Neuronal conversion of human glioblastoma cells by neural transcription factors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA678662 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13066378.fastq.gz | Fastqsanger.gz | |||
| SRR13066379.fastq.gz | Fastqsanger.gz | |||
| SRR13066380.fastq.gz | Fastqsanger.gz | |||
| SRR13066381.fastq.gz | Fastqsanger.gz | |||
| SRR13066382.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: To test the neuronal conversion and other effects induced by neural transcription factor Neurog2 or Ascl1 in human glioblastoma cells Methods: Retroviral expression of Ascl1, Neurog2 or control GFP in cultured human U251 cells at 6 DPI
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2012-04-07 | E-GEOD-36246 | biostudies-arrayexpress
Project description:Forced expression of pro-neural transcription factors was shown to mediate direct neuronal conversion of human fibroblasts. Since neurons are postmitotic, the conversion efficiency represents an important parameter. Here we present a minimalist approach combining two factor neuronal programming with small molecule-based inhibition of GSK3ß and SMAD signaling, which gives rise to functional neuron-like cells (iNs) of various neurotransmitter phenotypes with an overall yield of up to >200% and a final neuronal purity of up to >80%.
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Project description:Neuronal restricted progenitors (NRPs) represent a type of transitional intermediate cells that lie between multipotent neural progenitors (NPs) and terminal differentiated neurons during neurogenesis. These NRPs have the ability to self-renew and differentiate into neurons, but not into glial cells, which is considered as an advantage for cellular therapy of human neurodegenerative diseases. However, difficulty in the extraction of highly purified NPRs from normal nervous tissue prevents further studies and applications. In this study, we reported conversion of human fetal dermal fibroblasts into human induced neuronal restricted progenitors (hiNRPs) in seven days by using just three defined factors: Sox2, c-Myc, and either Brn2 or Brn4. The hiNRPs exhibited distinct neuronal characteristics, including cell morphology, multiple neuronal markers expression, self-renewal capacity, and genome-wide transcriptional profile. Moreover, hiNRPs were able to differentiate into various terminal neurons with functional membrane properties, but not glial cells. Direct generation of hiNRPs from somatic cells will provide a new source of cells for cellular replacement therapy of human neurodegenerative diseases. This is a general expression microarray design (NimbleGen platform). It includes 5 samples.
2013-10-24 | E-GEOD-51580 | biostudies-arrayexpress
Project description:Neuronal conversion from human fibroblasts can be induced by lineage-specific transcription factors, holding great promise for human neurological disease modeling and regenerative medicine. However, the introduction of ectopic genes limits their therapeutic applications. Here, we report that neuronal cells could be directly induced from human fibroblasts by a chemical cocktail of seven small molecules bypassing neural progenitor stage. These chemical-induced neuronal cells (hciN cells) resembled hES-derived neurons regarding morphology, gene expression profiles, and electrophysiological properties. Our further experiments show that hciN cells were able to develop into mature neurons in vivo in embryonic mouse brain. Moreover, this approach was further applied to induce hciN cells from fibroblasts of familial Alzheimer’s disease patients and the hciN cells showed abnormal A? production. Together, we established a transgene-free chemical approach to directly induce neuronal cells from human fibroblasts, thus providing alternative strategies for modeling of related neurological diseases and regenerative medicine. We used microarray to comparethe global gene expression patterns of hES-derived neurons (control neurons), HAFs, pre-hciN cells (VCRFSGY-treated HAFs at day 3 and 7) and hciN cells (induced with VCRFSGY for 14 days) hciNs RNA samples were selected at different time points, i.e. pre-hciN cells (VCRFSGY-treated HAFs at day 3 and 7) and hciN cells (induced with VCRFSGY for 14 days), to study molecular mechanism and marker gene expression happened at the early stage of chemical induction by compared with hES-neurons (positve control) and HAFs (negtive control).
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Project description:Neuronal restricted progenitors (NRPs) represent a type of transitional intermediate cells that lie between multipotent neural progenitors (NPs) and terminal differentiated neurons during neurogenesis. These NRPs have the ability to self-renew and differentiate into neurons, but not into glial cells, which is considered as an advantage for cellular therapy of human neurodegenerative diseases. However, difficulty in the extraction of highly purified NPRs from normal nervous tissue prevents further studies and applications. In this study, we reported conversion of human fetal dermal fibroblasts into human induced neuronal restricted progenitors (hiNRPs) in seven days by using just three defined factors: Sox2, c-Myc, and either Brn2 or Brn4. The hiNRPs exhibited distinct neuronal characteristics, including cell morphology, multiple neuronal markers expression, self-renewal capacity, and genome-wide transcriptional profile. Moreover, hiNRPs were able to differentiate into various terminal neurons with functional membrane properties, but not glial cells. Direct generation of hiNRPs from somatic cells will provide a new source of cells for cellular replacement therapy of human neurodegenerative diseases.
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Project description:The neural behavior of glioblastoma, including the formation of tumor microtubes and synaptic circuitry, is increasingly understood to be pivotal for disease manifestation (Osswald et al. 2015; Venkatesh et al. 2015; Weil et al. 2017; Venkataramani et al. 2019; Venkatesh et al. 2019; Alcantara Llaguno et al. 2019; Venkataramani et al. 2022). Nonetheless, the few approved treatments for glioblastoma target its oncological nature, while its neural vulnerabilities remain incompletely mapped and clinically unexploited. Here, we systematically survey the neural molecular dependencies and cellular heterogeneity across 27 glioblastoma patients and diverse model systems. In patient tumor samples taken directly after surgery, we identify a spectrum of neural stem cell morphologies indicative of poor prognosis, and discover a set of repurposable neuroactive drugs with unexpected and consistent anti-glioma efficacy. Glioblastoma cells exhibit functional dependencies on highly expressed drug targets including neurological ion channels and receptors, while interpretable molecular machine learning reveals downstream convergence on secondary drug targets (COSTAR) involving AP-1-driven tumor suppression. COSTAR enables in silico drug screening on >1 million compounds that are validated with high accuracy. Multi-omic profiling of drug-treated glioblastoma cells confirms rapid Ca2+-driven AP-1 pathway induction to represent a tumor-intrinsic vulnerability at the intersection of oncogenesis and neural activity-dependent signaling. Finally, the consistent anti-glioma activity across patients and model systems is epitomized by the antidepressant Vortioxetine, which synergizes in vivo with approved glioblastoma chemotherapies. In all, our global analysis reveals that the neural vulnerabilities of glioblastoma converge on an AP-1 mediated gene regulatory network with direct translatable potential.
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Project description:Although transcription factor(TF)s regulate differentiation-related processes, including dedifferentiation and direct conversion, functional interactions between TFs regulating these processes are not well understood. Here we show that TFs preventing dedifferentiation are able to induce direct conversion. Using a neural lineage cell line and a large number of TFs expressed in it, we found a subset of TFs whose overexpression strongly interfered with dedifferentiation triggered by a procedure to induce induced pluripotent stem cells (iPSC), through a maintenance mechanism of the cell-type-specific transcriptional profile. Strikingly, the maintenance activity of the interfering TF set was strong enough to induce the cell line-specific transcriptional profile when overexpressed in a heterologous cell type. In addition, TFs that interfered with dedifferentiation in hepatic lineage cells involved known TFs with induction activity for hepatic lineage cells. Our results suggest that dedifferentiation suppresses a cell-type-specific transcriptional profile, which is primarily maintained by a small subset of TFs capable of inducing direct conversion. We anticipate that this functional correlation might be applicable in various cell types, which may include cancer cells, and might facilitate identification of TFs with induction activity to understand differentiation and tumorigenesis Examination of binding of 3 transcription factors and histone modifications in Neural progenitor like cells.
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Project description:Direct cell reprogramming has enabled the direct conversion of skin fibroblasts into functional neurons and oligodendrocytes using a minimal set of cell lineage-specific transcription factors. This approach has substantial advantages since it is rapid and simple, generating the cell type of interest in a single step. However, it remains unknown whether this technology can be applied for directly reprogramming skin cells into astrocytes, the third neural lineage. Astrocytes play crucial roles in neuronal homeostasis and their dysfunctions contribute to the origin and progression of multiple human diseases. Herein, we carried out a screening using several transcription factors involved in defining the astroglial cell fate and identified NFIA, NFIB and SOX9 to be sufficient to convert with high efficiency embryonic and post-natal mouse fibroblasts into astrocytes (iAstrocytes). We proved both by gene expression profiling and functional tests that iAstrocytes are comparable to native brain astrocytes. This protocol can be then employed to generate functional iAstrocytes for a wide range of experimental applications. Induced astrocytes (iAstro) were compared to Fibroblasts (Fibro) as negative control and to primary astrocytes (astro) as positive control. Three biological replicates were analyzed for each experimental group.
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