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- Edsbagge, Josefina, 1973
(författare)
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The significance of blood vessels in organogenesis and cadherins in exploratory behaviour
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Organogenesis of epithelial organs requires interaction between epithelial andmesenchymal tissues. In pancreas development three different mesenchymal derivedstructures, the notochord, the endothelial cells and the splanchnic mesenchyme inducespecification, growth and further differentiation of the pancreatic epithelium.Previously, N-cadherin deficient embryos were shown to suffer from agenesis ofthe dorsal pancreas due to apoptosis of the pancreatic mesenchyme. However, byexpressing N- and E-cadherin selectively in the heart, the pancreatic phenotype was shownto be secondary to the non-functional cardiac- and vascular-system in N-cadherin-/-embryos. In addition, plasma from wild-type embryos rescued dorsal pancreas formationin N-cadherin-/- explants, suggesting factors from the circulation to be involved inpancreatic ontogeny. Recently, sphingosine-1-phosphate receptor-1 was shown to berequired for proper recruitment of vascular smooth muscle cells to the aortic wall.Vascular smooth muscle cells and dorsal pancreatic mesenchyme may originate from acommon cellular source, the splanchnic mesenchyme, and migrate to endothelial andepithelial cells, respectively, in close vicinity, suggesting that they may be regulated bysimilar developmental regulatory pathways. Consequently, the ligand, a blood bornesphingolipid metabolite, sphingosine-1-phosphate, may be involved in pancreas ontogenyas well. Indeed, the sphingosine-1-phosphate rescued dorsal pancreas in N-cadherin-/-explants by inducing proliferation of the mesenchyme. To clarify the requirement forsphingosine-1-phosphate in pancreas development, embryos deficient in sphingosine-1-phosphate receptor-1 were analysed. Whereas initial development of dorsal and ventralpancreas proceeded normally, obvious morphological changes of the dorsal pancreaticepithelium were observed at later stages, indicating defective mesenchymal-to-epithelialinteractions. The sphingosine-1-phosphate receptor-1 was mainly expressed in endothelialcells, suggesting that sphingosine-1-phosphate signals to the mesenchyme via endothelialcells. Altogether, we show for the first time that vascular function and spingosine-1-phosphate-mediating signalling regulate pancreas ontogeny by inducing mesenchymal-toepithelialsignalling.Cadherins are cell-to-cell adhesion molecules localised at the synaptic junctions,mediating synaptogenesis and neuronal path finding during development. By using theCre/loxP-system, an in vivo model was established where a dominant negative cadherinwas expressed selectively in the neurons of the central nervous system in the adult mouse.Cadherins role in neural plasticity and behaviour was analysed and demonstrated normalsynaptic transmission, long term potentiation, spatial learning and anxiety responses, whilerearing behaviour, a component in exploration was significantly reduced. Datademonstrate, for the first time, a functional role for cadherins in modifying rearing andexploratory behaviour in vivo.
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| 3. |
- Edsbagge, Josefina, 1973, et al.
(författare)
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Vascular function and sphingosine-1-phosphate regulate development of the dorsal pancreatic mesenchyme
- 2005
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Ingår i: DEVELOPMENT. - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 132:5, s. 1085-1092
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Tidskriftsartikel (refereegranskat)abstract
- Early growth and differentiation of the pancreatic endoderm is regulated by soluble factors from the pancreatic mesenchyme. Previously, we demonstrated that N-cadherin-deficient mice lack a dorsal pancreas, due to a critical role of N-cadherin in dorsal pancreatic mesenchymal cell survival. Here, we show that restoring cardiac and circulatory function in N-cadherin null mice by cardiac-specific expression of N-cadherin, rescues formation of the dorsal pancreas, indicating that the phenotype is secondary to defects related to cardiac/vascular function. Based on this observation, we demonstrate that soluble factors present in plasma, such as sphingosine-1-phosphate, rescue formation of the dorsal pancreas in N-cadherin-deficient mice. We also show that sphingosine-1-phosphate indirectly promotes budding of the pancreatic endoderm by stimulating pancreatic mesenchymal cell proliferation. Finally, we identify sphingosine-1-phosphate receptors within the mesenchyme and show that pertussis toxin blocks the sphingosine-1-phosphate-induced actions, suggesting the involvement of G-protein-coupled sphingosine-1-phosphate receptors. Thus,we propose a new model where blood vessel-derived sphingosine-1-phosphate stimulates growth and budding of the dorsal pancreatic endoderm by induction of mesenchymal cell proliferation.
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- Holmgren, Gustav, et al.
(författare)
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Long-Term Chronic Toxicity Testing Using Human Pluripotent Stem Cell-Derived Hepatocytes
- 2014
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Ingår i: Drug Metabolism and Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 42:9, s. 1401-1406
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Tidskriftsartikel (refereegranskat)abstract
- Human pluripotent stem cells (hPSC) have the potential to become important tools for the establishment of new models for in vitro drug testing of, for example, toxicity and pharmacological effects. Late-stage attrition in the pharmaceutical industry is to a large extent caused by selection of drug candidates using nonpredictive preclinical models that are not clinically relevant. The current hepatic in vivo and in vitro models show clear limitations, especially for studies of chronic hepatotoxicity. For these reasons, we evaluated the potential of using hPSC-derived hepatocytes for long-term exposure to toxic drugs. The differentiated hepatocytes were incubated with hepatotoxic compounds for up to 14 days, using a repeated-dose approach. The hPSC-derived hepatocytes became more sensitive to the toxic compounds after extended exposures and, in addition to conventional cytotoxicity, evidence of phospholipidosis and steatosis was also observed in the cells. This is, to the best of our knowledge, the first report of a long-term toxicity study using hPSC-derived hepatocytes, and the observations support further development and validation of hPSC-based toxicity models for evaluating novel drugs, chemicals, and cosmetics.
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