine mono-phosphate (AMP) to adenosine tri-phosphate (ATP) ratio. This results in AMPK activation and causes inhibition of mammalian target of rapamycin (mTOR). mTOR plays an important role in T cell differentiation and mTOR deficient T cells differentiate into regulatory T cells. In this manner, metformin enhances immunoregulatory response in an individual. mTOR is responsible for B cell proliferation and germinal center (GC) differentiation. Thus, reduction of B cell differentiation into antibody-producing plasma cells occurs via downregulation of mTOR. Due to the lack of suggested treatment for SS, metformin has been considered as a treatment strategy and is expected to ameliorate salivary gland function.
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Affiliation(s)
- Joa Kim
- Division of Rheumatology, Department of Internal Medicine, Chosun University Hospital, Gwangju 61453, Korea; (J.K.); (Y.-S.K.)
| | - Yun-Sung Kim
- Division of Rheumatology, Department of Internal Medicine, Chosun University Hospital, Gwangju 61453, Korea; (J.K.); (Y.-S.K.)
| | - Sung-Hwan Park
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
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Refaie AF, Elbassiouny BL, Kloc M, Sabek OM, Khater SM, Ismail AM, Mohamed RH, Ghoneim MA. From Mesenchymal Stromal/Stem Cells to Insulin-Producing Cells: Immunological Considerations. Front Immunol 2021; 12:690623. [PMID: 34248981 PMCID: PMC8262452 DOI: 10.3389/fimmu.2021.690623] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 06/09/2021] [Indexed: 12/24/2022] Open
Abstract
Mesenchymal stem cell (MSC)-based therapy for type 1 diabetes mellitus (T1DM) has been the subject matter of many studies over the past few decades. The wide availability, negligible teratogenic risks and differentiation potential of MSCs promise a therapeutic alternative to traditional exogenous insulin injections or pancreatic transplantation. However, conflicting arguments have been reported regarding the immunological profile of MSCs. While some studies support their immune-privileged, immunomodulatory status and successful use in the treatment of several immune-mediated diseases, others maintain that allogeneic MSCs trigger immune responses, especially following differentiation or in vivo transplantation. In this review, the intricate mechanisms by which MSCs exert their immunomodulatory functions and the influencing variables are critically addressed. Furthermore, proposed avenues to enhance these effects, including cytokine pretreatment, coadministration of mTOR inhibitors, the use of Tregs and gene manipulation, are presented. As an alternative, the selection of high-benefit, low-risk donors based on HLA matching, PD-L1 expression and the absence of donor-specific antibodies (DSAs) are also discussed. Finally, the necessity for the transplantation of human MSC (hMSC)-derived insulin-producing cells (IPCs) into humanized mice is highlighted since this strategy may provide further insights into future clinical applications.
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Affiliation(s)
- Ayman F Refaie
- Nephrology Department, Urology and Nephrology Center, Mansoura, Egypt
| | | | - Malgorzata Kloc
- Department of Immunobiology, The Houston Methodist Research Institute, Houston, TX, United States.,Department of Surgery, The Houston Methodist Hospital, Houston, TX, United States.,Department of Genetics, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, United States
| | - Omaima M Sabek
- Department of Surgery, The Houston Methodist Hospital, Houston, TX, United States.,Department of Cell and Microbiology Biology, Weill Cornell Medical Biology, New York, NY, United States
| | - Sherry M Khater
- Pathology Department, Urology and Nephrology Center, Mansoura, Egypt
| | - Amani M Ismail
- Immunology Department, Urology and Nephrology Center, Mansoura, Egypt
| | - Rania H Mohamed
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
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20
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Wedzinska A, Figiel-Dabrowska A, Kozlowska H, Sarnowska A. The Effect of Proinflammatory Cytokines on the Proliferation, Migration and Secretory Activity of Mesenchymal Stem/Stromal Cells (WJ-MSCs) under 5% O 2 and 21% O 2 Culture Conditions. J Clin Med 2021; 10:1813. [PMID: 33919308 PMCID: PMC8122617 DOI: 10.3390/jcm10091813] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/24/2021] [Accepted: 04/17/2021] [Indexed: 11/16/2022] Open
Abstract
Treatment with Mesenchymal Stem/Stromal Cells (MSCs) in clinical trials is becoming one of the most-popular and fast-developing branches of modern regenerative medicine, as it is still in an experimental phase. The cross-section of diseases to which these cells are applied is very wide, ranging from degenerative diseases, through autoimmune processes and to acute inflammatory diseases, e.g., viral infections. Indeed, now that first clinical trials applying MSCs against COVID-19 have started, important questions concern not only the therapeutic properties of MSCs, but also the changes that might occur in the cell features as a response to the "cytokine storm" present in the acute phase of an infection and capable of posing a risk to a patient. The aim of our study was thus to assess changes potentially occurring in the biology of MSCs in the active inflammatory environment, e.g., in regards to the cell cycle, cell migration and secretory capacity. The study using MSCs derived from Wharton's jelly (WJ-MSCs) was conducted under two aerobic conditions: 21% O2 vs. 5% O2, since oxygen concentration is one of the key factors in inflammation. Under both oxygen conditions cells were exposed to proinflammatory cytokines involved significantly in acute inflammation, i.e., IFNγ, TNFα and IL-1β at different concentrations. Regardless of the aerobic conditions, WJ-MSCs in the inflammatory environment do not lose features typical for mesenchymal cells, and their proliferation dynamic remains unchanged. Sudden fluctuations in proliferation, the early indicator of potential genetic disturbance, were not observed, while the cells' migration activity increased. The presence of pro-inflammatory factors was also found to increase the secretion of such anti-inflammatory cytokines as IL-4 and IL-10. It is concluded that the inflammatory milieu in vitro does not cause phenotype changes or give rise to proliferation disruption of WJ-MSCs, and nor does it inhibit the secretory properties providing for their use against acute inflammation.
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Affiliation(s)
- Aleksandra Wedzinska
- Mossakowski Medical Research Centre, Translational Platform for Regenerative Medicine, Polish Academy of Sciences, 02-106 Warsaw, Poland; (A.W.); (A.F.-D.)
| | - Anna Figiel-Dabrowska
- Mossakowski Medical Research Centre, Translational Platform for Regenerative Medicine, Polish Academy of Sciences, 02-106 Warsaw, Poland; (A.W.); (A.F.-D.)
| | - Hanna Kozlowska
- Mossakowski Medical Research Centre, Laboratory of Advanced Microscopy Techniques, Polish Academy of Sciences, 02-106 Warsaw, Poland;
| | - Anna Sarnowska
- Mossakowski Medical Research Centre, Translational Platform for Regenerative Medicine, Polish Academy of Sciences, 02-106 Warsaw, Poland; (A.W.); (A.F.-D.)
- Mossakowski Medical Research Centre, Stem Cell Bioengineering Unit, Polish Academy of Sciences, 02-106 Warsaw, Poland
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21
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Pers YM, Bony C, Duroux-Richard I, Bernard L, Maumus M, Assou S, Barry F, Jorgensen C, Noël D. miR-155 Contributes to the Immunoregulatory Function of Human Mesenchymal Stem Cells. Front Immunol 2021; 12:624024. [PMID: 33841404 PMCID: PMC8033167 DOI: 10.3389/fimmu.2021.624024] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 03/05/2021] [Indexed: 12/17/2022] Open
Abstract
Objectives Mesenchymal stem/stromal cells (MSCs) are widely investigated in regenerative medicine thanks to their immunomodulatory properties. They exert their anti-inflammatory function thanks to the secretion of a number of mediators, including proteins and miRNAs, which can be released in the extracellular environment or in the cargo of extracellular vesicles (EVs). However, the role of miRNAs in the suppressive function of MSCs is controversial. The aim of the study was to identify miRNAs that contribute to the immunomodulatory function of human bone marrow-derived MSCs (BM-MSCs). Methods Human BM-MSCs were primed by coculture with activated peripheral blood mononuclear cells (aPBMCs). High throughput miRNA transcriptomic analysis was performed using Human MicroRNA TaqMan® Array Cards. The immunosuppressive function of miRNAs was investigated in mixed lymphocyte reactions and the delayed type hypersensitivity (DTH) murine model. Results Upon priming, 21 out of 377 tested miRNAs were significantly modulated in primed MSCs. We validated the up-regulation of miR-29a, miR-146a, miR-155 and the down-regulation of miR-149, miR-221 and miR-361 in additional samples of primed MSCs. We showed that miR-155 significantly reduced the proliferation of aPBMCs in vitro and inflammation in vivo, using the DTH model. Analysis of miRNA-mRNA interactions revealed miR-221 as a potential target gene that is down-regulated by miR-155 both in primed MSCs and in aPBMCs. Conclusion Here, we present evidence that miR-155 participates to the immunosuppressive function of human BM-MSCs and down-regulates the expression of miR-221 as a possible inflammatory mediator.
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MESH Headings
- Animals
- Cell Proliferation
- Cells, Cultured
- Coculture Techniques
- Disease Models, Animal
- Extracellular Vesicles/genetics
- Extracellular Vesicles/immunology
- Extracellular Vesicles/metabolism
- Gene Expression Profiling
- Humans
- Hypersensitivity, Delayed/genetics
- Hypersensitivity, Delayed/immunology
- Hypersensitivity, Delayed/metabolism
- Hypersensitivity, Delayed/prevention & control
- Leukocytes, Mononuclear/immunology
- Leukocytes, Mononuclear/metabolism
- Lymphocyte Culture Test, Mixed
- Male
- Mesenchymal Stem Cell Transplantation
- Mesenchymal Stem Cells/immunology
- Mesenchymal Stem Cells/metabolism
- Mice, Inbred C57BL
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Transcriptome
- Mice
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Affiliation(s)
- Yves-Marie Pers
- IRMB, University of Montpellier, INSERM, CHU Montpellier, Montpellier, France
- Clinical Immunology and Osteoarticular Diseases Therapeutic Unit, Department of Rheumatology, Lapeyronie University Hospital, Montpellier, France
| | - Claire Bony
- IRMB, University of Montpellier, INSERM, CHU Montpellier, Montpellier, France
| | | | - Laurène Bernard
- IRMB, University of Montpellier, INSERM, CHU Montpellier, Montpellier, France
| | - Marie Maumus
- IRMB, University of Montpellier, INSERM, CHU Montpellier, Montpellier, France
| | - Said Assou
- IRMB, University of Montpellier, INSERM, CHU Montpellier, Montpellier, France
| | - Frank Barry
- REMEDI, Regenerative Medicine Institute, National University of Ireland Galway, Galway, Ireland
| | - Christian Jorgensen
- IRMB, University of Montpellier, INSERM, CHU Montpellier, Montpellier, France
- Clinical Immunology and Osteoarticular Diseases Therapeutic Unit, Department of Rheumatology, Lapeyronie University Hospital, Montpellier, France
| | - Danièle Noël
- IRMB, University of Montpellier, INSERM, CHU Montpellier, Montpellier, France
- Clinical Immunology and Osteoarticular Diseases Therapeutic Unit, Department of Rheumatology, Lapeyronie University Hospital, Montpellier, France
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22
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Jiang LL, Liu L. Effect of metformin on stem cells: Molecular mechanism and clinical prospect. World J Stem Cells 2020; 12:1455-1473. [PMID: 33505595 PMCID: PMC7789120 DOI: 10.4252/wjsc.v12.i12.1455] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 09/28/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023] Open
Abstract
Metformin is a first-line medication for type II diabetes. Numerous studies have shown that metformin not only has hypoglycemic effects, but also modulates many physiological and pathological processes ranging from aging and cancer to fracture healing. During these different physiological activities and pathological changes, stem cells usually play a core role. Thus, many studies have investigated the effects of metformin on stem cells. Metformin affects cell differentiation and has promising applications in stem cell medicine. It exerts anti-aging effects and can be applied to gerontology and regenerative medicine. The potential anti-cancer stem cell effect of metformin indicates that it can be an adjuvant therapy for cancers. Furthermore, metformin has beneficial effects against many other diseases including cardiovascular and autoimmune diseases. In this review, we summarize the effects of metformin on stem cells and provide an overview of its molecular mechanisms and clinical prospects.
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Affiliation(s)
- Lin-Li Jiang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lei Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China.
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23
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Kaul NC, Mohapatra SR, Adam I, Tucher C, Tretter T, Opitz CA, Lorenz HM, Tykocinski LO. Hypoxia decreases the T helper cell-suppressive capacity of synovial fibroblasts by downregulating IDO1-mediated tryptophan metabolism. Rheumatology (Oxford) 2020; 59:1148-1158. [PMID: 31846032 DOI: 10.1093/rheumatology/kez587] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 10/07/2019] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVE The development of RA is linked to local infiltration of immune cells and to changes in the phenotype of synovial fibroblasts. Synovial fibroblasts possess the capacity to suppress T cell responses through indoleamine 2, 3-dioxygenase 1 (IDO1)-mediated tryptophan metabolism. However, synovial fibroblasts from RA patients are restricted in this immune-modulatory function. Moreover, hypoxic conditions are detected within synovial tissues of RA patients, with oxygen tensions of only 3.2% O2. This study aims at investigating the effects of hypoxia on the interaction between T cells and synovial fibroblasts, particularly on the T cell-suppressive capacities of synovial fibroblasts. METHODS Synovial fibroblasts were cultured with Th cells under normoxic and hypoxic conditions (3% O2). Th cell proliferation was detected by flow cytometry. Tryptophan and kynurenine amounts were measured by HPLC. IDO1 expression and signal transducer and activator of transcription 1 (STAT1) phosphorylation were quantified by real-time PCR or western blot, and cytokine secretion by ELISA. RESULTS Hypoxic conditions strongly diminished the Th cell-suppressive capacities of both OA synovial fibroblasts and RA synovial fibroblasts. Accordingly, IDO1 mRNA and protein expression, STAT1 phosphorylation and tryptophan metabolism were greatly reduced in OA synovial fibroblasts by hypoxia. MMP-3, IL-6, IL-10 and IFNγ secretion were significantly decreased under hypoxia in synovial fibroblast-Th cell co-cultures, while IL-17A levels were elevated. Supplementation with IFNγ, a well-known inducer of IDO1 expression, could rescue neither IDO1 expression nor Th cell suppression under hypoxic conditions. CONCLUSION Hypoxia strongly affected the crosstalk between synovial fibroblasts and Th cells. By reducing the efficiency of synovial fibroblasts to restrict Th cell proliferation and by increasing the expression of IL-17A, hypoxia might have implications on the pathophysiology of RA.
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Affiliation(s)
- Nathalie-Christin Kaul
- Division of Rheumatology, Department of Internal Medicine V, Heidelberg University Hospital
| | - Soumya R Mohapatra
- Brain Cancer Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Isabell Adam
- Brain Cancer Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Christine Tucher
- Division of Rheumatology, Department of Internal Medicine V, Heidelberg University Hospital
| | - Theresa Tretter
- Division of Rheumatology, Department of Internal Medicine V, Heidelberg University Hospital
| | - Christiane A Opitz
- Brain Cancer Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hanns-Martin Lorenz
- Division of Rheumatology, Department of Internal Medicine V, Heidelberg University Hospital
| | - Lars-Oliver Tykocinski
- Division of Rheumatology, Department of Internal Medicine V, Heidelberg University Hospital
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24
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Jang SG, Lee J, Hong SM, Kwok SK, Cho ML, Park SH. Metformin enhances the immunomodulatory potential of adipose-derived mesenchymal stem cells through STAT1 in an animal model of lupus. Rheumatology (Oxford) 2020; 59:1426-1438. [PMID: 31904843 DOI: 10.1093/rheumatology/kez631] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 11/21/2019] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVES Mesenchymal stem cells (MSCs) are considered potential therapeutic agents for treating autoimmune disease because of their immunomodulatory capacities and anti-inflammatory effects. However, several studies have shown that there is no consistency in the effectiveness of the MSCs to treat autoimmune disease, including SLE. In this study, we investigated whether metformin could enhance the immunoregulatory function of MSCs, what mechanism is relevant, and whether metformin-treated MSCs could be effective in an animal lupus model. METHODS Adipose-derived (Ad)-MSCs were cultured for 72 h in the presence of metformin. Immunoregulatory factors expression was analysed by real-time PCR and ELISA. MRL/lpr mice weekly injected intravenously with 1 × 106 Ad-MSCs or metformin-treated Ad-MSCs for 8 weeks. 16-week-old mice were sacrificed and proteinuria, anti-dsDNA IgG antibody, glomerulonephritis, immune complex, cellular subset were analysed in each group. RESULTS Metformin enhanced the immunomodulatory functions of Ad-MSCs including IDO, IL-10 and TGF-β. Metformin upregulated the expression of p-AMPK, p-STAT1 and inhibited the expression of p-STAT3, p-mTOR in Ad-MSCs. STAT1 inhibition by siRNA strongly diminished IDO, IL-10, TGF-β in metformin-treated Ad-MSCs. As a result, metformin promoted the immunoregulatory effect of Ad-MSCs by enhancing STAT1 expression, which was dependent on the AMPK/mTOR pathway. Administration of metformin-treated Ad-MSCs resulted in significant disease activity improvement including inflammatory phenotype, glomerulonephritis, proteinuria and anti-dsDNA IgG antibody production in MRL/lpr mice. Moreover, metformin-treated Ad-MSCs inhibited CD4-CD8- T-cell expansion and Th17/Treg cell ratio. CONCLUSION Metformin optimized the immunoregulatory properties of Ad-MSCs and may be a novel therapeutic agent for the treatment of lupus.
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Affiliation(s)
- Se Gwang Jang
- The Rheumatism Research Center, Catholic Research Institute of Medical ScienceThe Catholic University of Korea, Seoul, Republic of Korea.,Department of Biomedicine & Health Sciences, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jaeseon Lee
- The Rheumatism Research Center, Catholic Research Institute of Medical ScienceThe Catholic University of Korea, Seoul, Republic of Korea
| | - Seung-Min Hong
- The Rheumatism Research Center, Catholic Research Institute of Medical ScienceThe Catholic University of Korea, Seoul, Republic of Korea
| | - Seung-Ki Kwok
- The Rheumatism Research Center, Catholic Research Institute of Medical ScienceThe Catholic University of Korea, Seoul, Republic of Korea.,Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Mi-La Cho
- The Rheumatism Research Center, Catholic Research Institute of Medical ScienceThe Catholic University of Korea, Seoul, Republic of Korea
| | - Sung-Hwan Park
- The Rheumatism Research Center, Catholic Research Institute of Medical ScienceThe Catholic University of Korea, Seoul, Republic of Korea.,Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Department of Biomedicine & Health Sciences, The Catholic University of Korea, Seoul, Republic of Korea
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25
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Liu J, Liu Q, Chen X. The Immunomodulatory Effects of Mesenchymal Stem Cells on Regulatory B Cells. Front Immunol 2020; 11:1843. [PMID: 32922398 PMCID: PMC7456948 DOI: 10.3389/fimmu.2020.01843] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 07/09/2020] [Indexed: 12/16/2022] Open
Abstract
The therapeutic potential of mesenchymal stem cells (MSCs) has been investigated in many preclinical and clinical studies. This potential is dominantly based on the immunosuppressive properties of MSCs. Although the therapeutic profiles of MSC transplantation are still not fully characterized, accumulating evidence has revealed that B cells change after MSC infusion, in particular inducing regulatory B cells (Bregs). The immunosuppressive effects of Bregs have been demonstrated, and these cells are being evaluated as new targets for the treatment of inflammatory diseases. MSCs are capable of educating B cells and inducing regulatory B cell production via cell-to-cell contact, soluble factors, and extracellular vesicles (EVs). These cells thus have the potential to complement each other's immunomodulatory functions, and a combined approach may enable synergistic effects for the treatment of immunological diseases. However, compared with investigations regarding other immune cells, investigations into how MSCs specifically regulate Bregs have been superficial and insufficient. In this review, we discuss the current findings related to the immunomodulatory effects of MSCs on regulatory B cells and provide optimal strategies for applications in immune-related disease treatments.
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Affiliation(s)
- Jialing Liu
- 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
| | - Xiaoyong Chen
- The Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China.,Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
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26
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Li X, Zhao J, Kasinath V, Uehara M, Jiang L, Banouni N, McGrath MM, Ichimura T, Fiorina P, Lemos DR, Shin SR, Ware CF, Bromberg JS, Abdi R. Lymph node fibroblastic reticular cells deposit fibrosis-associated collagen following organ transplantation. J Clin Invest 2020; 130:4182-4194. [PMID: 32597832 PMCID: PMC7410068 DOI: 10.1172/jci136618] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 04/22/2020] [Indexed: 02/05/2023] Open
Abstract
Although the immune response within draining lymph nodes (DLNs) has been studied for decades, how their stromal compartment contributes to this process remains to be fully explored. Here, we show that donor mast cells were prominent activators of collagen I deposition by fibroblastic reticular cells (FRCs) in DLNs shortly following transplantation. Serial analysis of the DLN indicated that the LN stroma did not return to its baseline microarchitecture following organ rejection and that the DLN contained significant fibrosis following repetitive organ transplants. Using several FRC conditional-knockout mice, we show that induction of senescence in the FRCs of the DLN resulted in massive production of collagen I and a proinflammatory milieu within the DLN. Stimulation of herpes virus entry mediator (HVEM) on FRCs by its ligand LIGHT contributed chiefly to the induction of senescence in FRCs and overproduction of collagen I. Systemic administration of ex vivo-expanded FRCs to mice decreased DLN fibrosis and strengthened the effect of anti-CD40L in prolonging heart allograft survival. These data demonstrate that the transformation of FRCs into proinflammatory myofibroblasts is critically important for the maintenance of a proinflammatory milieu within a fibrotic DLN.
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Affiliation(s)
- Xiaofei Li
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University School of Pharmaceutical Sciences, Wuhan, Hubei, China
| | - Jing Zhao
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Vivek Kasinath
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Mayuko Uehara
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Liwei Jiang
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Naima Banouni
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Martina M. McGrath
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University School of Pharmaceutical Sciences, Wuhan, Hubei, China
| | | | - Paolo Fiorina
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Dario R. Lemos
- Renal Division, Brigham and Women’s Hospital
- Harvard Stem Cell Institute, and
| | - Su Ryon Shin
- Division of Engineering in Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Carl F. Ware
- Infectious and Inflammatory Diseases Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA
| | - Jonathan S. Bromberg
- Department of Surgery and Microbiology and Immunobiology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Reza Abdi
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
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27
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Oh H, Park SH, Kang MK, Kim YH, Lee EJ, Kim DY, Kim SI, Oh SY, Na W, Lim SS, Kang YH. Asaronic Acid Inhibited Glucose-Triggered M2-Phenotype Shift Through Disrupting the Formation of Coordinated Signaling of IL-4Rα-Tyk2-STAT6 and GLUT1-Akt-mTOR-AMPK. Nutrients 2020; 12:E2006. [PMID: 32640667 PMCID: PMC7400890 DOI: 10.3390/nu12072006] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 06/21/2020] [Accepted: 07/03/2020] [Indexed: 12/12/2022] Open
Abstract
Macrophage polarization has been implicated in the pathogenesis of metabolic diseases such as obesity, diabetes, and atherosclerosis. Macrophages responsiveness to polarizing signals can result in their functional phenotype shifts. This study examined whether high glucose induced the functional transition of M2 macrophages, which was inhibited by asaronic acid, one of purple perilla constituents. J774A.1 murine macrophages were incubated with 40 ng/mL interleukin (IL)-4 or exposed to 33 mM glucose in the presence of 1-20 μΜ asaronic acid. In macrophages treated with IL-4 for 48 h, asaronic acid further accelerated cellular induction of the M2 markers of IL-10, arginase-1, CD163, and PPARγ via increased IL-4-IL-4Rα interaction and activated Tyk2-STAT6 pathway. Asaronic acid promoted angiogenic and proliferative capacity of M2-polarized macrophages, through increasing expression of VEGF, PDGF, and TGF-β. In glucose-loaded macrophages, there was cellular induction of IL-4, IL-4 Rα, arginase-1, and CD163, indicating that high glucose skewed naïve macrophages toward M2 phenotypes via an IL-4-IL-4Rα interaction. However, asaronic acid inhibited M2 polarization in diabetic macrophages in parallel with inactivation of Tyk2-STAT6 pathway and blockade of GLUT1-mediated metabolic pathway of Akt-mTOR-AMPKα. Consequently, asaronic acid deterred functional induction of COX-2, CTGF, α-SMA, SR-A, SR-B1, and ABCG1 in diabetic macrophages with M2 phenotype polarity. These results demonstrated that asaronic acid allayed glucose-activated M2-phenotype shift through disrupting coordinated signaling of IL-4Rα-Tyk2-STAT6 in parallel with GLUT1-Akt-mTOR-AMPK pathway. Thus, asaronic acid has therapeutic potential in combating diabetes-associated inflammation, fibrosis, and atherogenesis through inhibiting glucose-evoked M2 polarization.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Young-Hee Kang
- Department of Food Science and Nutrition and The Korean Institute of Nutrition, Hallym University, Chuncheon 24252, Korea; (H.O.); (S.-H.P.); (M.-K.K.); (Y.-H.K.); (E.-J.L.); (D.Y.K.); (S.-I.K.); (S.Y.O.); (W.N.); (S.S.L.)
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28
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Loretelli C, Ben Nasr M, Giatsidis G, Bassi R, Lancerotto L, D'Addio F, Valderrama-Vasquez A, Scherer SS, Salvatore L, Madaghiele M, Abdelsalam A, Ippolito E, Assi E, Usuelli V, El Essawy B, Sannino A, Pietramaggiori G, Zuccotti GV, Orgill DP, Fiorina P. Embryonic stem cell extracts improve wound healing in diabetic mice. Acta Diabetol 2020; 57:883-890. [PMID: 32124076 DOI: 10.1007/s00592-020-01500-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 02/09/2020] [Indexed: 12/13/2022]
Abstract
AIMS/HYPOTHESIS Impaired wound healing significantly impacts morbidity and mortality in diabetic patients, necessitating the development of novel treatments to improve the wound healing process. We here investigated the topical use of acellular embryonic stem cell extracts (EXTs) in wound healing in diabetic db/db mice. METHODS Wounds were induced in diabetic db/db mice, which were subsequently treated with EXTs, with 3T3 fibroblast cell line protein extracts (3T3XTs) or with saline as a control. Pathology and mechanistic assays were then performed. RESULTS The in vivo topical administration of EXTs facilitates wound closure, contraction and re-epithelialization. Moreover, EXTs reduced the number of wound-infiltrating CD45+ inflammatory cells and increased the rate of repair and of angiogenesis as compared to controls. Interestingly, the EXT effect was partly enhanced by the use of a collagen-based biocompatible scaffold. In vivo, topical administration of EXTs increased the percentage of regulatory T cells in the wounded tissue, while in vitro EXT treatment reduced T cell-mediated IFN-γ production. Proteomic screening revealed 82 proteins differentially segregating in EXTs as compared to 3T3 extracts, with APEX1 identified as a key player for the observed immunomodulatory effect of EXTs. CONCLUSIONS EXTs are endowed with immunoregulatory and anti-inflammatory properties; their use improves wound healing in diabetic preclinical models.
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Affiliation(s)
- Cristian Loretelli
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC L. Sacco, Università degli Studi di Milano, Milan, Italy
| | - Moufida Ben Nasr
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC L. Sacco, Università degli Studi di Milano, Milan, Italy
- Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Enders Building 5th Floor, Rm EN530, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Giorgio Giatsidis
- Tissue Engineering and Wound Healing Laboratory, Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Roberto Bassi
- Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Enders Building 5th Floor, Rm EN530, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Luca Lancerotto
- Department of Plastic Surgery, St. John's Hospital, NHS Lothian, Edinburgh, Scotland, UK
| | - Francesca D'Addio
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC L. Sacco, Università degli Studi di Milano, Milan, Italy
| | - Alessandro Valderrama-Vasquez
- Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Enders Building 5th Floor, Rm EN530, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Saja Sandra Scherer
- Tissue Engineering and Wound Healing Laboratory, Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Luca Salvatore
- Department of Engineering for Innovation, University of Salento, Lecce, Italy
| | - Marta Madaghiele
- Department of Engineering for Innovation, University of Salento, Lecce, Italy
| | - Ahmed Abdelsalam
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC L. Sacco, Università degli Studi di Milano, Milan, Italy
- Department of Biochemistry and Biotechnology, Heliopolis University, Cairo, Egypt
| | - Elio Ippolito
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC L. Sacco, Università degli Studi di Milano, Milan, Italy
| | - Emma Assi
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC L. Sacco, Università degli Studi di Milano, Milan, Italy
| | - Vera Usuelli
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC L. Sacco, Università degli Studi di Milano, Milan, Italy
| | - Basset El Essawy
- Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Medicine, Al-Azhar University, Cairo, Egypt
| | - Alessandro Sannino
- Department of Engineering for Innovation, University of Salento, Lecce, Italy
| | - Giorgio Pietramaggiori
- Tissue Engineering and Wound Healing Laboratory, Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Gian Vincenzo Zuccotti
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC L. Sacco, Università degli Studi di Milano, Milan, Italy
- Department of Pediatrics, Buzzi Children's Hospital, Milan, Italy
| | - Dennis Paul Orgill
- Tissue Engineering and Wound Healing Laboratory, Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Paolo Fiorina
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC L. Sacco, Università degli Studi di Milano, Milan, Italy.
- Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Enders Building 5th Floor, Rm EN530, 300 Longwood Avenue, Boston, MA, 02115, USA.
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy.
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29
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Deng L, Li H, Su X, Zhang Y, Xu H, Fan L, Fan J, Han Q, Bai X, Zhao RC. Chlorzoxazone, a small molecule drug, augments immunosuppressive capacity of mesenchymal stem cells via modulation of FOXO3 phosphorylation. Cell Death Dis 2020; 11:158. [PMID: 32123161 PMCID: PMC7052156 DOI: 10.1038/s41419-020-2357-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 02/14/2020] [Accepted: 02/14/2020] [Indexed: 12/26/2022]
Abstract
Nowadays, immune diseases are a large burden in healthcare. Mesenchymal stem cells (MSCs) have prominent ability in immunomodulation and have been applicated on treating many immune-related diseases. However, the clinical outcomes can be disparate and sometimes completely counterproductive beyond explanation of cell heterogeneity. The theory of immunomodulation plasticity in MSCs has then emerged to explain that MSCs can be induced into proinflammatory MSC1 or anti-inflammatory MSC2 responding to different immune environment. It would be safer and more efficient if we could induce MSCs into a certain immune phenotype, in most cases MSC2, prior to medical treatment. In this study, we screened and identified a classical FDA-approved drug, chlorzoxazone (CZ). Unlike traditional method induced by IFN-γ, CZ can induce MSC into MSC2 phenotype and enhance the immunosuppressive capacity without elevation of immunogenicity of MSCs. CZ-treated MSCs can better inhibit T cells activation and proliferation, promote expression of IDO and other immune mediators in vitro, and alleviate inflammatory infiltration and tissue damage in acute kidney injury rat model more effectively. Moreover, we discovered that CZ modulates phosphorylation of transcriptional factor forkhead box O3 (FOXO3) independent of classical AKT or ERK signaling pathways, to promote expression of downstream immune-related genes, therefore contributing to augmentation of MSCs immunosuppressive capacity. Our study established a novel and effective approach to induce MSC2, which is ready for clinical application.
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Affiliation(s)
- Luchan Deng
- Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of New Drug Development and Clinical Trial of Stem Cell Therapy (BZ0381), Beijing, 100005, PR China
| | - Hongling Li
- Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of New Drug Development and Clinical Trial of Stem Cell Therapy (BZ0381), Beijing, 100005, PR China
| | - Xiaodong Su
- Brain Tumor Research Center, Beijing Neurosurgical Institute, Beijing Tiantan Hospital Affliated to Capital Medical University, Beijing Laboratory of Biomedical Materials, Beijing, 100007, PR China
| | - Yingjie Zhang
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, 100853, PR China
| | - Haoying Xu
- Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of New Drug Development and Clinical Trial of Stem Cell Therapy (BZ0381), Beijing, 100005, PR China
| | - Linyuan Fan
- Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of New Drug Development and Clinical Trial of Stem Cell Therapy (BZ0381), Beijing, 100005, PR China
| | - Junfen Fan
- Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of New Drug Development and Clinical Trial of Stem Cell Therapy (BZ0381), Beijing, 100005, PR China
| | - Qin Han
- Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of New Drug Development and Clinical Trial of Stem Cell Therapy (BZ0381), Beijing, 100005, PR China.
| | - Xueyuan Bai
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, 100853, PR China.
| | - Robert Chunhua Zhao
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Peking Union Medical College Hospital, Beijing Key Laboratory of New Drug Development and Clinical Trial of Stem Cell Therapy (BZ0381); Qingdao University, Qingdao, PR China.
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30
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Ye F, Jiang J, Zong C, Yang X, Gao L, Meng Y, Li R, Zhao Q, Han Z, Wei L. Sirt1-Overexpressing Mesenchymal Stem Cells Drive the Anti-tumor Effect through Their Pro-inflammatory Capacity. Mol Ther 2020; 28:874-888. [PMID: 32027844 DOI: 10.1016/j.ymthe.2020.01.018] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 01/06/2020] [Accepted: 01/06/2020] [Indexed: 12/11/2022] Open
Abstract
The major obstacles for the efficacy of tumor immunotherapies are their immune-related systemic adverse events. Therefore, tumor tropism property and pro-inflammatory ability of mesenchymal stem cells (MSCs) could be utilized in combination to potentiate local immunity for cancer eradication. We previously observed that MSCs with the type III histone deacetylase silent information regulator 2 homologue 1 (Sirt1) overexpression displayed a pro-inflammatory capacity. However, the anti-tumor effect of Sirt1-overexpressing MSCs and the role of Sirt1 in regulating the pro-inflammatory capacity of MSCs still need to be clarified. In this study, utilizing the hepatic metastasis model of colorectal carcinoma, we demonstrated that Sirt1-overexpressing MSCs significantly exerted anti-tumor activity through increasing the number of CD8+ T cells. Furthermore, Sirt1 did not affect chemokine secretion in MSCs induced by inflammatory cytokines, but impaired the immunosuppressive ability of MSCs through suppressing inflammatory cytokine-stimulated inducible nitric oxide synthase (iNOS) production via deacetylating p65. iNOS overexpression negated the anti-tumor effect of Sirt1-overexpressing MSCs. Collectively, our data defined Sirt1 as the critical regulator for modulating the pro-inflammatory ability of MSCs, and they suggested that Sirt1-overexpressing MSCs secreting chemokines but little iNOS under the inflammatory milieu were capable of attracting immune cells to close proximity without suppressing their proliferation, thereby achieving a potent anti-tumor effect.
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Affiliation(s)
- Fei Ye
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
| | - Jinghua Jiang
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
| | - Chen Zong
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
| | - Xue Yang
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
| | - Lu Gao
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
| | - Yan Meng
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
| | - Rong Li
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
| | - Qiudong Zhao
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
| | - Zhipeng Han
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China.
| | - Lixin Wei
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai 200438, China.
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31
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Lyden J, Grant S, Ma T. Altered metabolism for neuroprotection provided by mesenchymal stem cells. Brain Circ 2019; 5:140-144. [PMID: 31620662 PMCID: PMC6785946 DOI: 10.4103/bc.bc_36_19] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 08/30/2019] [Accepted: 09/07/2019] [Indexed: 12/22/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent adult stem cells which have become popular research targets for their use in cellular therapy for tissue repair. While recent advancements in research have shown the MSCs have immunomodulatory functions which are altered in response to host inflammatory molecules, how these stimuli produce different functional outcomes is not understood. Here, we evaluate research examining how the proinflammatory cytokine interferon-γ (IFN-γ) affects the immunomodulatory functions of MSCs by altering their metabolism. This study indicates that IFN-γ causes an increase in glycolytic activity and uncoupling of glycolysis to tricarboxylic acid cycle and hence, the glycolytic metabolites and intermediates can be funneled toward the production of anti-inflammatory modulators indoleamine-2,3-dioxygenase and PGE2. A complete understanding of how MSCs' cellular metabolism affects their function is necessary for their employment in cellular therapy, as MSCs have been demonstrated to have pro- and anti-inflammatory functions. These findings are a large step forward in the understanding of the regulation of MSCs and toward their eventual use in cellular therapy, specifically for stroke recovery, in which MSCs have been shown to have powerful neuroprotective and neurogenerative effects.
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Affiliation(s)
- Jack Lyden
- Department of Neurosurgery and Brain Repair, College of Medicine, University of South Florida Morsani, Tampa, Tallahassee, FL, USA
| | - Samuel Grant
- Department of Chemical and Biomedical Engineering, Florida State University, Tallahassee, FL, USA
| | - Teng Ma
- Department of Chemical and Biomedical Engineering, Florida State University, Tallahassee, FL, USA
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32
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Yuan X, Rosenberg JT, Liu Y, Grant SC, Ma T. Aggregation of human mesenchymal stem cells enhances survival and efficacy in stroke treatment. Cytotherapy 2019; 21:1033-1048. [PMID: 31537468 DOI: 10.1016/j.jcyt.2019.04.055] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 04/12/2019] [Accepted: 04/15/2019] [Indexed: 12/13/2022]
Abstract
Human mesenchymal stem cells (hMSCs) have been shown to enhance stroke lesion recovery by mediating inflammation and tissue repair through secretion of trophic factors. However, low cell survival and reduced primitive stem cell function of culture-expanded hMSCs are the major challenges limiting hMSC therapeutic efficacy in stroke treatment. In this study, we report the effects of short-term preconditioning of hMSCs via three-dimensional (3D) aggregation on stroke lesion recovery after intra-arterial (IA) transplantation of 3D aggregate-derived hMSCs (Agg-D hMSCs) in a transient middle cerebral artery occlusion (MCAO) stroke model. Compared with two-dimensional (2D) monolayer culture, Agg-D hMSCs exhibited increased resistance to ischemic stress, secretory function and therapeutic outcome. Short-term preconditioning via 3D aggregation reconfigured hMSC energy metabolism and altered redox cycle, which activated the PI3K/AKT pathway and enhanced resistance to in vitro oxidative stress. Analysis of transplanted hMSCs in MCAO rats using ultra-high-field magnetic resonance imaging at 21.1 T showed increased hMSC persistence and stroke lesion reduction by sodium (23Na) imaging in the Agg-D hMSC group compared with 2D hMSC control. Behavioral analyses further revealed functional improvement in MCAO animal treated with Agg-D hMSCs compared with saline control. Together, the results demonstrated the improved outcome for Agg-D hMSCs in the MCAO model and suggest short-term 3D aggregation as an effective preconditioning strategy for hMSC functional enhancement in stroke treatment.
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Affiliation(s)
- Xuegang Yuan
- Department of Chemical and Biomedical Engineering; Florida State University, Tallahassee, Florida, USA
| | - Jens T Rosenberg
- Department of Chemical and Biomedical Engineering; Florida State University, Tallahassee, Florida, USA; The National High Magnetic Field Laboratory; Florida State University, Tallahassee, Florida, USA
| | - Yijun Liu
- Department of Chemical and Biomedical Engineering; Florida State University, Tallahassee, Florida, USA
| | - Samuel C Grant
- Department of Chemical and Biomedical Engineering; Florida State University, Tallahassee, Florida, USA; The National High Magnetic Field Laboratory; Florida State University, Tallahassee, Florida, USA.
| | - Teng Ma
- Department of Chemical and Biomedical Engineering; Florida State University, Tallahassee, Florida, USA
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33
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Sun T, Ju M, Dai X, Dong H, Gu W, Gao Y, Fu R, Liu X, Huang Y, Liu W, Ch Y, Wang W, Li H, Zhou Y, Shi L, Yang R, Zhang L. Multilevel defects in the hematopoietic niche in essential thrombocythemia. Haematologica 2019; 105:661-673. [PMID: 31289202 PMCID: PMC7049349 DOI: 10.3324/haematol.2018.213686] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 07/05/2019] [Indexed: 12/24/2022] Open
Abstract
The role of the bone marrow niche in essential thrombocythemia (ET) remains unclear. Here, we observed multilevel defects in the hematopoietic niche of patients with JAK2V617F-positive ET, including functional deficiency in mesenchymal stromal cells (MSC), immune imbalance, and sympathetic-nerve damage. Mesenchymal stromal cells from patients with JAK2V617F-positive essential thrombocythemia had a transformed transcriptome. In parallel, they showed enhanced proliferation, decreased apoptosis and senescence, attenuated ability to differentiate into adipocytes and osteocytes, and insufficient support for normal hematopoiesis. Additionally, they were inefficient in suppressing immune responses. For instance, they poorly inhibited proliferation and activation of CD4-positive T cells and the secretion of the inflammatory factor soluble CD40-ligand. They also poorly induced formation of mostly immunosuppressive T-helper 2 cells (Th2) and the secretion of the anti-inflammatory factor interleukin-4 (IL-4). Furthermore, we identified WDR4 as a potent protein with low expression and which was correlated with increased proliferation, reduced senescence and differentiation, and insufficient support for normal hematopoiesis in MSC from patients with JAK2V617F-positive ET. We also observed that loss of WDR4 in MSC cells downregulated the interleukin-6 (IL-6) level through the ERK–GSK3β–CREB signaling based on our in vitro studies. Altogether, our results show that multilevel changes occur in the bone marrow niche of patients with JAK2V617F-positive ET, and low expression of WDR4 in MSC may be critical for inducing hematopoietic related changes.
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Affiliation(s)
- Ting Sun
- State Key Laboratory of Experimental Hematology.,Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin
| | - Mankai Ju
- State Key Laboratory of Experimental Hematology.,Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin
| | - Xinyue Dai
- State Key Laboratory of Experimental Hematology
| | - Huan Dong
- State Key Laboratory of Experimental Hematology
| | - Wenjing Gu
- State Key Laboratory of Experimental Hematology
| | - Yuchen Gao
- State Key Laboratory of Experimental Hematology
| | - Rongfeng Fu
- State Key Laboratory of Experimental Hematology.,Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin.,Tianjin Laboratory of Blood Disease Gene Therapy.,CAMS Key Laboratory of Gene Therapy for Blood Diseases
| | - Xiaofan Liu
- State Key Laboratory of Experimental Hematology.,Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin.,Tianjin Laboratory of Blood Disease Gene Therapy.,CAMS Key Laboratory of Gene Therapy for Blood Diseases
| | - Yueting Huang
- State Key Laboratory of Experimental Hematology.,Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin.,Tianjin Laboratory of Blood Disease Gene Therapy.,CAMS Key Laboratory of Gene Therapy for Blood Diseases
| | - Wei Liu
- State Key Laboratory of Experimental Hematology.,Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin.,Tianjin Laboratory of Blood Disease Gene Therapy.,CAMS Key Laboratory of Gene Therapy for Blood Diseases
| | - Ying Ch
- State Key Laboratory of Experimental Hematology.,Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin.,Tianjin Laboratory of Blood Disease Gene Therapy.,CAMS Key Laboratory of Gene Therapy for Blood Diseases
| | - Wentian Wang
- State Key Laboratory of Experimental Hematology.,Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin.,Tianjin Laboratory of Blood Disease Gene Therapy.,CAMS Key Laboratory of Gene Therapy for Blood Diseases
| | - Huiyuan Li
- State Key Laboratory of Experimental Hematology.,Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin.,Tianjin Laboratory of Blood Disease Gene Therapy.,CAMS Key Laboratory of Gene Therapy for Blood Diseases
| | - Yuan Zhou
- State Key Laboratory of Experimental Hematology.,Tianjin Laboratory of Blood Disease Gene Therapy.,PUMC Department of Stem Cell and Regenerative Medicine, Tianjin, China
| | - Lihong Shi
- State Key Laboratory of Experimental Hematology .,Tianjin Laboratory of Blood Disease Gene Therapy.,CAMS Center for Stem Cell Medicine.,PUMC Department of Stem Cell and Regenerative Medicine, Tianjin, China
| | - Renchi Yang
- State Key Laboratory of Experimental Hematology .,National Clinical Research Center for Blood Diseases.,Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin.,Tianjin Laboratory of Blood Disease Gene Therapy.,CAMS Key Laboratory of Gene Therapy for Blood Diseases.,CAMS Center for Stem Cell Medicine
| | - Lei Zhang
- State Key Laboratory of Experimental Hematology .,National Clinical Research Center for Blood Diseases.,Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin.,Tianjin Laboratory of Blood Disease Gene Therapy.,CAMS Key Laboratory of Gene Therapy for Blood Diseases.,CAMS Center for Stem Cell Medicine.,PUMC Department of Stem Cell and Regenerative Medicine, Tianjin, China
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34
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López-Tello J, Pérez-García V, Khaira J, Kusinski LC, Cooper WN, Andreani A, Grant I, Fernández de Liger E, Lam BY, Hemberger M, Sandovici I, Constancia M, Sferruzzi-Perri AN. Fetal and trophoblast PI3K p110α have distinct roles in regulating resource supply to the growing fetus in mice. eLife 2019; 8:45282. [PMID: 31241463 PMCID: PMC6634971 DOI: 10.7554/elife.45282] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 06/25/2019] [Indexed: 01/07/2023] Open
Abstract
Studies suggest that placental nutrient supply adapts according to fetal demands. However, signaling events underlying placental adaptations remain unknown. Here we demonstrate that phosphoinositide 3-kinase p110α in the fetus and the trophoblast interplay to regulate placental nutrient supply and fetal growth. Complete loss of fetal p110α caused embryonic death, whilst heterozygous loss resulted in fetal growth restriction and impaired placental formation and nutrient transport. Loss of trophoblast p110α resulted in viable fetuses, abnormal placental development and a failure of the placenta to transport sufficient nutrients to match fetal demands for growth. Using RNA-seq we identified genes downstream of p110α in the trophoblast that are important in adapting placental phenotype. Using CRISPR/Cas9 we showed loss of p110α differentially affects gene expression in trophoblast and embryonic stem cells. Our findings reveal important, but distinct roles for p110α in the different compartments of the conceptus, which control fetal resource acquisition and growth.
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Affiliation(s)
- Jorge López-Tello
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Vicente Pérez-García
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.,Epigenetics Programme, The Babraham Institute, Cambridge, United Kingdom
| | - Jaspreet Khaira
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Laura C Kusinski
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.,Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Department of Obstetrics and Gynaecology, The Rosie Hospital, Cambridge, United Kingdom
| | - Wendy N Cooper
- Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Department of Obstetrics and Gynaecology, The Rosie Hospital, Cambridge, United Kingdom
| | - Adam Andreani
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Imogen Grant
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Edurne Fernández de Liger
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Brian Yh Lam
- Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Department of Obstetrics and Gynaecology, The Rosie Hospital, Cambridge, United Kingdom
| | - Myriam Hemberger
- Epigenetics Programme, The Babraham Institute, Cambridge, United Kingdom.,Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada.,Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Ionel Sandovici
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.,Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Department of Obstetrics and Gynaecology, The Rosie Hospital, Cambridge, United Kingdom
| | - Miguel Constancia
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.,Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Department of Obstetrics and Gynaecology, The Rosie Hospital, Cambridge, United Kingdom
| | - Amanda N Sferruzzi-Perri
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
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35
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Marijt KA, Sluijter M, Blijleven L, Tolmeijer SH, Scheeren FA, van der Burg SH, van Hall T. Metabolic stress in cancer cells induces immune escape through a PI3K-dependent blockade of IFNγ receptor signaling. J Immunother Cancer 2019; 7:152. [PMID: 31196219 PMCID: PMC6567539 DOI: 10.1186/s40425-019-0627-8] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 05/20/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND T-cell mediated immunotherapy brought clinical success for many cancer patients. Nonetheless, downregulation of MHC class I antigen presentation, frequently occurring in solid cancers, limits the efficacy of these therapies. Unraveling the mechanisms underlying this type of immune escape is therefore of great importance. We here investigated the immunological effects of metabolic stress in cancer cells as a result of nutrient deprivation. METHODS TC1 and B16F10 tumor cell lines were cultured under oxygen- and glucose-deprivation conditions that mimicked the tumor microenvironment of solid tumors. Presentation of peptide antigens by MHC class I molecules was measured by flow cytometry and via activation of tumor-specific CD8 T cell clones. The proficiency of the IFNy-STAT1 pathway was investigated by Western blots on phosphorylated proteins, transfection of constitutive active STAT1 constructs and qPCR of downstream targets. Kinase inhibitors for PI3K were used to examine its role in IFNy receptor signal transduction. RESULTS Combination of oxygen- and glucose-deprivation resulted in decreased presentation of MHC class I antigens on cancer cells, even in the presence of the stimulatory cytokine IFNy. This unresponsiveness to IFNy was the result of failure to phosphorylate the signal transducer STAT1. Forced expression of constitutive active STAT1 fully rescued the MHC class I presentation. Furthermore, oxygen- and glucose-deprivation increased PI3K activity in tumor cells. Pharmacological inhibition of this pathway not only restored signal transduction through IFNy-STAT1 but also improved MHC class I presentation. Importantly, PI3K inhibitors also rendered tumor cells sensitive for recognition by CD8 T cells in culture conditions of metabolic stress. CONCLUSIONS These data revealed a strong impact of metabolic stress on the presentation of tumor antigens by MHC class I and suggest that this type of tumor escape takes place at hypoxic areas even during times of active T cell immunity and IFNy release.
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Affiliation(s)
- Koen A Marijt
- Department of Medical Oncology, Oncode Institute, C7-P, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, the Netherlands.
| | - Marjolein Sluijter
- Department of Medical Oncology, Oncode Institute, C7-P, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, the Netherlands
| | - Laura Blijleven
- Department of Medical Oncology, Oncode Institute, C7-P, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, the Netherlands
| | - Sofie H Tolmeijer
- Department of Medical Oncology, Oncode Institute, C7-P, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, the Netherlands
| | - Ferenc A Scheeren
- Department of Medical Oncology, Oncode Institute, C7-P, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, the Netherlands
| | - Sjoerd H van der Burg
- Department of Medical Oncology, Oncode Institute, C7-P, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, the Netherlands
| | - Thorbald van Hall
- Department of Medical Oncology, Oncode Institute, C7-P, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, the Netherlands
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Jitschin R, Böttcher M, Saul D, Lukassen S, Bruns H, Loschinski R, Ekici AB, Reis A, Mackensen A, Mougiakakos D. Inflammation-induced glycolytic switch controls suppressivity of mesenchymal stem cells via STAT1 glycosylation. Leukemia 2019; 33:1783-1796. [PMID: 30679801 DOI: 10.1038/s41375-018-0376-6] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 11/19/2018] [Accepted: 12/07/2018] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSCs) represent key contributors to tissue homeostasis and promising therapeutics for hyperinflammatory conditions including graft-versus-host disease. Their immunomodulatory effects are controlled by microenvironmental signals. The MSCs' functional response towards inflammatory cues is known as MSC-"licensing" and includes indoleamine 2,3-dioxygenase (IDO) upregulation. MSCs use tryptophan-depleting IDO to suppress T-cells. Increasing evidence suggests that several functions are (co-)determined by the cells' metabolic commitment. MSCs are capable of both, high levels of glycolysis and of oxidative phosphorylation. Although several studies have addressed alterations of the immune regulatory phenotype elicited by inflammatory priming metabolic mechanisms controlling this process remain unknown. We demonstrate that inflammatory MSC-licensing causes metabolic shifts including enhanced glycolysis and increased fatty acid oxidation. Yet, only interfering with glycolysis impacts IDO upregulation and impedes T-cell-suppressivity. We identified the Janus kinase (JAK)/signal transducer and activator of transcription (STAT)1 pathway as a regulator of both glycolysis and IDO, and show that enhanced glucose turnover is linked to abundant STAT1 glycosylation. Inhibiting the responsible O-acetylglucosamine (O-GlcNAc) transferase abolishes STAT1 activity together with IDO upregulation. Our data suggest that STAT1-O-GlcNAcylation increases its stability towards degradation thus sustaining downstream effects. This pathway could represent a target for interventions aiming to enhance the MSCs' immunoregulatory potency.
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Affiliation(s)
- R Jitschin
- Department of Medicine 5 for Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - M Böttcher
- Department of Medicine 5 for Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - D Saul
- Department of Medicine 5 for Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - S Lukassen
- Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - H Bruns
- Department of Medicine 5 for Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - R Loschinski
- Department of Medicine 5 for Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - A B Ekici
- Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - A Reis
- Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - A Mackensen
- Department of Medicine 5 for Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - D Mougiakakos
- Department of Medicine 5 for Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
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Liu Y, Yuan X, Muñoz N, Logan TM, Ma T. Commitment to Aerobic Glycolysis Sustains Immunosuppression of Human Mesenchymal Stem Cells. Stem Cells Transl Med 2018; 8:93-106. [PMID: 30272389 PMCID: PMC6312448 DOI: 10.1002/sctm.18-0070] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 08/16/2018] [Indexed: 12/13/2022] Open
Abstract
Human mesenchymal stem cells (hMSCs) promote endogenous tissue repair in part by coordinating multiple components of the host immune system in response to environmental stimuli. Recent studies have shown that hMSCs are metabolically heterogeneous and actively reconfigure metabolism to support the biochemical demands of tissue repair. However, how hMSCs regulate their energy metabolism to support their immunomodulatory properties is largely unknown. This study investigates hMSC metabolic reconfiguration during immune activation and provides evidence that the hMSC metabolic state significantly influences their immunomodulatory properties. Specifically, hMSC immune polarization by interferon‐gamma (IFN‐γ) treatment leads to remodeling of hMSC metabolic pathways toward glycolysis, which is required to sustain the secretion of immunosuppressive factors. IFN‐γ exposure also inhibited mitochondrial electron transport activity, and the accumulation of mitochondrial reactive oxygen species plays an important signaling role in this metabolic reconfiguration. The results also show that activation of the Akt/mTOR signaling pathway is required for metabolic reconfiguration during immune polarization and that interruption of these metabolic changes alters the immune response in IFN‐γ licensed hMSCs. The results demonstrate the potential of altering hMSC metabolism to enhance their immunomodulatory properties and therapeutic efficacy in various diseases. Stem Cells Translational Medicine2019;8:93–106
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Affiliation(s)
- Yijun Liu
- Department of Chemical and Biomedical Engineering, Florida State University, Tallahassee, Florida, USA
| | - Xuegang Yuan
- Department of Chemical and Biomedical Engineering, Florida State University, Tallahassee, Florida, USA
| | - Nathalie Muñoz
- Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, USA
| | - Timothy M Logan
- Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, USA.,Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida, USA
| | - Teng Ma
- Department of Chemical and Biomedical Engineering, Florida State University, Tallahassee, Florida, USA.,Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, USA
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Maarouf OH, Uehara M, Kasinath V, Solhjou Z, Banouni N, Bahmani B, Jiang L, Yilmam OA, Guleria I, Lovitch SB, Grogan JL, Fiorina P, Sage PT, Bromberg JS, McGrath MM, Abdi R. Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing. JCI Insight 2018; 3:120546. [PMID: 29997302 DOI: 10.1172/jci.insight.120546] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 05/23/2018] [Indexed: 12/11/2022] Open
Abstract
The contribution of the kidney-draining lymph node (KLN) to the pathogenesis of ischemia-reperfusion injury (IRI) of the kidney and its subsequent recovery has not been explored in depth. In addition, the mechanism by which repetitive IRI contributes to renal fibrosis remains poorly understood. Herein, we have found that IRI of the kidney is associated with expansion of high endothelial venules (HEVs) and activation of fibroblastic reticular cells (FRCs) in the KLN, as demonstrated by significant expansion in the extracellular matrix. The lymphotoxin α signaling pathway mediates activation of FRCs, and chronic treatment with lymphotoxin β receptor-immunoglobulin fusion protein (LTβr-Ig) resulted in marked alteration of the KLN as well as augmentation of renal fibrosis. Depletion of FRCs reduced T cell activation in the KLN and ameliorated renal injury in acute IRI. Repetitive renal IRI was associated with senescence of FRCs, fibrosis of the KLN, and renal scarring, which were ameliorated by FRC administration. Therefore, our study emphasizes the critical role of FRCs in both the initiation and repair phases of injury following IRI of the kidney.
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Affiliation(s)
- Omar H Maarouf
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Renal Division, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA
| | - Mayuko Uehara
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Vivek Kasinath
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Zhabiz Solhjou
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Naima Banouni
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Baharak Bahmani
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Liwei Jiang
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Osman A Yilmam
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Indira Guleria
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Scott B Lovitch
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jane L Grogan
- Department of Cancer Immunology, Genentech, Inc., South San Francisco, California, USA
| | - Paolo Fiorina
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Peter T Sage
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jonathan S Bromberg
- Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Martina M McGrath
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Reza Abdi
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Jang IK, Jung HJ, Noh OK, Lee DH, Lee KC, Park JE. B7‑H1‑mediated immunosuppressive properties in human mesenchymal stem cells are mediated by STAT‑1 and not PI3K/Akt signaling. Mol Med Rep 2018; 18:1842-1848. [PMID: 29901104 DOI: 10.3892/mmr.2018.9102] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2017] [Accepted: 05/01/2018] [Indexed: 11/06/2022] Open
Abstract
Mesenchymal stem cells (MSCs), derived from either bone marrow (BM) or Wharton's jelly (WJ), inhibit the proliferation of activated T cells, and interferon (IFN)‑γ serves an important role in this process. This process is B7‑homolog (H)1‑dependent during cell contact inhibition. However, the signaling pathway involved in B7‑H1 expression in MSCs remains largely undefined. The present study demonstrated activation of B7‑H1 by engaging signal transducer and activator of transcription (STAT)‑1 signaling in MSCs. Human BM‑ and WJ‑MSCs were isolated and cultured. The immunosuppressive effect of BM‑ and WJ‑MSCs on phytohemagglutinin (PHA)‑induced T cell proliferation was compared using direct and indirect co‑culture systems. B7‑H1 expression on BM‑ and WJ‑MSCs was detected by flow cytometry. Small interfering (si)RNA was used to knock down the expression of STAT‑1. The inhibitory effect of MSCs on T lymphocytes was observed using PHA‑induced T cell proliferation assays. IFN‑γ‑induced B7‑H1 expression on human BM‑ and WJ‑MSCs increased in a time‑dependent manner. Furthermore, the inhibitory effect of MSCs on T cell proliferation was be restored when an anti‑B7‑H1 monoclonal antibody was used. When STAT‑1 signaling was inhibited by siRNA, B7‑H1 expression on IFN‑γ‑treated MSCs decreased and T cell proliferation was restored; however, the expression of B7‑H1 did not alter upon treatment with a phosphatidylinositol‑3‑kinase (PI3K) inhibitor (LY294002). These results demonstrated that the IFN‑γ‑induced immunosuppressive properties of B7‑H1 in human BM‑ and WJ‑MSCs were mediated by STAT‑1 signaling, and not by PI3K/RAC‑α serine/threonine‑protein kinase signaling. Understanding the intracellular mechanisms underlying IFN‑γ‑induced expression of B7‑H1 in MSCs may ultimately lead to an improved understanding of MSCs and provide insight into their use as cell therapy agents.
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Affiliation(s)
- In Keun Jang
- Department of Pediatrics, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Hyun Joo Jung
- Department of Pediatrics, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - O Kyu Noh
- Department of Radiation Oncology, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Doo-Hoon Lee
- Biomedical Research Institute, Lifeliver Co., Ltd., Yongin 16866, Republic of Korea
| | - Kwang Chul Lee
- Department of Pediatrics, College of Medicine, Korea University, Seoul 02841, Republic of Korea
| | - Jun Eun Park
- Department of Pediatrics, Ajou University School of Medicine, Suwon 16499, Republic of Korea
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41
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Zhu Y, Feng X. Genetic contribution to mesenchymal stem cell dysfunction in systemic lupus erythematosus. Stem Cell Res Ther 2018; 9:149. [PMID: 29793537 PMCID: PMC5968462 DOI: 10.1186/s13287-018-0898-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Allogeneic mesenchymal stem cell (MSC) transplantation has recently become a promising therapy for patients with systemic lupus erythematosus (SLE). MSCs are a kind of multipotent stem cell than can efficiently modulate both innate and adaptive immune responses, yet those from SLE patients themselves fail to maintain the balance of immune cells, which is partly due to the abnormal genetic background. Clarifying genetic factors associated with MSC dysfunction may be helpful to delineate SLE pathogenesis and provide new therapeutic targets. In this review, the scientific evidence on the genetic contribution to MSC dysfunction in SLE is summarized.
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Affiliation(s)
- Yantong Zhu
- Department of Rheumatology and Immunology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China
| | - Xuebing Feng
- Department of Rheumatology and Immunology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China.
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42
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Broekman W, Khedoe PPSJ, Schepers K, Roelofs H, Stolk J, Hiemstra PS. Mesenchymal stromal cells: a novel therapy for the treatment of chronic obstructive pulmonary disease? Thorax 2018; 73:565-574. [PMID: 29653970 PMCID: PMC5969341 DOI: 10.1136/thoraxjnl-2017-210672] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Revised: 03/18/2018] [Accepted: 03/26/2018] [Indexed: 12/11/2022]
Abstract
COPD is characterised by tissue destruction and inflammation. Given the lack of curative treatments and the progressive nature of the disease, new treatments for COPD are highly relevant. In vitro cell culture and animal studies have demonstrated that mesenchymal stromal cells (MSCs) have the capacity to modify immune responses and to enhance tissue repair. These properties of MSCs provided a rationale to investigate their potential for treatment of a variety of diseases, including COPD. Preclinical models support the hypothesis that MSCs may have clinical efficacy in COPD. However, although clinical trials have demonstrated the safety of MSC treatment, thus far they have not provided evidence for MSC efficacy in the treatment of COPD. In this review, we discuss the rationale for MSC-based cell therapy in COPD, the main findings from in vitro and in vivo preclinical COPD model studies, clinical trials in patients with COPD and directions for further research.
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Affiliation(s)
- Winifred Broekman
- Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands
| | - Padmini P S J Khedoe
- Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands
| | - Koen Schepers
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - Helene Roelofs
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - Jan Stolk
- Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands
| | - Pieter S Hiemstra
- Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands
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43
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Mesenchymal stromal cells (MSCs) and colorectal cancer: a troublesome twosome for the anti-tumour immune response? Oncotarget 2018; 7:60752-60774. [PMID: 27542276 PMCID: PMC5312417 DOI: 10.18632/oncotarget.11354] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 07/09/2016] [Indexed: 12/18/2022] Open
Abstract
The tumour microenvironment (TME) is an important factor in determining the growth and metastasis of colorectal cancer, and can aid tumours by both establishing an immunosuppressive milieu, allowing the tumour avoid immune clearance, and by hampering the efficacy of various therapeutic regimens. The tumour microenvironment is composed of many cell types including tumour, stromal, endothelial and immune cell populations. It is widely accepted that cells present in the TME acquire distinct functional phenotypes that promote tumorigenesis. One such cell type is the mesenchymal stromal cell (MSC). Evidence suggests that MSCs exert effects in the colorectal tumour microenvironment including the promotion of angiogenesis, invasion and metastasis. MSCs immunomodulatory capacity may represent another largely unexplored central feature of MSCs tumour promoting capacity. There is considerable evidence to suggest that MSCs and their secreted factors can influence the innate and adaptive immune responses. MSC-immune cell interactions can skew the proliferation and functional activity of T-cells, dendritic cells, natural killer cells and macrophages, which could favour tumour growth and enable tumours to evade immune cell clearance. A better understanding of the interactions between the malignant cancer cell and stromal components of the TME is key to the development of more specific and efficacious therapies for colorectal cancer. Here, we review and explore MSC- mediated mechanisms of suppressing anti-tumour immune responses in the colon tumour microenvironment. Elucidation of the precise mechanism of immunomodulation exerted by tumour-educated MSCs is critical to inhibiting immunosuppression and immune evasion established by the TME, thus providing an opportunity for targeted and efficacious immunotherapy for colorectal cancer growth and metastasis.
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The future of mesenchymal stem cell-based therapeutic approaches for cancer - From cells to ghosts. Cancer Lett 2017; 414:239-249. [PMID: 29175461 DOI: 10.1016/j.canlet.2017.11.025] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 11/19/2017] [Accepted: 11/21/2017] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cells (MSCs) are multipotent stromal cells which can differentiate into a variety of cell types including osteoblasts, adipocytes and chondrocytes. They are normally resident in adipose tissue, bone marrow and the umbilical cord, but can also be found in other tissues and are known to be recruited to sites of wound healing as well as growing tumours. The therapeutic potential of MSCs has been explored in a number of phase I/II and III clinical trials, of which several were targeted against graft-versus-host disease and to support engraftment of haematopoietic stem cells (HSCs), but currently only very few in the oncology field. There are now three clinical trials either ongoing or recruiting patients that use MSCs to treat tumour disease. In these, MSCs target gastrointestinal, lung and ovarian cancer, respectively. The first study uses MSCs loaded with a HSV-TK expression construct under the control of the CCL5 promoter, and has recently reported successful completion of Phase I/II. While no adverse side effects were seen during this study, no outcomes with respect to therapeutic benefits have been published. The other clinical trials targeting lung and ovarian cancer will be using MSCs expressing cytokines as therapeutic payload. Despite these encouraging early steps towards their clinical use, many questions are still unanswered regarding the biology of MSCs in normal and pathophysiological settings. In this review, in addition to summarising the current state of MSC-based therapeutic approaches for cancer, we will describe the remaining questions, obstacles and risks, as well as novel developments such as MSC-derived nanoghosts.
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45
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Tang BL. The use of mesenchymal stem cells (MSCs) for amyotrophic lateral sclerosis (ALS) therapy – a perspective on cell biological mechanisms. Rev Neurosci 2017; 28:725-738. [DOI: 10.1515/revneuro-2017-0018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 04/04/2017] [Indexed: 12/12/2022]
Abstract
AbstractRecent clinical trials of mesenchymal stem cells (MSCs) transplantation have demonstrated procedural safety and clinical proof of principle with a modest indication of benefit in patients with amyotrophic lateral sclerosis (ALS). While replacement therapy remained unrealistic, the clinical efficacy of this therapeutic option could be potentially enhanced if we could better decipher the mechanisms underlying some of the beneficial effects of transplanted cells, and work toward augmenting or combining these in a strategic manner. Novel ways whereby MSCs could act in modifying disease progression should also be explored. In this review, I discuss the known, emerging and postulated mechanisms of action underlying effects that transplanted MSCs may exert to promote motor neuron survival and/or to encourage regeneration in ALS. I shall also speculate on how transplanted cells may alter the diseased environment so as to minimize non-neuron cell autonomous damages by immune cells and astrocytes.
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Affiliation(s)
- Bor Luen Tang
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University Health System, Singapore
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Medical Drive, Singapore 117597, Singapore
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Caires HR, Esteves T, Quelhas P, Barbosa MA, Navarro M, Almeida CR. Macrophage interactions with polylactic acid and chitosan scaffolds lead to improved recruitment of human mesenchymal stem/stromal cells: a comprehensive study with different immune cells. J R Soc Interface 2017; 13:rsif.2016.0570. [PMID: 27628173 DOI: 10.1098/rsif.2016.0570] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 08/23/2016] [Indexed: 01/07/2023] Open
Abstract
Despite the importance of immune cell-biomaterial interactions for the regenerative outcome, few studies have investigated how distinct three-dimensional biomaterials modulate the immune cell-mediated mesenchymal stem/stromal cells (MSC) recruitment and function. Thus, this work compares the response of varied primary human immune cell populations triggered by different model scaffolds and describes its functional consequence on recruitment and motility of bone marrow MSC. It was found that polylactic acid (PLA) and chitosan scaffolds lead to an increase in the metabolic activity of macrophages but not of peripheral blood mononuclear cells (PBMC), natural killer (NK) cells or monocytes. PBMC and NK cells increase their cell number in PLA scaffolds and express a secretion profile that does not promote MSC recruitment. Importantly, chitosan increases IL-8, MIP-1, MCP-1 and RANTES secretion by macrophages while PLA stimulates IL-6, IL-8 and MCP-1 production, all chemokines that can lead to MSC recruitment. This secretion profile of macrophages in contact with biomaterials correlates with the highest MSC invasion. Furthermore, macrophages enhance stem cell motility within chitosan scaffolds by 44% but not in PLA scaffolds. Thus, macrophages are the cells that in contact with engineered biomaterials become activated to secrete bioactive molecules that stimulate MSC recruitment.
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Affiliation(s)
- Hugo R Caires
- i3S-Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal INEB-Instituto de Engenharia Biomédica, Porto, Portugal ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
| | - Tiago Esteves
- i3S-Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal INEB-Instituto de Engenharia Biomédica, Porto, Portugal Faculdade de Engenharia, Universidade do Porto, Rua Dr. Roberto Frias, s/n, 4200-465 Porto, Portugal
| | - Pedro Quelhas
- i3S-Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal INEB-Instituto de Engenharia Biomédica, Porto, Portugal
| | - Mário A Barbosa
- i3S-Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal INEB-Instituto de Engenharia Biomédica, Porto, Portugal ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
| | - Melba Navarro
- International Center for Numerical Methods in Engineering (CIMNE), Edificio Nexus (103) Carrer del Gran Capità, 2-4, 08034 Barcelona, Spain
| | - Catarina R Almeida
- i3S-Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal INEB-Instituto de Engenharia Biomédica, Porto, Portugal Department of Medical Sciences and Institute for Biomedicine-iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal
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Xiaoxia L, Jiaozi F, Shi Y, Yuming Z, Lihong G. [Clinical applications of stem cells from human exfoliated deciduous teeth in stem cell therapy]. HUA XI KOU QIANG YI XUE ZA ZHI = HUAXI KOUQIANG YIXUE ZAZHI = WEST CHINA JOURNAL OF STOMATOLOGY 2017; 35:533-537. [PMID: 29188652 DOI: 10.7518/hxkq.2017.05.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Stem cells from human exfoliated deciduous teeth (SHED) are one category of dental stem cells. They belong to ectodermal mesenchymal stem cells. As an ideal stem cell source, SHED possess great potential in stem cell therapy. This review demonstrates the biological characteristics and advantages of SHED in stem cell therapy and discusses its multiple functions in tissue regeneration and repair, including multiple differentiation potentiality, cell secretion of cytokines, and immunomodulatory ability. Furthermore, this article introduces the main findings regarding the potential clinical applications of SHED to a variety of diseases. This article demonstrates research progress in dentin-pulp regeneration, maxillofacial bone regeneration, and treatment of nervous system and immune system diseases with SHED for stem cell transplantation.
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Affiliation(s)
- Li Xiaoxia
- Dept. of Pediatric Dentistry, Peking University School and Hospital of Stomatology, Beijing 100081, China
| | - Fangteng Jiaozi
- Dept. of Pediatric Dentistry, Peking University School and Hospital of Stomatology, Beijing 100081, China
| | - Yu Shi
- Dept. of Pediatric Dentistry, Peking University School and Hospital of Stomatology, Beijing 100081, China
| | - Zhao Yuming
- Dept. of Pediatric Dentistry, Peking University School and Hospital of Stomatology, Beijing 100081, China
| | - Ge Lihong
- Dept. of Pediatric Dentistry, Peking University School and Hospital of Stomatology, Beijing 100081, China
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Wang L, Qing L, Liu H, Liu N, Qiao J, Cui C, He T, Zhao R, Liu F, Yan F, Wang C, Liang K, Guo X, Shen YH, Hou X, Chen L. Mesenchymal stromal cells ameliorate oxidative stress-induced islet endothelium apoptosis and functional impairment via Wnt4-β-catenin signaling. Stem Cell Res Ther 2017; 8:188. [PMID: 28807051 PMCID: PMC5557510 DOI: 10.1186/s13287-017-0640-0] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 07/09/2017] [Accepted: 07/24/2017] [Indexed: 12/26/2022] Open
Abstract
Background Islet dysfunction and destruction are the common cause for both type 1 and type 2 diabetes mellitus (T2DM). The islets of Langerhans are highly vascularized miniorgans, and preserving the structural integrity and full function of the microvascular endothelium is vital for protecting the islets from the infiltration of immune cells and secondary inflammatory attack. Mesenchymal stromal cell (MSC)-based therapies have been proven to promote angiogenesis of the islets; however, the underlying mechanism for the protective role of MSCs in the islet endothelium is still vague. Methods In this study, we used MS-1, a murine islet microvascular endothelium cell line, and an MSC-MS1 transwell culturing system to investigate the protective mechanism of rat bone marrow-derived MSCs under oxidative stress in vitro. Cell apoptosis was detected by TUNEL staining, annexin V/PI flow cytometry analysis, and cleaved caspase 3 western blotting analysis. Endothelial cell activation was determined by expression of intercellular cell adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), as well as eNOS phosphorylation/activation. The changes of VCAM-1, eNOS, and the β-catenin expression were also tested in the isolated islets of T2DM rats infused with MSCs. Results We observed that treating MS-1 cells with H2O2 triggered significant apoptosis, induction of VCAM expression, and reduction of eNOS phosphorylation. Importantly, coculturing MS-1 cells with MSCs prevented oxidative stress-induced apoptosis, eNOS inhibition, and VCAM elevation in MS-1 cells. Similar changes in VCAM-1 and eNOS phosphorylation could also be observed in the islets isolated from T2DM rats infused with MSCs. Moreover, MSCs cocultured with MS-1 in vitro or their administration in vivo could both result in an increase of β-catenin, which suggested activation of the β-catenin-dependent Wnt signaling pathway. In MS-1 cells, activation of the β-catenin-dependent Wnt signaling pathway partially mediated the protective effects of MSCs against H2O2-induced apoptosis and eNOS inhibition. Furthermore, MSCs produced a significant amount of Wnt4 and Wnt5a. Although both Wnt4 and Wnt5a participated in the interaction between MSCs and MS-1 cells, Wnt4 exhibited a protective role while Wnt5a seemed to show a destructive role in MS-1 cells. Conclusions Our observations provide evidence that the orchestration of the MSC-secreted Wnts could promote the survival and improve the endothelial function of the injured islet endothelium via activating the β-catenin-dependent Wnt signaling in target endothelial cells. This finding might inspire further in-vivo studies.
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Affiliation(s)
- Lingshu Wang
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Li Qing
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - He Liu
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Na Liu
- College of Public Health, Shandong University, Jinan, Shandong, 250012, China
| | - Jingting Qiao
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Chen Cui
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Tianyi He
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Ruxing Zhao
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Fuqiang Liu
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Fei Yan
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Chuan Wang
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Kai Liang
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Xinghong Guo
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Ying H Shen
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA.,Texas Heart Institute, Houston, TX, USA
| | - Xinguo Hou
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China.
| | - Li Chen
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China.
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Yin K, Zhu R, Wang S, Zhao RC. Low level laser (LLL) attenuate LPS-induced inflammatory responses in mesenchymal stem cells via the suppression of NF-κB signaling pathway in vitro. PLoS One 2017; 12:e0179175. [PMID: 28594941 PMCID: PMC5464618 DOI: 10.1371/journal.pone.0179175] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 05/24/2017] [Indexed: 11/26/2022] Open
Abstract
Background Considering promising results in animal models and patients, therapeutic use of MSCs for immune disease is likely to undergo continued evaluation. Low-lever laser (LLL) has been widely applied to retard the inflammatory reaction. LLL treatment can potentially be applied in anti-inflammatory therapy followed by stem cell therapy. Aim of the study The purpose of this study was to investigate the effect of LLL (660 nm) on the inflammatory reaction induced by LPS in human adipose derived mesenchymal stem cells (hADSCs) and pertinent mechanism. Materials and methods Anti-inflammatory activity of LLL was investigated by LPS-induced mesenchymal stem cells. The production and expression of pro-inflammatory cytokines were evaluated by ELISA kits and RT-qPCR. Nuclear translocation of NF-κB was indicated by immunofluorescent staining. Phosphorylation status of NF-κB p65 and IκBα were illustrated by western blot assay. ROS generation was measured with CM-H2DCFDA, and NO secretion was determined by DAF-FM. We studied surface expression of lymphocyte activation markers when Purified peripheral blood mononuclear cell (PBMC) were activated by phytohaemagglutinin (PHA) in the presence of 3 types of treated MSCs. Results LLL reduced the secretion of IL-1β, IL-6, IL8, ROS and NO in LPS treated MSCs. Immunofluorescent assay demonstrated the nuclear translocation decrease of NF-κB in LLL treated LPS induced MSCs. Western blot analysis also suggested that LLL suppressed NF-κB activation via regulating the phosphorylation of p65 and IκBα. MSC significantly reduced the expression of activation markers CD25 and CD69 on PHA-stimulated lymphocytes. Conclusion The results indicate that LLL suppressed the activation of NF-κB signaling pathway in LPS treated MSCs through inhibiting phosphorylation of p65 and IκBα, which results in good anti-inflammatory effect. In addition, LLL attenuated activation-associated markers CD25 and CD69 in co-cultures of PBMC and 3 types of treated MSCs.
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Affiliation(s)
- Kan Yin
- Centre of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Rongjia Zhu
- Centre of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Shihua Wang
- Centre of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Robert Chunhua Zhao
- Centre of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
- * E-mail:
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50
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Xu C, Fu F, Li X, Zhang S. Mesenchymal stem cells maintain the microenvironment of central nervous system by regulating the polarization of macrophages/microglia after traumatic brain injury. Int J Neurosci 2017; 127:1124-1135. [PMID: 28464695 DOI: 10.1080/00207454.2017.1325884] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cells (MSCs), which are regarded as promising candidates for cell replacement therapies, are able to regulate immune responses after traumatic brain injury (TBI). Secondary immune response following the mechanical injury is the essential factor leading to the necrosis and apoptosis of neural cells during and after the cerebral edema has subsided and there is lack of efficient agent that can mitigate such neuroinflammation in the clinical application. By means of three molecular pathways (prostaglandin E2 (PGE2), tumor-necrosis-factor-inducible gene 6 protein (TSG-6), and progesterone receptor (PR) and glucocorticoid receptors (GR)), MSCs induce the activation of macrophages/microglia and drive them polarize into the M2 phenotypes, which inhibits the release of pro-inflammatory cytokines and promotes tissue repair and nerve regeneration. The regulation of MSCs and the polarization of macrophages/microglia are dynamically changing based on the inflammatory environment. Under the stimulation of platelet lysate (PL), MSCs also promote the release of pro-inflammatory cytokines. Meanwhile, the statue of macrophages/microglia exerts significant effects on the survival, proliferation, differentiation and activation of MSCs by changing the niche of cells. They form positive feedback loops in maintaining the homeostasis after TBI to relieving the secondary injury and promoting tissue repair. MSC therapies have obtained great achievements in several central nervous system disease clinical trials, which will accelerate the application of MSCs in TBI treatment.
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Affiliation(s)
- Chao Xu
- a Institute of Traumatic Brain Injury and Neurology, Pingjin Hospital , Logistics University of Chinese People's Armed Police Forces , Tianjin 300162 , China
| | - Feng Fu
- a Institute of Traumatic Brain Injury and Neurology, Pingjin Hospital , Logistics University of Chinese People's Armed Police Forces , Tianjin 300162 , China
| | - Xiaohong Li
- a Institute of Traumatic Brain Injury and Neurology, Pingjin Hospital , Logistics University of Chinese People's Armed Police Forces , Tianjin 300162 , China
| | - Sai Zhang
- a Institute of Traumatic Brain Injury and Neurology, Pingjin Hospital , Logistics University of Chinese People's Armed Police Forces , Tianjin 300162 , China
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