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Platelet Biology and its Disorders
Slc35a1 deficiency causes thrombocytopenia due to impaired megakaryocytopoiesis and excessive platelet clearance in the liver
Ferrata Storti Foundation
Haematologica 2021 Volume 106(3):759-769
Xiaolin Ma,1,2,3* Yun Li,1,2* Yuji Kondo,4* Huiping Shi,1,2,4 Jingjing Han,1,2
Yizhi Jiang,1,2 Xia Bai,1,2,5 Stephanie A. Archer-Hartmann,6 Parastoo Azadi,6 Changgeng Ruan,1,2,5 Jianxin Fu1,4,7,# and Lijun Xia1,2,4,#
1Jiangsu Institute of Hematology, NHC Key Laboratory of Thrombosis and Hemostasis, The First Affiliated Hospital of Soochow University, Suzhou, China; 2Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; 3Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao, China; 4Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; 5State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China; 6Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA and 7Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
*XM, YL and YK contributed equally as co-first authors. #JF and LX contributed equally as co-senior authors.
ABSTRACT
Sialic acid is a common terminal residue of glycans on proteins and acidic sphingolipids such as gangliosides and has important biological functions. The sialylation process is controlled by more than 20 dif- ferent sialyltransferases, many of which exhibit overlapping functions. Thus, it is difficult to determine the overall biological function of sialyla- tion by targeted deletion of individual sialyltransferases. To address this issue, we established a mouse line with the Slc35a1 gene flanked by loxP sites. Slc35a1 encodes the cytidine-5’-monophosphate (CMP)-sialic acid transporter that transports CMP-sialic acid from the cytoplasm into the Golgi apparatus for sialylation. Here we report our study regarding the role of sialylation on megakaryocytes and platelets using a mouse line with sig- nificantly reduced sialylation in megakaryocytes and platelets (Plt Slc35a1– /–). The major phenotype of Plt Slc35a1–/– mice was thrombocytopenia. The number of bone marrow megakaryocytes in Plt Slc35a1–/– mice was reduced, and megakaryocyte maturation was also impaired. In addition, an increased number of desialylated platelets was cleared by Küpffer cells in the liver of Plt Slc35a1–/– mice. This study provides new insights into the role of sialylation in platelet homeostasis and the mechanisms of throm- bocytopenia in diseases associated with platelet desialylation, such as immune thrombocytopenia and a rare congenital disorder of glycosylation (CDG), SLC35A1-CDG, which is caused by SLC35A1 mutations.
Introduction
Platelets are among the most abundant blood cells in circulation. In addition to their well-established roles in hemostasis and thrombosis, platelets are involved in a broad spectrum of other physiological and pathological processes such as vascu- lar integrity, immunity, inflammation, and tumor metastasis.1-5 A stable number of platelets is of great importance to these functions. Platelet homeostasis is primarily regulated by the production and clearance of platelets. Platelet membrane receptors play a vital role in platelet hemostasis. Most of these proteins are glycoproteins (GP), including the GPIb-IX-V complex and GPIIb/IIIa complex.6 Major forms of glycosylation include N-linked glycans (N-glycans) and mucin-type O-linked gly- cans (O-glycans).7 Both N- and O-glycans are commonly “capped” by sialic acids, a process named sialylation.8,9 Sialylation plays essential biological roles, especially in cell-cell interactions.8 The significance of sialylation in other biological processes,
Correspondence:
LIJUN XIA
Lijun-xia@omrf.org
Received: May 7, 2019. Accepted: March 19, 2020. Pre-published: April 17, 2020.
https://doi.org/10.3324/haematol.2019.225987
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