CLEC-2 in Megakaryocytes is Critical for Maintenance of Hematopoietic Stem Cells in the Bone Marrow

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2015 Nov 11

PMID 26552707

Citations 67

Authors

Ayako Nakamura-Ishizu

Keiyo Takubo

Hiroshi Kobayashi

Katsue Suzuki-Inoue

Toshio Suda

Affiliations

Soon will be listed here.

Abstract

Hematopoietic stem cells (HSCs) depend on the bone marrow (BM) niche for their maintenance, proliferation, and differentiation. The BM niche is composed of nonhematopoietic and mature hematopoietic cells, including megakaryocytes (Mks). Thrombopoietin (Thpo) is a crucial cytokine produced by BM niche cells. However, the cellular source of Thpo, upon which HSCs primarily depend, is unclear. Moreover, no specific molecular pathway for the regulation of Thpo production in the BM has been identified. Here, we demonstrate that the membrane protein C-type lectin-like receptor-2 (CLEC-2) mediates the production of Thpo and other factors in Mks. Mice conditionally deleted for CLEC-2 in Mks (Clec2(MkΔ/Δ)) produced lower levels of Thpo in Mks. CLEC-2-deficient Mks showed down-regulation of CLEC-2-related signaling molecules Syk, Lcp2, and Plcg2. Knockdown of these molecules in cultured Mks decreased expression of Thpo. Clec2(MkΔ/Δ) mice exhibited reduced BM HSC quiescence and repopulation potential, along with extramedullary hematopoiesis. The low level of Thpo production may account for the decline in HSC potential in Clec2(MkΔ/Δ) mice, as administration of recombinant Thpo to Clec2(MkΔ/Δ) mice restored stem cell potential. Our study identifies CLEC-2 signaling as a novel molecular mechanism mediating the production of Thpo and other factors for the maintenance of HSCs.

Citing Articles

Cellular crosstalk in the bone marrow niche.

Huang Z, Iqbal Z, Zhao Z, Liu J, Alabsi A, Shabbir M J Transl Med. 2024; 22(1):1096.

PMID: 39627858 PMC: 11613879. DOI: 10.1186/s12967-024-05900-6.

Versatility of megakaryocytes in homeostasis and disease.

Wang D, Xie J, Zhao M Blood Sci. 2024; 6(4):e00212.

PMID: 39620204 PMC: 11608743. DOI: 10.1097/BS9.0000000000000212.

LMAN1 serves as a cargo receptor for thrombopoietin.

Everett L, Lin Z, Friedman A, Tang V, Myers G, Balbin-Cuesta G JCI Insight. 2024; 9(24).

PMID: 39499573 PMC: 11665562. DOI: 10.1172/jci.insight.175704.

The evolving hematopoietic niche during development.

Sanchez-Lanzas R, Jimenez-Pompa A, Ganuza M Front Mol Biosci. 2024; 11:1488199.

PMID: 39417006 PMC: 11480086. DOI: 10.3389/fmolb.2024.1488199.

Systemic and local regulation of hematopoietic homeostasis in health and disease.

Carpenter R, Maryanovich M Nat Cardiovasc Res. 2024; 3(6):651-665.

PMID: 39196230 DOI: 10.1038/s44161-024-00482-4.

References

Kaser A, Brandacher G, Steurer W, Kaser S, Offner F, Zoller H . Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis. Blood. 2001; 98(9):2720-5. DOI: 10.1182/blood.v98.9.2720. View

Chow A, Lucas D, Hidalgo A, Mendez-Ferrer S, Hashimoto D, Scheiermann C . Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J Exp Med. 2011; 208(2):261-71. PMC: 3039855. DOI: 10.1084/jem.20101688. View

Wolber E, Fandrey J, Frackowski U, Jelkmann W . Hepatic thrombopoietin mRNA is increased in acute inflammation. Thromb Haemost. 2002; 86(6):1421-4. View

Kawamoto T . Use of a new adhesive film for the preparation of multi-purpose fresh-frozen sections from hard tissues, whole-animals, insects and plants. Arch Histol Cytol. 2003; 66(2):123-43. DOI: 10.1679/aohc.66.123. View

Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K . Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004; 118(2):149-61. DOI: 10.1016/j.cell.2004.07.004. View

Schofield R . The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells. 1978; 4(1-2):7-25. View

Fandrey J, BUNN H . In vivo and in vitro regulation of erythropoietin mRNA: measurement by competitive polymerase chain reaction. Blood. 1993; 81(3):617-23. View

Kuter D, Rosenberg R . The reciprocal relationship of thrombopoietin (c-Mpl ligand) to changes in the platelet mass during busulfan-induced thrombocytopenia in the rabbit. Blood. 1995; 85(10):2720-30. View

McCarty J, Sprugel K, Fox N, Sabath D, Kaushansky K . Murine thrombopoietin mRNA levels are modulated by platelet count. Blood. 1995; 86(10):3668-75. View

10.

Zucker-Franklin D, Kaushansky K . Effect of thrombopoietin on the development of megakaryocytes and platelets: an ultrastructural analysis. Blood. 1996; 88(5):1632-8. View

11.

Villeval J, Titeux M, Lok S, Vainchenker W, Wendling F . Constitutive expression of Mpl ligand transcripts during thrombocytopenia or thrombocytosis. Blood. 1996; 88(7):2578-84. View

12.

Kabaya K, Akahori H, Shibuya K, Nitta Y, Ida M, Kusaka M . In vivo effects of pegylated recombinant human megakaryocyte growth and development factor on hematopoiesis in normal mice. Stem Cells. 1996; 14(6):651-60. DOI: 10.1002/stem.140651. View

13.

Nomura S, Ogami K, Kawamura K, Tsukamoto I, Kudo Y, Kanakura Y . Cellular localization of thrombopoietin mRNA in the liver by in situ hybridization. Exp Hematol. 1997; 25(7):565-72. View

14.

Murray L, Luens K, Estrada M, Bruno E, Hoffman R, Cohen R . Thrombopoietin mobilizes CD34+ cell subsets into peripheral blood and expands multilineage progenitors in bone marrow of cancer patients with normal hematopoiesis. Exp Hematol. 1998; 26(3):207-16. View

15.

Qian S, Fu F, Li W, Chen Q, de Sauvage F . Primary role of the liver in thrombopoietin production shown by tissue-specific knockout. Blood. 1998; 92(6):2189-91. View

16.

Schacht V, Dadras S, Johnson L, Jackson D, Hong Y, Detmar M . Up-regulation of the lymphatic marker podoplanin, a mucin-type transmembrane glycoprotein, in human squamous cell carcinomas and germ cell tumors. Am J Pathol. 2005; 166(3):913-21. PMC: 1602360. DOI: 10.1016/S0002-9440(10)62311-5. View

17.

Suzuki-Inoue K, Fuller G, Garcia A, Eble J, Pohlmann S, Inoue O . A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. Blood. 2005; 107(2):542-9. DOI: 10.1182/blood-2005-05-1994. View

18.

Katayama Y, Battista M, Kao W, Hidalgo A, Peired A, Thomas S . Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell. 2006; 124(2):407-21. DOI: 10.1016/j.cell.2005.10.041. View

19.

Kollet O, Dar A, Shivtiel S, Kalinkovich A, Lapid K, Sztainberg Y . Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat Med. 2006; 12(6):657-64. DOI: 10.1038/nm1417. View

20.

Sugiyama T, Kohara H, Noda M, Nagasawa T . Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity. 2006; 25(6):977-88. DOI: 10.1016/j.immuni.2006.10.016. View