Angiopoietin-like 5 and IGFBP2 stimulate ex vivo expansion of human cord blood hematopoietic stem cells as assayed by NOD/SCID transplantation
Angiopoietin-like 5 and IGFBP2 stimulate ex vivo expansion of human cord blood hematopoietic stem cells as assayed by NOD/SCID transplantation
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DOI：
10.1182/blood-2007-11-122119
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发表时间：
2008-04-01
期刊：
影响因子：
20.3
通讯作者：
Lodish, Harvey F.
中科院分区：
文献类型：
--
作者：
Zhang, Cheng Cheng;Kaba, Megan;Lodish, Harvey F.
造血干细胞（HSCs）是骨髓移植的基础，也是造血基因治疗的靶细胞，但HSCs体外扩增困难严重阻碍了HSCs的临床应用。特别是，脐带血用于成人移植受到HSC数量的极大限制。此前，我们发现血管内皮素样蛋白和胰岛素样生长因子结合蛋白2（IGFBP 2）是新的激素，它们与其他因子一起可以在培养中扩增小鼠骨髓HSC。在这里，我们测量的多能人类严重联合免疫缺陷（SCID）-再生细胞（SRCs）的活性移植到非肥胖糖尿病SCID（NOD/SCID）小鼠，二次移植进行评估SRCs的自我更新潜力。含有SCF、TPO和FGF-1或Flt 3 - 1 L的无血清培养基不能显著支持人脐带血CD 133（+）细胞中存在的SRC的扩增。添加血管生成素样5或IGF-结合蛋白2的文化导致了相当大的扩展HSC的数量，通过NOD/SCID移植测定。含有SCF、TPO、FGF-1、血管生成素样5和IGFBP 2的无血清培养物支持再生人脐带血HSC的约20倍净扩增，这一数目潜在地适用于包括HSC移植在内的若干临床过程。
Hematopoietic stem cells (HSCs) are the basis of bone marrow transplantation and are attractive target cells for hematopoietic gene therapy, but these important clinical applications have been severely hampered by difficulties in ex vivo expansion of HSCs. In particular, the use of cord blood for adult transplantation is greatly limited by the number of HSCs. Previously we identified angiopoletin-like proteins and IGF-binding protein 2 (IGFBP2) as new hormones that, together with other factors, can expand mouse bone marrow HSCs in culture. Here, we measure the activity of multipotent human severe combined immunodeficient (SCID)-repopulating cells (SRCs) by transplantation into the nonobese diabetic SCID (NOD/SCID) mice; secondary transplantation was performed to evaluate the self-renewal potential of SRCs. A serum-free medium containing SCF, TPO, and FGF-1 or Flt3-1L cannot significantly support expansion of the SRCs present in human cord blood CD133(+) cells. Addition of either angiopoietin-like 5 or IGF-binding protein 2 to the cultures led to a sizable expansion of HSC numbers, as assayed by NOD/SCID transplantation. A serum-free culture containing SCF, TPO, FGF-1, angiopoietin-like 5, and IGFBP2 supports an approximately 20-fold net expansion of repopulating human cord blood HSCs, a number potentially applicable to several clinical processes including HSC transplantation.