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Viral Delivery Of GDNF Promotes Functional Integration Of Human Stem Cell Grafts In Parkinson’s Disease

ABSTRACT: Viral Delivery Of GDNF Promotes Functional Integration Of Human Stem Cell Grafts In Parkinson’s Disease

PROVIDER: PRJNA599014 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10828923_1.fastq.gz	Fastqsanger.gz
	SRR10828923_2.fastq.gz	Fastqsanger.gz
	SRR10828924_1.fastq.gz	Fastqsanger.gz
	SRR10828924_2.fastq.gz	Fastqsanger.gz
	SRR10828925_1.fastq.gz	Fastqsanger.gz

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Viral Delivery Of GDNF Promotes Functional Integration Of Human Stem Cell Grafts In Parkinson’s Disease

Project description:Dopaminergic neurons (DAn), generated from human pluripotent stem cells (hPSC), are capable of functionally integrating following transplantation and have recently advanced to clinical trials for Parkinson’s disease (PD). However, pre-clinical studies have highlighted the low proportion of DAn within hPSC-derived grafts and their inferior plasticity compared to fetal tissue. Here we examined whether delivery of a developmentally critical protein, glial cell line-derived neurotrophic factor (GDNF), could improve graft outcomes. We tracked the response of DAn implanted into either a GDNF-rich environment, or after a delay in exposure. Early GDNF promoted survival and plasticity of non-DAn, leading to enhanced motor recovery in PD rats. Delayed exposure to GDNF promoted functional recovery through increases in DAn specification, DAn plasticity and dopamine metabolism. Transcriptional profiling revealed a role for MAPK-signalling downstream of GDNF. Collectively these results demonstrate the potential of neurotrophic gene therapy strategies to improve hPSC graft outcomes.

2020-01-06 | GSE143136 | GEO

Human iPSC-derived neural progenitor cells secreting GDNF provide protection in rodent models of ALS and retinal degeneration

Project description:Expanded populations of human fetal-derived neural progenitor cells transduced to produce GDNF (fNPC-GDNF) have now been shown to survive for over three years following injection into the human spinal cord and can provide neuroprotection in many animal models. However, low availability of starting material limits their widespread use. Human induced pluripotent stem cells (iPSCs) are an alternative, renewable cell source that can be differentiated into NPCs and transduced with GDNF (iNPC-GDNF). The goal of the current study was to characterize iNPC-GDNF cells and test their therapeutic potential and safety. Single nuclei RNA- seq showed that fNPC-GDNF and iNPC-GDNF had both overlapping and unique clusters of cells, suggesting that the two products were not identical. When transplanted into the subretinal space of a rodent model of retinal degeneration, iNPC-GDNF preserved photoreceptors and visual function. Transplantation of iNPC-GDNF into the lumbar spinal cord of a rodent model of ALS preserved motor neurons. Finally, to evaluate long-term safety and tolerability, iNPC-GDNF were transplanted into the spinal cord of athymic nude rats for 9 months. Surviving grafts secreting GDNF were found in all animals with no signs of tumor formation or cell proliferation. iNPC-GDNF survive long-term, are safe, and provide neuroprotection in models of both retinal degeneration and ALS, indicating their potential for clinical trials as a cell and gene therapy-based treatment for various neurodegenerative diseases.

2023-04-19 | GSE214210 | GEO

Omics data integration suggests a potential idiopathic Parkinson’s disease signature

Project description:Omics data integration suggests a potential idiopathic Parkinson’s disease signature

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Porcine IVM GDNF

Project description:Treatment of oocytes derived from large (4-6 mm; LG) or small (>3 mm; SM) follicles with glial cell line-derived neurotrophic factor (GDNF) during in vitro maturation. Four-condition experiment, SM and LG oocytes, each with and without GDNF. Biological replicates: 9 per condition, independently collected. Pools of three replicates per array.

2012-11-09 | E-GEOD-42198 | biostudies-arrayexpress

Omics data integration suggests a potential idiopathic Parkinson’s disease signature

Project description:Identification of early transcriptomic and metabolic alterations consistent across different idiopathic Parkinson’s disease (IPD) patients might reveal the potential basis of increased dopaminergic neuron vulnerability and primary disease mechanisms. In this study, we combine systems biology and data integration approaches to identify differences in transcriptomic and metabolic signatures between IPD patient and healthy individual-derived midbrain neural precursor cells. Characterization of gene expression and metabolic modeling reveal pyruvate, several amino acid and lipid metabolism as the most dysregulated metabolic pathways in IPD neural precursors. Furthermore, we show that IPD neural precursors endure mitochondrial metabolism impairment and a reduced total NAD pool. Accordingly, we show that treatment with NAD precursors increases ATP yield hence demonstrating a potential to rescue early IPD-associated metabolic changes.

2023-11-01 | GSE207088 | GEO

Porcine IVM GDNF

Project description:Treatment of oocytes derived from large (4-6 mm; LG) or small (>3 mm; SM) follicles with glial cell line-derived neurotrophic factor (GDNF) during in vitro maturation.

2012-11-09 | GSE42198 | GEO

GDNF-regulated gene expression in cultured mouse spermatogonial stem cells

Project description:GDNF-regulated gene expression was studied in cultures of actively self-renewing spermatogonial stem cells established from 6 day old male mice. GDNF is the essential growth factor regulating mouse spermatogonial stem cell self-renewal. Using a serum-free chemically defined culture system that supports mouse spermatogonial stem cell self-renewal for extended periods of time, GDNF-regulated genes were identified using microarray profiling. Keywords: GDNF withdrawal and time-course replacement

2006-05-11 | GSE4799 | GEO

GDNF-Regulated Gene Expression in Cultures of Rat Spermatogonial Stem Cells

Project description:Expression of GDNF-regulated genes was studied in cultures of self-renewing rat spermatogonial stem cells established from 8-10 day old rat pups maintained in a defined serum free medium. GDNF is the primary regulator of spermatogonial stem cell self renewal in the rat. GDNF regulated genes were identified using microarray profiling rat spermatogonial stem cells in the presence and absence of GDNF.

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GDNF/GFRA1 signaling contributes to chemo- and radioresistance in glioblastoma

Project description:Glioblastoma (GBM) is the most common primary brain tumor in adults, characterized by an inherent aggressivity and resistance to treatment leading to poor prognoses. While some resistance mechanisms have been elucidated, a deeper understanding of these mechanisms is needed to increase therapeutic efficacy. In this study we first discovered glial-cell derived neurotrophic factor (GDNF) to be upregulated in patient-derived glioblastoma spheroid cultures after chemotherapeutic temozolomide (TMZ) treatment, through RNA-Seq experiments. Therefore, we investigated the role of the GDNF/GDNF receptor alpha 1 (GFRA1) signaling pathway as a resistance mechanism to chemotherapy with temozolomide and lomustine as well as irradiation using patient-derived glioblastoma spheroid cultures. With qPCR experiments we showed a consistent upregulation of GDNF and its primary receptor GFRA1 following all three lines of treatment. Moreover, CRISPR/Cas9 knock-outs of GDNF in two patient-derived models sensitized these cells to chemotherapy treatment, but not radiotherapy. The increased sensitivity was completely reversed by the addition of exogeneous GDNF, confirming the key role of this factor in chemoresistance. Finally, a CRISPR KO of GFRA1 demonstrated a similar increased sensitivity to temozolomide and lomustine treatment, as well as radiotherapy. Together, our findings support the role of the GDNF/GFRA1 signaling pathway in glioblastoma chemo and radioresistance.

2024-02-13 | GSE255581 | GEO

GDNF drives rapid tubule morphogenesis in novel 3D in vitro model for ADPKD [GDNF RNAseq]

Project description:We report a significant change in epithelial differentiation pathways and principal cell specific transcription factors in tubuloids with a GDNF pulse, when compared to control tubuloid cultures.

2020-06-08 | GSE151949 | GEO

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