Acceleration of neural maturation in vitro to generate fully functional human neurons

The Kaji lab studies molecular mechanisms of cellular reprogramming to understand how to control cell fate, and to realize efficient and rapid generation of desired cell types. Recently the lab found that modulation of one signalling pathway could dramatically improve iPSC generation efficiency and speed up the kinetics of reprogramming. Moreover, activation of the same signalling pathway during transdfferentiation of human fibroblasts into neurons by Ascl1,Brn2, Mytl1, and NeuroD shortened the time required for the generation of mature neurons from 50 days to 23 days. This finding is very exciting because the production of fully functional mature human neurons from ESCs/iPSCs takes at least 50 days, and this hurdle currently limits the full application of iPSC technology. Such neurons can be used for toxicology tests, drug screening, and eventually for autologous cell transplantation therapies.
In this project we aim to understand how acceleration of neural maturation happens by modulation of this signalling pathway during transcription factor-mediated transdifferentiating at the molecular levels. The project involves state-of-the-art molecular biology, CRISPR/Cas9 genome editing, lentiviral vector infection, human iPSC/ESC culture and differentiation, Next Generation Sequencing, and Bioinformatics. Day-to-day supervision will be provided by Dr Kaji and Dr Kunath, and basic bioinformatics training will be provided by Stem Cell Bioinformatics Service at MRC CRM. In addition, we will also explore strategies to accelerate generation of a specific neuronal subtype, namely dopaminergic (DA) neurons in both ESC/iPSC differentiation and transdifferentiation in collaboration with the Kunath lab.