Platelet C-type Lectin-like Receptor 2 (CLEC-2) is Required for Optimal Regulation of Erythropoiesis
ISTH Academy. Otake S. Jul 10, 2019; 273881; OC 79.2
Shimon Otake
Shimon Otake
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OC 79.2

Platelet C-type Lectin-like Receptor 2 (CLEC-2) is Required for Optimal Regulation of Erythropoiesis

S. Otake1, T. Shirai1, N. Tsukiji1, T. Sasaki2, K. Satoh3, S. Tamura4, K. Takano5, Y. Ozaki6, K. Suzuki-Inoue1,2
1University of Yamanashi, Faculty of Medicine, Department of Clinical and Laboratory Medicine, Chuo, Japan, 2University of Yamanashi Hospital, Division of Laboratory Medicine, Chuo, Japan, 3University of Yamanashi Hospital, Clinical Trial Management Office, Chuo, Japan, 4Nagoya University Graduate School of Medicine, Department of Pathophysiological Laboratory Sciences, Nagoya, Japan, 5University of Yamanashi Hospital, Division of Transfusion Medicine and Cell Therapy, Chuo, Japan, 6Fuefuki Central Hospital, Fuefuki, Japan

Main Topic: Platelets and Megakaryocytes
Category: Platelets Beyond Hemostasis

Background: CLEC-2 is a platelet activating receptor, which was first identified as a receptor for a snake venom, rhodocytin. CLEC-2 is mainly expressed on platelets and megakaryocytes (Mgk). We also identified podoplanin (PDPN) as an endogenous ligand for CLEC-2. We have previously reported that PDPN-expressing stromal cells positively regulate megakaryocytic expansion and proplatelet formation via CLEC-2 (Tamura et al., Blood, 2016). Although deletion of CLEC-2 in mice exhibits significant anemia and thrombocytopenia, its contribution to erythropoiesis remains unknown.
Aims: The aims of this study were to uncover a role of CLEC-2 in erythropoiesis.
Methods: We used flow cytometry to analyze maturation of erythroblasts, apoptotic cell death, and cell cycle distribution. Conditioned media, prepared from PDPN-expressing stromal cells stimulated with CLEC-2 and Mgk stimulated with PDPN, were analyzed by cytokine array and ELISA, and co-cultured with immature erythroblasts.
Results: We analyzed maturation of erythroblasts in bone marrow from Mgk/platelet-specific CLEC-2 knockout (CLEC-2 cKO) and wild-type mice using CD71/Ter119 flow-cytometric assay (Figure). The number of subpopulation 2 (S2; CD71+ Ter119+), S3 (CD71dim Ter119+) and S4 (CD71- Ter119+), but not S1 (CD71- Ter119-), were decreased in CLEC-2 cKO mice. We further found that apoptotic cell death was increased in S2, without alteration of cell cycle distribution. These data indicated that increased cell death and/or maturation arrest were responsible for the anemia. We next prepared conditioned media from PDPN-expressing stromal cells stimulated with CLEC-2 and Mgk stimulated with PDPN. The former medium contained high concentration of β-chemokines and IL-6. Among them, only IL-6 showed anti-apoptotic effects on immature erythroblasts. The latter one contained high concentration of TGF-β, which exhibited erythroblast maturing effects. These data suggest that insufficient secretion of those cytokines/chemokines was one of the causes for the anemia in CLEC-2 cKO mice.
Conclusions: CLEC-2 on Mgk/platelets not only contribute to megakaryopoiesis but also positively regulate erythropoiesis.

[Erythroid cells are divided into subpopulations S1 to S4 based on their CD71/TER119 expression.]

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