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Identification of ASCL1 as a determinant for human iPSC-derived dopaminergic neurons

ABSTRACT: To better understand how human pluripotent stem cells (hPSCs) differentiate from progenitor cells into distinct neuronal states, we performed 10x single cell RNA sequencing on in vitro directed differentiation cultures. We established differentiation platforms that model neural induction from human induced pluripotent stem cells (iPSCs) and single cell profiled two systems: 1) co-culture of progenitors and neurons and 2) purified neurons.

ORGANISM(S): Homo sapiens

PROVIDER: GSE185275 | GEO | 2021/12/02

REPOSITORIES: GEO

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Identification of ASCL1 as a determinant for human iPSC-derived dopaminergic neurons.

Project description:During cellular specification, transcription factors orchestrate cellular decisions through gene regulation. By hijacking these transcriptional networks, human pluripotent stem cells (hPSCs) can be specialized into neurons with different molecular identities for the purposes of regenerative medicine and disease modeling. However, molecular fine tuning cell types to match their in vivo counterparts remains a challenge. Directing cell fates often result in blended or incomplete neuron identities. A better understanding of hPSC to neuron gene regulation is needed. Here, we used single cell RNA sequencing to resolve some of these graded molecular identities during human neurogenesis from hPSCs. Differentiation platforms were established to model neural induction from stem cells, and we characterized these differentiated cell types by 10x single cell RNA sequencing. Using single cell trajectory and co-expression analyses, we identified a co-regulated transcription factor module expressing achaete-scute family basic helix-loop-helix transcription factor 1 (ASCL1) and neuronal differentiation 1 (NEUROD1). We then tested the function of these transcription factors in neuron subtype differentiation by gene knockout in a novel human system that reports the expression of tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine synthesis. ASCL1 was identified as a necessary transcription factor for regulating dopaminergic neurotransmitter selection.

| S-EPMC8593045 | biostudies-literature

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

Predicting the functional states of human iPSC-derived neurons with single-cell RNA-seq and electrophysiology

Project description:Neural progenitors derived from human pluripotent stem cells (hPSCs) develop into electrophysiologically active neurons at heterogeneous rates, which can confound disease-relevant discoveries in neurology and psychiatry. The goal of this study was to resolve the diversity of functional states of hPSC-derived neurons in vitro by combining patch clamping with morphological and RNA-sequencing analysis of single neurons (Patch-seq).

2020-10-07 | GSE159074 | GEO

Deriving Dopaminergic Neurons for Clinical Use. A Practical Approach.

Project description:Identification of new small molecules that regulate the step-wise differentiation of hPSC into dopaminergic neurons population. Furthermore, the naturally occurring steroid, guggulsterone, was found to be the most effective inducer of neural stem cells into dopaminergic neurons. Total RNA extracted at different stages of neural differentiation from human pluripotent stem cells

2013-04-24 | E-GEOD-42265 | biostudies-arrayexpress

Untargeted Mass Spectrometry Metabolomic Profiles of iPSC-derived Dopaminergic Neurons from Clinically Discordant Brothers with Identical PRKN Deletions

Project description:We have previously reported on two brothers, PM and SM, who carry identical compound heterozygous PRKN mutations but present with very different clinical Parkinson’s disease (PD) phenotypes, with PM, but not SM having been diagnosed with early onset disease. The occurrence of juvenile cases demonstrates that PD is not necessarily an age-associated disease, indeed evidence is accumulating that there is a developmental component to PD pathogenesis. We hypothesize that additional genetic modifiers, potentially including genetic loci relevant to mesencephalic dopamine neuron development may play a role. We differentiated human-induced pluripotent stem cells (hiPSCs) derived from SM and PM into mitotically active mesencephalic neural precursor cells and early postmitotic dopaminergic neurons and performed whole exome sequencing, transcriptomic- and metabolomic analyses. No significant differences in canonical markers of differentiation were observed between SM and PM. Yet our transcriptomic analysis revealed a significant down regulation of three neurodevelopmentally relevant cell adhesion molecules, CNTN6, CNTN4 and CHL1 in PM- compared to SM cultures on days 11 and 25 of differentiation. In addition, several HLA genes, known to play a role in neurodevelopment, independent of their well-established function in immunity, were differentially regulated in PM and SM developing dopamine neurons. EN2, a transcription factor crucial for mesencephalic dopamine neuron development, was also differentially regulated. We further observed differences in cellular processes relevant to dopamine homeostasis. Lastly, our whole exome sequencing, transcriptomics and metabolomics data of SM and PM neurons revealed differences in GSH homeostasis, the dysregulation of which has been associated with PD.

2021-10-13 | ST001957 | MetabolomicsWorkbench

Uncovering the role of FOXA2 in the development of human serotonin neurons [scRNA-seq]

Project description:We used single cell RNA sequencing (scRNA-seq) to analyze the diversity of serotonin neurons derived from human pluripotent stem cells (hPSCs) and to compare the transcriptomic differences between FOXA2 knockout and wide type hPSCs-derived serotonin neurons.

2023-09-07 | GSE232698 | GEO

Isolation of human iPSC-derived dopaminergic progenitors by cell sorting

Project description:Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (DA) neurons for cell replacement therapy for Parkinson’s disease. However, iPSC-derived donor cells may inevitably contain tumorigenic or inappropriate cells. Purification of neural progenitor cells or DA neurons as suitable donor cells has been attempted, but the isolation of DA progenitor cells derived from human pluripotent stem cells has so far been unsuccessful. Here we show human iPSC-derived DA progenitor cells can be efficiently isolated by cell sorting using a floor plate marker, Corin. we were able to develop a method for 1) scalable DA neuron induction on human laminin fragment and 2) sorting DA progenitor cells using an anti-Corin antibody. Furthermore, we determined the optimal timing for the cell sorting and transplantation. The grafted cells survived well and functioned as midbrain DA neurons in the 6-OHDA-lesioned rats, and showed minimal risk of tumor formation. The sorting of Corin-positive cells is favorable in terms of both safety and efficiency, and our protocol will contribute to the clinical application of human iPSCs for Parkinson’s disease. Differentiated human iPSC-derived neural progenitors just after sorting (day12 unsorted, day12 Corin+) and dopaminergic progenitors after an aggregation culture (day28 and day42, unsorted and day12-sorted, respectively), and human fetal ventral mesencephalon and dorsal mesencephalon (gestational age of 7.5 weeks) were subjected to RNA extraction and hybrdization on Affymetrix microarrays. Each sample except for human mesencephalon, undifferentiated iPSC, and day12-unsorted, day42-sample has 3 or 4 repeats.

2014-03-07 | E-GEOD-51214 | biostudies-arrayexpress

Characterization of human iPSC-derived dopaminergic neurons with 16p11.2 CNVs

Project description:We studied human induced pluripotent stem cells (iPSCs)-derived dopaminergic (DA) neuron populations carrying CNVs of 16p11.2 duplication and 16p11.2 deletion. Previously, healthy human iPSCs were edited using CRISPR-Cas9 method to produce isogenic lines with 16p11.2 deletion or 16p11.2 duplication. We differentiated these isogenic iPSC lines into neural precursor cells and dopaminergic neurons and collected RNA samples for gene expression analyses with RNA sequencing. Our aim was to identify differences in the expression of synaptic markers, neuronal differentiation markers, and neuron specific receptors that affect functionality of the neurons with 16p11.2 CNVs compared to isogenic control lines. We also studied physiological properties of these isogenic iPSC-derived DA neurons with 16p11.2 CNVs. In addition, we studied expression and activation of a specific molecular pathway KCTD13-RHOA in the iPSC derived DA neuron populations with 16p11.2 CNVs.

| EGAS00001005137 | EGA

Identification of ASCL1 as a determinant for human iPSC-derived dopaminergic neurons

Project description:Identification of ASCL1 as a determinant for human iPSC-derived dopaminergic neurons

| PRJNA768433 | ENA

Expression data from human iPS cells treated by a small molecule KY02111

Project description:Human pluripotent stem cells (hPSCs) such as embryonic stem cells and induced pluripotent stem cells are promising materials for cell-based regenerative therapies to heart diseases. However, until realization there are many hurdles such as high efficiency of cardiac differentiation of hPSCs and production of clinical-grade cardiac cells derived from hPSCs. Here, we show that a novel small molecule KY02111 robustly enhances differentiation to functional cardiomyocytes from hPSCs. To reveal how KY02111 function on promoting cardiac differentiation of hPSCs, we analyzed the gene expression profiles in KY02111-treated IMR90-1 hiPSCs using the microarray technique. At Day3 of cardiac differentiation from hiPSCs, KY02111 or DMSO was added in the culture and then the cell population was harvested after 12 or 24 hours for RNA extraction.

2012-10-30 | E-GEOD-33622 | biostudies-arrayexpress

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