Friel Jutta, Schiedlmeier Bernhard, Geldmacher Maren, Ostertag Wolfram
University Hospital Eppendorf, Department of Oncology and Hematology, Transplantation Unit, Hamburg, Germany.
Growth Factors. 2006 Jun;24(2):97-105. doi: 10.1080/08977190600581269.
Key players in self-renewal of hemopoietic stem cells are homeobox (HOX) transcription factors. In murine cells, overexpression of HOXB4 results in expansion of hematopoietic stem- and committed progenitor cells in vitro without obvious hematopoietic alterations. In vivo, HOXB4 induced HSC expansion continued until stem cell regeneration reached pretransplantation levels. HOXB4 is thus an attractive candidate for amplification of stem cells provided that human HOXB4 overexpressing cells can also be restricted to normal growth in vivo. The stromal microenvironment provides the regulatory mechanisms controlling the balance of stem cell self-renewal and differentiation. Here, we compared the response of HOXB4- and GFP-control vector transduced human CD34(+) cells to stroma encoded signals in vitro. In serum-sustained cocultures MS-5 stroma contact reduced the output of late CD34- HOXB4(+) cells in relation to GFP-controls 9-fold whereas the expansion of early CD34(+)HOXB4(+) cells remained unchanged as compared to liquid cultures. In presence of insulin HOXB4 overexpressing cells do not react to stroma encoded growth-restricting signals. Our results show that ectopic expression of HOXB4 in combination with MS-5 stroma exerts different effects in early and late human cord blood CD34(+) cells resulting in an enhanced proliferation of early CD34(+) cells in absence or presence of MS-5 stroma and an impaired output of late committed CD34(+) cells on MS-5 stroma.
造血干细胞自我更新的关键参与者是同源盒（HOX）转录因子。在鼠细胞中，HOXB4的过表达导致造血干细胞和定向祖细胞在体外扩增，且无明显的造血改变。在体内，HOXB4诱导的造血干细胞扩增持续到干细胞再生达到移植前水平。因此，HOXB4是干细胞扩增的一个有吸引力的候选者，前提是过表达人HOXB4的细胞在体内也能被限制为正常生长。基质微环境提供了控制干细胞自我更新和分化平衡的调节机制。在这里，我们比较了转导了HOXB4和绿色荧光蛋白（GFP）对照载体的人CD34(+)细胞在体外对基质编码信号的反应。在血清维持的共培养中，MS-5基质接触使晚期CD34-HOXB4(+)细胞的产量相对于GFP对照降低了9倍，而早期CD34(+)HOXB4(+)细胞的扩增与液体培养相比保持不变。在有胰岛素存在的情况下，过表达HOXB4的细胞对基质编码的生长限制信号没有反应。我们的结果表明，HOXB4的异位表达与MS-5基质相结合，对早期和晚期人脐血CD34(+)细胞产生不同的影响，导致在有无MS-5基质的情况下早期CD34(+)细胞增殖增强，而在MS-5基质上晚期定向CD34(+)细胞的产量受损。
