Aberrant peribiliary gland niche exacerbates fibrosis in primary sclerosing cholangitis and a potential therapeutic strategy

Wu, Shouyan; Cao, Yuhan; Lu, Henglei; Qi, Xinming; Sun, Jianhua; Yang, Yong; Gong, Likun

doi:10.1016/j.biopha.2022.113512

Cited by 3 publications

(2 citation statements)

References 42 publications

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“…Wu et al. ( 99 ) showed that the transcription of POU6F1 in biliary epithelial cells activates monocyte chemotactic protein-1 (MCP-1) and promotes peripheral M1 and M2 macrophage recruitment and infiltration into peribiliary gland (PBG) niche, producing chronic inflammation, resulting in dilated PBG compartments and the formation of “onionskin” fibrosis characterized by multifocal fibrosis around intrahepatic and extrahepatic bile ducts in a mouse model of primary sclerosing cholangitis.…”

Section: The Effect Of Hime For Different Chronic Liver Diseases On T...mentioning

confidence: 99%

Ongoing involvers and promising therapeutic targets of hepatic fibrosis: The hepatic immune microenvironment

et al. 2023

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Hepatic fibrosis is often secondary to chronic inflammatory liver injury. During the development of hepatic fibrosis, the damaged hepatocytes and activated hepatic stellate cells (HSCs) caused by the pathogenic injury could secrete a variety of cytokines and chemokines, which will chemotactic innate and adaptive immune cells of liver tissue and peripheral circulation infiltrating into the injury site, mediating the immune response against injury and promoting tissue reparation. However, the continuous release of persistent injurious stimulus-induced inflammatory cytokines will promote HSCs-mediated fibrous tissue hyperproliferation and excessive repair, which will cause hepatic fibrosis development and progression to cirrhosis even liver cancer. And the activated HSCs can secrete various cytokines and chemokines, which directly interact with immune cells and actively participate in liver disease progression. Therefore, analyzing the changes in local immune homeostasis caused by immune response under different pathological states will greatly enrich our understanding of liver diseases’ reversal, chronicity, progression, and even deterioration of liver cancer. In this review, we summarized the critical components of the hepatic immune microenvironment (HIME), different sub-type immune cells, and their released cytokines, according to their effect on the development of progression of hepatic fibrosis. And we also reviewed and analyzed the specific changes and the related mechanisms of the immune microenvironment in different chronic liver diseases.Moreover, we retrospectively analyzed whether the progression of hepatic fibrosis could be alleviated by modulating the HIME.We aimed to elucidate the pathogenesis of hepatic fibrosis and provide the possibility for exploring the therapeutic targets for hepatic fibrosis.

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Section: The Effect Of Hime For Different Chronic Liver Diseases On T...mentioning

confidence: 99%

Ongoing involvers and promising therapeutic targets of hepatic fibrosis: The hepatic immune microenvironment

et al. 2023

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“…Previous maps of PSC have mainly considered sorted populations of immune cells (11,12). These and other studies using bulk tissue expression have variously implicated CD4+ T cells (11), neutrophils (13), dendritic cells (12), antibody-producing B cells (14,15), and macrophages (16)(17)(18)(19)(20)(21) in the development of disease. However, the narrow scope and low cellular resolution of these studies leave many uncertainties in the underlying cause and consequences of PSC inflammation preventing the development of targeted treatments.…”

Section: Introductionmentioning

confidence: 99%

Single-cell and spatial transcriptomics reveals the human liver immunological landscape and myeloid dysfunction in PSC

Andrews,

Nakib,

Perciani

et al. 2023

Preprint

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Background: Primary sclerosing cholangitis (PSC) is a serious immune-mediated cholestatic liver disease characterized by bile retention, biliary tree destruction, and progressive fibrosis leading to end stage liver disease and transplantation. There is an unmet need to understand the cellular composition of the PSC liver and how it underlies disease pathogenesis. As such, we generated a comprehensive atlas of the PSC liver and a reference healthy liver dataset using multiple multi-omic modalities with functional validation. Methods: In this work, we employed single-cell (12,000 cells), single-nuclei (23,000 nuclei) and spatial transcriptomics (1 sample by 10x Visium and 3 samples with multi-region profiling by Nanostring GeoMx DSP) to profile the cellular ecosystem in 5 patients with PSC. Transcriptomic profiles were compared to 100k single cell transcriptomes and spatial transcriptomics controls from 24 healthy neurologically deceased donor (NDD) livers. Flow cytometry and intracellular cytokine staining was performed to validate PSC-specific differences in immune phenotype and function. Results: PSC explants with cirrhosis of the liver parenchyma and prominent periductal fibrosis were associated with a unique population of hepatocytes which transformed to a cholangiocyte-like phenotype. Those hepatocytes were surrounded by diverse immune cell populations, including monocyte-like macrophages, liver-resident and circulating natural killer (NK) cells. Cytokines released by inflamed cholangiocytes and fibrosis-resident hepatic stellate cells and endothelial cells recruited CD4+T-cells, dendritic cells, and neutrophils to PSC liver tissues. Tissue-resident macrophages, by contrast, were reduced in number and exhibited a dysfunctional inflammatory response to LPS and IFN-Ɣ stimulation. Conclusions: We present the first comprehensive atlas of the PSC liver and demonstrate hyper-activation and exhaustion-like phenotypes of myeloid cells and markers of chronic cytokine expression in late-stage PSC lesions.

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Single-cell, single-nucleus, and spatial transcriptomics characterization of the immunological landscape in the healthy and PSC human liver

Andrews,

Nakib,

Perciani

et al. 2024

Journal of Hepatology

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Aberrant peribiliary gland niche exacerbates fibrosis in primary sclerosing cholangitis and a potential therapeutic strategy

Cited by 3 publications

References 42 publications

Ongoing involvers and promising therapeutic targets of hepatic fibrosis: The hepatic immune microenvironment

Ongoing involvers and promising therapeutic targets of hepatic fibrosis: The hepatic immune microenvironment

Single-cell and spatial transcriptomics reveals the human liver immunological landscape and myeloid dysfunction in PSC

Single-cell, single-nucleus, and spatial transcriptomics characterization of the immunological landscape in the healthy and PSC human liver

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