Conditional deletion of STAT5 in adult mouse hematopoietic stem cells causes loss of quiescence and permits efficient nonablative stem cell replacement
Conditional deletion of STAT5 in adult mouse hematopoietic stem cells causes loss of quiescence and permits efficient nonablative stem cell replacement
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DOI：
10.1182/blood-2008-09-181107
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发表时间：
2009-05-14
期刊：
影响因子：
20.3
通讯作者：
Bunting, Kevin D.
中科院分区：
文献类型：
--
作者：
Wang, Zhengqi;Li, Geqiang;Bunting, Kevin D.
目前，在造血干细胞（HSC）移植中主要需要开发不引起DNA损伤和相关毒性并且允许更广泛的患者接受治疗的降低强度的方案。通过c-Kit和c-Mpl的细胞因子受体信号可以调节HSC的静止和植入，但在移植过程中介导这些作用的细胞内信号和转录因子尚未确定。在这里，我们表明，一个等位基因的信号转导和转录激活因子5（STAT 5）的非消融成年突变小鼠允许移植野生型HSC。使用Mx 1-Cre有条件地删除STAT 5导致STAT 5 mRNA的最大减少（> 97%），并迅速减少静止相关的c-Mpl下游靶点（Tie-2，p57），增加HSC循环，并逐渐降低存活率和耗尽长期HSC库。STAT 5的宿主缺失是持久的，并且允许在没有消融性调节的情况下在原发性和继发性宿主中有效的供体长期HSC植入。总体而言，这些研究建立了靶向STAT 5作为新的移植调节的原则证据，并首次证明，STAT 5是大多数细胞类型（包括造血祖细胞）中的促有丝分裂因子，是在稳态造血过程中维持HSC静止的关键转录调节因子。（血。2009;113：4856-4865）
Currently, there is a major need in hematopoietic stem cell (HSC) transplantation to develop reduced-intensity regimens that do not cause DNA damage and associated toxicities and that allow a wider range of patients to receive therapy. Cytokine receptor signals through c-Kit and c-Mpl can modulate HSC quiescence and engraftment, but the intracellular signals and transcription factors that mediate these effects during transplantation have not been defined. Here we show that loss of one allele of signal transducer and activator of transcription 5 (STAT5) in nonablated adult mutant mice permitted engraftment with wild-type HSC. Conditional deletion of STAT5 using Mx1-Cre caused maximal reduction in STAT5 mRNA (> 97%) and rapidly decreased quiescence-associated c-Mpl downstream targets (Tie-2, p57), increased HSC cycling, and gradually reduced survival and depleted the long-term HSC pool. Host deletion of STAT5 was persistent and permitted efficient donor long-term HSC engraftment in primary and secondary hosts in the absence of ablative conditioning. Overall, these studies establish proof of principle for targeting of STAT5 as novel transplantation conditioning and demonstrate, for the first time, that STAT5, a mitogenic factor in most cell types, including hematopoietic progenitors, is a key transcriptional regulator that maintains quiescence of HSC during steady-state hematopoiesis. (Blood. 2009;113:4856-4865)