Mouse hepatocytes and LSEC proteome reveal novel mechanisms of ischemia/reperfusion damage and protection by A2aR stimulation

Mandili, Giorgia; Alchera, Elisa; Merlin, Simone; Imarisio, Chiara; Chandrashekar, Bangalore R.; Riganti, Chiara; Bianchi, Alberto; Novelli, Francesco; Follenzi, Antonia; Carini, Rita

doi:10.1016/j.jhep.2014.10.007

Cited by 30 publications

(21 citation statements)

References 35 publications

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“…55 Both A2A and A2B have been shown to be involved in prevention of liver IRI. 56,57 Human hepatic cDCs express comparatively high levels of CD39 compared with blood-borne cDCs. 58 Interestingly, CD39 expression by mouse hepatic cDCs attenuates inflammation in liver cold IRI 58 and CD39-deficient liver grafts suffer worse IRI due to increased inflammatory activation of cDCs.…”

Section: Hdc-mediated Anti-inflammatory Responses In Liver Ischemia-rmentioning

confidence: 99%

Hepatic Dendritic Cells, the Tolerogenic Liver Environment, and Liver Disease

et al. 2018

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The unique liver immune microenvironment favors resistance to inflammation that promotes normal physiological function. At the same time, it endows the liver with tolerogenic properties that may promote pathological processes. Hepatic dendritic cells (HDCs) initiate and orchestrate immune responses depending on signals they receive from the local environment and are thought to contribute to liver tolerance. Thus, HDCs facilitate impaired T cell responses that are observed in persistent hepatitis C virus (HCV) infection, hepatocellular carcinoma progression, and liver allograft transplantation. HDCs also participate in anti-inflammatory responses in liver ischemia-reperfusion injury (IRI). Moreover, they promote the regression of fibrosis from various fibrogenic liver injuries. These findings suggest that HDCs regulate intrahepatic immune responses, allowing the liver to maintain homeostasis and integrity even under pathological conditions. This review focuses on the tolerogenic properties of HDCs based on recent research and in relation to liver disease pathogenesis and its therapy.

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Section: Hdc-mediated Anti-inflammatory Responses In Liver Ischemia-rmentioning

confidence: 99%

Hepatic Dendritic Cells, the Tolerogenic Liver Environment, and Liver Disease

et al. 2018

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“…Oxidative stress is a phenomenon caused by an imbalance between the production of free radicals (species with one or more unpaired electrons), reactive metabolites, or ROS and their elimination through antioxidant mechanisms [25][26][27]. Oxidative stress is able to modify the phenotype of many hepatic cell types including hepatocytes, HSC, and inflammatory cells [28], but LSEC are probably the most sensitive liver cell type to oxidative stress [29,30] due to several reasons: first, ROS have been described as key drivers in the initiation of liver injury and LSEC response [30][31][32][33]; second, ROS selectively damage LSEC and alter LSEC phenotype during liver injury [20,27,29]; and third, LSEC are prone to oxidative stress due to a reduction in their enzymatic detoxifying capacity of H 2 O 2 [34][35][36]. In addition to the classical antioxidant response, LSEC have additional mechanisms, such as autophagy (a degradation process that maintains LSEC homeostasis), able to detoxify oxidative species and necessary for a proper adaptive response to stress.…”

Section: Triggers For Lsec Dysfunctionmentioning

confidence: 99%

The Endothelium as a Driver of Liver Fibrosis and Regeneration

Lafoz

Ruart

Anton

et al. 2020

Cells

105

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Liver fibrosis is a common feature of sustained liver injury and represents a major public health problem worldwide. Fibrosis is an active research field and discoveries in the last years have contributed to the development of new antifibrotic drugs, although none of them have been approved yet. Liver sinusoidal endothelial cells (LSEC) are highly specialized endothelial cells localized at the interface between the blood and other liver cell types. They lack a basement membrane and display open channels (fenestrae), making them exceptionally permeable. LSEC are the first cells affected by any kind of liver injury orchestrating the liver response to damage. LSEC govern the regenerative process initiation, but aberrant LSEC activation in chronic liver injury induces fibrosis. LSEC are also main players in fibrosis resolution. They maintain liver homeostasis and keep hepatic stellate cell and Kupffer cell quiescence. After sustained hepatic injury, they lose their phenotype and protective properties, promoting angiogenesis and vasoconstriction and contributing to inflammation and fibrosis. Therefore, improving LSEC phenotype is a promising strategy to prevent liver injury progression and complications. This review focuses on changes occurring in LSEC after liver injury and their consequences on fibrosis progression, liver regeneration, and resolution. Finally, a synopsis of the available strategies for LSEC-specific targeting is provided.

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“…However, the comparison of the LSEC populations obtained by CD146+ MACS to our technique showed that significant higher proportions of macrophages (4.85±1.11%) and unidentified cells (9.20±2.63%) were still present in the final cell population using the CD146+ MACS technique. To increase purity of LSEC isolated using this method, some authors optimized the procedure by adding a CD45magnetic sorting to remove blood cells [29,56]. Further, we observed a decreased viability in the population obtained by the CD146+ MACS technique, suggesting that the positive sorting either led to a non-specific retention of dead cells or decreased cell viability.…”

Section: Discussionmentioning

confidence: 86%

An optimized method for mouse liver sinusoidal endothelial cell isolation

Meyer

Lacotte

Morel

et al. 2016

Experimental Cell Research

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The objective of the present study was to develop an accurate and reproducible method for liver sinusoidal endothelial cell (LSEC) isolation in mice. Non-parenchymal cells were isolated using a modified two-step collagenase digestion combined with Optiprep density gradient centrifugation. LSEC were further purified using two prevalent methods, short-term selective adherence and CD146+ magnetic-activated cell sorting (MACS), and compared in terms of cell yield, viability and purity to our purification technique using CD11b cell depletion combined with long-term selective adherence. LSEC purification using our technique allowed to obtain 7.07±3.80 million LSEC per liver, while CD146+ MACS and short-term selective adherence yielded 2.94±1.28 and 0.99±0.66 million LSEC, respectively. Purity of the final cell preparation reached 95.10±2.58% when using our method. In contrast, CD146+ MACS and short-term selective adherence gave purities of 86.75±3.26% and 47.95±9.82%, respectively. Similarly, contamination by non-LSEC was the lowest when purification was performed using our technique, with a proportion of contaminating macrophages of only 1.87±0.77%. Further, isolated cells analysed by scanning electron microscopy presented typical LSEC fenestrations organized in sieve plates, demonstrating that the technique allowed to isolate bona fide LSEC. In conclusion, we described a reliable and reproducible technique for the isolation of high yields of pure LSEC in mice. This protocol provides an efficient method to prepare LSEC for studying their biological functions.

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Mouse hepatocytes and LSEC proteome reveal novel mechanisms of ischemia/reperfusion damage and protection by A2aR stimulation

Cited by 30 publications

References 35 publications

Hepatic Dendritic Cells, the Tolerogenic Liver Environment, and Liver Disease

Hepatic Dendritic Cells, the Tolerogenic Liver Environment, and Liver Disease

The Endothelium as a Driver of Liver Fibrosis and Regeneration

An optimized method for mouse liver sinusoidal endothelial cell isolation

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