Role Of Pancreatic Stellate Cells Research Articles

"The Role of Pancreatic Stellate Cells in the Repair of Pancreatic Injury"

"The Role of Pancreatic Stellate Cells in the Repair of Pancreatic Injury"

Targeting pancreatic stellate cells in chronic pancreatitis: Focus on therapeutic drugs and natural compounds.

Chronic pancreatitis (CP) is a precancerous illness linked to pancreatic ductal adenocarcinoma (PDAC), although the evolutionary mechanism is uncertain. CP is distinguished by severe fibrosis caused by the activation of pancreatic stellate cells (PSCs). The current clinical therapeutic protocol for CP lacks specific therapeutic medicines for the prevention and suppression of inflammation and fibrosis aggravating in CP. More research on specifically targeting PSCs would help facilitate the development of novel therapies for pancreatic fibrosis. Notably, using natural compounds from medicinal plants as new antifibrotic agents has become a focus of recent research and is widely employed as an alternative and complementary approach. Our goal was to shed light on the role of PSCs in the development of CP and provide a focused update on the new potential therapeutic strategies against PSCs in CP models. Future studies can refer to these possible strategies for drug design, bioavailability, pharmacokinetics, and other issues to obtain better clinical outcomes for treating CP.

Activated Stellate Cell Paracrine HGF Exacerbated Pancreatic Cancer Cell Ferroptosis Resistance.

As a refractory tumor, pancreatic carcinoma is more vulnerable to ferroptosis, a novel regulated cell death mode. However, the exact role of pancreatic stellate cells (PSCs) in pancreatic cancer ferroptosis is still unclear. Using the coculture system, we revealed that activated PSCs promote pancreatic cancer cell ferroptosis resistance. Mechanistically, activated PSCs secreted HGF, which further activated the HGF receptor, c-MET, in pancreatic cancer cells, prevented lipid peroxidation, and ultimately triggered pancreatic cancer cell ferroptosis resistance in vitro and in vivo. TCGA and GEPIA databases also revealed a strong correlation between c-MET and antiferroptosis indicators. Our study supplied the evidence for the cross-talk between activated PSCs and pancreatic cancer cells in ferroptosis, which suggested a strategy to inhibit PSC paracrine signaling for preventing pancreatic carcinoma ferroptosis resistance.

Pancreatic Stellate Cells Prolong Ex Vivo Islet Viability and Function and Improve Engraftment.

Preserving islet health and function is critical during pretransplant culture to improve islet transplantation outcome and for ex vivo modeling of diabetes for pharmaceutical drug discovery. The limited islet engraftment potential is primarily attributable to loss of extracellular matrix (ECM) support and interaction. Multipotent cells with ECM depositing competency improve islet survival during short coculture period. However, role of pancreatic stellate cells (PSCs) and their ECM support in preserving ex vivo islet physiology remains largely unknown. Here, we report novel cytoprotective effects of culture-adapted porcine PSCs and role of their ECM-mediated intercellular communication on pig, mouse and human islets ex vivo. Using direct-contact coculture system, we demonstrate that porcine PSCs preserve and significantly prolong islet viability and function from 7 ± 3 days to more than 28 ± 5 (P < .001) days in vitro. These beneficial effects of PSCs on islet health are not species-specific. Using NSC47924 to specifically inhibit 37/67 kDa laminin receptor (LR), we identified that LR-mediated intercellular communication is essential for PSCs to protect functional viability of islets in vitro. Finally, our results demonstrate that PSC co-transplantation improved function and enhanced capacity of syngeneic islets to reverse hyperglycemia in mice with preexisiting diabetes. Cumulatively, our findings unveil novel effects of culture-adapted PSCs on islet health likely mirroring in vivo niche interaction. Furthermore, islet and PSC coculture may aid in development of ex vivo diabetes modeling and also suggests that a combined islet-PSC tissue engineered implant may significantly improve islet transplantation outcome.

Histological Structure of Pancreas in Chronic Pancreatitis and The Role of Pancreatic Stellate Cells

Background: Chronic pancreatitis is a progressive inflammatory disease that causes damage and fibrosis of the parenchyma of pancreas, thus leads to endocrine and exocrine dysfunction. Objective: The goals of this review were to analyze morphological alterations in pancreatic tissue during chronic pancreatitis and this analysis addresses the effect of pancreatic stellate cells (PSCs), on chronic pancreatitis, and collagen fiber deposition. Results: This review also discussed the different immunohistochemical markers for PSCs. Alpha smooth muscle actin (α-SMA) is an excellent marker for activated PSCs. Transforming growth factor beta (TGFβ) is an important profibrogenic cytokine that appears to act by stimulating collagen production by PSCs. Conclusion: It was concluded that chronic pancreatitis caused a significant and progressive serious effects on the acinar cells, duct system, and islets of Langerhans in the form of intracellular vacuolations, decreased zymogen granules, pyknotic nuclei and thickening of the duct wall, and extensive fibrosis. It is hypothesised that during pancreatic injury, PSCs are activated and proliferated exhibiting positive staining for the cytoskeletal protein α- SMA, and synthesising amounts of extracellular matrix proteins, particularly collagen.

Cold Atmospheric Plasma Treatment for Pancreatic Cancer-The Importance of Pancreatic Stellate Cells.

Simple SummaryThis review aims to highlight the potential of cold plasma, the fourth state of matter, as anti-cancer treatment for pancreatic cancer, and the importance of pancreatic stellate cells in the response to this treatment. Currently, a significant lack of basic research on cold plasma considering both pancreatic cancer and stellate cells exists. However, co-cultures of these populations can be advantageous, as they resemble the cell-to-cell interactions occurring in a tumor in response to therapy. Even more, these studies should be performed prior to clinical trials of cold plasma to avoid unforeseen responses to treatment. This review article provides a framework for future research of cold plasma therapies for pancreatic cancer, considering the critical role of pancreatic stellate cells in the disease and treatment outcome.Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with low five-year survival rates of 8% by conventional treatment methods, e.g., chemotherapy, radiotherapy, and surgery. PDAC shows high resistance towards chemo- and radiotherapy and only 15–20% of all patients can have surgery. This disease is predicted to become the third global leading cause of cancer death due to its significant rise in incidence. Therefore, the development of an alternative or combinational method is necessary to improve current approaches. Cold atmospheric plasma (CAP) treatments could offer multiple advantages to this emerging situation. The plasma-derived reactive species can induce oxidative damage and a cascade of intracellular signaling pathways, which could lead to cell death. Previous reports have shown that CAP treatment also influences cells in the tumor microenvironment, such as the pancreatic stellate cells (PSCs). These PSCs, when activated, play a crucial role in the propagation, growth and survival of PDAC tumors. However, the effect of CAP on PSCs is not yet fully understood. This review focuses on the application of CAP for PDAC treatment and the importance of PSCs in the response to treatment.

Multifunctional role of pancreatic stellate cells in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths with a dismal 5-year survival rate of only 8%. PDAC is characterised by extensive desmoplasia constituting about 50–80% of the tumour volume. Activated pancreatic stellate cells (PSC) are the major cellular source for stromal collagen; these cells drive pancreatic fibrosis and progression of PDAC. PSC are known to be activated by paracrine signals from several sources including injured epithelium, cancer cells, extracellular matrix, immune cells and nerve cells. Stromal-tumour interactions are now recognised as key processes in the development and progression of PDAC. Improved understanding of the mechanisms underlying stromal-tumour interactions may be the key for the discovery of new therapeutic targets in PDAC. This review summarises current knowledge regarding the role of PSCs in cancer biology and discusses the potential for development of novel therapeutic approaches targeting factors such as dysregulated signalling pathways, the stromal reaction itself and epigenetic changes in stromal and/or cancer cells.

Role of stellate cells in the morphogenesis of chronic pancreatitis

This review presents an analysis of the literature on the role of pancreatic stellate cells (PSCs) in the pathogenesis of fibrosis, a predominant histological feature of chronic alcoholic pancreatitis. It is shown that ethanol and toxic products of its metabolism can affect PSCs directly and indirectly, facilitating their transformation from a quiescent to an activated state. During the pathological process, PSCs interact with parenchymal and immune cells of the pancreas through cytokines and growth factors. In activated PSCs, the proliferative and migratory activity, as well as the synthesis of extracellular matrix (ECM) proteins increases. A continuous activation of PSCs during the disease promotes the maintenance of inflammation, the deposition of excessive amounts of ECM proteins and the development of pancreatic fibrosis.

A role of pancreatic stellate cells in islet fibrosis and β-cell dysfunction in type 2 diabetes mellitus

ObjectivesTo investigate whether the activation of pancreatic stellate cells (PSCs) leads to pancreatic β-cell dysfunction in type 2 diabetes mellitus (T2DM). MethodsThe pancreases of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of T2DM, and patient with T2DM were analyzed. And the in vitro and in vivo effects of pirfenidone, an antifibrotic agent, on PSC activation, islet fibrosis, and β-cells were studied. ResultsThe extent of islet fibrosis and the percentage of activated PSCs, positive for α-smooth muscle actin, in the islets were significantly greater in OLETF rats compared with non-diabetic rats. Also, the extent of islet fibrosis in patients with T2DM was slightly greater compared with age- and BMI-matched non-diabetic patients. In rat PSCs cultured with high glucose for 72 h, pirfenidone produced decreases in cell proliferation, release of collagen, and the expression of fibronectin and connective tissue growth factor. Treatment of OLETF rats with pirfenidone for 16 weeks decreased the activation of PSCs and the extent of islet fibrosis, but did not enhance glucose tolerance, pancreatic insulin content, or β-cell mass. ConclusionsActivated PSCs in islets might lead to islet fibrosis in T2DM. However, PSC activation itself might not contribute significantly to progressive β-cell failure in T2DM.

Pancreatic stellate cell: Pandora's box for pancreatic disease biology.

Pancreatic stellate cells (PSCs) were identified in the early 1980s, but received much attention after 1998 when the methods to isolate and culture them from murine and human sources were developed. PSCs contribute to a small proportion of all pancreatic cells under physiological condition, but are essential for maintaining the normal pancreatic architecture. Quiescent PSCs are characterized by the presence of vitamin A laden lipid droplets. Upon PSC activation, these perinuclear lipid droplets disappear from the cytosol, attain a myofibroblast like phenotype and expresses the activation marker, alpha smooth muscle actin. PSCs maintain their activated phenotype via an autocrine loop involving different cytokines and contribute to progressive fibrosis in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). Several pathways (e.g., JAK-STAT, Smad, Wnt signaling, Hedgehog etc.), transcription factors and miRNAs have been implicated in the inflammatory and profibrogenic function of PSCs. The role of PSCs goes much beyond fibrosis/desmoplasia in PDAC. It is now shown that PSCs are involved in significant crosstalk between the pancreatic cancer cells and the cancer stroma. These interactions result in tumour progression, metastasis, tumour hypoxia, immune evasion and drug resistance. This is the rationale for therapeutic preclinical and clinical trials that have targeted PSCs and the cancer stroma.

Human pancreatic stellate cells modulate 3D collagen alignment to promote the migration of pancreatic ductal adenocarcinoma cells.

A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the ability for cancer cells to aggressively infiltrate and navigate through a dense stroma during the metastatic process. Key features of the PDAC stroma include an abundant population of activated pancreatic stellate cells (PSCs) and highly aligned collagen fibers; however, important questions remain regarding how collagen becomes aligned and what the biological manifestations are. To better understand how PSCs, aligned collagen, and PDAC cells might cooperate during the transition to invasion, we utilized a microchannel-based in vitro tumor model and advanced imaging technologies to recreate and examine in vivo-like heterotypic interactions. We found that PSCs participate in a collaborative process with cancer cells by orchestrating the alignment of collagen fibers that, in turn, are permissive to enhanced cell migration. Additionally, direct contact between PSCs, collagen, and PDAC cells is critical to invasion and co-migration of both cell types. This suggests PSCs may accompany and assist in navigating PDAC cells through the stromal terrain. Together, our data provides a new role for PSCs in stimulating the metastatic process and underscores the importance of collagen alignment in cancer progression.

Key role of pancreatic stellate cells in pancreatic cancer

Pancreatic stellate cells (PSCs) are responsible for producing the collagenous stroma in pancreatic cancer. Findings from the majority of in vitro and in vivo studies to date indicate that PSCs interact with cancer cells as well as with other cellular elements in the stroma including immune cells, endothelial cells and neuronal cells to set up a growth permissive microenvironment for pancreatic tumours. However, two recent studies reporting a protective effect of myofibroblasts in pancreatic cancer have served to remind researchers of the possibility that the role of PSCs in this disease may be context and time-dependent, such that any possible early protective role of PSCs is subverted in later stages by the ability of cancer cells to turn PSCs into cancer-promoting aides. This concept is supported by the development in recent years of several novel therapeutic approaches targeting the stroma that have been successfully applied in pre-clinical settings to inhibit disease progression. A multi-pronged approach aimed at tumour cells as well as stromal elements may be the key to achieving better clinical outcomes in patients with pancreatic cancer.

Pancreatic stellate cell

Ever since the first descriptions of methods to isolate pancreatic stellate cells (PSCs) from rodent and human pancreas 17 years ago, rapid advances have been made in our understanding of the biology of these cells and their functions in health and disease. This review updates recent literature in the field, which indicates an increasingly complex role for the cells in normal pancreas, pancreatitis and pancreatic cancer. Work reported over the past 12 months includes improved methods of PSC immortalization, a role for PSCs in islet fibrosis, novel factors causing PSC activation as well as those inducing quiescence, and translational research aimed at inhibiting the facilitatory effects of PSCs on disease progression in chronic pancreatitis as well as pancreatic cancer. Improved understanding of the role of PSCs in pancreatic pathophysiology has prompted a focus on translational studies aimed at developing novel approaches to modulate PSC function in a bid to improve clinical outcomes of two major fibrotic diseases of the pancreas: chronic pancreatitis and pancreatic cancer.

Chronic Hyperglycemia Induces Trans-Differentiation of Human Pancreatic Stellate Cells and Enhances the Malignant Molecular Communication with Human Pancreatic Cancer Cells

BackgroundDiabetes mellitus is linked to pancreatic cancer. We hypothesized a role for pancreatic stellate cells (PSC) in the hyperglycemia induced deterioration of pancreatic cancer and therefore studied two human cell lines (RLT-PSC, T3M4) in hyperglycemic environment.Methodology/Principal FindingsThe effect of chronic hyperglycemia (CHG) on PSCs was studied using mRNA expression array with real-time PCR validation and bioinformatic pathway analysis, and confirmatory protein studies. The stress fiber formation (IC: αSMA) indicated that PSCs tend to transdifferentiate to a myofibroblast-like state after exposure to CHG. The phosphorylation of p38 and ERK1/2 was increased with a consecutive upregulation of CDC25, SP1, cFOS and p21, and with downregulation of PPARγ after PSCs were exposed to chronic hyperglycemia. CXCL12 levels increased significantly in PSC supernatant after CHG exposure independently from TGF-β1 treatment (3.09-fold with a 2.73-fold without TGF-β1, p<0.05). The upregualtion of the SP1 transcription factor in PSCs after CHG exposure may be implicated in the increased CXCL12 and IGFBP2 production. In cancer cells, hyperglycemia induced an increased expression of CXCR4, a CXCL12 receptor that was also induced by PSC’s conditioned medium. The receptor-ligand interaction increased the phosphorylation of ERK1/2 and p38 resulting in activation of MAP kinase pathway, one of the most powerful stimuli for cell proliferation. Certainly, conditioned medium of PSC increased pancreatic cancer cell proliferation and this effect could be partially inhibited by a CXCR4 inhibitor. As the PSC conditioned medium (normal glucose concentration) increased the ERK1/2 and p38 phosphorylation, we concluded that PSCs produce other factor(s) that influence(s) pancreatic cancer behaviour.ConclusionsHyperglycemia induces increased CXCL12 production by the PSCs, and its receptor, CXCR4 on cancer cells. The ligand-receptor interaction activates MAP kinase signaling that causes increased cancer cell proliferation and migration.

Role of pancreatic stellate cells and periostin in pancreatic cancer progression.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and one of the five most lethal malignancies characterized by prominent desmoplastic reaction. Accumulating evidences indicate that tumor desmoplasia plays a pivotal role in PDAC progression, and it has been largely ignored until recent times. It has now been unequivocally shown that pancreatic stellate cells (PSCs) are the principal effector cells responsible for stroma production. Periostin, also known as osteoblast-specific factor 2, is a secretory protein and originally identified as an osteoblast-specific factor that expressed in periosteum. Periostin is exclusively produced by activated PSCs, and periostin overexpression presents in various malignant tumors and closely relates with disease progression. In addition, periostin has been suggested to stimulate pancreatic cancer cells proliferation and enhance their resistance to serum starvation and hypoxia. Therefore, the interplay between cancer cells and stromal cells plays a vital role in PDAC development. However, the function of periostin in pancreatic cancer development is controversial. This review summarizes existing knowledge about the role of PSCs in cancer stroma production, the interaction between PSCs and pancreatic cancer cells, tumor angiogenesis, and hypoxic microenvironment, with particular focus on the expression and function as well as signaling pathways of periostin in PDAC cells and PSCs.

HES 1 is essential for chemoresistance induced by stellate cells and is associated with poor prognosis in pancreatic cancer.

The role of pancreatic stellate cells (PSCs) has been established in many studies. However, the potential mechanism for the chemoresistance induced by PSCs has not been fully elucidated. In the present study, human pancreatic cancer cell lines were directly or indirectly co-cultured with PSCs. The inhibition rate and IC50 values were assessed to determine the ability of chemoresistance. RT-PCR and western blot analysis were used to evaluate Hes 1 and Jagged 1 expression before and after co-culture with PSCs. To determine the relationship between Hes 1 expression and survival in pancreatic cancer patients, Kaplan-Meier survival analysis was performed. PSCs promoted the expression of Hes 1 in both PANC-1 and BxPC-3 cell lines and induced chemoresistance to gemcitabine. A Notch signaling pathway inhibitor (L1790) and Hes 1 siRNA reversed the chemoresistance induced by PSCs. In 72resected pancreatic cancer patients, high Hes 1 expression was observed in 34patients with shorter overall and progression-free survival times. In conclusion, Hes 1 is essential for chemoresistance induced by PSCs and is associated with poor prognosis in pancreatic cancer patients. Therapy targeting the Notch signaling pathway may reverse chemoresistance and improve survival in patients with pancreatic cancer.

The role of pancreatic stellate cells in pancreas regeneration in copper-deficient diet model in rats

The role of pancreatic stellate cells in pancreas regeneration in copper-deficient diet model in rats

Oxidative stress and proinflammatory role of pancreatic stellate cells in response to tobacco and alcohol

s / Pancreatolog S54 Aims: To investigate the effects of LPS and hyperglycemia on PSC activation and effects of simvastatin on LPS induced PSC activation. Materials & methods: Primary cultures of rat PSCs were exposed to various concentrations of glucose and LPS with/without simvastatin. Quantification of proliferation was performed by Brd-U assay. PSC activation was assessed by expression of a-SMA and extracellular signal-regulated kinase (ERK) using Western blot. Results: LPS induced activation and proliferation of PSC. However, glucose did not affect PSC proliferation. The proliferative effect of LPS on PSC was not affected by glucose concentration in culture media. Simvastatin inhibited LPS induced activation and proliferation of PSC. The proliferative effect of LPS was mediated by activation of Erk 1/2 pathwaywhich was effectively inhibited by simvastatin. Conclusion: This study shows that LPS is one of the activating factors toward PSC. Endotoxemia which is frequently encountered in the clinical settings of acute and chronic pancreatitis may act as a triggering factor for initiating and persisting pancreatic fibrosis. Simvastain could be a therapeutic agent for preventing pancreatic fibrosis.

Role of pancreatic stellate cells in chemoresistance in pancreatic cancer.

Pancreatic cancer is highly chemoresistant. A major contributing factor is the characteristic extensive stromal or fibrotic reaction, which comprises up to 90% of the tumor volume. Over the last decade there has been intensive research into the role of the pro-fibrogenic pancreatic stellate cells (PSCs) and their interaction with pancreatic cancer cells. As a result of the significant alterations in the tumor microenvironment following activation of PSCs, tumor progression, and chemoresistance is enhanced. This review will discuss how PSCs contribute to chemoresistance in pancreatic cancer.

Pancreatic cancer and its stroma: a conspiracy theory.

Pancreatic cancer is characterised by a prominent desmoplastic/stromal reaction that has received little attention until recent times. Given that treatments focusing on pancreatic cancer cells alone have failed to significantly improve patient outcome over many decades, research efforts have now moved to understanding the pathophysiology of the stromal reaction and its role in cancer progression. In this regard, our Group was the first to identify the cells (pancreatic stellate cells, PSCs) that produced the collagenous stroma of pancreatic cancer and to demonstrate that these cells interacted closely with cancer cells to facilitate local tumour growth and distant metastasis. Evidence is accumulating to indicate that stromal PSCs may also mediate angiogenesis, immune evasion and the well known resistance of pancreatic cancer to chemotherapy and radiotherapy. This review will summarise current knowledge regarding the critical role of pancreatic stellate cells and the stroma in pancreatic cancer biology and the therapeutic approaches being developed to target the stroma in a bid to improve the outcome of this devastating disease.