Abstract
Background. Pancreatic or islet fibrosis is often associated with activated pancreatic stellate cells (PSCs). PSCs are considered not only to promote fibrosis, but also to be associated with glucose intolerance in some diseases. We therefore evaluated morphological and functional relationships between islets and PSCs in the normal mouse pancreas and transplanted islets.Methods. Immunohistochemistry was used to map the presence of PSCs in the normal mouse pancreas and islets implanted under the renal capsule. We isolated and cultured mouse PSCs and characterized them morphologically by immunofluorescence staining. Furthermore, we measured their cytokine production and determined their effects on insulin release from simultaneously cultured islets.Results. PSCs were scattered throughout the pancreas, with occasional cells within the islets, particularly in the islet capsule. In islet transplants they were found mainly in the graft periphery. Cultured PSCs became functionally activated and produced several cytokines. Throughout the culture period they linearly increased their production of interleukin-6 and mammalian keratinocyte-derived chemokine. PSC cytokine production was not affected by acute hyperglycemia. Syngeneic islets co-cultured with PSCs for 24–48 h increased their insulin release and lowered their insulin content. However, short-term insulin release in batch-type incubations was unaffected after 48 h of co-culture. Increased islet cell caspase-3 activation and a decreased islet cell replication were consistently observed after co-culture for 2 or 7 days.Conclusion. Activated PSCs may contribute to impaired islet endocrine function seen in exocrine pancreatitis and in islet fibrosis associated with some cases of type 2 diabetes.
Highlights
Pancreatic islets constitute complex organs distributed within the pancreas of almost all vertebrates
Desmin-positive pancreatic stellate cells (PSCs) were found throughout the mouse pancreas, associated with intra- and interlobular connective tissue in the exocrine parenchyma and within and surrounding the islets (Figure 1A)
When concentrations of cytokine released into the medium by cultured PSCs were followed for 33 days we found a linear increase in IL-6 and mammalian keratinocyte chemoattractant (mKC) concentrations, and the increase in concentration was most pronounced in the former (Figure 6E)
Summary
Pancreatic islets constitute complex organs distributed within the pancreas of almost all vertebrates. Islets contain a complex stroma, with many cells contributing to the unique microenvironment needed for optimal endocrine function. Pancreatic stellate cells (PSCs) are matrixproducers distributed throughout the endocrine and exocrine parts of the gland [2]. It may be that PSCs contribute to impaired islet function, in exocrine pancreatic disease and in certain types of diabetes. In view of the possible and ambiguous effects of PSCs on islet function, we performed this study to evaluate in more detail the distribution of these cells in the normal mouse pancreas and in transplanted islets and to characterize functional interactions between beta-cells and culture-activated PSCs in vitro
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