IGF binding protein 2 supports the survival and cycling of hematopoietic stem cells
IGF binding protein 2 supports the survival and cycling of hematopoietic stem cells
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DOI：
10.1182/blood-2011-01-331876
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发表时间：
2011-09-22
期刊：
影响因子：
20.3
通讯作者：
Zhang, Cheng Cheng
中科院分区：
文献类型：
--
作者：
Huynh, HoangDinh;Zheng, Junke;Zhang, Cheng Cheng
IGF结合蛋白2（IGFBP 2）在细胞生长中的作用是有趣的，并且在很大程度上未被定义。先前我们鉴定IGFBP 2为支持造血干细胞（HSC）的离体扩增的外在因子。在这里，我们发现IGFBP 2缺失小鼠的HSC比野生型小鼠少。虽然IGFBP 2对HSC功能几乎没有细胞自主作用，但我们发现在原发性和继发性移植IGFBP 2无效受体中HSC的体内再增殖减少。重要的是，缺乏IGFBP 2的骨髓基质细胞支持再生HSC扩增的能力显著降低。为了研究IGFBP 2支持HSC活性的机制，我们证明IGFBP 2缺失小鼠中的HSC存活率和周期减少，抗凋亡因子Bcl-2的表达下调，细胞周期抑制剂p21，p16，p19，p57和PTEN的表达上调。此外，我们发现，C-末端，而不是RGD结构域，外源性IGFBP 2是必不可少的支持HSC的活动。IGF I型受体的缺陷信号传导不能挽救IGFBP 2缺失受体中HSC再增殖的减少，这表明IGFBP 2对HSC的环境作用不依赖于IGF-IR介导的信号传导。因此，作为一种环境因子，IGFBP 2支持HSC的存活和循环。（血。2011;118（12）：3236-3243）
The role of IGF binding protein 2 (IGFBP2) in cell growth is intriguing and largely undefined. Previously we identified IGFBP2 as an extrinsic factor that supports ex vivo expansion of hematopoietic stem cells (HSCs). Here we showed that IGFBP2-null mice have fewer HSCs than wild-type mice. While IGFBP2 has little cell-autonomous effect on HSC function, we found decreased in vivo repopulation of HSCs in primary and secondary transplanted IGFBP2-null recipients. Importantly, bone marrow stromal cells that are deficient for IGFBP2 have significantly decreased ability to support the expansion of repopulating HSCs. To investigate the mechanism by which IGFBP2 supports HSC activity, we demonstrated that HSCs in IGFBP2-null mice had decreased survival and cycling, down-regulated expression of antiapoptotic factor Bcl-2, and up-regulated expression of cell cycle inhibitors p21, p16, p19, p57, and PTEN. Moreover, we found that the C-terminus, but not the RGD domain, of extrinsic IGFBP2 was essential for support of HSC activity. Defective signaling of the IGF type I receptor did not rescue the decreased repopulation of HSCs in IGFBP2-null recipients, suggesting that the environmental effect of IGFBP2 on HSCs is independent of IGF-IR mediated signaling. Therefore, as an environmental factor, IGFBP2 supports the survival and cycling of HSCs. (Blood. 2011;118(12):3236-3243)