Resolving the graft ischemia-reperfusion injury during liver transplantation at the single cell resolution

Wang, Linhe; Li, Jie; He, Shuai; Chen, Haitian; He, Shujiao; Yin, Meizhen; Zou, Dawei; Xu, Jinghong; Chen, Shirui; Luo, Tao; Yu, Xinyu; Bei, Jin‐Xin; Guo, Zhiyong; He, Xiaoshun

doi:10.1101/2021.01.10.426087

Cited by 5 publications

(5 citation statements)

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“…Ischemia-based IRI followed by reperfusion occurs in all transplanted organs in a more or less severe form [44]. A significant part of damage to the ischemic organ develops not during ischemia, but during and after reperfusion and leads primarily to the dysfunction of the epithelial cells of the renal tubules [10,17], as well as the epithelium of the bile ducts [45], contributing to the development of acute injury, delayed graft functioning, as well as acute and chronic organ rejection [13].…”

Section: Discussionmentioning

confidence: 99%

Effect of the Peptide Calcium Channel Blocker ω-hexatoxin-Hv1a on Cell Death during Ischemia/Reperfusion in vitro

Iurova¹,

Beloborodov²,

Saenko³

et al. 2023

Sovrem Tehnol Med

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Apoptosis and necrosis during reperfusion after ischemia are key mechanisms at the cellular level leading to damage. The development of pathological conditions is preceded by intracellular calcium ion overload both at the stage of ischemia and at the stage of reperfusion. In this regard, one of the strategies aimed at reducing damage during ischemia/reperfusion is associated with the use of calcium channel blockers.The aim of the study was to study the effect of a peptide toxin, a calcium channel blocker ω-hexatoxin-Hv1a, on different types of epithelial cell death during in vitro reconstruction of ischemia/reperfusion conditions characteristic of organ transplantation.Materials and Methods. In this study, we used CHO-K1 epithelial cell culture. Changes in apoptosis, necrosis, cell index, and calcium ion concentration were assessed when modeling ischemia/reperfusion processes in vitro with the addition of a calcium channel blocker toxin. Ischemic and reperfusion injury was achieved by oxygen and nutrient deprivation followed by reperfusion in a complete nutrient medium. The measurements were performed using a multimodal plate reader-fluorimeter.Results. An increase in apoptosis, necrosis, and the concentration of calcium ions was recorded when modeling ischemia/reperfusion processes. A decrease in the level of apoptosis and necrosis, as well as the concentration of calcium ions to a physiological level or a level close to physiological, was noted when the toxin was added at a concentration of 50 nM at the reperfusion stage. The cell index showed a faster restoration in the presence of the toxin.Conclusion. The experimental data confirm the hypothesis of a beneficial effect of peptide calcium channel blockers on the state of epithelial cells during reperfusion after ischemia and can be considered for further study as a strategy for organ adaptation before reperfusion.

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Section: Discussionmentioning

confidence: 99%

Effect of the Peptide Calcium Channel Blocker ω-hexatoxin-Hv1a on Cell Death during Ischemia/Reperfusion in vitro

Iurova¹,

Beloborodov²,

Saenko³

et al. 2023

Sovrem Tehnol Med

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“…Another scRNA-seq study on healthy liver-resident CD45 + immune cells by Zhao et al 30 has classified NK cells cNK and LrNK cells. An scRNA-seq study of liver transplantation samples by Wang et al 49 has subdivided the liver NK cell population into 4 subsets according to the top 5 highly expressed genes but has not described their functional characteristics. In this study, we analyzed 46,726 liver-resident NK cells from 9 samples, including NK cells from healthy livers (n = 3), HCC tumors (n = 4), HCC tumor-adjacent liver tissues (n = 1), and blood samples (n = 1), to define the heterogeneity of NK cells in the human liver.…”

Section: Discussionmentioning

confidence: 99%

Panoramic comparison between NK cells in healthy and cancerous liver through single-cell RNA sequencing

et al. 2022

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Objective: NK cells play crucial roles in the immune defense mechanisms against viral infections and transformed cells. However, the developmental progression, transcriptomic landscape, and functional subtypes of liver NK cells are not well defined. Hepatocellular carcinoma (HCC) accounts for approximately 80% of primary liver cancer worldwide, yet the biological characteristics of NK cells in the HCC environment are unclear. Therefore, we aimed to determine these cells’ roles in tumorigenesis and prognosis. Methods: We compared the single-cell RNA sequencing profiles of NK cells purified from blood (n = 1), healthy liver tissues (n = 3), HCC tumor tissues (n = 4), and peritumor liver tissues (n = 1) to identify NK cell subsets. Furthermore, we performed bioinformatics analysis by using The Cancer Genome Atlas (TCGA) data to identify prognostic biomarkers simultaneously overexpressed in the blood and tumor tissues of patients with HCC. Results: Transcriptomic analysis revealed 5 NK cell subsets (L1-NK-CD56bright, L2-NK-CD56dim, L3-NK-HLA, L4-LrNK-FCGR3A, and L5-LrNK-XCL1) in the healthy liver tissues. However, the transitional L3 subset and the CXCR6+CD16+ L4 subset with strong anti-tumor activity were absent in the HCC and peritumor liver tissues. Furthermore, 4 common prognosis-associated genes (RHOB, TALDO1, HLA-DPA1, and TKT) were significantly overexpressed in the paired tumor tissue and blood. Conclusions: Our study revealed 5 specific subsets of NK cells in healthy human liver tissues. However, only 3 of the 5 NK cell subsets were present in HCC and peritumor tissues. The cytotoxic NK cell subsets were absent in HCC tissues. Furthermore, we identified 4 potential non-invasive prognostic biomarkers in patients with HCC.

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“…In experimental stroke, scRNA-seq did not highlight immune checkpoints; but the majority of monocytes infiltrating ischemic brain parenchyma did express Ctsl and Thbs1 , two genes overexpressed in the monocyte cluster associated with poor outcomes in our study of CA (Zheng et al, 2022). In scRNA- seq analysis of human liver 2h after transplantation and reperfusion, a CD8 + T cell subset had enrichment of the PD-1 signaling gene set, but there were no immune checkpoints highlighted in other cell subpopulations (Wang et al, 2021). Blockade of the PD-1 /PD-L1/2 axis worsened tissue injury in both experimental cardiac and renal IRI, via macrophage polarization or regulatory T cell functions, respectively (Jaworska et al, 2015; Xia et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Single-cell transcriptomics reveal hyperacute cytokine and immune checkpoint axis in patients with poor neurological outcomes after cardiac arrest

Tamura

Cheng

Merriam

et al. 2022

Preprint

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Neurological injury is a major driver of mortality among patients hospitalized after cardiac arrest (CA). The early systemic inflammatory response after CA is associated with neurological injury and mortality but remains poorly defined. We determine the innate immune network induced by clinical CA at single-cell resolution. Immune cell states diverge as early as 6h post-CA between patients with good or poor neurological outcomes at hospital discharge. Nectin-2+ monocyte and Tim-3+ natural killer (NK) cell subpopulations associate with poor outcomes, and interactome analysis highlights their crosstalk via cytokines and immune checkpoints. Ex vivo studies on peripheral blood cells from CA patients demonstrate that immune checkpoints are a compensatory mechanism against inflammation after CA. IFNγ/IL-10 induce Nectin-2 on monocytes; in a negative feedback loop, Nectin-2 suppresses IFNγ production by NK cells. The initial hours after CA may represent a window for therapeutic intervention in the resolution of inflammation via immune checkpoints.

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Resolving the graft ischemia-reperfusion injury during liver transplantation at the single cell resolution

Cited by 5 publications

References 50 publications

Effect of the Peptide Calcium Channel Blocker ω-hexatoxin-Hv1a on Cell Death during Ischemia/Reperfusion in vitro

Effect of the Peptide Calcium Channel Blocker ω-hexatoxin-Hv1a on Cell Death during Ischemia/Reperfusion in vitro

Panoramic comparison between NK cells in healthy and cancerous liver through single-cell RNA sequencing

Single-cell transcriptomics reveal hyperacute cytokine and immune checkpoint axis in patients with poor neurological outcomes after cardiac arrest

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