The significance of acute-phase small-for-size liver graft injury in mobilization of circulating EPCS/MDSCS/TREGS after LDLT for HCC patients

Abstract

OBJECTIVE: We aim to investigate the impact of acute-phase small-for-size graft injury on mobilization of circulating endothelial progenitor cells (EPCs), myeloid-derived suppressive cells (MDSCs) and regulatory T cells (Tregs) in HCC patients after liver transplantation and to explore the molecular mechanism therein. METHODS: From May 2000 to November 2009, 115 HCC recipients were included. The intragraft microRNA profiles of the grafts greater (Group 1) and less than 60% (Group 2) of standard liver weight (SLW) were characterized by Low Density Array (LDA) analysis. Circulating EPCs (CD34+CD133+CD45-), MDSCs (CD34+CD13+CD33+) and Tregs (CD4+CD25+FOXP3+) were compared by FACS analysis. Hepatic stellate cell activation, macrophage infiltration and intragraft expression of Rac, Pyk2, Egr-1 and VEGF were detected. Clinical-pathological data including the incidence of tumor recurrence and metastasis were compared. RESULTS: The patients were grouped into Group 1 (>= 60% SLW, n=37) and Group 2 (< 60% SLW, n=78). The numbers of patients beyond Milan criteria [15/37(40.5%) vs 29/49(59.2%), p=0.838] or UCSF criteria [9/37(24.3%) vs 19/60(31.7%), p=1] were similar in the two groups. Much more patients in Group 2 developed tumor recurrence and lung metastasis [19/78(24.4%) vs 3/37(8%), p=0.04] with significant shorter disease free survival. Circulating EPCs was significantly higher in Group 1 (Day 3: 0.09% vs 0.002%, p=0.019; Week 4: 0.12% vs 0.033%, p=0.037; Week 8: 0.0585% vs 0.025%, p=0.018; Week 12: 0.055% vs 0.028%, p=0.025). A tendency of larger populations of circulating MDSCs/Tregs was found in Group 2. microRNA LDA analysis showed that mir-233, mir-141, mir-1308, mir-548 and mir-576 were differentially expressed between the two groups. These mirRNAs were predicted to regulate targeting genes linked to graft injury (MAPK, CCL4 and Egr-1), tumor invasiveness (STAT5, CDC2 and EGFR), angiogenesis (VEGF, FLT4 and ANGPTL5), and macrophage infiltration (MIP2). CONCLUSION: A significantly higher population of postoperative circulating EPCs, which are mobilized by small-for-size graft injury, may lead to a higher incidence of tumor recurrence and metastasis after LDLT. The distinct intragraft miRNA expression profile linked to acute-phase injury and angiogenesis may play a role in the mobilization of circulating EPCs, MDSCs, and Tregs.