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In vivo self-renewing divisions of haematopoietic stem cells are increased in the absence of the early G1-phase inhibitor, p18INK4C

Nature Cell Biology volume 6, pages 436–442 (2004)Cite this article

Abstract

Self-renewal of stem cells is critical for tissue repair and maintenance of organ integrity in most mammalian systems. The relative asymmetry between self-renewal and differentiation in balance with apoptosis determines the size and durability of a stem-cell pool. Regulation of the cell cycle is one of the fundamental mechanisms underlying determination of cell fate. Absence of p21Cip1/Waf1, a late G1-phase cyclin-dependent kinase inhibitor (CKI), has previously been shown to enable cell-cycle entry of haematopoietic stem cells, but leads to premature exhaustion of the stem cells under conditions of stress. We show here that deletion of an early G1-phase CKI, p18INK4C, results in strikingly improved long-term engraftment, largely by increasing self-renewing divisions of the primitive cells in murine transplant models. Therefore, different CKIs have highly distinct effects on the kinetics of stem cells, possibly because of their active position in the cell cycle, and p18INK4C appears to be a strong inhibitor limiting the potential of stem-cell self-renewal in vivo.

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Figure 1: Preferential outgrowth of p18−/− hematopoietic cells during long-term engraftment after primary or secondary cBMT.
Figure 2: Enlarged pools of HSCs or early HPCs in p18−/− mice under steady-state conditions.
Figure 3: Accelerated repopulation after p18−/− HSC transplantation.
Figure 4: Favoured primitive phenotype after divisions of p18−/− haematopoietic cells in vivo.

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Acknowledgements

The authors thank Dr Joel Greenberger and Dr Richard A. Steinman for their suggestions on this manuscript. The authors also thank Ying Shao and Shaonan Cao for their technical assistance, and Matthew Boyer for editing the manuscript. This work was supported by National Institutes of Health grants (DK02761, HL70561), a PTEI technology development grant (T.C.). T.C. was a recipient of the Innovative Award from the PNC Foundation (2002), an Outstanding Overseas Scholar Award from the Chinese Natural Science Foundation (2002), and the Scholar Award from the American Society of Hematology (2003).

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  1. Youzhong Yuan and Hongmei Shen: These authors contributed equally to this work.

Authors and Affiliations

  1. University of Pittsburgh Cancer Institute and Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, 15213, PA, USA

    Youzhong Yuan, Hongmei Shen & Tao Cheng

  2. Department of Biological Science, Purdue University, West Lafayette, 47907, IN, USA

    David S. Franklin

  3. Center for Regenerative Medicine and Technology, Massachusetts General Hospital, Harvard Medical School, Boston, 02129, MA, USA

    David T. Scadden

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Correspondence to Tao Cheng.

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Yuan, Y., Shen, H., Franklin, D. et al. In vivo self-renewing divisions of haematopoietic stem cells are increased in the absence of the early G1-phase inhibitor, p18INK4C. Nat Cell Biol 6, 436–442 (2004). https://doi.org/10.1038/ncb1126

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