HOXB4 overexpression mediates very rapid stem cell regeneration and competitive hematopoietic repopulation
HOXB4 overexpression mediates very rapid stem cell regeneration and competitive hematopoietic repopulation
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DOI：
10.1016/s0301-472x(01)00681-6
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发表时间：
2001-09-01
影响因子：
2.6
通讯作者：
Humphries, RK
中科院分区：
文献类型：
--
作者：
Antonchuk, J;Sauvageau, G;Humphries, RK
Objective. Hox转录因子已成为造血的重要调节因子。特别是，我们已经表明，小鼠骨髓中HOXB 4的过表达可以大大提高造血干细胞HSC再生的水平，在移植后的晚期（> 4个月）实现。本研究的目的是解决HOXB 4是否增加HSC再生的速率和/或持续时间，并且还观察这种增强是否与终末细胞的产生受损相关，或者是否会导致所有隔室的竞争性重建。用GFP报告基因+/-HOXB 4产生逆转录病毒载体，以使得能够分离和直接追踪培养物中或移植后的转导细胞。采用有限稀释法测定长期竞争性再生细胞（CRU）的干细胞回收率。HOXB 4过表达细胞在体外具有增强的生长，如它们在混合培养物中的快速优势和它们缩短的群体倍增时间所证明的。此外，HOXB 4转导的细胞在体内原始和成熟区室中都具有明显的竞争性再增殖优势。HOXB 4受体的CRU恢复非常迅速，在移植后14天达到正常值的25%或比对照移植受体高80倍，并在12周达到正常值。移植了更高数量的HOXB 4转导的CRU的小鼠再生达到但不超过正常的CRU水平。HOXB 4是原始造血细胞生长的有效增强剂，可能通过增加自我更新概率，但不损害HSC群体大小的稳态控制或成熟终末细胞的产生和维持速率。(C)2001年国际实验血液学学会。出版社：Elsevier Science Inc.
Objective. Hox transcription factors have emerged as important regulators of hematopoiesis. In particular, we have shown that overexpression of HOXB4 in mouse bone marrow can greatly enhance the level of hematopoietic stem cell HSC regeneration achieved at late times (> 4 months) posttransplantation. The objective of this study was to resolve if HOXB4 increases the rate and/or duration of HSC regeneration, and also to see if this enhancement was associated with impaired production of end cells or would lead to competitive reconstitution of all compartments.Methods. Retroviral vectors were generated with the GFP reporter gene +/- HOXB4 to enable the isolation and direct tracking of transduced cells in culture or following transplantation. Stem cell recovery was measured by limit dilution assay for long-term competitive repopulating cells (CRU).Results. HOXB4-overexpressing cells have enhanced growth in vitro, as demonstrated by their rapid dominance in mixed cultures and their shortened population doubling time. Furthermore, HOXB4-transduced cells have a marked competitive repopulating advantage in vivo in both primitive and mature compartments. CRU recovery in HOXB4 recipients was extremely rapid, reaching 25% of normal by 14 days posttransplant or some 80-fold greater than control transplant recipients, and attaining normal numbers by 12 weeks. Mice transplanted with even higher numbers of HOXB4-transduced CRU regenerated up to but not beyond the normal CRU levels.Conclusion. HOXB4 is a potent enhancer of primitive hematopoietic cell growth, likely by increasing self-renewal probability but without impairing homeostatic control of HSC population size or the rate of production and maintenance of mature end cells. (C) 2001 International Society for Experimental Hematology. Published by Elsevier Science Inc.