Group Marlen Knobloch
| Somatic stem cells require a tight balance between proliferation and quiescence to ensure life-long replenishment of tissues. A disturbance in this balance can have severe consequences. The role of metabolism in this process has only recently gained attention and remains poorly understood. A better knowledge of metabolic stem cell regulation may offer new avenues to control stem cell behavior and may have important clinical implications. |  |
The main focus of the Laboratory of Stem Cell Metabolism are adult neural stem cells (NSPCs), which give rise to new neurons throughout adulthood. This process is called adult neurogenesis and has been shown to be disturbed in various cognitive diseases. We are interested in the metabolic regulation of neurogenesis in health, aging and disease, covering basic aspects of metabolic regulation as well as extrinsic influences on NSPC metabolism.
Furthermore, we are exploring whether there are common mechanism of metabolic regulation in different somatic stem cell compartments.
Schematic representation of the major metabolic pathways in NSPCs and their neuronal progeny. Shown are the major changes in metabolic pathways occurring in quiescent and proliferating NSPCs as well as in immature neurons in the adult dentate gyrus and the developing forebrain. From Knobloch & Jessberger, Current Opinion in Neurobiology 2017
We are using innovative techniques such as CRISPR/Cas9 mediated genetic modifications, various transgenic mouse models, virus-mediated gene expression in vitro and in vivo, time-lapse imaging, mass spectrometry imaging as well as proteomic, metabolomic and lipidomic approaches to address the following main topics:
1. Basic biology of lipid metabolism in NSPCs.
We have previously shown that lipid metabolism is indeed crucial for NSPC behavior (Knobloch et al. Nature 2013, Knobloch et al. 2017, in revision). However, why these lipids are so important for NSPCs and how they exert their influence on NSPC behavior remains poorly understood. We will address how lipid metabolism changes during cell cycle, fate choice and differentiation, and what the lipids are used for.
The protein Spot14, involved in regulating lipid metabolism, has been identified as a novel marker for quiescent NSPCs (Knobloch et al. Nature 2013). Shown are the Spot14+ NSPCs (in green) surrounded by immature newborn neurons (in red, Doublecortin+). Insert: Palmitic acid, the main product of fatty acid synthase, is important for adult neurogenesis (Image © Knobloch & Jessberger).
2. Extrinsic influences on metabolism in NSPCs.
Many extrinsic factors are known to influence neurogenesis, such as for instance nutrition, physical activity, aging and various diseases. However, how this pro-and anti-neurogenic stimuli are translated into changed NSPC behavior remains unclear. We will address how NSPC metabolism changes upon these different stimuli.
Neurogenesis is drastically reduced with age, as illustrated by the decreased number of Spot14+ NSPCs over time. Shown is the dentate gyrus of Spot14 GFP reporter mice at various ages (From Knobloch et al. Stem Cell Reports. 2014).
3. Common mechanisms of metabolic regulation in different somatic stem cell compartments.
It is highly likely that different somatic stem cells share similar mechanisms of metabolic regulation. However, this possibility has not been addressed in depth. We will compare metabolic processes in different somatic stem cells, focusing on lipid metabolism, to determine the degree of conserved stem cell control mechanisms.
Marlen Knobloch - Group leader
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Marlen Knobloch has obtained her PhD at the University of Zurich in the Group of Prof. Nitsch, where she developed and characterized a novel mouse model for Alzheimer’s disease. During her PhD, she furthermore contributed to an innovative immunization approach against Alzheimer’s disease, which is currently in a clinical phase 3 trial led by Biogen. Dr. Knobloch moved on to do her postdoc in the Group of Prof. Jessberger at the University of Zurich, where she has been studying the metabolic requirements of adult neural stem cells. Her work has uncovered important novel mechanisms how lipid metabolism controls neural stem cell activity. She has further been a guest postdoc at EPFL in the Group of Prof. Luetolf. In 2017, Dr. Knobloch has obtained an assistant professorship in the Department of Physiology at the University of Lausanne where she has established the Laboratory of Stem Cell Metabolism.
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Sofia Madsen, PhD student
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Sofia obtained her Bachelor and Master in Biomedicine at Lund University. She did her master thesis in Johan Jakobsson’s lab, where she studied the role of autophagy and miRNA biogenesis in various mutant huntingtin overexpressing models. Thereafter she stayed in Johan Jakobsson’s lab for additional internships where she worked with CRISPR/Cas9 to study epigenetics in neurons. Sofia joined Marlen Knobloch’s group in June 2017 as a PhD student and is currently working on the role of lipid droplets in neural stem cells. |
Mergim Ramosaj, PhD student
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Mergim obtained his Bachelor in Biology and his Master in Molecular Life Science at the University of Lausanne. During his pre-master thesis, he worked on the identification of factors necessary for the survival of primary CD4+ T cells in culture under the supervision of Angela Ciuffi. Then, he joined Nicole Déglon’s lab for his master thesis. During his master, he worked on small interfering RNAs for Huntington’s disease and more precisely on evaluation of lentiviral vector retrograde transport and optimization of cutting edge tools for pre-clinical validation of this approach. Mergim joined Marlen Knobloch’s group in April 2017 as a PhD student and is currently working on the role of lipid droplets in neural stem cells. |
Daniel Sudria - PhD student
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Daniel obtained his Bachelor in Biomedicine at the University of Barcelona and his master in Neuroscience at the University of Regensburg. During his master’s thesis in Christian Wetzel’s lab, he studied the mitochondrial function of fibroblasts obtained from depressed patients and optimized protocols to convert them into iPSCs and neurons. In addition, Daniel obtained a second master’s degree in Bioinformatics and Biostatistics at the Open University of Catalonia. During this master’s thesis under the supervision of Melchor Sanchez Martinez, Daniel worked on the computational design of molecules with a therapeutic potential for the treatment of Niemann-Pick type C disease. Daniel joined Marlen Knobloch’s lab in July 2018 as a PhD student and is currently working on establishing cerebral organoid systems for the study of lipid metabolism during development. |
Valentina Scandella - PhD student
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Valentina obtained her Bachelor in Biology and her Master in Medical biology at the University of Lausanne. As a first step project, she joined Caroline Pot’s group where she worked on the interplay between lipid metabolites and gut flora during experimental autoimmune encephalomyelitis. For her master thesis, she joined Olivier Bonny’s lab. She was interested in the effect of vitamin D on the level of serum and urinary uric acid and on the expression of the different urate transporters. Thereafter, she worked as a scientific collaborator in Dmitri Firsov’s group for 6 months. She started a project to investigate the role of the peroxisomes in the kidney and she joined Marlen Knobloch’s lab in September 2018 as a PhD student. Valentina is working on the metabolic profile of adult neural stem cells. |
Alumni
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Gabriela Radulova, Summer Student SUR program, Sofia University “St. Kliment Ohridski”, working with Sofia Madsen
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Naoya Yuizumi, Summer Student, University of Tokyo, working with Mergim Ramosaj
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Knobloch, M*., Pilz, G.A., Ghesquière, B., Kovacs, W.J., Wegleiter, T., Moore, D.L., Hruzova, M., Zamboni, N. Carmeliet, P., Jessberger, S. A fatty acid oxidation-dependent metabolic shift regulates adult neural stem cell activity. Cell Reports. 2017 Aug 29, Vol. 20, 2144-2155. (*co-corresponding author)
Knobloch M. The Role of Lipid Metabolism for Neural Stem Cell Regulation. Brain Plasticity, in press
Knobloch M. & Jessberger S. Metabolism and neurogenesis. Current Opinion in Neurobiology 2017, 42:45–52
Knobloch M & Jessberger S. Metabolic control of adult neural stem cell behavior. Frontiers in Biology. 2015 Apr, Vol. 10 (2), 100-106
Knobloch M, von Schoultz C, Zurkirchen L, Braun SMG, Jessberger S. SPOT14-positive neural stem/progenitor cells in the hippocampus respond dynamically to neurogenic regulators. Stem Cell Reports. 2014 Nov 11, Vol. 3., 735–742
Knobloch M, Jessberger S. Stem Cells and Neurogenesis. Encyclopedia of the Neurological Sciences. 2014. 2nd Edition, Elsevier. Vol. 4 300-303.
Knobloch M, Braun SMG, Zurkirchen L, von Schoultz C, Zamboni N, Araúzo-Bravo MJ, Kovacs WJ, Karalay O, Suter U, Machado RAC, Roccio M, Lutolf MP, Semenkovich CF, Jessberger S. Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis. Nature. 2013 Jan 10;493(7431):226-30.
Roccio M, Schmitter D, Knobloch M, Okawa Y, Sage D, Lutolf MP. Predicting stem cell fate changes by differential cell cycle progression patterns. Development. 2013 Jan;140(2):459-70.
Bracko O, Singer T, Aigner S, Knobloch M, Winner B, Ray J, Clemenson Jr GD, Suh H, Couillard-Despres S, Aigner L, Gage FH, Jessberger S. Gene expression profiling of neural stem cells and their neuronal progeny reveals IGF2 as a regulator of adult hippocampal neurogenesis. J. Neurosci. 2012 March 7; 32(10):3376 –3387.
Karalay O, Doberauer K, Vadodaria KC, Knobloch M, Berti L, Miquelajauregui A, Schwark M, Jagasia R, Taketo MM, Tarabykin V, Lie DC, Jessberger S. Prospero-related homeobox 1 gene (Prox1) is regulated by canonical Wnt signaling and has a stage-specific role in adult hippocampal neurogenesis. Proc Natl Acad Sci U S A. 2011 Apr 5; 108(14):5807-12.
Knobloch M, Jessberger S. Perspectives on adult neurogenesis. Eur J Neurosci. 2011 Mar; 33(6):1013-7.
