Abstract
The mammalian diffuse stellate cell system comprises retinoid-storing cells capable of remarkable transformations from a quiescent to an activated myofibroblast-like phenotype. Activated pancreatic stellate cells (PSCs) attract attention owing to the pivotal role they play in development of tissue fibrosis in chronic pancreatitis and pancreatic cancer. However, little is known about the actual role of PSCs in the normal pancreas. These enigmatic cells have recently been shown to respond to physiological stimuli in a manner that is markedly different from their neighbouring pancreatic acinar cells (PACs). Here, we demonstrate the capacity of PSCs to generate nitric oxide (NO), a free radical messenger mediating, for example, inflammation and vasodilatation. We show that production of cytosolic NO in PSCs is unambiguously related to cytosolic Ca2+ signals. Only stimuli that evoke Ca2+ signals in the PSCs elicit consequent NO generation. We provide fresh evidence for the striking difference between signalling pathways in PSCs and adjacent PACs, because PSCs, in contrast to PACs, generate substantial Ca2+-mediated and NOS-dependent NO signals. We also show that inhibition of NO generation protects both PSCs and PACs from necrosis. Our results highlight the interplay between Ca2+ and NO signalling pathways in cell–cell communication, and also identify a potential therapeutic target for anti-inflammatory therapies.
Highlights
Mammalian stellate cells (Latin stella—star) are retinoid-storing cells woven into the tissue of various organs [1] including the liver, pancreas, kidney, spleen, lung and vocal folds
It has previously been shown that cytosolic calcium signals can be elicited in cultured [32] and in normal [33] pancreatic stellate cells
This study reveals that these signals are interlinked with cytosolic nitric oxide signals
Summary
Mammalian stellate cells (Latin stella—star) are retinoid-storing cells woven into the tissue of various organs [1] including the liver, pancreas, kidney, spleen, lung and vocal folds. Stellate cells are capable of transformations from a quiescent to an activated myofibroblast-like phenotype [2]. Activated stellate cells have attracted attention owing to the pivotal role they play in pathological fibrosis: they overproduce extracellular matrix proteins to repair the chronic stress-induced injuries in the tissue [1,2,3]. We studied the primary signalling events, evoked by either oxidative stress or proinflammatory mediators, in stellate cells (PSCs) and neighbouring acinar cells (PACs) in the normal mouse pancreas, and identified a link between calcium and nitric oxide signalling pathways in PSCs. In the normal pancreas acetylcholine (ACh) or cholecystokinin (CCK) evoke Ca2þ signals regulating the processes of enzyme release from zymogen granules deposited in the apical parts of PACs [4,5,6,7,8,9,10].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
