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Single-cell profiling reveals distinct immune phenotypes that contribute to ischaemia-reperfusion injury after steatotic liver transplantation.

ABSTRACT:

Objectives

The discrepancy between supply and demand of organ has led to an increased utilization of steatotic liver for liver transplantation (LT). Hepatic steatosis, however, is a major risk factor for graft failure due to increased susceptibility to ischaemia-reperfusion (I/R) injury during transplantation.

Materials and methods

To assess the plasticity and phenotype of immune cells within the microenvironment of steatotic liver graft at single-cell level, single-cell RNA-sequencing (scRNA-Seq) was carried out on 23 675 cells from transplanted rat livers. Bioinformatic analyses and multiplex immunohistochemistry were performed to assess the functional properties, transcriptional regulation, phenotypic switching and cell-cell interactions of different cell subtypes.

Results

We have identified 11 different cell types in transplanted livers and found that the highly complex ecosystem was shaped by myeloid-derived cell subsets that transit between different states and interact mutually. Notably, a pro-inflammatory phenotype of Kupffer cells (KCs) with high expression of colony-stimulating factor 3 (CSF3) that was enriched in transplanted steatotic livers was potentially participated in fatty graft injury. We have also detected a subset of dendritic cells (DCs) with highly expressing XCR1 that was correlated with CD8⁺ T cells, mediating the severer steatotic liver damage by I/R injury.

Conclusions

The findings of our study provide new insight into the mechanisms by which steatosis exacerbates liver damage from I/R injury. Interventions based on these observations create opportunities in attenuating fatty liver graft injury and expanding the donor pool.

SUBMITTER: Yang X

PROVIDER: S-EPMC8488562 | biostudies-literature |

REPOSITORIES: biostudies-literature

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