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Control iPSC lines with clinically annotated genetic variants for versatile multi-lineage differentiation

ABSTRACT: Induced Pluripotent Stem Cells (iPSC) derived from healthy individuals are important controls for disease modeling studies. To create a resource of genetically annotated iPSC, we reprogrammed footprint-free lines from four volunteers in the Personal Genome Project Canada (PGPC). Multilineage directed differentiation efficiently produced functional cortical neurons, cardiomyocytes and hepatocytes. Pilot users further demonstrated line versatility by generating kidney organoids, T-cells and sensory neurons. A frameshift knockout was introduced into MYBPC3 and these cardiomyocytes exhibited a hypertrophic phenotype as expected. WGS annotation of PGPC lines revealed on average 20 coding variants. Importantly, nearly all annotated PGPC and HipSci lines harboured at least one pre-existing or acquired variant with cardiac, neurological or other disease associations. Overall, PGPC lines were efficiently differentiated by multiple users into cell types found in six tissues for disease modelling, and clinical annotation highlighted variant-preferred lines for use as unaffected controls in specific disease settings.

PROVIDER: EGAS00001003684 | EGA |

REPOSITORIES: EGA

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Control iPSC lines with clinically annotated genetic variants for versatile multi-lineage differentiation

Project description:Induced Pluripotent Stem Cells (iPSC) derived from healthy individuals are important controls for disease modeling studies. To create a resource of genetically annotated iPSCs, we reprogrammed footprint-free lines from four volunteers in the Personal Genome Project Canada (PGPC). Multilineage directed differentiation efficiently produced functional cortical neurons, cardiomyocytes and hepatocytes. Pilot users further demonstrated line versatility by generating kidney organoids, T-lymphocytes and sensory neurons. A frameshift knockout was introduced into MYBPC3 and these cardiomyocytes exhibited the expected hypertrophic phenotype. Whole genome sequencing (WGS) based annotation of PGPC lines revealed on average 20 coding variants. Importantly, nearly all annotated PGPC and HipSci lines harboured at least one pre-existing or acquired variant with cardiac, neurological or other disease associations. Overall, PGPC lines were efficiently differentiated by multiple users into cell types found in six tissues for disease modeling, and clinical annotation highlighted variant-preferred lines for use as unaffected controls in specific disease settings.

2019-10-03 | GSE132012 | GEO

Project description:iPSC derived sensory neurons

| PRJNA1078586 | ENA

Affect of iPSC Passage Number on Neuronal Differentiation

Project description:Induced pluripotent stem cells (iPSCs) are a valuable resource for neurological disease-modeling and drug discovery, due to their ability to differentiate into neurons reflecting the genetics of the patient from which they are derived. iPSC-derived cultures, however, are highly variable due to differences in culture conditions. We investigated the effect of iPSC passage number on differentiation to optimize the generation of functional, mature sensory neurons (iPSC-dSNs). Three iPSC lines were differentiated into iPSC-dSNs at passage numbers within each of the following ranges: low (LP; 5-10), middle (MP; 20-26), and high (HP; 30-38). Morphology and pluripotency of the parent iPSCs were assessed prior to differentiation at each passage number. iPSC-dSNs were evaluated based on electrophysiological properties and expression of key neuronal markers. All iPSC lines displayed the same morphology and were similarly pluripotent across passage numbers. iPSC-dSNs were also morphologically comparable across passage numbers. However, the expression levels of neuronal markers and an analysis of sodium channel function indicated greater maturity in LP iPSC-dSNs. Our results demonstrate that lower passage numbers may be better suited for differentiation into peripheral sensory neurons. Further studies are warranted to elucidate factors that may contribute to the variability associated with iPSC passage number.

2022-07-19 | GSE193571 | GEO

Single cell sequencing of iPSC-dopamine neurons reconstructs disease progression and identifies HDAC4 as a regulator of Parkinson cell phenotypes

Project description:Induced pluripotent stem cell (iPSC)-derived dopamine neurons provide an opportunity to model Parkinson’s disease (PD) but neuronal cultures are confounded by cellular heterogeneity. By applying high-resolution single cell transcriptomic analyses to Parkinson’s iPSC-derived dopamine neurons carrying the GBA-N370S risk variant, we exploited intra-culture cellular heterogeneity to identify a progressive axis of gene expression variation leading to endoplasmic reticulum stress. Analysis of genes differentially-expressed (DE) along this axis identified the transcriptional repressor histone deacetylase 4 (HDAC4) as an upstream regulator of disease progression. HDAC4 was mislocalized to the nucleus in PD iPSC-derived dopamine neurons and repressed genes early in the disease axis, leading to late deficits in protein homeostasis. Treatment of iPSC-derived dopamine neurons with compounds known to modulate HDAC4 activity upregulated genes early in the DE axis, and corrected Parkinson’s-related cellular phenotypes. Our study demonstrates how single cell transcriptomics can exploit cellular heterogeneity to reveal disease mechanisms and identify therapeutic targets.

2018-10-17 | E-MTAB-7303 | biostudies-arrayexpress

e4e80b6b-f42f-4944-b55e-990b6a129d9f - samples

Project description:iPSC-derived motor neurons form familial ALS and Controls. 2 fALS iPSC lines and 3 Ctrl iPSC lines.

| EGAD00001008425 | EGA

095497af-5a52-4df9-8c01-8e6d42010aa4 - samples

Project description:iPSC-derived motor neurons form sporadic ALS and Controls. 4 sALS iPSC lines and 4 Ctrl iPSC lines.

| EGAD00001008424 | EGA

Mapping regulatory variation in sensory neurons using IPS lines from the HIPSCI project

Project description:Sensory neurons are nerve cells that are activated by sensory input such as heat, light and convey information to the brain. Although a key cell type in complex organisms, human sensory neurons are challenging to study because they are impossible to obtain from living donors. We have collaborated with the Neucentis Pharmaceutical Research Unit to differentiate sensory neuron like cells from human induced pluripotent stem cells derived as part of the Human Induced Pluripotent Stem Cells Initiative. We will sequence RNA from 100 IPS lines derived from healthy individuals and perform RNA-seq on the differentiated cells to identify noncoding variants that alter gene expression in human sensory neurons.

| EGAS00001001149 | EGA

EGAS00001001149-sc-20170117 - samples

| EGAD00001003145 | EGA

5658af53-befe-4737-9775-ec5f542df8a0 - samples

Project description:3 control iPSC lines differentiated into iPSC-derived motor neurons transduced with either EGFP or NOVA1 lentivirus.

| EGAD00001008423 | EGA

Characterisation of iPSC derived Sensory neurons with Single Cell RNA-seq

Project description:Despite the rapid development of protocols to differentiate human pluripotent stem cells (hPSCs) into neurons, those used to produce sensory neurons remain difficult to replicate and result in heterogenous populations. Moreover, there is a growing clinical burden of chronic pain conditions, highlighting a need for relevant human cellular models. This study presents a hybrid differentiation method to produce nociceptive sensory neurons from hPSCs. Cell lines harbouring an inducible NEUROG2 construct were patterned towards precursors with small molecules, followed by NEUROG2 overexpression. We profilled cells with single cell RNA sequencing, which revealed populations of nociceptors, demonstrated by the expression of key developmental and fucntional genes including volatge gated sodium and TRP channels. Overall, this study represents an optimisation of existing methods to efficiently produce nociceptive sensory neurons and provides a tool for chronic pain research and the development of treatments.

2022-11-17 | GSE188272 | GEO

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