Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist.
Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist.
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DOI：
10.1038/ncomms11007
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发表时间：
2016-03-15
影响因子：
16.6
通讯作者：
Nilsson SK
中科院分区：
文献类型：
--
作者：
Cao B;Zhang Z;Grassinger J;Williams B;Heazlewood CK;Churches QI;James SA;Li S;Papayannopoulou T;Nilsson SK
使用粒细胞集落刺激因子（G-CSF）用于造血干细胞（HSC）动员的固有缺点促使人们努力鉴定基于单剂量小分子的替代策略。在这里，我们显示用单剂量的小分子拮抗剂（BOP（N-（苯磺酰基）-L-prolyl-L-O-（1-吡咯烷羰基）酪氨酸））靶向α9β1/α4β1整联蛋白快速动员长期多谱系重建HSC。当BOP与AMD 3100联合给药时，观察到协同植入增强。令人印象深刻的是，用这种组合动员的等体积外周血（PB）中的HSC有效地胜过用G-CSF动员的PB。使用BOP和AMD 3100观察到的动员增强在人源化NODSCIDIL 2 R γ−/−模型中重现，表现为PB CD 34+细胞显著增加。使用BOP的相关荧光类似物（R-BC 154），我们表明这类拮抗剂通过骨内膜龛内内源性引发/激活的α9β1/α4β1优先结合人和小鼠HSC和祖细胞。这些结果支持使用双重α9β1/α4β1抑制剂作为有效、快速和短暂的动员剂，具有良好的临床应用前景。 动员造血干细胞到外周血已经在很大程度上取代骨髓移植作为临床策略。在此，Cao等人报告了在人源化小鼠模型中使用α9β1/α4β1整联蛋白拮抗剂诱导造血干细胞从骨髓中快速动员。
The inherent disadvantages of using granulocyte colony-stimulating factor (G-CSF) for hematopoietic stem cell (HSC) mobilization have driven efforts to identify alternate strategies based on single doses of small molecules. Here, we show targeting α9β1/α4β1 integrins with a single dose of a small molecule antagonist (BOP (N-(benzenesulfonyl)-L-prolyl-L-O-(1-pyrrolidinylcarbonyl)tyrosine)) rapidly mobilizes long-term multi-lineage reconstituting HSC. Synergistic engraftment augmentation is observed when BOP is co-administered with AMD3100. Impressively, HSC in equal volumes of peripheral blood (PB) mobilized with this combination effectively out-competes PB mobilized with G-CSF. The enhanced mobilization observed using BOP and AMD3100 is recapitulated in a humanized NODSCIDIL2Rγ−/− model, demonstrated by a significant increase in PB CD34+ cells. Using a related fluorescent analogue of BOP (R-BC154), we show that this class of antagonists preferentially bind human and mouse HSC and progenitors via endogenously primed/activated α9β1/α4β1 within the endosteal niche. These results support using dual α9β1/α4β1 inhibitors as effective, rapid and transient mobilization agents with promising clinical applications. Mobilizing haematopoietic stem cells to the peripheral blood has largely replaced bone marrow transplants as a strategy in the clinic. Here, Cao et al. report the use of an α9β1/α4β1 integrin antagonist to induce rapid mobilization of blood stem cells from the bone marrow in a humanized mouse model.