New Insights in Liver and Pancreatic Stellate Cells: The Roles of Toll-Like Receptor 5 - European Medical Journal

New Insights in Liver and Pancreatic Stellate Cells: The Roles of Toll-Like Receptor 5

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*Pietro Di Fazio,1 Isabell Theresa Böhm,1 Thaddeus Till Hippokrates Wissniowski2

The authors have declared no conflicts of interest.

EMJ Gastroenterol. ;6[1]:44-45. Abstract Review No. AR4.
Intercellular communication, microbiota, organ fibrogenesis, stellate cells, toll-like receptor (TLR)

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

Hepatic stellate cells are responsible for liver tissue’s ability to store vitamin A and 80% of whole-body retinol as cytosolic lipid droplets of retinyl palmitate.1 They are distributed in the space between the parenchymal and sinusoidal cells.2 Hepatic stellate cells are physiologically quiescent and are characterised by epithelial morphology.

Liver insult, damage, and/or epigenetic modifications cause the transdifferentiation of stellate cells into myofibroblasts.3 Once the stellate cells transactivate into mesenchymal cells, they can infiltrate the liver parenchyma and are responsible for the collagen secretion, which can lead to liver fibrosis, cirrhosis, and tumourigenesis.3,4

Pancreatic stellate cells (PSC) constitute the pancreas stroma. The cells carry out various functions, including the formation of the extracellular matrix, stimulation of amylase secretion, phagocytosis, and contributing to immunity.5 Quiescent PSC are characterised by vitamin A droplets; once active, they assume a myofibroblast-like morphology and are responsible for the fibrogenesis observed in pancreatitis and pancreatic ductal adenocarcinoma.6 Furthermore, it has been shown that PSC support tumour metabolism by inducing autophagic alanine secretion.7 Until now, the role exerted by PSC has been unclear, and it is not known if they exert a tumour-suppressing or a tumour-sustaining effect.

Our study highlights a possible intercommunication existing between the stellate cells, other pancreatic and liver cells, and the microbiota. In vitro studies show that LX28 and HPSC 2.29 immortalised stellate cells can be easily treated with low levels of tumour growth factor beta (TGF-β1), leading to their transdifferentiation into myofibroblasts. TGF-β1 was able to stimulate the stellate cells, promote their activation, and their change from a quiescent state to an active one, which characterises these cells in their liver and pancreatic tissue environment. The responsiveness to TGF-β1 highlights the fact that the stellate cells can be activated by signalling coming from both neighbouring and more distant cells. In particular, the presence of tumour cells in the surrounding parenchyma could be also responsible for stellate cell activation through the secretion of several growth stimulating factors, including TGF-β1.10

Currently, apart from their simple vitamin and fat storing role, the function of stellate cells is not yet fully understood; they could play a strategic role during tumourigenesis and promote intra and intercellular signalling, actively participating in the tumour environment.

Interestingly, TGF-β1 signalling was responsible in the proposed model for inducing the expression of toll-like receptor (TLR)5. This member of the TLR family is known for being easily activated by the bacterial protein flagellin. It was observed that knocking down the mRNA and protein level of TLR5 completely disabled TGF-β1 efficacy, leaving the liver and PSC in a quiescent state. The expression of TLR5 was essential for the stellate cells to acquire their active status and the efficacy of TGF-β1 was dispensable in cells knocked down for TLR5.

The importance of TLR5 in stellate cell activation offers new perspectives for understanding the mechanisms underlying stellate cells’ involvement in the tissue environment: in particular, the sensitivity of stellate cells to stimuli coming from micro-organisms populating the host body and the ability of micro-organisms to activate molecular and morphological changes in cells that play a specific role in the structure and functioning of the tissue or organ. Understanding the mechanisms of organ fibrogenesis in correlation with tumourigenesis and the influence of microbiota will open new directions for future treatment of diseases affecting the upper-midgut area of the human body.

Senoo H et al. The stellate cell system (vitamin A-storing cell system). Anat Sci Int. 2017;92(4):387-455. Senoo H. Structure and function of hepatic stellate cells. Med Electron Microsc. 2004;37(1):3-15. Wilson CL et al. Epigenetic reprogramming in liver fibrosis and cancer. Adv Drug Deliv Rev. 2017. [Epub ahead of print]. Caviglia JM et al. MicroRNA-21 and dicer are dispensable for hepatic stellate cell activation and the development of liver fibrosis. Hepatology. 2017. [Epub ahead of print]. Allam A et al. Pancreatic stellate cells in pancreatic cancer: In focus. Pancreatology. 2017;17(4):514-22. Bynigeri RR et al. Pancreatic stellate cell: Pandora’s box for pancreatic disease biology. World J Gastroenterol. 2017;23(3):382-405. Sousa CM et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature. 2016;536(7617):479-83. Xu L et al. Human hepatic stellate cell lines, LX-1 and LX-2: New tools for analysis of hepatic fibrosis. Gut. 2005;54(1):142-51. Jesnowski R et al. Immortalization of pancreatic stellate cells as an in vitro model of pancreatic fibrosis: Deactivation is induced by matrigel and N-acetylcysteine. Lab Invest. 2005;85(10):1276-91. Gore AJ et al. Pancreatic cancer-associated retinoblastoma 1 dysfunction enables TGF-β to promote proliferation. J Clin Invest. 2014;124(1):338-52.

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