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Mus musculus

ABSTRACT: Electromagnetic field-mediated direct lineage reprogramming into induced dopamine neurons in vivo for Parkinson’s disease therapy [ChIP-Seq]

PROVIDER: PRJNA340137 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR4064270_1.fastq.gz	Fastqsanger.gz
	SRR4064270_2.fastq.gz	Fastqsanger.gz
	SRR4064269_1.fastq.gz	Fastqsanger.gz
	SRR4064269_2.fastq.gz	Fastqsanger.gz

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Mus musculus

Project description:Electromagnetic field-mediated direct lineage reprogramming into induced dopamine neurons in vivo for Parkinson’s disease therapy [microarray2]

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Project description:Electromagnetic field-mediated direct lineage reprogramming into induced dopamine neurons in vivo for Parkinson’s disease therapy [microarray1]

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Electromagnetic field-mediated direct lineage reprogramming into induced dopamine neurons in vivo for Parkinson's disease therapy

Project description:Electromagnetic field-mediated direct lineage reprogramming into induced dopamine neurons in vivo for Parkinson's disease therapy

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Electromagnetic field-mediated direct lineage reprogramming into induced dopamine neurons in vivo for Parkinson’s disease therapy [microarray2]

Project description:Electromagnetic fields (EMF) are physical energy generated by electrically charged objects that can influence numerous biologic processes, including control of cell fate and plasticity. In this study, we show that magnetic gold nanoparticles in the presence of EMF can facilitate efficient direct lineage reprogramming to induced dopamine neurons both in vitro and in vivo. Remarkably, electromagnetic stimulation leads to the specific activation of the histone acetyl transferase Brd2, resulting in H3K27 acetylation and robust activation of neuronal-specific gene expression. In vivo reprogramming in conjunction with EMF stimulation efficiently alleviated symptoms in a mouse model of Parkinson’s disease (PD) in a noninvasive and controllable manner. These studies provide a proof of principle that EMF-based approaches may represent a viable and safe therapeutic strategy facilitating in vivo lineage conversion for neurodegenerative disorders.

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Electromagnetic field-mediated direct lineage reprogramming into induced dopamine neurons in vivo for Parkinson’s disease therapy [microarray1]

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3D Model Enhances Human Glia conversion to Neurons with Dopaminergic Functional and Molecular Traits Or: 3D Model Enhances Human Glia conver-sion to Induced Dopamine Neurons?

Project description:Parkinson’s disease (PD), a prevalent neurodegenerative disorder, is primarily characterized by progressive loss of ventral midbrain dopamine (DA) neurons. This focal degeneration makes PD suitable for cell replacement therapies and clinical trials using stem cell derived-DA neurons are ongoing. An emerging alternative to cell transplantation for brain repair is in vivo reprogramming, where resident glia is converted into neurons directly inside the brain. While functional neurons with potential therapeutic effects can be obtained via in vivo conversion in rodent studies, translating this to relevant human pre-clinical models has been limited to two-dimensional (2D) cultures. To mimic three-dimensional (3D) complexity and approximate in vivo-like conversion, we developed a 3D model for human glia conversion. Our model promotes neural conversion and generates functionally mature DA neurons at a faster pace than in 2D. Molecular profiling, single-nucleus transcriptomics and lineage tracing mapped glia heterogeneity, provided mechanistic insights of the reprogramming process and defined neuronal identity after conversion. Our results emphasize the advantages of utilizing 3D models as a reproducible and con-sistent platform for reprogramming studies.

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Project description:Induced pluripotent stem cell (iPSC)-derived dopamine neurons provide an opportunity to model Parkinson’s disease (PD) but neuronal cultures are confounded by cellular heterogeneity. By applying high-resolution single cell transcriptomic analyses to Parkinson’s iPSC-derived dopamine neurons carrying the GBA-N370S risk variant, we exploited intra-culture cellular heterogeneity to identify a progressive axis of gene expression variation leading to endoplasmic reticulum stress. Analysis of genes differentially-expressed (DE) along this axis identified the transcriptional repressor histone deacetylase 4 (HDAC4) as an upstream regulator of disease progression. HDAC4 was mislocalized to the nucleus in PD iPSC-derived dopamine neurons and repressed genes early in the disease axis, leading to late deficits in protein homeostasis. Treatment of iPSC-derived dopamine neurons with compounds known to modulate HDAC4 activity upregulated genes early in the DE axis, and corrected Parkinson’s-related cellular phenotypes. Our study demonstrates how single cell transcriptomics can exploit cellular heterogeneity to reveal disease mechanisms and identify therapeutic targets.

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Project description:First-in-human clinical trials illustrate the feasibility and translational potential of human pluripotent stem cell (hPSC)-based cell therapy in Parkinson’s disease (PD). However, a major unresolved challenge is the extensive cell death following transplantation with <10% of grafted dopamine neurons surviving. Here, we performed a pooled CRISPR/Cas9 screen to enhance survival of postmitotic dopamine neurons in vivo. We identified TP53-mediated apoptotic cell death as major contributor to dopamine neuron loss and uncovered a causal link of TNFa-NFκB signaling in limiting cell survival. A surface marker screen enabled the purification of midbrain dopamine neurons obviating the need for genetic reporters. Combining cell sorting with adalimumab pretreatment, a clinically approved TNFa inhibitor, enabled efficient engraftment of postmitotic dopamine neurons leading to extensive re-innervation and functional recovery in a preclinical PD mouse model. Thus, transient TNFa inhibition may present a clinically relevant strategy to enhance survival of human PSC-derived lineages in PD and beyond.

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