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Transcriptome and in Vitro Differentiation Profile of Human Embryonic Stem Cell Derived NKX2.1-Positive Neural Progenitors

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Abstract

The generation of inhibitory interneuron progenitors from human embryonic stem cells (ESCs) is of great interest due to their potential use in transplantation therapies designed to treat central nervous system disorders. The medial ganglionic eminence (MGE) is a transient embryonic structure in the ventral telencephalon that is a major source of cortical GABAergic inhibitory interneuron progenitors. These progenitors migrate tangentially to sites in the cortex and differentiate into a variety of interneuron subtypes, forming local synaptic connections with excitatory projection neurons to modulate activity of the cortical circuitry. The homeobox domain-containing transcription factor NKX2.1 is highly expressed in the MGE and pre-optic area of the ventral subpallium and is essential for specifying cortical interneuron fate. Using a combination of growth factor agonists and antagonists to specify ventral telencephalic fates, we previously optimized a protocol for the efficient generation of NKX2.1-positive MGE-like neural progenitors from human ESCs. To establish their identity, we now characterize the transcriptome of these MGE-like neural progenitors using RNA sequencing and demonstrate the capacity of these cells to differentiate into inhibitory interneurons in vitro using a neuron-astrocyte co-culture system. These data provide information on the potential origin of interneurons in the human brain.

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Acknowledgments

The authors would like to thank Dr. Andrew Elefanty for his generous gift of providing the hES3 NKX2.1:GFP hESCs. They also thank Dr. Evan Jellison at the University of Connecticut Health Flow Cytometry Center for his assistance with FACS. This work was funded by grant 13-SCC-WES-01 from the Connecticut Regenerative Medicine Research Fund to L. Grabel.

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  1. Department of Biology, Wesleyan University, 52 Lawn Avenue, Middletown, CT, 06459, USA

    Christopher Y. Chen, Nickesha C. Anderson, Daniel Moakley, Trinithas Boyi, Carolyn Dundes, Chelsea Lassiter & Laura Grabel

  2. Department of Genetics and Genome Sciences, Institute for Systems Genomics, 400 Farmington Avenue, UCONN Health, Farmington, CT, 06030, USA

    Alex Plocik & Brenton R. Graveley

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  1. Christopher Y. Chen
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Supplementary Figure 1

Log2 transformed FPKM values for FACS isolated NKX2.1:GFP+ and NKX2.1:GFP- day 21 and 30 samples from both sequencing rounds. Values shown are ± SE. (JPEG 1591 kb)

Supplementary Figure 2

In vitro maturation of hESNPs. A) FPKM values of day 21 and 30 NKX2.1:GFP-positive cell populations from sequencing round 2 (green and red bars, respectively). Asterisk signifies statistical significance (P < 0.05) in calculated gene expression. B) Immunocytochemistry of NKX2.1:GFP, MAP2 and CB expression in day 21 and 30 FACS isolated GFP-positive cells. Day 21 and 30 scale bar =20 μm. C) Day 21 and 30 quantification analysis indicates higher percentage of the cell population expressing mature neuronal subtype markers at day 30. (JPEG 3111 kb)

Supplementary Figure 3

Heatmap and hierarchical clustering of the top A) 500 and B) 1000 genes with the largest gene expression fold change from day 21 and 30 hESNP differentiation experiments. Genes associated with selected Gene Ontologies are indicated (black). Gene expression represented as log2-transformed FPKM fold change values (NKX2–1+ / NKX2–1-). (JPEG 910 kb)

Supplementary Figure 4

Statistically significant changes in gene expression from two independent hESNP differentiation experiments are strongly correlated. Log2-transformed fold change FPKM values (NKX2–1+ / NKX2–1-) are shown for gene expression changes identified as statistically significant in one (grey points; Spearman =0.63) or both experiments (black circles; Spearman =0.81). In each quadrant, the number of gene expression changes is indicated for changes that were greater than 2-fold changed and statistically significant in one (grey) or both (black). Red lines (solid, dashed, and dotted) indicate 2, 4, and 8 fold changes. (JPEG 1545 kb)

Supplementary Table 1

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Supplementary Table 2

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Supplementary Table 3

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Supplementary Table 4

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Chen, C.Y., Plocik, A., Anderson, N.C. et al. Transcriptome and in Vitro Differentiation Profile of Human Embryonic Stem Cell Derived NKX2.1-Positive Neural Progenitors. Stem Cell Rev and Rep 12, 744–756 (2016). https://doi.org/10.1007/s12015-016-9676-2

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