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

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 ␣-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. STEM

Hematopoietic stem cell mobilization

“…2,18 In this view, recent data document the mobilization of HSC after myocardial infarction 3 or ischemia/reperfusion liver injury following liver transplantation. 4 The mechanisms leading to human HSC recruitment to the damaged liver of immunodeficient mice were recently investigated by Kollet et al 2 Taken together, these results underline the concept that bone marrow mobilized stem cells show a much broader differentiating potential than that exploited by conventional stem cell transplantation to reconstitute bone marrow function in cancer patients.…”

Effect of liver regeneration on malignant hepatic tumors

“…Several studies have reported that liver surgery and acute liver injury can lead to mobilization of progenitor cells, both after partial hepatectomy in general and in HCC patients [75,[83][84][85][86] . The exact mechanism is still not fully clarified.…”

A hypothesis for an embryonic origin of pluripotent Oct-4+ stem cells in adult bone marrow and other tissues

“…77 Other groups found that cells expressing markers for early tissue committed stem/ progenitor cells circulate during skeletal muscle 78,79 and retina epithelium damage, 80 lung injuries, 81 bone fracture, 82 ischemic damage of the kidney 83 and injury of the liver. 84 We noticed that the number of circulating non-hematopoietic stem cells expressing pluripotent/tissue committed markers (e.g., Oct-4 þ ) in peripheral blood could be increased by some mobilizing agents, for example, G-CSF. 85 in combination with compounds that block CXCR4 (e.g., T140 or AMD3100) 86,87 Do ESC-like Oct-4 þ cells initiate tumor development?…”