Thromb Haemost 2021; 121(04): 495-505
DOI: 10.1055/s-0040-1718761
Cellular Haemostasis and Platelets

Immune Thrombocytopenia Plasma-Derived Exosomes Impaired Megakaryocyte and Platelet Production through an Apoptosis Pathway

Wenjing Miao
1   National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
2   Institute of Blood and Marrow Transplantation, Soochow University, Suzhou, China
3   Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
,
Baoquan Song
1   National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
2   Institute of Blood and Marrow Transplantation, Soochow University, Suzhou, China
3   Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
,
Bingyu Shi
1   National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
2   Institute of Blood and Marrow Transplantation, Soochow University, Suzhou, China
3   Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
,
Qi Wan
4   Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, of China
,
Quansheng Lv
1   National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
,
Hanqing Chen
1   National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
,
Mingqing Zhu
1   National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
,
Leisheng Zhang
5   The Postdoctoral Research Station, School of Medicine, Nankai University, Tianjin, China
6   Division of Precision Medicine, Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd., Tianjin, China
,
Yue Han
1   National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
2   Institute of Blood and Marrow Transplantation, Soochow University, Suzhou, China
3   Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
,
Depei Wu
1   National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
2   Institute of Blood and Marrow Transplantation, Soochow University, Suzhou, China
3   Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
› Author Affiliations
Funding This work was supported by the National Natural Science Foundation of China (No. 81700119), China Postdoctoral Science Foundation (2019M661033), the Natural Science Foundation of Tianjin (19JCQNJC12500).

Abstract

Reduced megakaryocyte (MK) apoptosis and insufficient platelet production play important roles in the pathogenesis of immune thrombocytopenia (ITP). The contribution of plasma-derived exosomes to the decreased platelet count in ITP has not been entirely understood. Here, we found the percentage of apoptotic MKs in patients with ITP was significantly lower than those in healthy volunteers. In the presence of ITP plasma-derived exosomes (ITP-Exo), the apoptosis of MKs was reduced during the process of MK differentiation in vitro, which contributed to the reduced platelet production by Bcl-xL/caspase signaling. Furthermore, in vivo study demonstrated that ITP-Exo administration led to significantly delayed platelet recovery in mice after 3.5 Gy of irradiation. All these findings indicated that ITP-Exo, as a regulator of platelet production, impaired MK apoptosis and platelet production through Bcl-xL/caspase signaling, unveiling new mechanisms for reduced platelet count in ITP.

W.M. and B.S. contributed equally to this study.


Supplementary Material



Publication History

Received: 18 August 2019

Accepted: 15 September 2020

Article published online:
29 October 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Houwerzijl EJ, Blom NR, van der Want JJL, Vellenga E, de Wolf JT. Megakaryocytic dysfunction in myelodysplastic syndromes and idiopathic thrombocytopenic purpura is in part due to different forms of cell death. Leukemia 2006; 20 (11) 1937-1942
  • 2 Cines DB, Cuker A, Semple JW. Pathogenesis of immune thrombocytopenia. Presse Med 2014; 43 (4, Pt 2): e49-e59
  • 3 Iraqi M, Perdomo J, Yan F, Choi PY, Chong BH. Immune thrombocytopenia: antiplatelet autoantibodies inhibit proplatelet formation by megakaryocytes and impair platelet production in vitro. Haematologica 2015; 100 (05) 623-632
  • 4 Ballem PJ, Segal GM, Stratton JR, Gernsheimer T, Adamson JW, Slichter SJ. Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance. J Clin Invest 1987; 80 (01) 33-40
  • 5 Rivière É, Viallard JF, Guy A. et al. Intrinsically impaired platelet production in some patients with persistent or chronic immune thrombocytopenia. Br J Haematol 2015; 170 (03) 408-415
  • 6 Zufferey A, Kapur R, Semple JW. Pathogenesis and therapeutic mechanisms in immune thrombocytopenia (ITP). J Clin Med 2017; 6 (02) 16
  • 7 Vrbensky JR, Nazy I, Toltl LJ. et al. Megakaryocyte apoptosis in immune thrombocytopenia. Platelets 2018; 29 (07) 729-732
  • 8 Tkach M, Théry C. Communication by extracellular vesicles: where we are and where we need to go. Cell 2016; 164 (06) 1226-1232
  • 9 Xu R, Greening DW, Zhu HJ, Takahashi N, Simpson RJ. Extracellular vesicle isolation and characterization: toward clinical application. J Clin Invest 2016; 126 (04) 1152-1162
  • 10 Wang J, Hendrix A, Hernot S. et al. Bone marrow stromal cell-derived exosomes as communicators in drug resistance in multiple myeloma cells. Blood 2014; 124 (04) 555-566
  • 11 Manier S, Liu CJ, Avet-Loiseau H. et al. Prognostic role of circulating exosomal miRNAs in multiple myeloma. Blood 2017; 129 (17) 2429-2436
  • 12 Del Re M, Marconcini R, Pasquini G. et al. PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC. Br J Cancer 2018; 118 (06) 820-824
  • 13 Qin X, Yu S, Xu X, Shen B, Feng J. Comparative analysis of microRNA expression profiles between A549, A549/DDP and their respective exosomes. Oncotarget 2017; 8 (26) 42125-42135
  • 14 Rabinowits G, Bowden M, Flores LM. et al. Comparative analysis of MicroRNA expression among benign and malignant tongue tissue and plasma of patients with tongue cancer. Front Oncol 2017; 7: 191
  • 15 Zhang Z, Li X, Sun W. et al. Loss of exosomal miR-320a from cancer-associated fibroblasts contributes to HCC proliferation and metastasis. Cancer Lett 2017; 397: 33-42
  • 16 Giudice V, Banaszak LG, Gutierrez-Rodrigues F. et al. Circulating exosomal microRNAs in acquired aplastic anemia and myelodysplastic syndromes. Haematologica 2018; 103 (07) 1150-1159
  • 17 Kumar B, Garcia M, Weng L. et al. Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion. Leukemia 2018; 32 (03) 575-587
  • 18 Peng D, Wang H, Li L. et al. miR-34c-5p promotes eradication of acute myeloid leukemia stem cells by inducing senescence through selective RAB27B targeting to inhibit exosome shedding. Leukemia 2018; 32 (05) 1180-1188
  • 19 Wang L, Gu Z, Zhao X. et al. Extracellular vesicles released from human umbilical cord-derived mesenchymal stromal cells prevent life-threatening acute graft-versus-host disease in a mouse model of allogeneic hematopoietic stem cell transplantation. Stem Cells Dev 2016; 25 (24) 1874-1883
  • 20 Nakano M, Nagaishi K, Konari N. et al. Bone marrow-derived mesenchymal stem cells improve diabetes-induced cognitive impairment by exosome transfer into damaged neurons and astrocytes. Sci Rep 2016; 6: 24805
  • 21 Wen S, Dooner M, Cheng Y. et al. Mesenchymal stromal cell-derived extracellular vesicles rescue radiation damage to murine marrow hematopoietic cells. Leukemia 2016; 30 (11) 2221-2231
  • 22 Cui G-H, Wu J, Mou F-F. et al. Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice. FASEB J 2018; 32 (02) 654-668
  • 23 Boyiadzis M, Whiteside TL. Exosomes in acute myeloid leukemia inhibit hematopoiesis. Curr Opin Hematol 2018; 25 (04) 279-284
  • 24 Raimondo S, Saieva L, Vicario E. et al. Multiple myeloma-derived exosomes are enriched of amphiregulin (AREG) and activate the epidermal growth factor pathway in the bone microenvironment leading to osteoclastogenesis. J Hematol Oncol 2019; 12 (01) 2
  • 25 Xu H, Han H, Song S. et al. Exosome-transmitted PSMA3 and PSMA3-AS1 promote proteasome inhibitor resistance in multiple myeloma. Clin Cancer Res 2019; 25 (06) 1923-1935
  • 26 Liu XG, Liu S, Feng Q. et al. Thrombopoietin receptor agonists shift the balance of Fcγ receptors toward inhibitory receptor IIb on monocytes in ITP. Blood 2016; 128 (06) 852-861
  • 27 Swinkels M, Rijkers M, Voorberg J, Vidarsson G, Leebeek FWG, Jansen AJG. Emerging concepts in immune thrombocytopenia. Front Immunol 2018; 9: 880
  • 28 Marini I, Zlamal J, Faul C. et al. Autoantibody-mediated desialylation impairs human thrombopoiesis and platelet life span. Haematologica 2019; 19: 236117
  • 29 Josefsson EC, James C, Henley KJ. et al. Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets. J Exp Med 2011; 208 (10) 2017-2031
  • 30 Josefsson EC, Burnett DL, Lebois M. et al. Platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways. Nat Commun 2014; 5: 3455
  • 31 Perdomo J, Yan F, Chong BH. A megakaryocyte with no platelets: anti-platelet antibodies, apoptosis, and platelet production. Platelets 2013; 24 (02) 98-106
  • 32 Uçar C, Oren H, Irken G. et al. Investigation of megakaryocyte apoptosis in children with acute and chronic idiopathic thrombocytopenic purpura. Eur J Haematol 2003; 70 (06) 347-352
  • 33 Yang L, Wang L, Zhao CH. et al. Contributions of TRAIL-mediated megakaryocyte apoptosis to impaired megakaryocyte and platelet production in immune thrombocytopenia. Blood 2010; 116 (20) 4307-4316
  • 34 Leytin V. Apoptosis in the anucleate platelet. Blood Rev 2012; 26 (02) 51-63
  • 35 Kaluzhny Y, Yu G, Sun S. et al. BclxL overexpression in megakaryocytes leads to impaired platelet fragmentation. Blood 2002; 100 (05) 1670-1678
  • 36 Kozuma Y, Kojima H, Yuki S, Suzuki H, Nagasawa T. Continuous expression of Bcl-xL protein during megakaryopoiesis is post-translationally regulated by thrombopoietin-mediated Akt activation, which prevents the cleavage of Bcl-xL. J Thromb Haemost 2007; 5 (06) 1274-1282