Ex vivo expansion of human hematopoietic stem cells by direct delivery of the HOXB4 homeoprotein
Ex vivo expansion of human hematopoietic stem cells by direct delivery of the HOXB4 homeoprotein
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DOI：
10.1038/nm953
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发表时间：
2003-11-01
期刊：
影响因子：
82.9
通讯作者：
Fichelson, S
中科院分区：
文献类型：
--
作者：
Amsellem, S;Pflumio, F;Fichelson, S
人造血干细胞（HSC）的扩增是细胞治疗中的主要挑战，并且目前依赖于重组细胞因子的使用或转录因子的基因转移。其中，HOXB 4同源异型蛋白是特别感兴趣的，因为它促进小鼠HSC的扩增而不诱导白血病的发展。为了消除任何可能与稳定的HOXB 4基因转移到人类细胞中相关的有害影响，我们利用HOX蛋白被动易位通过细胞膜的能力。在这里，我们表明，当培养的基质细胞基因工程分泌HOXB 4，人类长期培养起始细胞（LTC-IC）和非肥胖糖尿病-严重联合免疫缺陷（NOD-SCID）小鼠再生细胞（SRC）分别扩大超过20和2.5倍，超过其输入数量。这种扩增与体内干细胞再生能力的增强和多能性的维持有关。该方法为使用未经遗传修饰的扩增HSC开发细胞治疗策略提供了基础。
Expansion of human hematopoietic stem cells (HSCs) is a major challenge in cellular therapy, and currently relies on the use of recombinant cytokines or on gene transfer of transcription factors. Of these, the HOXB4 homeoprotein protein is of particular interests as it promotes the expansion of mouse HSCs without inducing the development of leukemia. To eliminate any deleterious effects that might be associated with stable HOXB4 gene transfer into human cells, we took advantage of the ability of HOX proteins to passively translocate through cell membranes. Here we show that when cultured on stromal cells genetically engineered to secrete HOXB4, human long-term culture-initiating cells (LTC-ICs) and nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mouse repopulating cells (SRCs) were expanded by more than 20- and 2.5-fold, respectively, over their input numbers. This expansion was associated with enhanced stem cell repopulating capacity in vivo and maintenance of pluripotentiality. This method provides a basis for developing cell therapy strategies using expanded HSCs that are not genetically modified.