CD11B+ Ly6G+ myeloid derived suppressor cells promote liver regeneration in a murine model of major hepatectomy

Abstract

Background: Liver regeneration depends on sequential activation of multiple pathways and cell types involving the remaining organ in recovery of mass. Proliferation of parenchyma is dependent on angiogenesis. Understanding liver regeneration associated neovascularization may be useful for future development of clinical interventions. Myeloid Derived Suppressor Cells (MDSCs) promote immune suppression and tumor angiogenesis, and play a role in normal developmental processes that necessitate rapid vascularization. The role of MDSCs in liver regeneration has not been studied. Materials & Methods: The proportion of MDSC populations was assessed within remnant livers following major hepatectomy (Hx). The effect of CD11b+Ly6G+ MDSCs (G-MDSCs) depletion on post-operative mortality, liver injury, regeneration, and angiogenesis was evaluated. Transcriptional and functional characterization of regenerating liver-derived G-MDSCs was performed. All animal studies were conducted according to protocols approved by the institutional animal care and use committee of Tel-Aviv Sourasky Medical Center, strictly observing national, local, and institutional guidelines. Approval no. 13-4-16 Results: G-MDSCs were enriched within regenerating livers, and their depletion led to increased post-operative mortality, reduced liver weights, increased liver injury, decreased hepatic vascularization and hepatocyte proliferation, and to aberrant liver function indices in peripheral blood. Global gene expression profiling of regenerating liver-derived G-MDSCs demonstrated a large-scale transcriptional response, involving key pathways related to angiogenesis. Functionally, enhanced reactive oxygen species production and angiogenic capacities of regenerating liver-derived G-MDSCs were confirmed. A comparative analysis revealed that the transcriptional response of G-MDSCs during liver regeneration highly resembled that of peripheral blood G-MDSCs during progression of abdominal tumors, suggesting a common G-MDSC gene expression profile promoting angiogenesis. Conclusions: This study provides the first evidence that MDSCs contribute to early stages of liver regeneration by exerting pro-angiogenic functions using a unique transcriptional program.