SALL4 is a robust stimulator for the expansion of hematopoietic stem cells
SALL4 is a robust stimulator for the expansion of hematopoietic stem cells
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DOI：
10.1182/blood-2011-01-333641
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发表时间：
2011-07-21
期刊：
影响因子：
20.3
通讯作者：
Ma, Yupo
中科院分区：
文献类型：
--
作者：
Aguila, Jerell R.;Liao, Wenbin;Ma, Yupo
造血干细胞是一种罕见的细胞，具有独特的自我更新和分化为所有造血系细胞的能力。缺乏捐赠者和目前无法快速有效地扩大造血干细胞是开发成功的细胞疗法的障碍。因此，人类造血干细胞体外扩增的挑战仍然是一个非常重要的研究领域。在此，我们发现从动员的外周血中获得的SALL4A或SALL4B转导的人HSCs在适当的细胞因子存在的情况下，能够在体外快速有效地扩增CD34(+)/CD38(-)和CD34(+)/CD38(+)细胞10000倍。我们发现这些细胞保留了造血祖细胞的免疫表型和形态，以及在体外或体内正常的分化潜能。SALL4介导的扩增与干细胞植入和体内长期再繁殖能力增强相关。此外，我们还证明了SALL4的结构性表达抑制了粒细胞的分化，并允许未分化的细胞在32D的髓系祖细胞中扩张。此外，TAT-SALL4B融合可以迅速扩增CD34(+)细胞，因此将这项研究转化为临床环境是可行的。我们的发现为研究干细胞自我更新的机制和实现临床上有意义的人类造血干细胞扩增提供了新的途径。(血。2011；118(3)：576-585)
HSCs are rare cells that have the unique ability to self-renew and differentiate into cells of all hematopoietic lineages. The lack of donors and current inability to rapidly and efficiently expand HSCs are roadblocks in the development of successful cell therapies. Thus, the challenge of ex vivo human HSC expansion remains a fertile and critically important area of investigation. Here, we show that either SALL4A- or SALL4B-transduced human HSCs obtained from the mobilized peripheral blood are capable of rapid and efficient expansion ex vivo by > 10 000-fold for both CD34(+)/CD38(-) and CD34(+)/CD38(+) cells in the presence of appropriate cytokines. We found that these cells retained hematopoietic precursor cell immunophenotypes and morphology as well as normal in vitro or vivo potential for differentiation. The SALL4-mediated expansion was associated with enhanced stem cell engraftment and long-term repopulation capacity in vivo. Also, we demonstrated that constitutive expression of SALL4 inhibited granulocytic differentiation and permitted expansion of undifferentiated cells in 32D myeloid progenitors. Furthermore, a TAT-SALL4B fusion rapidly expanded CD34(+) cells, and it is thus feasible to translate this study into the clinical setting. Our findings provide a new avenue for investigating mechanisms of stem cell self-renewal and achieving clinically significant expansion of human HSCs. (Blood. 2011;118(3):576-585)