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Stem cell repopulation efficiency but not pool size is governed by p27kip1

Nature Medicine volume 6, pages 1235–1240 (2000)Cite this article

Abstract

Sustained blood cell production requires preservation of a quiescent, multipotential stem cell pool that intermittently gives rise to progenitors with robust proliferative potential. The ability of cells to shift from a highly constrained to a vigorously active proliferative state is critical for maintaining stem cells while providing the responsiveness necessary for host defense. The cyclin-dependent kinase inhibitor (CDKI), p21cip1/waf1 (p21) dominates stem cell kinetics. Here we report that another CDKI, p27kip1 (p27), does not affect stem cell number, cell cycling, or self-renewal, but markedly alters progenitor proliferation and pool size. Therefore, distinct CDKIs govern the highly divergent stem and progenitor cell populations. When competitively transplanted, p27-deficient stem cells generate progenitors that eventually dominate blood cell production. Modulating p27 expression in a small number of stem cells may translate into effects on the majority of mature cells, thereby providing a strategy for potentiating the impact of transduced cells in stem cell gene therapy.

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Figure 1: The long-term culture and colony-forming assays demonstrate an unchanged stem cell pool size and an enlarged progenitor pool in the p27−/− mice.
Figure 2: Altered cell cycle profile of progenitor cells, but not stem cells, in the p27−/− marrow.
Figure 3: Treatment with 5-FU in vivo demonstrates more active cell cycling in the progenitor pool, but not in the stem cell pool of the p27−/− mice.
Figure 4: Serial bone marrow transplantation (BMT) demonstrates an unaltered self-renewal of hematopoietic stem cells and an enhanced activity of progenitor cells in the p27−/− transplanted mice.
Figure 5: Competitive repopulation assay demonstrates preferential outgrowth of p27−/− progenitor and mature cells following long-term engraftment.

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Acknowledgements

This work was supported by NIH grants HL 44851, DK 50234, and HL 55718 (D.T.S.), AI07387 and DK02761 (T.C.), the Richard Saltonstall Charitable Foundation (D.T.S.) and the Deutscher Akademischer Austuaschdienst (S.S). The authors thank Andrew Koff (Sloan-Kettering Cancer Center, New York) for p27+/− mice, Youngguang Yang, Nadia Carlesso, and Frederic Preffer for technical assistance and helpful discussions.

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  1. Massachusetts General Hospital AIDS Research Center and MGH Cancer Center, Harvard Medical School, 149 13th Street, Room 5212, Boston, 02129, Massachusetts

    Tao Cheng, Neil Rodrigues, David Dombkowski, Sebastian Stier & David T. Scadden

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Correspondence to Tao Cheng or David T. Scadden.

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Cheng, T., Rodrigues, N., Dombkowski, D. et al. Stem cell repopulation efficiency but not pool size is governed by p27kip1. Nat Med 6, 1235–1240 (2000). https://doi.org/10.1038/81335

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