MRI of activated hepatic stellate cells using vitamin A functionalized magnetolipossomes as an early marker of liver fibrosis

Garcia Ribeiro R., van Santvoort A., Kektar-Atre A., Bueters R., de Schaepdrijver L., van Heerden M., Rangarajan J., Himmelreich U., ''MRI of activated hepatic stellate cells using vitamin A functionalized magnetolipossomes as an early marker of liver fibrosis'', European molecular imaging meeting - EMIM 2015, March 18-20, 2015, Tübingen, Germany.Introduction Hepatic fibrosis is a common outcome for many chronic liver diseases with significant clinical implications. The predominant mechanism of liver fibrosis is the proliferation of hepatic stellate cells (HSCs) and their activation into myofibroblasts with progressive deposition of extracellular matrix proteins, including collagen. Currently, there are no suitable biomarkers for the detection of liver fibrosis onset: invasive liver biopsies are the golden standard for the diagnosis of liver fibrosis. The aim of this project was to find an accurate, reproducible, non-invasive and easily applied method for the detection of liver fibrosis. Therefore we investigated wether MRI imaging with vitamin A functionalized magnetoliposomes (vit.A-MLs), designed to specifically target the vitamin A storage capacity of HSCs, could be used as an early marker for liver fibrosis. Methods We performed three studies with induction of liver fibrosis in Sprague-Dawley rats and correlated the MRI imaging with histopathological evaluation. In a first study, the carbon tetrachloride (CCl4)-induced liver fibrosis model was used to evaluate the possibility to detect the onset of liver fibrosis in rats, in particular the activation and proliferation of HSCs. In a second study, a test compound inducing liver fibrosis by a different mechanism, was used to confirm these results and in a third study we used the same test compound for the longitudinal evaluation of liver fibrosis onset and progression. Changes in MRI signal intensity were recorded and histopathological evaluation of livers stained with hematoxylin eosin stain (HE) and alpha smooth muscle actin (αSMA), was performed to correlate these changes with liver fibrosis and HSC activation. Results A granular (‘cobbled stone’) appearance was noted in liver tissue after vit.A-MLs administration, indicating a change in distribution for the uptake of vit.A-MLs in the livers. Histograms showed a shift in signal intensity and the appearance of a second peak which correlated in the majority of these rats to HSC activation and proliferation. Immunohistochemical staining with αSMA, confirmed the onset of liver fibrosis for some rats in both studies and a Perl’s stain demonstrated the presence of iron, indicating MLs uptake by the liver. Conclusions Preliminary results show that MRI imaging with vit.A functionalized MLs may be a promising in vivo method to detect the onset of liver fibrosis. Acknowledgement This research project was supported by a grant from the Flemish agency for innovation by science and technology.status: publishe