scholarly journals Role of Liver-Mediated Tolerance in Nanoparticle-Based Tumor Therapy

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1985
Author(s):  
Maximiliano L. Cacicedo ◽  
Carolina Medina-Montano ◽  
Leonard Kaps ◽  
Cinja Kappel ◽  
Stephan Gehring ◽  
...  
Keyword(s):  
Hepatic Stellate Cells ◽  
Liver Diseases ◽  
Potential Role ◽  
Current Knowledge ◽  
Tumor Therapy ◽  
Stellate Cells ◽  
Liver Sinusoidal Endothelial Cells ◽  
Parenchymal Cells ◽  
Systemic Application

In the last decades, the use of nanocarriers for immunotherapeutic purposes has gained a lot of attention, especially in the field of tumor therapy. However, most types of nanocarriers accumulate strongly in the liver after systemic application. Due to the default tolerance-promoting role of liver non-parenchymal cells (NPCs), Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), and hepatic stellate cells (HSCs), their potential role on the immunological outcome of systemic nano-vaccination approaches for therapy of tumors in the liver and in other organs needs to be considered. Concerning immunological functions, KCs have been the focus until now, but recent studies have elucidated an important role of LSECs and HSCs as well. Therefore, this review aims to summarize current knowledge on the employment of nanocarriers for immunotherapeutic therapy of liver diseases and the overall role of liver NPCs in the context of nano-vaccination approaches. With regard to the latter, we discuss strategies on how to address liver NPCs, aiming to exploit and modulate their immunological properties, and alternatively how to avoid unwanted engagement of nano-vaccines by liver NPCs for tumor therapy.

scholarly journals The role of hepatic stellate cells in fibrotic liver diseases

2020 ◽  
Vol 35 (2) ◽  
pp. 113-118
Author(s):  
Hye Jin Cho ◽  
Jae Young Jang ◽  
Tae Min Kim
Keyword(s):  
Hepatic Stellate Cells ◽  
Liver Diseases ◽  
Stellate Cells ◽  
Fibrotic Liver

scholarly journals Hepatic stellate cells-specific Loxl1 deficiency abrogates hepatic inflammation, fibrosis, and corrects lipid metabolic abnormalities in non-obese NASH mice

2021 ◽  
Author(s):  
Aiting Yang ◽  
Xuzhen Yan ◽  
Xu Fan ◽  
Yiwen Shi ◽  
Tao Huang ◽  
...  
Keyword(s):  
Hepatic Stellate Cells ◽  
Therapeutic Strategy ◽  
Potential Role ◽  
Lysyl Oxidase ◽  
Control Diet ◽  
Stellate Cells ◽  
Metabolic Abnormalities ◽  
Deficient Mice ◽  
Specific Deletion

Abstract Background & Aims: Lysyl oxidase-like-1 (LOXL1), a vital crosslinking enzyme in extracellular matrix (ECM) protein maintenance, is well established in fibrosis via mediating ECM stabilization. However, the potential role of LOXL1 in the pathogenesis of nonalcoholic steatohepatitis (NASH) has not been previously studied.Methods: We generated Loxl1fl/fl mice to selectively delete Loxl1 in hepatic stellate cells (HSCs) (Loxl1fl/flGfapcre; Loxl1fl/fl as littermate controls) and then examined liver pathology and metabolic context in Loxl1fl/flGfapcre fed a choline-deficient L-amino acid-defined (CDAA) diet or an isocaloric control diet for 16 weeks. We confirmed study findings in 23 patients with biopsy-proven NAFLD.Results: LOXL1 was significantly increased in CDAA induced non-obese NASH compared with control diet. Here, utilizing a HSCs-specific deletion of Loxl1 model, we found that Loxl1 deficient in HSCs ameliorated CDAA-induced inflammation and fibrosis, with reduced expression of pro-inflammation and pro-fibrogenic genes. Interestingly, CDAA-fed Loxl1 deficient mice was associated with improved body weight and attenuated hepatic steatosis and to an up-regulation of leptin in adipose tissue and in serum, without changes in hepatic lipogenesis gene expression, compared with CDAA-fed control mice. Most importantly, analyses of serum LOXL1 and leptin levels from NAFLD patients revealed that LOXL1 was positively correlated with histological fibrosis progression, whereas was inversely correlated with leptin levels, especially in non-obese NAFLD patients.Conclusion: In a mouse model of CDAA-induced non-obese NASH, selective deletion of Loxl1 from HSCs attenuated steatohepatitis, hepatic fibrosis and improved lipid metabolic abnormalities. Hence, LOXL1 inhibition may serve as a new therapeutic strategy for NASH.

scholarly journals Hepatitis C Virus-Infected Apoptotic Hepatocytes Program Macrophages and Hepatic Stellate Cells for Liver Inflammation and Fibrosis Development: Role of Ethanol as a Second Hit

Biomolecules ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 113 ◽  
Author(s):  
Murali Ganesan ◽  
Larisa Poluektova ◽  
Chijioke Enweluzo ◽  
Kusum Kharbanda ◽  
Natalia Osna
Keyword(s):  
Lipid Peroxidation ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hepatic Stellate Cells ◽  
Parenchymal Cell ◽  
Human Monocyte ◽  
Stellate Cells ◽  
Liver Inflammation ◽  
Parenchymal Cells

Hepatocyte apoptosis is a crucially important mechanism for liver disease pathogenesis, and the engulfment of apoptotic bodies (AB) by non-parenchymal cells serves as a leading mechanism of inflammation and fibrosis progression. Previously, we have shown that hepatitis C virus (HCV) and alcohol metabolites induce massive apoptosis in hepatocytes and the spread of HCV-infection to the neighboring uninfected cells. Here, we hypothesize that the capturing of AB by non-parenchymal cells, macrophages and hepatic stellate cells (HSC) changes their phenotype to promote inflammation and fibrosis. In this regard, we generated AB from Huh7.5CYP2E1 (RLW) cells also treated with an acetaldehyde-generating system (AGS) and incubated them with human monocyte-derived macrophages (MDMs) and HSC (LX2 cells). Activation of inflammasomes and pro-fibrotic markers has been tested by RT-PCR and linked to HCV expression and AGS-induced lipid peroxidation in RLW cells. After exposure to AB we observed activation of inflammasomes in MDMs, with a higher effect of AB HCV+, further enhanced by incubation of MDMs with ethanol. In HSC, activation of inflammasomes was modest; however, HCV and AGS exposure induced pro-fibrotic changes. We conclude that HCV as well as lipid peroxidation-adducted proteins packaged in AB may serve as a vehicle for delivery of parenchymal cell cargo to non-parenchymal cells to activate inflammasomes and pro-fibrotic genes and promote liver inflammation and fibrosis.

scholarly journals Wnt/?-Catenin Signalling during Liver Metabolism, Chronic Liver Disease and Hepatocarcinogenesis

2018 ◽  
Vol 2 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Gayatri D Shirolkar ◽  
Sara Pasic ◽  
Jully Gogoi-Tiwari ◽  
Manoj K Bhat ◽  
John K Olynyk ◽  
...  
Keyword(s):  
Hepatic Stellate Cells ◽  
Liver Diseases ◽  
Hepatic Metabolism ◽  
Stellate Cells ◽  
Chronic Liver ◽  
Chronic Liver Diseases ◽  
Global Challenges ◽  
End Stage

Chronic liver diseases (CLDs) are increasing in prevalence and their end-stage complications, namely, cirrhosis, liver failure and hepatocellular carcinoma represent major global challenges. The most common initiators of progressive CLD are viral hepatitis and long-term alcohol abuse as well as steatosis and steatohepatitis. Irrespective of the underlying aetiology, a common feature of CLD is the formation of hepatic ductular reactions, involving the proliferation of liver progenitor cells (LPCs) and their signalling to fibrosis-driving hepatic stellate cells. The Wnt/?-catenin pathway has been found to regulate development, stemness and differentiation, and alterations in its activity have been associated with tumour development. Recent data highlight the role of Wnt/?-catenin signalling in hepatic metabolism, steatosis and cancer, and suggest targeting of this pathway as a promising molecular strategy to potentially inhibit CLD progression and hepatocarcinogenesis.

scholarly journals Generation of liver organoids by 3D co-culturing of hepatocytes, hepatic stellate cells, and liver sinusoidal endothelial cells

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Sean C. Mulligan, MS1 ◽  
Wenjun Zhang, PhD ◽  
Lester J. Smith, PhD ◽  
Erika Gramelspacher, BS ◽  
Ping Li, PhD ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Hepatic Stellate Cells ◽  
Liver Diseases ◽  
Culture Media ◽  
Stellate Cells ◽  
Liver Sinusoidal Endothelial Cells ◽  
Sinusoidal Endothelial Cells ◽  
Condition Optimization ◽  
Liver Organoids

Background and Hypothesis: Recent progress with combination of chemicals in cell culture media prolongs hepatocyte (HC) function in vitro. However, without other cells of hepatic lineage that comprise natural liver, HC alone are not suitable for the study of complex liver diseases. Hepatic stellate cells (HSC) and liver sinusoidal endothelial cells (LSEC) play vital roles in physiological and pathological liver function in situ. We hypothesized that coculturing primary HC with HSC and LSEC as 3D liver organoids in the same chemical conditioned media would uphold HC function over time, creating a better physiological 3D liver microenvironment for liver disease research. Experimental Design: Freshly thawed primary human HCs were combined with immortalized human HSC alone, or together with immortalized human LSECs, to generate 3D liver spheroids. Spheroids were formed in HC maintenance media (HMM, Lonza) using low adhesion 96-well plates for 6 days before switching to the media with different combination of chemicals (SB31542, Forskolin, IWP2, DAPT, and LDN193189) for culturing another 14 days. Spheroids characterization, albumin secretion, mRNA transcription (CYP3A4), and histological analysis were performed for HC differentiation, maturation, and function. Results: Both co-cultures of HC:HSC (2.5:1 ratio), and HC:HSC:LSEC (2.5:1:1) formed spheroids in HMM within 4 to 6 days (Fig.1A). The introduction of the different chemical-based media affected the roundness and diameter of spheroids differently (Fig.1B). In the presence of all 5 chemicals (5C), HC function was better maintained up to 21 days in HC:HSC:LSEC spheroids, measured by albumin, CYP3A4, and CK-19 secretion (Fig.1C). Surprisingly, 5C-based media significantly upregulated the expression of CK-19, which is one of the markers for cholangiocytes and liver precursor cells. Conclusion and Potential Impact: 3D liver organoids composed of HC, HSC, and LSEC would create a niche environment mimicking the in vivo condition. Optimization of complex hepatic spheroids, as well as optimization of complex hepatic spheroid culturing media, would allow for the generation of a unique model for studying complex liver diseases.

Neurotoxic and Neuroprotective Role of Exosomes in Parkinson’s Disease

2020 ◽  
Vol 25 (42) ◽  
pp. 4510-4522 ◽  
Author(s):  
Biancamaria Longoni ◽  
Irene Fasciani ◽  
Shivakumar Kolachalam ◽  
Ilaria Pietrantoni ◽  
Francesco Marampon ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Potential Role ◽  
Current Knowledge ◽  
Biological Fluids ◽  
Cell Communication ◽  
Target Cells ◽  
Cellular Debris ◽  
The Brain

: Exosomes are extracellular vesicles produced by eukaryotic cells that are also found in most biological fluids and tissues. While they were initially thought to act as compartments for removal of cellular debris, they are now recognized as important tools for cell-to-cell communication and for the transfer of pathogens between the cells. They have attracted particular interest in neurodegenerative diseases for their potential role in transferring prion-like proteins between neurons, and in Parkinson’s disease (PD), they have been shown to spread oligomers of α-synuclein in the brain accelerating the progression of this pathology. A potential neuroprotective role of exosomes has also been equally proposed in PD as they could limit the toxicity of α-synuclein by clearing them out of the cells. Exosomes have also attracted considerable attention for use as drug vehicles. Being nonimmunogenic in nature, they provide an unprecedented opportunity to enhance the delivery of incorporated drugs to target cells. In this review, we discuss current knowledge about the potential neurotoxic and neuroprotective role of exosomes and their potential application as drug delivery systems in PD.

scholarly journals Mitochondrial Mechanisms of Apoptosis and Necroptosis in Liver Diseases

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Qingfei Chu ◽  
Xinyu Gu ◽  
Qiuxian Zheng ◽  
Jing Wang ◽  
Haihong Zhu
Keyword(s):  
Cell Death ◽  
Liver Cirrhosis ◽  
Liver Disease ◽  
Programmed Cell Death ◽  
Liver Diseases ◽  
Current Knowledge ◽  
Therapeutic Strategies ◽  
Cellular Energetics ◽  
Liver Cell Death

In addition to playing a pivotal role in cellular energetics and biosynthesis, mitochondrial components are key operators in the regulation of cell death. In addition to apoptosis, necrosis is a highly relevant form of programmed liver cell death. Differential activation of specific forms of programmed cell death may not only affect the outcome of liver disease but may also provide new opportunities for therapeutic intervention. This review describes the role of mitochondria in cell death and the mechanism that leads to chronic liver hepatitis and liver cirrhosis. We focus on mitochondrial-driven apoptosis and current knowledge of necroptosis and discuss therapeutic strategies for targeting mitochondrial-mediated cell death in liver diseases.

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