Kupffer cells (KCs) are key regulators of liver immunity composing the principal part of hepatic macrophages even body tissue macrophages. They reside in liver sinusoids towards portal vein. The micro-environment shapes KCs unique immunosuppressive features and functions. KCs express specific surface markers that distinguish from other liver macrophages. By engulfing gut-derived foreign products and apoptotic cells without triggering excessive inflammation, KCs maintain homeostasis of liver and body. Heterogeneity of KCs has been identified in different studies. In terms of the origin, adult KCs are derived from progenitors of both embryo and adult bone marrow. Embryo-derived KCs compose the majority of KCs in healthy and maintain by self-renewal. Bone marrow monocytes replenish massively when embryo-derived KC proliferation are impaired. The phenotype of KCs is also beyond the traditional dogma of M1-M2. Functionally, KCs play central roles in pathogenesis of acute and chronic liver injury. They contribute to each pathological stage of liver disease. By initiating inflammation, regulating fibrosis, cirrhosis and tumor cell proliferation, KCs contribute to the resolution of liver injury and restoration of tissue architecture. The underlying mechanism varied by damage factors and pathology. Understanding the characteristics and functions of KCs may provide opportunities for the therapy of liver injury. Herein, we attempt to afford insights on heterogeneity and functions of KCs in liver injury using the existing findings.

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Heterogeneity and Function of Kupffer Cells in Liver Injury

Gut Microbiota Modulation: A Viable Strategy to Address Medical Needs in Hepatocellular Carcinoma and Liver Transplantation

Mortality in patients with end‐stage liver disease above model for end‐stage liver disease 3.0 of 40

The past decades have witnessed great advances in organoid technology. Liver is the biggest solid organ, performing multifaceted physiological functions. Nowadays, liver organoids have been applied in many fields including pharmaceutical research, precision medicine and disease models. Compared to traditional 2-dimensional cell line cultures and animal models, liver organoids showed the unique advantages. More importantly, liver organoids can well model the features of the liver and tend to be novel and promising modalities for exploring liver injury, thus finding potential treatment targets and repairing liver injury. In this review, we reviewed the history of the development of liver organoids and summarized the application of liver organoids and recent studies using organoids to explore and further repair the liver injury. These novel modalities could provide new insights about the process of liver injury. 

/pdf/liver-organoids-novel-and-promising-modalities-for-exploring-2e599cfv.pdf

Liver Organoids, Novel and Promising Modalities for Exploring and Repairing Liver Injury

Liver transplantation (LT) is an effective strategy for the treatment of end-stage liver disease, but immune rejection remains a significant detriment to the survival and prognosis of these LT patients. While immune rejection is closely related to cytokines, the cytokines investigated within previous studies have been limited and have not included a systematic analysis of proinflammatory cytokines. In the present study, we used a protein chip system and proteomics to detect and analyze serum proinflammatory cytokines and differentially expressed proteins in liver tissue in a mouse model of liver transplantation. In addition, bioinformatics analysis was employed to analyze the proinflammatory cytokines and differential changes in proteins in response to this procedure. With these analyses, we found that serum contents of GC-CSF, CXCL-1, MCP-5, and CXCL-2 were significantly increased after liver transplantation, while IL-5, IL-10, and IL-17 were significantly decreased. Results from Gene Ontology (GO) and KEGG pathway analyses revealed that the cytokine-cytokine receptor, Th1/Th2 cell differentiation, and JAK-STAT signaling pathway were enriched in a network associated with the activation of immune response. Results from our proteomic analysis of liver tissue samples revealed that 470 proteins are increased and 50 decreased, including Anxa1, Anxa2, Acsl4, Sirpa, S100a8, and S100a9. KEGG pathway analysis indicated that the neutrophil extracellular trap formation, NOD-like receptor signaling pathway, and leukocyte transendothelial migration were all associated with liver transplant rejection in these mice. Bioinformatics analysis results demonstrated that CXCL-1/CXCL-2 and S100a8/S100a9 were the genes most closely related to the functions of neutrophils and the mononuclear phagocyte system. These findings provide new insights into some of the critical factors associated with liver transplant rejection and thus offer new targets for the treatment and prevention of this condition.

https://downloads.hindawi.com/journals/omcl/2022/5188584.pdf

Characterization and Proteomic Analyses of Proinflammatory Cytokines in a Mouse Model of Liver Transplant Rejection

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.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cpr.13116

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

E2F7 promotes mammalian target of rapamycin inhibitor resistance in hepatocellular carcinoma after liver transplantation

SULT2B1-CS-DOCK2 axis regulates effector T cell exhaustion in hepatocellular carcinoma microenvironment.

https://doi.org/10.1016/j.tranon.2022.101422

Quantitative proteomic profiling of hepatocellular carcinoma at different serum alpha-fetoprotein level

Background A high model of end-stage liver disease (MELD) score (>30) adversely affects outcomes even if patients receive prompt liver transplantation (LT). Therefore, balanced allocation of donor grafts is indispensable to avoid random combinations of donor and recipient risk factors, which often lead to graft or recipient loss. Predictive models aimed at avoiding donor risk factors in high-MELD score recipients are urgently required to obtain satisfactory outcomes. Method Data of patients with MELD score >30 who underwent LT at three transplantation institutes between 2015 and 2018 were retrospectively reviewed. Early allograft dysfunction (EAD), length of intensive care unit (ICU) stay, and graft loss were recorded. Corresponding independent risk factors were analyzed using stepwise multivariable regression analysis. A prediction model of graft loss was developed, and discrimination and calibration were measured. Results After applying the exclusion criteria, 778 patients were enrolled. The incidence of EAD was 34.8% (271/778). Donor graft macrovesicular steatosis, graft-to-recipient weight ratio (GRWR), warm ischemia time (WIT), cold ischemia time (CIT), and ABO blood incompatibility, together with donor serum albumins, were independent predictors of EAD. The incidence of ICU stay over 10 days was 64.7% (503/778). Donor age, recipient's MELD score, Child score, and CIT were independent predictors of ICU stay. The 3-year graft survival rates (GSRs) in the training and validation cohorts were 64.2 and 59.3%, respectively. The independent predictors of graft loss were recipient's Child score, ABO blood type incompatibility, donor serum total bilirubin over 17.1 μmol/L, and cold CIT. A nomogram based on these variables was internally and externally validated and showed good performance (area under the receiver operating characteristic curve = 70.8 and 66.0%, respectively). For a recipient with a high MELD score, the avoidance of ABO blood type incompatibility and CIT ≥6 h would achieve a 3-year GSR of up to 78.4%, whereas the presence of the aforementioned risk factors would decrease the GSR to 35.4%. Conclusion The long-term prognosis of recipients with MELD scores >30 could be greatly improved by avoiding ABO blood type incompatibility and CIT ≥6 h.

Rui Wang

Papers

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

E2F7 promotes mammalian target of rapamycin inhibitor resistance in hepatocellular carcinoma after liver transplantation

SULT2B1-CS-DOCK2 axis regulates effector T cell exhaustion in hepatocellular carcinoma microenvironment.

Quantitative proteomic profiling of hepatocellular carcinoma at different serum alpha-fetoprotein level

Development of a Novel Prognostic Nomogram for High Model for End-Stage Liver Disease Score Recipients Following Deceased Donor Liver Transplantation