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Molecular factors controlling human brain development

Our lab has a long-standing interest in studying the pathways controlling regionalisation and specification of the human developing brain. This work involves analysis of fetal brain anatomy, and identification of key genes and noncoding RNAs controlling the compartmentalisation of the brain. Through the use of human embryonic stem cells (hESCs), we can mimic brain development towards different regions of the human brain, and thereby investigate the effect of novel genes on neural differentiation.
We also work on more sophisticated 3D culturing methods to model human brain development on an anatomical level with hESCs. In this project, involving engineers from LTH, we apply advanced microfluidic techniques to culture hESCs under the influence of chemical gradients to mimic the environment around the developing brain in the fetus, thereby generating neural tissue with anatomical characteristics resembling the developing human brain.

Developing human dopamine neurons for clinical translation

As we have a strong focus on developing cells for cell replacement therapy in Parkinson’s disease, we are currently adapting our protocols for GMP compliance through the EU-funded network NeuroStemcellRepair. In line with this aim, we also perform extensive preclinical validation of the human dopamine neurons derived from our protocol in rat models of Parkinson’s disease. This includes long-term survival of transplanted cells in vivo to assess cell fate, maturation and integration, as well as functional behavioural assessment for graft function in vivo.
As a member of the European clinical trial TRANSEURO we also perform preclinical validation of human fetal dopamine neurons for clinical use. This also allows us the unique opportunity to directly compare our hESC-derived dopamine neurons with those sourced from human fetal tissue both in vitro and in vivo.

New methodologies for in vivo assessment of human neurons generated from stem cells or via reprogramming

We monitor our cells after transplantation using standard in vivo assessments as listed above. However, with a growing number of novel cell sources (stem cells and reprogrammed cells) it becomes important to develop new methodologies for a more thorough assessment of human neurons generated using these approaches. Thus we have recently established a number of new technologies to reveal how transplants function and integrate with the host brain.
We utilise monosynaptic tracing technology, using pseudotyped rabies vectors, in order to visualise the synaptic contacts formed between host neurons and graft human cells. This approach has opened up for a number of possibilities to assess graft integration in vivo that has so far been relatively unaddressed in the field. While expanding our knowledge of graft integration, we also investigate how that occurs at a functional level by utilising optogenetics in combination with highly sensitive and quantitative methods assessing neuronal function, such as electrophysiology and in vivo amperometry.