SP 9

Human iPS cell-based neuronal cultures for modeling neuropsychiatric disease

Despite intensive research and recent scientific successes, understanding of the cellular pathomechanisms underlying neuropsychiatric diseases such as schizophrenia, depression, and bipolar disorder remains incomplete. Currently, developmental deficits, aberrant neuronal connectivity, alterations in the excitatory-inhibitory balance, and dysregulation of neurotrophins are being discussed as possible causes. In this context, research into the molecular basis of neuropsychiatric disease is extremely difficult, since access to primary patient brain tissue is very limited. In 2007, the group of Shinya Yamanaka published the first report of the generation of so-called human induced pluripotent stem cells (iPSC) from skin cells. This was achieved through the transient overexpression of essential pluripotent genes. This approach is termed cellular reprogramming.

Culture of human induced pluripotent stem cells and neural progeny derived thereof. (A) Culture of human induced pluripotent stem cells (hiPSCs). The phase contrast picture illustrates the typical growth of hiPSCs in large colonies. (B) HiPSCs express pluripotency-associated cell surface markers (e.g. Tra-1-81), which can be detected by immunocytochemistry. (C) HiPSCs are able to differentiate efficiently into βIII-tubulin-positive neurons under defined culture conditions. These neurons exhibit a typical morphology, which is characterized by long and often multi-branched processes. The neurons depicted in this photograph express the cortical transcription factor TBR1. (D) HiPSCs can also be efficiently differentiated into glial cells, e.g. astrocytes, which express a specific cytoplasmic filament protein (GFAP). The nuclei have been counterstained with a fluorescent dye (DAPI). Scale bars: A+B: 100 µm; C+D: 50 µm.

Human iPSC represent a type of “all-rounder” cell, which can proliferate practically indefinitely, and mature - under certain conditions - into any cell type. In the case of schizophrenia, changes in synaptic transmission have already been observed in iPSC derived nerve cells. These results show that in principle, cellular reprogramming offers the potential to develop human disease models for neuropsychiatric disorders. In collaboration with SP2 and SP3, we obtain access to the material of schizophrenia- and bipolar disorder patients with genetic profiles of particular interest to our research. We anticipate that firstly, neural cells obtained in SP9 via cellular reprogramming and differentiation technologies will enable the performance of gene- and protein expression studies in cooperation with SP1, SP6, and SP8. Secondly, genotype-phenotype studies of functional disease-specific nerve cells can be linked to the functional imaging findings of the respective patients (in cooperation with SP4). Finally, we anticipate that iPSC generated in SP9 will serve as a tool for drug testing and development.