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Cell Stem Cell. 2017 Jan 5;20(1):29-40. doi: 10.1016/j.stem.2016.10.003. Epub 2016 Oct 27.

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

Author information

1
Ludwig Institute for Cancer Research, Box 240, 171 77 Stockholm, Sweden; Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden. Electronic address: nigel.kee@licr.ki.se.
2
Ludwig Institute for Cancer Research, Box 240, 171 77 Stockholm, Sweden.
3
Department of Experimental Medical Science, Lund Stem Cell Centre, Lund University, 221 84 Lund, Sweden.
4
Department for Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, 751 24 Uppsala, Sweden.
5
Ludwig Institute for Cancer Research, Box 240, 171 77 Stockholm, Sweden; Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.
6
Ludwig Institute for Cancer Research, Box 240, 171 77 Stockholm, Sweden; Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden. Electronic address: thomas.perlmann@ki.se.

Abstract

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.

KEYWORDS:

Parkinson’s disease; development; dopamine; embryogenesis; graph clustering; hypothalamus; neurogenesis; single cell RNA-seq; stem cell; subthalamic nucleus

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PMID:
28094018
DOI:
10.1016/j.stem.2016.10.003
[Indexed for MEDLINE]
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