Myeloid-Derived Suppressor Cells mediate hepatocyte proliferation and immune suppression during liver regeneration following resection

Abstract Introduction: Liver regeneration following resection is a complex process relying on coordinated pathways and cell types in the remnant organ. Myeloid-Derived Suppressor Cells (MDSCs) have a role in liver regeneration-related angiogenesis but their influence on hepatocyte proliferation and immune modulation during liver regeneration is unclear. Methods We examined the transcriptional response of regenerating liver hepatocytes after major resection in mice with CD11b⁺Ly6G⁺ MDSCs (G-MDSCs) depletion using RNA sequencing. Immune changes within regenerating livers post-resection upon MDSC depletion were assessed via cytometry by time-of-flight (CyTOF). Results Global gene expression profiling of regenerating hepatocytes upon G-MDSC depletion revealed disrupted transcriptional progression from day one to day two after major liver resection. Key genes and pathways related to hepatocyte proliferation and immune response were differentially expressed upon MDSC depletion. CyTOF analysis of intra-liver immune milieu upon MDSC depletion in regenerating livers post-resection demonstrated marked increases in natural killer cell and activated T cell proportions, alongside changes in other immune cell populations. Conclusions This study provides evidence that MDSCs contribute to early liver regeneration by promoting hepatocyte proliferation and modulating the intra-liver immune response. These findings illuminate the multifaceted role of MDSCs in liver regeneration.