Hepatic and pancreatic stellate cells in focus

2009 ◽  
Vol 390 (10) ◽  
Author(s):  
Claus Kordes ◽  
Iris Sawitza ◽  
Dieter Häussinger
Keyword(s):  
Cell Biology ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Differentiation Potential ◽  
Undifferentiated Cells ◽  
Cell Niche ◽  
Space Of Disse

Abstract Stellate cells are vitamin A-storing cells of liver and pancreas and have been described in all vertebrates ranging from lampreys (primitive fish) to humans, demonstrating their major importance. This cell type is thought to contribute to fibrosis, a condition characterized by an excess deposition of extracellular matrix proteins. Recently, the expression of stem/progenitor cell markers, such as CD133 (prominin-1) and Oct4, was discovered in hepatic stellate cells (HSCs) of rats. Moreover, HSCs possess signaling pathways important for maintenance of stemness and cell differentiation, such as hedgehog, β-catenin-dependent Wnt, and Notch signaling, and are resistant to CD95-mediated apoptosis. In analogy to a stem cell niche, some characteristics of quiescent HSC are maintained by aid of a special microenvironment located in the space of Dissé. Finally, stellate cells display a differentiation potential as investigated in vitro and in vivo. Collectively all these properties are congruently found in stem/progenitor cells and support the concept that stellate cells are undifferentiated cells, which might play an important role in liver regeneration. The present review highlights findings related to this novel aspect of stellate cell biology.

Isolation of Quiescent Human Pancreatic Stellate Cells: A Promising in vitro Tool for Studies of Human Pancreatic Stellate Cell Biology

Pancreatology ◽  
2010 ◽  
Vol 10 (4) ◽  
pp. 434-443 ◽  
Author(s):  
Alain Vonlaufena ◽  
Phoebe A. Phillipsa ◽  
Lu Yanga ◽  
Zhihong Xua ◽  
Eva Fiala-Beera ◽  
...  
Keyword(s):  
Cell Biology ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Pancreatic Stellate Cell

scholarly journals ITGA5 inhibition in pancreatic stellate cells attenuates desmoplasia and potentiates efficacy of chemotherapy in pancreatic cancer

2019 ◽  
Vol 5 (9) ◽  
pp. eaax2770 ◽  
Author(s):  
Praneeth R. Kuninty ◽  
Ruchi Bansal ◽  
Susanna W. L. De Geus ◽  
Deby F. Mardhian ◽  
Jonas Schnittert ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Tumor Stroma ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Tumor Penetration ◽  
Desmoplastic Stroma ◽  
Integrin Α5

Abundant desmoplastic stroma is the hallmark for pancreatic ductal adenocarcinoma (PDAC), which not only aggravates the tumor growth but also prevents tumor penetration of chemotherapy, leading to treatment failure. There is an unmet clinical need to develop therapeutic solutions to the tumor penetration problem. In this study, we investigated the therapeutic potential of integrin α5 (ITGA5) receptor in the PDAC stroma. ITGA5 was overexpressed in the tumor stroma from PDAC patient samples, and overexpression was inversely correlated with overall survival. In vitro, knockdown of ITGA5 inhibited differentiation of human pancreatic stellate cells (hPSCs) and reduced desmoplasia in vivo. Our novel peptidomimetic AV3 against ITGA5 inhibited hPSC activation and enhanced the antitumor effect of gemcitabine in a 3D heterospheroid model. In vivo, AV3 showed a strong reduction of desmoplasia, leading to decompression of blood vasculature, enhanced tumor perfusion, and thereby the efficacy of gemcitabine in co-injection and patient-derived xenograft tumor models.

Influence of caveolin on constitutively activated recombinant eNOS: insights into eNOS dysfunction in BDL rat liver

2003 ◽  
Vol 285 (3) ◽  
pp. G652-G660 ◽  
Author(s):  
H. Hendrickson ◽  
S. Chatterjee ◽  
S. Cao ◽  
M. Morales Ruiz ◽  
W. C. Sessa ◽  
...  
Keyword(s):  
Rat Liver ◽  
Hepatic Stellate Cells ◽  
Fluorescent Protein ◽  
Stellate Cell ◽  
Active Form ◽  
Stellate Cells ◽  
Liver Cells ◽  
No Production

Diminished endothelial nitric oxide (NO) synthase (eNOS)-derived NO production from the hepatic vascular endothelium contributes to hepatic vasoconstriction in portal hypertension. The aim of this study was to examine the mechanism of this process by testing the influence of a constitutively active form of eNOS (S1179DeNOS) in both primary and propagated liver cells in vitro and in the sham and bile duct ligated (BDL) rat liver in vivo, using an adenoviral vector encoding green fluorescent protein (AdGFP) and S1179DeNOS (AdS1179DeNOS). AdS1179DeNOS transduction augmented basal and agonist-stimulated NO generation in nonparenchymal liver cells. Sham rats transduced in vivo with AdS1179DeNOS evidenced a decreased pressor response to incremental doses of the vasoconstrictor methoxamine compared with sham rats transduced with AdGFP. However, BDL rats transduced with AdS1179DeNOS did not display improved vasodilatory responses as evidenced by similar flow-dependent pressure increases to that observed in BDL rats transduced with AdGFP, despite similar levels of viral transgene expression. We next examined the influence of the eNOS inhibitory protein caveolin on S1179DeNOS dysfunction in cirrhotic liver. Immunogold electron microscopic analysis of caveolin in BDL liver demonstrated prominent expression not only in liver endothelial cells, but also in hepatic stellate cells. In vitro studies in the LX2 hepatic stellate cell line demonstrate that caveolin precipitates recombinant S1179DeNOS in LX2 cells, that recombinant S1179DeNOS coprecipitates caveolin, and that binding is enhanced in the presence of overexpression of caveolin. Furthermore, caveolin overexpression inhibits recombinant S1179DeNOS activity. These studies indicate that recombinant S1179DeNOS protein functions appropriately in normal liver cells and tissue but evidences dysfunction in the cirrhotic rat liver and that caveolin expression and inhibition in BDL nonparenchymal cells, including hepatic stellate cells, may account for this dysfunction.

scholarly journals High Glucose Aggravates the Detrimental Effects of Pancreatic Stellate Cells on Beta-Cell Function

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Min Zha ◽  
Wei Xu ◽  
Qing Zhai ◽  
Fengfei Li ◽  
Bijun Chen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
High Glucose ◽  
Cell Function ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
High Concentration ◽  
Gk Rats ◽  
Chop Expression

Background and Aims. We here assess the effects of PSCs onβ-cell function and apoptosisin vivoandin vitro.Materials and Methods.PSCs were transplanted into Wistar and Goto-Kakizaki (GK) rats. Sixteen weeks after transplantation,β-cell function, apoptosis, and islet fibrosis were assessed.In vitrothe effects of PSCs conditioned medium (PSCs-CM) and/or high concentration of glucose on INS-1 cell function was assessed by measuring insulin secretion, INS-1 cell survival, apoptosis, and endoplasmic reticulum stress (ER stress) associated CHOP expression.Results. PSCs transplantation exacerbated the impairedβ-cell function in GK rats, but had no significant effects in Wistar rats.In vitro, PSCs-CM caused impaired INS-1 cell viability and insulin secretion and increased apoptosis, which were more pronounced in the presence of high glucose.Conclusion.Our study demonstrates that PSCs induceβ-cell failurein vitroandin vivo.

scholarly journals Pregnenolone-16α-carbonitrile inhibits rodent liver fibrogenesis via PXR (pregnane X receptor)-dependent and PXR-independent mechanisms

2005 ◽  
Vol 387 (3) ◽  
pp. 601-608 ◽  
Author(s):  
Carylyn J. MAREK ◽  
Steven J. TUCKER ◽  
Dimitrios K. KONSTANTINOU ◽  
Lucy J. ELRICK ◽  
Dee HAEFNER ◽  
...  
Keyword(s):  
Carbon Tetrachloride ◽  
Hepatic Stellate Cells ◽  
Stellate Cell ◽  
Direct Interaction ◽  
Pregnane X Receptor ◽  
Stellate Cells ◽  
Liver Growth ◽  
Liver Fibrogenesis

The effect of liver growth stimulation [using the rodent PXR (pregnane X receptor) activator PCN (pregnenolone-16α-carbonitrile)] in rats chronically treated with carbon tetrachloride to cause repeated hepatocyte necrosis and liver fibrogenesis was examined. PCN did not inhibit the hepatotoxicity of carbon tetrachloride. However, transdifferentiation of hepatic stellate cells and the extent of fibrosis caused by carbon tetrachloride treatment was significantly inhibited by PCN in vivo. In vitro, PCN directly inhibited hepatic stellate cell transdifferentiation to a profibrogenic phenotype, although the cells did not express the PXR (in contrast with hepatocytes), suggesting that PCN acts independently of the PXR. Mice with a functionally disrupted PXR gene (PXR−/−) did not respond to the antifibrogenic effects of PCN, in contrast with wild-type (PXR+/+) mice, demonstrating an antifibrogenic role for the PXR in vivo. However, PCN inhibited the transdifferentiation of PXR−/−-derived mouse hepatic stellate cells in vitro, confirming that there is also a PXR-independent antifibrogenic effect of PCN through a direct interaction with hepatic stellate cells. These data suggest that the PXR is antifibrogenic in rodents in vivo and that a PXR-independent target for PXR activators exists in hepatic stellate cells that also functions to inhibit fibrosis.

scholarly journals Targeting integrin alpha5 receptor in pancreatic stellate cells to diminish tumor-promoting effects in pancreatic cancer

2018 ◽  
Author(s):  
Praneeth R. Kuninty ◽  
Ruchi Bansal ◽  
Sanne W.L. De Geus ◽  
Jonas Schnittert ◽  
Joop van Baarlen ◽  
...  
Keyword(s):  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Cancer Associated Fibroblasts ◽  
Poor Overall Survival ◽  
Fibronectin Receptor ◽  
Cancer Aggressiveness ◽  
Novel Therapeutic

AbstractPancreatic stellate cells (PSCs) are the main precursors of cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDAC), known to induce cancer aggressiveness. Integrin alpha5 (ITGA5), a fibronectin receptor, was found to be overexpressed by CAFs in stroma and linked to poor overall survival (log-rank p=0.022, n=137) of patients with PDAC. In vitro, knockdown of ITGA5 in human PSCs (hPSCs) inhibited their adhesion, migration, and proliferation and also inhibited TGF-β-mediated differentiation. In vivo, co-injection of PANC-1 tumor cells and hPSCs (sh-ITGA5) developed tumors with reduced fibrosis and slower growth rate compared to those composed of PANC-1 and hPSC (sh-Ctrl). Furthermore, we developed a ITGA5-antagonizing peptidomimetic (AV3) which inhibited TGFβ-mediated hPSC differentiation by blocking ITGA5/FAK pathway. In vivo, treatment with AV3 intraperitoneally attenuated tumor fibrosis and thereby enhanced the efficacy of gemcitabine in patient-derived xenografts in mice. Altogether, this study reports the therapeutic importance of ITGA5 in PDAC and provides novel therapeutic peptidomimetic to enhance the effect of chemotherapy.

scholarly journals BMP2 inhibits TGF-β-induced pancreatic stellate cell activation and extracellular matrix formation

2013 ◽  
Vol 304 (9) ◽  
pp. G804-G813 ◽  
Author(s):  
Xuxia Gao ◽  
Yanna Cao ◽  
Wenli Yang ◽  
Chaojun Duan ◽  
Judith F. Aronson ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Steady Increase ◽  
Pathological Feature

Activation of pancreatic stellate cells (PSCs) by transforming growth factor (TGF)-β is the key step in the development of pancreatic fibrosis, a common pathological feature of chronic pancreatitis (CP). Bone morphogenetic proteins (BMPs), members of the TGF-β superfamily, have anti-fibrogenic functions, in contrast to TGF-β, in the kidney, lung, and liver. However, it is not known whether BMPs have an anti-fibrogenic role in the pancreas. The current study was designed to investigate the potential anti-fibrogenic role of BMPs in the pancreas using an in vivo CP model and an in vitro PSC model. CP was induced by repetitive intraperitoneal injections of cerulein in adult Swiss Webster mice. The control mice received saline injections. Compared with the control, cerulein injections induced a time-dependent increase in acinar injury and progression of fibrosis and a steady increase in inflammation. Cerulein injections also induced increases of the extracellular matrix (ECM) protein fibronectin and of α-smooth muscle actin (α-SMA)-positive stellate cells (PSCs). The mice receiving cerulein injections showed increased BMP2 protein levels and phosphorylated Smad1 levels up to 4 wk and then declined at 8 wk to similar levels as the control. In vitro, the isolated mouse and human PSCs were cultured and pretreated with BMP2 followed by TGF-β treatment. BMP2 pretreatment inhibited TGF-β-induced α-SMA, fibronectin, and collagen type Ia expression. Knocking down Smad1 with small-interfering RNA reversed the inhibitory effect of BMP2 on TGF-β-induced α-SMA and fibronectin expression. Thus, BMP2 opposes the fibrogenic function of TGF-β in PSCs through the Smad1 signaling pathway.

Evaluation of triptolide pro-drug (Minnelide) as an anti-stromal and anti-tumoral therapeutic option for pancreatic cancer.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 262-262
Author(s):  
Sulagna Banerjee ◽  
Shrey Modi ◽  
Xianda Zhao ◽  
Vikas Dudeja ◽  
Ashok Saluja
Keyword(s):  
Drug Delivery ◽  
Pancreatic Cancer ◽  
Stellate Cell ◽  
Therapeutic Option ◽  
Stellate Cells ◽  
Water Soluble ◽  
Pancreatic Stellate Cells ◽  
Tissue Cell ◽  
Boyden Chamber

262 Background: In pancreatic cancer, the stromal microenvironment is considered to be the major reason behind the failure of conventional and targeted therapy. The desmoplastic stroma is responsible for compression of vasculature in the tumor resulting in impaired drug delivery. Pancreatic stellate cells contribute extensively to this desmoplastic reaction. Our group has recently evaluated a water-soluble pro-drug of triptolide (Minnelide) in pre-clinical studies for pancreatic cancer with very promising results. The current study evaluates the ability of Minnelide to deplete the stromal architecture and the stellate cell population in pancreatic cancer resulting in increased drug delivery. Methods: Patient tumor xenografts in SCID mice (PDX) and KRASG12DTP53-PDX-Cre spontaneous pancreatic tumor mice (KPC) were treated with 0.42mg/kg Minnelide. Vascular patency was studied by terminal perfusion of mice with 4% PFA following injection with tomato lectin. Drug delivery was determined by quantitating accumulated doxorubicin in the tumor tissue. Cell viability was studied by MTT assay and the invasion of cells in vitro was studied using Boyden Chamber assay. Results: Minnelide treatment decreased Hyaluronic acid (HA) in PDX (48% of control) as well as in KPC model (52% of control). Expression of HA synthase (HAS) genes were decreased in both tumor models in response to Minnelide (22% of control in PDX and 35% of control in KPC tumors). HAS Enzyme activity also consistently decreased in both the models after treatment with Minnelide (28% of control in PDX and 31% of control in KPC). In vitro, triptolide decreased the invasion of the tumor cells towards the stellate cells indicating an inhibition of crosstalk. Treatment with Minnelide resulted in “open” and functional vessels in the treated animals resulting in increased drug delivery. Median survival of animals increased by 38 days after treatment with Minnelide. Conclusions: Our study showed that Minnelide depleted the stromal architecture leading to increased functional vasculature and enhanced drug delivery in the tumor. This is an extremely promising observation for Minnelide that is currently under clinical trial.

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