The use of human induced pluripotent stem cells (hiPSCs) facilitates studying the genesis of human cell types in an ethically approved setting. However, exploiting the full potency of stem cells is only possible with very few differentiated cell types. In particular, the generation of neurons is in its infancy: of the many neuronal types present in the brain, only very few of the more than 300 cell types have been generated in vitro. So far, neuronal differentiation protocols are multifaceted and tailored to individual cell types. The molecular events that occur during reprogramming remain enigmatic. Hence, we cannot confer these protocols easily on producing different neurons of interest. The idea of these ERC actions was to induce transcription factors (TFs) as differentiation control buttons in hiPSCs and to explore their potency to trigger in vitro neurogenesis systematically.
Although highly important for biomedical research, there is a steady increasing societal pressure to reduce and to ban research using animal models. Therefore, programming certain human neuronal cell types from hiPSCs in high quality and quantity might substitute for some research that currently requires animal experimentation. These hiPSC-derived neurons represent potent model systems to study human pathologies but also basic cellular functions in a dish. In addition, differentiated human neurons such as photoreceptors for retinal degenerative diseases or dopaminergic neurons for Parkinson disease are of high interest for cell replacement therapies to repair vision and brain function.
All major objectives of the ProNeurons ERC actions were accomplished. A comprehensive human TF library was established and used for efficient forward programming of hiPSC to neurons (Ng, Khoshakhlagh et al. Nature Biotech 2020). Of particular interest was the discovery of three TFs that drive hiPSCs to photoreceptor precursor cells in just ten days in high efficiencies. These cells are currently evaluated as source material for transplantation therapies. Induced neurons were functionally, transcriptomically and anatomically characterized (Kutsche et al. Cell Systems 2018 and (Ng, Khoshakhlagh et al. Nature Biotech 2020). We have also developed and prototyped novel bioinformatic analyses to study the dynamically changing transcriptome from stem cell to neuron. Thereby, we could reveal the molecular blue prints of cell conversions (Kutsche et al. Cell Systems 2018).
