Rapid Ngn2-induction of excitatory neurons from hiPSC-derived neural progenitor cells.

paper Cited Public

Authors: Ho, Seok-Man; Hartley, Brigham J; Tcw, Julia; Beaumont, Michael; Stafford, Khalifa; Slesinger, Paul A; Brennand, Kristen J
Year: 2016
Journal: Methods (San Diego, Calif.)
PMID: 26626326
DOI: 10.1016/j.ymeth.2015.11.019
PMCID: PMC4860098

Fig. 1

Scheme of Ngn2-neuronal induction from human NPCs and the accelerated neuronal morphology of Ngn2-NPCs. (A) Schematic of mNgn2 and hNGN2 neuronal induction, starting from hiPSC-derived NPCs. (B) Representative bright-field images of hiPSCs, NPCs and mNgn2-induced neurons. Scale bar 100 μm. (C) Timeline of mNgn2 and hNGN2-neuronal induction strategy. (D) GFP images of NPCs transduced with GFP-PuroR lentivirus (images taken before and 24 h after doxycycline treatment). Scale bar 100 μm. (E) FACS quantification of the percentage of GFP-positive cells across ten NPC lines transduced with hNGN2-eGFP-PuroR (presented as the average of three NPC lines each from two controls, and one NPC line each from a third control as well as three schizophrenia patients). (F) GFP images of live GFP-, mNgn2- and hNGN2-transduced NPCs at various induction time points, showing that Ngn2-NPCs acquire neuronal morphology faster than GFP-NPCs. Scale bar 50 μm. (G) Averaged MAP2AB fluorescent intensity of GFP-, mNgn2 and hNGN2-induced neurons at three weeks induction. Error bars are SEM (Standard Error of the Mean). *p < 0.05, **p < 0.01, ***p < 0.001.

Fig. 2

Accelerated increase in MAP2AB protein and RNA by Ngn2-transduction. (A) Representative images of mNgn2-induced neurons and GFP-NPCs at two weeks immunostained with neuronal dendrite marker MAP2AB (red), GFP (green) and DAPI-stained nuclei (blue). Scale bar 30 μm. (B) Averaged MAP2AB fluorescent intensity of GFP-NPCs and mNgn2-induced neurons at two weeks induction. MAP2AB intensity was normalized to total DAPI-positive nuclei per image, and further standardized to GFP-NPCs; mNgn2-induced neurons showed a 1.3-fold increase in MAP2AB intensity over GFP-NPCs. (C) Real-time qPCR analysis of MAP2AB mRNA expression from GFP-NPCs and mNgn2-induced neurons at two weeks of age. The expression level is normalized to GAPDH, and further standardized to GFP-NPCs; mNgn2-neurons showed 2.4-fold increase in MAP2AB. (D) Representative images of two-week-old and three-week-old mNgn2-induced neurons stained with MAP2AB (red) and DAPI (blue). Scale bar 30 μm. (E) Averaged MAP2AB fluorescent intensity of two-week-old and three-week-old mNgn2-induced neurons, normalized to two-week-old mNgn2-induced neurons; there was a 1.35-fold increased MAP2AB intensity in three-week-old mNgn2-induced neurons. Error bars are SEM (Standard Error of the Mean). *p < 0.05, **p < 0.01, ***p < 0.001.

Fig. 3

Evoked activity recorded from Ngn2-induced neurons. (A) Voltage clamp recording shows putative voltage-gated Na+ (inward) and K+ (outward) currents. Voltage pulses shown below (−100 to +70 mV). Holding potential was −70 mV. (B) Current clamp recording from the same neuron shows evoked action potentials. Dashed line indicates −60 mV. Current injection pulses shown below (−16 pA to 48 pA).

Fig. 4

Accelerated synaptic differentiation of Ngn2-induced neurons by neuronal induction. (A) Representative images of mNgn2-neurons and GFP-NPCs at three weeks, immunostained with presynaptic marker SYN1 (red) and MAP2AB (magenta). Scale bar 4 μm. (B) SYN1 puncta count, normalized to MAP2AB+ area, of mNgn2-induced neurons and GFP-NPCs at three weeks (gradual doxycycline withdrawal from day 2). The SYN1 puncta ratio was increased 1.9-fold relative to matched GFP-NPCs. (C) Real-time qPCR analysis of SYN1, vGLUT1, vGLUT2 and PSD95 mRNA expression from GFP-NPCs and mNgn2-induced neurons at three weeks, normalized to GAPDH, relative to GFP-NPCs. mNgn2-neurons showed increased SYN1 (2.3-fold), vGLUT1 (4.5-fold), vGLUT2 (3.8-fold); there no significant difference in PSD95 expression. (D) qPCR analysis of TH, GAD67, vGAT, TPH1, GFAP and S100β mRNA expression between three-week-old mNgn2-induced neurons and 6-week-old hiPSC forebrain (FB) neurons derived by directed differentiation; Ngn2-induced neurons showed decreased TH (6.3-fold), GAD67 (1.5-fold), comparably low levels of vGAT and TPH1, and decreased GFAP (13.6-fold) and S100β(3.2-fold) expression relative to 6-week-old forebrain neurons. (E) Representative images of 3-week-old mNgn2-induced neurons and PuroR-NPCs, stained with the dopaminergic marker TH, the GABAergic marker GAD65/67 and the astrocyte marker GFAP. DAPI-stained nuclei (blue). Scale bar 30 μm. (F) Representative bright-field images of 3-week-old hNGN2-induced neurons treated with 0 M, 10 nM, 50 nM, 100 nM and 1 μM Ara-C from days 6–20. Scale bar 30 μm. (G) Representative images of 3-week–old hNGN2-induced neurons (from two independent controls) treated with 0 nM, 10 nM, 50 nM, and 100 nM Ara-C from days 6–20, stained with the replication marker Ki67. DAPI-stained nuclei (blue). Scale bar 30 μm. (H) Percentage of Ki67-positive cells in three-week-old Ngn2-induced neuron populations treated with between 0 and 100 nM Ara-C. Error bars are SEM. *p < 0.05, **p < 0.01, ***p < 0.001.

Fig. 5

Transient Ngn2 is sufficient to generate induced neurons. (A) Timeline of mNgn2-neuronal induction strategy with different doxycycline lengths. Doxycycline was withdrawn at day two (D2), day eight (D8), day fourteen (D14) or not at all (No W/D). (B) Representative images of three-week-old mNgn2-induced neurons immunostained with MAP2AB (red) and DAPI (blue). Scale bar 30 μm. (C) Average MAP2AB fluorescent intensity at three weeks. (D) Representative images mNgn2-induced neurons immunostained with the presynaptic marker SYN1 (red) and MAP2AB (magenta). Scale bar 4 μm. (E) SYN1 puncta count, normalized to MAP2AB+ area at three-weeks. (F) Real-time qPCR analysis of SYN1, vGLUT1, vGLUT2 and PSD95 mRNA expression at three-weeks. Error bars are SEM. *p < 0.05, **p < 0.01, ***p < 0.001.

Fig. 6

Electrical activity of Ngn2-induced neurons from NPCs. (A) 5-min MEA raster plot of spontaneous activity from a neural network of 14-day-old neurons, with 0-days (left panel) or 14-days (right panel) doxycycline treatment to induce mNgn2 expression. The response over multiple electrodes is a measurement of network connectivity. Each thin black line is representative of an action potential. Bursts of electrical activity are indicated with solid blue blocks. (B) The percentage of active electrodes per well (left panel) or percentage of spikes in bursts (right panel) following either 0 days (white bar), 2 days (pink bar), 8 days (light red) or 14 days (dark red) of doxycycline treatment to induce mNgn2 expression in 14-day-old neurons. (C) Total number of spikes (left panel) or mean firing rate (Hz) (right panel) following treatment with vehicle control (DMSO), picrotoxin (PTX), 6-cyano-7-nitroquinoxaline-2,3-dion (CNQX) and tetrodotoxin (TTX) on 21-day-old hNGN2-neurons. Error bars are SEM. *p < 0.05, **p < 0.01, ***p < 0.001.

Fig. 7

Inter-individual efficiencies in Ngn2-induction between NPC lines. Representative bright-field images of hNGN2-neurons from six individuals (three controls and three schizophrenia patients) over three independent experiments. Varying the initial seeding density of individual NPC lines (NPC plating densities inset) is required if achieving a consistent neuronal density at the end-point is desired.

#	Section	Preview
60	4. Discussion	In this study, we described a method by which mouse or human Ngn2 transduction can rapidly induce…

Name	Type
24-well plate local	cohort
accutase	drug
action potential firing	phenotype
Allen Brain Span Atlas local	cohort
AquaPolymount mounting solution local	drug
Ara-C	drug
artificial cerebral spinal fluid (ACSF) local	drug
Ascl1	gene
astrocytes	phenotype
astroglia	anatomy
blocking/permeabilization buffer local	drug
brain development	phenotype
Brn2	gene
Ca2+	drug
calcium chloride	drug
Cases_and_controls local	cohort
cDNA	drug
cell attachment local	phenotype
chloroform	drug
cholinergic neurons	phenotype
CNQX	drug
coating mixture local	drug
control GFP transduced NPCs local	cohort
controls	cohort
cortex	anatomy
culture medium	drug
Cytosineβ-D-arabinofuranoside hydrochloride local	drug
DAPI	drug
DEPC-treated water local	drug
Dlg4	gene
DMEM	drug
DNAse kit (Ambion, AM1907) local	drug
donkey serum	drug
dopaminergic neurons	anatomy
doxycycline	drug
Dulbecco's Modified Eagle Medium	drug
early fetal human cortical tissue local	anatomy
eGFP	drug
EGTA	drug
enhanced neuronal maturation local	phenotype
Fast SYBR green master mix local	drug
fetal forebrain tissue local	anatomy
forebrain	anatomy
forebrain NPCs local	anatomy
GABA	phenotype
GABAergic neuronal differentiation local	phenotype
GAD1	gene
GAD65/67 local	phenotype
GFAP	gene
GFP	drug
glucose	drug
glutamatergic neurons	phenotype
growth factors	drug
HEK293T cells local	cohort
HEPES	drug
hiPSC-based induction local	cohort
hiPSCs local	drug
hNGN2 local	variant
hNGN2-induced neurons local	cohort
hNGN2-neurons local	cohort
induced neurons	phenotype
Isl1	gene
isopropanol	drug
K+ channel local	drug
Ki67-positive replicative cells local	phenotype
laminin	drug
lentivirus	drug
LHX3	gene
liquid nitrogen	drug
magnesium chloride	drug
MAP2	gene
MAP2AB	gene
MAP2AB local	phenotype
matrigel	drug
MEA plate local	cohort
Mg2+	drug
miR-124	drug
miR-9	drug
mNgn2 local	variant
mNgn2-induced neurons local	cohort
mNgn2-induced neurons local	phenotype
motor neuron identity local	phenotype
motor neurons local	phenotype
mouse brain	anatomy
Myt1l	gene
Na2ATP	drug
Na3GTP local	drug
Na+ channel local	drug
NaHCO3	drug
Nanodrop	drug
Neural progenitor cells (NPC) local	cohort
neurite growth local	phenotype
neuroblast stage local	phenotype
NEUROD1	gene
NEUROG2	gene
neurogenesis	phenotype
neuronal activity	phenotype
neuronal differentiation	phenotype
neuronal fate	phenotype
neuronal induction local	phenotype
neuronal morphology	phenotype
neuron medium local	drug
neurons local	drug
neurons	phenotype
Neuropsychiatric_disorders local	phenotype
Ngn2	gene
Ngn family local	gene
non-neuronal cell proliferation local	phenotype
NPC	drug
NPC-based induction local	cohort
NPC line local	cohort
NPC lines local	cohort
NPC medium local	drug
NPCs	cohort
NSB1442-4-3 local	cohort
NSB2513-1-4 local	cohort
NSB2607-1-4 local	cohort
NSB2607-3-1 local	cohort
NSB2607-4-1 local	cohort
NSB553-1-1 local	cohort
NSB553-2-3 local	cohort
NSB553-3-C local	cohort
NSB581-1-2 local	cohort
NSB690-1-4 local	cohort
paraformaldehyde	drug
PBSCa2+Mg2+ local	drug
PFA/medium mix local	drug
picrotoxin	drug
polyethylenimine	drug
poly-l-ornithine	drug
poly-ornithine	drug
postsynaptic maturation local	phenotype
potassium chloride	drug
potassium-D-gluconate local	drug
presynaptic maturation local	phenotype
primary antibody	drug
proliferative cells	phenotype
PSD95	gene
psychiatric disorders	phenotype
PTX	drug
puromycin	drug
PuroR local	gene
reduced dendritic arborization local	phenotype
reduced synaptic density local	phenotype
resting potential local	phenotype
RNA	drug
RNABee local	drug
RNAse-free 75% ethanol local	drug
rtTa	drug
S100B local	gene
schizophrenia	phenotype
secondary antibody	drug
six independent individuals local	cohort
six-week-old hiPSC forebrain neurons local	cohort
Slc17a6	gene
Slc17a7	gene
SLC32A1	gene
small molecules	drug
sodium chloride	drug
sodium creatine phosphate local	drug
sodium phosphate local	drug
SOX11	gene
spinal cord	anatomy
Spinfection local	drug
study cohort	cohort
Superscript III reverse transcription kit (ThermoFisher Scientific, 11752-050) local	drug
SYN1	gene
synaptogenesis	phenotype
TetO-hNGN2-P2A-eGFP-T2A-PuroR local	drug
TetO-hNGN2-P2A-PuroR local	drug
TetO-mNgn2-P2A-PuroR local	drug
tetrodotoxin	drug
Th	gene
three-week-old mNgn2-induced neurons local	cohort
TPH1	gene
transduction efficiency local	phenotype
Triton-X	drug
TTX	drug
vGLUT1	gene
vGLUT2	gene
viral medium local	drug
VSVG local	gene

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A translational genomics approach identifies IL10RB as the top candidate gene target for COVID-19 susceptibility.	Voloudakis G et al.	—	2022	→
Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy.	Lee A et al.	—	2022	→
Combining NGN2 programming and dopaminergic patterning for a rapid and efficient generation of hiPSC-derived midbrain neurons.	Sheta R et al.	—	2022	→
Making neurons, made easy: The use of Neurogenin-2 in neuronal differentiation.	Hulme AJ et al.	—	2022	→
Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression.	Seah C et al.	—	2022	→
Topologically controlled circuits of human iPSC-derived neurons for electrophysiology recordings.	Girardin S et al.	—	2022	→
Analysis framework and experimental design for evaluating synergy-driving gene expression.	Schrode N et al.	—	2021	→
Cell type-specific changes in transcriptomic profiles of endothelial cells, iPSC-derived neurons and astrocytes cultured on microfluidic chips.	Middelkamp HHT et al.	—	2021	→
Differential acute impact of therapeutically effective and overdose concentrations of lithium on human neuronal single cell and network function.	Izsak J et al.	—	2021	→
Efficient Derivation of Excitatory and Inhibitory Neurons from Human Pluripotent Stem Cells Stably Expressing Direct Reprogramming Factors.	Song S et al.	—	2021	→
Fitness selection of hyperfusogenic measles virus F proteins associated with neuropathogenic phenotypes.	Ikegame S et al.	—	2021	→
<i>MED12</i>-Related (Neuro)Developmental Disorders: A Question of Causality.	Plassche SV et al.	—	2021	→
Improved Method for Efficient Generation of Functional Neurons from Murine Neural Progenitor Cells.	Soni A et al.	—	2021	→
Intronic enhancer region governs transcript-specific <i>Bdnf</i> expression in rodent neurons.	Tuvikene J et al.	—	2021	→
Modulating the Electrical and Mechanical Microenvironment to Guide Neuronal Stem Cell Differentiation.	Oh B et al.	—	2021	→
Physiological and Pathological Ageing of Astrocytes in the Human Brain.	Verkerke M et al.	—	2021	→
SOX9-induced Generation of Functional Astrocytes Supporting Neuronal Maturation in an All-human System.	Neyrinck K et al.	—	2021	→
Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors.	Lagomarsino VN et al.	—	2021	→
Transformative Network Modeling of Multi-omics Data Reveals Detailed Circuits, Key Regulators, and Potential Therapeutics for Alzheimer's Disease.	Wang M et al.	—	2021	→
Using the dCas9-KRAB system to repress gene expression in hiPSC-derived <i>NGN2</i> neurons.	Li A et al.	—	2021	→
ASCL1- and DLX2-induced GABAergic neurons from hiPSC-derived NPCs.	Barretto N et al.	—	2020	→
Cell Type-Specific In Vitro Gene Expression Profiling of Stem Cell-Derived Neural Models.	Gregory JA et al.	—	2020	→
CRISPR-based functional evaluation of schizophrenia risk variants.	Rajarajan P et al.	—	2020	→
Doublecortin-like Kinase 1 Regulates α-Synuclein Levels and Toxicity.	Vázquez-Vélez GE et al.	—	2020	→
Emerging Developments in Human Induced Pluripotent Stem Cell-Derived Microglia: Implications for Modelling Psychiatric Disorders With a Neurodevelopmental Origin.	Hanger B et al.	—	2020	→
Global Landscape and Dynamics of Parkin and USP30-Dependent Ubiquitylomes in iNeurons during Mitophagic Signaling.	Ordureau A et al.	—	2020	→
High-throughput screening identifies histone deacetylase inhibitors that modulate GTF2I expression in 7q11.23 microduplication autism spectrum disorder patient-derived cortical neurons.	Cavallo F et al.	—	2020	→
Integrating CRISPR Engineering and hiPSC-Derived 2D Disease Modeling Systems.	Rehbach K et al.	—	2020	→
Investigation of Schizophrenia with Human Induced Pluripotent Stem Cells.	Powell SK et al.	—	2020	→
Modeling neuronal consequences of autism-associated gene regulatory variants with human induced pluripotent stem cells.	Ross PJ et al.	—	2020	→
Neuronal differentiation strategies: insights from single-cell sequencing and machine learning.	Konstantinides N et al.	—	2020	→
The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer's disease.	Hur JY et al.	—	2020	→
Transcription Factor-Based Fate Specification and Forward Programming for Neural Regeneration.	Flitsch LJ et al.	—	2020	→
Direct Neuronal Reprogramming Reveals Unknown Functions for Known Transcription Factors.	Colasante G et al.	—	2019	→
Human iPSC application in Alzheimer's disease and Tau-related neurodegenerative diseases.	Tcw J	—	2019	→
<i>CNTN5</i><sup>-</sup><i><sup>/+</sup></i>or <i>EHMT2</i><sup>-</sup><i><sup>/+</sup></i>human iPSC-derived neurons from individuals with autism develop hyperactive neuronal networks.	Deneault E et al.	—	2019	→
Molecular Interaction Networks to Select Factors for Cell Conversion.	Ouyang JF et al.	—	2019	→
mTOR and autophagy pathways are dysregulated in murine and human models of Schaaf-Yang syndrome.	Crutcher E et al.	—	2019	→
Neuronal impact of patient-specific aberrant NRXN1α splicing.	Flaherty E et al.	—	2019	→
Overexpression of NEUROG2 and NEUROG1 in human embryonic stem cells produces a network of excitatory and inhibitory neurons.	Lu C et al.	—	2019	→
Robust Generation of Person-Specific, Synchronously Active Neuronal Networks Using Purely Isogenic Human iPSC-3D Neural Aggregate Cultures.	Izsak J et al.	—	2019	→
Synergistic effects of common schizophrenia risk variants.	Schrode N et al.	—	2019	→
Synthetic mRNAs Drive Highly Efficient iPS Cell Differentiation to Dopaminergic Neurons.	Xue Y et al.	—	2019	→
Best Practices for Translational Disease Modeling Using Human iPSC-Derived Neurons.	Engle SJ et al.	—	2018	→
Convergence of independent DISC1 mutations on impaired neurite growth via decreased UNC5D expression.	Srikanth P et al.	—	2018	→
Genetics of Alcohol Use Disorder: A Role for Induced Pluripotent Stem Cells?	Prytkova I et al.	—	2018	→
Inhibition of STEP<sub>61</sub> ameliorates deficits in mouse and hiPSC-based schizophrenia models.	Xu J et al.	—	2018	→
Modeling Neuropsychiatric and Neurodegenerative Diseases With Induced Pluripotent Stem Cells.	LaMarca EA et al.	—	2018	→
Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk.	Rajarajan P et al.	—	2018	→
Application of CRISPR/Cas9 to the study of brain development and neuropsychiatric disease.	Powell SK et al.	—	2017	→
Discovery of Compounds that Positively Modulate the High Affinity Choline Transporter.	Choudhary P et al.	—	2017	→
Evaluating Synthetic Activation and Repression of Neuropsychiatric-Related Genes in hiPSC-Derived NPCs, Neurons, and Astrocytes.	Ho SM et al.	—	2017	→
Patient-derived hiPSC neurons with heterozygous CNTNAP2 deletions display altered neuronal gene expression and network activity.	Flaherty E et al.	—	2017	→
Personalized medicine in a dish: the growing possibility of neuropsychiatric disease drug discovery tailored to patient genetic variants using stem cells.	Brennand KJ	—	2017	→
Pluripotent stem cells in neuropsychiatric disorders.	Soliman MA et al.	—	2017	→
Prospects for Modeling Abnormal Neuronal Function in Schizophrenia Using Human Induced Pluripotent Stem Cells.	Prytkova I et al.	—	2017	→
Stem cell-derived neurons in the development of targeted treatment for schizophrenia and bipolar disorder.	Watmuff B et al.	—	2017	→
THC Treatment Alters Glutamate Receptor Gene Expression in Human Stem Cell-Derived Neurons.	Obiorah IV et al.	—	2017	→
Coenzyme A corrects pathological defects in human neurons of PANK2-associated neurodegeneration.	Orellana DI et al.	—	2016	→
Human pluripotent stem cells.	Carpenedo RL et al.	—	2016	→