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GSE77274
Mus musculus
6 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
To realize cell transplantation therapy for Parkinson's disease (PD), the grafted neurons should be integrated into the host neuronal circuit in order to restore the lost neuronal function. Here, using wheat germ agglutinin-based trans-synaptic tracing, we show that integrin 5 is selectively expressed in striatal neurons that are innervated by midbrain dopaminergic (DA) neurons from the mouse experiments. Additionally, we found that integrin 51 was activated by the administration of estradiol-2-benzoate (E2B) in striatal neurons of adult female rats. Importantly, we observed that the systemic administration of E2B into hemi-parkinsonian rat models facilitates the functional integration of grafted DA neurons derived from human induced pluripotent stem cells into the host striatal neuronal circuit via the activation of integrin 51. Finally, methamphetamine-induced abnormal rotation was recovered earlier in E2B-administrated rats than in rats that received other regimens. Our results suggest that the simultaneous administration of E2B with stem cell-derived DA progenitors can enhance the efficacy of cell transplantation therapy for PD.
Publication Title
Estradiol Facilitates Functional Integration of iPSC-Derived Dopaminergic Neurons into Striatal Neuronal Circuits via Activation of Integrin α5β1.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 15 Downloadable Samples
Illumina HiSeq 1500
Description
Seckel syndrome (SS) is a rare spectrum of congenital severe microcephaly and dwarfism. One SS-causative gene is Ataxia Telangiectasia and Rad3-Related Protein (ATR), and ATR (c.2101 A>G) mutation causes skipping of exon 9, resulting in a hypomorphic ATR defect in patients. Because ATR governs DNA repair response, the mutation has been considered the cause of an impaired response to DNA replication stress in neuronal progenitor cells (NPCs), which is associated with the pathogenesis of microcephaly. However, the precise mechanism through which the mutation causes SS remains unclear. To address this issue, we established induced pluripotent stem cells (iPSCs) from fibroblasts carrying the ATR mutation and an isogenic ATR-corrected counterpart iPSC clone by genome editing. Interestingly, SS-patient-derived iPSCs (SS-iPSCs) exhibited cell type-specific splicing; exon 9 was dominantly skipped in fibroblasts and iPSC-derived NPCs, but it was included in undifferentiated iPSCs and definitive endodermal cells. SS-iPSC-derived NPCs (SS-NPCs) showed distinct expression profiles from ATR non-mutated NPCs. In SS-NPCs, abnormal mitotic spindles were observed more frequently than in gene-corrected counterparts, and the alignment of NPCs in the surface of the neurospheres was perturbed. Finally, we tested several splicing-modifying compounds and found that a CLK1 inhibitor, TG003, could pharmacologically rescue the exon 9 skipping in SS-NPCs. Furthermore, treatment with TG003 restored the function of ATR in SS-NPCs and decreased the frequency of abnormal mitotic events. In conclusion, our iPSC model of SS revealed a novel function of the ATR mutation in NPCs and NPC-specific missplicing, proving its usefulness for dissecting the pathophysiology of ATR-SS. Overall design: RNA-sequencing was conducted to identify the transcriptomic profiling of iPSC-derived cells
Publication Title
Verification and rectification of cell type-specific splicing of a Seckel syndrome-associated ATR mutation using iPS cell model.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (mDA) neurons for cell replacement therapy for Parkinson's disease (PD). However, iPSC-derived donor cells inevitably contain tumorigenic or inappropriate cells. To eliminate these unwanted cells, cell sorting using antibodies for specific markers such as CORIN or ALCAM have been developed, but neither marker is specific for ventral midbrain. Here, we employed a double-selection strategy for cells expressing both CORIN and LMX1A::GFP and report a novel cell surface marker to enrich mDA progenitors, LRTM1. When transplanted into 6-OHDA-lesioned rats, human iPSC-derived LRTM1+ cells survived and differentiated into mDA neurons in vivo, resulting in significant improvement in motor behavior without tumor formation. In addition, LRTM1+ cells exhibited efficient survival of mDA neurons in the brain of an MPTP-treated monkey. Thus, LRTM1 can provide a powerful tool for efficient and safe cell therapy for PD patients.
Publication Title
Purification of functional human ES and iPSC-derived midbrain dopaminergic progenitors using LRTM1.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 20 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (DA) neurons for cell replacement therapy for Parkinsons 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 Parkinsons disease.
Publication Title
Isolation of human induced pluripotent stem cell-derived dopaminergic progenitors by cell sorting for successful transplantation.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 55 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
MiRNAs are essential mediators of many biological processes. The aim of this study was to investigate the dynamics of miRNA-mRNA regulatory networks during exercise and subsequent recovery period.
Publication Title
Dynamically regulated miRNA-mRNA networks revealed by exercise.
Sample Metadata Fields
Sex, Age
View Samples- Bos taurus
- 9 Downloadable Samples
- Affymetrix Bovine Genome Array (bovine)
Description
The bovine chromaffin cell (BCC) is a unique modela highly homogeneous and accessible neuroendocrine cellin which to study gene regulation through first messenger-initiated signaling pathways that are specific to post-mitotic cells. BCCs were treated with tumor necrosis factor (TNF) or pituitary adenylate cyclase activating polypeptide (PACAP), two critical regulators of neural cell transcriptional programming during inflammation that act on TNFR2 and PAC1 receptors, respectively, in post-mitotic neuroendocrine cells. Transcripts which were significantly up regulated by either or both first messenger were identified from microarray analysis using two bovine oligonucleotide arrays (Affymetrix and Agilent) followed by statistical analysis with Partek Genomic suite. Microarray data were combined from the two arrays using qRT-PCR sampling validation, and the first-messenger transcriptome derived from TNF and PACAP signaling were compared. More than 90 percent of the genes up regulated either by TNF or PACAP were specific to a single first messenger. BioBase suite, DIRE and Opossum were used to identify common promoter/enhancer response elements that control the expression of TNF- or PACAP-stimulated genes. Bioinformatic analysis revealed that distinct groups of transcription factors control the expression of genes up regulated by either TNF or PACAP . Most of the genes up regulated by TNF contained response elements for members of the Rel transcription factor family, suggesting TNF-TNFR2 signaling mainly through the NF-kB signaling pathway. On the other hand, the PACAP regulated genes showed no enrichment for any single response element, containing instead response elements for combinations of transcription factors allowing activation through multiple signaling pathways, including cAMP, calcium and ERK, in neuroendocrine cells. Pharmacological strategies for mimicking neuroprotection by either PACAP or TNF in the context of CNS injury or degeneration in disease might focus on individual downstream gene activation pathways to achieve greater specificity in vivo.
Publication Title
Neuropeptides, growth factors, and cytokines: a cohort of informational molecules whose expression is up-regulated by the stress-associated slow transmitter PACAP in chromaffin cells.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 69 Downloadable Samples
- Illumina HiSeq 2500
Description
RNA sequencing of duodenal polyps in FAP patients treated with plabebo or the drug combination, erlotinib + sulindac Overall design: 69 duodenal RNA sequencing datasets (17 baseline uninvolved from 17 FAP patients, 10 endpoint uninvolved and 16 polyp from 10 FAP patients on placebo, 10 endpont uninvolved and 16 polyp from 10 FAP patients on drug)
Publication Title
Chemoprevention with Cyclooxygenase and Epidermal Growth Factor Receptor Inhibitors in Familial Adenomatous Polyposis Patients: mRNA Signatures of Duodenal Neoplasia.
Sample Metadata Fields
Specimen part, Treatment, Subject, Time
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina HiSeq 2000
Description
The ability to generate defined null mutations in mice revolutionized the analysis of gene function in mammals. However, gene-deficient mice generated by using 129-derived embryonic stem (ES) cells may carry large segments of 129 DNA, even when extensively backcrossed to reference strains, such as C57BL/6J, and this may confound interpretation of experiments performed in these mice. Tissue plasminogen activator (tPA), encoded by the PLAT gene, is a fibrinolytic serine protease that is widely expressed in the brain. A large number of neurological abnormalities have been reported in tPA-deficient mice. The studies here compare genes differentially expressed in the brains of Plat-/- mice from two independent Plat-/- mouse derivations to wild-type C57BL/6J mice. One strain denoted “Old” was constructed in ES cells from a 129 mouse and backcrossed extensively to C57BL/6J, and one denoted “New” Plat-/- mouse was constructed using zinc finger nucleases directly in the C57BL/6J-Plat-/- mouse strain. We identify a significant set of genes that are differentially expressed in the brains of Old Plat-/- mice that preferentially cluster in the vicinity of Plat on chromosome 8, apparently linked to more than 20 Mbp of DNA flanking Plat being of 129 origin. No such clustering is seen in the New Plat-/- mice. Overall design: Whole-transcriptome profiling of the cerebral cortex of wild-type control C57BL/6J mice and two independent Plat-/- mice strains on the C57BL/6J background.
Publication Title
Passenger mutations and aberrant gene expression in congenic tissue plasminogen activator-deficient mouse strains.
Sample Metadata Fields
Age, Specimen part, Cell line, Subject
View Samples- Drosophila melanogaster
- 9 Downloadable Samples
- Affymetrix Drosophila Genome 2.0 Array (drosophila2)
Description
Dominantly inherited expanded repeat neurodegenerative diseases are typically caused by the expansion of existing variable copy number tandem repeat sequences in otherwise unrelated genes. Repeats located in translated regions encode polyglutamine that is thought to be the toxic agent, however in several instances the expanded repeat is in an untranslated region, necessitating multiple pathogenic pathways or an alternative common toxic agent. As numerous clinical features are shared by several of these diseases, and expanded repeat RNA is a common intermediary, RNA has been proposed as a common pathogenic agent. Various forms of repeat RNA are toxic in animal models, by multiple distinct pathways. In Drosophila, repeat-containing double-stranded RNA (rCAG.rCUG~100) toxicity is dependent on Dicer processing evident with the presence of single-stranded rCAG7, which have been detected in affected HD brains. Microarray analysis of Drosophila rCAG.rCUG~100 repeat RNA toxicity revealed perturbation of several pathways including innate immunity. Recent reports of elevated circulating cytokines prior to clinical onset, and age-dependent increased inflammatory signaling and microglia activation in the brain, suggest that immune activation precedes neuronal toxicity. Since the Toll pathway is activated by certain forms of RNA, we assessed the role of this pathway in RNA toxicity. We find that rCAG.rCUG~100 activates Toll signaling and that RNA toxicity is dependent on this pathway. The sensitivity of RNA toxicity to autophagy further implicates innate immune activation. Expression of rCAG.rCUG~100 was therefore directed in glial cells and found to be sufficient to cause neuronal dysfunction. Non-autonomous toxicity due to expanded repeat-containing double-stranded RNA mediated activation of innate immunity is therefore proposed as a candidate pathway for this group of human genetic diseases.
Publication Title
Distinct roles for Toll and autophagy pathways in double-stranded RNA toxicity in a Drosophila model of expanded repeat neurodegenerative diseases.
Sample Metadata Fields
Sex, Specimen part, Disease
View Samples- Homo sapiens
- 27 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
To investigate the role of p53 and DICER in the induction of ER stress, wildtype, p53 knockout or DICER mutant HCT116 colon cancer cells were treated with the ER stress inducers tunicamycin or brefeldin A for 24 hours.
Publication Title
A close connection between the PERK and IRE arms of the UPR and the transcriptional regulation of autophagy.
Sample Metadata Fields
Cell line, Treatment
View Samples