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

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, p21Cip1/Waf1 (p21), have an increased stem cell poo...

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Bibliographic Details
Published in:Blood 2003-08, Vol.102 (4), p.1260-1266
Main Authors: STIER, Sebastian, TAO CHENG, FORKERT, Randolf, LUTZ, Christoph, DOMBKOWSKI, David M, ZHANG, Jie Lin, SCADDEN, David T
Format: Article
Language:English
Subjects:
ADP-ribosyl Cyclase - metabolism
ADP-ribosyl Cyclase 1
Animals
Antigens, CD - metabolism
Antigens, CD34 - metabolism
Biological and medical sciences
Cell differentiation, maturation, development, hematopoiesis
Cell physiology
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p21
Cyclins - antagonists & inhibitors
Cyclins - genetics
DNA, Antisense - genetics
DNA, Antisense - pharmacology
Fetal Blood - cytology
Flow Cytometry
Fundamental and applied biological sciences. Psychology
Genetic Vectors - genetics
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - drug effects
Hematopoietic Stem Cells - physiology
Humans
Lentivirus - genetics
Membrane Glycoproteins
Mice
Mice, Inbred NOD
Mice, SCID
Molecular and cellular biology
Oligonucleotides, Antisense - genetics
Oligonucleotides, Antisense - pharmacology
Transduction, Genetic
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Summary: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, p21Cip1/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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2002-10-3053