The Pathology of Bleomycin-Induced Fibrosis Is Associated with Loss of Resident Lung Mesenchymal Stem Cells That Regulate Effector T-cell Proliferation§

Authors

  • Du Jun,

    1. Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology Program,University of Colorado Denver, Aurora, Colorado, USA
    2. Department of Medicine,University of Colorado Denver, Aurora, Colorado, USA
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  • Chrystelle Garat,

    1. Department of Medicine,University of Colorado Denver, Aurora, Colorado, USA
    2. Division of Pulmonary, Allergy and Critical Care Medicine,University of Colorado Denver, Aurora, Colorado, USA
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  • James West,

    1. Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine,Vanderbilt University Medical School, Nashville, Tennessee, USA
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  • Nathalie Thorn,

    1. Division of Pulmonary, Allergy and Critical Care Medicine, Simmons Center for Interstitial Lung Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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  • Kelsey Chow,

    1. Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology Program,University of Colorado Denver, Aurora, Colorado, USA
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  • Timothy Cleaver,

    1. Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology Program,University of Colorado Denver, Aurora, Colorado, USA
    2. Department of Medicine,University of Colorado Denver, Aurora, Colorado, USA
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  • Timothy Sullivan,

    1. Department of Medicine,University of Colorado Denver, Aurora, Colorado, USA
    2. Division of Pulmonary, Allergy and Critical Care Medicine,University of Colorado Denver, Aurora, Colorado, USA
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  • Enrique C. Torchia,

    1. Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology Program,University of Colorado Denver, Aurora, Colorado, USA
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  • Christine Childs,

    1. Cancer Center,University of Colorado Denver, Aurora, Colorado, USA
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  • Theodore Shade,

    1. Cancer Center,University of Colorado Denver, Aurora, Colorado, USA
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  • Mehrdad Tadjali,

    1. Department of Hematology, St. Jude Children's Hospital, Memphis, Tennessee, USA
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  • Abigail Lara,

    1. Department of Medicine,University of Colorado Denver, Aurora, Colorado, USA
    2. Division of Pulmonary, Allergy and Critical Care Medicine,University of Colorado Denver, Aurora, Colorado, USA
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  • Eva Nozik-Grayck,

    1. Critical Care Medicine, Department of Pediatrics, University of Colorado Denver, Aurora, Colorado, USA
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  • Stephen Malkoski,

    1. Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology Program,University of Colorado Denver, Aurora, Colorado, USA
    2. Department of Medicine,University of Colorado Denver, Aurora, Colorado, USA
    3. Division of Pulmonary, Allergy and Critical Care Medicine,University of Colorado Denver, Aurora, Colorado, USA
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  • Brian Sorrentino,

    1. Department of Hematology, St. Jude Children's Hospital, Memphis, Tennessee, USA
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  • Barbara Meyrick,

    1. Department of Pathology, Vanderbilt University Medical School, Nashville, Tennessee, USA
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  • Dwight Klemm,

    1. Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology Program,University of Colorado Denver, Aurora, Colorado, USA
    2. Department of Medicine,University of Colorado Denver, Aurora, Colorado, USA
    3. Division of Pulmonary, Allergy and Critical Care Medicine,University of Colorado Denver, Aurora, Colorado, USA
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  • Mauricio Rojas,

    1. Division of Pulmonary, Allergy and Critical Care Medicine, Simmons Center for Interstitial Lung Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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  • David H. Wagner Jr,

    1. Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology Program,University of Colorado Denver, Aurora, Colorado, USA
    2. Department of Medicine,University of Colorado Denver, Aurora, Colorado, USA
    3. Webb Waring Institute,University of Colorado Denver, Aurora, Colorado, USA
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  • Susan M. Majka

    Corresponding author
    1. Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology Program,University of Colorado Denver, Aurora, Colorado, USA
    2. Department of Medicine,University of Colorado Denver, Aurora, Colorado, USA
    • University of Colorado Health Sciences Center, Gates Center for Regenerative Medicine and Stem Cell Biology, 12,800 E 1nineth Ave, PO Box 6511, Mail stop 8320, Aurora, Colorado 80045, USA
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    • Ph: 303-724-3957, Fax: 303-724-3051


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

  • Author contributions: D.J.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing; C.G., K.C., T.S., C.C., T.S., and M.R.: collection and/or assembly of data, data analysis and interpretation; J.W., N.T., and A.L.: data analysis and interpretation; T.C. E.C.T., E.N.-G., and S.M.: collection and/or assembly of data; M.T., B.S., and B.M.: provision of study material or patients; D.K.: collection and/or assembly of data, data analysis and interpretation, manuscript writing; D.H.W. and S.M.M.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript.

  • §

    First published online in STEM CELLSEXPRESS February 3, 2011.

Abstract

Tissue-resident mesenchymal stem cells (MSCs) are important regulators of tissue repair or regeneration, fibrosis, inflammation, angiogenesis, and tumor formation. Here, we define a population of resident lung MSCs (luMSCs) that function to regulate the severity of bleomycin injury via modulation of the T-cell response. Bleomycin-induced loss of these endogenous luMSCs and elicited fibrosis (pulmonary fibrosis), inflammation, and pulmonary arterial hypertension (PAH). Replacement of resident stem cells by administration of isolated luMSCs attenuated the bleomycin-associated pathology and mitigated the development of PAH. In addition, luMSC modulated a decrease in numbers of lymphocytes and granulocytes in bronchoalveolar fluid and demonstrated an inhibition of effector T-cell proliferation in vitro. Global gene expression analysis indicated that the luMSCs are a unique stromal population differing from lung fibroblasts in terms of proinflammatory mediators and profibrotic pathways. Our results demonstrate that luMSCs function to protect lung integrity after injury; however, when endogenous MSCs are lost, this function is compromised illustrating the importance of this novel population during lung injury. The definition of this population in vivo in both murine and human pulmonary tissue facilitates the development of a therapeutic strategy directed at the rescue of endogenous cells to facilitate lung repair during injury. STEM Cells 2011;29:725–735

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