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Direct reprogramming of human fibroblasts to expandable induced dopaminergic neuronal progenitors for Parkinson’s disease therapy [Array]

ABSTRACT: Direct reprogramming of human fibroblasts to expandable induced dopaminergic neuronal progenitors for Parkinson’s disease therapy [Array]

PROVIDER: PRJNA661193 | ENA |

REPOSITORIES: ENA

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Direct reprogramming of human fibroblasts to expandable induced dopaminergic neuronal progenitors for Parkinson’s disease therapy [Array]

Project description:Personalized cell therapy is being explored as promising treatments for incurable diseases such as Parkinson’s disease (PD). Here, we directly reprogrammed human fibroblasts into induced dopaminergic neuronal progenitors (hiDPs) and assess their applicability for regenerative PD therapy. We found that hiDPs maintain progenitor characteristics over 20 passages and showed unaltered differentiation potential to midbrain dopaminergic neurons. By next-generation sequencing, we confirm that even long-term cultured hiDPs retain genomic stability, resulting in absence of tumorigenicity when transplanted, indicating preclinical safety. The hiDPs differentiate into highly pure dopaminergic neurons expressing markers associated with positive graft outcomes without unwanted serotonergic neurons known to cause graft-induced dyskinesia. The therapeutic effect and safety were confirmed by transplantation in rodent PD models. Because our optimized reprogramming conditions generate highly expandable hiDPs enabling scaled production of clonal cells and overcoming quality control issues, we propose that our hiDPs can become a preferred autologous therapy for aged and feeble PD patients vulnerable to immunosuppression regimens.

2023-08-31 | GSE157392 | GEO

Direct reprogramming of human fibroblasts to expandable induced dopaminergic neuronal progenitors for Parkinson’s disease therapy [ChIP-seq]

2023-08-31 | GSE157340 | GEO

Direct reprogramming of human fibroblasts to expandable induced dopaminergic neuronal progenitors for Parkinson’s disease therapy

Project description:Direct reprogramming of human fibroblasts to expandable induced dopaminergic neuronal progenitors for Parkinson’s disease therapy

| PRJNA661195 | ENA

Direct reprogramming of human fibroblasts to expandable induced dopaminergic neuronal progenitors for Parkinson’s disease therapy [ChIP-seq]

Project description:Direct reprogramming of human fibroblasts to expandable induced dopaminergic neuronal progenitors for Parkinson’s disease therapy [ChIP-seq]

| PRJNA661026 | ENA

Direct reprogramming of human fibroblasts to expandable induced dopaminergic neuronal progenitors for Parkinson’s disease therapy

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-08-31 | GSE157394 | GEO

Polyomic analyses of dopaminergic neurons isolated from human substantia nigra in Parkinson’s disease: An exploratory study.

Project description:In this exploratory study, we used laser microdissection to extract dopaminergic neurons from 10 human SNpc samples obtained at autopsy in Parkinson’s disease patients and control subjects. Extracted RNA and proteins were identified by RNA sequencing and nano-LC-MS/MS, respectively, and the differential expression between Parkinson’s disease and control group was assessed.

2021-06-30 | GSE169755 | GEO

Polyomic analyses of dopaminergic neurons isolated from human substantia nigra in Parkinson’s disease: An exploratory study.

Project description:Dopaminergic neurons of the substantia nigra pars compacta selectively and progressively degenerate in Parkinson’s disease. Until now, molecular analyses of dopaminergic neurons in PD have been limited to genomic and transcriptomic approaches, whereas, to the best of our knowledge, no proteomic or combined polyomic study examining the protein profile of these neurons, is currently available. In this exploratory study, we used laser microdissection to extract dopaminergic neurons from 10 human SNpc samples obtained at autopsy in Parkinson’s disease patients and control subjects. Extracted RNA and proteins were identified by RNA sequencing and nano-LC-MS/MS, respectively, and the differential expression between Parkinson’s disease and control group was assessed. Qualitative analyses confirmed that the microdissection protocol preserves the integrity of our samples and offers access to specific molecular pathways. This polyomic analysis highlighted differential expression of 52 genes and 33 proteins, including molecules of interest already known to be dysregulated in Parkinson’s disease, such as LRP2, PNMT, CXCR4, MAOA and CBLN1 genes, or the Aldehyde dehydrogenase 1 protein. On the other hand, despite the same samples were used for both analyses, correlation between RNA and protein expression was low, as exemplified by the CST3 gene encoding for the cystatin C protein. This is the first exploratory study analyzing both gene and protein expression of LMD-dissected neurons from substantia nigra pars compacta in Parkinson’s disease.

2021-12-30 | PXD024748 | Pride

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

Transcriptomics analysis of human iPSC-derived dopaminergic neurons reveals a novel model for sporadic Parkinson’s disease

Project description:First, we differentiated human iPSCs into dopaminergic neurons. To reproduce and to study sporadic PD, the cells were subsequently exposed to increasing concentrations of the neurotoxin MPP+, which is considered the standard for experimentally inducing Parkinsonism. Resulting cells were examined using temporal transcriptomics analysis at various time-points after 24h of exposure. The transcriptomics analysis revealed a strong time- and dose-dependent response with genes overrepresented across pathways involved in PD etiology such as “Parkinson’s Disease”, “Dopaminergic signaling” and “calcium signaling”.

2022-07-07 | GSE196190 | GEO

Phenotypic manifestation of alpha-synuclein strains from Parkinson’s disease and multiple system atrophy in human dopaminergic neruons

Project description:Although α-synucleinis implicated in the pathogenesis of Parkinson’s disease and related disorders, it remains unclear whether specific conformations or levels of α-synuclein assemblies are toxic and how they cause progressive loss of human dopaminergic neurons. To address this issue, we used iPSC-derived dopaminergic neurons with a-synuclein triplication or controls where endogenous α-synuclein was imprinted into synthetic or disease-relevant conformations. We used α-synuclein fibrils generated de novo or amplified from homogenates of brains affected with Parkinson’s disease (n=3) .We found that a 2.5-fold increase in α-synuclein levels in α-synuclein gene triplication neurons promoted seeded aggregation in a dose and time-dependent fashion, which was associated with a further increase in α-synuclein gene expression.Transcriptomic analysis and isogenic correction of α-synuclein triplication revealed that intraneuronal α-synuclein levels solely and sufficiently explained vulnerability to cell death.

2020-09-02 | GSE149632 | GEO

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