SummaryType 1 diabetes is characterized by the destruction of pancreatic β cells, and generating new insulin-producing cells from other cell types is a major aim of regenerative medicine. One promising approach is transdifferentiation of developmentally related pancreatic cell types, including glucagon-producing α cells. In a genetic model, loss of the master regulatory transcription factor Arx is sufficient to induce the conversion of α cells to functional β-like cells. Here, we identify artemisinins as small molecules that functionally repress Arx by causing its translocation to the cytoplasm. We show that the protein gephyrin is the mammalian target of these antimalarial drugs and that the mechanism of action of these molecules depends on the enhancement of GABAA receptor signaling. Our results in zebrafish, rodents, and primary human pancreatic islets identify gephyrin as a druggable target for the regeneration of pancreatic β cell mass from α cells.

Endothelial cells are a constitutive part of the heart and vasculature and form a crucial link between the cardiovascular system and the immune system. Besides their commonly accepted roles in angiogenesis, hemostasis, and the regulation of vascular tone, they are an essential and active component of immune responses. Expression of a range of innate pattern recognition receptors allows them to respond to inflammatory stimulation, and they control immune cell recruitment and extravasation into target tissues throughout the body.In this chapter, I will therefore summarize classical endothelial cell properties and functions and their cross talk with the immune system as well as the operational immunological role of endothelial cells in facilitating immune responses.

VEGF-A is the major trigger of vasculogenesis and physiologic angiogenesis. We have investigated to which extent the gene repertoire induced by VEGF-A in endothelial cells is distinct from that of other growth factors and inflammatory cytokines. Genes upregulated in human umbilical vein endothelial cells treated with VEGF, EGF or IL-1 were compared by microarray analysis and clusters characteristic for individual or combinations of inducers were defined. VEGF-A upregulated in comparison to EGF a five-fold larger gene repertoire, which surprisingly overlapped to 60% with the inflammatory repertoire of IL-1. As shown by real-time RT-PCR for selected genes, VEGF-induction was mostly mediated by VEGF receptor-2 and the capacity of VEGF-A to induce genes in common with IL-1 largely depended on activation of the calcineurin/NFAT pathway, since cyclosporin A inhibited this induction. Another angiogenic growth factor, bFGF, did not share a comparable induction of inflammatory genes, but partially induced a small group of genes in common with VEGF-A, which were not regulated by EGF. Thus, the data display that VEGF-A induces a distinct gene repertoire, which, contrasting with other growth factors such as EGF or bFGF, includes an inherent inflammatory component possibly contributing to the cross-regulation of angiogenesis and inflammation as further indicated by the VEGF-mediated induction of leukocyte adhesion. Furthermore, a small group of genes selectively induced by VEGF-A with potential importance for angiogenesis is defined.

Over the last decade, zebrafish has proven to be a powerful model in cancer research. Zebrafish form tumors that histologically and genetically resemble human cancers. The live imaging and cost-effective compound screening possible with zebrafish especially complement classic mouse cancer models. Here, we report recent progress in the field, including genetically engineered zebrafish cancer models, xenotransplantation of human cancer cells into zebrafish, promising approaches toward live investigation of the tumor microenvironment, and identification of therapeutic strategies by performing compound screens on zebrafish cancer models. Given the recent advances in genome editing, personalized zebrafish cancer models are now a realistic possibility. In addition, ongoing automation will soon allow high-throughput compound screening using zebrafish cancer models to be part of preclinical precision medicine approaches.

Precise regulation of signaling pathways in single cells underlies tissue development, maintenance and repair in multicellular organisms, but our ability to monitor signaling dynamics in living vertebrates is currently limited. We implemented kinase translocation reporter (KTR) technology to create DREKA (“dynamic reporter of Erk activity”) zebrafish, which allow one to observe Erk activity in vivo at single cell level with high temporal resolution. DREKA zebrafish faithfully reported Erk activity after muscle cell wounding and revealed the kinetics of small compound uptake. Our results promise that kinase translocation reporters can be adapted for further applications in developmental biology, disease modeling, and in vivo pharmacology in zebrafish.