Rap1 signal modulators control the maintenance of hematopoietic progenitors in bone marrow and adult long-term hematopoiesis
Rap1 signal modulators control the maintenance of hematopoietic progenitors in bone marrow and adult long-term hematopoiesis
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DOI：
10.1111/cas.13974
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发表时间：
2019-04-01
期刊：
影响因子：
5.7
通讯作者：
Minato, Nagahiro
中科院分区：
文献类型：
--
作者：
Imai, Takahiko;Tanaka, Hiroki;Minato, Nagahiro
成人长期造血依赖于维持骨髓（BM）龛中的造血干/祖细胞（HSPC），其中它们的静止、自我更新和造血分化的平衡受到严格调节。尽管已经鉴定了产生小生境因子的各种BM基质细胞，但是HSPC对小生境因子的内在响应性的调节仍然是难以捉摸的。我们以前报道过，缺乏Sipa 1（Rap 1 GTP酶激活蛋白）的小鼠会出现迟发性多种造血系统疾病。在这里，我们发现，移植表达膜靶向C3 G（C3 G-F）（一种Rap 1 GTP/GDP交换剂）的BM细胞，导致BM中HSPC数量随着时间的推移而逐渐减少，并损害了所有细胞谱系的长期造血。C3 G-F/HSPC在脾脏中持续数月，保留造血潜能，但这些细胞不能有效地促进整体造血重建。C3 G-F/HSPC表现出对干细胞因子（SCF）响应的增强的增殖和分化以及加速的祖细胞耗竭。使用Ba/F3细胞系，我们证实，增加基础Rap 1GTP水平与C3 G-F表达引起的c-Kit受体和下游信号通过SCF连接的激活显着延长。与Vect/HSPC相比，C3 G-F/HSPC的少数群体在血小板生成素（TPO）存在下也显示出增强的增殖。目前的结果表明，HSPC的基础Rap 1激活状态在其维持BM中的重要作用，以维持长期的成人造血。
Adult long-term hematopoiesis depends on sustaining hematopoietic stem/progenitor cells (HSPC) in bone marrow (BM) niches, where their balance of quiescence, self-renewal, and hematopoietic differentiation is tightly regulated. Although various BM stroma cells that produce niche factors have been identified, regulation of the intrinsic responsiveness of HSPC to the niche factors remains elusive. We previously reported that mice deficient for Sipa1, a Rap1 GTPase-activating protein, develop diverse hematopoietic disorders of late onset. Here we showed that transplantation of BM cells expressing membrane-targeted C3G (C3G-F), a Rap1 GTP/GDP exchanger, resulted in the progressive decline of the numbers of HSPC repopulated in BM with time and impaired long-term hematopoiesis of all cell lineages. C3G-F/HSPC were sustained for months in spleen retaining hematopoietic potential, but these cells inefficiently contributed to overall hematopoietic reconstitution. C3G-F/HSPC showed enhanced proliferation and differentiation with accelerated progenitor cell exhaustion in response to stem cell factor (SCF). Using a Ba/F3 cell line, we confirmed that the increased basal Rap1GTP levels with C3G-F expression caused a markedly prolonged activation of c-Kit receptor and downstream signaling through SCF ligation. A minor population of C3G-F/HSPC also showed enhanced proliferation in the presence of thrombopoietin (TPO) compared to Vect/HSPC. Current results suggest an important role of basal Rap1 activation status of HSPC in their maintenance in BM for sustaining long-term adult hematopoiesis.