Molecular Diversity of Midbrain Development in Mouse, Human, and Stem Cells

• Published in: Cell 2016-10, Vol.167 (2), p.566-580.e19
• Main Authors: La Manno, Gioele, Gyllborg, Daniel, Codeluppi, Simone, Nishimura, Kaneyasu, Salto, Carmen, Zeisel, Amit, Borm, Lars E., Stott, Simon R.W., Toledo, Enrique M., Villaescusa, J. Carlos, Lönnerberg, Peter, Ryge, Jesper, Barker, Roger A., Arenas, Ernest, Linnarsson, Sten
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Cellular Reprogramming Techniques; dopaminergic neuron; Dopaminergic Neurons - cytology; human; Humans; Machine Learning; Medicin och hälsovetenskap; Mesencephalon - cytology; Mesencephalon - embryology; Mesencephalon - metabolism; Mice; mouse; Neural Stem Cells - cytology; Neurogenesis; Neuroglia - cytology; Pluripotent Stem Cells - cytology; Resource; Sequence Analysis, RNA - methods; Single-Cell Analysis - methods; single-cell RNA-seq; ventral midbrain
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2016.09.027

Understanding human embryonic ventral midbrain is of major interest for Parkinson’s disease. However, the cell types, their gene expression dynamics, and their relationship to commonly used rodent models remain to be defined. We performed single-cell RNA sequencing to examine ventral midbrain development in human and mouse. We found 25 molecularly defined human cell types, including five subtypes of radial glia-like cells and four progenitors. In the mouse, two mature fetal dopaminergic neuron subtypes diversified into five adult classes during postnatal development. Cell types and gene expression were generally conserved across species, but with clear differences in cell proliferation, developmental timing, and dopaminergic neuron development. Additionally, we developed a method to quantitatively assess the fidelity of dopaminergic neurons derived from human pluripotent stem cells, at a single-cell level. Thus, our study provides insight into the molecular programs controlling human midbrain development and provides a foundation for the development of cell replacement therapies. [Display omitted] •Species differences in developmental timing and cell proliferation•Multiple radial glia subtypes biased toward distinct fates•Adult dopaminergic neuron subtypes emerge postnatally•A machine learning method to score dopaminergic differentiation of stem cells Analyzing the time course of ventral midbrain development in mouse, human, and stem cells by single-cell RNA-sequencing provides insight into dopaminergic neuron development and offers a strategy to assess the composition of stem-cell-derived preparations for clinical applications.