Single-Cell Analysis Reveals a Close Relationship between Differentiating Dopamine and Subthalamic Nucleus Neuronal Lineages

Publication date: Available online 27 October 2016
Source:Cell Stem Cell
Author(s): Nigel Kee, Nikolaos Volakakis, Agnete Kirkeby, Lina Dahl, Helena Storvall, Sara Nolbrant, Laura Lahti, Åsa K. Björklund, Linda Gillberg, Eliza Joodmardi, Rickard Sandberg, Malin Parmar, Thomas Perlmann
Stem cell engineering and grafting of mesencephalic dopamine (mesDA) neurons is a promising strategy for brain repair in Parkinson's disease (PD). Refinement of differentiation protocols to optimize this approach will require deeper understanding of mesDA neuron development. Here, we studied this process using transcriptome-wide single-cell RNA sequencing of mouse neural progenitors expressing the mesDA neuron determinant Lmx1a. This approach resolved the differentiation of mesDA and neighboring neuronal lineages and revealed a remarkably close relationship between developing mesDA and subthalamic nucleus (STN) neurons, while also highlighting a distinct transcription factor set that can distinguish between them. While previous hESC mesDA differentiation protocols have relied on markers that are shared between the two lineages, we found that application of these highlighted markers can help to refine current stem cell engineering protocols, increasing the proportion of appropriately patterned mesDA progenitors. Our results, therefore, have important implications for cell replacement therapy in PD.

Graphical abstract

Teaser

Kee et al. use single-cell RNA-seq to reconstruct Lmx1a+ differentiation in silico, revealing an unexpectedly close relationship between mesDA and STN neuronal lineages during differentiation. Application of markers that distinguish the two can help optimize mesDA differentiation of hESCs with a view to improving therapeutic translation.


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