Ex vivo targeting of p21Cip1/Waf1 permits relative expansion of human hematopoietic stem cells

被引:56
作者
Stier, S
Cheng, T
Forkert, R
Lutz, C
Dombrowski, DM
Zhang, JL
Scadden, DT
机构
[1] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA USA
[2] Ctr AIDS Res, Ctr Regenerat Med & Technol, Boston, MA USA
关键词
D O I
10.1182/blood-2002-10-3053
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Relative quiescence is a defining characteristic of hematopoietic stem cells. Reasoning that inhibitory tone dominates control of stem cell cycling, we previously showed that mice engineered to be deficient in the cyclin-dependent kinase inhibitor, p21(Cip1/Waf1) (p21), have an increased stem cell pool under homeostatic conditions. Since p21 was necessary to maintain stem cell quiescence and its absence sufficient to permit increased murine stem cell cycling, we tested whether reduction of p21 alone in human adult-derived stem cells could affect stem cell proliferation. We demonstrate here that interrupting p21 expression ex vivo resulted in expanded stem cell number and in vivo stem cell function compared with control, manipulated cells. Further, we demonstrate full multilineage reconstitution capability in cells where p21 expression was knocked down. Therefore, lifting the brake on cell proliferation by altering cell cycle checkpoints provides an alternative paradigm for increasing hematopoietic stem cell numbers. This approach may be useful for relative ex vivo human stem cell expansion. (C) 2003 by The American Society of Hematology.
引用
收藏
页码:1260 / 1266
页数:7
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