Human CD34+ hematopoietic stem cells capable of multilineage engrafting NOD/SCID mice express flt3:: distinct flt3 and c-kit expression and response patterns on mouse and candidate human hematopoietic stem cells
Human CD34+ hematopoietic stem cells capable of multilineage engrafting NOD/SCID mice express flt3:: distinct flt3 and c-kit expression and response patterns on mouse and candidate human hematopoietic stem cells
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DOI：
10.1182/blood-2002-06-1694
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发表时间：
2003-08-01
期刊：
影响因子：
20.3
通讯作者：
Jacobsen, SEW
中科院分区：
文献类型：
--
作者：
Sitnicka, E;Buza-Vidas, N;Jacobsen, SEW
细胞因子酪氨酸激酶受体c-kit和flt 3在小鼠和人的早期造血中表达并发挥作用。通过其促进原始人造血祖细胞的离体扩增和肿瘤逆转录病毒转导的能力，flt 3配体（FL）已经成为候选人造血干细胞（HSC）的关键刺激物。然而，最近在小鼠中的研究表明，尽管它存在于短期重建细胞上，但flt 3在骨髓长期重建HSC上不表达，而长期重建HSC是细胞替代和基因治疗发展的最终靶点。在此，我们证明，虽然只有一小部分成人骨髓和脐带血CD 34（+）长期培养起始细胞（LTC-IC）表达flt 3，但大多数能够在体内重建非肥胖糖尿病/严重联合免疫缺陷（NOD/SCID）小鼠的脐带血淋巴髓样HSC是flt 3（+）。小鼠和候选人HSC上flt 3和c-kit表达的显著差异转化为flt 3和c-kit功能的相应差异，因为FL在支持候选人HSC的存活方面比SCIF更有效。相比之下，SCF作为小鼠HSC的活力因子远远优于FL上级。因此，目前的数据提供了令人信服的证据，对比表达和响应模式的flt 3和c-kit对小鼠和人的HSC。
The cytokine tyrosine kinase receptors c-kit and flt3 are expressed and function in early mouse and human hematopoiesis. Through its ability to promote ex vivo expansion and oncoretroviral transduction of primitive human hematopoietic progenitors, the flt3 ligand (FL) has emerged as a key stimulator of candidate human hematopoietic stem cells (HSCs). However, recent studies in the mouse suggest that though it is present on short-term repopulating cells, flt3 is not expressed on bone marrow long-term reconstituting HSCs, the ultimate target for the development of cell replacement and gene therapy. Herein we demonstrate that though only a fraction of human adult bone marrow and cord blood CD34(+) long-term culture-initiating cells (LTC-ICs) express flt3, most cord blood lymphomyeloid HSCs capable of in vivo reconstituting nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice are flt3(+). The striking difference in flt3 and c-kit expression on mouse and candidate human HSCs translated into a corresponding difference in flt3 and c-kit function because FL was more efficient than SCIF at supporting the survival of candidate human HSCs. In contrast, SCF is far superior to FL as a viability factor for mouse HSCs. Thus, the present data provide compelling evidence for a contrasting expression and response pattern of flt3 and c-kit on mouse and human HSCs.