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TISSUE-SPECIFIC STEM CELLS

A Limited Role for p21^Cip1/Waf1 in Maintaining Normal Hematopoietic Stem Cell Functioning

^aDepartment of Cell Biology, Section Stem Cell Biology,
^bDepartment of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Key Words. Cobblestone area-forming cells • Aging • Hematopoietic stem cells • p21 • Stem cell exhaustion Competitive repopulation

Correspondence: Ronald van Os, Ph.D., Department of Cell Biology, Section Stem Cell Biology, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, Groningen, The Netherlands. Telephone: +31503632727; Fax: +31503637477; e-mail: r.p.van.os{at}med.umcg.nl

Received October 5, 2006; accepted for publication December 5, 2006.
First published online in STEM CELLS EXPRESS   December 14, 2006.



Several studies have suggested that the cyclin-dependent kinase (CDK) inhibitor p21 plays a crucial role in regulating hematopoietic stem and progenitor pool size. To allow assessment of long-term stem cell functioning in vivo, we have backcrossed a p21 null allele to C57BL/6 (B6) mice, the most commonly used mouse strain in hematopoietic stem cell research. In various in vitro assays, the homozygous deletion of the p21 allele did not affect the number of hematopoietic cells in B6 mice. Furthermore, the competitive repopulation ability was not different between p21-deficient and wild-type stem cells from both young and aged (20-month-old) mice. These results show that p21 is not essential for regulation of stem cell number in steady state. When proliferative stress was applied on p21-deficient stem cells by serial transplantation of 1,500 Lin^–Sca-1⁺c-kit⁺ (LSK) cells, again no detrimental effect was observed on cobblestone area-forming cell (CAFC) frequency and competitive repopulating ability. However, when bone marrow cells from mice that received 2 Gy of irradiation were transplanted, p21 deficiency resulted in a more than fourfold reduction in competitive repopulation index. Finally, we did not find major differences in cell cycle status and global gene expression patterns between LSK cells from p21-deficient and wild-type mice. Our findings indicate that the background of mice used for studying the function of a gene by genetic modification may determine the outcome. Cumulatively, our data fail to support the notion that p21 is essential for stem cell function during steady-state hematopoiesis, but may be relatively more important under conditions of cellular stress.

Disclosure of potential conflicts of interest is found at the end of this article.