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Stefan Liebau: using iPS cells for studying neural development

With the appointment of Stefan Liebau as professor of neuroanatomy, iPS cell research has found its way into the Institute of Anatomy at the University of Tübingen. The physician and neuroscientist explores the development of human nerve cells and specialises in working with stem cells. Liebau and his team are currently dealing with the question as to how neural stem cells develop into retinal precursor cells. The researchers are also studying the differentiation of auditory hair cells.

Prof. Dr. Stefan Liebau, born in 1973, was appointed professor (W3) of neuroanatomy at the University of Tübingen’s Institute of Anatomy in October 2013. © Lehmann

Prof. Dr. Stefan Liebau has dealt intensively with neurology for more than ten years and the field has lost none of its fascination for him. “Neurology was already an exciting undiscovered area that I wanted to explore when I was a student,” the researcher recalls. This is why he originally wanted to study biology, but was discouraged by a careers advisor. “Back then, the career prospects for biologists were not that good,” said Liebau who then decided to study medicine with the firm intention of eventually going into research. 

And that’s exactly what happened: at the turn of the millennium, Liebau started his research career in experimental neurology at the University of Ulm, where he was awarded his doctorate in 2004. His doctoral thesis focussed on the comparative analysis of gene expression profiles of adult human neural stem cells. Liebig thus entered the field of basic research in which he has stayed until this day. “I did not want to work in clinical research and I did not want to work with animal models either. Moreover, neural stem cells were something new and little was known about them.” The fascination for the unknown that has always attracted Liebau’s attention was back. 

Early on during his post-doctoral studies at the Institute of Anatomy and Cell Biology at the University of Ulm, Liebau became head of an own research group and, in cooperation with colleagues from the Department of Internal Medicine, established research into murine embryonic stem cells (ES) at the University of Ulm. “We started off studying the differentiation of germ layers,” said Liebau. Studies on the differentiation of neural stem cells in mice and rats followed. Amongst other things, Liebau was interested in the reasons why stem cells leave their niche and in the signalling pathways that triggered their differentiation. “We found out that cellular morphology and metabolism changed when we modulated the ion channels in the cell membrane. This was initial evidence that cells start to divide due to changes in their ionic environment,” explained the researcher. Liebau and his colleagues found similar modulations in pluripotent murine stem cells, which, in contrast to embryonic stem cells, are unable to develop into a new organism, but can develop into a variety of tissue-specific cells.

Why and how do neural stem cells leave their niches and develop into nerve cells?

These neurons differentiated from iPS cells. Specific cellular proteins were stained immunocytochemically: tyrosine hydroxylase was stained red, tubuline (nerve cell marker) magenta and the synaptic vesicle protein synaptophysin green. © Liebau, University of Tübingen

His work with pluripotent stem cells triggered Liebau’s interest in iPS cells (induced pluripotent stem cells). These cells are similar to ES cells in many ways. However, in the laboratory they are derived from tissue-specific stem cells such as hair follicle cells which are responsible for the production of keratin (i.e. hair) in the adult organism. Using state-of-the-art cell and molecular biology methods, adult cells such as these can be reprogrammed to reach a quasi-embryonic stage. IPS cells have the huge advantage that working with them is not associated with the ethical problems that have, in Germany at least, led to major limitations in the use of embryonic stem cells. 

Liebau started working with iPS cells derived from hair follicle cells around five years ago, originally with the aim of exploring the mechanisms of nervous system developmental disorders. The researchers focussed on the synapses of motor neurons, i.e. the connecting structures between nerve cells and muscle cells, which transmit signals to the muscle and lead to muscular contraction. “The stability of the synapses is due to adhesion molecules in neural cell membranes. The lack of adhesion molecules or the presence of defective ones prevent plastic changes in the synapses, which can lead to severe neural diseases,” said Liebau. 

Mimicking neural mechanisms in Petri dishes

A motor neuron, recognisable by magenta-stained tubulin, innervates muscle cells (structural proteins of the muscle cells are labelled red, nuclei blue). The synapse can be recognised by the green-labelled vesicle protein synaptophysin. © Liebau, University of Tübingen

Liebau’s team began to cultivate motor neurons in Petri dishes – alone and together with muscle cells – in order to explore in detail the impact of adhesion molecules on synaptic activity and look for ways of influencing the processes on a therapeutic level. “However, it is difficult to analyse the mechanisms of generalised muscle weakness with cell cultures,” said Liebig. This may be one reason why he now wants the Tübingen team to concentrate on another system, namely the human retina. “It is one of only a handful systems that can be studied effectively with cell cultures. We have direct signalling pathways, a clear projection and an organ in which a certain amount of regeneration takes place. Many aspects can be studied using stem cells.” 

Liebau is currently laying the foundation for this type of research. He and his team are working on establishing cell cultures in order to produce iPS cells from hair follicle cells and differentiate them into retinal precursor cells. Liebau is also addressing the question as to how these precursor cells can be turned into auditory hair cells. “We assume that auditory hair cells and photoreceptor cells of the retina have similar precursor cells, not only in adult systems, but also during early germ layer differentiation. “We are interested in the factors and signals that are responsible for ensuring the development of certain subpopulations. We want to know where the cells separate during the course of development,” Liebau said. In order to deal with such complex issues, Liebau has plans to work with other experts in Tübingen. He is already in contact with Prof. Dr. Marius Ueffing from the Institute for Ophthalmic Research at the University of Tübingen. He also wants to work with Prof. Dr. Marlies Knipper from the Tübingen Hearing Research Centre.

iPS cells to study the development of the human retina

At present, Liebau’s team consists of six people who assist him in setting up the planned research activities. “I see my role primarily in providing assistance and taking care of our networks. I think it is very important to leave the research projects to the scientists. I want them to grow with their project. I believe that this fosters the pleasure of doing research,” said Liebau. This approach is also helpful because Liebau will take on further teaching responsibilities next year. He already runs the neuroseminar for medical students in which he can refer to the experience from his practical year and as a junior doctor in the field of neurology. In addition, he will in future cover all teaching responsibilities related to anatomical issues. At present, Liebau is still supported in his work by the head of the Department of Cellular Neurobiology, Prof. Dr. Hans Joachim Wagner. Wagner too began his career as a neuroscientist in Ulm, where he worked in the 1970s and early 1980s. As Wagner is due to retire in 2014, he is gradually handing over his teaching responsibilities to Liebau.

Further information:

University of Tübingen
Institute of Neuroanatomy
Prof. Dr. Stefan Liebau
Österbergstraße 3
72074 Tübingen
E-mail: stefan.liebau@uni-tuebingen.de
Tel.: 07071 29-78234

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/stefan-liebau-using-ips-cells-for-studying-neural-development