CD82/KAI1 Maintains the Dormancy of Long- Term Hematopoietic Stem Cells through Interaction with DARC- Expressing Macrophages
CD82/KAI1 Maintains the Dormancy of Long- Term Hematopoietic Stem Cells through Interaction with DARC- Expressing Macrophages
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DOI：
10.1016/j.stem.2016.01.013
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发表时间：
2016-04-07
期刊：
影响因子：
23.9
通讯作者：
Kim, Hyo-Soo
中科院分区：
文献类型：
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作者：
Hur, Jin;Choi, Jae-Il;Kim, Hyo-Soo
造血是由长期再生造血干细胞（LT-HSC）和支持骨髓（BM）中的小生境细胞之间的串扰调节的。在这里，我们研究了CD82/KAI1在小生境介导的LT-HSC维持中的作用。我们发现CD82/KAI1主要在LT-HSC上表达，很少在其他造血干祖细胞（HSPCs）上表达。在Cd82 +/-/+/-小鼠中，LTHSC在退出静止期和分化时选择性丢失。在机制上，基于CD82的TGF-β 1/Smad3信号转导导致诱导CDK抑制剂和细胞周期抑制。CD82结合伴侣DARC/CD234在巨噬细胞上表达，并稳定LT-HSC上的CD82，促进其静止。当DARC + BM巨噬细胞被消融时，LT-HSC上的表面CD82水平降低，导致细胞周期进入、增殖和分化。类似的相互作用似乎与人HSPC相关。因此，CD82是LT-HSC的功能性表面标志物，其通过与BM干细胞龛中表达DARC的巨噬细胞相互作用来维持静止。
Hematopoiesis is regulated by crosstalk between long-term repopulating hematopoietic stem cells (LT-HSCs) and supporting niche cells in the bone marrow (BM). Here, we examine the role of CD82/ KAI1 in niche-mediated LT-HSC maintenance. We found that CD82/ KAI1 is expressed predominantly on LT-HSCs and rarely on other hematopoietic stem-progenitor cells (HSPCs). In Cd82 +/-/+/- mice, LTHSCs were selectively lost as they exited from quiescence and differentiated. Mechanistically, CD82based TGF-b1/ Smad3 signaling leads to induction of CDK inhibitors and cell-cycle inhibition. The CD82 binding partner DARC/ CD234 is expressed on macrophages and stabilizes CD82 on LT-HSCs, promoting their quiescence. When DARC + BMmacrophages were ablated, the level of surface CD82 on LT-HSCs decreased, leading to cell-cycle entry, proliferation, and differentiation. A similar interaction appears to be relevant for human HSPCs. Thus, CD82 is a functional surface marker of LT-HSCs that maintains quiescence through interaction with DARC-expressing macrophages in the BM stem cell niche.