Cell Autonomous and Nonautonomous Mechanisms Drive Hematopoietic Stem/progenitor Cell Loss in the Absence of DNA Repair§

Authors

  • Joon Seok Cho,

    1. University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
    2. Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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  • Sung Ho Kook,

    1. University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
    2. Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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  • Andria Rasile Robinson,

    1. University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
    2. Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania USA
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  • Laura J. Niedernhofer,

    Corresponding author
    1. University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
    2. Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    • Department of Metabolism & Aging, The Scripps Research Institute, Jupiter, Florida, USA
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    • Telephone: 561-228-2142; Fax: 561-228-2143

  • Byeong-Chel Lee

    Corresponding author
    1. University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
    2. Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    • Hillman Cancer Center, 2.32d, 5117 Centre Avenue, Pittsburgh, Pennsylvania 15213, USA
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    • Telephone: 412-623-2285; Fax: 412-623-7828


  • Author contributions: J.S.C., S.H.K., and A.R.R.: collection and/or assembly of data, data analysis and interpretation; L.J.N. and B.L: data analysis and interpretation, conception and design, manuscript writing, and final approval of manuscript provision. J.S.C. and S.H.K. contributed equally to this work.

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

  • §

    First published online in STEM CELLSEXPRESS October 23, 2012.

Abstract

Daily, cells incur tens of thousands of DNA lesions caused by endogenous processes. Due to their long-lived nature, adult stem cells may be particularly susceptible to the negative impact of this constant genotoxic stress. Indeed, in murine models of DNA repair deficiencies, there is accumulation of DNA damage in hematopoietic stem cells and premature loss of function. Herein, we demonstrate that mice expressing reduced levels of ERCC1-XPF DNA repair endonuclease (Ercc1−/Δ mice) spontaneously display a progressive decline in the number and function of hematopoietic stem/progenitor cells (HSPCs). This was accompanied by increased cell death, expression of senescence markers, reactive oxygen species, and DNA damage in HSPC populations, illustrating cell autonomous mechanisms that contribute to loss of function. In addition, the bone marrow microenvironment of Ercc1−/Δ mice was not permissive for the engraftment of transplanted normal stem cells. Bones from Ercc1−/Δ mice displayed excessive osteoclastic activity, which alters the microenvironment in a way that is unfavorable to HSPC maintenance. This was accompanied by increased proinflammatory cytokines in the bone marrow of Ercc1−/Δ mice. These data provide novel evidence that spontaneous, endogenous DNA damage, if not repaired, promotes progressive attrition of adult stem cells via both cell autonomous and nonautonomous mechanisms. STEM CELLS2013;31:511–525

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