Divergent Inflammatory, Fibrogenic, and Liver Progenitor Cell Dynamics in Two Common Mouse Models of Chronic Liver Injury

Complications of end-stage chronic liver disease signify a major cause of mortality worldwide. Irrespective of the underlying cause, most chronic liver diseases are characterized by hepatocellular necrosis, inflammation, fibrosis, and proliferation of liver progenitor cells or ductular reactions..

Widespread GLI expression but limited canonical hedgehog signaling restricted to the ductular reaction in human chronic liver disease

Canonical Hedgehog (Hh) signaling in vertebrate cells occurs following Smoothened activation/translocation into the primary cilia (Pc), followed by a GLI transcriptional response. Nonetheless, GLI activation can occur independently of the canonical Hh pathway. Using a murine model of liver injury, we previously identified the importance of canonical Hh signaling within the Pc+ liver progenitor cell (LPC) population and noted that SMO-independent, GLI-mediated signals were important in multiple Pc-ve GLI2+ intrahepatic populations. This study extends these observations to human liver tissue, and analyses the effect of GLI inhibition on LPC viability/gene expression. Human donor and cirrhotic liver tissue specimens were evaluated for SHH, GLI2 and Pc expression using immunofluorescence and qRT-PCR. Changes to viability and gene expression in LPCs in vitro were assessed following GLI inhibition. Identification of Pc (as a marker of canonical Hh signaling) in human cirrhosis was predominantly confined to the ductular reaction and LPCs. In contrast, GLI2 was expressed in multiple cell populations including Pc-ve endothelium, hepatocytes, and leukocytes. HSCs/myofibroblasts (>99%) expressed GLI2, with only 1.92% displaying Pc. In vitro GLI signals maintained proliferation/viability within LPCs and GLI inhibition affected the expression of genes related to stemness, hepatocyte/biliary differentiation and Hh/Wnt signaling. At least two mechanisms of GLI signaling (Pc/SMO-dependent and Pc/SMO-independent) mediate chronic liver disease pathogenesis. This may have significant ramifications for the choice of Hh inhibitor (anti-SMO or anti-GLI) suitable for clinical trials. We also postulate GLI delivers a pro-survival signal to LPCs whilst maintaining stemness.Candice Alexandra Grzelak, Nicholas David Sigglekow, Janina Elke Eleonore Tirnitz-Parker, Elizabeth Jane Hamson, Alessandra Warren, Bharvi Maneck, Jinbiao Chen, Bramilla Patkunanathan, Jade Boland, Robert Cheng, Nicholas Adam Shackel, Devanshi Seth, David Geoffrey Bowen, Luciano Gaston Martelotto, D. Neil Watkins, Geoffrey William McCaugha

The experience of spatial interaction: Conceptualizing the user experience of virtual environments

This paper examines the issue of User Experience (UX) as applied to immersive Virtual Reality from the standpoint of environmental psychology and related fields as a complement to principles from the fields of product design, psychology of emotion, formal aesthetics etc. Partly on account of its generality, multidisciplinary nature, and broad applicability, UX continues to defy a single commonly accepted definition, a fact which necessitates a holistic treatment of the subject of spatial interaction design. Various approaches and models of environmental psychology, as well as approaches to usability and UX are outlined in light of the need to highlight the influence and effects of particular spatial designs to particular dimensions of UX. Additionally, the concept and constituent dimensions of environmental appraisal are similarly defined and analysed, and indicative experimental designs currently under development are briefly described