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Mei J, Jiao F, Li Y, Cui J, Yang H, Wang L. Application of thrombopoietic agents in cancer therapy-induced thrombocytopenia: A comprehensive review. Blood Rev 2025; 70:101257. [PMID: 39809679 DOI: 10.1016/j.blre.2025.101257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 11/30/2024] [Accepted: 01/07/2025] [Indexed: 01/16/2025]
Abstract
Cancer therapy-induced thrombocytopenia (CT-IT) is one of the most common hematological toxicities of anti-cancer therapy, often leading to treatment dose reduced, postponed, or treatment plans altered or even discontinued. Thrombopoietin (TPO) is the only key regulatory factor in platelet production, and TPO receptor is considered an ideal target for the treatment of thrombocytopenia. Thrombopoietic agents, including recombinant human thrombopoietin (rhTPO) and thrombopoietin receptor agonists (TPO-RAs), bind to different regions of the TPO receptor, activating downstream signaling pathways to increase platelet levels. In recent years, numerous studies have demonstrated the effectiveness of thrombopoietic agents in the management of CT-IT. These agents can reduce bleeding risk, decrease platelet transfusions, and maintain relative dose intensity (RDI) of anti-cancer treatments. This article provides a review of the current progress in the application of thrombopoietic agents for CT-IT management.
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Affiliation(s)
- Junyang Mei
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, China
| | - Feng Jiao
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yiping Li
- Department of Oncology, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan 430065, China
| | - Jiujie Cui
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
| | - Haiyan Yang
- Department of Oncology, SinoUnited Hospital, Shanghai 200002, China.
| | - Liwei Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, China; Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
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Zhao Y, Wang C, Du J, Wang W, Wu J, Liu T, Xue P, Ju Y, Hong X, Zheng J, Qu W, Zhang Y. Cadmium biphasically impacts the adaptive immune system via regulating mitochondrial activation of hematopoietic stem cells in mice. Toxicol Appl Pharmacol 2025; 495:117216. [PMID: 39725238 DOI: 10.1016/j.taap.2024.117216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/13/2024] [Accepted: 12/21/2024] [Indexed: 12/28/2024]
Abstract
Cadmium (Cd) is a highly toxic metal in human body, and therefore understanding the immunotoxicity of Cd is significant for public health. The aim of this study was to investigate the role of hematopoietic stem cells (HSC) in regulating the immunotoxicity of Cd. After exposure to 10 ppm Cd via drinking water for up to 9 months, C57BL/6 mice had a suppressed adaptive immune system at day 135 but had an enhanced adaptive immune system at day 270 during Cd exposure. The biphasic impacts of Cd on the adaptive immune system were correlated to the mitochondrial (MT) activation of HSC. Mechanistically, a direct action of Cd activated the non-canonical Wnt signaling to increase MT activation in HSC in the bone marrow (BM) at day 90, thus resulting in an impaired adaptive immune system in mice at day 135 during Cd exposure; conversely, Cd reduced the production of thrombopoietin (TPO) by osteoblasts in the BM to suppress MT activation in HSC at day 180, which in turn caused an enhanced adaptive immune system in mice at day 270 during Cd exposure. Thus, Cd biphasically impacts the adaptive immune system via regulating MT activation of HSC, providing a novel angle for understanding the immunotoxicology of metals.
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Affiliation(s)
- Yifan Zhao
- Experimental Center for Research, School of Public Health and Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai 200032, China
| | - Chuanxuan Wang
- Experimental Center for Research, School of Public Health and Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai 200032, China
| | - Jun Du
- Amway (Shanghai) Innovation & Science Co., Ltd, Shanghai 201203, China
| | - Wei Wang
- Experimental Center for Research, School of Public Health and Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai 200032, China
| | - Jiaojiao Wu
- Experimental Center for Research, School of Public Health and Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai 200032, China
| | - Ting Liu
- Experimental Center for Research, School of Public Health and Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai 200032, China
| | - Peng Xue
- Experimental Center for Research, School of Public Health and Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai 200032, China
| | - Yingzi Ju
- Experimental Center for Research, School of Public Health and Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai 200032, China
| | - Xinyu Hong
- Institute of Chemical Toxicity Testing/State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, Shanghai Municipal Center for Disease Control and Prevention, Shanghai 200336, China.
| | - Jianheng Zheng
- Amway (Shanghai) Innovation & Science Co., Ltd, Shanghai 201203, China.
| | - Weidong Qu
- Experimental Center for Research, School of Public Health and Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai 200032, China
| | - Yubin Zhang
- Experimental Center for Research, School of Public Health and Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai 200032, China.
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Kumar V, Stewart Iv JH. Platelet's plea to Immunologists: Please do not forget me. Int Immunopharmacol 2024; 143:113599. [PMID: 39547015 DOI: 10.1016/j.intimp.2024.113599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 10/07/2024] [Accepted: 11/06/2024] [Indexed: 11/17/2024]
Abstract
Platelets are non-nucleated mammalian cells originating from the cytoplasmic expulsion of the megakaryocytes. Megakaryocytes develop during hematopoiesis through megakaryopoiesis, whereas platelets develop from megakaryocytes through thrombopoiesis. Since their first discovery, platelets have been studied as critical cells controlling hemostasis or blood coagulation. However, coagulation and innate immune response are evolutionarily linked processes. Therefore, it has become critical to investigate the immunological functions of platelets to maintain immune homeostasis. Advances in immunology and platelet biology research have explored different critical roles of platelets, including phagocytosis, release of different immune mediators, and controlling functions of different immune cells by direct interaction and immune mediators. The current article discusses platelet's development and their critical role as innate immune cells, which express different pattern recognition receptors (PRRs), recognizing different pathogen or microbe-associated molecular patterns (PAMPs or MAMPs) and death/damage-associated molecular patterns (DAMPs) and their direct interactions with innate and adaptive immune cells to maintain immune homeostasis.
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Affiliation(s)
- Vijay Kumar
- Department of Surgery, Laboratory of Tumor Immunology and Immunotherapy, Medical Education Building-C, Morehouse School of Medicine, 720 Westview Drive, Atlanta, GA 30310 USA.
| | - John H Stewart Iv
- Department of Surgery, Laboratory of Tumor Immunology and Immunotherapy, Medical Education Building-C, Morehouse School of Medicine, 720 Westview Drive, Atlanta, GA 30310 USA
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Meng P, Liu W, Lao J, Liu X, Zhang Y, Sun Y, Zhou R, Du C, Wang J, Zhao D, Lin Q, Zhang Y. Paclitaxel improves thrombopoiesis in the absence of thrombopoietin receptor (Mpl). J Thromb Haemost 2024; 22:3599-3613. [PMID: 39307245 DOI: 10.1016/j.jtha.2024.08.025] [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: 01/08/2024] [Revised: 08/02/2024] [Accepted: 08/19/2024] [Indexed: 10/17/2024]
Abstract
BACKGROUND Platelets are critical for thrombosis and hemostasis. The THPO-MPL pathway is the primary pathway for generating thrombocytes. Dysregulation of thrombopoiesis results in platelet formation and/or function-related disorders, such as thrombocytopenia. Paclitaxel is an extensively utilized chemotherapeutic agent and its activity may be related to platelets, but the effect of paclitaxel on thrombocytopoiesis warrants comprehensive exploration. OBJECTIVES We focused on identifying factors that regulate thrombocyte production and elucidating paclitaxel's regulatory mechanisms on thrombocytopoiesis, with a particular emphasis on discovering mechanisms that bypass THPO-MPL pathways. METHODS We performed drug screenings using the Tg(mpl:eGFP) zebrafish model in vivo to identify Food and Drug Administration-approved compounds capable of boosting thrombocyte production. An injury experiment was used to evaluate thrombocyte function. Bromodeoxyuridine assays, terminal deoxynucleotidyl transferase dUTP nick-end labeling, and RNA sequencing analyses were performed to explore cytological and molecular mechanisms. Routine blood testing and flow cytometry were used to analyze mouse phenotypes. RESULTS We found that paclitaxel expands thrombocytes by accelerating the proliferation of thrombocytic lineage cells in zebrafish and elevates platelet levels in mice. This effect occurs by bypassing the thrombopoietin receptor (Mpl). We found that paclitaxel promotes thrombopoiesis, potentially involving the JAK2-ERK1/2 MAPK signaling cascade, a pathway integral to MPL and other regulators. Our results further demonstrate that ERK1/2 is at least partially downstream of JAK2 in paclitaxel-induced thrombopoiesis. CONCLUSION Paclitaxel could promote thrombopoiesis by bypassing Mpl but presumably via the JAK2-ERK1/2 MAPK pathways. It will aid in understanding the relationship between paclitaxel and platelets clinically, and paclitaxel may have potential value for safeguarding platelets and improving thrombocytosis in related diseases.
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Affiliation(s)
- Panpan Meng
- The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou, China; Key Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases of Guangdong Higher Education Institutes, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Wenyu Liu
- The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou, China
| | - Jiawen Lao
- The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou, China
| | - Xunwei Liu
- The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou, China
| | - Yangping Zhang
- Key Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases of Guangdong Higher Education Institutes, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Ying Sun
- Key Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases of Guangdong Higher Education Institutes, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Riyang Zhou
- Key Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases of Guangdong Higher Education Institutes, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Changhong Du
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University, Chongqing, China
| | - Junping Wang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University, Chongqing, China
| | - Dejian Zhao
- Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, China
| | - Qing Lin
- The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou, China; Department of Hematology, the Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
| | - Yiyue Zhang
- The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou, China.
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Lin GL, Chang HH, Lin WT, Liou YS, Lai YL, Hsieh MH, Chen PK, Liao CY, Tsai CC, Wang TF, Chu SC, Kau JH, Huang HH, Hsu HL, Sun DS. Dachshund Homolog 1: Unveiling Its Potential Role in Megakaryopoiesis and Bacillus anthracis Lethal Toxin-Induced Thrombocytopenia. Int J Mol Sci 2024; 25:3102. [PMID: 38542074 PMCID: PMC10970148 DOI: 10.3390/ijms25063102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 03/04/2024] [Accepted: 03/05/2024] [Indexed: 04/04/2024] Open
Abstract
Lethal toxin (LT) is the critical virulence factor of Bacillus anthracis, the causative agent of anthrax. One common symptom observed in patients with anthrax is thrombocytopenia, which has also been observed in mice injected with LT. Our previous study demonstrated that LT induces thrombocytopenia by suppressing megakaryopoiesis, but the precise molecular mechanisms behind this phenomenon remain unknown. In this study, we utilized 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced megakaryocytic differentiation in human erythroleukemia (HEL) cells to identify genes involved in LT-induced megakaryocytic suppression. Through cDNA microarray analysis, we identified Dachshund homolog 1 (DACH1) as a gene that was upregulated upon TPA treatment but downregulated in the presence of TPA and LT, purified from the culture supernatants of B. anthracis. To investigate the function of DACH1 in megakaryocytic differentiation, we employed short hairpin RNA technology to knock down DACH1 expression in HEL cells and assessed its effect on differentiation. Our data revealed that the knockdown of DACH1 expression suppressed megakaryocytic differentiation, particularly in polyploidization. We demonstrated that one mechanism by which B. anthracis LT induces suppression of polyploidization in HEL cells is through the cleavage of MEK1/2. This cleavage results in the downregulation of the ERK signaling pathway, thereby suppressing DACH1 gene expression and inhibiting polyploidization. Additionally, we found that known megakaryopoiesis-related genes, such as FOSB, ZFP36L1, RUNX1, FLI1, AHR, and GFI1B genes may be positively regulated by DACH1. Furthermore, we observed an upregulation of DACH1 during in vitro differentiation of CD34-megakaryocytes and downregulation of DACH1 in patients with thrombocytopenia. In summary, our findings shed light on one of the molecular mechanisms behind LT-induced thrombocytopenia and unveil a previously unknown role for DACH1 in megakaryopoiesis.
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Affiliation(s)
- Guan-Ling Lin
- Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan; (G.-L.L.); (H.-H.C.); (P.-K.C.)
- Integration Center of Traditional Chinese and Modern Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97004, Taiwan
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 97004, Taiwan; (W.-T.L.); (Y.-S.L.); (Y.-L.L.); (M.-H.H.)
| | - Hsin-Hou Chang
- Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan; (G.-L.L.); (H.-H.C.); (P.-K.C.)
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 97004, Taiwan; (W.-T.L.); (Y.-S.L.); (Y.-L.L.); (M.-H.H.)
| | - Wei-Ting Lin
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 97004, Taiwan; (W.-T.L.); (Y.-S.L.); (Y.-L.L.); (M.-H.H.)
| | - Yu-Shan Liou
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 97004, Taiwan; (W.-T.L.); (Y.-S.L.); (Y.-L.L.); (M.-H.H.)
| | - Yi-Ling Lai
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 97004, Taiwan; (W.-T.L.); (Y.-S.L.); (Y.-L.L.); (M.-H.H.)
| | - Min-Hua Hsieh
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 97004, Taiwan; (W.-T.L.); (Y.-S.L.); (Y.-L.L.); (M.-H.H.)
| | - Po-Kong Chen
- Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan; (G.-L.L.); (H.-H.C.); (P.-K.C.)
| | - Chi-Yuan Liao
- Department of Obstetrics and Gynecology, Mennonite Christian Hospital, Hualien 97004, Taiwan; (C.-Y.L.); (C.-C.T.)
| | - Chi-Chih Tsai
- Department of Obstetrics and Gynecology, Mennonite Christian Hospital, Hualien 97004, Taiwan; (C.-Y.L.); (C.-C.T.)
| | - Tso-Fu Wang
- Department of Hematology and Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97004, Taiwan; (T.-F.W.); (S.-C.C.)
- Department of Medicine, College of Medicine, Tzu Chi University, Hualien 97004, Taiwan
- Buddhist Tzu Chi Stem Cells Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97004, Taiwan
| | - Sung-Chao Chu
- Department of Hematology and Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97004, Taiwan; (T.-F.W.); (S.-C.C.)
- Department of Medicine, College of Medicine, Tzu Chi University, Hualien 97004, Taiwan
- Buddhist Tzu Chi Stem Cells Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97004, Taiwan
| | - Jyh-Hwa Kau
- Institute of Preventive Medicine, National Defense Medical Center, Taipei 11490, Taiwan; (J.-H.K.); (H.-H.H.); (H.-L.H.)
| | - Hsin-Hsien Huang
- Institute of Preventive Medicine, National Defense Medical Center, Taipei 11490, Taiwan; (J.-H.K.); (H.-H.H.); (H.-L.H.)
| | - Hui-Ling Hsu
- Institute of Preventive Medicine, National Defense Medical Center, Taipei 11490, Taiwan; (J.-H.K.); (H.-H.H.); (H.-L.H.)
| | - Der-Shan Sun
- Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan; (G.-L.L.); (H.-H.C.); (P.-K.C.)
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 97004, Taiwan; (W.-T.L.); (Y.-S.L.); (Y.-L.L.); (M.-H.H.)
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Cai X, Gui RY, Wu J, Wang CC, Zhu XL, Fu HX, Zhang XH. Decreased Expression of IL-35 and Its Receptor Contributes to Impaired Megakaryopoiesis in the Pathogenesis of Immune Thrombocytopenia. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2305798. [PMID: 38225757 DOI: 10.1002/advs.202305798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 12/15/2023] [Indexed: 01/17/2024]
Abstract
Recent findings have shown that the level of interleukin-35 (IL-35) is abnormal in several autoimmune diseases. Nonetheless, whether IL-35 participates in the pathogenesis of immune thrombocytopenia (ITP) remains unclear. The current study investigates whether IL-35 modulates megakaryopoiesis. The results show that IL-35 receptors are progressively expressed on bone marrow megakaryocytes during the in vitro differentiation of CD34+ progenitors. IL-35 increases the number of megakaryocyte colony-forming units through the Akt pathway. The level of bone marrow IL-35 is reduced in ITP patients, and the decreased level of IL-35 may inhibit megakaryopoiesis. Then, the potential causes of decreased IL-35 in ITP patients are explored. The primary type of cell that secretes IL-35, known as IL-35-producing regulatory T cells (iTr35), is reduced in ITP patients. Bone marrow mesenchymal stem cells (MSCs) from ITP patients exhibit an impaired capability of inducing iTr35 due to enhanced apoptosis, which may contribute to the reduced level of bone marrow IL-35 in ITP patients. Iguratimod promotes megakaryocyte development and differentiation by elevating the expression of IL-35 receptors on megakaryocytes. Iguratimod improves response rates and reduces bleeding symptoms in corticosteroid-resistant ITP patients.
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Affiliation(s)
- Xuan Cai
- Peking University People's Hospital, Beijing, 100044, China
- Peking University Institute of Hematology, Beijing, 100044, China
- National Clinical Research Center for Hematologic Disease, Beijing, 100044, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
| | - Ruo-Yun Gui
- Peking University People's Hospital, Beijing, 100044, China
- Peking University Institute of Hematology, Beijing, 100044, China
- National Clinical Research Center for Hematologic Disease, Beijing, 100044, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
| | - Jin Wu
- Peking University People's Hospital, Beijing, 100044, China
- Peking University Institute of Hematology, Beijing, 100044, China
- National Clinical Research Center for Hematologic Disease, Beijing, 100044, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
| | - Chen-Cong Wang
- Peking University People's Hospital, Beijing, 100044, China
- Peking University Institute of Hematology, Beijing, 100044, China
- National Clinical Research Center for Hematologic Disease, Beijing, 100044, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
| | - Xiao-Lu Zhu
- Peking University People's Hospital, Beijing, 100044, China
- Peking University Institute of Hematology, Beijing, 100044, China
- National Clinical Research Center for Hematologic Disease, Beijing, 100044, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
| | - Hai-Xia Fu
- Peking University People's Hospital, Beijing, 100044, China
- Peking University Institute of Hematology, Beijing, 100044, China
- National Clinical Research Center for Hematologic Disease, Beijing, 100044, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
| | - Xiao-Hui Zhang
- Peking University People's Hospital, Beijing, 100044, China
- Peking University Institute of Hematology, Beijing, 100044, China
- National Clinical Research Center for Hematologic Disease, Beijing, 100044, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
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Trivanović D, Mojsilović S, Bogosavljević N, Jurišić V, Jauković A. Revealing profile of cancer-educated platelets and their factors to foster immunotherapy development. Transl Oncol 2024; 40:101871. [PMID: 38134841 PMCID: PMC10776659 DOI: 10.1016/j.tranon.2023.101871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 12/03/2023] [Accepted: 12/15/2023] [Indexed: 12/24/2023] Open
Abstract
Among multiple hemostasis components, platelets hyperactivity plays major roles in cancer progression by providing surface and internal components for intercellular crosstalk as well as by behaving like immune cells. Since platelets participate and regulate immunity in homeostatic and disease states, we assumed that revealing platelets profile might help in conceiving novel anti-cancer immune-based strategies. The goal of this review is to compile and discuss the most recent reports on the nature of cancer-associated platelets and their interference with immunotherapy. An increasing number of studies have emphasized active communication between cancer cells and platelets, with platelets promoting cancer cell survival, growth, and metastasis. The anti-cancer potential of platelet-directed therapy has been intensively investigated, and anti-platelet agents may prevent cancer progression and improve the survival of cancer patients. Platelets can (i) reduce antitumor activity; (ii) support immunoregulatory cells and factors generation; (iii) underpin metastasis and, (iv) interfere with immunotherapy by expressing ligands of immune checkpoint receptors. Mediators produced by tumor cell-induced platelet activation support vein thrombosis, constrain anti-tumor T- and natural killer cell response, while contributing to extravasation of tumor cells, metastatic potential, and neovascularization within the tumor. Recent studies showed that attenuation of immunothrombosis, modulation of platelets and their factors have a good perspective in immunotherapy optimization. Particularly, blockade of intra-tumoral platelet-associated programmed death-ligand 1 might promote anti-tumor T cell-induced cytotoxicity. Collectively, these findings suggest that platelets might represent the source of relevant cancer staging biomarkers, as well as promising targets and carriers in immunotherapeutic approaches for combating cancer.
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Affiliation(s)
- Drenka Trivanović
- Group for Hematology and Stem Cells, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Dr. Subotica 4, PBOX 102, 11129, Belgrade 11000, Serbia.
| | - Slavko Mojsilović
- Group for Hematology and Stem Cells, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Dr. Subotica 4, PBOX 102, 11129, Belgrade 11000, Serbia
| | | | - Vladimir Jurišić
- Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34000, Serbia
| | - Aleksandra Jauković
- Group for Hematology and Stem Cells, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Dr. Subotica 4, PBOX 102, 11129, Belgrade 11000, Serbia
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8
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Marín-Quílez A, Díaz-Ajenjo L, Di Buduo CA, Zamora-Cánovas A, Lozano ML, Benito R, González-Porras JR, Balduini A, Rivera J, Bastida JM. Inherited Thrombocytopenia Caused by Variants in Crucial Genes for Glycosylation. Int J Mol Sci 2023; 24:5109. [PMID: 36982178 PMCID: PMC10049517 DOI: 10.3390/ijms24065109] [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: 12/30/2022] [Revised: 02/13/2023] [Accepted: 03/03/2023] [Indexed: 03/30/2023] Open
Abstract
Protein glycosylation, including sialylation, involves complex and frequent post-translational modifications, which play a critical role in different biological processes. The conjugation of carbohydrate residues to specific molecules and receptors is critical for normal hematopoiesis, as it favors the proliferation and clearance of hematopoietic precursors. Through this mechanism, the circulating platelet count is controlled by the appropriate platelet production by megakaryocytes, and the kinetics of platelet clearance. Platelets have a half-life in blood ranging from 8 to 11 days, after which they lose the final sialic acid and are recognized by receptors in the liver and eliminated from the bloodstream. This favors the transduction of thrombopoietin, which induces megakaryopoiesis to produce new platelets. More than two hundred enzymes are responsible for proper glycosylation and sialylation. In recent years, novel disorders of glycosylation caused by molecular variants in multiple genes have been described. The phenotype of the patients with genetic alterations in GNE, SLC35A1, GALE and B4GALT is consistent with syndromic manifestations, severe inherited thrombocytopenia, and hemorrhagic complications.
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Affiliation(s)
- Ana Marín-Quílez
- Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-U765, 30003 Murcia, Spain
| | - Lorena Díaz-Ajenjo
- IBSAL, CIC, IBMCC, Universidad de Salamanca-CSIC, 37007 Salamanca, Spain
| | | | - Ana Zamora-Cánovas
- Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-U765, 30003 Murcia, Spain
| | - María Luisa Lozano
- Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-U765, 30003 Murcia, Spain
| | - Rocío Benito
- IBSAL, CIC, IBMCC, Universidad de Salamanca-CSIC, 37007 Salamanca, Spain
| | - José Ramón González-Porras
- Department of Hematology, Complejo Asistencial Universitario de Salamanca (CAUSA), Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca (USAL), 37007 Salamanca, Spain
| | - Alessandra Balduini
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
- Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA
| | - José Rivera
- Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-U765, 30003 Murcia, Spain
| | - José María Bastida
- Department of Hematology, Complejo Asistencial Universitario de Salamanca (CAUSA), Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca (USAL), 37007 Salamanca, Spain
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9
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Huang L, Xu J, Zhang H, Wang M, Zhang Y, Lin Q. Application and investigation of thrombopoiesis-stimulating agents in the treatment of thrombocytopenia. Ther Adv Hematol 2023; 14:20406207231152746. [PMID: 36865986 PMCID: PMC9972067 DOI: 10.1177/20406207231152746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 01/06/2023] [Indexed: 03/02/2023] Open
Abstract
Platelets, derived from a certain subpopulation of megakaryocytes, are closely related to hemostasis, coagulation, metastasis, inflammation, and cancer progression. Thrombopoiesis is a dynamic process regulated by various signaling pathways in which thrombopoietin (THPO)-MPL is dominant. Thrombopoiesis-stimulating agents could promote platelet production, showing therapeutic effects in different kinds of thrombocytopenia. Some thrombopoiesis-stimulating agents are currently used in clinical practices to treat thrombocytopenia. The others are not in clinical investigations to deal with thrombocytopenia but have potential in thrombopoiesis. Their potential values in thrombocytopenia treatment should be highly regarded. Novel drug screening models and drug repurposing research have found many new agents and yielded promising outcomes in preclinical or clinical studies. This review will briefly introduce thrombopoiesis-stimulating agents currently or potentially valuable in thrombocytopenia treatment and summarize the possible mechanisms and therapeutic effects, which may enrich the pharmacological armamentarium for the medical treatment of thrombocytopenia.
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Affiliation(s)
- Lejun Huang
- Division of Cell, Developmental and Integrative
Biology, School of Medicine, South China University of Technology,
Guangzhou, P.R. China
| | - Jianxuan Xu
- Division of Cell, Developmental and Integrative
Biology, School of Medicine, South China University of Technology,
Guangzhou, P.R. China
| | - Huaying Zhang
- Division of Cell, Developmental and Integrative
Biology, School of Medicine, South China University of Technology,
Guangzhou, P.R. China
| | - Mengfan Wang
- Division of Cell, Developmental and Integrative
Biology, School of Medicine, South China University of Technology,
Guangzhou, P.R. China
| | - Yiyue Zhang
- Division of Cell, Developmental and Integrative
Biology, School of Medicine, South China University of Technology,
Guangzhou, P.R. China
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10
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Wang J, Xie J, Wang D, Han X, Chen M, Shi G, Jiang L, Zhao M. CXCR4 high megakaryocytes regulate host-defense immunity against bacterial pathogens. eLife 2022; 11:e78662. [PMID: 35904250 PMCID: PMC9374440 DOI: 10.7554/elife.78662] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 07/28/2022] [Indexed: 11/13/2022] Open
Abstract
Megakaryocytes (MKs) continuously produce platelets to support hemostasis and form a niche for hematopoietic stem cell maintenance in the bone marrow. MKs are also involved in inflammatory responses; however, the mechanism remains poorly understood. Using single-cell sequencing, we identified a CXCR4 highly expressed MK subpopulation, which exhibited both MK-specific and immune characteristics. CXCR4high MKs interacted with myeloid cells to promote their migration and stimulate the bacterial phagocytosis of macrophages and neutrophils by producing TNFα and IL-6. CXCR4high MKs were also capable of phagocytosis, processing, and presenting antigens to activate T cells. Furthermore, CXCR4high MKs also egressed circulation and infiltrated into the spleen, liver, and lung upon bacterial infection. Ablation of MKs suppressed the innate immune response and T cell activation to impair the anti-bacterial effects in mice under the Listeria monocytogenes challenge. Using hematopoietic stem/progenitor cell lineage-tracing mouse lines, we show that CXCR4high MKs were generated from infection-induced emergency megakaryopoiesis in response to bacterial infection. Overall, we identify the CXCR4high MKs, which regulate host-defense immune response against bacterial infection.
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Affiliation(s)
- Jin Wang
- Department of Endocrinology & Metabolism, The Third Affiliated Hospital, Sun Yat-sen UniversityGuangzhouChina
| | - Jiayi Xie
- RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen UniversityGuangzhouChina
- Key Laboratory of Stem Cells and Tissue Engineering, Zhongshan School of Medicine, Sun Yat-sen University, Ministry of EducationGuangzhouChina
| | - Daosong Wang
- Key Laboratory of Stem Cells and Tissue Engineering, Zhongshan School of Medicine, Sun Yat-sen University, Ministry of EducationGuangzhouChina
| | - Xue Han
- RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen UniversityGuangzhouChina
- Key Laboratory of Stem Cells and Tissue Engineering, Zhongshan School of Medicine, Sun Yat-sen University, Ministry of EducationGuangzhouChina
| | - Minqi Chen
- Key Laboratory of Stem Cells and Tissue Engineering, Zhongshan School of Medicine, Sun Yat-sen University, Ministry of EducationGuangzhouChina
| | - Guojun Shi
- Department of Endocrinology & Metabolism, The Third Affiliated Hospital, Sun Yat-sen UniversityGuangzhouChina
| | - Linjia Jiang
- RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen UniversityGuangzhouChina
| | - Meng Zhao
- RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen UniversityGuangzhouChina
- Key Laboratory of Stem Cells and Tissue Engineering, Zhongshan School of Medicine, Sun Yat-sen University, Ministry of EducationGuangzhouChina
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11
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Chen Y, Xie J, Shen Z, Shi J, Chen S, Wang G. Clinical and molecular characteristics of acute myeloid leukemia with MPL mutation. Hematology 2022; 27:530-534. [PMID: 35544613 DOI: 10.1080/16078454.2022.2066244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
OBJECTIVES The current study aimed to explore the incidence of MPL mutations and the clinical and molecular characteristics of AML with MPL mutation. METHODS In total, 1509 patients with newly diagnosed AML were retrospectively analyzed between January 2017 and December 2020. MPL mutations were detected via next-generation sequencing. During the same period, we also enrolled 30 patients with other myeloid neoplasms (MNs) with MPL mutation, which included myelodysplastic syndrome (n = 15), myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) (n = 6), and MPN (n = 9). The clinical characteristics of MPL-mutated AML and other types of MNs or MPL-wide type (MPL-wt) AML were compared, and the spectrum of co-mutations and MPL mutation profiles in MPL-mutated AML were analyzed. RESULTS MPL mutations were identified in 19 (1.26%) of 1509 patients with AML. The waterfall diagram showed that the co-mutations were mainly epigenetic modifications (TET2, IDH1, and EZH2), spliceosomes (SRSF2), and transcription factors (RUNX1). The platelet count of the AML group was significantly lower than that of the MPN group (p = 0.001). MPL mutations were commonly observed in the intracellular region in AML but the transmembrane region in MPN (p = 0.013). The MPL-mutated AML group had a lower white blood cell count and a lower rate of complete remission than the MPL wild-type AML group (p = 0.037). CONCLUSION MPL mutations are clinically relevant in patients with AML, and they may be a novel subtype characterized by lower white blood cell counts and poor complete remission rates. However, further studies must be conducted to identify its correlated mechanism.
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Affiliation(s)
- Yu Chen
- Department of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China.,National Clinical Research Center for Hematologic Diseases, Suzhou, People's Republic of China.,Department of Hematology, the Second Affiliated Hospital of Wannan Medical College, Wuhu, People's Republic of China
| | - Jundan Xie
- Department of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China.,National Clinical Research Center for Hematologic Diseases, Suzhou, People's Republic of China
| | - Zhen Shen
- Department of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China.,National Clinical Research Center for Hematologic Diseases, Suzhou, People's Republic of China
| | - Jie Shi
- Department of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China.,National Clinical Research Center for Hematologic Diseases, Suzhou, People's Republic of China
| | - Suning Chen
- Department of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China.,National Clinical Research Center for Hematologic Diseases, Suzhou, People's Republic of China
| | - Gang Wang
- Department of Hematology, the Second Hospital of Shanxi Medical University, Taiyuan, People's Republic of China
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12
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Wang Q, Wei J, Jia X, Feng X, Ji Z, Ji X, Shao X. Downregulation of ADAM17 in pediatric immune thrombocytopenia impairs proplatelet formation. BMC Pediatr 2022; 22:164. [PMID: 35354403 PMCID: PMC8966352 DOI: 10.1186/s12887-022-03237-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 03/23/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Immune thrombocytopenia (ITP) is the most common etiology of acquired thrombocytopenia diseases in children. ITP is characterized by the immune-mediated decreased formation and excessive destruction of platelets. The pathogenesis and management of pediatric ITP are distinct from adult ITP. A disintegrin and metalloproteinase 17 (ADAM17) mediates the shedding of platelet receptor glycoprotein Ib α (GPIb α) in extracellular domain, functioning in the platelet activation and clearance. Our study aims to probe the roles and mechanisms of ADAM17 in pediatric ITP. METHODS The differently expressed ADAM17 in megakaryocytes was obtained from children with ITP through the next-generation RNA-Sequence. Hematoxylin-eosin and Giemsa staining were performed for cell morphology identification. Flow cytometry was applied to assess autoantibodies against platelets, subtypes of lymphocytes, the surface expression level of ADAM17 and polyploidization of megakaryocytes, as well as the full-length GP Ib α. RESULTS ADAM17 was significantly downregulated in megakaryocytes and platelets in children with ITP. Higher values of PDW and positive autoantibodies presence were observed in children with ITP. Loss of ADAM17 in mice led to defects in proplatelet formation and significantly elevated expression of phosphorylated myosin light chain (p-MLC) in megakaryocytes. CONCLUSIONS Our study indicated that the downregulation of ADAM17 might be an innate cause of inefficient platelet production in pediatric ITP.
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Affiliation(s)
- Qi Wang
- Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou, 215025, Jiangsu Province, China.
| | - Jia Wei
- Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou, 215025, Jiangsu Province, China
| | - Xi Jia
- Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou, 215025, Jiangsu Province, China
| | - Xiao Feng
- Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou, 215025, Jiangsu Province, China
| | - Zhenghua Ji
- Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou, 215025, Jiangsu Province, China
| | - Xueqiang Ji
- Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou, 215025, Jiangsu Province, China
| | - Xuejun Shao
- Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou, 215025, Jiangsu Province, China.
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13
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14
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Steadman E, Fandaros M, Yin W. SARS-CoV-2 and Plasma Hypercoagulability. Cell Mol Bioeng 2021; 14:513-522. [PMID: 34221178 PMCID: PMC8238024 DOI: 10.1007/s12195-021-00685-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 06/14/2021] [Indexed: 02/07/2023] Open
Abstract
Hypercoagulability has emerged as a prominent consequence of COVID-19. This presents challenges not only in the clinic, but also in thrombosis research. Health and safety considerations, the status of the blood and plasma supply, the infection status of individual donors, and the mechanisms by which SARS-CoV-2 activates coagulation are all of concern. In this review, we discuss these topics from the basic research perspective. As in other respiratory illnesses, blood and plasma from COVID-19 positive patients carries minimal to no risk of infection to practitioners or researchers. There are currently no special regulatory mandates directing individual donors (for research purposes), blood centers/services or vendors (for blood products for research) to test blood/plasma for SARS-CoV-2 or antibodies. We discuss current theories about how SARS-CoV-2 leads to hyper-coagulant state in severe cases of COVID-19. Our current understanding of the mechanisms behind COVID-19 associated thromboembolic events have centered around three different pathways: (1) direct activation of platelets, enhancing coagulation; (2) direct infection and indirect activation (e.g. cytokine storm) of endothelial cells by SARS-CoV-2, shifting endothelium from an anti-thrombotic to a pro-thrombotic state; and (3) direct activation of complement pathways, promoting thrombin generation. Further investigation on how SARS-CoV-2 affects thrombosis in COVID-19 patients may bring novel anti-thrombotic therapies to combat the disease.
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Affiliation(s)
- Elisabeth Steadman
- Department of Biomedical Engineering, Stony Brook University, Bioengineering Building, Room 109, Stony Brook, NY 11794 USA
| | - Marina Fandaros
- Department of Biomedical Engineering, Stony Brook University, Bioengineering Building, Room 109, Stony Brook, NY 11794 USA
| | - Wei Yin
- Department of Biomedical Engineering, Stony Brook University, Bioengineering Building, Room 109, Stony Brook, NY 11794 USA
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15
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Mojzisch A, Brehm MA. The Manifold Cellular Functions of von Willebrand Factor. Cells 2021; 10:2351. [PMID: 34572000 PMCID: PMC8466076 DOI: 10.3390/cells10092351] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 08/26/2021] [Accepted: 09/02/2021] [Indexed: 12/13/2022] Open
Abstract
The plasma glycoprotein von Willebrand factor (VWF) is exclusively synthesized in endothelial cells (ECs) and megakaryocytes, the precursor cells of platelets. Its primary function lies in hemostasis. However, VWF is much more than just a "fishing hook" for platelets and a transporter for coagulation factor VIII. VWF is a true multitasker when it comes to its many roles in cellular processes. In ECs, VWF coordinates the formation of Weibel-Palade bodies and guides several cargo proteins to these storage organelles, which control the release of hemostatic, inflammatory and angiogenic factors. Leukocytes employ VWF to assist their rolling on, adhesion to and passage through the endothelium. Vascular smooth muscle cell proliferation is supported by VWF, and it regulates angiogenesis. The life cycle of platelets is accompanied by VWF from their budding from megakaryocytes to adhesion, activation and aggregation until the end in apoptosis. Some tumor cells acquire the ability to produce VWF to promote metastasis and hide in a shell of VWF and platelets, and even the maturation of osteoclasts is regulated by VWF. This review summarizes the current knowledge on VWF's versatile cellular functions and the resulting pathophysiological consequences of their dysregulation.
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Affiliation(s)
- Angelika Mojzisch
- Dermatology and Venerology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;
| | - Maria A. Brehm
- School of Life Sciences, University of Siegen, 57076 Siegen, Germany
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16
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Mbiandjeu S, Balduini A, Malara A. Megakaryocyte Cytoskeletal Proteins in Platelet Biogenesis and Diseases. Thromb Haemost 2021; 122:666-678. [PMID: 34218430 DOI: 10.1055/s-0041-1731717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Thrombopoiesis governs the formation of blood platelets in bone marrow by converting megakaryocytes into long, branched proplatelets on which individual platelets are assembled. The megakaryocyte cytoskeleton responds to multiple microenvironmental cues, including chemical and mechanical stimuli, sustaining the platelet shedding. During the megakaryocyte's life cycle, cytoskeletal networks organize cell shape and content, connect them physically and biochemically to the bone marrow vascular niche, and enable the release of platelets into the bloodstream. While the basic building blocks of the cytoskeleton have been studied extensively, new sets of cytoskeleton regulators have emerged as critical components of the dynamic protein network that supports platelet production. Understanding how the interaction of individual molecules of the cytoskeleton governs megakaryocyte behavior is essential to improve knowledge of platelet biogenesis and develop new therapeutic strategies for inherited thrombocytopenias caused by alterations in the cytoskeletal genes.
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Affiliation(s)
- Serge Mbiandjeu
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
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17
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Konno S, Yanagisawa R, Kubota N, Ogiso Y, Nishimura N, Sakashita K, Tozuka M. Investigation of patient factors associated with the number of transfusions required during chemotherapy for high-risk neuroblastoma. Vox Sang 2021; 117:71-79. [PMID: 34197634 DOI: 10.1111/vox.13128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 04/12/2021] [Accepted: 04/15/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Blood transfusion is an important supportive care for high-risk neuroblastoma. When the number of transfusions increases, transfusion-associated adverse reactions may be more problematic. However, the factors determining the degree of myelosuppression and the number of transfusions during chemotherapy for high-risk neuroblastoma remain unclear. MATERIALS AND METHODS We investigated patient factors determining the number of required transfusions in 15 high-risk neuroblastoma patients who received five courses of chemotherapy. Clinical data, cytokine profile and colony-forming assay with bone marrow samples at diagnosis were analysed. RESULTS The required number of transfusions of both platelets and erythrocytes decreased once in the second course and then increased as the course progressed. The variability among cases increased as the chemotherapy course progressed. In cases of low peripheral blood platelet count and lower fibrinogen level at diagnosis, the number of platelet transfusions was higher during chemotherapy. In contrast, there was a negative correlation between the forming ability of granulocyte-macrophage or erythroid colonies and the number of erythrocyte transfusions in the latter period. CONCLUSION In the early stages of chemotherapy, bone marrow infiltration in neuroblastoma and/or coagulopathy complication may cause thrombocytopenia and requirement of platelet transfusion; conversely, in the later stages, the number of erythrocyte transfusions may be defined by the patient's inherent hematopoietic ability. These factors may be useful in predicting the required number of transfusions.
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Affiliation(s)
- Saori Konno
- Life Science Research Centre, Nagano Children's Hospital, Azumino, Japan.,Division of Blood Transfusion, Shinshu University Hospital, Matsumoto, Japan.,Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan
| | - Ryu Yanagisawa
- Life Science Research Centre, Nagano Children's Hospital, Azumino, Japan.,Division of Blood Transfusion, Shinshu University Hospital, Matsumoto, Japan.,Centre for Advanced Cell Therapy, Shinshu University Hospital, Matsumoto, Japan
| | - Noriko Kubota
- Department of Laboratory Medicine, Nagano Children's Hospital, Azumino, Japan
| | - Yoshifumi Ogiso
- Department of Laboratory Medicine, Nagano Children's Hospital, Azumino, Japan
| | - Noriyuki Nishimura
- Department of Public Health, Kobe University Graduate School of Health Science, Kobe, Japan
| | - Kazuo Sakashita
- Department of Haematology and Oncology, Nagano Children's Hospital, Azumino, Japan
| | - Minoru Tozuka
- Life Science Research Centre, Nagano Children's Hospital, Azumino, Japan.,Department of Laboratory Medicine, Nagano Children's Hospital, Azumino, Japan
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18
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Zhao HY, Zhang YY, Xing T, Tang SQ, Wen Q, Lyu ZS, Lv M, Wang Y, Xu LP, Zhang XH, Kong Y, Huang XJ. M2 macrophages, but not M1 macrophages, support megakaryopoiesis by upregulating PI3K-AKT pathway activity. Signal Transduct Target Ther 2021; 6:234. [PMID: 34140465 PMCID: PMC8211642 DOI: 10.1038/s41392-021-00627-y] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 04/25/2021] [Accepted: 05/05/2021] [Indexed: 12/19/2022] Open
Abstract
Dysfunctional megakaryopoiesis hampers platelet production, which is closely associated with thrombocytopenia (PT). Macrophages (MФs) are crucial cellular components in the bone marrow (BM) microenvironment. However, the specific effects of M1 MФs or M2 MФs on regulating megakaryocytes (MKs) are largely unknown. In the current study, aberrant BM-M1/M2 MФ polarization, characterized by increased M1 MФs and decreased M2 MФs and accompanied by impaired megakaryopoiesis-supporting abilities, was found in patients with PT post-allotransplant. RNA-seq and western blot analysis showed that the PI3K-AKT pathway was downregulated in the BM MФs of PT patients. Moreover, in vitro treatment with PI3K-AKT activators restored the impaired megakaryopoiesis-supporting ability of MФs from PT patients. Furthermore, we found M1 MФs suppress, whereas M2 MФs support MK maturation and platelet formation in humans. Chemical inhibition of PI3K-AKT pathway reduced megakaryopoiesis-supporting ability of M2 MФs, as indicated by decreased MK count, colony-forming unit number, high-ploidy distribution, and platelet count. Importantly, genetic knockdown of the PI3K-AKT pathway impaired the megakaryopoiesis-supporting ability of MФs both in vitro and in a MФ-specific PI3K-knockdown murine model, indicating a critical role of PI3K-AKT pathway in regulating the megakaryopoiesis-supporting ability of M2 MФs. Furthermore, our preliminary data indicated that TGF-β released by M2 MФs may facilitate megakaryopoiesis through upregulation of the JAK2/STAT5 and MAPK/ERK pathways in MKs. Taken together, our data reveal that M1 and M2 MФs have opposing effects on MKs in a PI3K-AKT pathway-dependent manner, which may lead to new insights into the pathogenesis of thrombocytopenia and provide a potential therapeutic strategy to promote megakaryopoiesis.
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Affiliation(s)
- Hong-Yan Zhao
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Yuan-Yuan Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Tong Xing
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Shu-Qian Tang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Qi Wen
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Zhong-Shi Lyu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Meng Lv
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Yu Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Lan-Ping Xu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Xiao-Hui Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Yuan Kong
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China.
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China.
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
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19
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Yang J, Luan J, Shen Y, Chen B. Developments in the production of platelets from stem cells (Review). Mol Med Rep 2020; 23:7. [PMID: 33179095 PMCID: PMC7673345 DOI: 10.3892/mmr.2020.11645] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 10/13/2020] [Indexed: 01/01/2023] Open
Abstract
Platelets are small pieces of cytoplasm that have become detached from the cytoplasm of mature megakaryocytes (MKs) in the bone marrow. Platelets modulate vascular system integrity and serve important role, particularly in hemostasis. With the rapid development of clinical medicine, the demand for platelet transfusion as a life‑saving intervention increases continuously. Stem cell technology appears to be highly promising for transfusion medicine, and the generation of platelets from stem cells would be of great value in the clinical setting. Furthermore, several studies have been undertaken to investigate the potential of producing platelets from stem cells. Initial success has been achieved in terms of the yields and function of platelets generated from stem cells. However, the requirements of clinical practice remain unmet. The aim of the present review was to focus on several sources of stem cells and factors that induce MK differentiation. Updated information on current research into the genetic regulation of megakaryocytopoiesis and platelet generation was summarized. Additionally, advanced strategies of platelet generation were reviewed and the progress made in this field was discussed.
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Affiliation(s)
- Jie Yang
- Department of Hematology and Oncology, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Jianfeng Luan
- Jinling Hospital Department of Blood Transfusion, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Yanfei Shen
- Medical School, School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Baoan Chen
- Department of Hematology and Oncology, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210009, P.R. China
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20
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Boscher J, Guinard I, Eckly A, Lanza F, Léon C. Blood platelet formation at a glance. J Cell Sci 2020; 133:133/20/jcs244731. [DOI: 10.1242/jcs.244731] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
ABSTRACT
The main function of blood platelets is to ensure hemostasis and prevent hemorrhages. The 1011 platelets needed daily are produced in a well-orchestrated process. However, this process is not yet fully understood and in vitro platelet production is still inefficient. Platelets are produced in the bone marrow by megakaryocytes, highly specialized precursor cells that extend cytoplasmic projections called proplatelets (PPTs) through the endothelial barrier of sinusoid vessels. In this Cell Science at a Glance article and the accompanying poster we discuss the mechanisms and pathways involved in megakaryopoiesis and platelet formation processes. We especially address the – still underestimated – role of the microenvironment of the bone marrow, and present recent findings on how PPT extension in vivo differs from that in vitro and entails different mechanisms. Finally, we recapitulate old but recently revisited evidence that – although bone marrow does produce megakaryocytes and PPTs – remodeling and the release of bona fide platelets, mainly occur in the downstream microcirculation.
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Affiliation(s)
- Julie Boscher
- Université de Strasbourg, INSERM, EFS Grand Est, BPPS UMR-S 1255, F-67000 Strasbourg, France
| | - Ines Guinard
- Université de Strasbourg, INSERM, EFS Grand Est, BPPS UMR-S 1255, F-67000 Strasbourg, France
| | - Anita Eckly
- Université de Strasbourg, INSERM, EFS Grand Est, BPPS UMR-S 1255, F-67000 Strasbourg, France
| | - François Lanza
- Université de Strasbourg, INSERM, EFS Grand Est, BPPS UMR-S 1255, F-67000 Strasbourg, France
| | - Catherine Léon
- Université de Strasbourg, INSERM, EFS Grand Est, BPPS UMR-S 1255, F-67000 Strasbourg, France
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21
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Bussel J, Kulasekararaj A, Cooper N, Verma A, Steidl U, Semple JW, Will B. Mechanisms and therapeutic prospects of thrombopoietin receptor agonists. Semin Hematol 2019; 56:262-278. [PMID: 31836033 DOI: 10.1053/j.seminhematol.2019.09.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 07/30/2019] [Accepted: 09/30/2019] [Indexed: 12/13/2022]
Abstract
The second-generation thrombopoietin (TPO) receptor agonists eltrombopag and romiplostim are potent activators of megakaryopoiesis and represent a growing treatment option for patients with thrombocytopenic hematological disorders. Both TPO receptor agonists have been approved worldwide for the treatment of children and adults with chronic immune thrombocytopenia. In the EU and USA, eltrombopag is approved for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy and in the USA for the first-line treatment of severe aplastic anemia in combination with immunosuppressive therapy. Eltrombopag has also shown efficacy in several other disease settings, for example, chemotherapy-induced thrombocytopenia, selected inherited thrombocytopenias, and myelodysplastic syndromes. While both TPO receptor agonists stimulate TPO receptor signaling and enhance megakaryopoiesis, their vastly different biochemical structures bestow upon them markedly different molecular and functional properties. Here, we review and discuss results from preclinical and clinical studies on the functional and molecular mechanisms of action of this new class of drug.
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Affiliation(s)
- James Bussel
- Pediatric Hematology/Oncology, Weill Cornell Medicine, New York, NY.
| | | | | | - Amit Verma
- Albert Einstein College of Medicine, New York, NY
| | | | - John W Semple
- Division of Hematology and Transfusion Medicine, Lund University, Lund, Sweden
| | - Britta Will
- Albert Einstein College of Medicine, New York, NY.
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22
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Lei XH, Yang YQ, Ma CY, Duan EK. Induction of differentiation of human stem cells ex vivo: Toward large-scale platelet production. World J Stem Cells 2019; 11:666-676. [PMID: 31616542 PMCID: PMC6789181 DOI: 10.4252/wjsc.v11.i9.666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 05/12/2019] [Accepted: 08/27/2019] [Indexed: 02/06/2023] Open
Abstract
Platelet transfusion is one of the most reliable strategies to cure patients suffering from thrombocytopenia or platelet dysfunction. With the increasing demand for transfusion, however, there is an undersupply of donors to provide the platelet source. Thus, scientists have sought to design methods for deriving clinical-scale platelets ex vivo. Although there has been considerable success ex vivo in the generation of transformative platelets produced by human stem cells (SCs), the platelet yields achieved using these strategies have not been adequate for clinical application. In this review, we provide an overview of the developmental process of megakaryocytes and the production of platelets in vivo and ex vivo, recapitulate the key advances in the production of SC-derived platelets using several SC sources, and discuss some strategies that apply three-dimensional bioreactor devices and biochemical factors synergistically to improve the generation of large-scale platelets for use in future biomedical and clinical settings.
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Affiliation(s)
- Xiao-Hua Lei
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Yi-Qing Yang
- Faculty of Laboratory Medical Science, Hebei North University, Zhangjiakou 075000, Hebei Province, China
| | - Chi-Yuan Ma
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - En-Kui Duan
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
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23
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Lei XH, Yang YQ, Ma CY, Duan EK. Induction of differentiation of human stem cellsex vivo: Toward large-scale platelet production. World J Stem Cells 2019. [DOI: dx.doi.org/10.4252/wjsc.v11.i9.666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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24
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Kizilyer A, Singh MV, Singh VB, Suwunnakorn S, Palis J, Maggirwar SB. Inhibition of Tropomyosin Receptor Kinase A Signaling Negatively Regulates Megakaryopoiesis and induces Thrombopoiesis. Sci Rep 2019; 9:2781. [PMID: 30808933 PMCID: PMC6391490 DOI: 10.1038/s41598-019-39385-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 12/05/2018] [Indexed: 02/07/2023] Open
Abstract
Neurotrophin signaling modulates the differentiation and function of mature blood cells. The expression of neurotrophin receptors and ligands by hematopoietic and stromal cells of the bone marrow indicates that neurotrophins have the potential to regulate hematopoietic cell fate decisions. This study investigates the role of neurotrophins and Tropomyosin receptor kinases (Trk) in the development of megakaryocytes (MKs) and their progeny cells, platelets. Results indicate that primary human MKs and MK cells lines, DAMI, Meg-01 and MO7e express TrkA, the primary receptor for Nerve Growth Factor (NGF) signaling. Activation of TrkA by NGF enhances the expansion of human MK progenitors (MKPs) and, to some extent, MKs. Whereas, inhibition of TrkA receptor by K252a leads to a 50% reduction in the number of both MKPs and MKs and is associated with a 3-fold increase in the production of platelets. In order to further confirm the role of TrkA signaling in platelet production, TrkA deficient DAMI cells were generated using CRISPR-Cas9 technology. Comparative analysis of wild-type and TrkA-deficient Dami cells revealed that loss of TrkA signaling induced apoptosis of MKs and increased platelet production. Overall, these findings support a novel role for TrkA signaling in platelet production and highlight its potential as therapeutic target for Thrombocytopenia.
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Affiliation(s)
- Ayse Kizilyer
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United States of America
- Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Burdur Mehmet Akif Ersoy University, Burdur, Turkey
| | - Meera V Singh
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United States of America
| | - Vir B Singh
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United States of America
| | - Sumanun Suwunnakorn
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United States of America
| | - James Palis
- Department of Pediatrics, Hematology and Oncology, University of Rochester Medical Center, Rochester, NY, United States of America
| | - Sanjay B Maggirwar
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United States of America.
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25
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Ortiz-Rivero S, Baquero C, Hernández-Cano L, Roldán-Etcheverry JJ, Gutiérrez-Herrero S, Fernández-Infante C, Martín-Granado V, Anguita E, de Pereda JM, Porras A, Guerrero C. C3G, through its GEF activity, induces megakaryocytic differentiation and proplatelet formation. Cell Commun Signal 2018; 16:101. [PMID: 30567575 PMCID: PMC6299959 DOI: 10.1186/s12964-018-0311-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 12/03/2018] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Megakaryopoiesis allows platelet formation, which is necessary for coagulation, also playing an important role in different pathologies. However, this process remains to be fully characterized. C3G, an activator of Rap1 GTPases, is involved in platelet activation and regulates several differentiation processes. METHODS We evaluated C3G function in megakaryopoiesis using transgenic mouse models where C3G and C3GΔCat (mutant lacking the GEF domain) transgenes are expressed exclusively in megakaryocytes and platelets. In addition, we used different clones of K562, HEL and DAMI cell lines with overexpression or silencing of C3G or GATA-1. RESULTS We found that C3G participates in the differentiation of immature hematopoietic cells to megakaryocytes. Accordingly, bone marrow cells from transgenic C3G, but not those from transgenic C3GΔCat mice, showed increased expression of the differentiation markers CD41 and CD61, upon thrombopoietin treatment. Furthermore, C3G overexpression increased the number of CD41+ megakaryocytes with high DNA content. These results are supported by data obtained in the different models of megakaryocytic cell lines. In addition, it was uncovered GATA-1 as a positive regulator of C3G expression. Moreover, C3G transgenic megakaryocytes from fresh bone marrow explants showed increased migration from the osteoblastic to the vascular niche and an enhanced ability to form proplatelets. Although the transgenic expression of C3G in platelets did not alter basal platelet counts, it did increase slightly those induced by TPO injection in vivo. Moreover, platelet C3G induced adipogenesis in the bone marrow under pathological conditions. CONCLUSIONS All these data indicate that C3G plays a significant role in different steps of megakaryopoiesis, acting through a mechanism dependent on its GEF activity.
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Affiliation(s)
- Sara Ortiz-Rivero
- Instituto de Biología Molecular y Celular del Cáncer (IMBCC), Universidad de Salamanca-CSIC, Salamanca, Spain.,Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
| | - Cristina Baquero
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Luis Hernández-Cano
- Instituto de Biología Molecular y Celular del Cáncer (IMBCC), Universidad de Salamanca-CSIC, Salamanca, Spain
| | - Juan José Roldán-Etcheverry
- Servicio de Hematología y Hemoterapia, Hospital Clínico San Carlos, IdISSC, Departamento de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Sara Gutiérrez-Herrero
- Instituto de Biología Molecular y Celular del Cáncer (IMBCC), Universidad de Salamanca-CSIC, Salamanca, Spain.,Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
| | - Cristina Fernández-Infante
- Instituto de Biología Molecular y Celular del Cáncer (IMBCC), Universidad de Salamanca-CSIC, Salamanca, Spain
| | - Víctor Martín-Granado
- Instituto de Biología Molecular y Celular del Cáncer (IMBCC), Universidad de Salamanca-CSIC, Salamanca, Spain.,Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
| | - Eduardo Anguita
- Servicio de Hematología y Hemoterapia, Hospital Clínico San Carlos, IdISSC, Departamento de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - José María de Pereda
- Instituto de Biología Molecular y Celular del Cáncer (IMBCC), Universidad de Salamanca-CSIC, Salamanca, Spain
| | - Almudena Porras
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
| | - Carmen Guerrero
- Instituto de Biología Molecular y Celular del Cáncer (IMBCC), Universidad de Salamanca-CSIC, Salamanca, Spain. .,Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain. .,Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain. .,Centro de Investigación del Cáncer, Campus Unamuno s/n, Salamanca, Spain.
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26
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Gupta S, Cherpokova D, Spindler M, Morowski M, Bender M, Nieswandt B. GPVI signaling is compromised in newly formed platelets after acute thrombocytopenia in mice. Blood 2018; 131:1106-1110. [PMID: 29295843 PMCID: PMC5863702 DOI: 10.1182/blood-2017-08-800136] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 12/20/2017] [Indexed: 02/08/2023] Open
Abstract
At sites of vascular injury, exposed subendothelial collagens trigger platelet activation and thrombus formation by interacting with the immunoreceptor tyrosine-based activation motif (ITAM)-coupled glycoprotein VI (GPVI) on the platelet surface. Platelets are derived from the cytoplasm of megakaryocytes (MKs), which extend large proplatelets into bone marrow (BM) sinusoids that are then released into the bloodstream, where final platelet sizing and maturation occurs. The mechanisms that prevent activation of MKs and forming proplatelets in the collagen-rich BM environment remain largely elusive. Here, we demonstrate that newly formed young platelets (NFYPs) released after antibody-mediated thrombocytopenia in mice display a severe and highly selective signaling defect downstream of GPVI resulting in impaired collagen-dependent activation and thrombus formation in vitro and in vivo. The diminished GPVI signaling in NFYPs is linked to reduced phosphorylation of key downstream signaling proteins, including Syk, LAT, and phospholipase Cγ2, whereas the G protein-coupled receptor and C-type lectin-like receptor 2 signaling pathways remained unaffected. This GPVI signaling defect was overcome once the platelet counts were restored to normal in the circulation. Overall, these results indicate that the GPVI-ITAM signaling machinery in NFYPs after antibody-mediated thrombocytopenia only becomes fully functional in the blood circulation.
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Affiliation(s)
- Shuchi Gupta
- Institute of Experimental Biomedicine I, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany
- Department of Medicine and Pharmacology, University of Pennsylvania, Philadelphia, PA
| | - Deya Cherpokova
- Institute of Experimental Biomedicine I, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA; and
- Department of Pediatrics, Harvard Medical School, Boston, MA
| | - Markus Spindler
- Institute of Experimental Biomedicine I, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany
| | - Martina Morowski
- Institute of Experimental Biomedicine I, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany
| | - Markus Bender
- Institute of Experimental Biomedicine I, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany
| | - Bernhard Nieswandt
- Institute of Experimental Biomedicine I, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany
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27
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Time course of immature platelet count and its relation to thrombocytopenia and mortality in patients with sepsis. PLoS One 2018; 13:e0192064. [PMID: 29381746 PMCID: PMC5790259 DOI: 10.1371/journal.pone.0192064] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Accepted: 01/16/2018] [Indexed: 02/06/2023] Open
Abstract
Introduction The pathogenesis of thrombocytopenia in patients with sepsis is not fully understood. The aims of this study were to investigate changes in thrombopoietic activity over time by using absolute immature platelet counts (AIPC) and to examine the impact of platelet production on thrombocytopenia and mortality in patients with sepsis. Methods This retrospective observational study included adult patients with sepsis admitted to the intensive care unit at a university hospital. Two hundred five consecutive sepsis patients were stratified into four groups according to nadir platelet count: severe (nadir ≤40×103/μL), moderate (41–80×103/μL), or mild thrombocytopenia (81–120×103/μL), or normal-increased platelet count (>120×103/μL). The development of thrombocytopenia was assessed during the first week; mortality was assessed at day 28. Result Of the 205 patients included, 61 (29.8%) developed severe thrombocytopenia. On admission, AIPC did not differ among the four groups. In patients with severe thrombocytopenia, AIPC decreased significantly from days 2 to 7, but remained within or above the normal range in the other three groups (overall group comparison, P<0.0001). Multivariate analysis including coagulation biomarkers revealed that AIPC was independently associated with the development of severe thrombocytopenia (day 3 AIPC, odds ratio 0.49 [95% confidence interval (CI) 0.35–0.66], P<0.0001; day 5 AIPC, 0.59 [95% CI 0.45–0.75], P<0.0001). AIPC was a significant predictor of 28-day mortality in Cox hazard models adjusted for Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores (day 3 AIPC, hazard ratio 0.70 [95% CI 0.52–0.89], P = 0.0029; day 5 AIPC, 0.68 [95% CI 0.49–0.87], P = 0.0012). Conclusions Thrombopoietic activity was generally maintained in the acute phase of sepsis. However, a decrease in AIPC after admission was independently associated with the development of severe thrombocytopenia and mortality, suggesting the importance of suppressed thrombopoiesis in the pathophysiology of sepsis-induced thrombocytopenia.
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28
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Li Y, Jin C, Bai H, Gao Y, Sun S, Chen L, Qin L, Liu PP, Cheng L, Wang QF. Human NOTCH4 is a key target of RUNX1 in megakaryocytic differentiation. Blood 2018; 131:191-201. [PMID: 29101237 PMCID: PMC5757696 DOI: 10.1182/blood-2017-04-780379] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 10/13/2017] [Indexed: 12/19/2022] Open
Abstract
Megakaryocytes (MKs) in adult marrow produce platelets that play important roles in blood coagulation and hemostasis. Monoallelic mutations of the master transcription factor gene RUNX1 lead to familial platelet disorder (FPD) characterized by defective MK and platelet development. However, the molecular mechanisms of FPD remain unclear. Previously, we generated human induced pluripotent stem cells (iPSCs) from patients with FPD containing a RUNX1 nonsense mutation. Production of MKs from the FPD-iPSCs was reduced, and targeted correction of the RUNX1 mutation restored MK production. In this study, we used isogenic pairs of FPD-iPSCs and the MK differentiation system to identify RUNX1 target genes. Using integrative genomic analysis of hematopoietic progenitor cells generated from FPD-iPSCs, and mutation-corrected isogenic controls, we identified 2 gene sets the transcription of which is either up- or downregulated by RUNX1 in mutation-corrected iPSCs. Notably, NOTCH4 expression was negatively controlled by RUNX1 via a novel regulatory DNA element within the locus, and we examined its involvement in MK generation. Specific inactivation of NOTCH4 by an improved CRISPR-Cas9 system in human iPSCs enhanced megakaryopoiesis. Moreover, small molecules known to inhibit Notch signaling promoted MK generation from both normal human iPSCs and postnatal CD34+ hematopoietic stem and progenitor cells. Our study newly identified NOTCH4 as a RUNX1 target gene and revealed a previously unappreciated role of NOTCH4 signaling in promoting human megakaryopoiesis. Our work suggests that human iPSCs with monogenic mutations have the potential to serve as an invaluable resource for discovery of novel druggable targets.
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Affiliation(s)
- Yueying Li
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Chen Jin
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Hao Bai
- Division of Hematology, Department of Medicine and
- Stem Cell Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD; and
| | - Yongxing Gao
- Division of Hematology, Department of Medicine and
- Stem Cell Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD; and
| | - Shu Sun
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Lei Chen
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Lei Qin
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Paul P Liu
- Translational and Functional Genomics Branch, National Institutes of Health, National Human Genome Research Institute, Bethesda, MD
| | - Linzhao Cheng
- Division of Hematology, Department of Medicine and
- Stem Cell Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD; and
| | - Qian-Fei Wang
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
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29
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Mahfoudhi E, Lordier L, Marty C, Pan J, Roy A, Roy L, Rameau P, Abbes S, Debili N, Raslova H, Chang Y, Debussche L, Vainchenker W, Plo I. P53 activation inhibits all types of hematopoietic progenitors and all stages of megakaryopoiesis. Oncotarget 2017; 7:31980-92. [PMID: 26959882 PMCID: PMC5077990 DOI: 10.18632/oncotarget.7881] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Accepted: 02/23/2016] [Indexed: 02/07/2023] Open
Abstract
TP53 also known as p53 is a tumor suppressor gene mutated in a variety of cancers. P53 is involved in cell cycle, apoptosis and DNA repair mechanisms and is thus tightly controlled by many regulators. Recently, strategies to treat cancer have focused on the development of MDM2 antagonists to induce p53 stabilization and restore cell death in p53 non-mutated cancers. However, some of these molecules display adverse effects in patients including induction of thrombocytopenia. In the present study, we have explored the effect of SAR405838 not only on human megakaryopoiesis but also more generally on hematopoiesis. We compared its effect to MI-219 and Nutlin, which are less potent MDM2 antagonists than SAR405838. We found that all these compounds induce a deleterious effect on all types of hematopoietic progenitors, as well as on erythroid and megakaryocytic differentiation. Moreover, they inhibit both early and late stages of megakaryopoiesis including ploidization and proplatelet formation. In conclusion, MDM2 antagonists induced a major hematopoietic defect in vitro as well as an inhibition of all stages of megakaryopoiesis that may account for in vivo thrombocytopenia observed in treated patients.
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Affiliation(s)
- Emna Mahfoudhi
- INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France.,UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France.,Gustave Roussy, Villejuif, France.,Laboratory of Excellence GR-Ex, Villejuif, France.,Laboratoire d'Hématologie Moléculaire et Cellulaire, Institut Pasteur de Tunis, Université de Tunis El Manar, Belvédère, Tunisie
| | - Larissa Lordier
- INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France.,UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France.,Gustave Roussy, Villejuif, France
| | - Caroline Marty
- INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France.,UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France.,Gustave Roussy, Villejuif, France
| | - Jiajia Pan
- INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France.,UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France.,Gustave Roussy, Villejuif, France
| | - Anita Roy
- INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France.,UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France.,Gustave Roussy, Villejuif, France
| | - Lydia Roy
- Départment of Clinical Hematology, Hôpital Henri-Mondor, Créteil, France
| | | | - Salem Abbes
- Laboratoire d'Hématologie Moléculaire et Cellulaire, Institut Pasteur de Tunis, Université de Tunis El Manar, Belvédère, Tunisie
| | - Najet Debili
- INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France.,UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France.,Gustave Roussy, Villejuif, France
| | - Hana Raslova
- INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France.,UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France.,Gustave Roussy, Villejuif, France
| | - Yunhua Chang
- INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France.,UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France.,Gustave Roussy, Villejuif, France
| | | | - William Vainchenker
- INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France.,UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France.,Gustave Roussy, Villejuif, France.,Laboratory of Excellence GR-Ex, Villejuif, France
| | - Isabelle Plo
- INSERM, UMR 1170, Laboratory of Excellence GR-Ex, Villejuif, France.,UMR 1170, Université Paris-Saclay, Gustave Roussy, Villejuif, France.,Gustave Roussy, Villejuif, France.,Laboratory of Excellence GR-Ex, Villejuif, France
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30
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Alberio L. Do we need antiplatelet therapy in thrombocytosis? Pro. Hamostaseologie 2017; 36:227-240. [DOI: 10.5482/hamo-14-11-0074] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2014] [Accepted: 02/13/2015] [Indexed: 12/26/2022] Open
Abstract
SummaryThrombocytosis (defined as platelets >450 × 109/l) has several aetiologies. After having excluded spurious thrombocytosis (e. g., due to microspherocytes, schistocytes, cryoglobulins, or bacteria), the differential diagnosis of true thrombocytosis encompasses secondary causes (as diverse as inflammation, infection, malignancy, iron deficiency, or asplenia), primary hereditary (rare forms of familial thrombocytosis) and primary acquired entities (either in the context of a myelodys-plastic syndrome or more frequently a myeloproliferative neoplasia). This manuscript addresses the following aspects: 1) diagnostic approach to thrombocytosis; 2) various mechanisms leading to a high platelet count; 3) potential of some of these mechanisms to modulate platelet function, producing hyper-reactive platelets and thus exerting a direct impact on the thrombotic risk; 4) indication of anti-thrombotic treatment in patients with thrombocytosis. There is a single prospective randomized clinical trial showing the benefit of acetyl-salicylic acid in polycythaemia vera. For other types of primary thrombocytosis and for secondary forms, treatment decisions have to be individualized according to the patient thrombotic and bleeding risks, taking into account the mechanism causing thrombocytosis. This manuscript discusses experimental and clinical data suggesting that besides patients with essential thrombocythaemia and other forms of primary thrombocytosis also those with thrombocytosis in the context of chronic inflammation, malignancy, or exposure to high altitude might benefit from anti-platelet treatment.
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Zhang X, Chuai Y, Nie W, Wang A, Dai G. Thrombopoietin receptor agonists for prevention and treatment of chemotherapy-induced thrombocytopenia in patients with solid tumours. Cochrane Database Syst Rev 2017; 11:CD012035. [PMID: 29178132 PMCID: PMC6486270 DOI: 10.1002/14651858.cd012035.pub2] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Chemotherapy-induced thrombocytopenia (CIT) is defined as a peripheral platelet count less than 100×109/L, with or without bleeding in cancer patients receiving myelosuppressive chemotherapy. CIT is a significant medical problem during chemotherapy, and it carries the risk of sub-optimal overall survival and bleeding. Alternative interventions to platelet transfusion are limited. Different stages of preclinical and clinical studies have examined the thrombopoietin receptor agonists (TPO-RAs) for CIT in patients with solid tumours. OBJECTIVES To assess the effects of TPO-RAs to prevent and treat CIT in patients with solid tumours:(1) to prevent CIT in patients without thrombocytopenia before chemotherapy, (2) to prevent recurrence of CIT, and (3) to treat CIT in patients with thrombocytopenia during chemotherapy. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL, to 28 September 2017), MEDLINE (from 1950 to 28 September 2017), as well as online registers of ongoing trials (Clinical Trials, Chinese Clinical Trial Register, Australian New Zealand Clinical Trial Registry, WHO ICTRP Search Portal, International Standard Randomised Controlled Trial Number registry, GlaxoSmithKline Clinical Study Register, and Amgen Clinical Trials) and conference proceedings (American Society of Hematology, American Society of Clinical Oncology, European Hematology Association, European Society of Medical Oncology, and Conference Proceedings Citation Index-Science, from 2002 up to September 2017) for studies. SELECTION CRITERIA Randomised controlled trials (RCTs) comparing TPO-RAs alone, or in combination with other drugs, to placebo, no treatment, other drugs, or another TPO-RAs for CIT in patients with solid tumours. DATA COLLECTION AND ANALYSIS Two review authors independently screened the results of the search strategies, extracted data, assessed risk of bias, and analysed data according to standard methodological methods expected by Cochrane. MAIN RESULTS We identified six trials eligible for inclusion, of which two are ongoing, and one awaiting classification study. The three included trials were conducted at many different sites in Europe, America, and Asia. All of the three studies recruited adult and elder participants (no children were included) with solid tumours, and compared TPO-RAs with placebo. No studies compared TPO-RAs alone, or in combination with other drugs, to no treatment, or other drugs, or another TPO-RAs.We judged the overall risk of bias as high as we found a high risk for detection bias. We assessed the risk of bias arising from inadequate blinding of outcome assessors as high for number and severity of bleeding episodes (one of the primary outcomes).To prevent CIT: We included two trials (206 participants) comparing TPO-RAs (eltrombopag, multiple-dose oral administration with chemotherapy) with placebo. The use of TPO-RAs may make little or no difference to the all-cause mortality at 33 weeks of follow-up (RR 1.35, 95% CI 0.53 to 3.45; one trial, 26 participants; low quality of evidence). There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one bleeding episode of any severity (RR 0.62, 95% CI 0.22 to 1.78; two trials, 206 participants; very low quality of evidence). There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one severe/life-threatening bleeding episode (RR 0.36, 95% CI 0.06 to 2.06; two trials, 206 participants; very low quality of evidence). No studies were found that looked at overall survival (one of the primary outcomes), the number of treatment cycles with at least one bleeding episode, the number of days on which bleeding occurred, the amount of bleeding, or quality of life.To prevent recurrence of CIT: We included one trial (62 participants) comparing TPO-RAs (romiplostim, single-dose subcutaneous administration with chemotherapy) with placebo. There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one bleeding episode of any severity (RR 2.80, 95% CI 0.17 to 47.53; one trial, 62 participants; very low quality of evidence). There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one severe/life-threatening bleeding episode (no severe/life-threatening bleeding episodes; one trial, 62 participants; very low quality of evidence). No studies were found that looked at overall survival (one of the primary outcomes), the number of treatment cycles with at least one bleeding episode, the number of days on which bleeding occurred, the amount of bleeding, or quality of life. We found one ongoing study (expected recruitment 74 participants), it is planned to give TPO-RAs (romiplostim, subcutaneous administration with chemotherapy) to participants, but to date this trial has not reported any outcomes.To treat CIT: We found one ongoing study (expected recruitment 83 participants), which is planned to give TPO-RAs (eltrombopag, seven days orally) to participants when their platelet counts are less than 75×109/L during chemotherapy. This trial was originally planned to complete in March 2017, however, the completion date has passed and no results are reported.The one awaiting classification study included patients without thrombocytopenia before chemotherapy (to prevent CIT), patients with thrombocytopenia during chemotherapy (to prevent recurrence of CIT), and other patients during chemotherapy (uncertain whether CIT had happened). There was no evidence for a difference in the number of patients with at least one bleeding episode of any severity (RR 0.27, 95% CI 0.07 to 1.02; one trial, 75 participants). There was no evidence for a difference in the number of patients with at least one severe/life-threatening bleeding episode (RR 0.44, 95% CI 0.03 to 6.77; one trial, 75 participants). This study did not address overall survival or quality of life. AUTHORS' CONCLUSIONS No certain conclusions can be drawn due to the lack of strong evidence in the review. The available weak evidence did not support the use of TPO-RAs for preventing CIT or preventing recurrence of CIT in patients with solid tumours. There was no evidence to support the use of TPO-RAs for treating CIT in patients with solid tumours.
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Affiliation(s)
- Xia Zhang
- Chinese PLA General HospitalDepartment of OncologyBeijingChina
| | - Yunhai Chuai
- Navy General HospitalDepartment of Obstetrics and GynaecologyFucheng RoadBeijingChina100048
| | - Wei Nie
- No.425 Hospital of Chinese PLADepartment of Internal MedicineSanya Bay Road No.86SanyaChina572000
| | - Aiming Wang
- Navy General HospitalDepartment of Obstetrics and GynaecologyFucheng RoadBeijingChina100048
| | - Guanghai Dai
- Chinese PLA General HospitalDepartment of OncologyBeijingChina
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Larsen SB, Grove EL, Würtz M, Neergaard-Petersen S, Hvas AM, Kristensen SD. The influence of low-grade inflammation on platelets in patients with stable coronary artery disease. Thromb Haemost 2017; 114:519-29. [DOI: 10.1160/th14-12-1007] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 05/07/2015] [Indexed: 12/19/2022]
Abstract
SummaryInflammation is likely to be involved in all stages of atherosclerosis. Numerous inflammatory biomarkers are currently being studied, and even subtle increases in inflammatory biomarkers have been associated with increased risk of cardiovascular events in patients with coronary artery disease (CAD). Low-grade inflammation may influence both platelet production and platelet activation potentially leading to enhanced platelet aggregation. Thrombopoietin is considered the primary regulator of platelet production, but it likely acts in conjunction with numerous cytokines, of which many have altered levels in CAD. Previous studies have shown that high-sensitive C-reactive protein (CRP) independently predicts increased platelet aggregation in stable CAD patients. Increased levels of CRP, fibrinogen, interleukin-6, stromal cell-derived factor-1, CXC motif ligand 16, macrophage migration inhibitory factor, RANTES, calprotectin, and copeptin have been associated with increased risk of cardiovascular events in CAD patients. Additionally, some of these inflammatory markers have been associated with enhanced platelet activation and aggregation. However, CRP and other inflammatory markers provide only limited additional predictive value to classical risk factors such as smoking, blood pressure, and cholesterol levels. Existing data do not clarify whether inflammation simply accompanies CAD and increased production and aggregation of platelets, or whether a causal relationship exists. In this review, we provide a comprehensive overview of inflammatory markers in stable CAD with particular emphasis on platelet production, activation, and aggregation in CAD patients.
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Christiansen MK, Larsen SB, Nyegaard M, Neergaard-Petersen S, Würtz M, Grove EL, Hvas AM, Jensen HK, Kristensen SD. The SH2B3 and KCNK5 loci may be implicated in regulation of platelet count, volume, and maturity. Thromb Res 2017; 158:86-92. [PMID: 28865245 DOI: 10.1016/j.thromres.2017.08.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 07/21/2017] [Accepted: 08/17/2017] [Indexed: 01/11/2023]
Abstract
INTRODUCTION In recent genome-wide association studies, coronary artery disease (CAD) and myocardial infarction (MI) have been linked to a number of genetic variants, but their role in thrombopoiesis is largely unknown. AIM We investigated the association between CAD and MI-associated genetic variants and five thrombopoiesis-related indices: platelet count (PC), mean platelet volume (MPV), immature platelet count (IPC), immature platelet fraction (IPF), and serum thrombopoietin (TPO). METHODS We genotyped 45 genome-wide significant CAD/MI-markers in 879 stable CAD patients. A genetic risk score was calculated to assess the combined risk associated with all the genetic variants. Platelet indices were analysed using the Sysmex XE-2100 haematology analyser. TPO was measured by ELISA. RESULTS Two variants were nominally associated with several indices; for rs10947789 (KCNK5), the adjusted geometric mean was 2% higher for MPV (95% confidence interval: 1-2%, p=0.002), 6% for IPC (0-12%, p=0.033), and 9% for IPF (3-16%, p=0.004) per CAD risk allele. Moreover, an 11% lower TPO (3-19%, p=0.010) was observed. Rs3184504 (SH2B3) was associated with a higher adjusted geometric mean of 3% (1-6%, p=0.003) per CAD risk allele for PC, and an 11% (5-17%, p<0.001) lower TPO. Furthermore, the adjusted IPC was 5% (0-9%, p=0.037) lower per CAD risk allele for PC, whereas IPF levels did not vary across genotypes. CONCLUSION As a novel finding, our study suggests a role for KCNK5 in the regulation of platelet size and maturity. Furthermore, our findings confirm an association between the SH2B3-locus and platelet count.
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Affiliation(s)
- Morten K Christiansen
- Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; Faculty of Health, Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Sanne B Larsen
- Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
| | - Mette Nyegaard
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | | | - Morten Würtz
- Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
| | - Erik L Grove
- Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; Faculty of Health, Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Anne-Mette Hvas
- Faculty of Health, Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Henrik K Jensen
- Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; Faculty of Health, Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Steen D Kristensen
- Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; Faculty of Health, Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
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Berlian G, Tandrasasmita OM, Tjandrawinata RR. Trombinol, a bioactive fraction of Psidium guajava , stimulates thrombopoietin expression in HepG2 cells. Asian Pac J Trop Biomed 2017. [DOI: 10.1016/j.apjtb.2016.09.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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Larsen SB, Grove EL, Neergaard-Petersen S, Würtz M, Hvas AM, Kristensen SD. Thrombopoietin and platelet aggregation in patients with stable coronary artery disease. Platelets 2017; 28:822-824. [PMID: 28436258 DOI: 10.1080/09537104.2017.1296567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Thrombopoietin (TPO) may facilitate platelet activation and aggregation. However, data on the impact of TPO on platelet aggregation in patients with stable coronary artery disease (CAD) are scarce. We aimed to investigate associations between TPO and platelet aggregation and activation in patients with stable coronary artery disease (CAD). We studied 900 stable CAD patients. Serum TPO was assessed by ELISA. Platelet aggregation was evaluated using the Multiplate Analyzer (agonists: arachidonic acid [AA] and collagen) and the VerifyNow Aspirin Assay. Platelet activation was evaluated by soluble (s)P-selectin. Cyclooxygenase-1 inhibition was evaluated by serum thromboxane B2 (TXB2). We found that TPO correlated weakly with platelet aggregation evaluated by Multiplate using AA (r = -0.09, p = 0.01) and collagen as agonists (r = -0.03, p = 0.43) and by VerifyNow (r = 0.07, p = 0.03). We found no correlation between TPO and sP-selectin (r = -0.01, p = 0.70). Independent predictors of AA-induced platelet aggregation by Multiplate included high levels of sP-selectin and serum TXB2, high platelet count, increasing age and body mass index, female sex, and active smoking. Independent predictors of TPO included low AA-induced platelet aggregation by Multiplate, high levels of hs-CRP, active smoking, and high platelet aggregation evaluated by VerifyNow. In conclusion, TPO levels did not correlate with platelet activation and only weak associations were found between TPO and platelet aggregation, suggesting that TPO did not substantially facilitate platelet aggregation in stable CAD patients.
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Affiliation(s)
- Sanne Bøjet Larsen
- a Department of Cardiology , Aarhus University Hospital , Aarhus , Denmark
| | - Erik Lerkevang Grove
- a Department of Cardiology , Aarhus University Hospital , Aarhus , Denmark.,b Faculty of Health, Institute of Clinical Medicine , Aarhus University , Aarhus , Denmark
| | | | - Morten Würtz
- a Department of Cardiology , Aarhus University Hospital , Aarhus , Denmark
| | - Anne-Mette Hvas
- b Faculty of Health, Institute of Clinical Medicine , Aarhus University , Aarhus , Denmark.,c Department of Clinical Biochemistry , Aarhus University Hospital , Aarhus , Denmark
| | - Steen Dalby Kristensen
- a Department of Cardiology , Aarhus University Hospital , Aarhus , Denmark.,b Faculty of Health, Institute of Clinical Medicine , Aarhus University , Aarhus , Denmark
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Menter DG, Davis JS, Tucker SC, Hawk E, Crissman JD, Sood AK, Kopetz S, Honn KV. Platelets: “First Responders” in Cancer Progression and Metastasis. PLATELETS IN THROMBOTIC AND NON-THROMBOTIC DISORDERS 2017:1111-1132. [DOI: 10.1007/978-3-319-47462-5_74] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Hatami J, Ferreira FC, da Silva CL, Tiago J, Sequeira A. Computational modeling of megakaryocytic differentiation of umbilical cord blood-derived stem/progenitor cells. Comput Chem Eng 2016. [DOI: 10.1016/j.compchemeng.2016.07.027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Roy A, Lordier L, Pioche-Durieu C, Souquere S, Roy L, Rameau P, Lapierre V, Le Cam E, Plo I, Debili N, Raslova H, Vainchenker W. Uncoupling of the Hippo and Rho pathways allows megakaryocytes to escape the tetraploid checkpoint. Haematologica 2016; 101:1469-1478. [PMID: 27515249 DOI: 10.3324/haematol.2016.149914] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 08/08/2016] [Indexed: 01/03/2023] Open
Abstract
Megakaryocytes are naturally polyploid cells that increase their ploidy by endomitosis. However, very little is known regarding the mechanism by which they escape the tetraploid checkpoint to become polyploid. Recently, it has been shown that the tetraploid checkpoint was regulated by the Hippo-p53 pathway in response to a downregulation of Rho activity. We therefore analyzed the role of Hippo-p53 pathway in the regulation of human megakaryocyte polyploidy. Our results revealed that Hippo-p53 signaling pathway proteins are present and are functional in megakaryocytes. Although this pathway responds to the genotoxic stress agent etoposide, it is not activated in tetraploid or polyploid megakaryocytes. Furthermore, Hippo pathway was observed to be uncoupled from Rho activity. Additionally, polyploid megakaryocytes showed increased expression of YAP target genes when compared to diploid and tetraploid megakaryocytes. Although p53 knockdown increased both modal ploidy and proplatelet formation in megakaryocytes, YAP knockdown caused no significant change in ploidy while moderately affecting proplatelet formation. Interestingly, YAP knockdown reduced the mitochondrial mass in polyploid megakaryocytes and decreased expression of PGC1α, an important mitochondrial biogenesis regulator. Thus, the Hippo pathway is functional in megakaryocytes, but is not induced by tetraploidy. Additionally, YAP regulates the mitochondrial mass in polyploid megakaryocytes.
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Affiliation(s)
- Anita Roy
- Institut National de la Santé et la Recherche Médicale (INSERM) UMR1170, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Villejuif, France.,Université Paris-Saclay, Villejuif, France.,Gustave Roussy, Villejuif, France
| | - Larissa Lordier
- Institut National de la Santé et la Recherche Médicale (INSERM) UMR1170, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Villejuif, France.,Université Paris-Saclay, Villejuif, France.,Gustave Roussy, Villejuif, France
| | - Catherine Pioche-Durieu
- Université Paris-Saclay, Villejuif, France.,Gustave Roussy, Villejuif, France.,Centre Nationale de la Recherche Scientifique (CNRS), UMR 8126, Gustave Roussy, Villejuif, France
| | - Sylvie Souquere
- Université Paris-Saclay, Villejuif, France.,Gustave Roussy, Villejuif, France.,CNRS UMR 8122, Gustave Roussy, Villejuif, France
| | - Lydia Roy
- Institut National de la Santé et la Recherche Médicale (INSERM) UMR1170, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Villejuif, France.,Assistance Publique des Hôpitaux de Paris (AP-HP), Service d'Hématologie Clinique, Hôpital Henri Mondor, Créteil, France
| | | | | | - Eric Le Cam
- Université Paris-Saclay, Villejuif, France.,Gustave Roussy, Villejuif, France.,Centre Nationale de la Recherche Scientifique (CNRS), UMR 8126, Gustave Roussy, Villejuif, France
| | - Isabelle Plo
- Institut National de la Santé et la Recherche Médicale (INSERM) UMR1170, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Villejuif, France.,Université Paris-Saclay, Villejuif, France.,Gustave Roussy, Villejuif, France
| | - Najet Debili
- Institut National de la Santé et la Recherche Médicale (INSERM) UMR1170, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Villejuif, France.,Université Paris-Saclay, Villejuif, France.,Gustave Roussy, Villejuif, France
| | - Hana Raslova
- Institut National de la Santé et la Recherche Médicale (INSERM) UMR1170, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Villejuif, France.,Université Paris-Saclay, Villejuif, France.,Gustave Roussy, Villejuif, France
| | - William Vainchenker
- Institut National de la Santé et la Recherche Médicale (INSERM) UMR1170, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Villejuif, France .,Université Paris-Saclay, Villejuif, France.,Gustave Roussy, Villejuif, France
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40
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Daly ME. Transcription factor defects causing platelet disorders. Blood Rev 2016; 31:1-10. [PMID: 27450272 DOI: 10.1016/j.blre.2016.07.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 06/10/2016] [Accepted: 07/12/2016] [Indexed: 01/19/2023]
Abstract
Recent years have seen increasing recognition of a subgroup of inherited platelet function disorders which are due to defects in transcription factors that are required to regulate megakaryopoiesis and platelet production. Thus, germline mutations in the genes encoding the haematopoietic transcription factors RUNX1, GATA-1, FLI1, GFI1b and ETV6 have been associated with both quantitative and qualitative platelet abnormalities, and variable bleeding symptoms in the affected patients. Some of the transcription factor defects are also associated with an increased predisposition to haematologic malignancies (RUNX1, ETV6), abnormal erythropoiesis (GATA-1, GFI1b, ETV6) and immune dysfunction (FLI1). The persistence of MYH10 expression in platelets is a surrogate marker for FLI1 and RUNX1 defects. Characterisation of the transcription factor defects that give rise to platelet function disorders, and of the genes that are differentially regulated as a result, are yielding insights into the roles of these genes in platelet formation and function.
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Affiliation(s)
- Martina E Daly
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX, UK.
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Liongue C, Sertori R, Ward AC. Evolution of Cytokine Receptor Signaling. THE JOURNAL OF IMMUNOLOGY 2016; 197:11-18. [DOI: 10.4049/jimmunol.1600372] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
Abstract
Cytokines represent essential mediators of cell–cell communication with particularly important roles within the immune system. These secreted factors are produced in response to developmental and/or environmental cues and act via cognate cytokine receptors on target cells, stimulating specific intracellular signaling pathways to facilitate appropriate cellular responses. This review describes the evolution of cytokine receptor signaling, focusing on the class I and class II receptor families and the downstream JAK–STAT pathway along with its key negative regulators. Individual components generated over a long evolutionary time frame coalesced to form an archetypal signaling pathway in bilateria that was expanded extensively during early vertebrate evolution to establish a substantial “core” signaling network, which has subsequently undergone limited diversification within discrete lineages. The evolution of cytokine receptor signaling parallels that of the immune system, particularly the emergence of adaptive immunity, which has likely been a major evolutionary driver.
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Affiliation(s)
- Clifford Liongue
- School of Medicine, Deakin University, Waurn Ponds, Victoria 3216, Australia; and Centre for Molecular and Medical Research, Deakin University, Waurn Ponds, Victoria 3216, Australia
| | - Robert Sertori
- School of Medicine, Deakin University, Waurn Ponds, Victoria 3216, Australia; and Centre for Molecular and Medical Research, Deakin University, Waurn Ponds, Victoria 3216, Australia
| | - Alister C. Ward
- School of Medicine, Deakin University, Waurn Ponds, Victoria 3216, Australia; and Centre for Molecular and Medical Research, Deakin University, Waurn Ponds, Victoria 3216, Australia
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Bone marrow niche in immune thrombocytopenia: a focus on megakaryopoiesis. Ann Hematol 2016; 95:1765-76. [PMID: 27236577 DOI: 10.1007/s00277-016-2703-1] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Accepted: 05/23/2016] [Indexed: 12/18/2022]
Abstract
Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by increased bleeding tendency and thrombocytopenia. In fact, the precise pathogenesis of this disease is still not clear. Megakaryopoiesis involves complete differentiation of megakaryocyte (MK) progenitors to functional platelets. This complex process occurs in specific bone marrow (BM) niches composed of several hematopoietic and non-hematopoietic cell types, soluble factors, and extracellular matrix proteins. These specialized microenvironments sustain MK maturation and localization to sinusoids as well as platelet release into circulation. However, MKs in ITP patients show impaired maturation and signs of degradation. Intrinsic defects in MKs and their extrinsic environment have been implicated in altered megakaryopoiesis in this disease. In particular, aberrant expression of miRNAs directing MK proliferation, differentiation, and platelet production; defective MK apoptosis; and reduced proliferation and differentiation rate of the MSC compartment observed in these patients may account for BM defects in ITP. Furthermore, insufficient production of thrombopoietin is another likely reason for ITP development. Therefore, identifying the signaling pathways and transcription factors influencing the interaction between MKs and BM niche in ITP patients will contribute to increased platelet production in order to prevent incomplete MK maturation and destruction as well as BM fibrosis and apoptosis in ITP. In this review, we will examine the interaction and role of BM niches in orchestrating megakaryopoiesis in ITP patients and discuss how these factors can be exploited to improve the quality of patient treatment and prognosis.
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Ru YX, Dong SX, Liang HY, Zhao SX. Platelet production of megakaryocyte: A review with original observations on human in vivo cells and bone marrow. Ultrastruct Pathol 2016; 40:163-70. [PMID: 27159022 DOI: 10.3109/01913123.2016.1170744] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Megakaryocytes (MKs) build characteristic structures to produce platelets in a series of steps. Although mechanisms of demarcation membrane system (DMS) and open canalicular system transformation have been proposed based on experimental studies in recent decades, the related evidence is lacking in human cells in vivo. The present review describes and discusses the development of MKs, transformation of DMS, and the release and maturation of proplatelets based on our observation of human MKs in vivo and bone marrow biopsy by light microscope and transmission electron microscope. Four stages were subdivided from megakaryoblasts to matured cells; presumption of DMS transformation from endoplasmic reticulum and Golgi apparatus were evidenced in contrast to another presumption of DMS transformation from plasma membrane in this review. Effectors of interaction between hematopoietic cells, the sucking and shearing force of sinus blood flow on movement of MKs, and release of proplatelets were emphasized. Additionally, the mechanism of secondary splitting of proplatelets in circulation was demonstrated ultrastructurally. These findings and conceptions might significantly promote our understanding of the mechanism of platelet production in human in vivo cells.
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Affiliation(s)
- Yong-Xin Ru
- a Institute of Hematology & Blood Diseases Hospital, State Key Laboratory of Experimental Hematology, Peking Union Medical College , Tianjin , China
| | - Shu-Xu Dong
- a Institute of Hematology & Blood Diseases Hospital, State Key Laboratory of Experimental Hematology, Peking Union Medical College , Tianjin , China
| | - Hao-Yue Liang
- a Institute of Hematology & Blood Diseases Hospital, State Key Laboratory of Experimental Hematology, Peking Union Medical College , Tianjin , China
| | - Shi-Xuan Zhao
- a Institute of Hematology & Blood Diseases Hospital, State Key Laboratory of Experimental Hematology, Peking Union Medical College , Tianjin , China
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Zhao L, Xu D, Qiao L, Zhang X. Bone Marrow Megakaryocytes May Predict Therapeutic Response of Severe Thrombocytopenia in Patients with Systemic Lupus Erythematosus. J Rheumatol 2016; 43:1038-44. [DOI: 10.3899/jrheum.150829] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/18/2016] [Indexed: 12/25/2022]
Abstract
Objective.To analyze the predictive value of megakaryocyte counts in bone marrow (BM-MK) for determining the therapeutic response of severe thrombocytopenia (TP) in patients with systemic lupus erythematosus (SLE).Methods.Thirty-five patients with SLE with severe TP (platelet count ≤ 50 × 109/l) from the Peking Union Medical College Hospital admitted between 2007 and 2014 with appreciable bone marrow aspiration results were analyzed retrospectively. The associations between therapeutic response and clinical manifestations, laboratory findings including BM-MK counts, were evaluated.Results.Seventeen (49%) and 8 (23%) patients achieved a complete response (CR) and a partial response (PR), respectively, and 10 had no response (NR). The BM-MK counts in each group were 102 ± 25 (0–322), 136 ± 48 (2–419), and 28 ± 12 (0–105) per slide, respectively. Significant differences were observed in the counts of BM-MK between patients who achieved a clinical response (CR + PR) and those who did not (NR; p = 0.007). Patients in the NR group exhibited fewer BM-MK compared with those in the CR and PR groups (p = 0.017 and p = 0.006, respectively). A receiver-operation characteristic analysis identified that a cutoff value of BM-MK counts at 20 performed pretty well in discriminating patients with differential responses to immunotherapy, with sensitivity and specificity and area under the curve of 88%, 70%, and 0.798, respectively.Conclusion.BM-MK count may serve as a good predicting factor for immunotherapeutic response in patients with SLE with severe TP. Patients with BM-MK counts < 20 per slide tend to exhibit poor clinical response.
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Podoplanin-positive periarteriolar stromal cells promote megakaryocyte growth and proplatelet formation in mice by CLEC-2. Blood 2016; 127:1701-10. [DOI: 10.1182/blood-2015-08-663708] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2015] [Accepted: 01/16/2016] [Indexed: 12/14/2022] Open
Abstract
Key Points
BM FRC-like cells regulate megakaryocytic clonal expansion via CLEC-2/PDPN interactions. CLEC-2/PDPN binding stimulates BM FRC-like cells to secrete the proplatelet formation-promoting factor, CCL5.
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46
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Zhang X, Chuai Y, Nie W, Wang A, Dai G. Thrombopoietin receptor agonists for prevention and treatment of chemotherapy-induced thrombocytopenia in patients with solid tumours. Cochrane Database Syst Rev 2016. [DOI: 10.1002/14651858.cd012035] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Xia Zhang
- Chinese PLA General Hospital; Department of Oncology; Beijing China
| | - Yunhai Chuai
- Navy General Hospital; Department of Obstetrics and Gynaecology; Fucheng Road Beijing China 100048
| | - Wei Nie
- Changzheng Hospital, Second Military Medical University; Department of Respiratory Medicine; Fengyang Road No. 415 Shanghai China 200003
| | - Aiming Wang
- Navy General Hospital; Department of Obstetrics and Gynaecology; Fucheng Road Beijing China 100048
| | - Guanghai Dai
- Chinese PLA General Hospital; Department of Oncology; Beijing China
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47
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Lyu M, Li Y, Hao Y, Sun T, Liu W, Lyu C, Fu R, Li H, Xue F, Liu X, Zhang L, Yang R. Stromal cell-derived factor-1 rs2297630 polymorphism associated with platelet production and treatment response in Chinese patients with chronic immune thrombocytopenia. Platelets 2015; 27:338-43. [PMID: 26587874 DOI: 10.3109/09537104.2015.1103368] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Mingen Lyu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Yang Li
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Yating Hao
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Tiantian Sun
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Wenjie Liu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Cuicui Lyu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Rongfeng Fu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Huiyuan Li
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Feng Xue
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Xiaofan Liu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Lei Zhang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Renchi Yang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
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48
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Megakaryocytic differentiation of mouse embryonic stem cells via coculture with immortalized OP9 stromal cells. Exp Cell Res 2015; 339:44-50. [DOI: 10.1016/j.yexcr.2015.10.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 09/12/2015] [Accepted: 10/02/2015] [Indexed: 12/14/2022]
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49
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Wentz JM, Vainstein V, Oldson D, Gluzman-Poltorak Z, Basile LA, Stricklin D. Mathematical model of radiation effects on thrombopoiesis in rhesus macaques and humans. J Theor Biol 2015; 383:44-60. [PMID: 26232694 DOI: 10.1016/j.jtbi.2015.07.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Revised: 07/01/2015] [Accepted: 07/16/2015] [Indexed: 12/20/2022]
Abstract
A mathematical model that describes the effects of acute radiation exposure on thrombopoiesis in primates and humans is presented. Thrombopoiesis is a complex multistage dynamic process with potential differences between species. Due to known differences in cellular radiosensitivities, nadir times, and cytopenia durations, direct extrapolation from rhesus to human platelet dynamics is unrealistic. Developing mathematical models of thrombopoiesis for both humans and primates allows for the comparison of the system's response across species. Thus, data obtained in primate experiments can be extrapolated to predictions in humans. Parameter values for rhesus macaques and humans were obtained either from direct experimental measurements or through optimization procedures using dynamic data on platelet counts following radiation exposure. Model simulations accurately predict trends observed in platelet dynamics: at low radiation doses platelet counts decline after a time lag, and nadir depth is dose dependent. The models were validated using data that was not used during the parameterization process. In particular, additional experimental data was used for rhesus, and accident and platelet donor data was used for humans. The model aims to simulate the average response in rhesus and humans following irradiation. Variation in platelet dynamics due to individual variability can be modeled using Monte Carlo simulations in which parameter values are sampled from distributions. This model provides insight into the time course of the physiological effects of radiation exposure, information which could be valuable for disaster planning and survivability analysis and help in drug development of radiation medical countermeasures.
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Affiliation(s)
- J M Wentz
- Applied Research Associates, Inc., Arlington, VA, United States.
| | - V Vainstein
- Neumedicines, Inc., Pasadena, CA, United States
| | - D Oldson
- Applied Research Associates, Inc., Arlington, VA, United States
| | | | - L A Basile
- Neumedicines, Inc., Pasadena, CA, United States
| | - D Stricklin
- Applied Research Associates, Inc., Arlington, VA, United States
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50
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Balduini A, Di Buduo CA, Kaplan DL. Translational approaches to functional platelet production ex vivo. Thromb Haemost 2015; 115:250-6. [PMID: 26353819 DOI: 10.1160/th15-07-0570] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Accepted: 08/11/2015] [Indexed: 12/13/2022]
Abstract
Platelets, which are released by megakaryocytes, play key roles in haemostasis, angiogenesis, immunity, tissue regeneration and wound healing. The scarcity of clinical cures for life threatening platelet diseases is in a large part due to limited insight into the mechanisms that control the developmental process of megakaryocytes and the mechanisms that govern the production of platelets within the bone marrow. To overcome these limitations, functional human tissue models have been developed and studied to extrapolate ex vivo outcomes for new insight on bone marrow functions in vivo. There are many challenges that these models must overcome, from faithfully mimicking the physiological composition and functions of bone marrow, to the collection of the platelets generated and validation of their viability and function for human use. The overall goal is to identify innovative instruments to study mechanisms of platelet release, diseases related to platelet production and new therapeutic targets starting from human progenitor cells.
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Affiliation(s)
- Alessandra Balduini
- Alessandra Balduini, Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA 02155, USA, Tel.: +1 617 627 2580, Fax: +1 617 627 3231, E-mail:
| | | | - David L Kaplan
- David L. Kaplan, Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA 02155, USA, Tel.: +1 617 627 2580, Fax: +1 617 627 3231, E-mail:
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