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Single Cell Transcriptomics Identifies Stem Cell-Derived Graft Composition in a Model of Parkinson’s Disease

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE118412 | GEO | 2020/03/01

REPOSITORIES: GEO

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Single cell transcriptomics identifies stem cell-derived graft composition in a model of Parkinson’s disease.

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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Human midbrain dopaminergic neuronal differentiation markers predict cell therapy outcome in a Parkinson's disease model

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Human midbrain dopaminergic neuronal differentiation markers predict cell therapy outcome in a Parkinson's disease model

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Project description:Cell replacement therapies for Parkinson’s Disease (PD) based on transplantation of dopaminergic neurons generated from pluripotent stem cell sources are now entering clinical trials. Here, we present the quality, safety and efficacy data supporting a first-in-human clinical trial in PD using an embryonic stem cell product STEM-PD, as well as the design of the trial itself. The cryopreserved STEM-PD product was manufactured under Good Manufacturing Practice (GMP) and fully quality-tested in vitro for regulatory compliance. The product was further tested in an extensive 39-week Good Laboratory Practice (GLP) safety study in immunodeficient rats for toxicity, tumourigenicity and biodistribution, as well as in a 24-week non-GLP efficacy study. These studies showed that the transplanted STEM-PD cells could induce full functional recovery in a pre-clinical rat model of PD, and that the treatment did not give rise to any adverse effects. This cell batch will be used for all participants in the STEM-PD Phase I/IIa clinical trial, where the first of 8 patients with moderate PD have now been transplanted. Furthermore, we observed highly comparable in vivo efficacy results between two different GMP batches of STEM-PD cells, verifying that this product has the potential to be serially manufactured for widespread clinical use.

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Preclinical quality, safety and efficacy of a human embryonic stem cell-derived product for treatment of people with moderate Parkinson’s Disease (STEM-PD) I

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Quantitative proteomic analysis reveals the effects of human neural stem cells on multiple brain regions

Project description:Parkinson’s disease (PD) is one of the most common neurodegenerative disease caused by diminution of neurons in the substantia nigra (SN) which projects dopaminergic (DA) axons to the striatum and other target areas. Recently, accumulating data demonstrated the prospects of cell replacement therapy by using neural stem cell (NSCs) transplantation. However the mechanisms underlying the potential efficacy are not fully understood. To gain new insights into the mechanisms of 6-OHDA induced lesion and potential efficacy of hNSCs transplantation, Intrastriatal 6-Hydroxydopamine (6-OHDA) injected parkinsonian mice were unilaterally engrafted with undifferentiated human NSCs to striatum (ST). High-throughput quantitative proteomic approach was utilized to characterize the proteome profiles of PD related brain regions in these mice including SN, ST, olfactory bulb (OB) and subventricular zone (SVZ). The abundance of more than 5000 proteins with high confidence in each region was determined in this study which represents the most extensive proteomic study of PD mouse models to date. In addition to the disruption of the DA system, the quantitative analysis demonstrated the profound disturbance of SVZ proteome after 6-OHDA insult, in which the abundance of more than 20% proteins was significantly changed. After hNSCs engraftment, the proteome of SVZ was restored and the astrocytes in ST was greatly activated in companion with the increase in neurotrophic factors. Furthermore, bioinformatics analysis demonstrated that changes in proteome was not caused by the proliferation of hNSCs or their progeny, but rather by the reaction of endogenous cells. Overall, this study reveals that hNSCs benefits parkinsonian animals by eliciting endogenous responses in multiple brain regions, and discovers the unexpected role of SVZ cells in PD progress and treatment, providing new therapeutic targets.

2017-03-29 | PXD004152 | Pride

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