Dataset Information

Single-cell transcriptome reveals a novel mechanism of C-Kit⁺-liver sinusoidal endothelial cells in NASH.

ABSTRACT:

Aim

To understand how liver sinusoidal endothelial cells (LSECs) respond to nonalcoholic steatohepatitis (NASH).

Methods

We profiled single-LSEC from livers of control and MCD-fed mice. The functions of C-Kit⁺-LSECs were determined using coculture and bone marrow transplantation (BMT) methods.

Results

Three special clusters of single-LSEC were differentiated. C-Kit⁺-LSECs of cluster 0, Msr1⁺-LSECs of cluster 1 and Bmp4⁺Selp⁺-VECs of cluster 2 were revealed, and these cells with diverse ectopic expressions of genes participated in regulation of endothelial, fibrosis and lipid metabolism in NASH. The number of C-Kit⁺-primary LSECs isolated from MCD mice was lower than control mice. Immunofluorescence co-staining of CD31 and C-KIT showed C-Kit⁺-LSECs located in hepatic sinusoid were also reduced in NASH patients and MCD mice, compared to AIH patients and control mice respectively. Interestingly, lipotoxic hepatocytes/HSCs cocultured with C-Kit⁺-LSECs or the livers of MCD mice receipting of C-Kit⁺-BMCs (bone marrow cells) showed less steatosis, inflammation and fibrosis, higher expression of prolipolytic FXR and PPAR-α, lower expression of TNF-α and α-SMA. Furthermore, coculturing or BMT of C-Kit⁺-endothelial derived cells could increase the levels of hepatic mitochondrial LC3B, decrease the degree of mitochondrial damage and ROS production through activating Pink1-mediated mitophagy pathway in NASH.

Conclusions

Hence, a novel transcriptomic view of LSECs was revealed to have heterogeneity and complexity in NASH. Importantly, a cluster of C-Kit⁺-LSECs was confirmed to recovery Pink1-related mitophagy and NASH progression.

SUBMITTER: Li HY

PROVIDER: S-EPMC10925010 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Publications

Single-cell transcriptome reveals a novel mechanism of C-Kit<sup>+</sup>-liver sinusoidal endothelial cells in NASH.

Li Hui-Yi HY Gao Yu-Xuan YX Wu Jun-Cheng JC Li Jing-Ze JZ Fu Seng-Wang SW Xu Ming-Yi MY

Cell & bioscience 20240309 1

<h4>Aim</h4>To understand how liver sinusoidal endothelial cells (LSECs) respond to nonalcoholic steatohepatitis (NASH).<h4>Methods</h4>We profiled single-LSEC from livers of control and MCD-fed mice. The functions of C-Kit<sup>+</sup>-LSECs were determined using coculture and bone marrow transplantation (BMT) methods.<h4>Results</h4>Three special clusters of single-LSEC were differentiated. C-Kit<sup>+</sup>-LSECs of cluster 0, Msr1<sup>+</sup>-LSECs of cluster 1 and Bmp4<sup>+</sup>Selp<sup>+< ...[more]

PMID: 38461242

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Project description:Background & aimsLiver sinusoidal endothelial cells (SECs) promote the proliferation of hepatocytes during liver regeneration. However, the specific subset of SECs and its mechanisms during the process remain unclear. In this study, we investigated the potential role of c-kit+ SECs, a newly identified subset of SECs in liver regeneration.MethodsPartial hepatectomy mice models were established to induce liver regeneration. Hepatic c-kit expression was detected by quantitative reverse-transcription polymerase chain reaction, immunofluorescent staining, and fluorescence-activated cell sorting. VE-cadherin-cyclization recombinase-estrogen receptor (Cdh5-Cre-ERT) Notch intracellular domain and Cdh5-Cre recombination signal binding protein Jκfloxp mice were introduced to mutate Notch signaling. c-Kit+ SECs were isolated by magnetic beads. Single-cell RNA sequencing was performed on isolated SECs. Liver injuries were induced by CCl4 or quantitative polymerase chain reaction injection.ResultsHepatic c-kit is expressed predominantly in SECs. Liver resident SECs contribute to the increase of c-kit during partial hepatectomy-induced liver regeneration. Isolated c-kit+ SECs promote hepatocyte proliferation in vivo and in vitro by facilitating angiocrine. The distribution of c-kit shows distinct spatial differences that are highly coincident with the liver zonation marker wingless-type MMTV integration site family, member2 (Wnt2). Notch mutation reshapes the c-kit distribution and liver zonation, resulting in altered hepatocyte proliferation. c-Kit+ SECs were shown to regulate hepatocyte regeneration through angiocrine in a Wnt2-dependent manner. Activation of the Notch signaling pathway weakens liver regeneration by inhibiting positive regulatory effects of c-kit+ SECs on hepatocytes. Furthermore, c-kit+ SEC infusion attenuates toxin-induced liver injuries in mice.ConclusionsOur results suggest that c-kit+ SECs contributes to liver zonation and regeneration through Wnt2 and is regulated by Notch signaling, providing opportunities for novel therapeutic approaches to liver injury in the future. Transcript profiling: GEO (accession number: GSE134037).

Project description:BackgroundLiver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs; liver resident macrophages) form the body's most effective scavenger cell system for the removal of harmful blood-borne substances, ranging from modified self-proteins to pathogens and xenobiotics. Controversies in the literature regarding the LSEC phenotype pose a challenge when determining distinct functionalities of KCs and LSECs. This may be due to overlapping functions of the two cells, insufficient purification and/or identification of the cells, rapid dedifferentiation of LSECs in vitro, or species differences. We therefore characterized and quantitatively compared expressed gene products of freshly isolated, highly pure LSECs (fenestrated SE-1/FcγRIIb2+) and KCs (CD11b/c+) from Sprague Dawley, Crl:CD (SD), male rats using high throughput mRNA-sequencing and label-free proteomics.ResultsWe observed a robust correlation between the proteomes and transcriptomes of the two cell types. Integrative analysis of the global molecular profile demonstrated the immunological aspects of LSECs. The constitutive expression of several immune genes and corresponding proteins of LSECs bore some resemblance with the expression in macrophages. LSECs and KCs both expressed high levels of scavenger receptors (SR) and C-type lectins. Equivalent expression of SR-A1 (Msr1), mannose receptor (Mrc1), SR-B1 (Scarb1), and SR-B3 (Scarb2) suggested functional similarity between the two cell types, while functional distinction between the cells was evidenced by LSEC-specific expression of the SRs stabilin-1 (Stab1) and stabilin-2 (Stab2), and the C-type lectins LSECtin (Clec4g) and DC-SIGNR (Clec4m). Many immune regulatory factors were differentially expressed in LSECs and KCs, with one cell predominantly expressing a specific cytokine/chemokine and the other cell the cognate receptor, illustrating the complex cytokine milieu of the sinusoids. Both cells expressed genes and proteins involved in antigen processing and presentation, and lymphocyte co-stimulation.ConclusionsOur findings support complementary and partly overlapping scavenging and immune functions of LSECs and KCs. This highlights the importance of including LSECs in studies of liver immunity, and liver clearance and toxicity of large molecule drugs and nano-formulations.

Dataset Information

Single-cell transcriptome reveals a novel mechanism of C-Kit⁺-liver sinusoidal endothelial cells in NASH.

Aim

Methods

Results

Conclusions

Publications

Single-cell transcriptome reveals a novel mechanism of C-Kit<sup>+</sup>-liver sinusoidal endothelial cells in NASH.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Single-cell transcriptome reveals a novel mechanism of C-Kit+-liver sinusoidal endothelial cells in NASH.

Aim

Methods

Results

Conclusions

Publications

Single-cell transcriptome reveals a novel mechanism of C-Kit<sup>+</sup>-liver sinusoidal endothelial cells in NASH.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Single-cell transcriptome reveals a novel mechanism of C-Kit⁺-liver sinusoidal endothelial cells in NASH.