Activated pancreatic stellate cells can impair pancreatic islet function in mice

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.

Key words:

• Beta-cell replication
• insulin release
• pancreatic islets
• stellate cells

Acknowledgements

The skilled assistance of Ing-Britt Hallgren is gratefully acknowledged. Leif Jansson and Andreea Barbu contributed equally to this work.

Funding: This work was supported by The Swedish Research Council (521-2011-3777), the Juvenile Diabetes Research Foundation, an EFSD/Novo Nordisk grant, the Swedish Diabetes Association and the Family Ernfors Fund. The study was also supported by grants in the name of Michael Welsh, Uppsala University (Swedish Diabetes Association, Swedish Research Council and Swedish Cancer Association).

Declaration of interest: There are no conflicts of interest that could be perceived as prejudicing the impartiality of the research reported.