Understanding the molecular signals that guide early cells in the embryo to develop into different organs provides insight into ways that tissues regenerate and how stem cells can be used for new therapies. With regenerated cells, researchers hope to one day fill the acute shortage in pancreatic and liver tissue available for transplantation in cases of type I diabetes and acute liver failure.
Previous studies on pancreas and liver development have focused on individual molecular signals that induce these tissues to mature from a common precursor cell population. In a new study researchers investigated a trio of cell-signalling pathways that work simultaneously, converging to direct pancreas and liver progenitor cells to mature into their final state. They looked at how BMP, TGF-beta, and FGF signalling pathways turn on genes that guide cells to ultimately become pancreas or liver tissue.
The structure of the cell-signalling network provides insight into the basis of tissue development and how it can be manipulated to facilitate pancreas and liver-cell regeneration and development from embryonic stem cells.
"For my entire scientific life, I've been intrigued by how cells early in development make ‘decisions’ to turn on one genetic program and exclude others," says Kenneth S. Zaret, PhD, Professor of Cell and Developmental Biology and Associate Director at the Institute for Regenerative Medicine at the University of Pennsylvania School of Medicine.
How the developing embryo starts to apportion different functions to different cell types is a key question for developmental biology and regenerative medicine.
Guidance along the correct path is provided by genetic regulatory proteins that attach to chromosomes, marking part of the genome to be turned on or off. But first the two meters of tightly coiled DNA inside the nucleus of every cell must be loosened a bit. The regulatory proteins help with this, exposing a small domain near the target gene. They then act as a landing pad on which other proteins assemble to continue the gene activation process.
The paper addresses how chemical signals from neighbouring cells in the embryo tell early progenitor cells to activate genes encoding the regulatory proteins. The regulatory proteins, in turn, guide the cells to become a liver cell or a pancreas cell. "In the current study we mapped the signalling pathways being turned on before they connected with the target genes," explains Zaret. "We monitored these cues before the cell displayed any overt signs of differentiation. While my lab and others had previously looked at individual signals that influence development, in this paper we simultaneously mapped three signal paths that converge to induce liver and pancreas cells. We’re starting to construct a network of the common signals that govern development of these specific cell types. The complexity of this system is somewhat like our 26-letter alphabet being able to encode Shakespeare or a menu at a restaurant."
Many investigators are now trying to broadly reprogram cells into desired cell fates for potential therapeutic uses. "By better understanding how a cell is normally programmed we will eventually be able to directly reprogram other cells," notes Zaret. "An analogy I use here is if a watch is broken and you want to know how to reassemble it, the best thing is to go the factory and see how it is assembled in the first place. That may not be the solution to fixing it, but it's a good place to start."
In the near term, the team also aims to generate liver and pancreas cells for research and to screen drugs that repair defects or facilitate cell growth.
The work was funded by the National Institutes of Health, including the Institute of General Medical Sciences and the Institutes for Diabetes, Digestive, and Kidney Disorders.
University of Pennsylvania School of Medicine
New mechanisms of action found for drugs used to treat anxiety disorders
In the course of his or her life, every seventh German will develop an anxiety disorder that will require treatment. Standard anti-anxiety medications (anxiolytics) are based on the benzodiazepine class of drugs. These calm the patient and quickly diminish feelings of anxiety. However, undesirable side effects like tiredness, drug intolerance and withdrawal problems make the long-term use of these drugs problematic. Scientists working under Rainer Rupprecht, Fellow of the Max Planck Institute of Psychiatry in Munich, succeeded in proving, for the first time, that new anxiolytics can be developed using an innovative mechanism based on neurosteroids derived from the hormone progesterone. This kind of drug displayed significantly fewer side effects, both in the animal tests and in a clinical trial.
A patient may be suffering from an anxiety disorder if he or she experiences feelings of anxiety that exceed the normal level and there is no identifiable cause of these feelings. Those affected by such disorders usually suffer considerably, both in their private and professional lives. In addition to psychotherapy and anti-depressives, which take a long time to take effect, benzodiazepines can usually alleviate the fear quickly and in the short term. However, these drugs can have considerable side effects if taken over longer periods, including, for example, the development of tolerance, dependence and withdrawal symptoms.
As part of their quest for new mechanisms of action for anti-depressives and anxiolytics, Florian Holsboer and Rainer Rupprecht at the Max Planck Institute of Psychiatry in Munich have been researching for years how neurosteroids influence the neuronal communication in the brain. They examined the effect of a new class of substances in co-operation with the Department of Psychiatry of the Ludwig-Maximilians-Universität Munich and the Novartis pharmaceutical concern in Basel. The substance in question, XBD173, had a positive influence on the synthesis of the body’s neurosteroids and, as the scientists were able to prove with the help of mouse brain tissue, triggered the attenuation of neuronal communication as a result. XBD173 also displayed an anxiolytic effect on the behavioural level in the animal model without observing any sedating effects that arise, for example, with benzodiazepines. "I am absolutely delighted that the hypothesis we developed years ago, that anxiolytic effects can be attained by influencing the body’s neurosteroids, has been scientifically confirmed today," says Florian Holsboer in response to this latest finding.
In order to test the effect of XBD173 in humans for the first time, the doctors designed a clinical trial, in which 70 healthy volunteer subjects were tested. The subjects were injected with the neuropeptide fragment CCK-4, which triggered a short anxiety and panic attack lasting two to five minutes. When XBD173 was also administered to the subjects, the panic attack could not be triggered in this way. The benzodiazepine Alprazolam also curbed feelings of anxiety. However, in contrast to XBD173, the participants in the trial reported undesired fatigue on taking the drug and withdrawal symptoms on its discontinuation.
Thus, through the stimulation of neurosteroid synthesis using the translocator protein 18, the researchers discovered a new mechanism for the treatment of anxiety disorders that displays a better side-effect profile than benzodiazepine. In addition, the conditions were defined under which such studies can be carried out on healthy subjects. "The successful implementation of an experimentally inducible anxiety model in healthy subjects will facilitate the development of innovative anxiolytics in the future, as the testing of active ingredients in their early phase of development does not necessarily have to be carried out on patients," says Rainer Rupprecht. He is, however, aware that insights gained on healthy subjects cannot necessarily be transferred to patients on a 1:1 basis. "They do not replace the necessary acceptance tests on patient groups."
Max Planck Institute of Psychiatry
www.uphs.upenn.edu/news/News_Releases/2009/06/liver-pancreas-cell-development/
