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Estradiol facilitates functional integration of induced pluripotent stem cell-derived dopaminergic neurons into striatal neuronal circuits via activation of integrin α5β1

ABSTRACT: To realize cell transplantation therapy for Parkinson's disease (PD), the grafted neurons should be integrated into the host neuronal circuit in order to restore the lost neuronal function. Here, using wheat germ agglutinin-based trans-synaptic tracing, we show that integrin α5 is selectively expressed in striatal neurons that are innervated by midbrain dopaminergic (DA) neurons from the mouse experiments. Additionally, we found that integrin α5β1 was activated by the administration of estradiol-2-benzoate (E2B) in striatal neurons of adult female rats. Importantly, we observed that the systemic administration of E2B into hemi-parkinsonian rat models facilitates the functional integration of grafted DA neurons derived from human induced pluripotent stem cells into the host striatal neuronal circuit via the activation of integrin α5β1. Finally, methamphetamine-induced abnormal rotation was recovered earlier in E2B-administrated rats than in rats that received other regimens. Our results suggest that the simultaneous administration of E2B with stem cell-derived DA progenitors can enhance the efficacy of cell transplantation therapy for PD.

ORGANISM(S): Mus musculus

PROVIDER: GSE77274 | GEO | 2016/03/31

SECONDARY ACCESSION(S): PRJNA309941

REPOSITORIES: GEO

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Estradiol facilitates functional integration of induced pluripotent stem cell-derived dopaminergic neurons into striatal neuronal circuits via activation of integrin Î±5Î²1

Project description:To realize cell transplantation therapy for Parkinson's disease (PD), the grafted neurons should be integrated into the host neuronal circuit in order to restore the lost neuronal function. Here, using wheat germ agglutinin-based trans-synaptic tracing, we show that integrin Î±5 is selectively expressed in striatal neurons that are innervated by midbrain dopaminergic (DA) neurons from the mouse experiments. Additionally, we found that integrin Î±5Î²1 was activated by the administration of estradiol-2-benzoate (E2B) in striatal neurons of adult female rats. Importantly, we observed that the systemic administration of E2B into hemi-parkinsonian rat models facilitates the functional integration of grafted DA neurons derived from human induced pluripotent stem cells into the host striatal neuronal circuit via the activation of integrin Î±5Î²1. Finally, methamphetamine-induced abnormal rotation was recovered earlier in E2B-administrated rats than in rats that received other regimens. Our results suggest that the simultaneous administration of E2B with stem cell-derived DA progenitors can enhance the efficacy of cell transplantation therapy for PD. 0.5 ÂµL of 1% WGA Alexa Fluor 488 solution was stereotactically injected into the bilateral SNpc (from the bregma: A -3.0, L Â±1.2, V -4.2 and TB 0) of mouse. Two days after injection, a striatum sample was dissected from the mouse brain and dissociated into a single cell population by Accumax (Innovated Cell Technologies, Inc., CA, USA). To separate a two-cell population, Alexa Fluor 488+ cells and Alexa Fluor 488- cells were sorted using a FACSAria III cell sorter. Dead cells were identified and eliminated by 7-amino-actinomycin D (7-AAD) staining.

2016-03-31 | E-GEOD-77274 | biostudies-arrayexpress

Time Course of Gene Expression in the Substantia Nigra in Response to Intrastriatal 6-hydroxydopamine in the rat.

Project description:The 6-hydroxydopamine (6OHDA) rat model of parkinsonism is among the first, and most commonly used, animal models of Parkinson’s disease. It provides insight into the compensatory changes that occur in the brain after dopamine (DA) neuron degeneration. In order to better define the consequences of substantia nigra DA neuron loss on the neural and glial populations during and following nigrostriatal degeneration, tissue was collected and evaluated from the substantia nigra of 6OHDA or vehicle treated, or naïve rats at 1, 2, 4, 6 & 16 weeks. Comprehensive gene expression analysis was conducted to detect significant differences in gene expression. Comparisons were conducted within the same treatment groups over time as well as across treatments within the same post-treatment interval. Longitudinal expression patterns were parsed using a k-means clustering algorithm as a method for finding patterns indicative of neuronal loss, upregulation in response to lesion or surgical damage exclusive of lesion. Tissue was collected from the substantia nigra of 6OHDA treated, sham and naïve rats at 1, 2, 4, 6 & 16 weeks post-treatment. A unilateral striatal lesion was employed that results in a 99% striatal DA reduction and an 80% loss of DA neurons in the substantia nigra. 6OHDA lesions were confirmed via catecholamine quantitation by HPLC. RNA integrity was assessed with an Agilent 2100 Bioanalyzer with minimum RIN acceptance criteria of 8.0. Multidimensional plots and Pearson Correlations were used to establish group/treatment homogeneity. Tissue was subjected to comprehensive gene expression analysis using the Affymetrix Rat Gene 1.0ST array.

2014-06-21 | E-GEOD-58710 | biostudies-arrayexpress

Identification of neurexophilin 3 as a novel maturation factor for induced pluripotent stem cell-derived dopaminergic neuron progenitors

Project description:To develop more potent cell transplantation therapy for neurodegenerative disorder such as Parkinson’s disease (PD), the condition of the host brain environment should be considered to improve the outcome of grafted neurons. However, we never know which condition of host brain environment is suitable and supportive for the donor cells. In addition, what endogenous factor(s) do contribute to improve the engraftment of donor cells in host brain? Therefore, the identification of such effective factor(s) strongly contribute to improve the overcome of cell transplantation therapy. Here, we constructed the experimental approach to identify the effective soluble factor(s) for cell-grafting by comparison between various parkinsonian mouse brain condition and transplantation outcome using induced pluripotent stem cell (iPSC)-derived dopaminergic (DA) neuron progenitors. According to our experimental approach, we have identified secreted peptide, neurexophilin 3 (NXPH3) that enhance the survival of grafted-iPSC-derived DA neurons. Grafted-iPSC-derived DA neurons were increased by local supplement of NXPH3 protein. In addition, the expression level of NXPH3 in putamen of PD patients was significantly decreased than that of normal controls by using postmortem samples. These findings would be expected to contribute the new experimental strategy to indentify the endogenous effective factors for cell-grafting as in vivo application of stem cell technology. Mice were divided into three groups as follows: (i) 1 week after acute administration (four times by every 2 h) of free base MPTP HCl (20 mg/kg, 80 mg/kg in total, intraperitoneally). (ii) 8 weeks after chronic administration (once a day for 20 consecutive days) of free base MPTP HCl (4 mg/kg per day, 80 mg/kg in total). (iii) 1 week after injection (four times by every 2 h) of saline (control).

2015-06-12 | E-GEOD-60080 | biostudies-arrayexpress

Mus musculus

Project description:Estradiol facilitates functional integration of induced pluripotent stem cell-derived dopaminergic neurons into striatal neuronal circuits via activation of integrin α5β1

| PRJNA309941 | ENA

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.

2014-03-07 | GSE51214 | GEO

Subcellular and regional localization of mRNA translation in midbrain dopamine neurons

Project description:Local translation within excitatory and inhibitory neurons is known to be involved in neuronal development and synaptic plasticity. Despite the extensive dendritic and axonal arborizations of monoaminergic neurons, the subcellular localization of protein synthesis has not been well-characterized in these populations. Here, we investigated mRNA localization in midbrain dopaminergic (mDA) neurons, cells with enormous axonal and dendritic projections, both of which can release dopamine (DA). Using highly-sensitive sequencing and imaging approaches in mDA axons, we found no evidence for axonal mRNA localization or translation. In contrast, we found that mDA neuronal dendritic projections into the substantia nigra reticulata (SNr) contain ribosomes and mRNAs encoding the DA synthesis, release, and reuptake machinery. Surprisingly, we found dendritic localization of mRNAs encoding synaptic vesicular release proteins in mDA neurons. Our results are consistent with a role for local translation in the regulation of DA transmission from dendrites, but not striatal axons. Finally, we defined a molecular signature of sparse mDA neurons in the SNr, including enrichment of an ER calcium pump previously undescribed in mDA neurons.

2021-07-27 | GSE180913 | GEO

sVEGFR-1 signaling through α5β1 integrin

Project description:Soluble VEGFR-1 (sVEGFR-1) acts both as a decoy receptor for VEGFs and as an extracellular matrix protein for α5β1 integrin. A sVEGFR-1-derived peptide that interacts with α5β1 integrin promotes angiogenesis. However, canonical signal downstream integrin activation is not induced, resulting into lack of focal adhesion maturation. We performed a gene expression profile of endothelial cells adhering on sVEGFR-1 compared to that of cells adhering on fibronectin, the principal α5β1 integrin ligand. Three protein kinase-C substrates, adducin, MARCKS, and radixin were differently modulated. Adducin and MARCKS were less phosphorylated whereas radixin was higher phosphorylated in sVEGFR-1 adhering cells, the latter leading to prolonged small GTPase Rac1 activation and induction of a pathway involving the heterotrimeric G protein α13. Altogether, our data indicated endothelial cell acquisition of an highly motile phenotype when adherent on sVEGFR-1. Finally, we indicated radixin as accountable for the angiogenic effect of α5β1 integrin interaction with sVEGFR-1 that in turn depends on an active VEGF-A/VEGFR-2 signaling.

2014-01-20 | GSE32560 | GEO

Gene expression profile of 2-D or 3-D neural cultures derived from an H1 hESC cell line

Project description:Striatal neurons and striatal DA neuron fusions make up the mesolimbic pathway and respond to substances of abuse. We use scRNAseq to define the composition of our culture conditions and study their transcriptional responses to dopamine, cocaine, and morphine.

2023-04-14 | GSE225497 | GEO

Functional blockade of α5β1 integrin induces scattering and genomic landscape remodeling of hepatic progenitor cells

Project description:Cells treated with a specific antibody against α5β1 integrin exhibited cell spreading and scattering, over-expression of liver stem/progenitor cell markers and activation of the ERK1/2 and p38 MAPKs signaling cascades, in a similar manner to the process triggered by HGF/SF1 stimulation. Gene expression profiling revealed marked transcriptional changes of genes involved in cell adhesion and migration, as well as genes encoding chromatin remodeling factors. These responses were accompanied by conspicuous spatial reorganization of centromeres, while integrin genes conserved their spatial positioning in the interphase nucleus. Untreated cells versus HGF/SF1 treated or α5β1 integrin-mediated cell migration

2010-08-26 | E-GEOD-23853 | biostudies-arrayexpress

Transcriptome profiling in 6-hydroxydopamine hemiparkinsonian rats reveals methamphetamine-mediated dopamine-independent changes in striatal gene expression.

Project description:Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle (MFB) is used extensively as a model of Parkinson’s disease. The present experiments examined whether a single injection of methamphetamine (METH) (2.5 mg/kg) could still influence striatal gene expression after 6-hydroxydopamine (DA)-induced destruction of the nigrostriatal dopaminergic pathway in the rat. Unilateral injections of 6-hydroxydopamine into the MFB resulted in total striatal dopamine depletion on the lesioned side. This injection also caused decreased striatal serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels. DA depletion was associated with increases in 5-HIAA/5-HT ratios which were potentiated by the METH injection. Microarray analyses revealed changes (+ 1.7-fold, p < 0.025) in the expression of 67 genes on the lesioned side in comparison to the intact side of the saline-treated hemiparkinsonian animals. These include follistatin, neuromedin U, and tachykinin 2 which were up-regulated. METH administration caused increases in the expression of several genes including c-fos, Egr1, and NOR-1 on the intact side. On the DA-depleted side, METH administration also increased the expression of 61 genes including Pdgfd and COX-2. There were METH-induced changes in 16 genes that were common in the DA-innervated and DA-depleted sides. These include c-fos and NOR-1 which show greater changes on the normal DA side. The present study documents METH-mediated DA-independent transcriptional alterations of several genes in the DA-denervated striatum. Our results also implicate serotonin as an important player in METH-induced gene expression because the METH injection also caused significant increases in 5-HIAA/5-HT ratios on the DA-depleted side. 31 samples. MNL (6), ML (6), SNL (5), SL (6), CS (4), CM (4)

2010-09-21 | E-GEOD-24233 | biostudies-arrayexpress

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