Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 14, 2018; 24(2): 170-178
Published online Jan 14, 2018. doi: 10.3748/wjg.v24.i2.170
Antifibrogenic effects of vitamin D derivatives on mouse pancreatic stellate cells
Peter Wallbaum, Sarah Rohde, Luise Ehlers, Falko Lange, Alexander Hohn, Carina Bergner, Sarah Marie Schwarzenböck, Bernd Joachim Krause, Robert Jaster
Peter Wallbaum, Sarah Rohde, Luise Ehlers, Robert Jaster, Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock 18057, Germany
Falko Lange, Oscar-Langendorff-Institute of Physiology, Rostock University Medical Center, Rostock 18057, Germany
Alexander Hohn, Carina Bergner, Sarah Marie Schwarzenböck, Bernd Joachim Krause, Department of Nuclear Medicine, Rostock University Medical Center, Rostock 18057, Germany
Author contributions: Jaster R, Schwarzenböck SM and Krause BJ designed the study; Wallbaum P, Rohde S, Ehlers L, Lange F, Bergner C, Hohn A and Jaster R performed the experiments; all authors analyzed the data; and Jaster R wrote the manuscript.
Supported by FORUN program of the Rostock University Medical Center.
Conflict-of-interest statement: The authors declare that there is no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Robert Jaster, MD, Academic Research, Professor, Senior Scientist, Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, E.-Heydemann-Str. 6, Rostock 18057, Germany. jaster@med.uni-rostock.de
Telephone: +49-381-4947349 Fax: +49-381-4947482
Received: October 10, 2017
Peer-review started: October 10, 2017
First decision: October 30, 2017
Revised: November 15, 2017
Accepted: November 27, 2017
Article in press: November 27, 2017
Published online: January 14, 2018
Processing time: 96 Days and 21.9 Hours
ARTICLE HIGHLIGHTS
Research background

Chronic pancreatitis and pancreatic cancer are accompanied by an extended fibrosis that plays an active role in disease progression. Pancreatic stellate cells (PSCs) are the main source of extracellular matrix proteins in the diseased organ. To this end, there is a lack of specific antifibrotic agents for preclinical evaluation and potential clinical applications.

Research motivation

Vitamin D has recently been suggested to modulate the pancreatic stroma in a way that pancreatitis is suppressed and pancreatic cancer therapy is enhanced. PSCs were identified as a target of vitamin D action. The molecular mechanisms of vitamin D action in PSCs are only partially understood, and the relative efficiencies of different vitamin D derivatives have not been elucidated yet.

Research objectives

The objective of this study was to analyze and to compare the biological and molecular effects of three different D-vitamins, vitamin D2, vitamin D3 and calcipotriol, in PSCs.

Research methods

Murine PSCs were exposed to D-vitamins as primary cultures (early activated PSCs) and upon re-culturing (fully-activated cells). Exhibition of vitamin A containing lipid droplets and expression of α-smooth muscle actin were used as surrogate markers of PSC activation. Therefore, oil red staining, immunofluorescence studies and immunoblot analyses were performed. Gene expression was monitored by real-time PCR, and interleukin-6 (IL-6) protein levels were quantified by ELISA. Furthermore, 18Fproline was employed to measure the cellular uptake of proline.

Research results

The results of this study show for the first time that vitamin D exerts distinct effects on quiescent and activated PSCs in vitro. In quiescent PSCs, vitamin D prevented the exhibition of a myofibroblastic phenotype. Once the cells were fully activated, vitamin D failed to induce a complete reversal of the myofibroblastic phenotype, but still exerted antifibrotic effects on PSCs by inhibiting uptake of proline and expression of IL-6. Three vitamin D derivatives, vitamin D2, vitamin D3 and calcipotriol, displayed very similar biological effects.

Research conclusions

D-vitamins are efficient inhibitors of PSC activation in vitro, but cannot reverse the phenotype once the cells are fully activated. In line with other publications in the field, our findings encourage a further evaluation of vitamin D effects in pancreatic cancer and chronic pancreatitis. A modulation of the stroma response by vitamin D might hold potential as part of a multimodal concept for the treatment of both diseases.

Research perspectives

These investigations have shown that vitamin D2, vitamin D3 and calcipotriol are similarly effective with respect to the inhibition of PSC activation in vitro. Directions of future research should include both mechanistic studies on the molecular basis of vitamin D action in PSCs, and experimental studies on vitamin D efficiency in the context pancreatic cancer and chronic pancreatitis. Therefore, advanced cell culture models such as human stellate cells and animal models of pancreatic fibrosis need to be employed.