Kit regulates maintenance of quiescent hematopoietic stem cells
Kit regulates maintenance of quiescent hematopoietic stem cells
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DOI：
10.4049/jimmunol.180.4.2045
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发表时间：
2008-02-15
影响因子：
4.4
通讯作者：
Jacobsen, Sten-Eirik W.
中科院分区：
文献类型：
--
作者：
Thoren, Lina A.;Liuba, Karina;Jacobsen, Sten-Eirik W.
造血干细胞（HSC）的数量在出生后的造血过程中受到严格的调节和维持。大量研究支持细胞因子酪氨酸激酶受体Kit在移植后与野生型造血干细胞竞争时维持造血干细胞循环的作用，但在稳定状态的成人骨髓中维持静止的造血干细胞的作用。在本研究中，我们研究了Kit部分功能缺失的White spots 41 （Kit(W41/W41)）小鼠的HSC调控。虽然胎儿HSC的广泛扩增与Kit无关，但成年Kit（W41/W41）小鼠的长期HSC几乎减少了2倍，这反映了在12周龄时大约损失了10,000个Lin(-)Sca(-)1+Kit(high) (LSK)CD34(-)Flt3（-）长期HSC，而LSKCD34(+)Flt3（-）短期HSC和LSKCD34(+)Flt3（+）多能祖细胞受到的影响较小。尽管在清髓受体中，Kit（W41/W41）骨髓细胞的归巢和初始重构接近正常，但在竞争性和非竞争性移植试验中，自我更新Kit（W41/W41）造血干细胞逐渐耗尽。抗凋亡调节因子BCL-2的过表达部分挽救了移植后Kit(W41/W41) HSC缺陷，这表明Kit可能至少在移植后环境中通过促进HSC存活来部分维持HSC数量。最值得注意的是，体内BrdU掺入和细胞周期动力学的加速暗示了Kit在成人稳态造血中维持静止hsc的作用。
Hematopoietic stem cell (HSC) numbers are tightly regulated and maintained in postnatal hematopoiesis. Extensive studies have supported a role of the cytokine tyrosine kinase receptor Kit in sustaining cycling HSCs when competing with wild-type HSCs posttransplantation, but not in maintenance of quiescent HSCs in steady state adult bone marrow. In this study, we investigated HSC regulation in White Spotting 41 (Kit(W41/W41)) mice, with a partial loss of function of Kit. Although the extensive fetal HSC expansion was Kit-independent, adult Kit(W41/W41) mice had an almost 2-fold reduction in long-term HSCs, reflecting a loss of roughly 10,000 Lin(-)Sca(-)1+Kit(high) (LSK)CD34(-)Flt3(-) long-term HSCs by 12 wk of age, whereas LSKCD34(+)Flt3(-) short-term HSCs and LSKCD34(+)Flt3(+) multipotent progenitors were less affected. Whereas homing and initial reconstitution of Kit(W41/W41) bone marrow cells in myeloablated recipients were close to normal, self-renewing Kit(W41/W41) HSCs were progressively depleted in not only competitive but also noncompetitive transplantation assays. Overexpression of the anti-apoptotic regulator BCL-2 partially rescued the posttransplantation Kit(W41/W41) HSC deficiency, suggesting that Kit might at least in the posttransplantation setting in part sustain HSC numbers by promoting HSC survival. Most notably, accelerated in vivo BrdU incorporation and cell cycle kinetics implicated a previously unrecognized role of Kit in maintaining quiescent HSCs in steady state adult hematopoiesis.