Time-resolved single-cell transcriptomics reveals the landscape and dynamics of hepatic cells in sepsis-induced acute liver dysfunction

Gan, Chunfang; Ren, Chao; Xiao, Yao; Wang, Yujing; Yao, Ren-qi; Wang, Quan; You, Guoxiang; Su, Yan; Zhang, Xiaoyong; Zhang, Jun; Yao, Yong-ming; Zhou, Hong

doi:10.1016/j.jhepr.2023.100718

Cited by 6 publications

(5 citation statements)

References 61 publications

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“…A scRNA-seq study looking at CLP-induced changes in non-parenchymal cells of the liver was able to identify 4 distinct EC subpopulations, which were all uniquely affected by CLP (196). Out of these 4 subsets, 2 were nearly exclusively present under sepsis conditions.…”

Section: Organotypic Changes In Sepsis: Single Cell Rna-seqmentioning

confidence: 99%

“…Out of these 4 subsets, 2 were nearly exclusively present under sepsis conditions. Although they both displayed a proinflammatory phenotype, they presented at different stages during infection, with expression data suggesting that one subset likely plays a role in EC activation while the other contributes to the adaptive immune response to infection as antigen presenting cells (196). Similarly, scRNA-seq of non-neuronal cells of the mouse cerebral cortex identified 6 main EC subsets under basal conditions, with an additional minor subpopulation of venous ECs characterized by the presence of Icam-1 and Vcam-1 (47).…”

Section: Organotypic Changes In Sepsis: Single Cell Rna-seqmentioning

confidence: 99%

“…Furthermore, many of these markers are expressed by ECs in multiple organs, and changes in blood levels may thus represent either general EC dysfunction or organ-specific EC damage. Especially the latter would be valuable for diagnostic and prognostic purposes since several studies have indicated that EC dysfunction precedes organ failure (195,196). Therefore, being able to identify organotypic EC-derived proteins in the circulation could be used to predict organ dysfunction so preventive measures can be taken.…”

Section: Ec Heterogeneity In Sepsis-molecular Treasure Trove and Phar...mentioning

confidence: 99%

“…Once the true impact of this disease became apparent, the scientific community quickly rallied to employ methods such as (single cell) RNA-seq and spatial transcriptomics to generate testable hypotheses leading to a better understanding of the molecular mechanisms driving the host response and general patho(physio)logy of this devastating disease (90, [217][218][219][220][221][222]. Although several parallels can be drawn between COVID-19 and sepsis, including the presence of endotheliopathy (219,221), it is interesting to note that studies using these relatively new technologies have only started to emerge recently in the sepsis field (195,196). Nonetheless, these are expected to make a great stride forward in elucidating the complexity of sepsis.…”

Section: Integration Of -Omics Studiesmentioning

confidence: 99%

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Organotypic heterogeneity in microvascular endothelial cell responses in sepsis—a molecular treasure trove and pharmacological Gordian knot

Cleuren,

Molema

2023

Front. Med.

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In the last decades, it has become evident that endothelial cells (ECs) in the microvasculature play an important role in the pathophysiology of sepsis-associated multiple organ dysfunction syndrome (MODS). Studies on how ECs orchestrate leukocyte recruitment, control microvascular integrity and permeability, and regulate the haemostatic balance have provided a wealth of knowledge and potential molecular targets that could be considered for pharmacological intervention in sepsis. Yet, this information has not been translated into effective treatments. As MODS affects specific vascular beds, (organotypic) endothelial heterogeneity may be an important contributing factor to this lack of success. On the other hand, given the involvement of ECs in sepsis, this heterogeneity could also be leveraged for therapeutic gain to target specific sites of the vasculature given its full accessibility to drugs. In this review, we describe current knowledge that defines heterogeneity of organ-specific microvascular ECs at the molecular level and elaborate on studies that have reported EC responses across organ systems in sepsis patients and animal models of sepsis. We discuss hypothesis-driven, single-molecule studies that have formed the basis of our understanding of endothelial cell engagement in sepsis pathophysiology, and include recent studies employing high-throughput technologies. The latter deliver comprehensive data sets to describe molecular signatures for organotypic ECs that could lead to new hypotheses and form the foundation for rational pharmacological intervention and biomarker panel development. Particularly results from single cell RNA sequencing and spatial transcriptomics studies are eagerly awaited as they are expected to unveil the full spatiotemporal signature of EC responses to sepsis. With increasing awareness of the existence of distinct sepsis subphenotypes, and the need to develop new drug regimen and companion diagnostics, a better understanding of the molecular pathways exploited by ECs in sepsis pathophysiology will be a cornerstone to halt the detrimental processes that lead to MODS.

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Section: Organotypic Changes In Sepsis: Single Cell Rna-seqmentioning

confidence: 99%

Section: Organotypic Changes In Sepsis: Single Cell Rna-seqmentioning

confidence: 99%

Section: Ec Heterogeneity In Sepsis-molecular Treasure Trove and Phar...mentioning

confidence: 99%

Section: Integration Of -Omics Studiesmentioning

confidence: 99%

See 2 more Smart Citations

Organotypic heterogeneity in microvascular endothelial cell responses in sepsis—a molecular treasure trove and pharmacological Gordian knot

Cleuren,

Molema

2023

Front. Med.

View full text Add to dashboard Cite

show abstract

“…Sepsis is recognized as the systemic inflammatory response syndrome and a significant contributor to organ failure. 1 This condition is featured by an uncontrolled systemic inflammatory response of the organism to infection (or pathogenic products), resulting in organ dysfunction, shock, and even multi-organ dysfunction 2 , 3 . Sepsis has been reported as the main reason for death in intensive care units (ICUs), which shows high morbidity and mortality rates.…”

Section: Introductionmentioning

confidence: 99%