Ayako Nakamura-Ishizu
   Department   School of Medicine, School of Medicine
   Position   Professor and Division head
Article types Original article
Language English
Peer review Peer reviewed
Title CLEC-2 in megakaryocytes is critical for maintenance of hematopoietic stem cells in the bone marrow.
Journal Formal name:The Journal of experimental medicine
Abbreviation:J Exp Med
ISSN code:15409538/00221007
Domestic / ForeginForegin
Volume, Issue, Page 212(12),pp.2133-46
Author and coauthor Nakamura-Ishizu Ayako, Takubo Keiyo, Kobayashi Hiroshi, Suzuki-Inoue Katsue, Suda Toshio
Publication date 2015/11
Summary 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.
DOI 10.1084/jem.20150057
PMID 26552707