Stellate Cells and Hepatic Fibrosis

Hasegawa, Daisuke; Wallace, M. Christopher; Friedman, Scott L.

doi:10.1016/b978-0-12-800134-9.00004-x

Cited by 15 publications

(46 citation statements)

References 162 publications

(217 reference statements)

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“…HSC (perisinusoidal cells, fat‐storing cells, and lipocytes) comprise ≈10% of all liver cells and are the major source of myofibroblasts and fibrosis . They reside in Disse's space, throwing out long cytoplasmic extensions (≈40 μm) , and hold ≈80% of vitamin A and retinoid stores .…”

Section: Major Blood Group and Histocompatibility Complex Antigen Expmentioning

confidence: 99%

“…HSC activate in two stages . “Initiation” involves transdifferentiation, proliferation, and migration to injury sites .…”

Section: Major Blood Group and Histocompatibility Complex Antigen Expmentioning

confidence: 99%

“…“Initiation” involves transdifferentiation, proliferation, and migration to injury sites . “Perpetuation” involves autocrine and paracrine signals, the latter from damaged/apoptotic hepatocytes (including transforming growth factor‐β1 [TGF‐β1] and reactive oxygen species), activated KC, inflammatory cells, and altered ECM composition . Activated HSC elaborate inflammatory cytokines and chemokines .…”

Section: Major Blood Group and Histocompatibility Complex Antigen Expmentioning

confidence: 99%

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Functional Immune Anatomy of the Liver—As an Allograft

Demetris

Bellamy

Gandhi

et al. 2016

American Journal of Transplantation

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The liver is an immunoregulatory organ in which a tolerogenic microenvironment mitigates the relative "strength" of local immune responses. Paradoxically, necro-inflammatory diseases create the need for most liver transplants. Treatment of hepatitis B virus, hepatitis C virus, and acute T cell-mediated rejection have redirected focus on long-term allograft structural integrity. Understanding of insults should enable decades of morbidity-free survival after liver replacement because of these tolerogenic properties. Studies of long-term survivors show low-grade chronic inflammatory, fibrotic, and microvascular lesions, likely related to some combination of environment insults (i.e. abnormal physiology), donor-specific antibodies, and T cell-mediated immunity. The resultant conundrum is familiar in transplantation: adequate immunosuppression produces chronic toxicities, while lightened immunosuppression leads to sensitization, immunological injury, and structural deterioration. The "balance" is more favorable for liver than other solid organ allografts. This occurs because of unique hepatic immune physiology and provides unintended benefits for allografts by modulating various afferent and efferent limbs of allogenic immune responses. This review is intended to provide a better understanding of liver immune microanatomy and physiology and thereby (a) the potential structural consequences of low-level, including allo-antibody-mediated injury; and (b) how liver allografts modulate immune reactions. Special attention is given to the microvasculature and hepatic mononuclear phagocytic system.

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Section: Major Blood Group and Histocompatibility Complex Antigen Expmentioning

confidence: 99%

“…HSC activate in two stages . “Initiation” involves transdifferentiation, proliferation, and migration to injury sites .…”

Section: Major Blood Group and Histocompatibility Complex Antigen Expmentioning

confidence: 99%

Section: Major Blood Group and Histocompatibility Complex Antigen Expmentioning

confidence: 99%

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Functional Immune Anatomy of the Liver—As an Allograft

Demetris

Bellamy

Gandhi

et al. 2016

American Journal of Transplantation

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“…Distinct from these are chronic liver diseases originating from the portal tracts (primary biliary cholangitis and primary sclerosing cholangitis) with high morbidity and mortality. Remarkable advancements have been made in identifying the cell types that co-ordinate fibrogenesis as well as the underlying inter-and intra-cellular signaling mechanisms (6)(7)(8)(9). Several animal models of liver fibrosis of various etiologies have been developed (10,11), and monoand co-culture systems established (8,12,13) to discover the mechanisms of cross-communication amongst the liver resident cells, infiltrating inflammatory cells and immune cells implicated in fibrosis at the organ and cellular/subcellular levels.…”

Section: Introductionmentioning

confidence: 99%

Pro- and Anti-fibrogenic Functions of Gram-Negative Bacterial Lipopolysaccharide in the Liver

Gandhi

2020

Front. Med.

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“…Perisinusoidal HSCs that constitute ;10% of the entire liver cell population become activated to a potent fibrogenic and contractile myofibroblast-like phenotype during liver injury [19]. They perform several other critical functions, and several laboratories, including our own, have provided strong evidence for a prominent role of HSCs in hepatic inflammation, immune responses, and acute liver injury [20,21].…”

Section: Introductionmentioning

confidence: 99%

Hepatic stellate cells increase the immunosuppressive function of natural Foxp3+ regulatory T cells via IDO-induced AhR activation

Kumar

Wang

Thomson

et al. 2016

Journal of Leukocyte Biology

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Immunosuppressive, naturally occurring CD4CD25forkhead box p3 (Foxp3) regulatory T cells (nT) offer potential for the treatment of immune-mediated inflammatory disorders. However, potential instability of ex vivo-expanded nT following their adoptive transfer may be a significant limitation. LPS-stimulated hepatic stellate cells (HSCs) induce expansion and enhance the suppressive function and stability of allogeneic nT We aimed to delineate mechanisms underlying HSC-induced expansion and increased potency of nT HSCs and nT were isolated from mouse livers and spleens, respectively. Following coculture with LPS-pretreated allogeneic HSCs (LPS/HSCs), proliferation of nT was measured by CFSE dilution, and Foxp3 expression and acetylation were determined by immunoprecipitation (IP) and Western blotting analysis. Expression of various genes associated with immunologic tolerance was determined by quantitative RT-PCR (qRT-PCR). LPS stimulation increased the expression and activity of the immunoregulatory enzyme IDO1 in HSCs, and LPS/HSCs stimulated aryl hydrocarbon receptor (AhR) signaling in cocultured nT Reciprocally, T increased IDO1 expression in HSCs. IDO1 LPS/HSCs were inferior to WT LPS/HSCs in stimulating nT expansion. Pharmacologic inhibition of IDO1 in HSCs by 1-methyltryptophan (1MT) inhibited LPS/HSC-induced AhR signaling in nT, which was responsible for their expansion, Foxp3 expression, and stabilization of Foxp3 by increasing acetylation of lysine residues. Finally, HSCs cryopreserved, following 2-3 passages, were as potent as primary-cultured HSCs in expanding nT In conclusion, LPS/HSCs expand allogeneic nT through an IDO-dependent, AhR-mediated mechanism and increase their stability through lysine-acetylation of Foxp3. nT expanded by cryopreserved HSCs may have potential for clinical use.

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Stellate Cells and Hepatic Fibrosis

Cited by 15 publications

References 162 publications

Functional Immune Anatomy of the Liver—As an Allograft

Functional Immune Anatomy of the Liver—As an Allograft

Pro- and Anti-fibrogenic Functions of Gram-Negative Bacterial Lipopolysaccharide in the Liver

Hepatic stellate cells increase the immunosuppressive function of natural Foxp3+ regulatory T cells via IDO-induced AhR activation

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