Single Cell Transcriptomics Identifies Stem Cell-Derived Graft Composition in a Model of Parkinson’s Disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA485495 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7669370.fastq.gz | Fastqsanger.gz | |||
| SRR7669380.fastq.gz | Fastqsanger.gz | |||
| SRR7669390.fastq.gz | Fastqsanger.gz | |||
| SRR7669400.fastq.gz | Fastqsanger.gz | |||
| SRR7669410.fastq.gz | Fastqsanger.gz |
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Project description:Single cell transcriptomics identifies stem cell-derived graft composition in a model of Parkinson’s disease.
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Project description:Cell replacement is a long-standing and realistic goal for the treatment of Parkinson’s disease (PD). Cells for transplantation can be obtained from fetal brain tissue or from stem cells. However, after transplantation dopamine (DA) neurons are a minor component of grafts and it has remained difficult to determine the identity of other cell types. Here, we report analysis by single cell RNA sequencing (scRNA-seq) combined with comprehensive histological analyses to characterize intracerebral grafts from human embryonic stem cells (hESCs) and fetal tissue after functional maturation in a pre-clinical rat PD model. We show that neurons and astrocytes are major components in both fetal and stem cell-derived grafts. Additionally, we identify a cell type closely resembling a class of newly identified perivascular-like cells in stem cell-derived grafts. Thus, this study uncovers previously unknown cellular diversity in a clinically relevant cell replacement PD model.
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Project description:Cell replacement is a long-standing and realistic goal for the treatment of Parkinson's disease (PD). Cells for transplantation can be obtained from fetal brain tissue or from stem cells. However, after transplantation, dopamine (DA) neurons are seen to be a minor component of grafts, and it has remained difficult to determine the identity of other cell types. Here, we report analysis by single-cell RNA sequencing (scRNA-seq) combined with comprehensive histological analyses to characterize intracerebral grafts from human embryonic stem cells (hESCs) and fetal tissue after functional maturation in a pre-clinical rat PD model. We show that neurons and astrocytes are major components in both fetal and stem cell-derived grafts. Additionally, we identify a cell type closely resembling a class of recently identified perivascular-like cells in stem cell-derived grafts. Thus, this study uncovers previously unknown cellular diversity in a clinically relevant cell replacement PD model.
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Project description:Molecular barcodes and single cell transcriptomics to map graft diversity and lineage of human DA neurons in a rat xenograft model of Parkinson’s Disease
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Project description:Stem cell treatments for neurodegenerative diseases are expected to reach clinical trials soon. Most of the approaches currently under development involve transplantation of immature progenitors that subsequently undergo phenotypic and functional maturation in vivo, and predicting the long term graft outcome already at the progenitor stage remains a challenge. Here, we took an unbiased approach to identify predictive markers expressed in dopamine neuron progenitors that correlate with graft outcome in an animal model of Parkinson's disease through gene expression analysis of >30 batches of grafted hESC-derived progenitors. We found that many of the commonly-used markers did not accurately predict in vivo subtype-specific maturation. Instead, we identified a specific set of markers associated with the caudal midbrain that correlate with high dopaminergic yield after transplantation in vivo. Using these markers, we developed a GMP differentiation protocol for highly efficient and reproducible production of transplantable dopamine progenitors from hESCs.
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Project description:Human pluripotent stem cells (PSCs) differentiated into dopamine (DA) neurons via a ventral floor plate intermediate provide an unlimited cell source for cell replacement therapy for Parkinson’s disease (PD). However, histology and scRNA-seq profiling of resulting grafts in in vivo models have revealed that seemingly homogenous cell preparations give rise to heterogenous grafts not only made up of dopamine neurons. Here, we used single nuclei RNA-seq combined with molecular barcode tracing delivered to the PSC-derived DA progenitors both in vitro and in vivo to show that three cell types (neurons, astrocytes and vascular leptomeningeal cells, VLMCs) make up the cellular composition of the grafts and that these cell types all share a common progenitor. Additionally, barcoding proliferative cells in vivo 1 month after transplantation, showed that a fraction of the cells retained their multipotent potential also after transplantation. Single-cell chromatin accessibility and RNA expression paired maps identified seemingly subtle chromatin accessibility differences among progenitors supporting their homogeneity, and together with the tracing data shows that the PSC-derived floor plate cells used for transplantation are tri-potent, giving rise to dopamine neurons, astrocytes and VLMCs.
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Project description:The significance of borderline changes (BL) in kidney allograft biopsies is widely debated. We examined differences in gene expression patterns between early clinical biopsy tissue and 3-month protocol biopsy tissue, all of which had histological BL changes and identified specific molecular BL patterns associated with poor graft outcome. The expression profiles were analyzed in training set of patients and next data were validated in validation cohort using RT-qPCR. Using the Illumina microarray technology, we observed greater expression of immunity- and inflammation-related genes in tissues from early clinical biopsies compared to 3-month protocol biopsies with BL findings. In tissues with early clinically manifested BL changes, graft deterioration within 24 months due to chronic rejection was associated with increased activation of immune, defense, and inflammatory processes, specifically with higher donor age and expression of macrophage receptor CLEC5A. In the 3-month protocol biopsies with BL changes, graft dysfunction was associated with increased expression of fibrinogen complex transcripts. This study highlights the molecular differences between clinical and subclinical biopsies with similar histological findings. The data also support a recommendation for frequent patient monitoring, especially in those who received grafts from expanded criteria donors (ECDs). The experiments were performed with total RNA derived from the renal graft biopsy samples of 28 different patients who had undergone a kidney transplantation. Only the patients with diagnosis of borderline changes early (M-bM-^IM-$2 months) or protocolar (3 months) were included in the study. RNA profiles of patients with stable and deteriorated graft function during 2 years after transplantation were compared. As microarray platform, Illumina HumanHT-12 v4.0 Expression BeadChips (Illumina) was used. The chip scanning was performed with a BeadStation 500 instrument (Illumina Inc), and the raw data were extracted with the BeadStudio Data Analysis Software (Illumina). The R software lumi package was used to further process the raw data. The quantile method was used for normalization.
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Project description:Grafting is an ancient cloning method that has been used widely for thousands of years in agricultural practices. However, the molecular mechanisms for graft union development are still largely unknown. The developmental stage of graft union was characterized based on micrografting method. Microarray data revealed a signal exchange process between cells of scion and stock at 1dag, which reestablished the communication network in graft union. This process was concomitant with the cleaning of cell debris, and both of the processes were initiated by a wound-induced program. The results demonstrate the feasibility and potential power of investigating various plant developmental processes by this method and represent a primary and significant step in interpretation of the molecular mechanisms underlying graft union development. WT/WT seedling grafts of 22-26 hours after grafting were collected for microarray, intact WT seedlings and ungrafted scions and stocks were as control. All three types of sample, grafts (marked as A: whole graft), ungrafted scions and stocks (marked as B: mixture of ungrafted scions and stocks) and intact seedlings (marked as C: whole seedling), were collected at the same time of 22-26 hours after grafting. For sample B, scions and stocks were cut at the same time during grafting. For sample C, intact seedlings were also reserved during grafting. Data were firstly compared between sample A and C, differential expressed probe sets were than tested based on A and B to obtain graft-specific probes.
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