Haematopoietic ESL-1 enables stem cell proliferation in the bone marrow by limiting TGFβ availability.
Haematopoietic ESL-1 enables stem cell proliferation in the bone marrow by limiting TGFβ availability.
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DOI：
10.1038/ncomms10222
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发表时间：
2016-01-08
影响因子：
16.6
通讯作者：
Hidalgo A
中科院分区：
文献类型：
--
作者：
Leiva M;Quintana JA;Ligos JM;Hidalgo A
造血干细胞和祖细胞（HSPC）的终身维持严重依赖于由构成造血生态位的细胞产生的环境信号。在这里，我们报告了一个细胞的内在机制，造血细胞限制骨髓内的增殖，并表明这一途径是由E-选择素配体1（ESL-1）抑制。ESL-1缺陷的小鼠显示异常的HSPC静止、未成熟池的扩增和生态位大小的减小。值得注意的是，当突变体和野生型前体在同一环境中共存时，这些性状是可移植的和显性的，但不依赖于ESL-1的血管受体E-选择素。相反，静止是由突变体HSPC不受限制地产生细胞因子TGFβ产生的，并且细胞因子的体内或体外阻断完全恢复了造血生态位的稳态特性。这些发现表明，造血细胞，包括更原始的隔室，可以主动塑造自己的环境。造血干细胞和祖细胞（HSPCs）的增殖受来自小生境的信号控制。在此，Leiva等人在小鼠体内显示，E-选择素配体1的缺失引起HSPC的静止和小生境大小的减小，这是由骨髓中TGF β水平的变化介导的。
The life-long maintenance of haematopoietic stem and progenitor cells (HSPCs) critically relies on environmental signals produced by cells that constitute the haematopoietic niche. Here we report a cell-intrinsic mechanism whereby haematopoietic cells limit proliferation within the bone marrow, and show that this pathway is repressed by E-selectin ligand 1 (ESL-1). Mice deficient in ESL-1 display aberrant HSPC quiescence, expansion of the immature pool and reduction in niche size. Remarkably, the traits were transplantable and dominant when mutant and wild-type precursors coexisted in the same environment, but were independent of E-selectin, the vascular receptor for ESL-1. Instead, quiescence is generated by unrestrained production of the cytokine TGFβ by mutant HSPC, and in vivo or in vitro blockade of the cytokine completely restores the homeostatic properties of the haematopoietic niche. These findings reveal that haematopoietic cells, including the more primitive compartment, can actively shape their own environment. Hematopoietic stem and progenitor cell (HSPCs) proliferation is controlled by signals from the niche. Here, Leiva et al. show in vivo in mice that deletion of E-selectin ligand 1 causes quiescence of HSPCs and a reduction in niche size, which is mediated by changes of TGFß levels in the bone marrow.