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

¹ Institute of Hematology and Medical Oncology "L.& A. Seràgnoli", University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy; Center for Stem Cell Research,University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
² Center for Stem Research, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy; Department of Internal Medicine and Hepatology, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
³ Department of Surgery and Organ Transplantation, University of Udine, Udine, Italy
⁴ Liver and Multi Organ Transplant Unit, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy

^* To whom correspondence should be addressed. E-mail: rmlemoli{at}med.unibo.it.

	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 (CFU-C) 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 alpha-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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