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Huang Y, Liu P, Xu Y, Qian C, Wu T, Li T. Plasma Exosomes Derived from Patients with Primary Immune Thrombocytopenia Attenuate TBX21 + Regulatory T Cell-Mediated Immune Suppression via MiR-363-3p. Inflammation 2025:10.1007/s10753-025-02275-8. [PMID: 40032779 DOI: 10.1007/s10753-025-02275-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 02/14/2025] [Accepted: 02/18/2025] [Indexed: 03/05/2025]
Abstract
Primary Immune Thrombocytopenia (ITP) is characterized by reduced immunosuppressive function of regulatory T cells (Tregs), contributing to immune imbalance and decreased platelet counts. However, the mechanisms behind this reduced efficacy of Tregs remain unclear. Our study used a variety of methods, including Treg function assays, cytokine analysis, and single-cell sequencing, to explore these mechanisms. We found that exosomes from ITP patients inhibited TBX21 expression in Tregs, and impaired their ability to suppress Th1 cells. At the single-cell level, Tregs with high TBX21 expression were identified, and the activity of the TBX21 regulon was found to be enhanced in early-stage Treg subpopulations. We also discovered that ARID3A interacted with SPI1 and TBX21 gene regions, indicating a regulatory relationship between ARID3A, SPI1, and TBX21. Additionally, exosomes in ITP patients' plasma contained elevated levels of miR-363-3p, which negatively correlated with platelet count. These exosomes transferred miR-363-3p to Tregs, downregulating ARID3A, SPI1, and TBX21 expression, thereby weakening Tregs' ability to suppress conventional CD4 + T cells. In conclusion, exosomes from ITP patients reduced Treg function through the ARID3A/SPI1/TBX21 axis by miR-363-3p, diminishing their ability to regulate Th1 cells and contributing to the immune dysfunction observed in ITP.
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Affiliation(s)
- Yuanlan Huang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Department of Blood Transfusion, Naval Specialty Medical Center, Naval Medical University, Shanghai, 200000, China
| | - Peng Liu
- Department of Blood Transfusion, No.971 Hospital of the PLA Navy, Qingdao, China
| | - Ying Xu
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Cheng Qian
- Department of Laboratory Medicine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Tianqin Wu
- Suzhou100 Hospital, Suzhou, 215006, China
| | - Tengda Li
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
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2
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Cilesiz K, Kocak U, Kaya Z, Yenicesu I. The role of eosinophil counts and megakaryocyte nuclei for distinction of acute and chronic immune thrombocytopenic purpura. Blood Coagul Fibrinolysis 2025; 36:1-7. [PMID: 39661538 DOI: 10.1097/mbc.0000000000001328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 10/05/2024] [Indexed: 12/13/2024]
Abstract
OBJECTIVE Immune thrombocytopenic purpura (ITP), the most common cause of thrombocytopenia, is clinically classified as acute and chronic. This study aimed to distinguish between acute/chronic ITP parameters examined at diagnosis via complete blood count (CBC), peripheral blood (PB) and bone marrow aspirate (BMA) smears. It would also contribute to early treatment options, cost-effective policies, and the life quality of patients. METHODS This study consisted of 304 ITP patients aged under 18 years diagnosed and followed up between 1982-2018. Differences between acute and chronic groups were compared by eosinophilia, megakaryocytes (MKs), and megakaryocyte nuclei. Diagnostic scales were created using simple parameters both to guide the distinction between acute and chronic ITP as well as for the prediction of the chronic progression of the patients at diagnosis. RESULTS Of the patients in this study, 71% had acute and 29% had chronic ITP. In CBC and PB smears, eosinophil and lymphocyte counts were higher in acute whereas neutrophil counts were higher in chronic ITP patients. Eosinophil counts in the BMA were also significantly higher in acute ITP patients. There was no significant difference in MK counts. However, the mean number of MK nuclei was higher in acute ITP patients. CONCLUSION Comparison analyses between acute/chronic ITP with the methods developed for the first time are low-cost and promising. Using only eosinophil percentages in the CBC and PB smear, we could identify acute cases by 100%. Further studies including the integration of our study and clinical risk scoring models would contribute to the diagnosis and treatment process of ITP.
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Affiliation(s)
| | - Ulker Kocak
- Department of Pediatric Hematology, Gazi University School of Medicine, Ankara, Turkey
| | - Zuhre Kaya
- Department of Pediatric Hematology, Gazi University School of Medicine, Ankara, Turkey
| | - Idil Yenicesu
- Department of Pediatric Hematology, Gazi University School of Medicine, Ankara, Turkey
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3
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Rong Y, Lu W, Huang X, Ji D, Tang D, Huang R, Zhou W, Chen G, He Y. Exosomal miR-146a-5p derived from bone marrow mesenchymal stromal cells regulate Th1/Th2 balance and alleviates immune thrombocytopenia in pregnancy. Hum Cell 2024; 38:31. [PMID: 39699695 DOI: 10.1007/s13577-024-01162-y] [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: 07/05/2024] [Accepted: 12/14/2024] [Indexed: 12/20/2024]
Abstract
Immune thrombocytopenia (ITP) is a common hematological disorder. Our previous study has found that exosomal miR-146a-5p derived from bone marrow mesenchymal stromal cells (BMSCs) regulate Th17/Treg balance to alleviate ITP. This work further investigated the role of miR-146a-5p in ITP with pregnancy. Compared with healthy pregnant volunteers, the levels of Th1 cells and IFN-γ were increased, the levels of Th2 cells and IL-4 were decreased in peripheral blood of ITP patients with pregnancy. Then, human BMSCs-exosomes repressed the ratio of Th1/Th2 cells in CD4+ T cells, while BMSCs-exosomes with miR-146a-5p inhibitor increased Th1/Th2 cell ratio. Moreover, an ITP mouse model with pregnancy was constructed by administering anti-CD41 antibody in pregnant mice to verify the role of BMSCs-Exo in vivo. BMSCs-Exo elevated the number of platelet and megakaryocyte, improved the function of gastric, spleen and thymus tissues in ITP mice with pregnancy, which attributed to delivery miR-146a-5p. Furthermore, miR-146a-5p interacted with CARD10, and then repressed CARD10/NF-κB signaling pathway. BMSCs-exosomes promoted proliferation and inhibited apoptosis of Dami cells. In conclusion, BMSCs-exosomal miR-146a-5p reduced Th1/Th2 cell ratio to elevate proliferation and inhibit apoptosis of Dami cells, thereby alleviating ITP with pregnancy development. Therefore, miR-146a-5p may be a target for ITP with pregnancy treatment.
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MESH Headings
- MicroRNAs/genetics
- MicroRNAs/physiology
- Female
- Mesenchymal Stem Cells
- Pregnancy
- Exosomes/metabolism
- Humans
- Animals
- Purpura, Thrombocytopenic, Idiopathic/therapy
- Purpura, Thrombocytopenic, Idiopathic/genetics
- Purpura, Thrombocytopenic, Idiopathic/immunology
- Mice
- Disease Models, Animal
- Th1-Th2 Balance
- Th1 Cells/immunology
- Th2 Cells/immunology
- Cells, Cultured
- NF-kappa B/metabolism
- Pregnancy Complications, Hematologic/therapy
- Pregnancy Complications, Hematologic/genetics
- Signal Transduction/genetics
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Affiliation(s)
- Yanyan Rong
- Department of Hematology, First Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi, China
| | - Wei Lu
- Department of Hematology, First Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi, China
| | - Xianbao Huang
- Department of Hematology, First Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi, China
| | - Dexiang Ji
- Department of Hematology, First Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi, China
| | - Dehong Tang
- Department of Blood Transfusion, First Affiliated Hospital of Gannan Medical College, Ganzhou, 341000, Jiangxi, China
| | - Ruibin Huang
- Department of Hematology, First Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi, China
| | - Wenhua Zhou
- Department of Hematology, First Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi, China
| | - Guoan Chen
- Department of Hematology, First Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi, China
| | - Yue He
- Department of Oncology, Donghu District, First Affiliated Hospital of Nanchang University, No. 17 Yongwaizheng Street, Nanchang, 330000, Jiangxi, China.
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Wang Z, Wei H, Li Y, Chen W, Lin Z, Lai Y, Ding L, Zhang L, Zeng H. Bone marrow mesenchymal stem cell-derived exosomes effectively ameliorate the outcomes of rats with acute graft-versus-host disease. FASEB J 2024; 38:e23751. [PMID: 38923701 DOI: 10.1096/fj.202302590rrrrr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 06/03/2024] [Accepted: 06/06/2024] [Indexed: 06/28/2024]
Abstract
Mesenchymal stem cells (MSCs) reveal multifaceted immunoregulatory properties, which can be applied for diverse refractory and recurrent disease treatment including acute graft-versus-host disease (aGVHD). Distinguishing from MSCs with considerable challenges before clinical application, MSCs-derived exosomes (MSC-Exos) are cell-free microvesicles with therapeutic ingredients and serve as advantageous alternatives for ameliorating the outcomes of aGVHD. MSC-Exos were enriched and identified by western blotting analysis, NanoSight, and transmission electron microscopy (TEM). Bone marrow-derived MSCs (denoted as MSCs) and exosomes (denoted as MSC-Exos) were infused into the aGVHD SD-Wister rat model via tail vein, and variations in general growth and survival of rats were observed. The level of inflammatory factors in serum was quantized by enzyme-linked immunosorbent assay (ELISA). The pathological conditions of the liver and intestine of rats were observed by frozen sectioning. The ratios of CD4+/CD8+ and Treg cell proportions in peripheral blood, together with the autophagy in the spleen and thymus, were analyzed by flow cytometry. After treatment with MSC-Exos, the survival time of aGVHD rats was prolonged, the clinical manifestations of aGVHD in rats were improved, whereas the pathological damage of aGVHD in the liver and intestine was reduced. According to ELISA, we found that MSC-Exos revealed ameliorative effect upon aGVHD inflammation (e.g., TNF-α, IL-2, INF-γ, IL-4, and TGF-β) compared to the MSC group. After MSC-Exo treatment, the ratio of Treg cells in peripheral blood was increased, whereas the ratio of CD4+/CD8+ in peripheral blood and the autophagy in the spleen and thymus was decreased. MSC-Exos effectively suppressed the activation of immune cells and the manifestation of the inflammatory response in the aGVHD rat model. Our data would supply new references for MSC-Exo-based "cell-free" biotherapy for aGVHD in future.
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Affiliation(s)
- Zhihong Wang
- Department of Hematology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Hong Wei
- Department of Cadres Health, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Yunfei Li
- Department of Neurology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Weimin Chen
- Department of Hematology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Zhifeng Lin
- Department of Hematology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Yiting Lai
- Department of Hematology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Lingling Ding
- Department of Hematology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Leisheng Zhang
- National Health Commission (NHC) Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, China
| | - Huake Zeng
- Department of Ophthalmology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
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5
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Cines DB. Pathogenesis of refractory ITP: Overview. Br J Haematol 2023; 203:10-16. [PMID: 37735546 PMCID: PMC10539016 DOI: 10.1111/bjh.19083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 06/09/2023] [Accepted: 07/31/2023] [Indexed: 09/23/2023]
Abstract
A subset of individuals with 'primary' or 'idiopathic' immune thrombocytopenia (ITP) who fail to respond to conventional first- and second-line agents or who lose responsiveness are considered to have 'refractory' disease (rITP), placing them at increased risk of bleeding and complications of intensive treatment. However, the criteria used to define the refractory state vary among studies, which complicates research and clinical investigation. Moreover, it is unclear whether rITP is simply 'more severe' ITP, or if there are specific pathogenic pathways that are more likely to result in refractory disease, and whether the presence or development of rITP can be established or anticipated based on these differences. This paper reviews potential biological features that may be associated with rITP, including genetic and epigenetic risk factors, dysregulation of T cells and cytokine networks, antibody affinity and specificity, activation of complement, impaired platelet production and alterations in platelet viability and clearance. These findings indicate the need for longitudinal studies using novel clinically available methodologies to identify and monitor pathogenic T cells, platelet antibodies and other clues to the development of refractory disease.
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Affiliation(s)
- Douglas B Cines
- Department of Pathology and Laboratory Medicine, Perelman-University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
- Department of Medicine, Perelman-University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
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Nelson VS, Jolink ATC, Amini SN, Zwaginga JJ, Netelenbos T, Semple JW, Porcelijn L, de Haas M, Schipperus MR, Kapur R. Platelets in ITP: Victims in Charge of Their Own Fate? Cells 2021; 10:3235. [PMID: 34831457 PMCID: PMC8621961 DOI: 10.3390/cells10113235] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/14/2021] [Accepted: 11/16/2021] [Indexed: 01/19/2023] Open
Abstract
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder. The pathophysiological mechanisms leading to low platelet levels in ITP have not been resolved, but at least involve autoantibody-dependent and/or cytotoxic T cell mediated platelet clearance and impaired megakaryopoiesis. In addition, T cell imbalances involving T regulatory cells (Tregs) also appear to play an important role. Intriguingly, over the past years it has become evident that platelets not only mediate hemostasis, but are able to modulate inflammatory and immunological processes upon activation. Platelets, therefore, might play an immuno-modulatory role in the pathogenesis and pathophysiology of ITP. In this respect, we propose several possible pathways in which platelets themselves may participate in the immune response in ITP. First, we will elaborate on how platelets might directly promote inflammation or stimulate immune responses in ITP. Second, we will discuss two ways in which platelet microparticles (PMPs) might contribute to the disrupted immune balance and impaired thrombopoiesis by megakaryocytes in ITP. Importantly, from these insights, new starting points for further research and for the design of potential future therapies for ITP can be envisioned.
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Affiliation(s)
- Vivianne S. Nelson
- Department of Hematology, Haga Teaching Hospital, 2545 AA The Hague, The Netherlands; (V.S.N.); (S.N.A.); (T.N.)
- Sanquin Research, Department of Experimental Immunohematology, Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, 1066 CX Amsterdam, The Netherlands; (A.-T.C.J.); (M.d.H.)
| | - Anne-Tess C. Jolink
- Sanquin Research, Department of Experimental Immunohematology, Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, 1066 CX Amsterdam, The Netherlands; (A.-T.C.J.); (M.d.H.)
| | - Sufia N. Amini
- Department of Hematology, Haga Teaching Hospital, 2545 AA The Hague, The Netherlands; (V.S.N.); (S.N.A.); (T.N.)
- Department of Hematology, Leiden University Medical Center (LUMC), 2333 ZA Leiden, The Netherlands;
| | - Jaap Jan Zwaginga
- Department of Hematology, Leiden University Medical Center (LUMC), 2333 ZA Leiden, The Netherlands;
- CCTR, Sanquin Blood Supply, 1066 CX Amsterdam, The Netherlands
| | - Tanja Netelenbos
- Department of Hematology, Haga Teaching Hospital, 2545 AA The Hague, The Netherlands; (V.S.N.); (S.N.A.); (T.N.)
| | - John W. Semple
- Division of Hematology and Transfusion Medicine, Lund University, 221 84 Lund, Sweden;
- Clinical Immunology and Transfusion Medicine, Office of Medical Services, 221 84 Lund, Sweden
| | - Leendert Porcelijn
- Sanquin Diagnostic Services, Department of Immunohematology Diagnostics, 1066 CX Amsterdam, The Netherlands;
| | - Masja de Haas
- Sanquin Research, Department of Experimental Immunohematology, Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, 1066 CX Amsterdam, The Netherlands; (A.-T.C.J.); (M.d.H.)
- Department of Hematology, Leiden University Medical Center (LUMC), 2333 ZA Leiden, The Netherlands;
- Sanquin Diagnostic Services, Department of Immunohematology Diagnostics, 1066 CX Amsterdam, The Netherlands;
| | - Martin R. Schipperus
- Department of Hematology, University Medical Center Groningen (UMCG), 9713 GZ Groningen, The Netherlands;
| | - Rick Kapur
- Sanquin Research, Department of Experimental Immunohematology, Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, 1066 CX Amsterdam, The Netherlands; (A.-T.C.J.); (M.d.H.)
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7
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Zhang LS, Yu Y, Yu H, Han ZC. Therapeutic prospects of mesenchymal stem/stromal cells in COVID-19 associated pulmonary diseases: From bench to bedside. World J Stem Cells 2021; 13:1058-1071. [PMID: 34567425 PMCID: PMC8422925 DOI: 10.4252/wjsc.v13.i8.1058] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/10/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
The ongoing outbreak of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 has become a sudden public emergency of international concern and seriously threatens millions of people’s life health. Two current studies have indicated a favorable role for mesenchymal stem/stromal cells (MSCs) in clinical remission of COVID-19 associated pulmonary diseases, yet the systematical elaboration of the therapeutics and underlying mechanism is far from satisfaction. In the present review, we summarize the therapeutic potential of MSCs in COVID-19 associated pulmonary diseases such as pneumonia induced acute lung injury, acute respiratory distress syndrome, and pulmonary fibrosis. Furthermore, we review the underlying mechanism of MSCs including direct- and trans-differentiation, autocrine and paracrine anti-inflammatory effects, homing, and neovascularization, as well as constitutive microenvironment. Finally, we discuss the prospects and supervision of MSC-based cytotherapy for COVID-19 management before large-scale application in clinical practice. Collectively, this review supplies overwhelming new references for understanding the landscapes of MSCs in the remission of COVID-19 associated pulmonary diseases.
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Affiliation(s)
- Lei-Sheng Zhang
- Qianfoshan Hospital & The First Affiliated Hospital, Shandong First Medical University, Jinan 250014, Shandong Province, China
- State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Disease, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
- School of Medicine, Nankai University, Tianjin 300071, China
- Precision Medicine Division, Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd., Tianjin 301700, China
| | - Yi Yu
- State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Disease, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
- The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Hao Yu
- School of Medicine, Nankai University, Tianjin 300071, China
- Cell Products of National Engineering Center & National Stem Cell Engineering Research Center, Tianjin IMCELL Stem Cell and Gene Technology Co., Ltd., Tianjin 300457, China
| | - Zhong-Chao Han
- State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Disease, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
- Precision Medicine Division, Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd., Tianjin 301700, China
- Cell Products of National Engineering Center & National Stem Cell Engineering Research Center, Tianjin IMCELL Stem Cell and Gene Technology Co., Ltd., Tianjin 300457, China
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8
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Sun Y, Hou Y, Meng G, Han P, Zhao Y, Wang H, Xu M, Wang Y, Qiu J, Peng J, Shao L, Sun L, Hou M. Proteomic analysis and microRNA expression profiling of plasma-derived exosomes in primary immune thrombocytopenia. Br J Haematol 2021; 194:1045-1052. [PMID: 34337736 DOI: 10.1111/bjh.17720] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 06/30/2021] [Accepted: 07/08/2021] [Indexed: 12/23/2022]
Abstract
Exosomes are released into extracellular fluids and have emerged as vital biological mediators in autoimmune diseases. Plasma-derived exosomes have been reported to take part in the pathogenesis of primary immune thrombocytopenia (ITP), but the protein and miRNA cargoes have not been entirely elucidated. Via proteomic analysis and RNA sequencing on plasma-derived exosomes from ITP patients and healthy controls, we found one upregulated exosomal protein (apolipoprotein E, ApoE), six downregulated exosomal miRNAs (miR-584-5p, miR-4433a-5p, miR-4433b-3p, miR-6842-3p, miR-130b-5p and miR-222-3p), and 10 upregulated exosomal miRNAs (miR-29a-3p, miR-142-5p, miR-16-2-3p, miR-29b-3p, miR-501-3p, miR-144-5p, miR-192-5p, miR-182-5p, miR-363-3p and miR-96-5p) in ITP patients. The elevated exosomal protein candidate ApoE in the ITP cohort was further validated using western blot. Via quantitative real-time polymerase chain reaction assays, three differentially expressed miRNAs (miR-584-5p, miR-142-5p and miR-29b-3p) were identified. This study provides direct evidence for a restricted signature of exosomal protein and miRNAs which distinguishes ITP from healthy controls. The results require further validation in larger independent ITP cohorts, which will provide insights into the potential pathophysiological significance of circulating exosomes in ITP.
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Affiliation(s)
- Yunqi Sun
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.,Department of Pain, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yu Hou
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Guiyue Meng
- Department of Geriatrics, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Panpan Han
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yajing Zhao
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Haoyi Wang
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Miao Xu
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yawen Wang
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jihua Qiu
- Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jun Peng
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.,Shandong Key Laboratory of Immunohematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Linlin Shao
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Lu Sun
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Ming Hou
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.,Shandong Key Laboratory of Immunohematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.,Leading Research Group of Scientific Innovation, Department of Science and Technology of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
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9
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Exosomal miR-486-5p derived from human placental microvascular endothelial cells regulates proliferation and invasion of trophoblasts via targeting IGF1. Hum Cell 2021; 34:1310-1323. [PMID: 33977502 PMCID: PMC8338855 DOI: 10.1007/s13577-021-00543-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 04/27/2021] [Indexed: 01/12/2023]
Abstract
Preeclampsia (PE) is a serious complication of pregnancy. Exosomes are known to be upregulated in PE. In this study, we sought to investigate the effect of miR-486-5p from human placental microvascular endothelial cells, on the function of trophoblast cells. To investigate the function of human placental microvascular endothelial cell (HPVEC)-derived exosomes on trophoblast cells, HPVECs were treated with hypoxia/reoxygenation (H/R). The separation efficiency of exosomes was determined by transmission electron microscopy, nanosight and Western blot. Cell Counting Kit-8, EdU staining, wound-healing, and transwell assay were performed to detect the effect of exosomally transferred miR-486-5p inhibitor on proliferation, migration and invasion of trophoblast cells. MiRDB and dual-luciferase report assay were used to find the target of miR-486-5p. Our data revealed that miR-486-5p was significantly upregulated in H/R-treated HPVEC-Exo, and miR-486-5p was enriched in HPVEC-Exo. miR-486-5p inhibitor carried by HPVEC-Exo significantly inhibited the proliferation, migration and invasion of trophoblast cells. Insulin-like growth factor 1 (IGF1) was found to be the target of miR-486-5p, and IGF1 overexpression notably reversed the effect of miR-486-5p inhibitor from HPVEC-Exo on trophoblast cell function. In summary, H/R-treated HPVEC-derived exosomally expressing miR-486-5p inhibitor significantly inhibited the proliferation, migration and invasion of trophoblast cells via downregulation of IGF1. The findings from the present study may be useful in the development of treatments for PE.
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