CD11b ⁺ Ly6G ⁺ myeloid‐derived suppressor cells promote liver regeneration in a murine model of major hepatectomy

Abstract

Liver regeneration depends on sequential activation of pathways and cells involving the remaining organ in recovery of mass. Proliferation of parenchyma is dependent on angiogenesis. Understanding liver regeneration–associated neovascularization may be useful for development of clinical interventions. Myeloid‐derived suppressor cells (MDSCs) promote tumor angiogenesis and play a role in developmental processes that necessitate rapid vascularization. We therefore hypothesized that the MDSCs could play a role in liver regeneration. Following partial hepatectomy, MDSCs were enriched within regenerating livers, and their depletion led to increased liver injury and postoperative mortality, reduced liver weights, decreased hepatic vascularization, reduced hepatocyte hypertrophy and proliferation, and aberrant liver function. Gene expression profiling of regenerating liver‐derived 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 MDSCs were confirmed. A comparative analysis revealed that the transcriptional response of MDSCs during liver regeneration resembled that of peripheral blood MDSCs during progression of abdominal tumors, suggesting a common MDSC gene expression profile promoting angiogenesis. In summary, our study shows that MDSCs contribute to early stages of liver regeneration possibly by exerting proangiogenic functions using a unique transcriptional program.—Nachmany, I., Bogoch, Y., Sivan, A., Amar, O., Bondar, E., Zohar, N., Yakubovsky, O., Fainaru, O., Klausner, J. M., Pencovich, N. CD11b+Ly6G+ myeloid‐derived suppressor cells promote liver regeneration in a murine model of major hepatectomy. FASEB J. 33, 5967–5978 (2019). http://www.fasebj.org

Murine breast cancers disorganize the liver transcriptome in a zonated manner

“…These results led to the hypothesis that neutrophils immigrating into the liver of cancer-bearing mice are predominantly immature, differentiating neutrophils, whereas neutrophils in the livers of sham mice are mature neutrophils. These immature neutrophils might represent myeloid-derived suppressor cells (i.e., pathologically activated neutrophils and monocytes) 30 , 31 .…”

MARCO+ Macrophage Dynamics in Regenerating Liver after 70% Liver Resection in Mice

“…The lack of pronounced inflammatory cell infiltration in remnant livers has been described in several studies [ 27 , 28 ]. However, with the advance of methods for the observation and detection of infiltrating immune cells, eventually evidence accumulated confirming the migration of certain cells to the liver after partial hepatectomy, notably eosinophils [ 29 ], macrophages and monocytes [ 12 , 13 ], and also neutrophils [ 30 ]. Thus, despite the less conspicuous character of infiltration, the model of liver regeneration after resections in laboratory animals is generally consistent with other cases of tissue repair in vertebrates in terms of definite involvement of the immune system.…”

Adoptively Transferred in vitro-Generated Myeloid-Derived Suppressor Cells Improve T-Cell Function and Antigen-Specific Immunity after Traumatic Lung Injury

“…CD11b + Gr-1 + cells found in the ascites of epithelial ovarian cancer-bearing mice at advance stages of disease augment the proliferation of functional CTLs in vitro [21] or T cells conditioned with MDSC exhibit an increased anti-tumor activity after adoptive T cell-based immunotherapy [22]. Besides acting as T-cell modulators, MDSCs promote liver regeneration and bone fracture healing or ameliorate renal fibrosis and heart failure [23][24][25][26], supposing that the multifarious functions of MDSCs are dictated by the local environment.…”