Mobilization of Bone Marrow-Derived Hematopoietic and Endothelial Stem Cells After Orthotopic Liver Transplantation and Liver Resection

Authors

  • Roberto M. Lemoli M.D.,

    Corresponding author
    1. Institute of Hematology and Medical Oncology “L.& A. Seràgnoli”, Bologna, Italy
    2. Center for Stem Cell Research, S.Orsola-Malpighi Hospital, Bologna, Italy
    • Institute of Hematology and Medical Oncology “L.& A. Seràgnoli” and Center for Stem Cell Research, Via Massarenti 9, 40138, Bologna, Italy. Telephone: +390516363680; Fax: +390516364037
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  • Lucia Catani,

    1. Institute of Hematology and Medical Oncology “L.& A. Seràgnoli”, Bologna, Italy
    2. Center for Stem Cell Research, S.Orsola-Malpighi Hospital, Bologna, Italy
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  • Simona Talarico,

    1. Institute of Hematology and Medical Oncology “L.& A. Seràgnoli”, Bologna, Italy
    2. Center for Stem Cell Research, S.Orsola-Malpighi Hospital, Bologna, Italy
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  • Elisabetta Loggi,

    1. Institute of Hematology and Medical Oncology “L.& A. Seràgnoli”, Bologna, Italy
    2. Department of Internal Medicine and Hepatology, S.Orsola-Malpighi Hospital, Bologna, Italy
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  • Annagiulia Gramenzi,

    1. Institute of Hematology and Medical Oncology “L.& A. Seràgnoli”, Bologna, Italy
    2. Department of Internal Medicine and Hepatology, S.Orsola-Malpighi Hospital, Bologna, Italy
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  • Umberto Baccarani,

    1. Department of Surgery and Organ Transplantation, University of Udine, Udine, Italy
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  • Miriam Fogli,

    1. Institute of Hematology and Medical Oncology “L.& A. Seràgnoli”, Bologna, Italy
    2. Center for Stem Cell Research, S.Orsola-Malpighi Hospital, Bologna, Italy
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  • Gian Luca Grazi,

    1. Liver and Multi Organ Transplant Unit-University of Bologna, S.Orsola-Malpighi Hospital, Bologna, Italy
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  • Michela Aluigi,

    1. Institute of Hematology and Medical Oncology “L.& A. Seràgnoli”, Bologna, Italy
    2. Center for Stem Cell Research, S.Orsola-Malpighi Hospital, Bologna, Italy
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  • Giulia Marzocchi,

    1. Institute of Hematology and Medical Oncology “L.& A. Seràgnoli”, Bologna, Italy
    2. Center for Stem Cell Research, S.Orsola-Malpighi Hospital, Bologna, Italy
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  • Mauro Bernardi,

    1. Institute of Hematology and Medical Oncology “L.& A. Seràgnoli”, Bologna, Italy
    2. Department of Internal Medicine and Hepatology, S.Orsola-Malpighi Hospital, Bologna, Italy
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  • Antonio Pinna,

    1. Liver and Multi Organ Transplant Unit-University of Bologna, S.Orsola-Malpighi Hospital, Bologna, Italy
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  • Fabrizio Bresadola,

    1. Department of Surgery and Organ Transplantation, University of Udine, Udine, Italy
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  • Michele Baccarani,

    1. Institute of Hematology and Medical Oncology “L.& A. Seràgnoli”, Bologna, Italy
    2. Center for Stem Cell Research, S.Orsola-Malpighi Hospital, Bologna, Italy
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  • Pietro Andreone

    1. Institute of Hematology and Medical Oncology “L.& A. Seràgnoli”, Bologna, Italy
    2. Department of Internal Medicine and Hepatology, S.Orsola-Malpighi Hospital, Bologna, Italy
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Abstract

In animals, the bone marrow (BM) is a source of liver-repopulating cells with therapeutic potential in case of tissue damage. However, the early response of human BM-derived stem cells (SC) to liver injury is still unknown. Here, we studied 24 patients undergoing orthotopic liver transplantation (OLT) for end-stage liver disease or hepatocellularcarcinoma, and 13 patients submitted to liver resection. The concentration of circulating BM-derived SC was determined by phenotypic analysis and clonogenic assays. Moreover, we assessed the serum level of inflammatory and tissue-specific cytokines. Reverse transcriptase-polymerase chain reaction and fluorescence-in situ hybridization were also used to characterize mobilized SC. At baseline, patients showed a significant lower concentration of circulating CD133+, CD34+ SC and clonogenic progenitors (colony-forming unit cells) than healthy controls. However, the time-course evaluation of peripheral blood cells after OLT demonstrated the significant early mobilization of multiple subsets of hematopoietic and endothelial stem/progenitor cells. Cytogenetic and molecular analyses of CD34+ cells showed the host origin of mobilized SC and the expression of transcripts for GATA-4, cytokeratin 19, and α-fetoprotein hepatocyte markers. In contrast with OLT, only total circulating CD34+ cells significantly increased after liver resection. Mobilization of BM cells after OLT or liver surgery was associated with increased serum levels of granulocyte-colony stimulating factor, interleukin-6, stem cell factor, hepatocyte growth factor, and vascular endothelial growth factor. In summary, we demonstrate that tissue damage after OLT and liver resection induces increased serum levels of multiple cytokines but only ischemia/reperfusion injury associated with OLT results in the remarkable mobilization of BM stem/progenitor cells.

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