Decoding the single-cell landscape and intercellular crosstalk in the transplanted liver: a 4-dimension mouse model

Abstract

Graft remodeling after transplantation maintains graft functionality and determines graft survival. However, a comprehensive understanding of cellular diversity and interplay during graft remodeling remains to be fully characterized. In this study, we established a well tolerant C57BL/6 to C57BL/6 orthotopic liver transplantation (LT) mice model and observed two stages of graft recovery including an acute phase and a steady phase. We next performed single-cell RNA sequencing (scRNA-seq) and cytometry by time-of-flight (CyTOF) and recorded the cellular hierarchy in the transplanted liver during the two stages. Besides the dynamic change of cell proportion, it was notable that recipient-derived cells took over the transplanted liver in most cell types (e.g., B cells, T cells, dendritic cells, granulocytes and monocytes) except CD206+ MerTK+ macrophages and CD161+ CD49a+ CD49b−natural killer cells. We then focused on macrophages and captured 5 distinct transcriptional signatures to define novel subclusters. Using a ligand-receptor interaction strategy, we identified specific macrophage-hepatocyte interactions during the acute and stable phases, causing metabolic remodeling in the transplanted liver. Our results delineated a 4-dimension cell atlas (type-proportion-source-time) of the transplanted liver, which sheds light on the physiological process of liver graft maintenance and graft-recipient crosstalk.

Assessing Donor Liver Quality and Restoring Graft Function in the Era of Extended Criteria Donors

“…In a study published on BioRxiv, we established a graft-tolerant mouse LT model and identified two stages of graft recovery, which included an acute and stable phases. 70 We also found that the interaction between CD206 + MerTK + macrophages and CD49a + CD49b − NK cells regulated metabolic and immune remodeling of the graft. 70…”

“…70 We also found that the interaction between CD206 + MerTK + macrophages and CD49a + CD49b − NK cells regulated metabolic and immune remodeling of the graft. 70…”

The role of macrophage TAM receptor family in the acute‐to‐chronic progression of liver disease: From friend to foe?

“…59 Using a mouse liver transplantation model, our previous study revealed the transcriptomic signature of MerTK + macrophages during IRI at singlecell level, showing a high expression of the anti-inflammatory gene IL-10. 62 We also found that the proportion of these cells among hepatic macrophages was significantly elevated during the repair phase and could promote graft homeostasis reconstitution after IRI. In myocardial IRI, DeBerge et al 63 ALF is a potentially fatal disease that has a high mortality rate and affects many organ systems.…”

“…Activation of the Gas6/MerTK signalling pathway in macrophages successfully reduced the production of these cytokines and thus suppressed inflammation 59 . Using a mouse liver transplantation model, our previous study revealed the transcriptomic signature of MerTK + macrophages during IRI at single‐cell level, showing a high expression of the anti‐inflammatory gene IL‐10 62 . We also found that the proportion of these cells among hepatic macrophages was significantly elevated during the repair phase and could promote graft homeostasis reconstitution after IRI.…”